Temozolomide and Radiation Therapy With or Without Bevacizumab in Treating Patients With Newly Diagnosed Glioblastoma
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| ClinicalTrials.gov Identifier: NCT00884741 |
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Recruitment Status :
Completed
First Posted : April 21, 2009
Results First Posted : October 12, 2016
Last Update Posted : July 24, 2019
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Sponsor:
National Cancer Institute (NCI)
Collaborators:
Radiation Therapy Oncology Group
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
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 or disease | Intervention/treatment | Phase |
|---|---|---|
| Glioblastoma Gliosarcoma Supratentorial Glioblastoma | Radiation: 3-Dimensional Conformal Radiation Therapy Biological: Bevacizumab Radiation: Intensity-Modulated Radiation Therapy Other: Laboratory Biomarker Analysis Other: Placebo Other: Quality-of-Life Assessment Drug: Temozolomide | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 637 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, 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 |
| Actual Study Start Date : | April 15, 2009 |
| Actual Primary Completion Date : | March 17, 2013 |
| Actual Study Completion Date : | March 17, 2013 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Arm I (radiation therapy, temozolomide, placebo)
Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks and receive temozolomide PO QD for up to 7 weeks. Beginning 4 weeks after completion of chemotherapy and radiation therapy, patients receive temozolomide PO QD on days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive placebo IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemotherapy and radiation therapy and continuing until the completion of temozolomide.
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Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3-dimentional conformal radiation therapy
Other Names:
Radiation: Intensity-Modulated Radiation Therapy Undergo intensity-modulated radiation therapy
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Other: Placebo Given IV
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Drug: Temozolomide Given orally
Other Names:
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Experimental: Arm II (radiation therapy, temozolomide, bevacizumab)
Patients undergo radiation therapy and receive temozolomide as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemoradiotherapy and continuing until the completion of adjuvant temozolomide.
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Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3-dimentional conformal radiation therapy
Other Names:
Biological: Bevacizumab Given IV
Other Names:
Radiation: Intensity-Modulated Radiation Therapy Undergo intensity-modulated radiation therapy
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Drug: Temozolomide Given orally
Other Names:
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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. ]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. ]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 ]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. ]
- 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. ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| 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
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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 fir 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
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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
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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
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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)
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00884741
Locations
Show 330 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
NRG Oncology
Investigators
| Principal Investigator: | Mark Gilbert | NRG Oncology |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00884741 |
| Other Study ID Numbers: |
NCI-2009-01670 NCI-2009-01670 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) RTOG-0825 RTOG 0825 CDR0000640428 RTOG-0825 ( Other Identifier: NRG Oncology ) RTOG-0825 ( Other Identifier: CTEP ) U10CA180868 ( U.S. NIH Grant/Contract ) U10CA021661 ( U.S. NIH Grant/Contract ) |
| First Posted: | April 21, 2009 Key Record Dates |
| Results First Posted: | October 12, 2016 |
| Last Update Posted: | July 24, 2019 |
| Last Verified: | July 2019 |
Additional relevant MeSH terms:
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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 Bevacizumab Antineoplastic Agents, Immunological Temozolomide Endothelial Growth Factors |
Antibodies Immunoglobulins Antibodies, Monoclonal Immunoglobulin G Antineoplastic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Immunologic Factors Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action |