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

Condition(s) targeted: Malignant Glioma; Glioblastoma Multiforme; Gliosarcoma

Intervention: Taking EIAEDs (enzyme-inducing anticonvulsant medications) (Other); NOT taking EIAEDs (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
James J Vredenburgh, MD, Principal Investigator, Affiliation: Duke University

Overall contact:
James J Vredenburgh, MD, Phone: 919-681-3824, Email: vrede001@mc.duke.edu

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.

Official title: Phase II Trial for Patients With Glioblastoma Multiforme (GBM) Treated With Gliadel Followed by Avastin Plus Irinotecan

Study design: Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Safety/Efficacy Study

Primary outcome: 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.

Secondary outcome:

To determine the progression-free survival following the combination of Gliadel followed by Avastin and irinotecan

To describe the toxicity of Gliadel followed by Avastin and irinotecan.

Detailed 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 GTR (gross total resection).

Phase 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 CPT-11.

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

- Irinotecan 125 mg/m2 (not taking EIAEDs) or 340 mg/m2 (taking EIAEDs) given every two

weeks on days 1, 15, 29, etc.;

- If the patient has the UGT 1A1 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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 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, ANC > or = 1,500 cells/microliters, platelets > or =

125,000 cells/microliters

- Serum creatinine < or = 1. 5 mg/dl, serum 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 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

James J Vredenburgh, MD, Phone: 919-681-3824, Email: vrede001@mc.duke.edu

Duke University Medical Center, Durham, North Carolina 27710, United States; Recruiting
James J Vredenburgh, MD, Phone: 919-681-3824, Email: vrede001@mc.duke.edu
Sarah Woodring, BS, Phone: 919-684-2527, Email: sarah.woodring@duke.edu
James J Vredenburgh, MD, Principal Investigator
Mary Lou Affronti, RN, MSN, ANP, Sub-Investigator

Duke University Medical Center Clinical Trials

The Preston Robert Tisch Brain Tumor Center

Starting date: December 2008
Ending date: December 2011
Last updated: August 4, 2009