Dose-finding study by continuous reassessment method (CRM) for topotecan (TT) in combination with ifosfamide (IF) as a second-line therapy for pediatric solid cancer: Preliminary report of phase I/II study.

Abstract

9546 Background: TT has already become a key drug for recurrent pediatric solid cancer especially in combination with cyclophosphamide (CY). The combination of TT and IF (TI) could be more effective because most recurrent cases are more sensitive to IF than CY. We conducted a dose-finding trial of TI as a second-line therapy with pharmacokinetic study. Methods: Pediatric recurrent solid cancer only with previous chemotherapy no more than 20 cycles is eligible. IF, fixed to 1.2g/m2/day, and TT, 0.6 (level 0), 0.75 (starting dose, level 1), 0.9 (level 2), 1.1 (level 3) mg/m2/day, were administered on days 1-5 with prophylactic use of G- CSF every 21 days. We defined the maximum tolerated dose (MTD) as the closest dose level to dose-limiting toxicity (DLT) occurrence rate of 30% and set target rate (recommended dose [RD]) at 20% by CRM estimation. Results: Safety profile of the first 11 pts resulted in termination of the phase I part. All 4 DLTs occurred on level 1 and included platelet transfusions twice/cycle (3/4), red blood cell transfusion (2/4), and prolonged febrile neutropenia (1/4). Occurrence rates of DLT estimated by CRM are 14.1% (0/5 pts), 41.8% (4/6 pts) in the level 0 and level 1, respectively (Table) at study termination. We determined RD is level 0 and MTD was level 1. No severe nonhematological toxicity was reported except for temporary nausea and anorexia. Pharmacokinetic studies indicated that IF administered on the schedule used in this study did not alter TP disposition as reported regarding concurrent use of CY. Responses were reported in 1PR /4 rhabdomyosarcoma, 1PR /1 hepatoblastoma. Conclusions: CRM could function to determine RD efficiently with minimum number of pts. IF, in combination with TT, appeared slightly more toxic than the equivalent dose of CY. This current trial is now continued as early phase II for assessment of efficacy. Level 0 Level 1 Level 2 Level 3 Expected probability of DLT occurrence rate before trial 5% 10% 30% 50% Pts DLT occurred/Pts treated 0/5 4/6 0/0 0/0 DLT occurrence rate 14.1% 41.8% 85.7% 94.7% Probability of more than 30% DLT occurrence rate 1.1% 73.4% 98.9% 99.7% No significant financial relationships to disclose.