This phase I trial is studying the side effects and best dose of vorinostat when given together with temozolomide in treating patients with malignant gliomas. Drugs used in chemotherapy, such as vorinostat and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may help temozolomide work better by making tumor cells more sensitive to the drug. Giving vorinostat together with temozolomide may kill more tumor cells.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of vorinostat (suberoylanilide hydroxamic acid \[SAHA\]) in combination with temozolomide in patients with malignant gliomas. II. To characterize the safety profile of vorinostat (SAHA) in combination with temozolomide. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics of vorinostat (SAHA) in combination with temozolomide. II. To determine efficacy of vorinostat (SAHA) in combination with temozolomide as measured by objective response. TERTIARY OBJECTIVES: I. To explore the association of response to treatment to the molecular phenotype of the tumor. II. To assess the effects of vorinostat (SAHA) on histone acetylation status in peripheral mononuclear cells. OUTLINE: This is a 2-part, dose-escalation study of vorinostat. PART I: Patients receive vorinostat orally (PO) once (QD) or twice daily (BID) on days 1-7 and 15-21 OR QD or BID on days 1-7. Patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Beginning in course 2, some patients may receive a higher dose of temozolomide. Treatment may continue beyond 13 courses at the discretion of the investigator. PART II: Patients receive vorinostat and temozolomide as in part 1\*. \[Note: \*Beginning in course 2, all patients receive a higher dose of temozolomide.\] After completion of study treatment, patients are followed up periodically.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
83
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
UCSF Medical Center-Mount Zion
San Francisco, California, United States
Moffitt Cancer Center
Tampa, Florida, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
National Cancer Institute Neuro-Oncology Branch
Bethesda, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Henry Ford Hospital
Detroit, Michigan, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
...and 7 more locations
MTD of vorinostat with temozolomide defined as the dose at which less than one-third of patients experience dose-limiting toxicity based on the CTC severity grading (Part I)
For both parts of the study, treatment administration will be described for all cycles. Doses administered, dose modifications/delays, and duration of therapy will be evaluated. Safety variables summarized by descriptive statistics. Adverse events that occur will be reported for each dose level and described in terms of incidence and severity. Laboratory data will be presented by dose level at each observation time. Values outside of normal limits will be identified and their frequency calculated. Distribution by CTC severity grade (when applicable) and clinical relevance will be given.
Time frame: 28 days
Efficacy in terms of anti-tumor activity based on clinical, radiographic, and biologic assessments (Part II)
A descriptive analysis of evidence of anti-tumor activity will be provided based on clinical, radiographic, and biologic assessments of efficacy.
Time frame: Up to 4 years
Plasma pharmacokinetic parameters of vorinostat
Presented in tabular and graphic form. Pharmacokinetic parameters of interest such as maximal plasma concentration (Cmax), time of maximal concentration (Tmax), area under the plasma concentration-time curve (AUCo-t and AUC-infinity), clearance (CL), apparent volume of distribution at steady state (Vdss), terminal half-life (t1/2), and tumor to plasma (whole blood) concentration ratio will be determined using non-compartmental methods. Dose proportionality in pharmacokinetic parameters will be determined by performing a one-way analysis of variance (ANOVA) on dose-normalized parameters.
Time frame: Baseline, 1, 2, 3, 4, 6, 8, and 24 hours post-dose day 1 of course 1
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