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

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.

Inclusion Criteria:

1. Willing and able to provide written informed consent;

2. Men and women ≥18 years of age;

3. Pathologically confirmed diagnosis of HER2 positive breast cancer of any stage
(previous treatment is allowed without limits on lines of prior therapy);

4. Scheduled to receive at least 3 consecutive cycles of THP or TCHP;

5. Performance status of 0-2 according to the ECOG scale;

6. Negative pregnancy test at time of informed consent for women of childbearing
potential;

7. Able to read, understand, follow the study procedure and complete crofelemer, rescue
medication, and bowel movement diaries;

8. Patients may enroll simultaneously on this study and other studies, including but not
limited to NSABP B52;

9. Patients with brain metastases (including concurrent steroid treatment) are allowed on
this study.

10. Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as
determined by either ECHO or MUGA

Exclusion Criteria:

1. Pregnant and/or breastfeeding;

2. Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to
ulcerative colitis, Crohn's disease, microscopic colitis, etc.);

3. Use of investigational drugs within 3 weeks of signing consent or foreseen use during
the study;

4. Use of chemotherapy, trastuzumab, or pertuzumab within the past 3 weeks;

5. 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);

6. Any type of ostomy;

7. Total colectomy;

8. Fecal incontinence;

9. Ongoing radiation induced diarrhea or constipation or planned radiotherapy to the
abdomen or pelvis while on study;

10. Active systemic infection requiring ongoing intervention, including but not limited to
oral and intravenous antibiotics, anti-fungals, anti-parasites, anti-virals;

11. Abdominal or pelvic surgery without recovery of bowel function;

12. Inadequate organ function for starting THP or TCHP, which may include the following
laboratory results within 28 days prior to signing consent:

1. Total bilirubin > upper limit of normal (ULN) (unless the patient has documented
Gilbert's syndrome)

2. Serum creatinine > 2.0 mg/dL or 177 μmol/L

3. AST (SGOT) and ALT (SPGT) > 2.5 ULN.