Vorinostat in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Trial of Suberoylanilide Hydroxamic Acid (SAHA) in Patients With Recurrent Glioblastoma

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: vorinostat
* Procedure: conventional surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed grade 4 astrocytoma (glioblastoma multiforme), including gliosarcoma, at primary diagnosis or recurrence Progressive or recurrent disease 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 Must have evidence of tumor progression by MRI or CT scan after radiotherapy More than 6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy, unless 1 of the following criteria is met: There is a separate lesion by MRI outside of the prior treatment field There is evidence of recurrent disease by biopsy, MRI spectroscopy, or positron-emission tomography scan More than 2 weeks since prior valproic acid

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum 1 (not undergoing surgery)<br>Patients receive oral vorinostat (SAHA) twice daily for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Procedure: conventional surgery<br>* Patients undergo surgery to remove tumor<br>* Other names: surgery, conventional;|
| Experimental: Stratum 2 (undergoing surgery)<br>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. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Procedure: conventional surgery<br>* Patients undergo surgery to remove tumor<br>* Other names: surgery, conventional;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Successes (Patients Alive and Progression-free) | Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients) and the Binomial 95% confidence interval estimated by the exact method. Definition of progression: Bidimensionally measurable disease: >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Estimated using Kaplan-Meier survival curve. | From study registration to date of death due to any cause or last follow-up (up to 5 years) | 
| Confirmed Tumor Response | A confirmed tumor response will be defined as an objective status of complete response (CR), partial response (PR), or regression (REGR) on two consecutive evaluations, which include neuroimaging, lasting during a period of at least 6 weeks. Confidence intervals for the true proportion will be calculated using the exact binomial method. Bidimensionally measurable disease:≥50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. Patient should be on stable or decreased steroid dose. | Assessed up to 5 years | 
| Time to Progression | Estimated using Kaplan-Meier survival curve. Definition of progression: Bidimensionally measurable disease: >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. Evaluable disease (i.e., contrast enhancing mass on MRI and/or CT that is not bidimensionally measurable but clearly evaluable for response to therapy): unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions. | From registration to disease progression (up to 5 years) |