Population-based Phase I Trial of Irinotecan and Epirubicin

Objectives: Preclinical studies have demonstrated anticancer synergism with the combination of inhibitors of topoisomerases I and II. A population-based phase I trial was conducted to determine a population-based maximum tolerated dose (pMTD) for combining 2 topoisomerase inhibitors, irinotecan and epirubicin. Methods: Two cohorts of patients with advanced solid tumors were enrolled: 27 patients had and 22 patients had not received prior chemotherapy. In each cohort, irinotecan and epirubicin were administered beginning at a predetermined dose level. The dose for each subsequent 21-day cycle was escalated or de-escalated within each patient based on the dose-limiting toxicity observed in the previous cycle and according to a predetermined schema of dose levels. An MTD was determined for each patient (iMTD) and the iMTDs were used to determine a pMTD for each cohort of patients. Results: The most common dose-limiting toxicity included neutropenia (51%), asthenia (10%), diarrhea (8%), and nausea/emesis (4%). The iMTDs ranged from dose level -3 to dose level 6. For previously chemotherapy-treated patients, the pMTD was 100 mg/m 2 of irinotecan and 50 mg/m 2 of epirubicin. For chemonaive patients, the pMTD was 150 mg/m 2 of irinotecan and 50 mg/m 2 of epirubicin. Conclusions: We have determined the pMTD of irinotecan and epirubicin administered every 3 weeks using a population-based approach. The pMTD is recommended for conducting phase II trials.