Trial Outcomes & Findings for A Phase 1/2 Study of HKI-272 (Neratinib) in Combination With Paclitaxel (Taxol) in Subjects With Solid Tumors and Breast Cancer (NCT NCT00445458)

Last Updated: 2018-07-26

Results Overview

Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

110 participants

Primary outcome timeframe

From first dose date through day 28

Results posted on

2018-07-26

Participant Flow

Participant milestones

Participant milestones
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m2 Neratinib 160 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m2 Neratinib 240 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle.	Arm A Neratinib (MTD) + Paclitaxel 80 mg/m2 Neratinib (MTD) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease.	Arm B Neratinib (MTD) + Paclitaxel 80 mg/m2 Neratinib (MTD) + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease.
Overall Study STARTED	3	5	71	31
Overall Study COMPLETED	0	0	3	3
Overall Study NOT COMPLETED	3	5	68	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m2 Neratinib 160 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m2 Neratinib 240 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle.	Arm A Neratinib (MTD) + Paclitaxel 80 mg/m2 Neratinib (MTD) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease.	Arm B Neratinib (MTD) + Paclitaxel 80 mg/m2 Neratinib (MTD) + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease.
Overall Study Disease Progression	3	4	54	27
Overall Study Withdrawal by Subject	0	0	7	0
Overall Study Adverse Event	0	0	3	0
Overall Study Death	0	1	2	0
Overall Study Physician Decision	0	0	1	1
Overall Study Surgery	0	0	1	0

Baseline Characteristics

A Phase 1/2 Study of HKI-272 (Neratinib) in Combination With Paclitaxel (Taxol) in Subjects With Solid Tumors and Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m2 n=3 Participants Neratinib 160 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m2 n=5 Participants Neratinib 240 mg qd + Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of a 28 day cycle.	Arm A Neratinib (MTD) + Paclitaxel n=71 Participants Neratinib (MTD) + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease	Arm B Neratinib (MTD) + Paclitaxel n=31 Participants Neratinib (MTD) + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease	Total n=110 Participants Total of all reporting groups
Age, Continuous	56.3 years STANDARD_DEVIATION 14.57 • n=5 Participants	49.6 years STANDARD_DEVIATION 11.72 • n=7 Participants	49.2 years STANDARD_DEVIATION 10.10 • n=5 Participants	51.4 years STANDARD_DEVIATION 8.50 • n=4 Participants	50.0 years STANDARD_DEVIATION 9.82 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	2 Participants n=7 Participants	71 Participants n=5 Participants	31 Participants n=4 Participants	105 Participants n=21 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	48 Participants n=5 Participants	25 Participants n=4 Participants	77 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	3 Participants n=7 Participants	22 Participants n=5 Participants	5 Participants n=4 Participants	30 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants

PRIMARY outcome

Timeframe: From first dose date through day 28

Population: Safety population of Study Part 1. Treated set including patients eligible for MTD determination.

Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.

Outcome measures

Outcome measures
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m² n=3 Participants Neratinib 160 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m² n=5 Participants Neratinib 240 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Dose Limiting Toxicity Incidence of Neratinib in Combination With Paclitaxel	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From first dose date through day 28.

Population: Safety population of Study Part 1. Treated set including patients eligible for MTD determination.

Maximum Tolerated Dose (MTD) of neratinib, daily, in combination with paclitaxel 80 mg/m², intravenous at days 1, 8, and 15, associated with the dose limiting toxicity data.

Outcome measures

Outcome measures
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m² n=8 Participants Neratinib 160 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m² Neratinib 240 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Maximum Tolerated Dose	240 mg	—

PRIMARY outcome

Timeframe: From first dose date to progression or last tumor assessment, up to 140 weeks

Population: All subjects, in Study part 2 evaluable population, who met the inclusion/exclusion criteria, received at least 2 weeks of neratinib and at least 2 doses of paclitaxel, and underwent at least 1 post-Baseline tumor assessment. Subjects who died or had symptomatic deterioration before the first scheduled post-Baseline tumor assessment were included.

Subjects with partial response (PR) or complete response (CR) with ERBB2 positive breast cancer treated at the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; and no progressive disease (PD) for non-target lesions, and no new lesions.

Outcome measures

Outcome measures
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m² n=68 Participants Neratinib 160 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m² n=31 Participants Neratinib 240 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Objective Response Rate	70.6 percentage of participants Interval 58.3 to 81.0	77.4 percentage of participants Interval 58.9 to 90.4

SECONDARY outcome

Timeframe: Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1.

