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A Phase I Study of Irinotecan As a 3-Week Schedule in Children With Refractory or Recurrent Solid Tumors

Gilles Vassal, Francois Doz, Didier Frappaz, Karima Imadalou, Evelyne Sicard, Alexandre Santos, John O’Quigley, Caroline Germa, Marie-Laure Risse, Dominique Mignard, Francois Pein

From the Department of Pediatric Oncology, Institut Gustave Roussy, and UPRES EA3535 Pharmacology and New Treatments of Cancer, Institut Gustave Roussy, Villejuif, France; the Departments of Pediatric Oncology and Biostatistics, Institut Curie, and Aventis Pharma SA, Paris, France; and the Department of Pediatric Oncology, Centre Léon Bérard, Lyon, France.

Address reprint requests to Gilles Vassal, MD, PhD, Department of Pediatrics, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: gvassal{at}igr.fr.

Purpose: A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors.

Patients and Methods: Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m². The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts.

Results: One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m² in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m² (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean ± standard deviation (SD) CPT-11 plasma clearance was 20.7 ± 9.5 L/h/m² (range, 5 to 54). The mean ± SD SN-38 metabolic ratio was 1.5% ± 1.1% (range, 0.15% to 5.55%).

Conclusion: The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m² in less heavily, and heavily pretreated children with solid tumors.

Presented at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15–18, 1999.

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