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

This study has been completed.
Sponsor:
Collaborators:
Genentech
Schering-Plough
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00597402
First received: January 10, 2008
Last updated: April 22, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Glioblastoma
Gliosarcoma
Brain Tumor
Drug: Avastin
Drug: Temozolomide
Radiation: Radiation Therapy (XRT)
Drug: Irinotecan
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Avastin in Combination With Radiation and Temozolomide, Followed by Avastin, Temozolomide and Irinotecan for Glioblastoma Multiformes and Gliosarcomas

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • 16-month Overall Survival (OS) [ Time Frame: 16 months ] [ Designated as safety issue: No ]
    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) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: 55 months ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 55 months ] [ Designated as safety issue: Yes ]
    Number of times a grade ≥ 4 hematologic or grade ≥ 3 non-hematologic toxicity was experienced


Enrollment: 125
Study Start Date: July 2007
Study Completion Date: May 2013
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Avastin, radiation, temozolomide, and irinotecan Drug: Avastin
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.
Other Name: Bevacizumab
Drug: Temozolomide
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.
Other Name: Temodar
Radiation: Radiation Therapy (XRT)
Treatment with standard XRT (radiation) for 6.5 weeks.
Drug: Irinotecan
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.)
Other Names:
  • CPT-11
  • Camptosar

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.

  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 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.
  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: NCT00597402

Locations
United States, North Carolina
Duke University Health System
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Genentech
Schering-Plough
Investigators
Principal Investigator: Annick Desjardins, MD, FRCPC Duke University Health System
  More Information

Additional Information:
No publications provided

Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00597402     History of Changes
Other Study ID Numbers: Pro00000458
Study First Received: January 10, 2008
Results First Received: December 12, 2012
Last Updated: April 22, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Duke University:
Avastin
Bevacizumab
Temozolomide
Temodar
Irinotecan
Camptosar
GBM
Glioblastoma Multiforme
Gliosarcoma
Brain tumor
Glioma
New GBM
Newly diagnosed GBM or gliosarcoma malignant brain tumor

Additional relevant MeSH terms:
Glioblastoma
Brain Neoplasms
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Bevacizumab
Temozolomide
Irinotecan
Dacarbazine
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014