PHASE-I STUDY OF ESCALATING TARGETED DOSES OF CARBOPLATIN COMBINED WITH IFOSFAMIDE AND ETOPOSIDE IN TREATMENT OF NEWLY-DIAGNOSED PEDIATRIC SOLID TUMORS

Background: The combination of carboplatin, ifosfamide, and etoposide has shown promising activity in a variety of relapsed childhood solid tumors but has not been studied in newly diagnosed patients. Purpose: The tolerance for and activity of escalating targeted doses of carboplatin combined with ifosfamide and etoposide (ICE) were assessed in children with advanced germ cell tumors or other rare solid tumors for which no standard therapy exists. Methods: Fifteen children with newly diagnosed solid tumors received ICE chemotherapy. Individualized carboplatin doses were calculated to achieve a target area under the concentration x time curve (AUC) and adjusted for the glomerular filtration rate (estimated by Tc-99m-labeled diethylenetriamine pentaacetic acid clearance). Cohorts of at least three patients received carboplatin at an initial target AUC of 6 mg . min/mL, with escalations of 2 mg . min/mL in subsequent cohorts. Carboplatin was given on day 1, followed by ifosfamide at 2 g/m2 per day and etoposide at 100 mg/m2 per day on days 2 through 4. All patients received at least two courses of therapy in the absence of progressive disease. and as many as eight courses could be given. Results: The 15 patients received a total of 46 assessable courses of ICE. Myelosuppression was the dominant toxicity; 30 courses (67%) resulted in hospitalization for febrile neutropenia. Neutropenia was dose limiting at the carboplatin target AUC of 12 mg min/mL. One complete and eight partial responses were seen in the 14 assessable patients; two additional patients had at least partial responses documented at surgery or autopsy. Six patients are without evidence of disease at a median of 548 days after diagnosis. Conclusion: ICE chemotherapy, with the carboplatin dose based on a target AUC of 10 mg . min/mL, is tolerable and has significant activity in a variety of rare malignancies, including extragonadal germ cell tumor. Implications: The combination of carboplatin, etoposide, and ifosfamide holds promise in the treatment of rare pediatric malignancies.