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

• ClinicalTrials.gov Identifier: NCT02400476
• Recruitment Status: Completed
• First Posted: March 27, 2015
• Results First Posted: May 6, 2022
• Last Update Posted: May 6, 2022
• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Early Stage HER2+ Breast Cancer
• Interventions: Drug: Neratinib; Drug: Loperamide; Drug: Colestipol; Drug: Budesonide
• Enrollment: 563

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description	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	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	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	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	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	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
Period Title: Overall Study
Started	137	64	136	104	60	62
Completed	76	52	95	74	45	46
Not Completed	61	12	41	30	15	16
Reason Not Completed
Adverse Event	57	10	22	19	5	8
Withdrawal by Subject	4	1	12	7	5	5
Lost to Follow-up	0	0	0	1	3	1
Physician Decision	0	0	1	1	0	1
Other, Disease Progression	0	1	2	1	2	1
Other, Decreased Quality of Life	0	0	2	0	0	0
Other, Noncompliance to Protocol Requirements	0	0	2	1	0	0

Baseline Characteristics

Arm/Group Title		Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2	Total
Arm/Group Description		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	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	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	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	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	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 of all reporting groups
Overall Number of Baseline Participants		137	64	136	104	60	62	563
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	137 participants	64 participants	136 participants	104 participants	60 participants	62 participants	563 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	116 84.7%	58 90.6%	117 86.0%	93 89.4%	51 85.0%	52 83.9%	487 86.5%
	>=65 years	21 15.3%	6 9.4%	19 14.0%	11 10.6%	9 15.0%	10 16.1%	76 13.5%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	137 participants	64 participants	136 participants	104 participants	60 participants	62 participants	563 participants
		53.39 (11.06)	49.11 (10.55)	52.49 (11.08)	51.94 (10.23)	51.90 (10.71)	53.82 (10.15)	52.31 (10.76)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	137 participants	64 participants	136 participants	104 participants	60 participants	62 participants	563 participants
	Female	137 100.0%	64 100.0%	133 97.8%	104 100.0%	60 100.0%	62 100.0%	560 99.5%
	Male	0 0.0%	0 0.0%	3 2.2%	0 0.0%	0 0.0%	0 0.0%	3 0.5%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	137 participants	64 participants	136 participants	104 participants	60 participants	62 participants	563 participants
	White	113 82.5%	50 78.1%	96 70.6%	80 76.9%	53 88.3%	52 83.9%	444 78.9%
	Black or African American	11 8.0%	5 7.8%	9 6.6%	8 7.7%	1 1.7%	2 3.2%	36 6.4%
	Asian	8 5.8%	4 6.3%	13 9.6%	9 8.7%	3 5.0%	1 1.6%	38 6.7%
	American Indian or Alaska Native	1 0.7%	0 0.0%	1 0.7%	0 0.0%	0 0.0%	0 0.0%	2 0.4%
	Native Hawaiian or Other Pacific Islander	0 0.0%	1 1.6%	3 2.2%	0 0.0%	0 0.0%	0 0.0%	4 0.7%
	Other	3 2.2%	2 3.1%	9 6.6%	0 0.0%	1 1.7%	3 4.8%	18 3.2%
	Unknown	0 0.0%	1 1.6%	2 1.5%	1 1.0%	0 0.0%	1 1.6%	5 0.9%
	Missing	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 1.6%	1 0.2%
	Not Reported	1 0.7%	1 1.6%	3 2.2%	6 5.8%	2 3.3%	2 3.2%	15 2.7%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	137 participants	64 participants	136 participants	104 participants	60 participants	62 participants	563 participants
Canada		0	0	4	10	6	7	27
Austria		0	0	0	0	0	4	4
United States		132	52	115	83	20	11	413
Australia		5	12	17	11	23	18	86
France		0	0	0	0	0	6	6
Germany		0	0	0	0	0	2	2
Spain		0	0	0	0	11	14	25

