Trial Outcomes & Findings for Study Evaluating HKI-272 (Neratinib) In Subjects With Advanced Breast Cancer (NCT NCT00300781)

Last Updated: 2018-08-14

Results Overview

16 week progression-free survival (PFS) rate of neratinib in women with human epidermal growth factor receptor 2 (HER2) positive breast cancer, either with prior trastuzumab or no prior trastuzumab therapy, evaluated by independent assessment of tumor scans collected at baseline and then every 8 weeks.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

136 participants

Primary outcome timeframe

From first dose to 16 weeks

Results posted on

2018-08-14

Participant Flow

Participant milestones

Participant milestones
Measure	Neratinib 240, Prior Trastuzumab Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen, in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with with no prior trastuzumab treatment.
Overall Study STARTED	66	70
Overall Study COMPLETED	3	8
Overall Study NOT COMPLETED	63	62

Reasons for withdrawal

Reasons for withdrawal
Measure	Neratinib 240, Prior Trastuzumab Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen, in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with with no prior trastuzumab treatment.
Overall Study Disease Progression	55	52
Overall Study Adverse Event	5	6
Overall Study Withdrawal by Subject	1	2
Overall Study Physician Decision	1	0
Overall Study Not Recorded	0	1
Overall Study Symptomatic Deterioration	1	0
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

Study Evaluating HKI-272 (Neratinib) In Subjects With Advanced Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Neratinib 240, Prior Trastuzumab n=66 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=70 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.	Total n=136 Participants Total of all reporting groups
Age, Continuous	51.62 years STANDARD_DEVIATION 10.67 • n=93 Participants	49.64 years STANDARD_DEVIATION 9.92 • n=4 Participants	50.60 years STANDARD_DEVIATION 10.30 • n=27 Participants
Sex: Female, Male Female	66 Participants n=93 Participants	70 Participants n=4 Participants	136 Participants n=27 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	6 Participants n=93 Participants	52 Participants n=4 Participants	58 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	2 Participants n=93 Participants	0 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) White	55 Participants n=93 Participants	15 Participants n=4 Participants	70 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=93 Participants	3 Participants n=4 Participants	6 Participants n=27 Participants

PRIMARY outcome

Timeframe: From first dose to 16 weeks

Population: Intent to Treat Population

Outcome measures

Outcome measures
Measure	Neratinib 240, Prior Trastuzumab n=66 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=70 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
16-week Progression Free Survival	58.2 percentage of participants Interval 45.3 to 71.2	77.8 percentage of participants Interval 67.6 to 88.1

SECONDARY outcome

Timeframe: From first dose date to progression or last tumor assessment, up to 46 months

Population: Intent to Treat population

Percentage of participants with Partial Response (PR) or Complete Response (CR) by independent assessment of tumor per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Neratinib 240, Prior Trastuzumab n=66 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=70 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
Objective Response Rate	24.2 percentage of participants Interval 14.5 to 36.4	52.9 percentage of participants Interval 40.6 to 64.9

SECONDARY outcome

Timeframe: From first dose date to progression or last tumor assessment, up to 46 months

Population: Intent to Treat population

Percentage of participants who experienced Complete Response (CR), Partial Response (PR), or Stable Disease (SD) ≥ 24 weeks by independent assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Neratinib 240, Prior Trastuzumab n=66 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=70 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
Clinical Benefit Rate	31.8 percentage of participants Interval 20.9 to 44.4	62.9 percentage of participants Interval 50.5 to 74.1

SECONDARY outcome

Timeframe: From start date of response to first PD/death, up to 46 months

Population: Subjects in Intent to Treat population with CR or PR

Number of weeks between Complete Response (CR) or Partial Response (PR) and the first date of disease progression (PD) or death per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions

Outcome measures

Outcome measures
Measure	Neratinib 240, Prior Trastuzumab n=16 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=37 Participants Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
Duration of Response	40.3 weeks Interval 32.3 to 80.1	60.0 weeks Interval 40.1 to 100.1

Adverse Events

Neratinib 240, Prior Trastuzumab

Serious events: 19 serious events

Other events: 66 other events

Deaths: 0 deaths

Neratinib 240, No Prior Trastuzumab

Serious events: 17 serious events

Other events: 70 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 240, Prior Trastuzumab n=66 participants at risk Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=70 participants at risk Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
Blood and lymphatic system disorders Anaemia	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Cardiac disorders Atrioventricular block	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Cardiac disorders Bradycardia	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Diarrhoea	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Nausea	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Vomiting	4.5% 3/66 • From first dose through 28 days after last dose, up to 46 months.	8.6% 6/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Asthenia	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Fatigue	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Malaise	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Pyrexia	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Disseminated tuberculosis	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Folliculitis	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Hepatitis E	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Mastitis	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Sinusitis	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Alanine aminotransferase increased	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Aspartate aminotransferase increased	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Blood creatinine increased	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Gamma-glutamyltransferase increased	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Metabolism and nutrition disorders Decreased appetite	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Metabolism and nutrition disorders Dehydration	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Metabolism and nutrition disorders Hyponatraemia	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Muscular weakness	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphangiosis carcinomatosa	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant ascites	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant pleural effusion	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders Dyskinesia	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders Headache	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders Neuropathy peripheral	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders VIIth nerve paralysis	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Psychiatric disorders Confusional state	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Renal and urinary disorders Nephrolithiasis	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Vascular disorders Lymphoedema	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.

