RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

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