A Study of Gliadel Followed by Avastin + Irinotecan for Glioblastoma Multiforme (GBM)

Duke University

Status and phase

Terminated

Phase 2

Conditions

Glioblastoma Multiforme

Gliosarcoma

Malignant Glioma

Treatments

Drug: Gliadel/Avastin/CPT-11

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00735436

Pro00006308

Details and patient eligibility

About

The primary objective of the study is to use 24 week survival to assess the efficacy of the combination of Gliadel followed by Avastin and irinotecan in the treatment of grade IV malignant glioma patients following surgical resection. The secondary objectives are to determine the progression-free survival following the combination of Gliadel followed by Avastin and irinotecan and to describe the toxicity of Gliadel followed by Avastin and irinotecan.

Full description

This is a phase II study of the combination of Gliadel followed by Avastin and irinotecan in grade IV malignant glioma patients. The study will have survival and toxicity endpoints. Subjects will be identified by the investigator as those patients who have histologically documented grade IV malignant glioma (glioblastoma multiforme or gliosarcoma) with recurrent or progressive disease who are able to undergo a gross total resection (GTR).

Part I: Gliadel wafer- 1-8 wafers inserted at time of gross total resection. Treatment cycle is 42 days in length. For patients with ≥ Grade 1 toxicity will allow 84 days prior to beginning therapy with Avastin and Irinotecan (CPT-11).

Part II: Avastin Plus Irinotecan (Cycles 1-12) consists of the following (cycle length is 6 weeks):

Irinotecan 125 mg/m2 (not taking enzyme-inducing anti-epileptic drugs (EIAEDs)) or 340 mg/m2 (taking EIAEDs) given every two weeks on days 1, 15, 29, etc.;
If the patient has the uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphism (7/7), they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction; For patients on an EIAED, the starting dose will be 275 mg/M2, and for patients not on an EIAED, the starting dose will be 75 mg/M2;
Avastin 10 mg/kg immediately after the irinotecan given every 2 weeks on days 1, 15, 29, etc.

The primary objective of this phase II study is to determine whether the administration of Gliadel wafers followed by Avastin and irinotecan to patients with recurrent GBM is a treatment regimen worthy of further investigation in a randomized clinical trial. The basis for making this decision will be the proportion of patients who survive at least 24 weeks after initiation of protocol treatment.

In the initial Phase I and II clinical trials, four potential Avastin-associated safety signals were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. The two major toxicities associated with irinotecan are myelosuppression and diarrhea. Side effects associated with Gliadel are seizures, brain edema (swelling), healing abnormalities, wound infection and body pain.

Enrollment

18 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be able to undergo a GTR.
Age > or = 18 years
Evidence of a unilateral, single focus of measurable central nervous system (CNS) neoplasm on contrast-enhanced MRI, unless medically contraindicated (CT scan will then be used)
Patients must have < or = 2 disease progressions
An interval of at least 4 weeks from the end of prior radiotherapy or one week from the end of a cycle of chemotherapy and enrollment on this protocol
Karnofsky > or = 70%
Hemoglobin > or = 9.0 g/dl, absolute neutrophil count (ANC) > or = 1,500 cells/microliters, platelets > or = 125,000 cells/microliters
Serum creatinine < or = 1.5 mg/dl, serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin < or = 1.5 times upper limit of normal
Patients on corticosteroids must have been on a stable dose for 1 week prior to entry, if clinically possible, and the dose should not be escalated over entry dose level
If patient received chemotherapy or investigational agent as part of their prior therapy, the patient must recover from all toxicities (> or = Grade 1) prior to enrollment on this protocol
Signed informed consent approved by the Institutional Review Board
No evidence of CNS hemorrhage on the baseline MRI or CT scans
If sexually active, patients will take contraceptive measures for the duration of treatment as stated in the informed consent

Exclusion criteria

Pregnancy or breast feeding. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to treatment administration
Multifocal disease
Prior treatment with Gliadel
Prior treatment with CPT-11 or Avastin
Prior stereotactic radiosurgery or brachytherapy
Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
Active infection requiring IV antibiotics
Acute or chronic renal insufficiency (a glomerular filtration rate (GFR) <30 mL/min/1.73m2) or acute renal insufficiency of any severity due to hepato-renal syndrome or in the peri-operative liver transplantation period
Inability, in the opinion of the study investigator, 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 Avastin cancer study
Life expectancy of less than 12 weeks
Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last five years
Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg)
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 Day 1
History of stroke or transient ischemic attack within 6 months prior to Day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
History of hemoptysis (> or = 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 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 Day 1
History of abdominal fistula, gastrointestinal perforation within 6 months prior to Day 1
Serious, non-healing wound, active ulcer, or untreated bone fracture
Proteinuria at screening as demonstrated by urinalysis (urine protein)
Known hypersensitivity to any component of Avastin
Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential