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

Inclusion Criteria

• •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.