Trial Outcomes & Findings for Study is Designed to Assess the Safety and Tolerability of AZD4547 at Increasing Doses in Patients With Advanced Tumours (NCT NCT00979134)

Last Updated: 2019-03-15

Results Overview

To investigate the safety and tolerability of AZD4547. System organ class (SOC), preferred term (PT), duration and severity all recorded.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

95 participants

Primary outcome timeframe

AEs are monitored from screenng through to 30 day follow up period

Results posted on

2019-03-15

Participant Flow

First patient enrolled: 21 October 2009 and last patient enrolled: 13 December 2013. This was a multicentre study conducted at a total of 29 centres in 7 countries.

In Parts A and B, a single dose was followed by a Washout Period of 5 to 10 days before multiple dosing commenced.

Participant milestones

Participant milestones
Measure	Part A Dose escalation	Part B Dose expansion phase (80mg bd tablet)	Part C Dose expansion in patients with FGFR gene-amplified tumours
Overall Study STARTED	43	6	45
Overall Study COMPLETED	10	0	5
Overall Study NOT COMPLETED	33	6	40

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A Dose escalation	Part B Dose expansion phase (80mg bd tablet)	Part C Dose expansion in patients with FGFR gene-amplified tumours
Overall Study Disease progression	18	2	5
Overall Study Adverse Event	0	0	2
Overall Study Withdrawal by Subject	1	1	2
Overall Study Lost to Follow-up	2	2	0
Overall Study Death	4	0	26
Overall Study Other	8	1	5

Baseline Characteristics

Study is Designed to Assess the Safety and Tolerability of AZD4547 at Increasing Doses in Patients With Advanced Tumours

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2 ) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation	Total n=94 Participants Total of all reporting groups
Age, Continuous	58.7 Years STANDARD_DEVIATION 8.1 • n=5 Participants	59.5 Years STANDARD_DEVIATION 10.82 • n=7 Participants	58.2 Years STANDARD_DEVIATION 11.77 • n=5 Participants	55.8 Years STANDARD_DEVIATION 10.1 • n=4 Participants	57.59 Years STANDARD_DEVIATION 10.57 • n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	16 Participants n=7 Participants	3 Participants n=5 Participants	18 Participants n=4 Participants	40 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	17 Participants n=7 Participants	9 Participants n=5 Participants	25 Participants n=4 Participants	54 Participants n=21 Participants

PRIMARY outcome

Timeframe: AEs are monitored from screenng through to 30 day follow up period

To investigate the safety and tolerability of AZD4547. System organ class (SOC), preferred term (PT), duration and severity all recorded.

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation
Number of Patients Who Experienced at Least 1 AE	6 Participants	33 Participants	12 Participants	43 Participants

PRIMARY outcome

Timeframe: AEs are continually assessed from screening up to 30 day FU period

To investigate the safety and tolerability of AZD4547. A causally related AE is an AE deemed to be causally related to AZD4547.

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation
Number of Participants Who Experienced at Least 1 Causally Related AE.	6 Participants	31 Participants	10 Participants	42 Participants

PRIMARY outcome

Timeframe: Ongoing up to discontinuation up to 30 day FU.

To investigate the safety and tolerability of AZD4547

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation
Number of Participants With at Least 1 AE of CTCAE >=G3	1 Participants	16 Participants	5 Participants	17 Participants

PRIMARY outcome

Timeframe: Ongoing up to discontinuation up to 30 day FU.

To investigate the safety and tolerability of AZD4547

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation
Number of Participants With at Least 1 Causally Related AE of CTCAE >=G3	0 Participants	8 Participants	3 Participants	12 Participants

PRIMARY outcome

Timeframe: Serious Adverse Events (SAEs) are continually assessed from Screening up to the end of the 30 day FU period.

To investigate the safety and tolerability of AZD4547. A SAE (Serious Adverse Event) is and AE (adverse Event) which fulfills one of the following criteria that the PI assesses closely such as results in death, immediately life-threatening, requires hospitalisation or prolongation of, results in significant disability, results in birth defect, may jepardise the patient or require intervention to prevent any of the previous outcomes.

