A study of Carboplatin with radiotherapy and Isotretinoin in patients with other than average risk medulloblastoma/PNET.

Medulloblastoma/PNET is the most common malignant childhood brain cancer. The goal of this study is
to determine whether radiosensitization with carboplatin or the addition of Isotretinoin to maintenance
therapy improves cure rates for children with other than average risk medulloblastoma/PNET. All
patients will receive standard therapy consisting of surgery, radiation therapy and chemotherapy. Subsets
of patients will be randomly assigned to receive carboplatin radiosensitization, Isotretinoin during
maintenance, both, or neither. Carboplatin has activity as a single agent against medulloblastoma and it
has been shown to enhance radiation-induced tumor cell kill. A previous study, CCG-99701,
demonstrated that it was feasible and safe to administer carboplatin on a daily basis during radiation
therapy. Laboratory-based studies have shown that Isotretinoin effectively kills patient-derived
medulloblastoma cells ex vivo and in animal models of medulloblastoma. Furthermore, this agent acts
synergistically with cisplatin in vitro and in animal models. Isotretinoin has previously been safely
administered to neuroblastoma patients at the same dose planned for this study. Correlative biology
studies are incorporated into the research design.

The goal of this study is to determine whether radiosensitization with carboplatin or the addition of Isotretinoin to maintenance therapy improves cure rates for children with other than average risk medulloblastoma/PNET.

The primary endpoint for the evaluation of treatment efficacy will be time to an event, which will be used to compute the event-free survival (EFS) percentage. An event comprises disease progression or recurrence, occurrence of a second malignant neoplasm, or death from any cause. Secondary endpoints in this analysis will be tumor response to radiation therapy ± carboplatin, and time to death, from which the survival (S) percentage will be computed.

Following neurosurgical procedure and staging, patients will be randomized to receive either 36 Gy craniospinal irradiation with appropriate boost to the tumor bed or the same radiation regimen with addition of carboplatin as a radiosensitizing agent. All patients must begin therapy within 31 days of surgery. The dose of carboplatin will be 35 mg/m2/day for 30 doses over 6 ½ weeks. All patients will receive vincristine 1.5 mg/m2 once per week during radiation therapy for a total of 6 doses.

Following radiation and a 6 week rest period, patients will then undergo Maintenance chemotherapy with cisplatin, vincristine, and cyclophosphamide in 28 day cycles for a total of 6 cycles. Note: Maintenance may be delayed up to 8 weeks.

Approximately 10% of patients will drop counts between 4-6 weeks after completing radiation therapy and Maintenance should not be initated until counts recover.
Patients will be randomized to receive either Isotretinoin during Maintenance or no additional drug.

Patients randomized to Isotretinoin will receive 80 mg/m2 twice daily on Day 1 and Days 16-28 in 28 day intervals during Maintenance and Days 15-28 during Continuation Therapy for a total of 12 cycles beginning concurrently with Maintenance chemotherapy and continuing for approximately six months after completion of chemotherapy.