Trial Outcomes & Findings for An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide (NCT NCT02400476)

NCT ID: NCT02400476

Last Updated: 2022-05-06

Results Overview

The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of \>=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 563 participants
• Primary outcome timeframe: From first dose of investigational product through 28 days after last dose, up to 15.5 months.
• Results posted on: 2022-05-06

Participant Flow

Participant milestones

Measure	Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Overall Study STARTED	137	64	136	104	60	62
Overall Study COMPLETED	76	52	95	74	45	46
Overall Study NOT COMPLETED	61	12	41	30	15	16

Reasons for withdrawal

Measure	Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Overall Study Adverse Event	57	10	22	19	5	8
Overall Study Withdrawal by Subject	4	1	12	7	5	5
Overall Study Lost to Follow-up	0	0	0	1	3	1
Overall Study Physician Decision	0	0	1	1	0	1
Overall Study Other, Disease Progression	0	1	2	1	2	1
Overall Study Other, Decreased Quality of Life	0	0	2	0	0	0
Overall Study Other, Noncompliance to Protocol Requirements	0	0	2	1	0	0

Baseline Characteristics

An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide

Baseline characteristics by cohort

Measure	Loperamide n=137 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide n=64 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide n=136 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed n=104 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 n=60 Participants 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 n=62 Participants 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide	Total n=563 Participants Total of all reporting groups
Age, Categorical <=18 years	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	0 Participants n=10 Participants	0 Participants n=115 Participants
Age, Categorical Between 18 and 65 years	116 Participants n=5 Participants	58 Participants n=7 Participants	117 Participants n=5 Participants	93 Participants n=4 Participants	51 Participants n=21 Participants	52 Participants n=10 Participants	487 Participants n=115 Participants
Age, Categorical >=65 years	21 Participants n=5 Participants	6 Participants n=7 Participants	19 Participants n=5 Participants	11 Participants n=4 Participants	9 Participants n=21 Participants	10 Participants n=10 Participants	76 Participants n=115 Participants
Age, Continuous	53.39 years STANDARD_DEVIATION 11.06 • n=5 Participants	49.11 years STANDARD_DEVIATION 10.55 • n=7 Participants	52.49 years STANDARD_DEVIATION 11.08 • n=5 Participants	51.94 years STANDARD_DEVIATION 10.23 • n=4 Participants	51.90 years STANDARD_DEVIATION 10.71 • n=21 Participants	53.82 years STANDARD_DEVIATION 10.15 • n=10 Participants	52.31 years STANDARD_DEVIATION 10.76 • n=115 Participants
Sex: Female, Male Female	137 Participants n=5 Participants	64 Participants n=7 Participants	133 Participants n=5 Participants	104 Participants n=4 Participants	60 Participants n=21 Participants	62 Participants n=10 Participants	560 Participants n=115 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	3 Participants n=115 Participants
Race/Ethnicity, Customized Race · White	113 Participants n=5 Participants	50 Participants n=7 Participants	96 Participants n=5 Participants	80 Participants n=4 Participants	53 Participants n=21 Participants	52 Participants n=10 Participants	444 Participants n=115 Participants
Race/Ethnicity, Customized Race · Black or African American	11 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants	8 Participants n=4 Participants	1 Participants n=21 Participants	2 Participants n=10 Participants	36 Participants n=115 Participants
Race/Ethnicity, Customized Race · Asian	8 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants	9 Participants n=4 Participants	3 Participants n=21 Participants	1 Participants n=10 Participants	38 Participants n=115 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	2 Participants n=115 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	4 Participants n=115 Participants
Race/Ethnicity, Customized Race · Other	3 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	3 Participants n=10 Participants	18 Participants n=115 Participants
Race/Ethnicity, Customized Race · Unknown	0 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	5 Participants n=115 Participants
Race/Ethnicity, Customized Race · Missing	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	1 Participants n=10 Participants	1 Participants n=115 Participants
Race/Ethnicity, Customized Race · Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants	2 Participants n=21 Participants	2 Participants n=10 Participants	15 Participants n=115 Participants
Region of Enrollment Canada	0 participants n=5 Participants	0 participants n=7 Participants	4 participants n=5 Participants	10 participants n=4 Participants	6 participants n=21 Participants	7 participants n=10 Participants	27 participants n=115 Participants
Region of Enrollment Austria	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	4 participants n=10 Participants	4 participants n=115 Participants
Region of Enrollment United States	132 participants n=5 Participants	52 participants n=7 Participants	115 participants n=5 Participants	83 participants n=4 Participants	20 participants n=21 Participants	11 participants n=10 Participants	413 participants n=115 Participants
Region of Enrollment Australia	5 participants n=5 Participants	12 participants n=7 Participants	17 participants n=5 Participants	11 participants n=4 Participants	23 participants n=21 Participants	18 participants n=10 Participants	86 participants n=115 Participants
Region of Enrollment France	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	6 participants n=10 Participants	6 participants n=115 Participants
Region of Enrollment Germany	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	2 participants n=10 Participants	2 participants n=115 Participants
Region of Enrollment Spain	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	11 participants n=21 Participants	14 participants n=10 Participants	25 participants n=115 Participants

PRIMARY outcome

Timeframe: From first dose of investigational product through 28 days after last dose, up to 15.5 months.