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation
Number of Participants Who Experienced at Least One SAE	1 Number of participants	10 Number of participants	3 Number of participants	11 Number of participants

PRIMARY outcome

Timeframe: SAEs are continually monitored from screening to end of 30 FU period

To investigate the safety and tolerability of AZD4547: SAEs are assessed and deemed as causally related or not to AZD4547

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=43 Participants Dose escalation
Number of Participants With at Least 1 Causally Related SAE	1 Number of participants	5 Number of participants	0 Number of participants	5 Number of participants

SECONDARY outcome

Timeframe: PK samples out to 96 hours "0 to 96 hours post-dose" after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.

Population: PK

To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) Dose expansion in patients with FGFR gene-amplified tumours	Part A n=42 Participants Dose escalation
AUC(0-infinity)	1818 ng*h/mL Geometric Coefficient of Variation 59.43	—	—	2697 ng*h/mL Geometric Coefficient of Variation 110.8

SECONDARY outcome

Timeframe: Baseline assessment, then assessment every 6 weeks after start of treatment until objective disease progression.

Population: Efficacy/Tumour response: All dosed patients meeting the final FISH 6 score criteria with a baseline tumour assessment and had a FGFR1 FISH ratio ≥2 if the patient was from Part C

To obtain a preliminary assessment of the anti tumour activity of AZD4547 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1. Objective response = CR + PR; CR=disappearance of all target lesions and PR is \>=30% reduction in sum of longest diameter of target lesions

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=43 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A n=12 Participants Dose escalation
Tumour Response (Best Objective Response) - Number of Patients With a Confirmed Response of Partial Response (PR) or Confirmed Response (CR)	0 Patients	1 Patients	0 Patients	0 Patients

SECONDARY outcome

Timeframe: PK samples out to 96 hours "0-96 hours post dose" after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.

Population: PK

To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=43 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A Dose escalation
Cmax (ng/mL)	112.0 ng/mL Geometric Coefficient of Variation 81.47	—	167.4 ng/mL Geometric Coefficient of Variation 112.1	—

SECONDARY outcome

Timeframe: PK samples out to 96 hours "0-96 hours post-dose" after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.

Population: PK

To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.

Outcome measures

Outcome measures
Measure	Part B n=6 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=32 Participants Dose expansion in patients with FGFR gene-amplified tumours	Part A Dose escalation
Css,Max (ng/mL)	289.3 ng/mL Geometric Coefficient of Variation 45.98	—	297.1 ng/mL Geometric Coefficient of Variation 123.5	—

SECONDARY outcome

Timeframe: PK samples out to 96 hours "0-96 hours post dose" after single dose (in parts A & B only). Steady state PK profile 3 weeks after the start of BD dosing.

Population: PK

To characterise the pharmacokinetics (PK) of AZD4547 following a single administration and at steady state after dosing when given orally.

Outcome measures

Outcome measures
Measure	Part B n=4 Participants Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) Dose expansion in patients with FGFR gene-amplified tumours	Part A n=31 Participants Dose escalation
AUC,ss(0-infinity)	2606 ng*h/mL Geometric Coefficient of Variation 41.32	—	—	2337 ng*h/mL Geometric Coefficient of Variation 125.2

Adverse Events

Part B

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Part C (FISH Ratio >= 2)

Serious events: 10 serious events

Other events: 33 other events

Deaths: 0 deaths

Part C (FISH Ratio < 2)

Serious events: 3 serious events

Other events: 12 other events

Deaths: 0 deaths

Part A

Serious events: 11 serious events

Other events: 43 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Donal Landers

AstraZeneca

Phone: +44 1625 231890

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	Part B n=6 participants at risk Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 participants at risk Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 participants at risk Dose expansionj in patients with FGFR gene-amplified tumours	Part A n=43 participants at risk Dose escalation
Renal and urinary disorders Renal failure	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	9.3% 4/43 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Blood and lymphatic system disorders Anaemia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Investigations ALT increased	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	6.1% 2/33 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Investigations GGT increased	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Renal and urinary disorders Hydronephrosis	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Renal and urinary disorders Nephrolithiasis	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Renal and urinary disorders Pelvi-ureteric obstruction	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders Pyrexia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Eye disorders Retinal detachment	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders Tumour associated fever	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Investigations Blood creatinine increased	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders General physical health deterioration	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	6.1% 2/33 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	8.3% 1/12 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders Asthenia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	8.3% 1/12 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Eye disorders Chorioretinopathy	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	6.1% 2/33 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Metabolism and nutrition disorders Dehydration	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	6.1% 2/33 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Vascular disorders Atrial flutter	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	8.3% 1/12 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Hepatobiliary disorders Bile duct obstruction	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Decreased appetite	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Psychiatric disorders Delirium	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	8.3% 1/12 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Epilepsy	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Social circumstances Euthanasia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Hypotension	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	8.3% 1/12 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Blood and lymphatic system disorders Pericardial effusion	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Infections and infestations Pneumonia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	8.3% 1/12 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Infections and infestations Sepsis	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Vomiting	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	3.0% 1/33 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	2.3% 1/43 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.