Measure	Neratinib 240, Prior Trastuzumab n=66 participants at risk Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with prior trastuzumab treatment.	Neratinib 240, No Prior Trastuzumab n=70 participants at risk Neratinib: 80mg capsules and 40mg coated tablets taken orally in prescribed dose of 240mg daily, as long as tolerated and disease does not worsen in participants with no prior trastuzumab treatment.
Blood and lymphatic system disorders Anaemia	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	11.4% 8/70 • From first dose through 28 days after last dose, up to 46 months.
Blood and lymphatic system disorders Leukopenia	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	2.9% 2/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Abdominal discomfort	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	7.1% 5/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Abdominal pain	28.8% 19/66 • From first dose through 28 days after last dose, up to 46 months.	8.6% 6/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Abdominal pain upper	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Constipation	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	2.9% 2/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Diarrhoea	95.5% 63/66 • From first dose through 28 days after last dose, up to 46 months.	91.4% 64/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Dry mouth	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Dyspepsia	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	10.0% 7/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Haemorrhoids	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Nausea	40.9% 27/66 • From first dose through 28 days after last dose, up to 46 months.	32.9% 23/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Stomatitis	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Gastrointestinal disorders Vomiting	24.2% 16/66 • From first dose through 28 days after last dose, up to 46 months.	32.9% 23/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Asthenia	4.5% 3/66 • From first dose through 28 days after last dose, up to 46 months.	14.3% 10/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Fatigue	39.4% 26/66 • From first dose through 28 days after last dose, up to 46 months.	10.0% 7/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Oedema peripheral	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	7.1% 5/70 • From first dose through 28 days after last dose, up to 46 months.
General disorders Pyrexia	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	17.1% 12/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Nasopharyngitis	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	7.1% 5/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Paronychia	0.00% 0/66 • From first dose through 28 days after last dose, up to 46 months.	8.6% 6/70 • From first dose through 28 days after last dose, up to 46 months.
Infections and infestations Urinary tract infection	10.6% 7/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Alanine aminotransferase increased	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	7.1% 5/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Aspartate aminotransferase increased	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	7.1% 5/70 • From first dose through 28 days after last dose, up to 46 months.
Investigations Weight decreased	4.5% 3/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Metabolism and nutrition disorders Decreased appetite	22.7% 15/66 • From first dose through 28 days after last dose, up to 46 months.	17.1% 12/70 • From first dose through 28 days after last dose, up to 46 months.
Metabolism and nutrition disorders Dehydration	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	4.3% 3/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Arthralgia	10.6% 7/66 • From first dose through 28 days after last dose, up to 46 months.	10.0% 7/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Back pain	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	11.4% 8/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Muscle spasms	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	2.9% 2/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	4.3% 3/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	4.3% 3/70 • From first dose through 28 days after last dose, up to 46 months.
Musculoskeletal and connective tissue disorders Pain in extremity	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	10.0% 7/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders Dizziness	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	8.6% 6/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders Dysgeusia	9.1% 6/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Nervous system disorders Headache	18.2% 12/66 • From first dose through 28 days after last dose, up to 46 months.	20.0% 14/70 • From first dose through 28 days after last dose, up to 46 months.
Psychiatric disorders Insomnia	4.5% 3/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Renal and urinary disorders Dysuria	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	8.6% 6/70 • From first dose through 28 days after last dose, up to 46 months.
Renal and urinary disorders Pollakiuria	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	1.4% 1/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Cough	12.1% 8/66 • From first dose through 28 days after last dose, up to 46 months.	8.6% 6/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.1% 8/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.5% 1/66 • From first dose through 28 days after last dose, up to 46 months.	7.1% 5/70 • From first dose through 28 days after last dose, up to 46 months.
Skin and subcutaneous tissue disorders Alopecia	4.5% 3/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Skin and subcutaneous tissue disorders Dermatitis acneiform	3.0% 2/66 • From first dose through 28 days after last dose, up to 46 months.	12.9% 9/70 • From first dose through 28 days after last dose, up to 46 months.
Skin and subcutaneous tissue disorders Dry skin	6.1% 4/66 • From first dose through 28 days after last dose, up to 46 months.	4.3% 3/70 • From first dose through 28 days after last dose, up to 46 months.
Skin and subcutaneous tissue disorders Nail disorder	7.6% 5/66 • From first dose through 28 days after last dose, up to 46 months.	0.00% 0/70 • From first dose through 28 days after last dose, up to 46 months.
Skin and subcutaneous tissue disorders Pruritus	12.1% 8/66 • From first dose through 28 days after last dose, up to 46 months.	5.7% 4/70 • From first dose through 28 days after last dose, up to 46 months.
Skin and subcutaneous tissue disorders Rash	21.2% 14/66 • From first dose through 28 days after last dose, up to 46 months.	12.9% 9/70 • From first dose through 28 days after last dose, up to 46 months.