Phase II Trial of Encapsulated Rapamycin to Reduce Polyp Burden Associated with Familial Adenomatous Polyposis.

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.