Phase II Trial of Suberoylanilide Hydroxamic Acid (SAHA) in Patients With Recurrent Glioblastoma
Phase II Trial of Suberoylanilide Hydroxamic Acid (SAHA) in Patients With Recurrent Glioblastoma
This phase II trial is studying how well vorinostat works in treating patients with progressive or recurrent glioblastoma multiforme. Drugs used in chemotherapy, such as vorinostat, 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. Giving vorinostat before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving it after surgery may kill any remaining tumor cells.
PRIMARY OBJECTIVES:
I. Determine the efficacy of vorinostat (SAHA), in terms of 6-month progression-free survival, in patients with progressive or recurrent glioblastoma multiforme.
II. Determine the safety and toxicity of this drug in these patients.
SECONDARY OBJECTIVES:
I. Determine the pharmacokinetics of this drug in these patients. II. Determine the biologic effect of this drug in target tissues, including primary tumor tissue, in these patients.
III. Correlate genetic alteration of tumors with response in patients treated with this drug.
OUTLINE: This is an open-label, multicenter study. Patients are stratified according to planned surgery (yes [stratum 1] vs no [stratum 2]) and number of prior chemotherapy regimens for progressive/recurrent disease (≤ 1 [stratum 1A] vs ≥ 2 [stratum 1B]).
STRATUM 1: Patients receive oral vorinostat (SAHA) twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. (not undergoing surgery)
STRATUM 2: Beginning 3 days prior to surgery, patients receive oral SAHA once or twice daily for a total of 6 doses. Patients then undergo surgery to remove the tumor. Beginning within 1-4 weeks after surgery, patients receive oral SAHA twice daily for 2 weeks. (undergoing surgery)
Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed periodically for up to 5 years.
Inclusion Criteria:
Histologically confirmed grade 4 astrocytoma (glioblastoma multiforme), including gliosarcoma, at primary diagnosis or recurrence
Measurable or evaluable disease by MRI or CT scan
Performance status - ECOG 0-2
WBC ≥ 3,000/mm^3
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 8 g/dL
AST ≤ 3 times upper limit of normal (ULN)
Bilirubin normal
Creatinine ≤ 1.5 times ULN
No myocardial infarction within the past 6 months
No congestive heart failure
No life-threatening ventricular arrhythmia requiring ongoing maintenance therapy
No known HIV positivity
Not immunocompromised except if related to the use of corticosteroids
No known hypersensitivity to any of the components of the study drug
No uncontrolled infection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 6 months after completion of study treatment
No other malignancy
No other severe disease that would preclude study participation
Prior adjuvant chemotherapy allowed
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)
More than 2 weeks since prior small molecule cell cycle inhibitor
Concurrent corticosteroids allowed as long as dose has been stable for ≥ 1 week
At least 8 weeks since prior radiotherapy
More than 6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy, unless 1 of the following criteria is met:
More than 2 weeks since prior valproic acid