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

Conditions

Early Stage HER2+ Breast Cancer

Keywords

HER2 +, Breast Cancer, Neratinib, Nerlynx, Loperamide, Colestipol, Budesonide

Brief summary

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 or other prophylactic measures.

Detailed description

This is an open-label, Phase 2 study that will investigate the incidence and severity of diarrhea in early-stage HER2+ breast cancer patients receiving neratinib with loperamide, alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant treatment, or neratinib dose escalation, who have previously undergone a course of trastuzumab therapy in the adjuvant setting. Patients will receive: * Neratinib 240 mg orally once daily with food for thirteen 28-day cycles. * Loperamide daily for two 28-day cycles and then as needed. * Amendment 3, an anti-inflammatory treatment for one cycle and loperamide to be administered daily for two 28-day cycles and then as needed. Closed to enrollment. * Amendment 4, colestipol for one cycle and loperamide to be administered one cycle and then as needed. Closed to enrollment. * Amendment 5, colestipol for one cycle and loperamide as needed. Closed to enrollment. * Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1-C1D7), followed by 160 mg neratinib for Week 2 (C1D8-C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 to end of treatment). Loperamide as needed. Closed to enrollment. * Amendment 7/7.1, 160 mg neratinib for the first 2 weeks (C1D1 - C1D14), followed by 200 mg neratinib for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib thereafter (C2D1 to end of treatment). Loperamide as needed.

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Physiological Reports2024-08-015 citations

10.14814/phy2.70008

Abstract PO1-17-08: Post-approval treatment patterns and tolerability of neratinib in HER2+ early-stage breast cancer

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Cancer Research2024-05-02

10.1158/1538-7445.sabcs23-po1-17-08

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer.

Chan A, Ruiz-Borrego M, Marx G, Chien AJ, Rugo HS, Brufsky A, Thirlwell M, Trudeau M, Bose R, García-Sáenz JA, Egle D, Pistilli B, Wassermann J, Cheong KA, Schnappauf B, Semsek D, Singer CF, Foruzan N, DiPrimeo D, McCulloch L, Hurvitz SA, Barcenas CH.

2022-12-1416 citations

10.1016/j.breast.2022.12.003

Abstract P5-18-02: Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer

Arlene Chan, Manuel Ruíz‐Borrego, Gavin Marx, Adam Brufsky, Jo Chien et al. (18 authors)

Cancer Research2022-02-152 citations

10.1158/1538-7445.sabcs21-p5-18-02

Abstract P2-13-21: Improved central nervous system outcomes in patients with early-stage HER2-positive breast cancer who receive neratinib for the recommended duration: Findings from the phase 3 ExteNET trial

Frankie A. Holmes, Debra A. Patt, Yvonne Manalo, Julie C Smith, Steven W. Papish et al. (11 authors)

Cancer Research2022-02-151 citations

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Association between treatment duration and overall survival in early-stage HER2+ breast cancer patients receiving extended adjuvant therapy with neratinib in the ExteNET trial.

Beverly Moy, Masato Takahashi, Shoichiro Ohtani, Ewa Chmielowska, Naohito Yamamoto et al. (9 authors)

Journal of Clinical Oncology2021-05-206 citations

10.1200/jco.2021.39.15_suppl.540

Dose escalation for mitigating diarrhea: Ranked tolerability assessment of anti-diarrheal regimens in patients receiving neratinib for early-stage breast cancer.

Gavin Marx, A. Jo Chien, José Á. García-Sáenz, Arlene Chan, Manuel Ruíz‐Borrego et al. (20 authors)

Journal of Clinical Oncology2021-05-203 citations

10.1200/jco.2021.39.15_suppl.536

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

Cristina Saura, Mafalda Oliveira, Yin‐Hsun Feng, Ming‐Shen Dai, Shang-Wen Chen et al. (36 authors)

Journal of Clinical Oncology2020-07-17586 citations

10.1200/jco.20.00147

Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial.

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.

2020-05-2576 citations

10.1016/j.annonc.2020.05.012

Abstract P5-14-03: Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2-positive early-stage breast cancer: Phase II CONTROL trial

Arlene Chan, Sara A. Hurvitz, Gavin Marx, Manuel Ruíz‐Borrego, Cynthia Farrell et al. (11 authors)

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10.1158/1538-7445.sabcs19-p5-14-03

Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial.