The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.

Outcome measures

Measure	Loperamide n=137 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide n=64 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide n=136 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed n=104 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 n=60 Participants 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 n=62 Participants 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	30.7 Percentage of participants Interval 23.1 to 39.1	28.1 Percentage of participants Interval 17.6 to 40.8	20.6 Percentage of participants Interval 14.1 to 28.4	32.7 Percentage of participants Interval 23.8 to 42.6	13.3 Percentage of participants Interval 5.9 to 24.6	27.4 Percentage of participants Interval 16.9 to 40.2

SECONDARY outcome

Timeframe: From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Assess the percentage of patients with diarrhea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following two different dose-escalation regimens of neratinib, by maximum CTC grade. Grade 1: an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.

Outcome measures

Measure	Loperamide n=137 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide n=64 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide n=136 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed n=104 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 n=60 Participants 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 n=62 Participants 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0. Percentage of Patients w Grade 1 Diarrhea	24.1 Percentage of participants	23.4 Percentage of participants	27.9 Percentage of participants	32.7 Percentage of participants	40.0 Percentage of participants	37.1 Percentage of participants
Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0. Percentage of Patients w Grade 2 Diarrhea	24.8 Percentage of participants	34.4 Percentage of participants	34.6 Percentage of participants	29.8 Percentage of participants	45.0 Percentage of participants	33.9 Percentage of participants
Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0. Percentage of Patients w Grade 3 Diarrhea	30.7 Percentage of participants	28.1 Percentage of participants	20.6 Percentage of participants	32.7 Percentage of participants	13.3 Percentage of participants	27.4 Percentage of participants

SECONDARY outcome

Timeframe: From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Population: All subjects who received at least one dose of neratinib.

Assess the percentage of patients with serious adverse events (SAEs) and other adverse events of special interest (AESI). AESIs were selected based on the known safety profile of neratinib as well as typical key body system toxicity concerns generally reviewed for any new drug. These AESIs were grouped into the following categories: gastrointestinal toxicity (diarrhea and stomatitis), hepatotoxicity, pulmonary toxicity (interstitial lung disease), cardiac toxicity (LVEF decreased), and dermatologic toxicity (rash and nail disorders). The AESIs were analyzed by searching the clinical database for all TEAEs and SAEs using either Standardized MedDRA Queries (SMQs) or, if an applicable SMQ did not exist, a Sponsor-defined list of MedDRA preferred terms.

Outcome measures

Measure	Loperamide n=137 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide n=64 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide n=136 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed n=104 Participants 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 n=60 Participants 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 n=62 Participants 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with SAEs	6.57 percentage of participants	6.25 percentage of participants	6.62 percentage of participants	2.88 percentage of participants	8.33 percentage of participants	8.06 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI-Gastrointestinal Toxicities (Diarrhoea and Stomatitis Broad Search)	81.75 percentage of participants	87.5 percentage of participants	83.82 percentage of participants	96.15 percentage of participants	98.33 percentage of participants	98.39 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	12.41 percentage of participants	7.81 percentage of participants	4.41 percentage of participants	4.81 percentage of participants	8.33 percentage of participants	4.84 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI- Interstitial Lung Disease SMQ (Broad Search)	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	5.84 percentage of participants	6.25 percentage of participants	10.29 percentage of participants	7.69 percentage of participants	10.00 percentage of participants	4.84 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI - Dermatologic Toxicities (Rash and Nail Disorders)	12.41 percentage of participants	37.50 percentage of participants	23.53 percentage of participants	18.27 percentage of participants	11.67 percentage of participants	30.65 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	80.29 percentage of participants	85.94 percentage of participants	83.09 percentage of participants	95.19 percentage of participants	98.33 percentage of participants	98.39 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	10.95 percentage of participants	7.81 percentage of participants	3.68 percentage of participants	3.85 percentage of participants	8.33 percentage of participants	4.84 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI- Interstitial Lung Disease SMQ (Narrow Search)	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	2.92 percentage of participants	0 percentage of participants	1.47 percentage of participants	0.96 percentage of participants	1.67 percentage of participants	0 percentage of participants

