A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients (CheckMate 143)

A Randomized Phase 3 Open Label Study of Nivolumab Versus Bevacizumab and Multiple Phase 1 Safety Cohorts of Nivolumab or Nivolumab in Combination With Ipilimumab Across Different Lines of Glioblastoma

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Glioblastoma
• Intervention / Treatment: Biological: Nivolumab; Biological: Ipilimumab; Biological: Bevacizumab

Detailed Description

Allocation: Randomized (Cohorts 1, 2 and Part B of 1c/1d), Non-Randomized (Cohorts 1b, and Part A of 1c/1d)

• Study Type: Interventional
• Enrollment (Actual): 529
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Local Institution
    • Liverpool, New South Wales, Australia, 2170
      • Local Institution - 0035
  • Victoria
    • East Bentleigh, Victoria, Australia, 3165
      • Local Institution
    • East Bentleigh, Victoria, Australia, 3165
      • Local Institution - 0034
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution - 0033
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Local Institution
    • Nedlands, Western Australia, Australia, 6009
      • Local Institution - 0032
• Belgium
  • Brussels, Belgium, 1090
    • Local Institution
  • Brussels, Belgium, 1090
    • Local Institution - 0050
  • Bruxelles, Belgium, 1200
    • Local Institution
  • Bruxelles, Belgium, 1200
    • Local Institution - 0051
• Denmark
  • Aarhus C, Denmark, 8000
    • Aarhus University Hospital
  • Aarhus C, Denmark, 8000
    • Local Institution - 0058
  • Odense C, Denmark, 5000
    • Odense University Hospital
  • Odense C, Denmark, 5000
    • Local Institution - 0057
• France
  • Bron cedex, France, 69677
    • Local Institution
  • Bron cedex, France, 69677
    • Local Institution - 0062
  • Marseille Cedex 5, France, 13385
    • Local Institution
  • Marseille Cedex 5, France, 13385
    • Local Institution - 0063
  • Paris, France, 75010
    • Local Institution
  • Paris, France, 75010
    • Local Institution - 0068
  • Paris cedex 13, France, 75651
    • Local Institution
  • Paris cedex 13, France, 75651
    • Local Institution - 0064
• Germany
  • Bonn, Germany, 53127
    • Universitaetsklinikum Bonn
  • Bonn, Germany, 53127
    • Local Institution - 0037
  • Frankfurt Am Main, Germany, 60528
    • Klinikum Der J. W. Goethe-Universitaet Frankfurt/Main
  • Frankfurt Am Main, Germany, 60528
    • Local Institution - 0036
  • Heidelberg, Germany, 69120
    • Local Institution
  • Heidelberg, Germany, 69120
    • Local Institution - 0038
  • Muenster, Germany, 48149
    • Universitaetsklinikum Muenster
  • Muenster, Germany, 48149
    • Local Institution - 0041
• Italy
  • Bologna, Italy, 40139
    • Local Institution
  • Bologna, Italy, 40139
    • Local Institution - 0010
  • Milano, Italy, 20133
    • Local Institution
  • Milano, Italy, 20133
    • Local Institution - 0011
  • Siena, Italy, 53100
    • Local Institution
  • Siena, Italy, 53100
    • Local Institution - 0012
  • Torino, Italy, 10126
    • Azienda Ospedaliera Citta della Salute e della Scienza
  • Torino, Italy, 10126
    • Local Institution - 0013
• Netherlands
  • Amsterdam, Netherlands, 1066CX
    • Local Institution
  • Amsterdam, Netherlands, 1066CX
    • Local Institution - 0067
  • Groningen, Netherlands, 9713 AP
    • Local Institution
  • Groningen, Netherlands, 9713 AP
    • Local Institution - 0066
• Poland
  • Gdansk, Poland, 80-952
    • Local Institution
  • Gdansk, Poland, 80-952
    • Local Institution - 0060
  • Warszawa, Poland, 02-781
    • Local Institution
  • Warszawa, Poland, 02-781
    • Local Institution - 0059
• Spain
  • Barcelona, Spain, 08035
    • Local Institution
  • Barcelona, Spain, 08035
    • Local Institution - 0047
  • Madrid, Spain, 28041
    • Local Institution
  • Madrid, Spain, 28009
    • Local Institution
  • Madrid, Spain, 28009
    • Local Institution - 0045
  • Madrid, Spain, 28041
    • Local Institution - 0046
  • Pamplona, Spain, 31008
    • Local Institution
  • Pamplona, Spain, 31008
    • Local Institution - 0070
• Switzerland
  • Lausanne, Switzerland, BT 02252
    • Centre Hospitalier Universitaire Vaudois (CHUV)
  • Lausanne, Switzerland, BT 02252
    • Local Institution - 0039
  • Zuerich, Switzerland, 8091
    • UniversitaetsSpital Zurich
  • Zuerich, Switzerland, 8091
    • Local Institution - 0040
• United Kingdom
  • Liverpool, United Kingdom, L7 8YA
