Trial Outcomes & Findings for Study of Efficacy and Safety of Myl1401O + Taxane vs Herceptin©+ Taxane for 1st Line, Met. Br. Ca. (NCT NCT02472964)

Last Updated: 2022-02-14

Results Overview

Tumor measurements were perform by centralized blinded reviewers using RECIST 1.1 criteria. Per RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to \<10 mm.Partial Response (PR): \>/= 30% decrease sum of the diameters of target lesions from baseline sum diameters. Progressive Disease (PD): \</= 20% increase in the sum of the diameters of target lesions, from the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions\* denotes disease progression. Stable Disease (SD): Neither sufficient decrease or increase. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions. Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target lesions. Progressive Disease (PD): Substantial, unequivocal progression of existing non-target lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

500 participants

Primary outcome timeframe

from time of First treatment to week 24

Results posted on

2022-02-14

Participant Flow

500 subjects enrolled at 95 sites across Eastern Europe, Russia, Asia Pacific, Africa and South America. The intent to treat1(ITT1) population of 458 was used to determine Primary Outcome of Overall Response Rate.

The primary efficacy analysis was derived fromITT1 population 230 (MYL-1401O) + 228 (Herceptin)= 458. Safety analysis was derived from the Safety Population 247(MYL-1401O)+246(Herceptin)= 493. Total Randomized population 249(MYL-1401O) +251(Herceptin)= 500.

Participant milestones

Participant milestones
Measure	Herceptin© + Taxane Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .	HerMyl 1401O Trastuzumab + Taxane Part 1:Myl 1401OTrastuzumab Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O( Mylan Trastuzumab) alone once every 3 weeks until DP or subject withdrawal.
Part 1 (up to Week 24) STARTED	246	247
Part 1 (up to Week 24) COMPLETED	171	185
Part 1 (up to Week 24) NOT COMPLETED	75	62
Part 2 (Week 24-week 48) STARTED	163	179
Part 2 (Week 24-week 48) COMPLETED	98	116
Part 2 (Week 24-week 48) NOT COMPLETED	65	63

Reasons for withdrawal

Reasons for withdrawal
Measure	Herceptin© + Taxane Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .	HerMyl 1401O Trastuzumab + Taxane Part 1:Myl 1401OTrastuzumab Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O( Mylan Trastuzumab) alone once every 3 weeks until DP or subject withdrawal.
Part 1 (up to Week 24) Adverse Event	2	4
Part 1 (up to Week 24) disease progression	58	47
Part 1 (up to Week 24) Death	3	6
Part 1 (up to Week 24) Physician Decision	3	1
Part 1 (up to Week 24) Lost to Follow-up	0	1
Part 1 (up to Week 24) Withdrawal by Subject	7	2
Part 1 (up to Week 24) Other	2	1
Part 2 (Week 24-week 48) Adverse Event	4	2
Part 2 (Week 24-week 48) Disease Progression	52	56
Part 2 (Week 24-week 48) Death	0	1
Part 2 (Week 24-week 48) Physician Decision	1	1
Part 2 (Week 24-week 48) Lost to Follow-up	2	1
Part 2 (Week 24-week 48) Withdrawal by Subject	3	1
Part 2 (Week 24-week 48) Protocol Violation	3	1

