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

• 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 ]
  

OBJECTIVES:

Primary

• To investigate the 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: Beginning 3-6 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 21 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.
• .
• 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.