Trial Outcomes & Findings for AZD9291 First Time In Patients Ascending Dose Study (NCT NCT01802632)

NCT ID: NCT01802632

Last Updated: 2024-01-18

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

603 participants

Primary outcome timeframe

RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Results posted on

2024-01-18

Participant Flow

Patients recruited to different cohorts. Dose escalation cohort of pre-treated patients in 5 dose groups. Dose expansion cohort (pre-treated) in same 5 dose groups. First line patient cohort. 80mg tablet cohort of pre-treated patients. Japan-only cohort (EGFR T790M+ by cytology). Phase II extension cohort in pre-treated EGFR T790M+ patients.

603 patients were enrolled and received treatment.

Participant milestones

Participant milestones
Measure	AZD9291 80mg Extension Phase II dose extension cohort in pre-treated EGFR T790M mutation positive patients in AZD9291 80mg tablet.	Dose Escalation Pre-treated patient cohort in doses 20, 40, 80, 160 and 240mg AZD9291 capsule.	Dose Expansion Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.	First Line Cohort of patients receiving first-line treatment for EGFRm advanced NSCLC, in 80mg and 160mg AZD9291 capsule.	80mg Tablet US-only cohort of pre-treated EGFR patients receiving the tablet formulation of AZD9291 (80 mg).	Japan Cytology Japan-only cohort of patients (EGFR T790M mutation status determined from cytology samples) receiving AZD9291 80 mg tablet.
Overall Study STARTED	201	31	271	60	12	28
Overall Study COMPLETED	0	0	0	0	0	0
Overall Study NOT COMPLETED	201	31	271	60	12	28

Reasons for withdrawal

Reasons for withdrawal
Measure	AZD9291 80mg Extension Phase II dose extension cohort in pre-treated EGFR T790M mutation positive patients in AZD9291 80mg tablet.	Dose Escalation Pre-treated patient cohort in doses 20, 40, 80, 160 and 240mg AZD9291 capsule.	Dose Expansion Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.	First Line Cohort of patients receiving first-line treatment for EGFRm advanced NSCLC, in 80mg and 160mg AZD9291 capsule.	80mg Tablet US-only cohort of pre-treated EGFR patients receiving the tablet formulation of AZD9291 (80 mg).	Japan Cytology Japan-only cohort of patients (EGFR T790M mutation status determined from cytology samples) receiving AZD9291 80 mg tablet.
Overall Study Death	28	1	38	0	2	0
Overall Study Withdrawal by Subject	4	2	7	3	0	1
Overall Study Objective Disease Progression	1	12	104	6	4	4
Overall Study Ongoing Study at Data Cut-off	168	16	115	50	6	22
Overall Study Other (not specified)	0	0	7	1	0	1

