Primary Outcome Measures:
- Maximum tolerated dose of vorinostat (Phase I) [ Designated as safety issue: Yes ]
- Overall survival (Phase II) [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Toxicity (Phase I) [ Designated as safety issue: Yes ]
- Time to tumor progression (Phase II) [ Designated as safety issue: No ]
- Safety (Phase II) [ Designated as safety issue: Yes ]
- Correlation of tumor molecular characteristics and expression
profile with response, survival, and safety [ Designated as safety issue: Yes ]
OBJECTIVES:
Primary
- To determine the maximum tolerated dose of vorinostat when administered with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme. (Phase I)
- To determine the efficacy of this regimen, in terms of overall survival, in these patients. (Phase II)
Secondary
- To determine the toxicity of this regimen in these patients. (Phase I)
- To determine progression-free survival of patients treated with this regimen. (Phase II)
- To further evaluate the safety profile of this regimen in these patients. (Phase II)
Tertiary
- To correlate tumor molecular characteristics and expression profile with outcome.
OUTLINE: This is a multicenter, phase I, dose-escalation study of vorinostat followed by a phase II study.
Patients undergo radiotherapy and receive oral vorinostat once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive oral temozolomide once daily on days 1-42. Beginning 4-6 weeks later, patients receive oral vorinostat once daily on days 1-7 and 15-21 and oral temozolomide once daily on days 1-5. Treatment with vorinostat and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I submit tumor tissue samples for correlative laboratory studies. Studies include assessment of histone acetylation status by immunohistochemistry; gene expression profiling; and assessment of MGMT methylation status by polymerase chain reaction.
After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 13 years.