Baseline Characteristics

The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Herceptin© + Taxane n=228 Participants Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal . Herceptin© 8mg/kg Iv over 90 minutes x 1 then Herceptin© 6 mg/kg IV over 30 minutes every 3 weeks Paclitaxel 80mg/m2 IV over 60 minutes weekly. Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle	MYL-1401O + Taxane n=230 Participants Part 1:MYL-1401O intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O alone once every 3 weeks until DP or subject withdrawal. MYL-1401O 8mg/kg Iv over 90 minutes x 1 then MYL-1401O 6 mg/kg IV over 30 minutes every 3 weeks Paclitaxel 80mg/m2 IV over 60 minutes weekly. Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle	Total n=458 Participants Total of all reporting groups
Age, Customized < 50years of age	86 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	74 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	160 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Age, Customized >/= 50years of age	142 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	156 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	298 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Sex: Female, Male Female	228 Participants n=5 Participants	230 Participants n=7 Participants	458 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Race (NIH/OMB) Asian	72 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	70 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	142 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	1 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	3 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Race (NIH/OMB) White	154 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	159 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	313 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Race (NIH/OMB) More than one race	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=7 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)	0 Participants n=5 Participants • The primary efficacy endpoint analysis was conducted in the intention to treat (IIT1)population ( only those patients randomized after the second amendment of the protocol)
Region of Enrollment Chile	4 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Czechia	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Georgia	23 participants n=5 Participants	26 participants n=7 Participants	49 participants n=5 Participants
Region of Enrollment Hungary	8 participants n=5 Participants	5 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment India	31 participants n=5 Participants	24 participants n=7 Participants	55 participants n=5 Participants
Region of Enrollment Latvia	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Philippines	18 participants n=5 Participants	30 participants n=7 Participants	48 participants n=5 Participants
Region of Enrollment Poland	6 participants n=5 Participants	13 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment Romania	5 participants n=5 Participants	3 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Russia	73 participants n=5 Participants	71 participants n=7 Participants	144 participants n=5 Participants
Region of Enrollment Serbia	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Slovakia	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment South Africa	3 participants n=5 Participants	8 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Thailand	23 participants n=5 Participants	16 participants n=7 Participants	39 participants n=5 Participants
Region of Enrollment Ukraine	28 participants n=5 Participants	24 participants n=7 Participants	52 participants n=5 Participants

PRIMARY outcome

Timeframe: from time of First treatment to week 24

Population: The primary efficacy analysis was conducted in the Intent To Treat population 1 (ITT1) ( all patients randomized after Amendment 2 of the protocol)

Outcome measures

Outcome measures
Measure	Herceptin© + Taxane n=228 Participants Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .	MYL-1401O Trastuzumab + Taxane n=230 Participants Part 1:Myl 1401OTrastuzumab Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O( Mylan Trastuzumab) alone once every 3 weeks until DP or subject withdrawal.
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population Complete Response	0 Participants	3 Participants
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population Partial Response	146 Participants	157 Participants
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population Stable Disease	49 Participants	48 Participants
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population Progressive Disease	20 Participants	9 Participants
Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population Not Evaluable	13 Participants	13 Participants

Adverse Events

Herceptin© + Taxane

Serious events: 91 serious events

Other events: 232 other events

Deaths: 0 deaths

Myl 1401O Trastuzumab + Taxane

Serious events: 97 serious events

Other events: 229 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Program Manager

Mylan Inc

Phone: 412-651-9530

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Herceptin© + Taxane n=246 participants at risk Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .	Myl 1401O Trastuzumab + Taxane n=247 participants at risk Part 1:Myl 1401OTrastuzumab Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O( Mylan Trastuzumab) alone once every 3 weeks until DP or subject withdrawal.
Blood and lymphatic system disorders Febrile Neutropenia	4.1% 10/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	4.5% 11/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Leukopenia	4.9% 12/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	2.0% 5/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Neutropenia	25.2% 62/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	27.5% 68/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Thrombocytopenia	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Cardiac disorders Acute Myocardial Infarction	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Cardiac disorders Cardiac Failure	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.81% 2/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Cardiac disorders Carditis	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Abdominal Pain	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Anal Fissure	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Diarrhoea	1.6% 4/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	1.2% 3/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Duodenal Ulcer Perforation	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Gastritis	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Gastrointestinal Toxicity	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Nausea	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.81% 2/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Rectal Perforation	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Vomiting	1.2% 3/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Death	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Fatigue	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Hyperthermia	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Malaise	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Multi-Organ Failure	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Pyrexia	0.81% 2/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Hepatobiliary disorders Cholecystitis Chronic	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Hepatobiliary disorders Cholelithiasis	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Hepatobiliary disorders Hepatic Failure	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Immune system disorders Anaphylactic Reaction	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.81% 2/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Immune system disorders Drug Hypersensitivity	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Immune system disorders Hypersensitivity	0.81% 2/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Bronchitis	0.81% 2/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Gastroenteritis	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	1.2% 3/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Influenza	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Mastitis	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Paronychia	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Pneumonia	2.0% 5/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	2.4% 6/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Rectal Abscess	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Renal Abscess	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Sepsis	1.2% 3/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Septic Shock	0.00% 0/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.40% 1/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Tubo-Ovarian Abscess	0.41% 1/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	0.00% 0/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.

