Vorinostat, Isotretinoin, and Combination Chemotherapy in Treating Young Patients Who Have Undergone Surgery for Embryonal Tumors of the Central Nervous System

• Percentage of study participants completing the three courses of induction therapy within 98 days [ Time Frame: From day 1 of treatment until day 98 ] [ Designated as safety issue: No ]
• Number of study participants who discontinue induction therapy because of toxicity [ Time Frame: From day 1 of treatment until the end of induction therapy (first three courses of therapy) ] [ Designated as safety issue: Yes ]

• Feasibility of regimen [ Designated as safety issue: No ]
• Toxicity of regimen according to NCI CTCAE Version 3.0 [ Designated as safety issue: Yes ]

• Objective response rate in patients with measurable residual disease [ Time Frame: At the end of induction therapy (first three courses of therapy) ] [ Designated as safety issue: No ]
  Brain imaging to assess response to therapy will be conducted at the end of induction therapy (first three courses of treatment). Objective response is defined as a complete response or a partial response to the treatment. The objective response rate will be reported separately for study participants with medulloblastoma and study participants with supratentorial primitive neuroectodermal tumors (PNET).
• Progression-free survival [ Time Frame: From day 1 of therapy until progression, death, second malignancy, or off study (last contact) ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: From day 1 of therapy until death or off study (last contact) ] [ Designated as safety issue: No ]
• Identify genes that are differentially expressed between responding and non-responding disease [ Time Frame: After the last patient has enrolled and completed or discontinued induction therapy ] [ Designated as safety issue: No ]
  Gene expression is assessed from specimens taken pre-therapy. Response to therapy is assessed at the end of induction therapy (first three courses). Gene expression analysis will occur after the last participant has enrolled on the study and all patients have either completed or discontinued induction therapy.
• Progression-free survival by gene expression [ Time Frame: From day 1 of treatment until progression, death, second malignancy, or off study (last contact) ] [ Designated as safety issue: No ]
  Gene expression is assessed from specimens taken pre-therapy. Progression-free survival is assessed from day 1 of treatment until progression, death, second malignancy, or last contact. Gene expression analysis will occur after the last participant has enrolled to the study and all participants have been followed for the progression-free survival endpoint.

• Preliminary response rate in patients with measurable residual disease [ Designated as safety issue: No ]
• Disease-specific progression-free and overall survival [ Designated as safety issue: No ]
• Prognostic values of histopathological classification and biological markers [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. A peripheral blood stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. This may allow more chemotherapy to be given so that more tumor cells are killed.

PURPOSE: This clinical trial is studying the side effects of giving vorinostat and isotretinoin together with combination chemotherapy and to see how well it works in treating young patients who have undergone surgery for embryonal tumors of the central nervous system.

OBJECTIVES:

Primary

• To investigate the safety and feasibility of administering vorinostat and isotretinoin for 3 days prior to and concurrently with cisplatin-based chemotherapy over three courses of induction chemotherapy in pediatric patients with embryonal tumors of the central nervous system.
• To describe the toxicity of this regimen in these patients.

Secondary

• To estimate the preliminary response rate of this regimen in patients with measurable residual disease (primary site and/or metastatic sites).
• To estimate the disease-specific progression-free and overall survival of these patients.
• To investigate the prognostic values of histopathological classification and biological markers.

OUTLINE: This is a multicenter study.

• Induction therapy: Patients receive oral vorinostat once daily and oral isotretinoin twice daily on days 1-4; vincristine sulfate 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 courses 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 courses in the absence of disease progression or unacceptable toxicity.

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 oral vorinostat once daily on days 1, 3, 5, 6, 8, 10, 12, and oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Tumor tissue and peripheral blood mononuclear cells are collected at baseline for gene expression analysis (by SNP array and tissue microarray) and protein and signaling pathway expression via IHC and FISH.

