Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients

Study Overview
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Brief Summary
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Chemotherapy induced diarrhea is seen in up to 40-80% of patients receiving this treatment for HER2 positive locally advanced or metastatic breast cancer. This diarrhea can significantly impact a patient's quality of life and ability to tolerate chemo/anti-HER2 therapy. This study will look at the efficacy of the drug crofelemer in preventing diarrhea in breast cancer patients.

Detailed Description
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Various anti-diarrheal agents, such as loperamide, codeine, octreotide, are available for diarrhea management, but few are used in the prophylactic setting and none provide a targeted approach for treating chemotherapy induced diarrhea (CID). Pre-clinical studies have suggested that blocking EGFR results in excess chloride secretion and thus diarrhea. Crofelemer is an extract from the blood red bark of Croton lechleri that inhibits luminal chloride efflux by blocking the calcium activated chloride channel (CaCC) and cystic fibrosis transmembrane regulator (CFTR) chloride channels. Due to its size and polarity, it acts only luminally and is not systemically absorbed. It is currently FDA approved for use in preventing diarrhea in HIV/AIDS patients on anti-retroviral therapy.

Official Title
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Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients Receiving Trastuzumab, Pertuzumab, and Docetaxel or Paclitaxel With or Without Carboplatin: HALT-D

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Crofelemer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent; Men and women ≥18 years of age; Pathologically confirmed diagnosis of HER2 positive breast cancer of any stage (previous treatment is allowed without limits on lines of prior therapy); Scheduled to receive at least 3 consecutive cycles of THP or TCHP; Performance status of 0-2 according to the ECOG scale; Negative pregnancy test at time of informed consent for women of childbearing potential; Able to read, understand, follow the study procedure and complete crofelemer, rescue medication, and bowel movement diaries; Patients may enroll simultaneously on this study and other studies, including but not limited to NSABP B52; Patients with brain metastases (including concurrent steroid treatment) are allowed on this study. Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as determined by either ECHO or MUGA Exclusion Criteria: Pregnant and/or breastfeeding; Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.); Use of investigational drugs within 3 weeks of signing consent or foreseen use during the study; Use of chemotherapy, trastuzumab, or pertuzumab within the past 3 weeks; Use of antibiotics within the past 7 days (up to 2 prophylactic doses of antibiotics for procedures including, but not limited to port placement, is permitted); Any type of ostomy; Total colectomy; Fecal incontinence; Ongoing radiation induced diarrhea or constipation or planned radiotherapy to the abdomen or pelvis while on study; Active systemic infection requiring ongoing intervention, including but not limited to oral and intravenous antibiotics, anti-fungals, anti-parasites, anti-virals; Abdominal or pelvic surgery without recovery of bowel function; Inadequate organ function for starting THP or TCHP, which may include the following laboratory results within 28 days prior to signing consent: Total bilirubin > upper limit of normal (ULN) (unless the patient has documented Gilbert's syndrome) Serum creatinine > 2.0 mg/dL or 177 μmol/L AST (SGOT) and ALT (SPGT) > 2.5 ULN.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crofelemer<br>Patients on the treatment arm will take one tablet of crofelemer twice a day (each tablet is 125 mg), to be swallowed whole without chewing or crushing, during cycles 1-2 of chemotherapy with THP or TCHP. Patient will be monitored off crofelemer during cycle 3 of chemotherapy. | Drug: Crofelemer<br>* Crofelemer 125 mg BID during cycles 1-2 of THP or TCHP<br>|
| No Intervention: Control<br>Patients on the control arm will be on the study for cycles 1-3 of THP or TCHP. Patients on the control arm will not receive crofelemer at any time on this study. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diarrhea for >= 2 Consecutive Days | Percentage of participants with any grade (based on CTCAE 4.0) diarrhea lasting 2 or more consecutive days during cycles 1 and 2 of chemotherapy. | Cycle 1, Cycle 2 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diarrhea Any Grade | Incidence of diarrhea of any grade, as measured by CTCAE v4.0, by cycle | Cycle 1, Cycle 2 (each cycle is 21 days) | 
| Grade 3-4 Diarrhea | number of patients with diarrhea of grade 3 or grade 4, as measured by CTCAE v4.0, by cycle and by stratum | Cycle 1, Cycle 2 (each cycle is 21 days) | 
| Diarrhea Onset | Time to onset of first episode of diarrhea of any grade, overall | from baseline through Cycle 3 (21 day cycles) | 
| Diarrhea Duration | Duration (days) of any grade diarrhea, defined from day 1 to day 21, by cycle in which the episode started | Cycle 1, Cycle 2 (each cycle is 21 days) | 
| Duration Grade 3-4 Diarrhea | Duration (days) of grade 3-4 diarrhea during cycle 1 through the end of cycle 2, defined from cycle day 1 to cycle 2 day 21 | End of Cycle 2 (each cycle is 21 days) | 
| Anti-diarrheal Medications | Use of anti-diarrheal medications (other than study drug), by cycle and arm | Cycle 1, Cycle 2 (each cycle is 21 days) | 
| FACIT-D Total Score | Quantitative FACIT-D (FACIT-D Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea) total score, collected day 1 of each cycle and at the time of study completion, cycles 1 and 2 reported; The higher the score the better the QOL; Score range 0-152. | Cycle 1, Cycle 2 (each cycle is 21 days) | 
| FACIT-D Diarrhea Score | Quantitative FACIT-D (FACIT-D Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea) diarrhea subscale (DS) score, by cycle; Score Range 0-44; the higher the score, the better the QOL. | Cycle 1, Cycle 2 (each cycle is 21 days) | 
| Stool Frequency Based on Consistency (Bristol Stool Scale) | Frequency of stool consistency of 6-7, as measured by the Bristol Stool scale (minimum 1-separate hard lumps, maximum 7-watery, no solid pieces), by cycle; Median in watery bowel movements (Bristol Stool Form Scale 6-7). | Cycle 1, Cycle 2 (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, pertuzumab, trastuzumab, docetaxel, paclitaxel, carboplatin, crofelemer, chemotherapy induced diarrhea