Bevacizumab and Irinotecan or Temozolomide in Treating Patients With Recurrent or Refractory Glioblastoma Multiforme or Gliosarcoma

PRIMARY OBJECTIVES:

I. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of 6-month
progression-free survival rate, in patients with recurrent or refractory intracranial
glioblastoma multiforme or gliosarcoma.

II. Determine the adverse event profile and tolerability of bevacizumab and temozolomide in
these patients.

SECONDARY OBJECTIVES:

I. Determine the efficacy of bevacizumab and temozolomide, in terms of 6-month
progression-free survival rate, in patients previously treated with temozolomide.

II. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of objective
response, in patients with measurable disease.

III. Determine the efficacy of bevacizumab and temozolomide, in terms of objective response,
in patients with measurable disease who were previously treated with temozolomide.

IV. Determine the toxicity profile and tolerability of bevacizumab and irinotecan
hydrochloride in these patients.

TERTIARY OBJECTIVES:

I. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as
an early indicator of response to therapy after 2 weeks of treatment with bevacizumab.

II. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as
a prognostic indicator based on images taken at baseline, at 2 weeks, and after 2 courses of
study treatment.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (<
50 vs >= 50 years of age) and Karnofsky performance status (70-80% vs 90-100%). Patients are
randomized to 1 of 2 treatment arms with a 2:1 ratio (arm I:arm II).

ARM I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral
temozolomide once daily on days 1-21.

ARM II: Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV
over 90 minutes on days 1 and 15.

In both arms, treatment repeats every 28 days for up to 24 courses in the absence of disease
progression or unacceptable toxicity. All patients undergo MRI at baseline and at every 2
courses (no 2-week MRI) per standard of care until progression or discontinuation of
treatment to assess areas of breakdown of the blood-brain barrier. Patients undergo an
additional MRI after study therapy. Consenting patients also undergo diffusion and perfusion
MRI and magnetic resonance spectroscopic imaging for correlative studies.

After completion of study therapy, patients are followed up for at least 1 month.

Inclusion Criteria:

- Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma

- Original histology of low-grade glioma with subsequent histological diagnosis of
GBM or gliosarcoma allowed

- Recurrent or refractory disease, meeting all of the following criteria:

- Must have received prior temozolomide

- Pathologic or imaging confirmation of tumor progression or regrowth required

- Confirmation of true progressive disease (rather than radiation necrosis) by
positron emission tomography, thallium scanning, MRI spectroscopy, or
surgical documentation required for patients who received prior interstitial
brachytherapy, Gliadel wafer, or stereotactic radiosurgery

- Unequivocal radiographic evidence of tumor progression by MRI within the past 14 days
(while on a stable dose of steroids for ? 5 days)

- No acute intratumoral hemorrhage on MRI

- Patients with MRI demonstrating old hemorrhage or subacute blood after a
neurosurgical procedure (biopsy or resection) are eligible

- Karnofsky performance status 70-100%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for at least 6 months
after completion of bevacizumab therapy

- Systolic blood pressure ? 160 mm Hg or diastolic blood pressure ? 90 mm Hg
(antihypertensive medication allowed)

- Able to undergo brain MRI scans with intravenous gadolinium

- Absolute neutrophil count ? 1,500 cells/mm?

- Platelet count ? 100,000 cells/mm?

- Hemoglobin ? 10 g/dL (transfusion or other intervention allowed)

- WBC ? 3,000 cells/mm?

- AST < 2 times upper limit of normal

- Bilirubin ? 1.6 mg/dL

- Creatinine < 1.5 mg/dL

- Urine protein:creatinine ratio ? 0.5 by urinalysis OR total urinary protein < 1,000 mg
by 24-hour urine collection

- INR < 1.4 (for patients not on warfarin)

- No patients with severely impaired renal function (i.e., estimated glomerular
filtration rate < 30 mL/min or on dialysis)

- No other prior invasive malignancy, except nonmelanomatous skin cancer or carcinoma in
situ of the cervix, unless the patient has been disease free and off therapy for that
disease for ? 3 years

- No severe, active comorbidity, defined as any of the following:

- Transmural myocardial infarction or unstable angina within the past 6 months

- Evidence of recent myocardial infarction or ischemia manifested as ST elevation
of ? 2 mm by EKG performed within the past 14 days

- New York Heart Association class II-IV congestive heart failure requiring
hospitalization within the past 12 months

- History of stroke or transient ischemic attack within the past 6 months

- Cerebrovascular accident within the past 6 months

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g., aortic aneurysm or history of aortic
dissection)

- Clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Serious or nonhealing wound, ulcer, or bone fracture

- Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 28 days

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of study entry

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within the past 14 days

- Acquired immune deficiency syndrome (AIDS)

- No significant traumatic injury within the past 28 days

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract
disease resulting in an inability to take oral medication; requirement for IV
alimentation; prior surgical procedures affecting absorption; or active peptic ulcer
disease)

- No disease that would obscure toxicity or dangerously alter drug metabolism

- No concurrent major surgical procedures

- Recovered from prior therapy

- Recent resection of recurrent or progressive tumor allowed provided the following
criteria are met:

- Failed prior radiotherapy that was completed ? 42 days ago

- Residual disease after resection of recurrent glioblastoma is not mandated

- More than 28 days since prior surgery or open biopsy

- More than 7 days since prior core or needle biopsy

- At least 28 days since prior investigational agents

- At least 14 days since prior vincristine

- At least 42 days since prior nitrosoureas

- At least 21 days since prior procarbazine

- At least 28 days since other prior cytotoxic therapy

- At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen,
thalidomide, or isotretinoin [except radiosensitizers])

- At least 14 days since prior enzyme-inducing antiepileptic drugs (EIAEDs)

- Concurrent non-hepatic EIAEDs allowed

- No other concurrent CYP3A4 inducers, such as rifampin or Hypericum perforatum (St.
John's wort)

- Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin)
allowed provided all of the following criteria are met:

- No active bleeding or pathological condition that carries a high risk of bleeding
(e.g., tumor involving major vessels or known varices)

- In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulants or
on a stable dose of low molecular weight heparin

- No concurrent highly active antiretroviral therapy

- No concurrent prophylactic use of growth factors