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

• Drug: carboplatin
  17 mg/kg/day on days 1 and 2 of the first 28 days of consolidation therapy (course 1). Treatment repeats every 28 days for a total of 3 courses of consolidation therapy.
  Other Name: Paraplatin
• Drug: cisplatin
  3.5 mg/kg/day on day 4 of the first 21 days of therapy (course 1 of induction therapy). Treatment repeats every 21 days for a total of 3 courses of induction therapy.
  Other Names:

  • Cis-diamminedichloroplatinum II
  • Platinol-AQ
• Drug: cyclophosphamide
  60 mg/m2/day on days 5 and 6 of the first 21 days of therapy (course 1 of induction therapy). Treatment repeats every 21 days for a total of 3 courses of induction therapy.
  Other Name: Cytoxan
• Drug: etoposide
  2.5 mg/kg/day on days 4, 5, and 6 of the first 21 days of therapy (course 1 of induction therapy). Treatment repeats every 21 days for a total of 3 courses of induction therapy.
  Other Names:

  • VePesid
  • Etopophos
  • VP-16
• Drug: isotretinoin
  80 mg/m2 twice daily on days 1, 2, 3, and 4 of the first 21 days of therapy (course 1 of induction therapy). Treatment repeats every 21 days for a total of 3 courses of induction therapy. 80 mg/m2 twice daily on days 1-14 of the first 28 days (course 1) of maintenance therapy. Treatment repeats every 28 days for a total of 12 courses of maintenance therapy.
  Other Names:

  • 13-cis-retinoic acid
  • RO-43,780
  • Accutane
  • Amnesteem
  • Claravis
  • Sotret
• Drug: thiotepa
  10 mg/kg/day on days 1 and 2 of the first 28 days of consolidation therapy (course 1). Treatment repeats every 28 days for a total of 2 courses of consolidation therapy.
  Other Names:

  • Tespa
  • Thiophosphamide
  • Triethylenethiophosphoramide
  • WR-45312
• Drug: vincristine sulfate
  0.05 mg/kg/day on days 4, 11, and 18 of the first 21 days of therapy (course 1 of induction therapy). Treatment repeats every 21 days for a total of 3 courses of induction therapy.
  Other Names:

  • Oncovin
  • VCR
  • LCR
• Drug: vorinostat
  230 mg/m2/day or 180 mg/m2/day on days 1-4 of the first 21 days of therapy (course 1 of induction). Treatment repeats during course 2 and course 3 for a total of 3 courses of induction therapy. 180 mg/m2/day on days 1, 3, 5, 6, 8, 10, 12, and 13 of the first 28 days (course 1) of maintenance therapy. Treatment repeats every 28 days for a total of 12 courses of maintenance therapy.
  Other Names:

  • SAHA
  • Zolinza
  • Suberoylanilide hydroxamic acid
• Radiation: Conformal radiation
  Radiation will be given once daily, 5 days/week for a cumulative dose of 45-54 Gy to the posterior fossa and 45-50.4 Gy to the supratentorial site. Radiation therapy will began within 3 weeks of completing consolidation therapy and end

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of one of the following:

  • Newly-diagnosed medulloblastoma

    • No localized [M0] dermoplastic medulloblastoma or atypical teratoid/rhabdoid tumor
  • Supratentorial primitive neuroectodermal tumors (including pineoblastomas)
• Patient must be suitable for stem cell apheresis
• Must have undergone definitive surgery within the past 31 days
• Adequate tumor samples available

PATIENT CHARACTERISTICS:

• Lansky performance status 30-100%
• ANC ≥ 1,000/mm^3 (unsupported)
• Platelet count ≥ 100,000/mm^3 (unsupported)
• Hemoglobin ≥ 8 g/dL (may be supported)
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN) for age or glomerular filtration rate ≥ 70 mL/min
• Bilirubin < 1.5 times ULN for age
• SGPT ≤ 1.5 times ULN for age
• No concurrent clinically significant, unrelated, systemic illness (e.g., serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with the study procedures or results
• Adequate pre-trial tumor available for biological studies
• Able to return for follow up visits and participate in required follow up studies
• No parabens allergy

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior therapy

  • Prior surgery and/or corticosteroids allowed
• At least 2 weeks since prior valproic acid
• No other concurrent anticancer or investigational agents