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.
Description	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.
Time Frame	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description:	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	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	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	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	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	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 Number of Participants Analyzed	137	64	136	104	60	62
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	30.7; (23.1 to 39.1)	28.1; (17.6 to 40.8)	20.6; (14.1 to 28.4)	32.7; (23.8 to 42.6)	13.3; (5.9 to 24.6)	27.4; (16.9 to 40.2)

2. Secondary Outcome

Title	Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.
Description	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.
Time Frame	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description:	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	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	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	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	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	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 Number of Participants Analyzed	137	64	136	104	60	62
Measure Type: Number; Unit of Measure: Percentage of participants
Percentage of Patients w Grade 1 Diarrhea	24.1	23.4	27.9	32.7	40.0	37.1
Percentage of Patients w Grade 2 Diarrhea	24.8	34.4	34.6	29.8	45.0	33.9
Percentage of Patients w Grade 3 Diarrhea	30.7	28.1	20.6	32.7	13.3	27.4

3. Secondary Outcome

Title	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest
Description	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.
Time Frame	From first dose of investigational product through 28 days after last dose, up to 15.5 months.

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of neratinib.

Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description:	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	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	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	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	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	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 Number of Participants Analyzed	137	64	136	104	60	62
Measure Type: Number; Unit of Measure: percentage of participants
Percentage of Patients with SAEs	6.57	6.25	6.62	2.88	8.33	8.06
Percentage of Patients with AESI-Gastrointestinal Toxicities (Diarrhoea and Stomatitis Broad Search)	81.75	87.5	83.82	96.15	98.33	98.39
Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	12.41	7.81	4.41	4.81	8.33	4.84
Percentage of Patients with AESI- Interstitial Lung Disease SMQ (Broad Search)	0	0	0	0	0	0
Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	5.84	6.25	10.29	7.69	10.00	4.84
Percentage of Patients with AESI - Dermatologic Toxicities (Rash and Nail Disorders)	12.41	37.50	23.53	18.27	11.67	30.65
Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	80.29	85.94	83.09	95.19	98.33	98.39
Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	10.95	7.81	3.68	3.85	8.33	4.84
Percentage of Patients with AESI- Interstitial Lung Disease SMQ (Narrow Search)	0	0	0	0	0	0
Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	2.92	0	1.47	0.96	1.67	0

