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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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
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Early Stage HER2+ Breast Cancer

Intervention / Treatment
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* Drug: Neratinib
* Drug: Loperamide
* Drug: Colestipol
* Drug: Budesonide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Loperamide<br>240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Loperamide<br> <br> |
| Experimental: Budesonide and Loperamide<br>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. | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Loperamide<br> <br> Drug: Budesonide<br>* 9 mg extended release tablets once daily with or without food for 28 days<br>|
| Experimental: Colestipol and Loperamide<br>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. | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Loperamide<br> <br> Drug: Colestipol<br>* 2 g twice daily with or without food for one 28 day cycle<br>|
| Experimental: Colestipol with Loperamide as needed<br>240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Loperamide<br> <br> Drug: Colestipol<br>* 2 g twice daily with or without food for one 28 day cycle<br>|
| Experimental: Neratinib Dose Escalation 1<br>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. | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Loperamide<br> <br> |
| Experimental: Neratinib Dose Escalation 2<br>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. | Drug: Neratinib<br> <br> * Other names: Nerlynx;Drug: Loperamide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose of investigational product through 28 days after last dose, up to 15.5 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From first dose of investigational product through 28 days after last dose, up to 15.5 months. | 
| 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. | From first dose of investigational product through 28 days after last dose, up to 15.5 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2 +, Breast Cancer, Neratinib, Nerlynx, Loperamide, Colestipol, Budesonide