Baseline Characteristics

AZD9291 First Time In Patients Ascending Dose Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AZD9291 80mg Extension n=201 Participants Phase II dose extension cohort in pre-treated EGFR T790M mutation positive patients in AZD9291 80mg tablet.	Dose Escalation n=31 Participants Pre-treated patient cohort in doses 20, 40, 80, 160 and 240mg AZD9291 capsule.	Dose Expansion n=271 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.	First Line n=60 Participants Cohort of patients receiving first-line treatment for EGFRm advanced NSCLC, in 80mg and 160mg AZD9291 capsule.	80mg Tablet n=12 Participants US-only cohort of pre-treated EGFR patients receiving the tablet formulation of AZD9291 (80 mg).	Japan Cytology n=28 Participants Japan-only cohort of patients (EGFR T790M mutation status determined from cytology samples) receiving AZD9291 80 mg tablet.	Total n=603 Participants Total of all reporting groups
Age, Customized <50 Years	30 Participants n=5 Participants	3 Participants n=7 Participants	42 Participants n=5 Participants	8 Participants n=4 Participants	3 Participants n=21 Participants	3 Participants n=8 Participants	89 Participants n=8 Participants
Age, Customized >=50-<65 Years	86 Participants n=5 Participants	19 Participants n=7 Participants	142 Participants n=5 Participants	23 Participants n=4 Participants	6 Participants n=21 Participants	13 Participants n=8 Participants	289 Participants n=8 Participants
Age, Customized >=65-<75 Years	64 Participants n=5 Participants	8 Participants n=7 Participants	59 Participants n=5 Participants	22 Participants n=4 Participants	3 Participants n=21 Participants	9 Participants n=8 Participants	165 Participants n=8 Participants
Age, Customized >=75 Years	21 Participants n=5 Participants	1 Participants n=7 Participants	28 Participants n=5 Participants	7 Participants n=4 Participants	0 Participants n=21 Participants	3 Participants n=8 Participants	60 Participants n=8 Participants
Sex: Female, Male Female	133 Participants n=5 Participants	20 Participants n=7 Participants	167 Participants n=5 Participants	45 Participants n=4 Participants	8 Participants n=21 Participants	21 Participants n=8 Participants	394 Participants n=8 Participants
Sex: Female, Male Male	68 Participants n=5 Participants	11 Participants n=7 Participants	104 Participants n=5 Participants	15 Participants n=4 Participants	4 Participants n=21 Participants	7 Participants n=8 Participants	209 Participants n=8 Participants
Race/Ethnicity, Customized Asian	114 Participants n=5 Participants	21 Participants n=7 Participants	160 Participants n=5 Participants	43 Participants n=4 Participants	4 Participants n=21 Participants	28 Participants n=8 Participants	370 Participants n=8 Participants
Race/Ethnicity, Customized Black Or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=8 Participants	5 Participants n=8 Participants
Race/Ethnicity, Customized Missing	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	2 Participants n=8 Participants
Race/Ethnicity, Customized Not Reported	4 Participants n=5 Participants	4 Participants n=7 Participants	11 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	20 Participants n=8 Participants
Race/Ethnicity, Customized Other	4 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	8 Participants n=8 Participants
Race/Ethnicity, Customized White	76 Participants n=5 Participants	5 Participants n=7 Participants	95 Participants n=5 Participants	14 Participants n=4 Participants	7 Participants n=21 Participants	0 Participants n=8 Participants	197 Participants n=8 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	1 Participants n=8 Participants

PRIMARY outcome

Timeframe: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Population: All pre-treated EGFR T790M mutation positive (by central testing) patients who received at least one dose of AZD9291.

Outcome measures

Outcome measures
Measure	Dose Expansion n=175 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.
Objective Response Rate (ORR) for Dose Expansion Population	61.7 % of participants Interval 54.1 to 68.9

PRIMARY outcome

Timeframe: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Population: All pre-treated EGFR T790M mutation positive (by central testing) patients who received at least one dose of AZD9291.

Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): \>= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Outcome measures

Outcome measures
Measure	Dose Expansion n=31 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.
Best Objective Response (BOR) for Dose Escalation Population Progressive disease	16.1 % of participants
Best Objective Response (BOR) for Dose Escalation Population Partial Response	58.1 % of participants Interval 54.1 to 68.9
Best Objective Response (BOR) for Dose Escalation Population Stable disease	19.4 % of participants
Best Objective Response (BOR) for Dose Escalation Population Not evaluable	6.5 % of participants

PRIMARY outcome

Timeframe: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Population: All patients in the 80mg AZD9291 extension part of the study (second line or later, EGFR T790M mutation positive by central testing) who received at least one dose of AZD9291 and had measurable disease (by independent central review) at baseline.

Outcome measures

Outcome measures
Measure	Dose Expansion n=199 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.
Objective Response Rate (ORR) for Extension Population	61.3 % of participants Interval 54.2 to 68.1

SECONDARY outcome

Timeframe: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Population: All pre-treated EGFR T790M mutation positive (by central testing) patients who received at least one dose of AZD9291.

Outcome measures

Outcome measures
Measure	Dose Expansion n=108 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.
Duration of Response (DoR) for Dose Expansion Population	11.1 months Interval 8.3 to 13.8

SECONDARY outcome

Timeframe: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Population: All pre-treated EGFR T790M mutation positive (by central testing) patients who received at least one dose of AZD9291.

Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Outcome measures

Outcome measures
Measure	Dose Expansion n=175 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.
Progression-Free Survival (PFS) for Dose Expansion Population	9.7 months Interval 8.3 to 12.5

SECONDARY outcome

Timeframe: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Outcome measures

Outcome measures
Measure	Dose Expansion n=201 Participants Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.
Best Objective Response (BOR) for 80mg AZD9291 Extension Population Complete Response	0.5 % of participants Interval 54.1 to 68.9
Best Objective Response (BOR) for 80mg AZD9291 Extension Population Partial response	70.1 % of participants
Best Objective Response (BOR) for 80mg AZD9291 Extension Population Stable disease	22.9 % of participants
Best Objective Response (BOR) for 80mg AZD9291 Extension Population Progressive disease	6.0 % of participants
Best Objective Response (BOR) for 80mg AZD9291 Extension Population Not evaluable	0.5 % of participants

Adverse Events

AZD9291 80mg Extension

Serious events: 41 serious events

Other events: 191 other events

Deaths: 0 deaths

Dose Escalation

Serious events: 9 serious events

Other events: 31 other events

Deaths: 0 deaths

Dose Expansion

Serious events: 78 serious events

Other events: 265 other events

Deaths: 0 deaths

First Line

Serious events: 14 serious events

Other events: 60 other events

Deaths: 0 deaths

80mg Tablet

Serious events: 4 serious events

Other events: 12 other events

Deaths: 0 deaths

Japan Cytology

Serious events: 4 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	AZD9291 80mg Extension n=201 participants at risk Phase II dose extension cohort in pre-treated EGFR T790M mutation positive patients in AZD9291 80mg tablet.	Dose Escalation n=31 participants at risk Pre-treated patient cohort in doses 20, 40, 80, 160 and 240mg AZD9291 capsule.	Dose Expansion n=271 participants at risk Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.	First Line n=60 participants at risk Cohort of patients receiving first-line treatment for EGFRm advanced NSCLC, in 80mg and 160mg AZD9291 capsule.	80mg Tablet n=12 participants at risk US-only cohort of pre-treated EGFR patients receiving the tablet formulation of AZD9291 (80 mg).	Japan Cytology n=28 participants at risk Japan-only cohort of patients (EGFR T790M mutation status determined from cytology samples) receiving AZD9291 80 mg tablet.
Blood and lymphatic system disorders Anaemia	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Thrombocytopenia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Cardiac disorders Cardiac failure congestive	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Constipation	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Diarrhoea	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Inguinal hernia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Nausea	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Vomiting	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Asthenia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Fatigue	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Localised oedema	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Oedema peripheral	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Hepatobiliary disorders Hepatic function abnormal	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Hepatobiliary disorders Jaundice	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Hepatobiliary disorders Liver disorder	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Appendicitis	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Bronchopneumonia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Influenza	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Pneumonia	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.0% 8/271 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Salmonella sepsis	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Urinary tract infection	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Urinary tract infection bacterial	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Viral infection	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Traumatic fracture	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Blood bilirubin increased	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Neutrophil count decreased	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Platelet count decreased	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Decreased appetite	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Hyponatraemia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic pain	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Cerebral haemorrhage	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Cerebrovascular accident	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Embolic stroke	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Renal and urinary disorders Renal failure	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.00% 2/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.7% 10/271 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Food poisoning	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Pancreatitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders General physical health deterioration	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Lower respiratory tract infection	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Streptococcal bacteraemia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Alanine aminotransferase increased	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Aspartate aminotransferase increased	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Seizure	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Syncope	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pulmonary artery thrombosis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Cardiac disorders Cardiac failure acute	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Cardiac disorders Myocardial infarction	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Cardiac disorders Pulseless electrical activity	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Cardiac disorders Stress cardiomyopathy	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Eye disorders Corneal erosion	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Dysphagia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Haematemesis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Oesophageal stenosis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Oesophagitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Small intestine ulcer	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Pyrexia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Hepatobiliary disorders Cholangitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Hepatobiliary disorders Cholecystitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Immune system disorders Anaphylactic reaction	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Abscess	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Bacteraemia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Bacterial sepsis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Bronchitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Cellulitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Device related infection	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Erysipelas	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Klebsiella infection	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Lung infection	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Mediastinitis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Pneumonia pneumococcal	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Post procedural infection	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Pyelonephritis acute	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Respiratory tract infection bacterial	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Sepsis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Septic shock	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Upper respiratory tract infection	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Viraemia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Fall	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Overdose	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Dehydration	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Costochondritis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Brain injury	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Cerebral cyst	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Convulsion	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Facial nerve disorder	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Headache	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Ischaemic stroke	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Nervous system disorder	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Partial seizures	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Presyncope	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Anxiety	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Confusional state	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Delusion	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Depression	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Insomnia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Suicide attempt	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Renal and urinary disorders Renal failure acute	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Renal and urinary disorders Renal impairment	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pulmonary granuloma	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Skin toxicity	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Vascular disorders Deep vein thrombosis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Vascular disorders Embolism	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Vascular disorders Peripheral artery thrombosis	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.