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Journal of Clinical Oncology2019-05-2012 citations

10.1200/jco.2019.37.15_suppl.548

Abstract P2-13-03: The impact of neratinib with or without anti-diarrheal prophylaxis on health-related quality of life in HER2+ early-stage breast cancer: Analyses from the ExteNET and CONTROL trials

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Denis M. Collins, N. Gaynor, Neil T. Conlon, G. Gullo, AJ Eustace et al. (6 authors)

Cancer Research2019-02-151 citations

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Abstract P6-03-02: Budesonide and colesevelam reduce neratinib-induced diarrhea in a rat model

J.G. Bowen, KR Secombe, IA Ball, Joseph Shirren, AD Wignall et al. (10 authors)

Cancer Research2019-02-15

10.1158/1538-7445.sabcs18-p6-03-02

Abstract P3-14-01: Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: The CONTROL trial

Sara A. Hurvitz, Arlene Chan, Nicholas Iannotti, Eiman Ibrahim, J Chien et al. (19 authors)

Cancer Research2018-02-1514 citations

10.1158/1538-7445.sabcs17-p3-14-01

Abstract CT128: Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients (pts) with HER2+ early-stage breast cancer (eBC): the CONTROL trial

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Cancer Research2017-07-0120 citations

10.1158/1538-7445.am2017-ct128

Abstract P2-11-03: Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): Interim analysis from the multicenter, open-label, phase II control trial

Carlos H. Bárcenas, Elizabeth Olek, Daniel Hunt, Debu Tripathy, Eiman Ibrahim et al. (21 authors)

Cancer Research2017-02-155 citations

10.1158/1538-7445.sabcs16-p2-11-03

Interventions

DRUGNeratinib

DRUGLoperamide

DRUGColestipol

2 g twice daily with or without food for one 28 day cycle

DRUGBudesonide

9 mg extended release tablets once daily with or without food for 28 days

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Age ≥18; male or female * Early breast cancer (stage I-3c) * Documented HER2+ tumor: HER2 immunohistochemistry (IHC) 3+ or ISH+ * Prior course of adjuvant trastuzumab given \>2 weeks and ≤1 year from enrollment * No evidence of local/regional recurrence or metastatic disease * Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 * Male patients with female partners of childbearing potential must agree and commit to use a condom and women of childbearing potential must not be pregnant and must agree and commit to the use of a highly effective non-hormonal method of contraception * Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or ECHO

Exclusion criteria

* Major surgery \< 30 days * Chemotherapy, investigational agents, other cancer therapy (except hormonal therapy) \< 14 days * Corrected QT Interval (QTc) \>0.450 seconds (males) or \>0.470 (females) or other active cardiac disease * Significant chronic GI disorder with diarrhea as a major symptom * Active, unresolved infections * Currently pregnant or breast-feeding

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	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.

Secondary

Measure	Time frame	Description
Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.	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.
Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	From first dose of investigational product through 28 days after last dose, up to 15.5 months.	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.

Countries

Australia, Austria, Canada, France, Germany, Spain, United States

Participant flow

Participants by arm

Arm	Count
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	137
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	64
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	136
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	104
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	60
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	62
Total	563

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Adverse Event	57	10	22	19	5	8
Overall Study	Lost to Follow-up	0	0	0	1	3	1
Overall Study	Other, Decreased Quality of Life	0	0	2	0	0	0
Overall Study	Other, Disease Progression	0	1	2	1	2	1
Overall Study	Other, Noncompliance to Protocol Requirements	0	0	2	1	0	0
Overall Study	Physician Decision	0	0	1	1	0	1
Overall Study	Withdrawal by Subject	4	1	12	7	5	5

