Trial Information

A Single-Arm, Open Label Limited-Institutional Phase II Study of Multi-Agent Intrathecal and Systemic Chemotherapy With Radiation Therapy for Children < or = 18 Years With Newly Diagnosed Central Nervous System Atypical Teratoid/Rhabdoid Tumor

OBJECTIVES:

Primary

- Determine the efficacy of intensive systemic and intrathecal chemotherapy and
radiotherapy, in terms of medial survival, in children with newly diagnosed central
nervous system atypical teratoid/rhabdoid tumors in comparison with historical outcomes
from prior trials.

Secondary

- Determine the toxicity profile and tolerability of this regimen in these patients.

- Determine the chemosensitivity of these patients' tumors by MRI after an attempt at
maximum surgical resection after 2 courses of this regimen.

- Determine the predictive value of the INI 1 gene mutation in determining prognosis by
comparing tumor samples from patients with vs without this mutation treated with this
regimen.

OUTLINE: This is a multicenter study.

- CNS/intrathecal therapy: All patients with M0 disease receive triple intrathecal (IT)
chemotherapy comprising methotrexate (MTX), cytarabine, and hydrocortisone on day 1 of
weeks 1, 2, 4, 7, 13, 19, 27, 33, 39, 45, and 51 followed by oral or IV leucovorin
calcium given 24 hours after each MTX dose. Patients with initially positive
cerebrospinal fluid (CSF) cytology (M+) receive triple IT chemotherapy weekly until 2
consecutive CSF samples are negative for malignant cells.

- Pre-irradiation induction therapy (weeks 1-6): Patients receive vincristine IV on day 1
of weeks 1-6; cisplatin IV over 8 hours on day 1 and doxorubicin IV continuously over
48 hours beginning on day 2 of weeks 1 and 4; cyclophosphamide IV continuously over 72
hours beginning on day 2 of week 1; etoposide IV over 1 hour on days 1-3 of week 4; and
filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 of week 1 and day 4 of week 4
and continuing until blood counts recover.

- Induction chemoradiotherapy (weeks 7-12): Patients receive vincristine IV on day 1 of
weeks 7-12; cisplatin IV over 8 hours on day 1, cyclophosphamide IV over 1 hour on day
2, etoposide IV over 1 hour on days 1-3 of weeks 7 and 10; and G-CSF SC daily beginning
on day 4 of weeks 7 and 10 and continuing until blood counts recover. Patients with M0
disease and patients under 3 years of age with M+ disease undergo radiotherapy to the
primary tumor daily on weeks 7-12. Patients 3 years of age and over with M+ disease
undergo craniospinal irradiation (CSI) daily on weeks 7-12 until negative CSF cytology
is achieved.

- Post-radiation induction therapy (weeks 13-18): Patients receive vincristine IV on day
1 of weeks 13 and 16; doxorubicin and cyclophosphamide as in pre-irradiation induction
therapy beginning on day 1 of week 13; cyclophosphamide IV over 1 hour on days 1-3 of
week 16; dactinomycin IV on days 1-5 of week 16; and G-CSF SC daily beginning on day 6
of weeks 13 and 16 and continuing until blood counts recover.

- Maintenance chemotherapy (weeks 19-42): Patients receive vincristine IV on day 1 of
weeks 27, 33, and 39 and days 1 and 5 of weeks 30, 36, and 42; doxorubicin and
cyclophosphamide as in pre-irradiation induction beginning on day 1 of weeks 27 and 33;
doxorubicin IV over 15 minutes and dexrazoxane (DX) IV over 15 minutes on days 1 and 2
of week 39; cyclophosphamide IV over 1 hour on days 1-3 of weeks 30, 36, 39, and 42;
dactinomycin IV on days 1-5 of weeks 30, 36, and 42 and on day 1 of weeks 19 and 23;
oral temozolomide on days 1-5 of weeks 19 and 23; and G-CSF SC daily beginning on day 6
of weeks 19, 23, 30, 36, and 42, day 5 of weeks 27 and 33, and day 4 of week 39 and
continuing until blood counts recover.

- Doxorubicin continuation therapy (for patients not receiving CSI and mediastinal
radiotherapy)(weeks 45-51): Patients receive vincristine IV on day 1 of weeks 45, 48,
and 51 and day 5 of week 48; doxorubicin IV over 15 minutes and DX IV over 15 minutes
on days 1 and 2 of weeks 45 and 51; cyclophosphamide IV over 1 hour on days 1-3 of
weeks 45, 48, and 51; dactinomycin IV on days 1-5 of week 48; and G-CSF SC daily
beginning on day 4 of weeks 45 and 51 and day 6 of week 48 and continuing until blood
counts recover.

- Non-doxorubicin continuation therapy (for patients receiving CSI or mediastinal
radiotherapy)(weeks 45-51): Patients receive cyclophosphamide and G-CSF as in
doxorubicin continuation therapy; vincristine IV on days 1 and 5 of weeks 45, 48, and
51; and dactinomycin IV on days 1-5 of weeks 45, 48, and 51.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then
annually for 2 years.

PROJECTED ACCRUAL: A total of 26 patients will be accrued for this study.