Adverse Events

Time Frame	From time of first dose, through 28 days after last dose, assessed up to 15.5 months.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
Arm/Group Description	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	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	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	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	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	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
All-Cause Mortality
	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Serious Adverse Events
	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	9/137 (6.57%)	4/64 (6.25%)	9/136 (6.62%)	3/104 (2.88%)	5/60 (8.33%)	5/62 (8.06%)
Eye disorders
Retinal detachment † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Colitis † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Diarrhoea † 1	2/137 (1.46%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Nausea † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Pancreatitis † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	1/62 (1.61%)
Stomatitis † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
General disorders
Fat necrosis † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Pyrexia † 1	0/137 (0.00%)	1/64 (1.56%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	1/62 (1.61%)
Hepatobiliary disorders
Cholecystitis † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	1/62 (1.61%)
Cholecystitis acute † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Cholelithiasis † 1	0/137 (0.00%)	1/64 (1.56%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Infections and infestations
Appendicitis † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	1/104 (0.96%)	0/60 (0.00%)	0/62 (0.00%)
Bacteraemia † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Breast cellulitis † 1	0/137 (0.00%)	1/64 (1.56%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Cellulitis † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	1/104 (0.96%)	0/60 (0.00%)	0/62 (0.00%)
Device related infection † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	1/62 (1.61%)
Gastroenteritis † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	1/104 (0.96%)	0/60 (0.00%)	0/62 (0.00%)
Gastroenteritis viral † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Influenza † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	1/62 (1.61%)
Listeriosis † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	1/62 (1.61%)
Lower respiratory tract infection † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Post procedural infection † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Sepsis † 1	1/137 (0.73%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Upper respiratory tract infection † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Urinary tract infection † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Wound infection † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Injury, poisoning and procedural complications
Rib fracture † 1	0/137 (0.00%)	1/64 (1.56%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Investigations
Alanine aminotransferase increased † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Aspartate aminotransferase increased † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Electrocardiogram QT prolonged † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Dehydration † 1	1/137 (0.73%)	0/64 (0.00%)	1/136 (0.74%)	1/104 (0.96%)	1/60 (1.67%)	0/62 (0.00%)
Hypokalaemia † 1	1/137 (0.73%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Nervous system disorders
