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

This study has been terminated.
(Study enrollment was halted due to slow accrual.)
Sponsor:
Collaborators:
Eisai Inc.
Genentech
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00735436
First received: August 13, 2008
Last updated: February 4, 2013
Last verified: December 2012
  Purpose

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.


Condition Intervention Phase
Malignant Glioma
Glioblastoma Multiforme
Gliosarcoma
Drug: Gliadel/Avastin/CPT-11
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial for Patients With Glioblastoma Multiforme (GBM) Treated With Gliadel Followed by Avastin Plus Irinotecan

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • 24-week Overall Survival [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The percentage of participants surviving 24 weeks from the start of study treatment


Secondary Outcome Measures:
  • 24-week Progression-free Survival (PFS) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The percentage of participants surviving 24 weeks from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to modified Macdonald criteria, or to death due to any cause.

  • Median Progression-free Survival (PFS) [ Time Frame: Time in months from the start of study treatment to the date of first progression according to modified Macdonald criteria or to death due to any cause, assessed up to 47 months ] [ Designated as safety issue: No ]
    Time in months from the start of study treatment to the date of first progression according to modified Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

  • Median Overall Survival (OS) [ Time Frame: Time in months from the start of study treatment to date of death due to any cause, assessed up to 47 months ] [ Designated as safety issue: No ]
    Time in months from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.

  • Incidence and Severity of Central Nervous System (CNS) Hemorrhage [ Time Frame: 47 months ] [ Designated as safety issue: Yes ]
    Incidence and severity of CNS hemorrhage

  • Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities [ Time Frame: 47 months ] [ Designated as safety issue: Yes ]
    Incidence of grade ≥ 4 hematologic and ≥ grade 3 non-hematologic toxicities


Enrollment: 18
Study Start Date: December 2008
Study Completion Date: October 2012
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Gliadel/Avastin/CPT-11
Gliadel/Avastin/CPT-11
Drug: Gliadel/Avastin/CPT-11
Other Names:
  • bevacizumab
  • 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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00735436

Locations
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Eisai Inc.
Genentech
Investigators
Principal Investigator: Annick Desjardins, MD, FRCPC Duke University
  More Information

Additional Information:
No publications provided

Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00735436     History of Changes
Other Study ID Numbers: Pro00006308
Study First Received: August 13, 2008
Results First Received: December 31, 2012
Last Updated: February 4, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Duke University:
Malignant glioma
Glioblastoma multiforme
GBM
Gliosarcoma
Gliadel
Carmustine
Irinotecan
CPT-11
Camptosar
Avastin
Bevacizumab

Additional relevant MeSH terms:
Glioblastoma
Glioma
Gliosarcoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Carmustine
Irinotecan
Bevacizumab
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antineoplastic Agents, Phytogenic
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014