Other adverse events

Other adverse events
Measure	AZD9291 80mg Extension n=201 participants at risk Phase II dose extension cohort in pre-treated EGFR T790M mutation positive patients in AZD9291 80mg tablet.	Dose Escalation n=31 participants at risk Pre-treated patient cohort in doses 20, 40, 80, 160 and 240mg AZD9291 capsule.	Dose Expansion n=271 participants at risk Pre-treated EGFR T790M mutation positive (by central testing) patient cohort. Dose groups were expanded to include more patients.	First Line n=60 participants at risk Cohort of patients receiving first-line treatment for EGFRm advanced NSCLC, in 80mg and 160mg AZD9291 capsule.	80mg Tablet n=12 participants at risk US-only cohort of pre-treated EGFR patients receiving the tablet formulation of AZD9291 (80 mg).	Japan Cytology n=28 participants at risk Japan-only cohort of patients (EGFR T790M mutation status determined from cytology samples) receiving AZD9291 80 mg tablet.
Blood and lymphatic system disorders Anaemia	9.0% 18/201 • Number of events 22 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	19.4% 6/31 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.3% 36/271 • Number of events 49 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	15.0% 9/60 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	17.9% 5/28 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Eye disorders Dry eye	6.0% 12/201 • Number of events 14 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.4% 20/271 • Number of events 21 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.7% 7/60 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Abdominal pain upper	6.0% 12/201 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.0% 19/271 • Number of events 26 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.3% 8/60 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Constipation	14.9% 30/201 • Number of events 31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	22.1% 60/271 • Number of events 65 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	15.0% 9/60 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Diarrhoea	46.3% 93/201 • Number of events 147 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	61.3% 19/31 • Number of events 38 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	53.1% 144/271 • Number of events 219 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	68.3% 41/60 • Number of events 62 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	41.7% 5/12 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	32.1% 9/28 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Dry mouth	6.5% 13/201 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.3% 17/271 • Number of events 18 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Nausea	16.9% 34/201 • Number of events 45 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.8% 8/31 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	26.6% 72/271 • Number of events 96 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 15/60 • Number of events 18 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	41.7% 5/12 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.7% 3/28 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Stomatitis	13.4% 27/201 • Number of events 28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.8% 8/31 • Number of events 14 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	18.5% 50/271 • Number of events 63 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	38.3% 23/60 • Number of events 36 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	17.9% 5/28 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Vomiting	11.4% 23/201 • Number of events 31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	22.6% 7/31 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	17.7% 48/271 • Number of events 73 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	15.0% 9/60 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Asthenia	9.5% 19/201 • Number of events 34 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.2% 25/271 • Number of events 36 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Fatigue	11.9% 24/201 • Number of events 27 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.1% 5/31 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	23.6% 64/271 • Number of events 68 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 15/60 • Number of events 16 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Oedema peripheral	7.5% 15/201 • Number of events 17 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.4% 20/271 • Number of events 22 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Pyrexia	6.0% 12/201 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 27/271 • Number of events 28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Nasopharyngitis	7.0% 14/201 • Number of events 16 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	19.4% 6/31 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.7% 21/271 • Number of events 26 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Paronychia	19.9% 40/201 • Number of events 48 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.8% 8/31 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	23.6% 64/271 • Number of events 75 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	38.3% 23/60 • Number of events 23 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	28.6% 8/28 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Upper respiratory tract infection	9.0% 18/201 • Number of events 20 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	19.4% 6/31 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 27/271 • Number of events 29 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	18.3% 11/60 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	33.3% 4/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Alanine aminotransferase increased	6.0% 12/201 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.9% 16/271 • Number of events 23 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 6/60 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Aspartate aminotransferase increased	7.0% 14/201 • Number of events 18 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.0% 19/271 • Number of events 27 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.7% 7/60 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Platelet count decreased	12.9% 26/201 • Number of events 38 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.9% 24/271 • Number of events 31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.3% 8/60 • Number of events 12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.7% 3/28 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations White blood cell count decreased	7.5% 15/201 • Number of events 19 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.0% 8/271 • Number of events 20 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 10/60 • Number of events 17 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	17.9% 5/28 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Decreased appetite	17.9% 36/201 • Number of events 41 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	38.7% 12/31 • Number of events 18 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.5% 69/271 • Number of events 80 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 15/60 