Seizure † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Syncope † 1	0/137 (0.00%)	0/64 (0.00%)	2/136 (1.47%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Psychiatric disorders
Confusional state † 1	0/137 (0.00%)	0/64 (0.00%)	1/136 (0.74%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Skin and subcutaneous tissue disorders
Rash † 1	0/137 (0.00%)	1/64 (1.56%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
Rash erythematous † 1	1/137 (0.73%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	0/60 (0.00%)	0/62 (0.00%)
1 Term from vocabulary, MedDRA (24.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Loperamide	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	137/137 (100.00%)	64/64 (100.00%)	136/136 (100.00%)	104/104 (100.00%)	60/60 (100.00%)	62/62 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	8/137 (5.84%)	5/64 (7.81%)	1/136 (0.74%)	5/104 (4.81%)	0/60 (0.00%)	0/62 (0.00%)
Ear and labyrinth disorders
Vertigo † 1	0/137 (0.00%)	4/64 (6.25%)	3/136 (2.21%)	0/104 (0.00%)	1/60 (1.67%)	0/62 (0.00%)
Gastrointestinal disorders
Abdominal discomfort † 1	7/137 (5.11%)	2/64 (3.13%)	7/136 (5.15%)	5/104 (4.81%)	2/60 (3.33%)	0/62 (0.00%)
Abdominal distension † 1	21/137 (15.33%)	5/64 (7.81%)	22/136 (16.18%)	15/104 (14.42%)	6/60 (10.00%)	10/62 (16.13%)
Abdominal pain † 1	36/137 (26.28%)	12/64 (18.75%)	26/136 (19.12%)	27/104 (25.96%)	13/60 (21.67%)	15/62 (24.19%)
Abdominal pain upper † 1	5/137 (3.65%)	7/64 (10.94%)	16/136 (11.76%)	7/104 (6.73%)	3/60 (5.00%)	8/62 (12.90%)
Constipation † 1	78/137 (56.93%)	48/64 (75.00%)	93/136 (68.38%)	39/104 (37.50%)	22/60 (36.67%)	15/62 (24.19%)
Diarrhoea † 1	109/137 (79.56%)	55/64 (85.94%)	113/136 (83.09%)	99/104 (95.19%)	59/60 (98.33%)	61/62 (98.39%)
Dry mouth † 1	18/137 (13.14%)	6/64 (9.38%)	12/136 (8.82%)	5/104 (4.81%)	4/60 (6.67%)	3/62 (4.84%)
Dyspepsia † 1	12/137 (8.76%)	10/64 (15.63%)	16/136 (11.76%)	13/104 (12.50%)	7/60 (11.67%)	6/62 (9.68%)
Flatulence † 1	5/137 (3.65%)	6/64 (9.38%)	5/136 (3.68%)	2/104 (1.92%)	1/60 (1.67%)	3/62 (4.84%)
Gastrooesophageal reflux disease † 1	10/137 (7.30%)	5/64 (7.81%)	10/136 (7.35%)	6/104 (5.77%)	2/60 (3.33%)	4/62 (6.45%)
Nausea † 1	78/137 (56.93%)	32/64 (50.00%)	83/136 (61.03%)	64/104 (61.54%)	27/60 (45.00%)	28/62 (45.16%)
Stomatitis † 1	7/137 (5.11%)	4/64 (6.25%)	14/136 (10.29%)	13/104 (12.50%)	6/60 (10.00%)	6/62 (9.68%)
Vomiting † 1	36/137 (26.28%)	16/64 (25.00%)	43/136 (31.62%)	25/104 (24.04%)	9/60 (15.00%)	5/62 (8.06%)
General disorders
Asthenia † 1	6/137 (4.38%)	1/64 (1.56%)	1/136 (0.74%)	4/104 (3.85%)	3/60 (5.00%)	2/62 (3.23%)
Fatigue † 1	73/137 (53.28%)	34/64 (53.13%)	65/136 (47.79%)	41/104 (39.42%)	28/60 (46.67%)	19/62 (30.65%)
Pyrexia † 1	6/137 (4.38%)	2/64 (3.13%)	10/136 (7.35%)	3/104 (2.88%)	2/60 (3.33%)	1/62 (1.61%)
Infections and infestations
Cellulitis † 1	3/137 (2.19%)	1/64 (1.56%)	0/136 (0.00%)	2/104 (1.92%)	3/60 (5.00%)	0/62 (0.00%)
Influenza † 1	2/137 (1.46%)	0/64 (0.00%)	3/136 (2.21%)	4/104 (3.85%)	3/60 (5.00%)	0/62 (0.00%)
Nasopharyngitis † 1	5/137 (3.65%)	4/64 (6.25%)	2/136 (1.47%)	3/104 (2.88%)	1/60 (1.67%)	1/62 (1.61%)
Upper respiratory tract infection † 1	5/137 (3.65%)	7/64 (10.94%)	7/136 (5.15%)	5/104 (4.81%)	6/60 (10.00%)	2/62 (3.23%)
Urinary tract infection † 1	10/137 (7.30%)	2/64 (3.13%)	8/136 (5.88%)	9/104 (8.65%)	6/60 (10.00%)	5/62 (8.06%)
Investigations
Alanine aminotransferase increased † 1	9/137 (6.57%)	4/64 (6.25%)	4/136 (2.94%)	3/104 (2.88%)	4/60 (6.67%)	2/62 (3.23%)
Aspartate aminotransferase increased † 1	4/137 (2.92%)	1/64 (1.56%)	3/136 (2.21%)	2/104 (1.92%)	3/60 (5.00%)	2/62 (3.23%)
Blood glucose increased † 1	0/137 (0.00%)	0/64 (0.00%)	0/136 (0.00%)	0/104 (0.00%)	3/60 (5.00%)	0/62 (0.00%)