Other adverse events
Measure	Herceptin© + Taxane n=246 participants at risk Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .	Myl 1401O Trastuzumab + Taxane n=247 participants at risk Part 1:Myl 1401OTrastuzumab Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint. Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Myl 1401O( Mylan Trastuzumab) alone once every 3 weeks until DP or subject withdrawal.
Skin and subcutaneous tissue disorders Alopecia	54.9% 135/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	57.9% 143/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Neutropenia	33.7% 83/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	36.8% 91/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Nervous system disorders Neuropathy Peripheral	12.2% 30/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	12.6% 31/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Diarrhea	19.9% 49/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	20.2% 50/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Musculoskeletal and connective tissue disorders Asthenia	16.7% 41/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	23.1% 57/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Leukopenia	17.1% 42/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	16.2% 40/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Nausea	15.0% 37/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	20.6% 51/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Blood and lymphatic system disorders Anemia	17.9% 44/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	16.6% 41/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Oedema Peripheral	12.6% 31/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	15.4% 38/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Fatigue	14.6% 36/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	12.1% 30/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Pyrexia	12.6% 31/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	9.7% 24/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Musculoskeletal and connective tissue disorders Myalgia	9.3% 23/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	10.1% 25/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Vomiting	8.5% 21/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	10.5% 26/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Gastrointestinal disorders Decreased Appetite	10.2% 25/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	9.3% 23/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Skin and subcutaneous tissue disorders Rash	10.2% 25/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	8.9% 22/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Musculoskeletal and connective tissue disorders Arthralgia	5.7% 14/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	13.4% 33/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Investigations Alanine Aminotransferase Increased	8.9% 22/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	8.9% 22/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Urninary Tract Infection	7.3% 18/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	9.3% 23/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Skin and subcutaneous tissue disorders Nail Disorder	8.9% 22/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	6.9% 17/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Investigations Aspartate Amniotransferase Increased	9.8% 24/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	6.5% 16/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Metabolism and nutrition disorders Hyperglycemia	7.7% 19/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	6.1% 15/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Musculoskeletal and connective tissue disorders Bone Pain	5.7% 14/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	8.5% 21/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Nervous system disorders Headache	11.4% 28/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	9.7% 24/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Respiratory, thoracic and mediastinal disorders Cough	7.3% 18/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	7.7% 19/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Respiratory, thoracic and mediastinal disorders Dyspnea	7.3% 18/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	6.1% 15/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Injury, poisoning and procedural complications Infusion Related Reaction	4.5% 11/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	6.9% 17/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Nervous system disorders Peripheral Sensory Neuropathy	14.6% 36/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	13.0% 32/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
General disorders Peripheral Swelling	5.3% 13/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	4.5% 11/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.
Infections and infestations Upper Respiratory Infection	2.0% 5/246 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.	7.3% 18/247 • ICF until 28 days( +/- 7 days) after last dose of IMP per patient. The active reporting period for AEs is from the time the patient receives the first dose until 28 days( +/- 7 days) after last administered dose of IMP per patient. However, SAEs should be reported any time after the active reporting period, when the Investigator becomes aware and the SAE is considered to be reasonably related to the study drug. The Investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as described previously. At each visit, the patient will be allowed time to spontaneously report any issues since the last visit or evaluation. The Investigator will then monitor and/or ask about or evaluate AEs using non-leading questions. Any clinically relevant observations made during the visit are also to be considered AEs.