Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System

PRIMARY OBJECTIVES:

I. To investigate the feasibility of administering vorinostat (SAHA) and isotretinoin for
three days prior and concomitant with cisplatin based chemotherapy over three courses of
induction chemotherapy.

II. To describe the toxicity of administering vorinostat (SAHA) and isotretinoin for three
days prior and concomitant with cisplatin based chemotherapy over three courses of induction
chemotherapy.

III. To investigate prognostic values of histopathological classification and biological
markers in the context of a feasibility study.

SECONDARY OBJECTIVES:

I. To estimate the preliminary response rate of this approach in patients with measurable
residual disease (primary site and/or metastatic sites).

II. To estimate disease specific progression-free and overall survival, in the context of a
feasibility study.

III. To explore the predictive values of biological markers in cerebrospinal fluid (CSF),
plasma, urine tumor material in the context of a feasibility study.

OUTLINE:

INDUCTION THERAPY: Patients receive vorinostat orally (PO) once daily (QD) and isotretinoin
PO twice daily (BID) on days 1-4; vincristine sulfate intravenously (IV) on days 4, 11, and
18; cisplatin IV over 6 hours on day 4; cyclophosphamide IV over 1 hour on days 5-6; and
etoposide phosphate IV over 1 hour on days 4-6. Treatment repeats every 21 days for 3 cycles
in the absence of disease progression or unacceptable toxicity. Patients also undergo
peripheral blood stem cell (PBSC) harvesting after each course.

CONSOLIDATION THERAPY: Within 6 weeks (10 weeks if patient is re-staged) after completion of
induction therapy, patients receive carboplatin IV over 2 hours and thiotepa IV over 2 hours
on days 1-2. Patients also receive autologous PBSC rescue infusion over 6 hours on day 4.
Treatment repeats every 28 days for 3 cycles in the absence of disease progression or
unacceptable toxicity. Beginning 3 weeks later, patients with M0 non-desmoplastic
medulloblastoma also undergo conformal radiotherapy* to the tumor bed.

NOTE: *Patients with supratentorial primary tumors or metastatic disease undergo radiotherapy
at the discretion of treating physician.

MAINTENANCE THERAPY: Beginning 4 weeks after completion of radiotherapy or immediately after
completion of consolidation therapy, patients receive vorinostat PO QD on days 1, 3, 5, 6, 8,
10, 12, and 13 and isotretinoin PO BID on days 1-14. Treatment repeats every 28 days for up
to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have a histologically confirmed, newly-diagnosed medulloblastoma (except
for patients with the histology of localized (M0) desmoplastic medulloblastoma or
atypical teratoid/rhabdoid tumor [ATRT]) or supratentorial primitive neuroectodermal
tumor (PNET) including pineoblastomas

- Patients must have not received any prior therapy other than surgery and/or steroids

- Patient must have adequate pre-trial formalin-fixed, paraffin-embedded (FFPE) tumor
material available for use in the biology studies and central pathology review; if
snap frozen tissue is not available, the study chair must be contacted to discuss
eligibility

- Patient must be a suitable candidate, by institutional standards for stem cell
apheresis

- Lansky performance score (LPS for =< 16 years of age) >= 30 assessed within two weeks
prior to registration

- Absolute neutrophil count (ANC) >= 1000/ul (unsupported) (within 14 days of
registration and within 7 days of the start of treatment)

- Platelets >= 100,000/ul (unsupported) (within 14 days of registration and within 7
days of the start of treatment)

- Hemoglobin >= 8 g/dL (may be supported) (within 14 days of registration and within 7
days of the start of treatment)

- Bilirubin < 1.5 times upper limit of normal for age (within 14 days of registration
and within 7 days of the start of treatment)

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 1.5
times institutional upper limit of normal for age (within 14 days of registration and
within 7 days of the start of treatment)

- Serum creatinine =< 1.5 times upper limit of institutional normal for age or
glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or estimated GFR (Schwartz
bedside) that is > 99 ml/min/1.73 m^2 (within 14 days of registration and within 7
days of the start of treatment)

- Parents/legal guardians must have the ability to understand and the willingness to
sign a written informed consent document according to institutional guidelines

Exclusion Criteria:

- Patients with diagnosis of atypical teratoid/rhabdoid tumor (ATRT by histology,
immunohistochemistry and/or molecular analysis) and desmoplastic M0 medulloblastoma
will be excluded from the study

- Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
that would compromise the patient's ability to tolerate protocol therapy or would
interfere with the study procedures or results

- Patients receiving any other anticancer or investigational drug therapy are excluded

- Patients having taken valproic acid within 2 weeks prior to initiation of treatment
are excluded

- Patients with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy

- Patients with a parabens allergy