Ph II SAHA and Bevacizumab for Recurrent Malignant Glioma Patients
Condition: Recurrent Glioblastoma Multiforme; Malignant Glioma; Adult Brain Tumor
MeSH terms: Glioblastoma; Glioma; Brain Neoplasms; Recurrence
Intervention: Vorinostat; Bevacizumab
Intervention MeSH terms: Bevacizumab; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: vorinostat; SAHA; bevacizumab; AVASTIN; malignant glioma; GBM; glioblastoma multiforme; 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.
    

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