Adverse Events

Loperamide

Serious events: 9 serious events

Other events: 137 other events

Deaths: 0 deaths

Budesonide and Loperamide

Serious events: 4 serious events

Other events: 64 other events

Deaths: 0 deaths

Colestipol and Loperamide

Serious events: 9 serious events

Other events: 136 other events

Deaths: 0 deaths

Colestipol With Loperamide as Needed

Serious events: 3 serious events

Other events: 104 other events

Deaths: 0 deaths

Neratinib Dose Escalation 1

Serious events: 5 serious events

Other events: 60 other events

Deaths: 0 deaths

Neratinib Dose Escalation 2

Serious events: 5 serious events

Other events: 62 other events

Deaths: 0 deaths

Serious adverse events

Measure	Loperamide n=137 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide n=64 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide n=136 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed n=104 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 n=60 participants at risk 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 n=62 participants at risk 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Eye disorders Retinal detachment	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Abdominal pain	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Colitis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Diarrhoea	1.5% 2/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Nausea	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Pancreatitis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Stomatitis	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
General disorders Fat necrosis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
General disorders Pyrexia	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Hepatobiliary disorders Cholecystitis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Hepatobiliary disorders Cholelithiasis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Appendicitis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.96% 1/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Bacteraemia	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Breast cellulitis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Cellulitis	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.96% 1/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Device related infection	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Gastroenteritis	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.96% 1/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Gastroenteritis viral	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Influenza	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Listeriosis	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Lower respiratory tract infection	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Post procedural infection	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Sepsis	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Upper respiratory tract infection	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Urinary tract infection	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Wound infection	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Alanine aminotransferase increased	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Aspartate aminotransferase increased	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Electrocardiogram QT prolonged	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Metabolism and nutrition disorders Decreased appetite	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Metabolism and nutrition disorders Dehydration	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.96% 1/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Metabolism and nutrition disorders Hypokalaemia	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Nervous system disorders Seizure	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Nervous system disorders Syncope	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.5% 2/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Psychiatric disorders Confusional state	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Skin and subcutaneous tissue disorders Rash	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Skin and subcutaneous tissue disorders Rash erythematous	0.73% 1/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.