Baseline characteristics

Characteristic	Budesonide and Loperamide	Colestipol and Loperamide	Colestipol With Loperamide as Needed	Loperamide	Neratinib Dose Escalation 1	Neratinib Dose Escalation 2	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	6 Participants	19 Participants	11 Participants	21 Participants	9 Participants	10 Participants	76 Participants
Age, Categorical Between 18 and 65 years	58 Participants	117 Participants	93 Participants	116 Participants	51 Participants	52 Participants	487 Participants
Age, Continuous	49.11 years STANDARD_DEVIATION 10.55	52.49 years STANDARD_DEVIATION 11.08	51.94 years STANDARD_DEVIATION 10.23	53.39 years STANDARD_DEVIATION 11.06	51.90 years STANDARD_DEVIATION 10.71	53.82 years STANDARD_DEVIATION 10.15	52.31 years STANDARD_DEVIATION 10.76
Race/Ethnicity, Customized Race American Indian or Alaska Native	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Race Asian	4 Participants	13 Participants	9 Participants	8 Participants	3 Participants	1 Participants	38 Participants
Race/Ethnicity, Customized Race Black or African American	5 Participants	9 Participants	8 Participants	11 Participants	1 Participants	2 Participants	36 Participants
Race/Ethnicity, Customized Race Missing	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander	1 Participants	3 Participants	0 Participants	0 Participants	0 Participants	0 Participants	4 Participants
Race/Ethnicity, Customized Race Not Reported	1 Participants	3 Participants	6 Participants	1 Participants	2 Participants	2 Participants	15 Participants
Race/Ethnicity, Customized Race Other	2 Participants	9 Participants	0 Participants	3 Participants	1 Participants	3 Participants	18 Participants
Race/Ethnicity, Customized Race Unknown	1 Participants	2 Participants	1 Participants	0 Participants	0 Participants	1 Participants	5 Participants
Race/Ethnicity, Customized Race White	50 Participants	96 Participants	80 Participants	113 Participants	53 Participants	52 Participants	444 Participants
Region of Enrollment Australia	12 participants	17 participants	11 participants	5 participants	23 participants	18 participants	86 participants
Region of Enrollment Austria	0 participants	0 participants	0 participants	0 participants	0 participants	4 participants	4 participants
Region of Enrollment Canada	0 participants	4 participants	10 participants	0 participants	6 participants	7 participants	27 participants
Region of Enrollment France	0 participants	0 participants	0 participants	0 participants	0 participants	6 participants	6 participants
Region of Enrollment Germany	0 participants	0 participants	0 participants	0 participants	0 participants	2 participants	2 participants
Region of Enrollment Spain	0 participants	0 participants	0 participants	0 participants	11 participants	14 participants	25 participants
Region of Enrollment United States	52 participants	115 participants	83 participants	132 participants	20 participants	11 participants	413 participants
Sex: Female, Male Female	64 Participants	133 Participants	104 Participants	137 Participants	60 Participants	62 Participants	560 Participants
Sex: Female, Male Male	0 Participants	3 Participants	0 Participants	0 Participants	0 Participants	0 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 137	0 / 64	0 / 136	0 / 104	0 / 60	0 / 62
other Total, other adverse events	137 / 137	64 / 64	136 / 136	104 / 104	60 / 60	62 / 62
serious Total, serious adverse events	9 / 137	4 / 64	9 / 136	3 / 104	5 / 60	5 / 62

Outcome results

Primary

Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.

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.

Arm	Measure	Value (NUMBER)
Loperamide	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	30.7 Percentage of participants
Budesonide and Loperamide	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	28.1 Percentage of participants
Colestipol and Loperamide	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	20.6 Percentage of participants
Colestipol With Loperamide as Needed	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	32.7 Percentage of participants
Neratinib Dose Escalation 1	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	13.3 Percentage of participants
Neratinib Dose Escalation 2	Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.	27.4 Percentage of participants

Secondary

Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.

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.

Arm	Measure	Group	Value (NUMBER)
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 2 Diarrhea	24.8 Percentage of participants
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
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 3 Diarrhea	30.7 Percentage of participants
Budesonide and 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 2 Diarrhea	34.4 Percentage of participants
Budesonide and 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	23.4 Percentage of participants
Budesonide and 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 3 Diarrhea	28.1 Percentage of participants
Colestipol and 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 2 Diarrhea	34.6 Percentage of participants
Colestipol and 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	27.9 Percentage of participants
Colestipol and 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 3 Diarrhea	20.6 Percentage of participants
Colestipol With Loperamide as Needed	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	29.8 Percentage of participants
Colestipol With Loperamide as Needed	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	32.7 Percentage of participants
Colestipol With Loperamide as Needed	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	32.7 Percentage of participants
Neratinib Dose Escalation 1	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	45.0 Percentage of participants
Neratinib Dose Escalation 1	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	40.0 Percentage of participants
Neratinib Dose Escalation 1	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	13.3 Percentage of participants
Neratinib Dose Escalation 2	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	37.1 Percentage of participants
Neratinib Dose Escalation 2	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	27.4 Percentage of participants
Neratinib Dose Escalation 2	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	33.9 Percentage of participants

Secondary

Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest

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.

