Trial Information

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

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.