Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Temozolomide (TMZ) and Radiation Therapy (RT) With or Without Bevacizumab in Treating Patients With Newly Diagnosed Glioblastoma Multiforme (GBM)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00884741
First received: April 18, 2009
Last updated: November 14, 2016
Last verified: November 2016
  Purpose
This randomized phase III trial studies temozolomide (TMZ) and radiation therapy (RT) to compare how well they work with or without bevacizumab in treating patients with newly diagnosed glioblastoma or gliosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as bevacizumab, may find tumor cells and help kill them. It is not yet known whether temozolomide and radiation therapy are more effective when given together with or without bevacizumab in treating glioblastoma or gliosarcoma.

Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Cognitive Side Effects of Cancer Therapy
Radiation: Radiation therapy pre-randomization
Biological: Bevacizumab
Drug: Placebo
Drug: Temozolomide pre-randomization
Drug: Temozolomide post-randomization
Radiation: Radiation therapy post-randomization
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phase III Double-Blind Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab Versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs after all 390 deaths have been reported. ] [ Designated as safety issue: No ]
    Survival time was defined as time from randomization to date of death from any cause and was estimated by the Kaplan-Meier method. Patients last known to be alive were censored at the date of last contact. This analysis was planned to occur when 390 deaths had been reported.

  • Progression-free Survival (PFS) [ Time Frame: From randomization to date of progression, death, or last follow-up for progression-free survival. Analysis occurs after all 390 deaths have been reported. ] [ Designated as safety issue: No ]
    Progression-free survival was defined as time from randomization to date of progression, death, or last follow-up, and was estimated by the Kaplan-Meier method. Patients last known to be alive were censored at the date of last contact. This analysis was planned to occur when 390 deaths had been reported.


Secondary Outcome Measures:
  • Incidence of Grade 3 and Higher Treatment-related Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 3.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    AEs are graded by using CTCAE 3.0. The difference between the two randomized arms in the percentage of patients with grade 3 or higher toxicities reported as possibly/probably/definitely related to protocol treatment will be tested using a chi square test.


Other Outcome Measures:
  • Quality of Life Measured by the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT Tool) and EORTC Quality of Life Questionnaire-Core/Brain Cancer Module( QLQ-C30/BCM20) [ Time Frame: Analysis can occur at or after time of primary outcome measure analysis. ] [ Designated as safety issue: No ]
  • Neurocognitive Function Measured by the Hopkins Verbal Learning Test-Revised(HVLT-R), Trail Making Test Part A, Trail Making Test Part B, Controlled Oral Word Association Test (COWAT) [ Time Frame: Analysis can occur at or after time of primary outcome measure analysis. ] [ Designated as safety issue: No ]

Enrollment: 637
Study Start Date: April 2009
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Pre-randomization: TMZ+RT
Temozolomide pre-randomization, radiation therapy pre-randomization
Radiation: Radiation therapy pre-randomization
The first 3 weeks of the full 6 weeks of RT treatment: One treatment of 2 Gy will be given daily 5 days per week for a total of 60 Gy over 6 weeks. The radiation therapy can be intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3DRT).
Drug: Temozolomide pre-randomization
Concurrent with RT: First 3 weeks of TMZ is administered continuously from day 1 of RT at a daily oral dose of 75 mg/m2.
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temodal
  • Temodar
  • TEMOZOLOMIDE
Active Comparator: Randomized Arm 1: TMZ+RT + Placebo
Temozolomide post-randomization,Radiation therapy post-randomization, placebo
Drug: Placebo
Each dose will be will be via IV, 10 mg/kg of actual body weight. Post-Randomization during concomitant RT: Days 1 and 15 of each 28-day cycle, at the beginning of the 4th week of radiation. Post-Radiation: At the beginning of the second week after completion of radiation. Then concurrently (same day) as the initiation of the first cycle of the post-radiation TMZ.
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy
Drug: Temozolomide post-randomization
Concurrent with RT: TMZ continues to be administered continuously for last 3 weeks of RT to the last day of RT at a daily oral dose of 75 mg/m2 for a maximum of 49 days from start of RT. Post-Radiation: TMZ is administered orally once per day for 5 consecutive days (days 1-5) of a 28-day cycle. The starting dose for the first cycle will be 150 mg/m2/day, with a single dose escalation to 200 mg/m2/day in subsequent cycles if no treatment-related adverse events > grade 2 are noted. At the completion of 6 cycles, patients may receive up to an additional 6 cycles of treatment (therefore, a maximum of 12 cycles).
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temodal
  • Temodar
  • TEMOZOLOMIDE
Radiation: Radiation therapy post-randomization
The last 3 weeks of the full 6 weeks of RT treatment: One treatment of 2 Gy will be given daily 5 days per week for a total of 60 Gy over 6 weeks. The radiation therapy can be intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3DRT).
Experimental: Randomized Arm 2: TMZ+RT + Bevacizumab
Temozolomide post-randomization, radiation therapy post-randomization, bevacizumab
Biological: Bevacizumab
Each dose will be will be via IV, 10 mg/kg of actual body weight. Post-Randomization during concomitant RT: Days 1 and 15 of each 28-day cycle, at the beginning of the 4th week of radiation. Post-Radiation: At the beginning of the second week after completion of radiation. Then concurrently (same day) as the initiation of the first cycle of the post-radiation TMZ.
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF
Drug: Temozolomide post-randomization
Concurrent with RT: TMZ continues to be administered continuously for last 3 weeks of RT to the last day of RT at a daily oral dose of 75 mg/m2 for a maximum of 49 days from start of RT. Post-Radiation: TMZ is administered orally once per day for 5 consecutive days (days 1-5) of a 28-day cycle. The starting dose for the first cycle will be 150 mg/m2/day, with a single dose escalation to 200 mg/m2/day in subsequent cycles if no treatment-related adverse events > grade 2 are noted. At the completion of 6 cycles, patients may receive up to an additional 6 cycles of treatment (therefore, a maximum of 12 cycles).
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temodal
  • Temodar
  • TEMOZOLOMIDE
Radiation: Radiation therapy post-randomization
The last 3 weeks of the full 6 weeks of RT treatment: One treatment of 2 Gy will be given daily 5 days per week for a total of 60 Gy over 6 weeks. The radiation therapy can be intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3DRT).

