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A phase I study of irinotecan in pediatric patients: a pediatric oncology group study
1Texas Children's Cancer Center/Baylor College of Medicine, Houston 77030, USA. sblaney@txccc.org
Insights
This Phase I trial determined irinotecan doses for children with solid tumors. Recommended Phase II doses are 39 mg/m2 for heavily pretreated patients and 50 mg/m2 for less-heavily pretreated patients.
Area of Science:
- Pediatric Oncology
- Clinical Pharmacology
Background:
- Refractory solid tumors in children present significant treatment challenges.
- Establishing safe and effective dosing for novel chemotherapeutics is crucial in pediatric oncology.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of irinotecan in pediatric patients with refractory solid tumors.
- To establish recommended Phase II doses for irinotecan based on prior treatment history.
Main Methods:
- A Phase I clinical trial involving 35 children with refractory solid tumors.
- Irinotecan administered intravenously over 60 minutes, daily for 5 days, every 21 days, with dose escalation from 30 mg/m2 to 65 mg/m2.
- Patients were stratified into heavily pretreated and less-heavily pretreated groups to define MTD and DLTs.
Main Results:
- Myelosuppression was the DLT in heavily pretreated patients; diarrhea was the DLT in less-heavily pretreated patients.
- The MTD was 39 mg/m2 in heavily pretreated children and 50 mg/m2 in less-heavily pretreated children.
- Partial responses were observed in neuroblastoma and hepatocellular carcinoma; stable disease was seen in seven patients across various malignancies.
Conclusions:
- The recommended Phase II dose of irinotecan is 39 mg/m2 for heavily pretreated children and 50 mg/m2 for less-heavily pretreated children with solid tumors.
- Irinotecan demonstrates manageable toxicities, with myelosuppression and diarrhea as primary dose-limiting factors, and shows potential activity in specific pediatric solid tumors.
Abstract:
A Phase I trial of irinotecan was performed to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the incidence and severity of other toxicities in children with refractory solid tumors. Thirty-five children received 146 courses of irinotecan administered as a 60-min i.v. infusion, daily for 5 days, every 21 days, after premedication with dexamethasone and ondansetron. Doses ranged from 30 mg/m2 to 65 mg/m2. An MTD was defined in heavily pretreated and less-heavily pretreated (i.e., two prior chemotherapy regimens, no prior bone marrow transplantation, and no radiation to the spine, skull, ribs, or pelvic bones) patients. Myelosuppression was the primary DLT in heavily pretreated patients, and diarrhea was the DLT in less-heavily pretreated patients. The MTD in the heavily pretreated patient group was 39 mg/m2, and the MTD in the less-heavily pretreated patients was 50 mg/m2. Non-dose-limiting diarrhea that was well controlled and of brief duration was observed in approximately 75% of patients. A partial response was observed in one patient with neuroblastoma, and in one patient with hepatocellular carcinoma. Stable disease (4-20 cycles) was observed in seven patients with a variety of malignancies including neuroblastoma, pineoblastoma, glioblastoma, brainstem glioma, osteosarcoma, hepatoblastoma, and a central nervous system rhabdoid tumor. In conclusion, the recommended Phase II dose of irinotecan administered as a 60-min i.v. infusion daily for 5 days, every 21 days, is 39 mg/m2 in heavily treated and 50 mg/m2 in less-heavily treated children with solid tumors.