RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

This is an interventional treatment trial for Adult Anaplastic Astrocytoma Read More

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