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

Phase II Study of Bevacizumab Plus Irinotecan and Carboplatin for Recurrent Malignant Glioma Patients

The purpose of this study is to determine whether Bevacizumab, CPT-11 and Carboplatin in combination are effective in the treatment of recurrent malignant glioma.

Three cohorts will accrue and will be assessed independently. Each cohort will evaluate a separate malignant glioma subpopulation. Cohort A will assess recurrent glioblastoma multiforme (GBM) subjects who have not previously failed either bevacizumab, irinotecan or carboplatin. Cohort B will assess recurrent grade 3 malignant glioma subjects who have not previously failed either bevacizumab, irinotecan or carboplatin. Cohort C will assess recurrent GBM subjects who have failed prior bevacizumab therapy but who have not failed prior irinotecan or carboplatin. The primary endpoint of each cohort will be 6-month progression-free survival. This study will be conducted at The Preston Robert Tisch Brain Tumor Center at Duke.

For each cohort, bevacizumab will be administered at 10 mg/kg with irinotecan every other week. The dose of irinotecan will be 125 mg/m2 for subjects not on Cytochrome P450, family 3, subfamily A (CYP3A)-inducing anti-epileptics (EIAEDs) and 340 mg/m2 for subjects on EIAEDs. All subjects will also receive carboplatin on day 1 of each 28-day treatment cycle. Carboplatin will be dosed to achieve an area under the curve (AUC) of 4.

Within 2 weeks of starting the study, subject's medical history and current medical conditions will be recorded. A physical examination including vital signs (temperature, respiratory rate, blood pressure, and pulse), height and weight, and neurological examination will be done. Subject will be asked about his or her ability to perform everyday tasks. Blood tests for assessment of a complete blood count including monitoring liver and kidney function and a urine test to check kidney function will be performed. For women of childbearing potential, a blood test to rule out pregnancy will be done prior to the start of treatment. Blood tests will also check for a specific gene, which may affect how much irinotecan subject is given. A magnetic resonance imaging (MRI) of will be performed within 2 weeks before starting study drugs as well as after every eight weeks to determine response and progression.

In total, approximately 3 teaspoons (15 mL) of blood will be drawn for the evaluations before starting study drug. These tests will be repeated every 8 weeks (blood chemistries), except a complete blood count (approximately 1 teaspoon), which will need to be repeated every week as well as when it is deemed clinically necessary to repeat. Every 4 weeks a urine test will be performed to test the amount of protein in subject's urine.

Placement of a central venous line may be required. Subjects will be seen in the clinic for a physical and neurological examination every four (4) weeks. Urine and blood laboratory tests will also be obtained at these visits. In addition, a complete blood count (about 1 teaspoon) will be obtained every week. Blood pressure measurement will be required every 2 weeks. MRI (Magnetic Resonance Imaging) scans will be done every 8 weeks (after every 2 cycles) to determine the effectiveness of the study drugs. If the tumor remains the same size or smaller, subject will continue to receive study drugs for 12 cycles unless there are bad side effects or unless there is evidence that the drug is not working. If evaluations show that there may be persistent tumor after 12 cycles, subject may continue treatment. Study drugs will stop if the subject's tumor gets larger.

Additional tests may be done at the discretion of the doctor as part of regular care throughout the study. These exams and tests will be done to monitor the effects of the study interventions.

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