RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

Inclusion Criteria:

* Histologically confirmed malignant glioma (phase I)

  * Glioblastoma
  * Anaplastic astrocytoma
  * Anaplastic oligodendroglioma
  * Mixed anaplastic oligoastrocytoma
* Histologically confirmed glioblastoma following radiotherapy and temozolomide (phase II)
* Progressive or recurrent disease after conformal external-beam radiation therapy and concurrent temozolomide, followed by ≥ 1 adjuvant course of temozolomide
* Measurable disease by MRI within the past 2 weeks
* Tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of malignant glioma completed and signed by a pathologist
* Karnofsky performance status 60-100%
* ANC ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 9 g/dL
* Total bilirubin normal
* AST and ALT ≤ 2.5 times upper limit of normal
* Creatinine normal OR creatinine clearance ≥ 60 mL/min

  * Urine protein: If proteinuria ≥ +2 protein, a protein level should be \< 1,000 mg by a 24-hour urine collection
* Electrolytes (calcium, chloride, magnesium, potassium, phosphorus, sodium) within institutional normal limits
* Fertile patients must use 2 forms of effective contraception before, during, and for ≥ 12 months (6 months phase II, bevacizumab arm only) after treatment
* Negative pregnancy test
* Not pregnant or nursing
* At least 5 years since prior malignancy except nonmelanoma skin cancer, or carcinoma in situ of the cervix, breast, or bladder
* Mini Mental State Exam score of ≥ 15
* Must be able to tolerate MRI

Exclusion Criteria:

* No serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive the treatment outline in this protocol with reasonable safety
* No history of allergic reactions attributed to compounds of similar chemical or biological composition to gamma-secretase inhibitor RO4929097 or bevacizumab
* Must be able to swallow capsules
* No malabsorption syndrome or other condition that would interfere with intestinal absorption
* No baseline QTcF \> 450 msec (male) or QTcF \> 470 msec (female)
* Not history of being serologically positive for hepatitis A, B, or C
* No history of cirrhosis
* No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia despite adequate electrolyte supplementation
* No uncontrolled intercurrent illness including, but not limited to, any of the following:

  * Ongoing or active infection
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * A history of torsades de pointes or other significant cardiac arrhythmias other than chronic, stable atrial fibrillation
  * Psychiatric illness and/or social situations that would limit compliance with study requirements
* No serious or non-healing wound, ulcer, or bone fracture
* No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
* No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within the past 6 months
* No clinically significant cardiovascular disease, including any of the following:

  * Inadequately controlled hypertension (systolic BP \> 160 mm Hg and/or diastolic BP \> 90 mm Hg) despite antihypertensive medication
  * History of cerebrovascular accident or transient ischemic attack at any time
  * Myocardial infarction or unstable angina within the past 12 months
  * NYHA grade II-IV congestive heart failure
  * Serious and inadequately controlled cardiac arrhythmia
  * Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)
  * Clinically significant peripheral vascular disease
* No evidence of bleeding diathesis or coagulopathy
* No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
* No requirement for antiarrhythmics or other medications known to prolong QTc
* One or 2 prior treatment regimens allowed
* Recovered from severe toxicity of prior therapy
* At least 3 months since prior radiotherapy
* At least 6 weeks since prior nitrosourea
* At least 3 weeks since prior chemotherapy
* At least 4 weeks since prior and no other concurrent investigational agents
* At least 2 weeks since prior non-cytotoxic, FDA-approved agent (e.g., Tarceva \[erlotinib hydrochloride\], hydroxychloroquine, bevacizumab, etc.)
* At least 28 days since any prior surgery
* No prior γ-secretase inhibitors and/or bevacizumab
* At least 10 days since prior and no concurrent enzyme-inducing anti-epileptic drug
* No concurrent combination antiretroviral therapy for HIV-positive patients