HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors

Due to the inferior response and event-free survival data of Regimens D and D2 on "Head Start
III" for all children with supratentorial embryonal tumors, in comparison with the published
data from "Head Start II" with Regimen A2 for metastatic patients, all such patients will
receive the "Head Start II" Induction Regimen A2, on "Head Start 4", for either three or five
cycles, depending upon whether or not they achieve complete remission by the end of Induction
cycle #3. They will then undergo randomization to either single cycle or three tandem cycles
of Consolidation marrow-ablative chemotherapy with AuHPCR.

Because of the unsatisfactory event-free survival for young children with
non-desmoplastic/extensive nodular medulloblastoma (predominantly non-Shh and non-Wnt
medulloblastoma subgroups) on Regimens D and D2 of "Head Start III", all these patients will
receive the "Head Start II" Induction Regimen A2 on ""Head Start 4"", for either three or
five cycles, depending upon whether or not they achieve complete remission by the end of
Induction cycle #3. They will then undergo randomization to either single cycle or three
tandem cycles of Consolidation marrow-ablative chemotherapy with AuHPCR.

Because of the excellent event-free and overall survival for young children with good risk
medullo-blastoma (Shh or Wnt subgroups) treated with up-front "Head Start" chemotherapy
strategies, such patients will undergo risk-tailored reduction of duration of Induction
therapy from five cycles to three cycles of the "Head Start II" Induction Regimen A2 on "Head
Start 4" for patients achieving a complete response to 3 cycles, followed, provided they are
also without evidence of residual tumor following recovery from Induction cycle #3. They will
NOT then undergo randomization, but will follow with a single cycle of Consolidation
marrow-ablative chemotherapy as in "Head Start" studies.

Inclusion Criteria:

- Patients 10 years of age at the time of definitive confirmatory eligible histologic or
cytologic diagnosis of eligible CNS tumor (brain or spinal cord)

- Patients may not have received irradiation or chemotherapy (except corticosteroids)

- Have histologically proven diagnosis of medulloblastoma or CNS embryonal tumors of the
brain or spinal cord

- Medulloblastoma

- Posterior fossa classic, desmoplastic or extensive nodular or anaplastic/large
cell medulloblastoma with appropriate and sufficient tumor material (FFPE or snap
frozen) for proposed assays: all stages, age less than 6 years at diagnosis

- Posterior fossa classic or anaplastic/large cell medulloblastoma with sufficient
tumor material (FFPE or snap frozen) for proposed assays: clinically high-stage
(neuraxis or extra-neural dissemination, M1-4), age greater than 6 years to less
than 10 years at diagnosis

- Posterior fossa medulloblastoma, those 6 years of age and above at diagnosis,
will only be eligible if they have evidence of neuraxis or extraneural
dissemination. Patients 6 years of age and above with low-stage (standard-risk,
M0) medulloblastoma will NOT be eligible for this study, irrespective of
molecular subgroup and extend of local resection

- CNS Embryonal Tumors:

- Pineoblastoma, CNS neuroblastoma, CNS ganglioneuroblastoma, embryonal tumor with
multi-layered rosettes (ETMR, including embryonal tumor with abundant neuropil and
true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified),
medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI1 intact) and CNS
embryonal tumor, not otherwise specified.

- Must commence Induction chemotherapy within 28 days of the most recent definitive
surgical procedure and within 21 days of the most recent neuro-imaging studies (MRI of
brain, performed with and without gadolinium contrast, and MRI of total spine,
performed with gadolinium contrast) and lumbar CSF cytological examination

- Patients must have adequate organ functions at the time of registration:

- Liver: bilirubin less than 1.5 mg/dL (except for patients with Gilbert's Syndrome
of indirect hyperbilirubinemia) and transaminases [SGPT or ALT, and SGOT or AST]
less than 2.5 (two and a half) times the upper limits of institutional normal.

- Renal: Creatinine clearance and/or glomerular filtration rate (GFR) greater than
or equal to 60 mL/min/1.73m² within 21 days of protocol therapy.

- Bone Marrow Function:

1. Peripheral absolute phagocyte count (APC) > 1000/ µL. APC = numbers of
banded neutrophils + segmented neutrophils + metamyelocytes + monocytes +
eosinophils Please note, if institution reports differential as a
percentage, then APC = [percentage of banded neutrophils + segmented
neutrophils+ metamyelocytes+monocytes+eosinophils] x total white cell count.

2. Platelet Count > 100,000/µL (transfusion independent)

3. Hemoglobin > 8 gm/dL (may have received RBC transfusions).

Exclusion Criteria:

- Patients older than 10 years of age at time of diagnosis

- Following diagnoses are not eligible for study enrollment: CNS atypical
teratoid/rhabdoid tumor (AT/RT); all ependymomas including anaplastic ependymomas of
the brain or spinal cord; all choroid plexus carcinomas; all high-grade glial and
glio-neuronal tumors; all primary CNS germ cell tumors; all primary CNS sarcomas; all
primary or metastatic CNS lymphomas and solid leukemic lesions (i.e., chloromas,
granulocytic sarcomas).

- Patients with unbiopsied diffuse intrinsic pontine tumors will NOT be eligible for
this study.