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 3/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Arthralgia	8.0% 16/201 • Number of events 18 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.6% 26/271 • Number of events 33 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Back pain	13.4% 27/201 • Number of events 29 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 27/271 • Number of events 30 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 6/60 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Muscle spasms	6.5% 13/201 • Number of events 14 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.9% 24/271 • Number of events 27 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.3% 8/60 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.5% 15/201 • Number of events 16 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.4% 20/271 • Number of events 20 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Headache	10.9% 22/201 • Number of events 22 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.1% 30/271 • Number of events 34 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Insomnia	9.5% 19/201 • Number of events 21 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 27/271 • Number of events 28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.7% 7/60 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Cough	15.9% 32/201 • Number of events 36 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	20.3% 55/271 • Number of events 64 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	15.0% 9/60 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.0% 18/201 • Number of events 19 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.7% 37/271 • Number of events 43 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	33.3% 4/12 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Dermatitis acneiform	6.0% 12/201 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.8% 32/271 • Number of events 39 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	26.7% 16/60 • Number of events 17 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Dry skin	21.4% 43/201 • Number of events 45 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.8% 8/31 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	22.9% 62/271 • Number of events 73 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	40.0% 24/60 • Number of events 29 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	33.3% 4/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	28.6% 8/28 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Pruritus	12.4% 25/201 • Number of events 29 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.8% 8/31 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	20.7% 56/271 • Number of events 61 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	23.3% 14/60 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 3/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.7% 3/28 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Rash	24.4% 49/201 • Number of events 58 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	35.5% 11/31 • Number of events 17 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	27.7% 75/271 • Number of events 101 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	33.3% 20/60 • Number of events 25 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.7% 3/28 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Skin fissures	6.0% 12/201 • Number of events 12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.1% 30/271 • Number of events 31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	15.0% 9/60 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Leukopenia	4.5% 9/201 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.7% 10/271 • Number of events 16 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.7% 3/28 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Lymphopenia	2.5% 5/201 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.2% 6/271 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Neutropenia	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.4% 12/271 • Number of events 12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	14.3% 4/28 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Blood and lymphatic system disorders Thrombocytopenia	5.0% 10/201 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.4% 20/271 • Number of events 25 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.7% 7/60 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Abdominal pain	5.0% 10/201 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.2% 25/271 • Number of events 27 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Dyspepsia	4.0% 8/201 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.9% 16/271 • Number of events 18 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Gastritis	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Gastrooesophageal reflux disease	2.5% 5/201 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.1% 11/271 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Mouth ulceration	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.3% 8/60 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Influenza like illness	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.0% 8/271 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Mucosal inflammation	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.9% 16/271 • Number of events 17 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	11.7% 7/60 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Conjunctivitis	3.0% 6/201 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.8% 5/271 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	13.3% 8/60 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Folliculitis	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.2% 14/271 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Oral herpes	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.74% 2/271 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Pharyngitis	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Urinary tract infection	5.0% 10/201 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.0% 19/271 • Number of events 26 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Electrocardiogram QT prolonged	3.0% 6/201 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 9/271 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.7% 3/28 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Lymphocyte count decreased	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Neutrophil count decreased	5.0% 10/201 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.9% 16/271 • Number of events 38 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	21.4% 6/28 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Weight decreased	3.0% 6/201 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.0% 19/271 • Number of events 19 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	21.7% 13/60 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Hyperkalaemia	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.0% 8/271 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.0% 19/271 • Number of events 20 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 6/60 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Myalgia	4.5% 9/201 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.8% 