Copyright © 2009 Derick Lau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose. Phase I trials of anticancer drugs are commonly conducted using the method of modified Fibonacci. We have developed a population-based design for phase I trials of combining anticancer drugs such as irinotecan and carboplatin. Patients and Methods. Intrapatient dose escalation of irinotecan and carboplatin was performed according to a predetermined schema to reach individual dose-limiting toxicity (DLT) in 50 patients with solid tumors refractory to previous chemotherapy. The individual toxicity-limiting dose levels were analyzed for normal distribution using the method of Ryan-Joiner and subsequently used to determine a population-based maximum tolerated dose (pMTD). For comparison, a simulation study was performed using the method of modified Fibonacci. Results. The most common dose-limiting toxicities (DLTs) included neutropenia (58%), thrombocytopenia (16%), and diarrhea (8%). The frequency of individual toxicity-limiting dose levels of 50 patients approximated a normal distribution. The dose levels associated with individual limiting toxicities ranged from level 1 (irinotecan 100 mg/m2 and carboplatin AUC = 4 mg/mL x min) to level 8 (irinotecan 350 mg/m2 and carboplatin AUC = 6). The pMTD was determined to be dose level 3 (150 mg/m2 for irinotecan and AUC = 5 for carboplatin). In contrast, the MTD was determined to be dose level 4 (200 mg/m2 for irinotecan and AUC 5 for carboplatin) by modified-Fibonacci simulation. Conclusions. The population-based design of phase I trial allows optimization of dose intensity and derivation of a pMTD. The pMTD has been applied in phase II trial of irinotecan and carboplatin in patients with small-cell lung cancer.