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Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas

Primary Purpose

Glioblastoma, Gliosarcoma, Brain Tumor

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Avastin
Temozolomide
Radiation Therapy (XRT)
Irinotecan
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Avastin, Bevacizumab, Temozolomide, Temodar, Irinotecan, Camptosar, GBM, Glioblastoma Multiforme, Gliosarcoma, Brain tumor, Glioma, New GBM, Newly diagnosed GBM or gliosarcoma malignant brain tumor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have histologically confirmed diagnosis of World Health Organization (WHO) grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 4 weeks of the last major surgical procedure.
  • Age > 18 years.
  • An interval of at least 2 weeks and not > 6 weeks between prior major surgical procedure and study enrollment.
  • No prior radiotherapy or chemotherapy for a brain tumor
  • Karnofsky ≥ 60 percent.
  • Hemoglobin ≥ 9.0 g/deciliter (dl), absolute neutrophil count (ANC) ≥ 1,500 cells/ microliter, platelets ≥ 125,000 cells/microliter.
  • Serum creatinine ≤ 1.5 mg/dl, serum serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal (ULN).
  • For patients on corticosteroids, they must be on a stable or decreasing dose for 1 week prior to entry, and the dose should not be escalated over entry dose level, if clinically possible.
  • Signed informed consent approved by the Institutional Review Board
  • No evidence of > grade 1 central nervous system (CNS) hemorrhage on the baseline MRI or CT scan.
  • 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.
  • Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.
  • Active infection requiring intravenous (IV) antibiotics.
  • Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor.
  • Evidence of > grade 1 CNS hemorrhage on baseline MRI on CT scan.

Avastin-Specific Concerns:

Subjects meeting any of the following criteria are ineligible for study entry:

  • Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study
  • Blood pressure of 150/100 mmHg
  • Unstable angina
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure
  • History of myocardial infarction within 6 months
  • History of stroke within 6 months
  • Clinically significant peripheral vascular disease
  • Evidence of bleeding diathesis
  • Coagulopathy (prothrombin time (PT) or partial thromboplastin time (PTT) >1.5x normal or a history of > three grade 2 or greater hemorrhages)
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first Avastin infusion during XRT/Temodar or anticipation of need for major surgical procedure during the course of the study
  • Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to first Avastin infusion during XRT/Temodar
  • Pregnant (positive pregnancy test) or lactating
  • Urine protein >1.0 + at screening
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to first Avastin infusion during XRT/Temodar
  • Serious, non-healing wound, ulcer, or bone fractures.
  • Inability to comply with study and/or follow-up procedures.

Sites / Locations

  • Duke University Health System

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Avastin, radiation, temozolomide, and irinotecan

Arm Description

Outcomes

Primary Outcome Measures

16-month Overall Survival (OS)
Percentage of participants surviving sixteen months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of death due to any cause.

Secondary Outcome Measures

12-month Progression-free Survival (PFS)
Percentage of participants surviving twelve months 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 the Macdonald criteria, or to death due to any cause.
Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage
Number of times a CNS hemorrhage or systemic hemorrhage was experienced
Number of Patients Experiencing a Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity
Number of times a grade ≥ 4 hematologic or grade ≥ 3 non-hematologic toxicity was experienced

Full Information

First Posted
January 10, 2008
Last Updated
April 22, 2014
Sponsor
Duke University
Collaborators
Genentech, Inc., Schering-Plough
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1. Study Identification

Unique Protocol Identification Number
NCT00597402
Brief Title
Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas
Official Title
Avastin in Combination With Radiation and Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma Multiformes and Gliosarcomas
Study Type
Interventional

2. Study Status

Record Verification Date
April 2014
Overall Recruitment Status
Completed
Study Start Date
July 2007 (undefined)
Primary Completion Date
August 2011 (Actual)
Study Completion Date
May 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Genentech, Inc., Schering-Plough

