HOUSTON—Preclinical studies showing that irinotecan(Drug information on irinotecan) (Camptosar) has broad-spectrum activity in vitro and in vivo in xenografts derived from pediatric tumors are being followed by phase I and phase II clinical trials. Susan Blaney, MD, associate professor of pediatrics at Texas Children’s Cancer Center in Houston said that irinotecan has shown activity in pediatric neuroblastoma, rhabdomyosarcoma, and medulloblastoma (including glioma) in preclinical studies.
Dr. Blaney and colleagues in the Pediatric Oncology Group (POG) conducted a phase I study (POG-9761) of irinotecan in pediatric patients with solid tumors. Irinotecan was given as a 1-hour infusion daily for 5 days, repeating every 21 days. Dose levels escalated from 30 mg/m2 to 65 mg/m2, and patients were premedicated with dexamethasone(Drug information on dexamethasone) and ondansetron(Drug information on ondansetron) (Zofran).
Patients were stratified into 3 groups: heavily pretreated, less-heavily pretreated, and over 1 and less than 6 years of age. The study enrolled 35 patients; 30 were evaluable. Median age was 9 years. Diagnoses included both central nervous system (CNS) and non-CNS tumors. Concurrent anticonvulsant medications were allowed.
Toxicities and Responses
"Dose-limiting toxicities were myelosuppression in the heavily pretreated patients and diarrhea and myelosuppression in the less heavily pretreated patients. The maximum tolerated dose (MTD) was 39 mg/m2 in the heavily pretreated patients and 50 mg/m2 in the less-heavily pretreated group," Dr. Blaney said. "Most patients had some diarrhea, but it was mostly mild and well-controlled with loperamide(Drug information on loperamide)."
Only two patients had objective responses, but many had stabilization of disease. Partial responses occurred in one patient with neuroblastoma and in one with hepatocellular carcinoma.
Researchers from St. Jude Children’s Research Hospital in Memphis conducted a phase I study of irinotecan using a similar schedule in 23 children with solid tumors. "This study included a fairly standard representation of pediatric solid tumors," Dr. Blaney said.
Patients were stratified according to whether or not they had significant prior irradiation. Dr. Blaney said that the dose-limiting toxicity was grade 3 or 4 diarrhea, which occurred in 3 of 9 patients at the 20 mg/m2 dose level (1 of whom had Clostridium difficile), 6 of 12 patients at the 24 mg/m2 dose level, and 1 of 2 patients at the 29 mg/m2 dose level. "The MTD in this study was 24 mg/m2, given daily for 5 days, in cycles repeating every 21 days," Dr. Blaney said.
Dr. Blaney said that partial responses were seen in five patients: three with rhabdomyosarcoma, one with neuroblastoma, and one with squamous cell carcinoma of the larynx. Disease stabilized in 16 patients for a median of 70 days (range 37 to 201 days).
Weekly Infusion Tested
The Texas Children’s Cancer Center researchers are currently conducting a phase I study testing irinotecan as a 90-minute infusion given weekly for 4 weeks with cycles repeating every 6 weeks. Patients are stratified according to level of pretreatment.
Dr. Blaney said that 13 patients have been studied to date. "The MTD in heavily pretreated patients was 125 mg/m2 on this weekly infusion. Studies to determine the MTD in less heavily pretreated patients are ongoing," she said.
Pharmacokinetic Studies
Pharmacokinetic studies have shown that children have higher concentrations of the irinotecan metabolite SN-38 relative to dose than is seen in adults. Dr. Blaney said that this is probably due to saturation kinetics but that there is significant interpatient variability. Irinotecan half-life in children is generally slightly shorter than in adults, and clearance is slightly more rapid. "However, it is important to remember that there is striking interpatient variability," she said.
These early trials have also shown that phenytoin(Drug information on phenytoin) significantly alters irinotecan metabolism. Dr. Blaney said that a patient in one trial had seizures, was started on phenytoin, and was able to tolerate an irinotecan dose fourfold higher while taking the anticonvulsant. Data comparing cycle 1 (without phenytoin) to cycle 6 (with phenytoin) revealed a major effect on irinotecan pharmacokinetics.
Irinotecan Combinations
Irinotecan is also being studied in phase I trials of combination therapy. The study regimens include irinotecan/cisplatin (Platinol), irinotecan/vincristine, and irinotecan/temozolamide (Temodar).
Ongoing phase II studies include a Children’s Oncology Group study in solid and CNS tumors, as well as trials in high-grade gliomas and in rhabdomyosarcoma.
"Multiple dosing schedules have been evaluated, but the optimal schedule of administration has not yet been determined. Dose-limiting toxicities are diarrhea and myelosuppression. Pharmacokinetic studies show marked interpatient variability in drug disposition, which may be related to the fact that irinotecan is a substrate for CYP3A4. Phenotype/genotype studies of this polymorphism are in progress," Dr. Blaney said.
Future directions for pediatric studies include determining the optimal schedule and combinations, determining optimal doses, and characterizing important drug interactions such as that with phenytoin.
