A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients
- Conditions
- Recurrent Glioblastoma
- Interventions
- Biological: NivolumabBiological: BevacizumabBiological: Ipilimumab
- Registration Number
- NCT02017717
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of the study is to compare the efficacy and safety of nivolumab administered alone versus bevacizumab in patients diagnosed with recurrent glioblastoma (a type of brain cancer, also known as GBM), and to evaluate the safety and tolerability of nivolumab administered alone or in combination with ipilimumab in patients with different lines of GBM therapy.
- Detailed Description
Allocation: Randomized (Cohorts 1, 2 and Part B of 1c/1d), Non-Randomized (Cohorts 1b, and Part A of 1c/1d)
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 529
- Participants with histologically confirmed Grade IV malignant glioma
- Previous treatment with radiotherapy and temozolomide (Cohorts 1, 1b and 2 only)
- First recurrence of GBM (Cohorts 1, 1b and 2 only)
- First diagnosis of GBM with resectable disease (Cohorts 1c Part A only)
- First diagnosis of unmethylated MGMT GBM (Cohort 1d and Cohort 1c Part B only)
- Karnofsky performance score of 70 or higher
- More than 1 recurrence of GBM (Cohorts 1, 1b and 2 only)
- Any recurrence of GBM (Cohorts 1c and 1d only)
- Presence of extracranial metastatic or leptomeningeal disease
- Active, known or suspected autoimmune disease
- Clinically significant cardiovascular disease
- Prior bevacizumab or other Vascular Endothelial Growth Factor (VEGF) or anti-angiogenic treatment (Cohort 2 only)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm N + I:Nivolumab + Ipilimumab Nivolumab Cohort 1: Nivolumab specified dose on specified days + Ipilimumab specified dose on specified days, then Nivolumab specified dose on specified days Cohort 1b: Nivolumab specified dose on specified days + Ipilimumab specified dose on specified days, then Nivolumab specified dose on specified days Arm N:Nivolumab Nivolumab Cohort 1, 1c, 1d and 2: Nivolumab specified dose on specified days Arm B: Bevacizumab Bevacizumab Cohort 2: Bevacizumab specified dose on specified days Arm N + I:Nivolumab + Ipilimumab Ipilimumab Cohort 1: Nivolumab specified dose on specified days + Ipilimumab specified dose on specified days, then Nivolumab specified dose on specified days Cohort 1b: Nivolumab specified dose on specified days + Ipilimumab specified dose on specified days, then Nivolumab specified dose on specified days
- Primary Outcome Measures
Name Time Method Percentage of Participants With Specific Laboratory Abnormalities in Thyroid Tests in Cohorts 1, 1b, 1c and 1d From first dose to 30 days post last dose (up to approximately 34 months). The percentage of participants who experienced a laboratory abnormality of the thyroid in each treatment arm.
MedDRA Version: 24.1
Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)
(A) Within a 2-week window after the abnormal TSH test date. (B) Includes participants with TSH abnormality and with no FT3/FT4 test values in the 2-week window or with non-abnormal value(s) from only one of the two tests and no value from the other test.Percentage of Participants With Drug-Related Adverse Events Leading to Discontinuation by Worst CTC Grade for All Treated Participants in Cohorts 1, 1b, 1c and 1d Who Permanently Discontinued Study Medication Prior to Completing Four Doses Includes events reported between first dose and 30 days after last dose of study therapy (up to 3 doses, up to approximately 2 months) The percentage of participants who experienced a drug-related adverse event leading to drug discontinuation by worst grade (grade 5 being the worst) prior to complete four-dose treatment. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1
Percentage of Participants With Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d From first dose to 30 days post last dose (up to approximately 34 months). The percentage of participants who experienced an adverse event by worst grade in each treatment arm. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1
Percentage of Participants With Serious Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d From first dose to 30 days post last dose (up to approximately 34 months). The percentage of participants who experienced a serious adverse event by worst grade in each treatment arm. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1
Percentage of Participants With Specific Laboratory Abnormalities in Liver Tests in Cohorts 1, 1b, 1c and 1d From first dose to 30 days post last dose (up to approximately 34 months). The percentage of participants who experienced a laboratory abnormality of the liver in each treatment arm.
