PRIMARY OBJECTIVES:

I. Determine whether carboplatin radiosensitization increases long-term, event-free survival
of pediatric patients with newly diagnosed, previously untreated, high-risk medulloblastoma
or supratentorial primitive neuroectodermal tumors.

II. Determine whether isotretinoin increases long-term, event-free survival of these
patients.

SECONDARY OBJECTIVES:

I. Compare residual disease response to radiotherapy alone versus radiotherapy and
carboplatin in these patients.

II. Identify molecular prognostic indicators suitable for patient stratification in future
trials.

OUTLINE: This is a randomized, open-label, factorial-designed, multicenter study. Patients
are stratified according to location of disease and dissemination status (M0 medulloblastoma
with > 1.5 cm² residual tumor vs M+ medulloblastoma vs M0 supratentorial primitive
neuroectodermal tumor [SPNET] with < 1.5 cm² residual tumor vs M0 SPNET with > 1.5 cm²
residual tumor vs M+ SPNET vs M0 diffusely anaplastic medulloblastoma). Patients are
randomized to 1 of 4 treatment arms.

ARM I (standard chemoradiotherapy and standard maintenance therapy):

CHEMOTHERAPY: Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26,
29-33, and 36-40 and receive vincristine IV over 1 minute on days 1, 8, 15, 22, 29, and 36.
Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive cisplatin IV over 6 hours on day 1, vincristine IV
over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients
also receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 4 and continuing
until blood counts recover (at least 10 days).

Treatment repeats every 28 days for a total of 6 courses in the absence of disease
progression or unacceptable toxicity.

ARM II (standard chemoradiotherapy plus carboplatin and standard maintenance therapy):

CHEMORADIOTHERAPY: Patients receive carboplatin IV over 15 minutes once daily on days 1-5,
8-12, 15-19, 22-26, 29-33, and 36-40 and undergo radiotherapy and receive vincristine as in
arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance
therapy.

MAINTENANCE THERAPY: Patients receive maintenance therapy as in arm I.

ARM III (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and
continuation therapy with isotretinoin):

CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in arm I. Six weeks after
completion of chemoradiotherapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive oral isotretinoin twice daily on day 1 and days 16-28
and cisplatin, vincristine, cyclophosphamide, and G-CSF as in arm I maintenance therapy.

Treatment repeats every 28 days for a total of 6 courses in the absence of disease
progression or unacceptable toxicity.

Patients then proceed to continuation therapy.

CONTINUATION THERAPY: Patients receive oral isotretinoin twice daily on days 15-28.

Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

ARM IV (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus
isotretinoin, and continuation therapy with isotretinoin):

CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in arm II. Six weeks after
completion of chemoradiotherapy, patients proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive maintenance therapy as in arm III. Patients then
proceed to continuation therapy.

CONTINUATION THERAPY: Patients receive continuation therapy as in arm III.

After completion of study treatment, patients are followed up periodically for up to 10
years.