Treatment of Atypical Teratoid/Rhabdoid Tumors (AT/RT) of the Central Nervous System With Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation

Trial Information

Treatment of Atypical Teratoid/Rhabdoid Tumors (AT/RT) of the Central Nervous System With Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation

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: This is a multicenter study. Patients are stratified according to age and tumor
histology (infants [< 36 months of age] with tumor histology and immunohistochemical [IH]
analysis diagnostic of atypical teratoid/rhabdoid CNS tumors [AT/RT] [stratum 1] vs infants
with INI1 mutation only-based diagnosis [i.e., histology is not consistent with AT/RT] vs
older children [≥ 36 months of age] with tumor histology and IH analysis diagnostic of AT/RT
vs older children with INI1 mutation only-based diagnosis).

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 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/μL 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 proceed to radiation therapy or consolidation
therapy depending on age, location of the tumor, and initial diagnosis (whether or not
disease is disseminated).**

CONSOLIDATION THERAPY AND STEM CELL RESCUE: Within 2-6 weeks after completion of induction
therapy or radiation 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: *Before (but after induction therapy) or after consolidation therapy and
stem cell rescue, patients undergo 3-dimensional conformal radiotherapy (3D-CRT) to the
brain (and the spine if needed) 5 days a week for 5-6 weeks.

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

NOTE: **Patients with localized posterior fossa tumors and ≥ 6 months of age at the end of
induction therapy OR with localized supratentorial tumors at diagnosis and ≥ 12 months of
age at the end of induction therapy proceed to radiotherapy followed by consolidation
therapy; patients with disseminated disease at diagnosis, patients with localized posterior
fossa tumors at diagnosis and < 6 months of age at the end of induction therapy, or patients
with localized supratentorial tumors at diagnosis and < 12 months of age at the end of
induction therapy proceed to consolidation therapy followed by radiotherapy. Previously
collected tumor tissue is analyzed for a mutation in the INI1 rhabdoid tumor suppressor gene
and stained for INI1 antibody.

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