MedDRA Version: 24.1
Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Denominator corresponds to participants with at least on one treatment measurement of the corresponding laboratory parameter. Includes laboratory results reported after the first dose and within 30 days of last dose of study therapy.Overall Survival (OS) for Cohort 2 Time between the date of randomization and the date of death due to any cause (up to 17Jun2019, approximately 5 years) OS was measured in months from the time of randomization to the event date (death) due to any cause. A participant who has not died will be censored at the last known alive date.
Based on Kaplan-Meier Estimates. Hazard ratio from Cox proportional hazard model stratified by presence of measurable lesions at baseline per IVRS. P-value from log-rank test stratified by presence of measurable lesions at baseline per IVRS.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) at 12 Months for Cohort 2 From randomization to 12 months following randomization OS(12) is measured as the percentage of participants alive at 12 months per Kaplan-Meier curve of OS. Z test with variance estimation based on Greenwood formula using log(-log) transformation.
Overall Survival (OS) for Cohorts 1c and 1d Time between the date of randomization and the date of death due to any cause (up to 17Jun2019, approximately 5 years) OS was measured in months from the time of randomization (Part B) or time of treatment (Part A) to the event date (death) due to any cause. A participant who has not died will be censored at the last known alive date.
Based on Kaplan-Meier Estimates.Progression Free Survival (PFS) for Cohort 2 Time from randomization to the date of the first documented tumor progression or death due to any cause (up to 17Jun2019, approximately 5 years) PFS was measured in months from the time of randomization to the date of the first documented tumor progression or death due to any cause. Based on Kaplan-Meier Estimates. Hazard ratio from Cox proportional hazard model stratified by presence of measurable lesions at baseline per IVRS.
Objective Response Rate (ORR) for Cohort 2 Time from randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 31 months) ORR was measured by the percentage of participants whose best overall response (BOR) is confirmed Complete Response (CR) or Partial Response (PR) divided by response evaluable participants. The best overall response (BOR) is determined once all the data for the participant is known. BOR is defined as the best response designation, as determined by investigators, recorded between the date of randomization and the date of objectively documented progression per RANO criteria, the date of subsequent therapy, or date of surgical resection, whichever occurs first.
Confidence interval based on the Clopper and Pearson method. For the comparison of the odds ratio of Nivolumab over Bevacizumab, the Cochran-Mantel-Haenszel (CMH) method of weighting was utilized.
Trial Locations
- Locations (87)
Local Institution - 0055
🇺🇸Los Angeles, California, United States
Johns Hopkins University School Of Medicine
🇺🇸Baltimore, Maryland, United States
Local Institution - 0008
🇺🇸Baltimore, Maryland, United States
Local Institution - 0035
🇦🇺Liverpool, New South Wales, Australia
Local Institution - 0060
🇵🇱Gdansk, Poland
Local Institution - 0066
🇳🇱Groningen, Netherlands
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Local Institution - 0040
🇨ðŸ‡Zuerich, Switzerland
UniversitaetsSpital Zurich
🇨ðŸ‡Zuerich, Switzerland
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Local Institution - 0001
🇺🇸New Haven, Connecticut, United States
Local Institution - 0014
🇺🇸San Francisco, California, United States
The Regents of the University of California, San Francisco
🇺🇸San Francisco, California, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Local Institution - 0005
