Combination Chemotherapy, Radiation Therapy, and an Autologous Peripheral Blood Stem Cell Transplant in Treating Young Patients With Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System

PRIMARY OBJECTIVES:

I. To determine the 6-, 12-, and 24-month event-free survival and overall survival of
children (birth to 21 years of age) with atypical teratoid/rhabdoid CNS tumors (AT/RT),
diagnosed based on histology, immunophenotyping, and modern molecular and immunohistochemical
analysis of INI1, treated with surgery, intensive chemotherapy combined with stem cell
rescue, and radiation therapy.

II. To compare the outcome of very young patients (under 3 years old) on this study whose
histologic diagnosis is AT/RT with infants identified as having AT/RT on POG-9233 and
CCG-9921.

SECONDARY OBJECTIVES:

I. To determine the feasibility and toxicity of the proposed chemotherapy regimen in
combination with radiation therapy.

II. To contribute tumor samples from which biologic and gene expression data can be developed
to yield prognostic indicators and provide direction for future treatment strategies.

III. To develop a clinical and biologic database on which future studies can be based.

OUTLINE:

INDUCTION THERAPY AND STEM CELL HARVEST: Patients receive vincristine IV on days 1, 8, and 15
and high-dose methotrexate IV over 4 hours on day 1. Beginning 24 hours after the start of
methotrexate, patients receive leucovorin calcium orally (PO) or IV every 6 hours until the
serum methotrexate level is < 0.1 micromoles. 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
filgrastim (G-CSF) IV or subcutaneously (SC) once daily beginning on day 7 and continuing
until ANC recovers. When ANC is > 1,000/uL post nadir, patients receive G-CSF twice daily for
stem cell mobilization. Approximately 2-4 days, later peripheral blood stem cells are
harvested once daily, as needed, after each course of induction therapy until a total of 6 x
10^6 CD34+ cells/kg have been collected. Treatment repeats every 21 days for 2 courses.

After completion of induction therapy, patients are re-evaluated. Patients with progressive
disease are removed from study. Patients with radiographic evidence of residual tumor are
encouraged to undergo second-look surgery prior to proceeding to radiotherapy or
consolidation therapy; patients with complete response, partial response, or stable disease
are assigned to 1 of 2 arm.

ARM I ((patients less than 6 months, infratentorial site with M0 involvement or patients less
than 12 months, supratentorial site with M0 involvement or patients with disseminated disease
of any primary site or age):

CONSOLIDATION THERAPY AND STEM CELL RESCUE: Within 2-6 weeks after completion of induction
therapy, patients begin consolidation therapy. Patients receive high-dose carboplatin IV over
4 hours and high-dose thiotepa IV over 2 hours on days 1 and 2 and undergo autologous
peripheral blood stem cell (PBSC) rescue on approximately day 4. Patients also receive G-CSF
IV or SC once daily beginning 24 hours after stem cell infusion and continuing until ANC
recovers. Treatment with consolidation therapy followed by stem cell rescue repeats every 28
days for 3 courses in the absence of disease progression or unacceptable toxicity.

RADIATION THERAPY: Patients undergo 3-dimensional conformal radiotherapy (3D-CRT) to the
brain (and the spine if needed) 5 days a week for 5-6 weeks.

ARM II (patients greater than or equal to 6 months, infratentorial site with M0 involvement
or patients greater than or equal to 12 months, supratentorial site with M0 involvement):
Patients undergo 3D-CRT as in Arm I. Within 2-6 weeks after completion of radiation therapy,
patients receive consolidation therapy and stem cell rescue as in Arm I

NOTE: *The administration of etoposide, cyclophosphamide, and cisplatin are dependant on the
prior clearance of methotrexate to a level of < 0.1 micromoles.

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

Inclusion Criteria:

- Diagnosis of CNS atypical teratoid/rhabdoid tumor (AT/RT) or tumors that have a
mutation of the INI1 gene (even if the tumor does not have the usual histologic
characteristics of AT/RT)

- Patients with extra neural metastasis (M4) or renal rhabdoid tumors are not
eligible

- Patients with MRI evidence of spinal disease are eligible

- Must have undergone definitive surgery in the past 31 days

- Cranial MRI (with and without gadolinium) must be done pre-operatively

- Post-operatively, cranial MRI (with and without gadolinium) must be done,
preferably within 48 hours of surgery or 10-28 days after surgery

- Entire spinal MRI must be obtained either pre-operatively (with gadolinium) or
post-operatively (10-28 days after surgery), prior to study enrollment (with and
without gadolinium)

- Life expectancy > 8 weeks

- ANC > 1,000/uL

- Platelet count > 100,000/uL (transfusion independent)

- Hemoglobin > 8 g/dL (RBC transfusions allowed)

- Creatinine clearance (minimum of 12-24 hour urine collection) or radioisotope GFR >=
60 mL/min

- Total bilirubin =< 1.5 times upper limit of normal (ULN) for age

- AST and ALT < 2 times ULN for age

- Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 47% by
radionuclide angiogram

- No evidence of dyspnea at rest

- Pulse oximetry > 94% on room air

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No prior radiotherapy or chemotherapy except for the following:

- Patients enrolled on protocol ACNS0334 whose tumors demonstrate the INI1 gene
mutation are eligible to transfer to this study even if they have received one
course of induction therapy (these patients must be re-consented to treatment and
restaged)

- Prior corticosteroids allowed