Measure	Part B n=6 participants at risk Dose expansion phase (80mg bd tablet)	Part C (FISH Ratio >= 2) n=33 participants at risk Dose expansion in patients with FGFR gene-amplified tumours	Part C (FISH Ratio < 2) n=12 participants at risk Dose expansionj in patients with FGFR gene-amplified tumours	Part A n=43 participants at risk Dose escalation
Skin and subcutaneous tissue disorders Nail disorder	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	21.2% 7/33 • Number of events 7 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	34.9% 15/43 • Number of events 15 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Vomiting	50.0% 3/6 • Number of events 3 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	30.3% 10/33 • Number of events 10 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	41.7% 5/12 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	25.6% 11/43 • Number of events 11 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	33.3% 11/33 • Number of events 11 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	50.0% 6/12 • Number of events 6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	27.9% 12/43 • Number of events 12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Nausea	50.0% 3/6 • Number of events 3 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	27.3% 9/33 • Number of events 9 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	25.6% 11/43 • Number of events 11 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders Fatigue	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	39.4% 13/33 • Number of events 13 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	33.3% 4/12 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	23.3% 10/43 • Number of events 10 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders Asthenia	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	12.1% 4/33 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	20.9% 9/43 • Number of events 9 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Eye disorders Dry eye	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	27.3% 9/33 • Number of events 9 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	18.6% 8/43 • Number of events 8 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Constipation	50.0% 3/6 • Number of events 3 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	39.4% 13/33 • Number of events 13 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	55.8% 24/43 • Number of events 24 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Skin and subcutaneous tissue disorders Alopecia	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	24.2% 8/33 • Number of events 8 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	48.8% 21/43 • Number of events 21 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Dry mouth	83.3% 5/6 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	45.5% 15/33 • Number of events 15 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	41.9% 18/43 • Number of events 18 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Stomatis	83.3% 5/6 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	30.3% 10/33 • Number of events 10 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	50.0% 6/12 • Number of events 6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	41.9% 18/43 • Number of events 18 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Metabolism and nutrition disorders Hyperphosphataemia	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	18.2% 6/33 • Number of events 6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	46.5% 20/43 • Number of events 20 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Skin and subcutaneous tissue disorders Dry skin	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	24.2% 8/33 • Number of events 8 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	41.9% 18/43 • Number of events 18 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Diarrhoea	50.0% 3/6 • Number of events 3 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	36.4% 12/33 • Number of events 12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	33.3% 4/12 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	32.6% 14/43 • Number of events 14 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	12.1% 4/33 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	16.3% 7/43 • Number of events 7 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	18.2% 6/33 • Number of events 6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	18.6% 8/43 • Number of events 8 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Headache	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	14.0% 6/43 • Number of events 6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
General disorders Pyrexia	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Abdominal pain	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Dysgeusia	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Dyspepsia	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Muscle spasms	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Nasal congestion	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Dysphonia	33.3% 2/6 • Number of events 2 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	9.3% 4/43 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Breath sounds abnormal	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	15.2% 5/33 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/43 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	30.2% 13/43 • Number of events 13 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Metabolism and nutrition disorders Ageusia	66.7% 4/6 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	18.6% 8/43 • Number of events 8 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	23.3% 10/43 • Number of events 10 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Lethargy	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	16.3% 7/43 • Number of events 7 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Eye disorders Oedema peripheral	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	16.3% 7/43 • Number of events 7 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Gastrointestinal disorders Dyspepsia	16.7% 1/6 • Number of events 1 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Investigations ALT increased	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	9.3% 4/43 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Blood and lymphatic system disorders Anaemia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	9.3% 4/43 • Number of events 4 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.
Nervous system disorders Insomnia	0.00% 0/6 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/33 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	0.00% 0/12 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.	11.6% 5/43 • Number of events 5 • AEs were collected on a continual basis from Screening up until the end of the 28 day follow up period.