Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

Clinical trial: Ph II SAHA and Bevacizumab for Recurrent Malignant Glioma Patients

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.

Detailed description: 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: 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

Relevance to patient case: not relevant