ACNS0821, Temozolomide with Irinotecan Versus Temozolomide, Irinotecan plus Bevacizumab for Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, A COG Randomized Phase II Screening Trial
Temozolomide is an orally administered alkylating agent of the imidazotetrazine derivatives with excellent CNS penetration. Phase II studies have shown variable response rates of 16-47% in children and adolescents with recurrent medulloblastomas/PNET. Irinotecan is a water-soluble campothecin derivative that inhibits topoisomerase I (topo I), an enzyme involved in DNA repair, transcription and replication. Irinotecan has been shown to have single agent activity against recurrent medulloblastomas. A British study found a 40% objective response rate to the combination of irinotecan and temozolomide in patients with recurrent MB/PNET. Bevacizumab is a humanized monoclonal neutralizing antibody binding all five isoforms of human vascular endothelial growth factor (VEGF). CNS tumors are potentially excellent targets for antiangiogenic therapy given the presence of tumor neo-vascularization and high concentrations of proangiogenic factors. Both irinotecan and temozolomide have activity against recurrent MB/PNET and the combination has been well tolerated in heavily pre-treated patients. The addition of bevacizumab theoretically may increase the efficacy of chemotherapy. Therefore, a phase II trial evaluating the addition of bevacizumab to the combination of irinotecan and temozolomide in MB/PNET of childhood will be performed. This study will use a randomized phase II screening design to compare temozolomide (150 mg/m2 PO for 5 days) with irinotecan (50 mg/m2 IV for 5 days) to temozolomide, irinotecan plus bevacizumab (10 mg/kg IV on Days 1 and 15), in children with recurrent MB/PNET. Patients must have measurable disease. Response will be evaluated prior to every other course. Therapy can be continued for up to 12 courses in the absence of disease progression or unacceptable side effects.
-- Age: Patients must be no greater than 21 years of age at the time of study enrollment.
-- Diagnosis: Medulloblastoma (CTEP SDC=10027107) or PNET of childhood (CTEP SDC=10056672) that has relapsed or become refractory to standard chemotherapy. Patients with pineoblastoma are eligible. Patients must have had histologic verification of the malignancy at original diagnosis or at the time of recurrence. Patients must have measurable residual disease, defined as tumor that is measurable in two perpendicular diameters on MRI.
-- Brain and Spine MRI: All patients must have a brain MRI with and without gadolinium and a spine MRI with gadolinium performed within 2 weeks prior to study enrollment.
-- Performance Level: Patients must have a Lansky or Karnofsky performance status score of ≥ 50%, corresponding to ECOG categories of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients <= 16 years of age.
-- Patients must have a life expectancy of ≥ 8 weeks.
-- Prior Therapy: Patients must have experienced at least one and at most two relapses prior to study enrollment. Patients with primary refractory disease are eligible.
-- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
-- Patients must have recovered from any surgical procedure before enrolling on this study
-- Hypertension must be well controlled
-- Growth factor(s): Must not have received within 7 days of entry onto this study.
-- Steroids: Patients who are receiving corticosteroids must be on a stable or decreasing dose for at least 7 days.
-- Study Specific: Patients must not be currently taking NSAIDs, clopidrogel, dipyridamole or aspirin therapy > 81 mg/day.
-- All patients must have adequate bone marrow, renal, liver and coagulation function
-- Urine protein should be screened by dipstick analysis.
-- Patients with a seizure disorder may be enrolled if well-controlled and on non-enzyme inducing anticonvulsants.
-- All patients and/or their parents or legal guardians must sign a written informed consent.
-- All institutional, FDA, and NCI requirements for human studies must be met.