13/271 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 3/12 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Pain in extremity	5.0% 10/201 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.0% 19/271 • Number of events 22 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	33.3% 4/12 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Dizziness	4.5% 9/201 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.2% 25/271 • Number of events 29 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Dysgeusia	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.5% 15/271 • Number of events 16 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 10/60 • Number of events 12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.0% 6/201 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.8% 13/271 • Number of events 14 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	15.0% 9/60 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Haemoptysis	4.0% 8/201 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.2% 6/271 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.5% 5/201 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.4% 20/271 • Number of events 20 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Acne	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.1% 11/271 • Number of events 12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Alopecia	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.7% 10/271 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	10.0% 6/60 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Eczema	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Erythema	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 9/271 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	7.1% 2/28 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Rash maculo-papular	4.5% 9/201 • Number of events 9 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.1% 11/271 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 5/60 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Skin exfoliation	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.2% 14/271 • Number of events 15 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.6% 1/28 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Vascular disorders Hypertension	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Eye disorders Blepharitis	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.8% 5/271 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Eye disorders Conjunctival haemorrhage	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Eye disorders Vision blurred	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Face oedema	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Bronchitis	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.2% 6/271 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Rash pustular	2.5% 5/201 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Gastrointestinal disorders Abdominal distension	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.8% 13/271 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
General disorders Non-cardiac chest pain	2.5% 5/201 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Infections and infestations Sinusitis	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Injury, poisoning and procedural complications Traumatic fracture	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.8% 5/271 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Investigations Renal function test abnormal	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Dehydration	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Metabolism and nutrition disorders Hypocalcaemia	3.0% 6/201 • Number of events 6 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.0% 8/271 • Number of events 8 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Muscle atrophy	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Musculoskeletal and connective tissue disorders Muscular weakness	1.5% 3/201 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.5% 4/271 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Paraesthesia	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Nervous system disorders Peripheral sensory neuropathy	0.50% 1/201 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	2.6% 7/271 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.3% 2/60 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Psychiatric disorders Anxiety	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.1% 11/271 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Dysphonia	1.00% 2/201 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.8% 13/271 • Number of events 13 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Hypoxia	2.5% 5/201 • Number of events 5 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/31 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.37% 1/271 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	12.9% 4/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	4.1% 11/271 • Number of events 11 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	5.0% 3/60 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	25.0% 3/12 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.5% 7/201 • Number of events 7 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.3% 17/271 • Number of events 17 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.7% 4/60 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	8.3% 1/12 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Nail discolouration	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/271 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Nail disorder	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	9.7% 3/31 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.7% 10/271 • Number of events 10 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.7% 1/60 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Vascular disorders Hypotension	2.0% 4/201 • Number of events 4 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	3.2% 1/31 • Number of events 1 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	16.7% 2/12 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.
Skin and subcutaneous tissue disorders Rash erythematous	0.00% 0/201 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	6.5% 2/31 • Number of events 2 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	1.1% 3/271 • Number of events 3 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/60 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/12 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.	0.00% 0/28 • AEs from start of study drug until 28 days post study treatment discontinuation, up to approximately 25 months (at time of analysis). Different cohorts started at different times and so some cohorts have collected AE data for a shorter length of time, e.g. Extension cohort was the last cohort and follow up is approximately 12 months at time of analysis. Systematic assessment due to regular investigator assessment at study visits.

Additional Information

Senior Medical Director, Tagrisso

AstraZeneca

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review, should the submission for publication be delayed in order to file patent application. The sponsor cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER