Background: Chemotherapy-induced diarrhea (CID) occurs in 40-80% of breast cancer patients on HER2 directed therapy with THP or TCHP. In the CLEOPATRA trial, 67% of patients who received THP had all grade and 8% had grade 3 diarrhea. In the TRYPHAENA trial, 72% of patients who received neoadjuvant TCHP had all grade and 11.8% had grade 3-4 diarrhea. In a phase 2 trial of trastuzumab and pertuzumab with weekly paclitaxel, 81% of patients had all grade and 3% had grade 3-4 diarrhea. In addition to impacting electrolytes and kidney function, diarrhea can also affect a patient’s quality of life. Studies suggest blocking epidermal growth family receptors such as HER2 can cause excess chloride secretion, causing impaired gut absorption and secretory diarrhea. Crofelemer is an extract from the bark of Croton lechleri. It inhibits luminal chloride efflux by blocking the calcium activated chloride channel and the cystic fibrosis transmembrane regulator, two chloride channels in the colon. We propose a trial of crofelemer versus standard of care to prevent CID in HER2 positive breast cancer patients on THP or TCHP. Methods: This is a 1:1 randomized, stratified, open-label phase II study in breast cancer patients on THP or TCHP. There will be three strata: 1) TCHP with docetaxel, 2) THP with paclitaxel, and 3) THP with docetaxel. The treatment group will receive oral crofelemer 125 mg twice daily during cycles 1-2 of THP or TCHP. The control group will receive standard of care (no prophylaxis). The primary endpoint is the total number of patients with all grade diarrhea for two or more consecutive days that is definitely, probably, or possibly due to THP or TCHP during cycles 1 and 2. All patients will keep a bowel movement diary. With a sample size of 46 patients, the study has 81% power to detect a 40% absolute decrease (from 60% to 20%) in the incidence of all grade diarrhea, with a two sided significance level of 0.10 using Fisher’s exact test. The analysis population is all randomized patients who complete 2 cycles of THP or TCHP. THP = trastuzumab, pertuzumab, docetaxel or paclitaxel TCHP = trastuzumab, pertuzumab, carboplatin, docetaxel or paclitaxel.