Company decided to stop development of drug - 7/31/12

This phase I/II trial is studying the side effects and the best dose of RO4929097 to see how well it works when given together with bevacizumab compared to bevacizumab alone in treating patients with progressive or recurrent malignant glioma. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving RO4929097 together with bevacizumab may kill more tumor cells.

Phase I

Primary Objective:

1. To assess the safety profile of R04929097 in combination with bevacizumab and to determine a recommended Phase II dose of R04929097 in combination with bevacizumab in patients with recurrent malignant glioma

   Secondary Objectives:

2. To describe the toxicity associated with this combination regimen

3. To assess pharmacokinetics of R04929097 in combination with bevacizumab

Phase II I. Assess the safety profile and the recommended phase II dose of gamma-secretase inhibitor RO4929097 (RO4929097) in combination with bevacizumab in patients with recurrent malignant glioma.

II. Assess the progression-free survival at 6 months of patients treated with this regimen.

III. Compare the overall survival of patients with recurrent glioblastoma treated with RO4929097 and bevacizumab versus bevacizumab alone.

SECONDARY OBJECTIVES:

I. Describe the toxicity associated with this regimen in these patients. II. Assess the pharmacokinetics of this regimen in these patients. III. Estimate the proportion of patients alive and progression-free survival at 6 months in patients treated with RO4929097 and bevacizumab versus bevacizumab alone.

IV. Evaluate the safety and tolerability of these regimens in these patients. V. Explore potential prognostic biomarkers from glioma tissue at baseline and potential association with Notch pathway inhibition.

OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor RO4929097 (RO4929097) followed by a randomized phase II study.

PHASE I: Patients receive oral RO4929097 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15 (days 2 or 3 and 15 of course 1 only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized* to 1 of 2 treatment arms.

ARM I: Patients receive oral RO4929097 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15.

ARM II: Patients receive bevacizumab as in arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *If phase II single-arm study demonstrates effectiveness, it will proceed to the phase II randomized study.

Some patients undergo blood sample collection for pharmacokinetic studies. Archived tumor tissue samples are analyzed for potential biomarkers and Notch pathway inhibition.

After completion of study therapy, patients are followed up every 2 months.

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