A phase I study of ifosfamide, oxaliplatin, and etoposide (IOE) in pediatric patients with refractory solid tumors.

Abstract

9545 Background: Carboplatin and cisplatin are highly active chemotherapeutic agents but have significant toxicities. Oxaliplatin is active in cisplatin-resistant cell lines with a different clinical toxicity profile (less renal, bone marrow, and ototoxicity). The combination of ifosfamide, carboplatin and etoposide is active in pediatric tumors but myelosuppression is dose-limiting. Substituting oxaliplatin in this regimen may allow further dose intensification or be useful in cisplatin-resistant tumors. This study evaluated the safety and estimated the maximum tolerated dose (MTD) of IOE in children with refractory solid tumors. Methods: Oxaliplatin was given intravenously (IV) on day 1 with IV ifosfamide and etoposide on days 1-3 of a 21-day course. Cohorts of 3-6 patients were enrolled at 2 dose levels (see table). A third level with filgrastim or pegfilgrastim (GCSF) support was also evaluated. Results: Twelve evaluable patients (median age 6 yrs, 8 M) received a total of 38 courses (median 2, range 1-7). Two inevaluable patients withdrew during course 1 with no dose-limiting toxicity (DLT). The table summarizes enrollment and DLT. Grade 4 thrombocytopenia occurred in 21 courses with a median of 1 platelet transfusion per course (range 0-10). Febrile neutropenia (one grade 4) complicated 6 courses. There was no hearing loss, >grade 1 elevated creatinine, or >grade 2 neurotoxicity. Of 8 patients with neuroblastoma previously treated with cisplatin, carboplatin, cyclophosphamide, and etoposide, 1 had a partial response after 4 courses, but electively withdrew before response confirmation, and 5 had stable disease (median 4 courses, range 2-7). Conclusions: IOE is tolerable with evidence of antitumor activity, even in some patients with prior cisplatin exposure. Neutropenia is the DLT. The MTD and recommended phase II dose without GCSF is oxaliplatin 130 mg/m2 onday 1, with ifosfamide 1200 mg/m2/day and etoposide 75 mg/m2/day on days 1-3. Dose level Oxaliplatin mg/m2 (day 1) Ifosfamide mg/m2/day (days 1,2,3) Etoposide mg/m2/day (days 1,2,3) No. of patients (No. evaluable) DLT (No. of patients) 1 130 1,500 75 4 (3) Neutropenia (2) 0 130 1,200 75 6 Neutropenia (1) 0 + GCSF 130 1,200 75 4 (3) None