Weight decreased † 1	10/137 (7.30%)	4/64 (6.25%)	11/136 (8.09%)	4/104 (3.85%)	1/60 (1.67%)	3/62 (4.84%)
Metabolism and nutrition disorders
Decreased appetite † 1	26/137 (18.98%)	11/64 (17.19%)	24/136 (17.65%)	26/104 (25.00%)	8/60 (13.33%)	8/62 (12.90%)
Dehydration † 1	7/137 (5.11%)	6/64 (9.38%)	5/136 (3.68%)	4/104 (3.85%)	2/60 (3.33%)	2/62 (3.23%)
Hypokalaemia † 1	4/137 (2.92%)	1/64 (1.56%)	8/136 (5.88%)	2/104 (1.92%)	1/60 (1.67%)	0/62 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	10/137 (7.30%)	14/64 (21.88%)	15/136 (11.03%)	13/104 (12.50%)	9/60 (15.00%)	4/62 (6.45%)
Back pain † 1	10/137 (7.30%)	5/64 (7.81%)	9/136 (6.62%)	10/104 (9.62%)	4/60 (6.67%)	2/62 (3.23%)
Muscle spasms † 1	15/137 (10.95%)	8/64 (12.50%)	14/136 (10.29%)	15/104 (14.42%)	12/60 (20.00%)	8/62 (12.90%)
Myalgia † 1	3/137 (2.19%)	4/64 (6.25%)	6/136 (4.41%)	5/104 (4.81%)	2/60 (3.33%)	3/62 (4.84%)
Pain in extremity † 1	7/137 (5.11%)	3/64 (4.69%)	7/136 (5.15%)	5/104 (4.81%)	2/60 (3.33%)	3/62 (4.84%)
Nervous system disorders
Dizziness † 1	19/137 (13.87%)	6/64 (9.38%)	21/136 (15.44%)	20/104 (19.23%)	9/60 (15.00%)	8/62 (12.90%)
Headache † 1	26/137 (18.98%)	12/64 (18.75%)	20/136 (14.71%)	24/104 (23.08%)	13/60 (21.67%)	8/62 (12.90%)
Neuropathy peripheral † 1	4/137 (2.92%)	3/64 (4.69%)	3/136 (2.21%)	6/104 (5.77%)	0/60 (0.00%)	1/62 (1.61%)
Paraesthesia † 1	3/137 (2.19%)	1/64 (1.56%)	3/136 (2.21%)	0/104 (0.00%)	5/60 (8.33%)	0/62 (0.00%)
Psychiatric disorders
Anxiety † 1	5/137 (3.65%)	4/64 (6.25%)	3/136 (2.21%)	3/104 (2.88%)	3/60 (5.00%)	2/62 (3.23%)
Insomnia † 1	6/137 (4.38%)	8/64 (12.50%)	10/136 (7.35%)	8/104 (7.69%)	3/60 (5.00%)	4/62 (6.45%)
Reproductive system and breast disorders
Breast pain † 1	4/137 (2.92%)	7/64 (10.94%)	8/136 (5.88%)	6/104 (5.77%)	1/60 (1.67%)	0/62 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	7/137 (5.11%)	7/64 (10.94%)	9/136 (6.62%)	8/104 (7.69%)	1/60 (1.67%)	0/62 (0.00%)
Dyspnoea † 1	9/137 (6.57%)	4/64 (6.25%)	4/136 (2.94%)	4/104 (3.85%)	3/60 (5.00%)	1/62 (1.61%)
Epistaxis † 1	2/137 (1.46%)	2/64 (3.13%)	9/136 (6.62%)	4/104 (3.85%)	3/60 (5.00%)	4/62 (6.45%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform † 1	2/137 (1.46%)	4/64 (6.25%)	5/136 (3.68%)	1/104 (0.96%)	1/60 (1.67%)	4/62 (6.45%)
Dry skin † 1	6/137 (4.38%)	8/64 (12.50%)	7/136 (5.15%)	10/104 (9.62%)	4/60 (6.67%)	9/62 (14.52%)
Onychoclasis † 1	5/137 (3.65%)	3/64 (4.69%)	6/136 (4.41%)	4/104 (3.85%)	3/60 (5.00%)	6/62 (9.68%)
Rash † 1	7/137 (5.11%)	12/64 (18.75%)	15/136 (11.03%)	10/104 (9.62%)	1/60 (1.67%)	8/62 (12.90%)
Vascular disorders
Hot flush † 1	8/137 (5.84%)	6/64 (9.38%)	17/136 (12.50%)	7/104 (6.73%)	7/60 (11.67%)	4/62 (6.45%)
1 Term from vocabulary, MedDRA (24.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Senior Director, Clinical Operations
• Organization: Puma Biotechnology, Inc.
• Phone: 1-424-248-6500
• EMail: clinicaltrials@pumabiotechnology.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Barcenas CH, Hurvitz SA, Di Palma JA, Bose R, Chien AJ, Iannotti N, Marx G, Brufsky A, Litvak A, Ibrahim E, Alvarez RH, Ruiz-Borrego M, Chan N, Manalo Y, Kellum A, Trudeau M, Thirlwell M, Garcia Saenz J, Hunt D, Bryce R, McCulloch L, Rugo HS, Tripathy D, Chan A; CONTROL Study Investigators. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann Oncol. 2020 Sep;31(9):1223-1230. doi: 10.1016/j.annonc.2020.05.012. Epub 2020 May 25.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT02400476
• Other Study ID Numbers: PUMA-NER-6201; 2015-004374-15 ( EudraCT Number )
• First Submitted: February 17, 2015
• First Posted: March 27, 2015
• Results First Submitted: February 28, 2022
• Results First Posted: May 6, 2022
• Last Update Posted: May 6, 2022