ph ii saha and bevacizumab for recurrent malignant glioma patients

Conditions: Recurrent Glioblastoma Multiforme; Malignant Glioma; Adult Brain Tumor

Summary: it has been shown that bevacizumab has significant anti-tumor activity in patients with recurrent glioblastoma multiforme. vorinostat has modest anti-tumor activity against malignant glioma and can enhance the action of both chemotherapy and anti-angiogenics. patients will be treated with a combination of bevacizumab and vorinostat.

there is no effective therapy for patients with recurrent glioblastoma multiforme (gbm) hence such patients remain a major unmet need in oncology. the investigators have recently demonstrated that bevacizumab (bv), a humanized monoclonal antibody against vascular endothelial growth factor, has significant anti-tumor activity among recurrent glioblastoma multiforme patients. vorinostat has modest anti-tumor activity against malignant glioma and can potentiate the action of both chemotherapy and anti-angiogenics. the current study is designed to evaluate the anti-tumor activity of vorinostat when combined with bv among recurrent glioblastoma multiforme patients.

Eligibility criteria:
inclusion criteria: * age \> 18 years. * an interval of at least 4 weeks between prior surgical resection or one week from stereotactic biopsy. * an interval of at least 12 weeks from the end of prior radiotherapy unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there is biopsy-proven tumor progression * an interval of at least 4 weeks from prior chemotherapy \[6 weeks for nitrosoureas, 1 week for daily administered chemotherapy (metronomic dosing)\] or investigational agent unless the patient has recovered from all anticipated toxicities associated with that therapy. * eastern cooperative oncology group (ecog) 0-1. * hematocrit ≥ 29%, hemoglobin ≥ 9, absolute neutrophil ≥1,500 cells/microliter, platelets ≥ 100,000 cells/microliters. * serum creatinine, serum glutamic oxaloacetic transaminase(sgot) and bilirubin \< 1.5 times upper limit of normal. * signed informed consent approved by the institutional review board prior to patient entry. * no evidence of hemorrhage on the baseline mri or ct scan other than those that are stable grade 1. * if sexually active, patients will take contraceptive measures for the duration of the treatments. medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, hysterectomy, vasectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (iud). exclusion criteria: disease-specific exclusions * more than 2 prior episodes of disease progression * prior therapy with histone deacetylase inhibitors; valproic acid is not permitted and patients previously treated with valproic acid must be off valproic acid for at least 30 days prior to initiation of study medication * prior bevacizumab therapy * co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids * active infection requiring intravenous antibiotics * severe hepatic insufficiency, active viral hepatitis or hiv infection * requires therapeutic anti-coagulation with warfarin general medical exclusions subjects meeting the following criteria are ineligible for study entry: * inability to comply with study and/or follow-up procedures bevacizumab-specific exclusions * inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 100 mmhg on antihypertensive medications) * any prior history of hypertensive crisis or hypertensive encephalopathy * new york heart association (nyha) grade ii or greater congestive heart failure (see appendix e) * history of myocardial infarction or unstable angina within 6 months prior to study enrollment * history of stroke or transient ischemic attack within 6 months prior to study enrollment * significant vascular disease (e.g., aortic aneurysm, aortic dissection) * symptomatic peripheral vascular disease * evidence of bleeding diathesis or coagulopathy * major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study * core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment * history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment * serious, non-healing wound, ulcer, or bone fracture * proteinuria at screening as demonstrated by either: * urine protein:creatinine (upc) ratio \>= 1.0 at screening or * urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). * known hypersensitivity to any component of bevacizumab * pregnant (positive pregnancy test) or lactating. refuse the use of effective means of contraception (men and women) in subjects of child-bearing potential

Keywords: vorinostat saha bevacizumab avastin malignant glioma gbm glioblastoma multiforme brain tumor