Bevacizumab Plus Irinotecan Plus Carboplatin for Recurrent Malignant Glioma (MG)

Inclusion Criteria:

Cohorts A and B only

* No prior failure or grade ≥ 3 toxicity to bevacizumab, irinotecan or carboplatin.

Cohort C only

* Failure on prior bevacizumab therapy
* No prior failure or grade ≥ 3 toxicity to either irinotecan or carboplatin.

All Cohorts

* Age \* 18 years
* Karnofsky Performance Status (KPS) ≥ 70%
* No more than 3 prior episodes of disease progression
* An interval of at least 4 weeks between prior surgical resection or one week from stereotactic biopsy
* An interval of at least 12 weeks from the end of prior radiotherapy unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there are progressive changes on MRI on at least two consecutive MRI scans at least four weeks apart, or there is biopsy-proven tumor progression
* An interval of at least 4 weeks from prior chemotherapy (6 weeks for nitrosoureas) or investigational agent unless the patient has recovered from all anticipated toxicities associated with that therapy
* Hematocrit ≥ 29%, absolute neutrophil count (ANC) ≥ 1,000 cells/\*l, platelets ≥ 100,000 cells/\*l
* Serum creatinine ≤ 1.5 times upper limit of normal, serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times upper limit of normal and bilirubin ≤ 2.0 times upper limit of normal
* International Normalized Ratio (INR) \< 1.5 or prothrombin time/partial thromboplastin time (PT/PTT) within 1.5 time upper limit of normal (ULN).
* Signed informed consent approved by the Institutional Review Board prior to patient entry
* No evidence of hemorrhage on the baseline MRI or CT scan other than those that are stable grade 1
* If sexually active, patients will take contraceptive measures for the duration of the treatments. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, hysterectomy, vasectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD)

Exclusion Criteria:

Disease-Specific Exclusions

* Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
* Active infection requiring intravenous antibiotics
* Requires therapeutic anti-coagulation with warfarin

General Medical Exclusions

Subjects meeting any of the following criteria are ineligible for study entry:

* Inability to comply with study and/or follow-up procedures
* Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study
* Severe hepatic insufficiency (ongoing grade 3 or greater hepatic adverse events) or known active chronic hepatitis
* Homozygosity for the \*28 uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) allele.

Bevacizumab-Specific Exclusions

* Inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications)
* Any prior history of hypertensive crisis or hypertensive encephalopathy
* New York Heart Association (NYHA) Grade II or greater congestive heart failure
* History of myocardial infarction or unstable angina within 6 months prior to study enrollment
* History of stroke or transient ischemic attack within 6 months prior to study enrollment
* Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
* Symptomatic peripheral vascular disease
* Evidence of bleeding diathesis or coagulopathy
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
* Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
* Serious, non-healing wound, ulcer, or bone fracture
* Proteinuria at screening as demonstrated by either:
* Urine protein:creatinine (UPC) ratio ≥ 1.0 at screening OR
* Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible)
* Known hypersensitivity to any component of bevacizumab, Chinese hamster ovary cell products or other recombinant human or humanized antibodies."
* Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential