A phase I and pharmacokinetic study of a powder-filled capsule formulation of oral irinotecan (CPT-11) given daily for 5 days every 3 weeks in patients with advanced solid tumors

Purpose: Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks. Patients and methods: Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC. Results: 20 patients (median age 61.5 years, range 40-75; M/F 12/8; ECOG PS 0 = 5, 1 = 11, 2 = 4) received oral irinotecan at dose levels of 30 (n = 3), 40 (n = 3), 50 (n = 6), and 60 (n = 8) mg/m²/day. Of the eight patients enrolled at 60 mg/m², three patients experienced DLT (≥ grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m² dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC_0-24) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated. Conclusion: Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m ²/d.