Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
This phase I/II trial studies the side effects and best dose of vorinostat when given together with temozolomide and radiation therapy and to see how well they work in treating patients with newly diagnosed glioblastoma multiforme. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with temozolomide and radiation therapy may kill more tumor cells.
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 version 3.0 (Phase I) [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
- Overall survival (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 ]Survival will be estimated using a Kaplan-Meier curve.
- Incidence of adverse events, based on CTC severity grade (Phase I) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]Safety variables will be summarized by descriptive statistics. AEs that occur will be reported for each 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 ]
- 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.
- Molecular characteristics of the tumor [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Correlated with expression profile of response, survival, and safety. For each test in the group of tests, a standard error of measurement will be used to derive the Reliable Change Index (RCI) which will be used to represent the 90% confidence interval for the difference in raw scores from baseline to follow-up assessment will be coded as 1 (deterioration), 2 (no change), and 3 (improved) according to the RCI. Percentage of patients in each treatment arm who show meaningful losses or gains in the various tests or test domains over the course of the study will be provided by frequency tables.
- Time to neurocognitive progression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Will be estimated by Kaplan-Meier method and analyzed by Cox regression model adjusting all stratification factors.
- Baseline neurocognitive test scores [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Baseline neurocognitive test scores will be correlated with overall survival. Will be analyzed using Cox proportional hazards model. Changes in cognitive function scores in each domain (memory, executive function and visual motor) among visits will be explored graphically and by repeated measurement models.
|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.