🇺🇸Nashville, Tennessee, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Local Institution - 0021
🇺🇸Aurora, Colorado, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Local Institution - 0009
🇺🇸Los Angeles, California, United States
Beth Israel Deaconess Med Ctr
🇺🇸Boston, Massachusetts, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States
Yale University School Of Medicine
🇺🇸New Haven, Connecticut, United States
Local Institution - 0002
🇺🇸Atlanta, Georgia, United States
Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Local Institution - 0006
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Local Institution - 0056
🇺🇸Boston, Massachusetts, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Preston Robert Tisch Brain Tumor Center at Duke University
🇺🇸Durham, North Carolina, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Thomas Jefferson University - Clinical Research Institute
🇺🇸Philadelphia, Pennsylvania, United States
Local Institution - 0049
🇺🇸Cleveland, Ohio, United States
Local Institution - 0023
🇺🇸Charleston, South Carolina, United States
Local Institution
🇬🇧Liverpool, United Kingdom
Local Institution - 0050
🇧🇪Brussels, Belgium
Local Institution - 0032
🇦🇺Nedlands, Western Australia, Australia
Local Institution - 0033
🇦🇺Heidelberg, Victoria, Australia
Aarhus University Hospital
🇩🇰Aarhus C, Denmark
Local Institution - 0051
🇧🇪Bruxelles, Belgium
Local Institution - 0057
🇩🇰Odense C, Denmark
Klinikum Der J. W. Goethe-Universitaet Frankfurt/Main
🇩🇪Frankfurt Am Main, Germany
Odense University Hospital
🇩🇰Odense C, Denmark
Local Institution - 0058
🇩🇰Aarhus C, Denmark
Local Institution - 0062
🇫🇷Bron cedex, France
Local Institution - 0068
🇫🇷Paris, France
Local Institution - 0037
🇩🇪Bonn, Germany
Universitaetsklinikum Bonn
🇩🇪Bonn, Germany
Local Institution - 0063
🇫🇷Marseille Cedex 5, France
Local Institution - 0064
🇫🇷Paris cedex 13, France
Universitaetsklinikum Muenster
🇩🇪Muenster, Germany
Local Institution - 0011
🇮🇹Milano, Italy
Local Institution - 0041
🇩🇪Muenster, Germany
Local Institution - 0036
🇩🇪Frankfurt Am Main, Germany
Local Institution - 0012
🇮🇹Siena, Italy
Local Institution - 0010
🇮🇹Bologna, Italy
Azienda Ospedaliera Citta della Salute e della Scienza
🇮🇹Torino, Italy
Local Institution - 0067
🇳🇱Amsterdam, Netherlands
Local Institution - 0059
🇵🇱Warszawa, Poland
Local Institution - 0013
🇮🇹Torino, Italy
Local Institution - 0047
🇪🇸Barcelona, Spain
Local Institution - 0045
🇪🇸Madrid, Spain
Local Institution - 0046
🇪🇸Madrid, Spain
Centre hospitalier universitaire Vaudois (CHUV)
🇨ðŸ‡Lausanne, Switzerland
Local Institution - 0007
🇺🇸Durham, North Carolina, United States
University Of Texas Md Anderson Cancer Ctr
🇺🇸Houston, Texas, United States
UCLA Neuro-Oncology Program
🇺🇸Los Angeles, California, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Local Institution - 0043
🇺🇸Boston, Massachusetts, United States
Local Institution - 0003
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Local Institution - 0020
🇺🇸Seattle, Washington, United States
University of Washington - Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
Swedish Neuroscience Institute
🇺🇸Seattle, Washington, United States
Local Institution - 0024
🇺🇸Houston, Texas, United States
Local Institution - 0034
🇦🇺East Bentleigh, Victoria, Australia
University Of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Medical University Of South Carolina
🇺🇸Charleston, South Carolina, United States
Local Institution - 0038
🇩🇪Heidelberg, Germany
Local Institution - 0039
🇨ðŸ‡Lausanne, Switzerland
Local Institution - 0070
🇪🇸Pamplona, Spain
Local Institution - 0018
🇬🇧London, Greater London, United Kingdom
Local Institution - 0015
🇬🇧Manchester, Greater Manchester, United Kingdom
Local Institution - 0017
🇬🇧Liverpool, United Kingdom
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States