A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children <36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue Versus the Same Therapy Without Methotrexate

Location:

Rochester, Minn.

Trial status:
Open for Enrollment
Why is this study being done?

PRIMARY OBJECTIVES: I. Determine if treatment of pediatric patients with newly diagnosed supratentorial primitive neuroectodermal CNS tumors or high-risk medulloblastoma with intensive induction chemotherapy comprising vincristine, etoposide, cyclophosphamide, and cisplatin in combination with high-dose methotrexate and leucovorin calcium followed by consolidation chemotherapy comprising carboplatin and thiotepa and peripheral blood stem cell rescue results in a higher complete response rate then in patients treated with the same regimen without high-dose methotrexate and leucovorin calcium. SECONDARY OBJECTIVES: I. Determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors from primitive neuroectodermal tumors (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs. II. Compare event-free survival and patterns of failure in patients treated with these regimens. III. Compare the acute, chronic, and late effects of these regimens, particularly in terms of tolerance to the same consolidation regimen after treatment with 2 different induction regimens, in these patients. IV. Compare the gastrointestinal and nutritional toxicities of these regimens in these patients. V. Compare the quality of life outcomes in patients treated with these regimens. VI. Compare the neuropsychological effects of these regimens in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to diagnosis* (M0 medulloblastoma with ≥ 1.5 cm² residual tumor vs M1 medulloblastoma [positive lumbar CSF cytology] vs M2, M3, or M4 medulloblastoma vs supratentorial PNET [any M-stage] vs M0 medulloblastoma < 8 months without residual disease or with < 1.5 cm² radiographic measurable residual tumor vs anaplastic M0 medulloblastoma without residual disease or with < 1.5 cm² radiographic measurable residual vs classic M0 (nondesmoplastic) medulloblastoma with < 1.5 cm² radiographic measurable residual tumor). NOTE: *All diagnoses are for children < 36 months unless otherwise noted. INDUCTION THERAPY: Patients are randomized to 1 of 2 induction treatment arms. ARM I: Patients receive vincristine IV on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive vincristine IV on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after the completion of chemotherapy and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. In both arms, patients with stable disease or partial response after induction therapy proceed to second-look surgery followed by consolidation therapy. Patients with a complete response after induction therapy proceed directly to consolidation therapy. CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 54 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Blood and tissue samples are collected at baseline for correlative studies, including gene expression profiling, biological marker analysis (i.e., cMyc, ErbB2/ErbB4), comparative genome analysis, and mutation analysis. After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.

Who is eligible to participate?

Inclusion Criteria: - Diagnosis of 1 of the following: - High-risk medulloblastoma defined by any of the following: - Residual disease > 1.5 cm² - Lumbar cerebral spinal fluid cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or ≥ 10 days after definitive surgery unless contraindicated - M0 disease in children < 8 months of age at diagnosis - M2 or M3 metastatic disease by MRI - M4 disease - Supratentorial primitive neuroectodermal tumor (PNET)(any M-stage) - Anaplastic medulloblastoma regardless of M-stage or residual tumor - M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically measurable residual disease < 1.5 cm^2 - MRI evidence of spinal disease - Tumor must be negative for INI1 gene - Has undergone definitive surgery within the past 31 days - No atypical teratoid rhabdoid tumors - Biological specimens must be available for correlative laboratory studies - Life expectancy > 8 weeks - Creatinine clearance or radioisotope glomerular filtration rate ≥ 60 mL/min - Bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST and ALT < 2 times ULN - Shortening fraction ≥ 27% by echocardiogram - Ejection fraction ≥ 47% by radionuclide angiogram - No evidence of dyspnea at rest - Pulse oximetry > 94% on room air - Absolute neutrophil count > 1,000/mm³ - Platelet count > 100,000/mm³ (transfusion independent) - Hemoglobin > 8 g/dL (RBC transfusions allowed) - Prior corticosteroids allowed - No prior radiation therapy or chemotherapy

Last updated:
2/5/2014
NCT ID:
NCT00336024
IRB Number:
07-006033