A Phase I Trial of Vorinostat in Combination With Bevacizumab & Irinotecan in Recurrent Glioblastoma

Inclusion Criteria: * Histologically proven intracranial glioblastoma or gliosarcoma with pathologic or radiographic confirmation of tumor progression or regrowth following standard front-line therapy. Patients will be eligible if original histology was low-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma was made. * History and physical examination, including neurologic examination and performance status, within 1 week prior to registration * Systolic blood pressure ≤ 160 mmHg and diastolic pressure ≤ 90 mmHg * Able to undergo brain magnetic resonance imaging (MRI) scans with intravenous gadolinium * Radiographic evidence for tumor progression by MRI within 14 days prior to registration * Karnofsky performance status ≥ 60 * Complete blood count (CBC)/differential obtained 14 days prior to registration, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500/microL; Platelets ≥ 100,000 cells/microL; Hemoglobin ≥ 10.0 gm/dL (use of transfusion or other intervention to achieve Hgb ≥ 10.0 is acceptable) * Adequate liver function within 14 days prior to registration, defined as follows: serum glutamic oxaloacetic transaminase (SGOT)\[aspartic transaminase (AST)\]/serum glutamic pyruvic transaminase (SGPT) \[alanine transaminase (ALT)\] \< 2.5 times the upper limit of normal; Bilirubin ≤ 1.6 mg/dL * Adequate renal function within 14 days prior to registration, defined as: Creatinine ≤ 1.5 mg/dL; Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio. For UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \<1000 mg. * If not on stable anticoagulation, prothrombin time (PT) must be within normal limits within 14 days prior to registration. * If on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria: No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices); In-range international normalized ratio (INR), usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin. * Have received prior concurrent and/or adjuvant temozolomide * Have recovered from toxic effects of prior therapy, and there must be a minimum time of 28 days from the administration of any prior cytotoxicity or investigational agent, except for nitrosureas (\>42 days) * Should not have been previously treated with any other histone deacetylase (HDAC) inhibitors (other than valproic acid for management of seizures). If they have been treated with valproic acid as treatment for seizures, the drug should be stopped at least 30 days before exposure to vorinostat. * Should not have been previously treated with bevacizumab and/or irinotecan * Should not have undergone more than 3 prior therapies * Patients having undergone recent resection of recurrent or progressive tumor must meet all of the following conditions: Patients must have recovered from the effects of surgery and a minimum of 28 days must have elapsed from the day of surgery to the day of registration; If a core or needle biopsy was performed, a minimum of 7 days must have elapsed prior to registration. * Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study. * Have failed prior radiation therapy and must have an interval of ≥ 42 days (6 weeks) from the completion of initial radiation therapy to registration * Must sign study-specific informed consent prior to registration * Women of childbearing potential (WOCBP) must have a negative β-HCG pregnancy test documented within 14 days prior to registration. * WOCBP must agree to use 2 forms of adequate contraceptive methods. These include (1) oral, injectable, or implantable hormonal contraceptive; (2) tubal ligation; (3) intra-uterine device; (4) barrier contraceptive with spermicide; or (5) vasectomized partner. Men must also protect their partner from becoming pregnant through use of condoms with spermicide or vasectomy. Patient must agree to have standard of care MRIs. Exclusion Criteria: * Prior invasive malignancy that is not the glioblastoma or gliosarcoma (except nonmelanomatous skin cancer or carcinoma in situ of the cervix) unless patient has been disease free and off therapy for that disease for at least 3 years * Acute intratumoral hemorrhage on MR imaging. Patients with MR imaging demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) will be eligible for treatment. * Must not have any significant medical illness that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy * Must not have any severe, active comorbidity, defined as: Transmural myocardial infarction or unstable angina within 6 months prior to study Registration; Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of ≥2 mm using the analysis of an electrocardiogram (EKG) performed within 14 days of registration; New York Heart Association (NYHA) grade II or greater or congestive heart failure requiring hospitalization within 12 months prior to registration; history of stroke or transient ischemic attack within 6 months; inadequately controlled hypertension despite antihypertensive medication; serious and inadequately controlled cardiac arrhythmia; significant vascular disease; clinically significant peripheral vascular disease; evidence of bleeding diathesis or coagulopathy; Patients on dialysis; Serious or non-healing wound, ulcer, or bone fracture; History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to registration; acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 14 days prior to registration; acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC); cannot be receiving highly active antiretroviral therapy (HAART); must not be diagnosed with hepatitis B or hepatitis C * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration * Anticipation of need for major surgical procedures during the course of the study * Core biopsy within 7 days prior to registration * Pregnant or nursing breastfeeding should be discontinued prior to enrollment * Fertile men and women who are sexually active and not willing/able to use medically acceptable forms of contraception during therapy and for at least 6 months after the completion of therapy * Known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies * Any condition that impairs ability to swallow pills * The clearance and metabolism of irinotecan is markedly enhanced in patients receiving drugs that induce the hepatic cytochrome p450 system. In brain tumor patients, these are typically certain types of anticonvulsants, termed enzyme-inducing anti-epileptic drugs (EIAEDs). Patients cannot be receiving EIAEDs or any CYP3A4 inhibitors; patients previously receiving these agents must have discontinued their use at least 2 weeks prior to registration.