HOUSTONPreclinical studies showing that 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
patients were premedicated with dexamethasone and 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."
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 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 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 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
"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.