Broderick, Joseph C

Abstract Purpose: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. Patients and Methods: Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months. Results: Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; P = 0.28), −33.33 % (IQR, 90; P = 0.04), and −38.6 % (IQR, 88.5; P = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; P = 0.37) and −26.3 % (IQR, 49.5; P = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (P = 0.04) and improved TPB at 12 months (P = 0.05) compared with daily dosing. Conclusions: eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.