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Primary objective: To use overall survival to assess the efficacy of the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan in the treatment of grade IV malignant glioma patients following surgical resection. Secondary objective: To determine the progression-free survival following the combination of radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan. Exploratory Objective: To explore the relationship between biomarkers and outcome (overall survival and progression-free survival) among patients with grade IV malignant glioma treated with radiation therapy, temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan. To describe the toxicity of radiation therapy,temozolomide and Avastin followed by Avastin, temozolomide, and irinotecan.
Detailed Description
The standard of care for grade IV gliomas is radiation therapy with daily temozolomide, followed by 6 months of temozolomide. The majority of patients progress and die of their tumor. Many glioma patients are resistant to temozolomide because the tumors have high O(6)-methylguanine-DNA methyltransferase (MGMT), conferring resistance. Irinotecan is synergistic with temozolomide, and the combination may overcome high MGMT. Vascular endothelial growth factor (VEGF) is present on the cell surface and around malignant gliomas. It appears that the presence of vascular endothelial growth factor is a prognostic growth factor with more VEGF expression correlating with a poor prognosis. Monoclonal antibodies to VEGF have inhibited growth of malignant gliomas in a mouse xenograft. Avastin is a humanized monoclonal immunoglobulin G (IGG) 1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor. The combination of Avastin and irinotecan was safe and demonstrated high activity against recurrent malignant gliomas. The combination of Avastin, temozolomide, and irinotecan as the initial therapy may maximize the chance for long-term survival. There are other studies completed or ongoing for newly diagnosed glioblastoma (GBM) patients, including a Radiation Therapy Oncology Group (RTOG) study that added irinotecan to temozolomide following standard radiation therapy and temozolomide, and a University of California, Los Angeles (UCLA) study that added Avastin to standard radiation therapy and temozolomide followed by Avastin and temozolomide.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Gliosarcoma, Brain Tumor
Keywords
Avastin, Bevacizumab, Temozolomide, Temodar, Irinotecan, Camptosar, GBM, Glioblastoma Multiforme, Gliosarcoma, Brain tumor, Glioma, New GBM, Newly diagnosed GBM or gliosarcoma malignant brain tumor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
125 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Avastin, radiation, temozolomide, and irinotecan
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Avastin
Other Intervention Name(s)
Bevacizumab
Intervention Description
Avastin will be administered 10 mg/kg every other week beginning a minimum of 28 days after last major surgical procedure, open biopsy, or significant traumatic injury. Following completion of XRT, patients will receive treatment that includes 6 cycles of Avastin, beginning a minimum of 14 days after last XRT.
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
Temodar
Intervention Description
Daily temozolomide 75 mg/m2/day for 6.5 weeks of radiation treatment. Following completion of XRT, patients will receive treatment including temozolomide 200 mg/m2/day on the 1st 5 days of each 28-day cycle.
Intervention Type
Radiation
Intervention Name(s)
Radiation Therapy (XRT)
Intervention Description
Treatment with standard XRT (radiation) for 6.5 weeks.
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Other Intervention Name(s)
CPT-11, Camptosar
Intervention Description
Following completion of XRT, patients will receive 6 cycles of treatment that includes irinotecan. Beginning a minimum of 14 days after last XRT, the irinotecan dose will depend on whether the patient is on enzyme-inducing antiepileptic drugs (EIAED). (EIAED:340 mg/m2 every other week, non-EIAED: 125 mg/m2.)
Primary Outcome Measure Information:
Title
16-month Overall Survival (OS)
Description
Percentage of participants surviving sixteen months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of death due to any cause.
Time Frame
16 months
Secondary Outcome Measure Information:
Title
12-month Progression-free Survival (PFS)
Description
Percentage of participants surviving twelve months 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 the Macdonald criteria, or to death due to any cause.
Time Frame
12 months
Title
Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage
Description
Number of times a CNS hemorrhage or systemic hemorrhage was experienced
Time Frame
55 months
Title
Number of Patients Experiencing a Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity
Description
Number of times a grade ≥ 4 hematologic or grade ≥ 3 non-hematologic toxicity was experienced
Time Frame
55 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically confirmed diagnosis of World Health Organization (WHO) grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients have to be within 4 weeks of the last major surgical procedure. Age > 18 years. An interval of at least 2 weeks and not > 6 weeks between prior major surgical procedure and study enrollment. No prior radiotherapy or chemotherapy for a brain tumor Karnofsky ≥ 60 percent. Hemoglobin ≥ 9.0 g/deciliter (dl), absolute neutrophil count (ANC) ≥ 1,500 cells/ microliter, platelets ≥ 125,000 cells/microliter. Serum creatinine ≤ 1.5 mg/dl, serum serum glutamic-oxaloacetic transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal (ULN). For patients on corticosteroids, they must be on a stable or decreasing dose for 1 week prior to entry, and the dose should not be escalated over entry dose level, if clinically possible. Signed informed consent approved by the Institutional Review Board No evidence of > grade 1 central nervous system (CNS) hemorrhage on the baseline MRI or CT scan. 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. Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids. Active infection requiring intravenous (IV) antibiotics. Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor. Evidence of > grade 1 CNS hemorrhage on baseline MRI on CT scan. Avastin-Specific Concerns: Subjects meeting any of the following criteria are ineligible for study entry: Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study Blood pressure of 150/100 mmHg Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease Evidence of bleeding diathesis Coagulopathy (prothrombin time (PT) or partial thromboplastin time (PTT) >1.5x normal or a history of > three grade 2 or greater hemorrhages) Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first Avastin infusion during XRT/Temodar or anticipation of need for major surgical procedure during the course of the study Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to first Avastin infusion during XRT/Temodar Pregnant (positive pregnancy test) or lactating Urine protein >1.0 + at screening History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to first Avastin infusion during XRT/Temodar Serious, non-healing wound, ulcer, or bone fractures. Inability to comply with study and/or follow-up procedures.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annick Desjardins, MD, FRCPC
Organizational Affiliation
Duke Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Health System
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.cancer.duke.edu/btc/
Description
The Preston Robert Tisch Brain Tumor Center at DUKE

Learn more about this trial

Avastin in Combination With Radiation (XRT) & Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma (GBM) and Gliosarcomas

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