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

Arm	Measure	Group	Value (NUMBER)
Loperamide	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
Loperamide	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
Loperamide	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
Loperamide	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
Loperamide	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
Loperamide	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
Loperamide	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
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
Loperamide	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
Loperamide	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
Budesonide and Loperamide	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)	87.5 percentage of participants
Budesonide and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with SAEs	6.25 percentage of participants
Budesonide and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	7.81 percentage of participants
Budesonide and Loperamide	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
Budesonide and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	6.25 percentage of participants
Budesonide and Loperamide	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)	37.50 percentage of participants
Budesonide and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	85.94 percentage of participants
Budesonide and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	7.81 percentage of participants
Budesonide and Loperamide	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
Budesonide and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	0 percentage of participants
Colestipol and Loperamide	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
Colestipol and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	3.68 percentage of participants
Colestipol and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with SAEs	6.62 percentage of participants
Colestipol and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	10.29 percentage of participants
Colestipol and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	4.41 percentage of participants
Colestipol and Loperamide	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)	83.82 percentage of participants
Colestipol and Loperamide	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)	23.53 percentage of participants
Colestipol and Loperamide	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
Colestipol and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	1.47 percentage of participants
Colestipol and Loperamide	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	83.09 percentage of participants
Colestipol With Loperamide as Needed	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	95.19 percentage of participants
Colestipol With Loperamide as Needed	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	3.85 percentage of participants
Colestipol With Loperamide as Needed	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)	96.15 percentage of participants
Colestipol With Loperamide as Needed	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	0.96 percentage of participants
Colestipol With Loperamide as Needed	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
Colestipol With Loperamide as Needed	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with SAEs	2.88 percentage of participants
Colestipol With Loperamide as Needed	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)	18.27 percentage of participants
Colestipol With Loperamide as Needed	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	7.69 percentage of participants
Colestipol With Loperamide as Needed	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
Colestipol With Loperamide as Needed	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	4.81 percentage of participants
Neratinib Dose Escalation 1	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	98.33 percentage of participants
Neratinib Dose Escalation 1	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
Neratinib Dose Escalation 1	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	10.00 percentage of participants
Neratinib Dose Escalation 1	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)	11.67 percentage of participants
Neratinib Dose Escalation 1	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with SAEs	8.33 percentage of participants
Neratinib Dose Escalation 1	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	8.33 percentage of participants
Neratinib Dose Escalation 1	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	1.67 percentage of participants
Neratinib Dose Escalation 1	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
Neratinib Dose Escalation 1	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	8.33 percentage of participants
Neratinib Dose Escalation 1	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)	98.33 percentage of participants
Neratinib Dose Escalation 2	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)	30.65 percentage of participants
Neratinib Dose Escalation 2	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Narrow Search)	0 percentage of participants
Neratinib Dose Escalation 2	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)	98.39 percentage of participants
Neratinib Dose Escalation 2	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with-Hepatotoxicities SMQ (Broad Search)	4.84 percentage of participants
Neratinib Dose Escalation 2	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Cardiac Toxicities SMQ (Broad Search)	4.84 percentage of participants
Neratinib Dose Escalation 2	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Gastrointestinal Toxicities (Narrow Search)	98.39 percentage of participants
Neratinib Dose Escalation 2	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
Neratinib Dose Escalation 2	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with AESI-Hepatotoxicities SMQ (Narrow Search)	4.84 percentage of participants
Neratinib Dose Escalation 2	Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest	Percentage of Patients with SAEs	8.06 percentage of participants
Neratinib Dose Escalation 2	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

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

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Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0.

Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.

Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest