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

Phase 2
18 Years
Not Enrolling
Malignant Glioma, Glioblastoma Multiforme, Gliosarcoma

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Trial Information

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

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

- 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.

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

24-week Overall Survival

Outcome Description:

The percentage of participants surviving 24 weeks from the start of study treatment

Outcome Time Frame:

24 weeks

Safety Issue:


Principal Investigator

Annick Desjardins, MD, FRCPC

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Institutional Review Board

Study ID:




Start Date:

December 2008

Completion Date:

October 2012

Related Keywords:

  • Malignant Glioma
  • Glioblastoma Multiforme
  • Gliosarcoma
  • Malignant glioma
  • Glioblastoma multiforme
  • GBM
  • Gliosarcoma
  • Gliadel
  • Carmustine
  • Irinotecan
  • CPT-11
  • Camptosar
  • Avastin
  • Bevacizumab
  • Glioblastoma
  • Glioma
  • Gliosarcoma



Duke University Medical CenterDurham, North Carolina  27710