Other adverse events

Measure	Loperamide n=137 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Neratinib Loperamide	Budesonide and Loperamide n=64 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Neratinib Loperamide Budesonide: 9 mg extended release tablets once daily with or without food for 28 days	Colestipol and Loperamide n=136 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Colestipol With Loperamide as Needed n=104 participants at risk 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Neratinib Loperamide Colestipol: 2 g twice daily with or without food for one 28 day cycle	Neratinib Dose Escalation 1 n=60 participants at risk 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Neratinib Loperamide	Neratinib Dose Escalation 2 n=62 participants at risk 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only. Neratinib Loperamide
Blood and lymphatic system disorders Anaemia	5.8% 8/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.8% 5/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 5/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Ear and labyrinth disorders Vertigo	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.2% 3/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Abdominal discomfort	5.1% 7/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.1% 2/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.1% 7/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 5/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.3% 2/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Abdominal distension	15.3% 21/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.8% 5/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	16.2% 22/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	14.4% 15/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.0% 6/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	16.1% 10/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Abdominal pain	26.3% 36/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	18.8% 12/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	19.1% 26/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	26.0% 27/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	21.7% 13/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	24.2% 15/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Abdominal pain upper	3.6% 5/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.9% 7/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	11.8% 16/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.7% 7/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.9% 8/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Constipation	56.9% 78/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	75.0% 48/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	68.4% 93/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	37.5% 39/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	36.7% 22/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	24.2% 15/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Diarrhoea	79.6% 109/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	85.9% 55/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	83.1% 113/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	95.2% 99/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	98.3% 59/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	98.4% 61/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Dry mouth	13.1% 18/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.4% 6/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	8.8% 12/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 5/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.7% 4/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 3/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Dyspepsia	8.8% 12/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	15.6% 10/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	11.8% 16/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 13/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	11.7% 7/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.7% 6/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Flatulence	3.6% 5/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.4% 6/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.7% 5/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.9% 2/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 3/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Gastrooesophageal reflux disease	7.3% 10/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.8% 5/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.4% 10/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.8% 6/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.3% 2/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.5% 4/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Nausea	56.9% 78/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	50.0% 32/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	61.0% 83/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	61.5% 64/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	45.0% 27/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	45.2% 28/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Stomatitis	5.1% 7/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.3% 14/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 13/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.0% 6/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.7% 6/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Gastrointestinal disorders Vomiting	26.3% 36/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	25.0% 16/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	31.6% 43/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	24.0% 25/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	15.0% 9/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	8.1% 5/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
General disorders Asthenia	4.4% 6/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.74% 1/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
General disorders Fatigue	53.3% 73/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	53.1% 34/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	47.8% 65/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	39.4% 41/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	46.7% 28/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	30.6% 19/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
General disorders Pyrexia	4.4% 6/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.1% 2/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.4% 10/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.9% 3/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.3% 2/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Cellulitis	2.2% 3/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.9% 2/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Influenza	1.5% 2/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.2% 3/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Nasopharyngitis	3.6% 5/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.5% 2/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.9% 3/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Upper respiratory tract infection	3.6% 5/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.9% 7/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.1% 7/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 5/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.0% 6/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Infections and infestations Urinary tract infection	7.3% 10/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.1% 2/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.9% 8/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	8.7% 9/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.0% 6/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	8.1% 5/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Alanine aminotransferase increased	6.6% 9/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.9% 4/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.9% 3/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.7% 4/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Aspartate aminotransferase increased	2.9% 4/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.2% 3/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.9% 2/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Blood glucose increased	0.00% 0/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Investigations Weight decreased	7.3% 10/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	8.1% 11/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 3/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Metabolism and nutrition disorders Decreased appetite	19.0% 26/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	17.2% 11/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	17.6% 24/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	25.0% 26/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	13.3% 8/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.9% 8/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Metabolism and nutrition disorders Dehydration	5.1% 7/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.4% 6/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.7% 5/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.3% 2/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Metabolism and nutrition disorders Hypokalaemia	2.9% 4/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.9% 8/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.9% 2/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Musculoskeletal and connective tissue disorders Arthralgia	7.3% 10/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	21.9% 14/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	11.0% 15/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 13/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	15.0% 9/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.5% 4/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Musculoskeletal and connective tissue disorders Back pain	7.3% 10/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.8% 5/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.6% 9/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.6% 10/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.7% 4/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Musculoskeletal and connective tissue disorders Muscle spasms	10.9% 15/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 8/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.3% 14/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	14.4% 15/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	20.0% 12/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.9% 8/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Musculoskeletal and connective tissue disorders Myalgia	2.2% 3/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.4% 6/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 5/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.3% 2/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 3/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Musculoskeletal and connective tissue disorders Pain in extremity	5.1% 7/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.7% 3/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.1% 7/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 5/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.3% 2/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.8% 3/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Nervous system disorders Dizziness	13.9% 19/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.4% 6/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	15.4% 21/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	19.2% 20/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	15.0% 9/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.9% 8/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Nervous system disorders Headache	19.0% 26/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	18.8% 12/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	14.7% 20/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	23.1% 24/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	21.7% 13/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.9% 8/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Nervous system disorders Neuropathy peripheral	2.9% 4/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.7% 3/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.2% 3/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.8% 6/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Nervous system disorders Paraesthesia	2.2% 3/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.2% 3/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	8.3% 5/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Psychiatric disorders Anxiety	3.6% 5/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.2% 3/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.9% 3/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.2% 2/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Psychiatric disorders Insomnia	4.4% 6/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 8/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.4% 10/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.7% 8/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.5% 4/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Reproductive system and breast disorders Breast pain	2.9% 4/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.9% 7/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.9% 8/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.8% 6/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Respiratory, thoracic and mediastinal disorders Cough	5.1% 7/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	10.9% 7/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.6% 9/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	7.7% 8/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.00% 0/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.6% 9/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	2.9% 4/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.6% 1/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.5% 2/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.1% 2/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.6% 9/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.5% 4/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Skin and subcutaneous tissue disorders Dermatitis acneiform	1.5% 2/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.2% 4/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.7% 5/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	0.96% 1/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.5% 4/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Skin and subcutaneous tissue disorders Dry skin	4.4% 6/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 8/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.1% 7/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.6% 10/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.7% 4/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	14.5% 9/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Skin and subcutaneous tissue disorders Onychoclasis	3.6% 5/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.7% 3/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	4.4% 6/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	3.8% 4/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	5.0% 3/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.7% 6/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Skin and subcutaneous tissue disorders Rash	5.1% 7/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	18.8% 12/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	11.0% 15/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.6% 10/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	1.7% 1/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.9% 8/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Vascular disorders Hot flush	5.8% 8/137 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	9.4% 6/64 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	12.5% 17/136 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.7% 7/104 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	11.7% 7/60 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.	6.5% 4/62 • From time of first dose, through 28 days after last dose, assessed up to 15.5 months.

Additional Information

Senior Director, Clinical Operations

Puma Biotechnology, Inc.

Phone: 1-424-248-6500

Email: clinicaltrials@pumabiotechnology.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place