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven diagnosis of glioblastoma or gliosarcoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration
  • Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient size for analysis of O-6-methylguanine-DNA methyltransferase (MGMT) and determination of molecular profile

    • Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present
    • CUSA (Cavitron ultrasonic aspirator)-derived material is not allowed; fresh frozen tumor tissue acquisition is encouraged
    • Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy is not allowed because it will not provide sufficient tissue for MGMT analysis
    • The tumor tissue should be sent as soon as possible to maximize the likelihood of eligibility; tumor tissue should be submitted by 4 weeks after the surgical procedure so that the study registration and treatment can commence by the mandatory 5 week post-surgery outer limit
    • Sites must submit tissue for central review in order to obtain the MGMT analysis; patients from sites not following protocol-specified process for obtaining MGMT results will be made ineligible
  • The tumor must have a supratentorial component
  • History/physical examination within 14 days prior to step 2 registration
  • The patient must have recovered from the effects of surgery, postoperative infection, and other complications before step 2 registration
  • A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy; the postoperative scan must be performed within 28 days prior to step 1 registration

    • An MRI or computed tomography (CT) scan (potentially in addition to the postoperative scan) must be obtained within 10 days prior to the start of radiation therapy and must not demonstrate significant postoperative hemorrhage defined as > 1 cm diameter of blood; if > 1 cm of acute blood is detected, the patient will be ineligible for this trial; the radiation planning MRI or CT scan may be used to determine presence of hemorrhage
    • Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and postoperative contrast-enhanced CT scans are obtained and are of sufficient quality; preoperative and postoperative scans must be the same type; such patients cannot be enrolled into the advanced imaging component
  • Documentation of steroid doses within 14 days prior to step 2 registration
  • Karnofsky performance status >= 70
  • Absolute neutrophil count (ANC) >= 1,800 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin >= 10.0 g/dL (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)
  • Blood urea nitrogen (BUN) =< 30 mg/dL within 14 days prior to step 2 registration
  • Creatinine =< 1.7 mg/dl within 14 days prior to step 2 registration
  • Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg
  • Bilirubin =< 2.0 mg/dl within 14 days prior to step 2 registration
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x normal range within 14 days prior to step 2 registration
  • Systolic blood pressure =< 160 mg Hg or diastolic pressure =< 90 mm Hg within 14 days prior to step 2 registration
  • Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior to step 2 registration
  • Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on warfarin confirmed by testing within 14 days prior to step 2 registration
  • Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet both of the following criteria:

    • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
    • In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of LMW heparin
  • Patient must provide study specific informed consent prior to study entry
  • Women of childbearing potential and male participants must practice adequate contraception
  • For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration

Exclusion Criteria:

  • Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for >= 3 years; (for example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible)
  • Recurrent or multifocal malignant gliomas
  • Metastases detected below the tentorium or beyond the cranial vault
  • Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable, except prior temozolomide or bevacizumab; prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
  • Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
  • Severe, active co-morbidity, defined as follows:

    • Unstable angina and/or congestive heart failure within the last 6 months
    • Transmural myocardial infarction within the last 6 months
    • Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 14 days of step 2 registration
    • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
    • History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months
    • Serious and inadequately controlled cardiac arrhythmia
    • Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease
    • Evidence of bleeding diathesis or coagulopathy
    • Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for tumor resection
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
    • Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive
    • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
    • Any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  • Pregnant or lactating women
  • Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study
  • For American College of Radiology Imaging Network (ACRIN) 6686 Advanced Imaging: inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker)
  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: NCT00884741

  Show 305 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mark Gilbert NRG Oncology
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00884741     History of Changes
Other Study ID Numbers: NCI-2009-01670  NCI-2009-01670  RTOG-0825  CDR0000640428  RTOG 0825  RTOG-0825  U10CA180868  U10CA021661 
Study First Received: April 18, 2009
Results First Received: December 18, 2015
Last Updated: November 14, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Bevacizumab
Temozolomide
Dacarbazine
Endothelial Growth Factors
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 02, 2016