Study design and patient selection

This was a retrospective, observational study of a cohort of consecutive adult patients treated with a novel Notch inhibitor (LY3039478, Eli Lilly and Company, Indianapolis, IN, USA) in phase I clinical trials at Gustave Roussy (Villejuif, France) and who were referred for drug-induced diarrhea to the gastroenterology department at Bicêtre University Hospital (Le Kremlin-Bicêtre, France) between October 2014 and October 2017. LY3039478 is a novel, potent, gamma secretase inhibitor that is in clinical development (Massard et al., 2018[17]; Mir et al., 2018[22]; Even et al., 2020[6]). Patients were randomized to increasing oral doses of LY3039478 in three-times-in-a-week (TIW) regimen or to two-week loading dose period and then 50 mg TIW (Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01695005","term_id":"NCT01695005"}}NCT01695005) (Massard et al., 2018[17]; Mir et al., 2018[22]; Even et al., 2020[6]). Each treatment cycle lasted 28 days. The Notch inhibitor was discontinued in the event of tumor progression or unacceptable toxicity. Patients referred to the gastroenterology department at Bicêtre University Hospital underwent a stool culture, a screen for Clostridioides difficile toxin, and flexible sigmoidoscopy with biopsies as part of routine care. Differential diagnoses (intestinal infection or tumor-related symptoms) were ruled out in order to establish a causal relationship between diarrhea and exposure to the gamma secretase inhibitor. The study was approved by an independent ethics committee (CPP Ile de France VII, Paris, France), and referenced in clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01695005","term_id":"NCT01695005"}}NCT01695005 and conducted in accordance with the tenets of the Declaration of Helsinki and its updates.