Maximum plasma concentration of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.

Outcome measures

Outcome measures
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m² n=3 Participants Neratinib 160 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m² n=94 Participants Neratinib 240 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Maximum Plasma Concentration of Neratinib	66.78 ng/mL Geometric Coefficient of Variation 25	80.42 ng/mL Geometric Coefficient of Variation 55

SECONDARY outcome

Timeframe: Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1.

Area under the concentration-time curve of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.

Outcome measures

Outcome measures
Measure	Neratinib 160 mg + Paclitaxel 80 mg/m² n=3 Participants Neratinib 160 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg + Paclitaxel 80 mg/m² n=94 Participants Neratinib 240 mg qd + Paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.
Area Under the Concentration-time Curve 0-24	684 h*ng/mL Geometric Coefficient of Variation 92	1274 h*ng/mL Geometric Coefficient of Variation 61

Adverse Events

Neratinib 160 mg + Paclitaxel 80 mg/m2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Neratinib 240 mg+ Paclitaxel 80 mg/m2

Serious events: 4 serious events

Other events: 5 other events

Deaths: 0 deaths

Arm A Neratinib 240 mg (MTD) + Paclitaxel 80 mg/m2

Serious events: 27 serious events

Other events: 70 other events

Deaths: 0 deaths

Arm B Neratinib 240 mg (MTD) + Paclitaxel 80 mg/m2

Serious events: 4 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Director, Clinical Operations

Puma Biotechnology, Inc.

Phone: +1 (424) 248-6500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Neratinib 160 mg + Paclitaxel 80 mg/m2 n=3 participants at risk Neratinib 160 mg qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle.	Neratinib 240 mg+ Paclitaxel 80 mg/m2 n=5 participants at risk Neratinib 240 mg qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle.	Arm A Neratinib 240 mg (MTD) + Paclitaxel 80 mg/m2 n=71 participants at risk Neratinib (MTD) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease	Arm B Neratinib 240 mg (MTD) + Paclitaxel 80 mg/m2 n=31 participants at risk Neratinib (MTD) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	40.0% 2/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	3.2% 1/31 • From first dose through 28 days after last dose, up to 140 weeks.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Blood and lymphatic system disorders Leukopenia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Cardiac disorders Sinus tachycardia	33.3% 1/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Eye disorders Cataract	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	3.2% 1/31 • From first dose through 28 days after last dose, up to 140 weeks.
Gastrointestinal disorders Abdominal discomfort	33.3% 1/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Gastrointestinal disorders Diarrhoea	33.3% 1/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	8.5% 6/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Gastrointestinal disorders Nausea	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Gastrointestinal disorders Vomiting	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	2.8% 2/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
General disorders Fatigue	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
General disorders Gait disturbance	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
General disorders Oedema peripheral	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	3.2% 1/31 • From first dose through 28 days after last dose, up to 140 weeks.
General disorders Pyrexia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Bacteraemia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Cellulitis	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Cystitis	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Fungaemia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Malaria	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Pneumonia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	2.8% 2/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Infections and infestations Sepsis	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Injury, poisoning and procedural complications Tibia fracture	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Investigations Ejection fraction decreased	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Investigations Electrocardiogram T wave inversion	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	2.8% 2/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer metastatic	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	5.6% 4/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	2.8% 2/71 • From first dose through 28 days after last dose, up to 140 weeks.	3.2% 1/31 • From first dose through 28 days after last dose, up to 140 weeks.
Nervous system disorders Brain oedema	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	3.2% 1/31 • From first dose through 28 days after last dose, up to 140 weeks.
Nervous system disorders Dizziness	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Nervous system disorders Loss of consciousness	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Nervous system disorders Transient ischaemic attack	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	3.2% 1/31 • From first dose through 28 days after last dose, up to 140 weeks.
Psychiatric disorders Anxiety	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Renal and urinary disorders Renal failure acute	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	2.8% 2/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	20.0% 1/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.
Skin and subcutaneous tissue disorders Ingrowing nail	0.00% 0/3 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/5 • From first dose through 28 days after last dose, up to 140 weeks.	1.4% 1/71 • From first dose through 28 days after last dose, up to 140 weeks.	0.00% 0/31 • From first dose through 28 days after last dose, up to 140 weeks.