Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Adult Giant Cell Glioblastoma
Radiation: 3-dimensional conformal radiation therapy
Procedure: cognitive assessment
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma|
- Maximum Tolerated Dose of Vorinostat, Defined as the Dose at Which Fewer Than One-third of Patients Experience DLTs, Graded According to NCI CTCAE (Common Toxicity Criteria for Adverse Effects) Version 3.0 (Phase I) [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
The Maximum Tolerated Dose (MTD) will be based on the assessment of Dose Limiting Toxicity (DLT) during the first 10 weeks of treatment only, and will be defined as the dose at which fewer than one-third of patients experience a DLT to vorinostat. The MTD is the dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT.
DLT will be defined as any of the following events occurring during treatment with vorinostat and temozolomide and attributable to one or both study drugs:
- Grade 3 or 4 thrombocytopenia, grade 4 anemia or grade 4 neutropenia lasting > 7 days
- Any non-hematologic grade 3 or greater adverse event, excluding alopecia and venous thromboembolism
- Grade 4 radiation-induced skin changes
- Failure to recover from toxicities to be eligible for re-treatment with vorinostat and temozolomide ≤ 14 days of the last dose of the two drugs
- Overall Survival at 15 Months (Phase II) [ Time Frame: Time from study registration to the date of death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]The primary endpoint will be survival status at 15 months (OS15). In addition, survival will be estimated using a Kaplan-Meier curve. For this analysis, patients who are still alive at the time of analysis have survival time censored at the last contact date.
- Incidence of Adverse Events, Based on CTC (Common Toxicity Criteria) Severity Grade [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]Safety variables will be summarized by descriptive statistics. Adverse Events (AEs) that occur will be reported for each phase and dose level and described in terms of incidence and severity. Parameters will be described based on the CTC severity grading. Distribution by CTC severity grade and clinical relevance will be given.
- Time to Tumor Progression (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Progression free survival time will be defined from date of registration to date of progression or death.
- Incidence of Adverse Events, as Per NCI CTCAE Version 3.0 (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing.
|Study Start Date:||July 2009|
|Primary Completion Date:||February 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (radiation therapy, vorinostat, temozolomide)
Patients undergo radiotherapy and receive vorinostat PO QD on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD 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.
Radiation: 3-dimensional conformal radiation therapy
Other Names:Drug: temozolomide
Other Names:Drug: vorinostat
Other Names:Procedure: cognitive assessment
Ancillary studiesOther: laboratory biomarker analysis
I. To determine the maximum tolerated dose (MTD) of vorinostat in patients with newly diagnosed glioblastoma multiforme (GBM) and gliosarcomas, who are also receiving concomitant radiation therapy (RT) and temozolomide (TMZ). (Phase I) II. To define the safety of vorinostat with RT and TMZ in this population. (Phase II) III. To determine the efficacy of vorinostat in combination with RT and TMZ followed by vorinostat in combination with TMZ in patients with newly-diagnosed GBM and gliosarcomas as measured by overall survival at 15 months (OS15). (Phase II)
I. To determine progression-free survival in newly diagnosed GBM and gliosarcoma patients treated with the study regimen. (Phase II) II. To further evaluate the safety profile of vorinostat in combination with RT and TMZ in this patient population. (Phase II) III. Determine the neurocognitive effects in patients treated on this protocol and correlate these results with outcome endpoints. (Phase II)
I. To explore the extent to which the tumor's molecular characteristics and expression profile correlate with outcome.
II. Evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression.
OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.
Patients undergo radiotherapy and receive vorinostat orally (PO) once daily (QD) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD 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.
After completion of study treatment, patients are followed up every 2 months for 1 year, every 3 months for 1 year and then every 6 months for 3 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00731731
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|Principal Investigator:||Evanthia Galanis||Alliance for Clinical Trials in Oncology|