    • Local Institution
  • Liverpool, United Kingdom, L7 8YA
    • Local Institution - 0017
  • Greater London
    • London, Greater London, United Kingdom, NW1 2PG
      • Local Institution
    • London, Greater London, United Kingdom, NW1 2PG
      • Local Institution - 0018
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Local Institution
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Local Institution - 0015
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3410
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Los Angeles, California, United States, 90095-1769
      • UCLA Neuro-Oncology Program
    • Los Angeles, California, United States, 90048
      • Local Institution - 0055
    • Los Angeles, California, United States, 90095-1769
      • Local Institution - 0009
    • San Francisco, California, United States, 94143-0372
      • The Regents of the University of California, San Francisco
    • San Francisco, California, United States, 94143-0372
      • Local Institution - 0014
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Anschutz Cancer Pavilion
    • Aurora, Colorado, United States, 80045
      • Local Institution - 0021
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School Of Medicine
    • New Haven, Connecticut, United States, 06520
      • Local Institution - 0001
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute
    • Atlanta, Georgia, United States, 30322
      • Local Institution - 0002
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School of Medicine
    • Baltimore, Maryland, United States, 21287
      • Local Institution - 0008
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med Ctr
    • Boston, Massachusetts, United States, 02215
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0006
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0043
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0056
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48202-2608
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Local Institution - 0003
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Durham, North Carolina, United States, 27710
      • Preston Robert Tisch Brain Tumor Center at Duke University
    • Durham, North Carolina, United States, 27710
      • Local Institution - 0007
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Cleveland, Ohio, United States, 44106
      • Local Institution - 0049
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University - Clinical Research Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Charleston, South Carolina, United States, 29425
      • Local Institution - 0023
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37232
      • Local Institution - 0005
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University Of Texas Md Anderson Cancer Ctr
    • Houston, Texas, United States, 77030-4009
      • Local Institution - 0024
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Neuroscience Institute
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance
    • Seattle, Washington, United States, 98122
      • Local Institution - 0020

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm N:Nivolumab; Cohort 1, 1c, 1d and 2: Nivolumab specified dose on specified days	Biological: Nivolumab; specified dose on specified days; Other Names: BMS-936558
Experimental: Arm N + I:Nivolumab + 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	Biological: Nivolumab; specified dose on specified days; Other Names: BMS-936558; Biological: Ipilimumab; specified dose on specified days; Other Names: Yervoy
Active Comparator: Arm B: Bevacizumab; Cohort 2: Bevacizumab specified dose on specified days	Biological: Bevacizumab; specified dose on specified days; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	Includes events reported between first dose and 30 days after last dose of study therapy (up to 3 doses, up to approximately 2 months)
Percentage of Participants With Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d	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	From first dose to 30 days post last dose (up to approximately 34 months).
Percentage of Participants With Serious Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d	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	From first dose to 30 days post last dose (up to approximately 34 months).
Percentage of Participants With Specific Laboratory Abnormalities in Liver Tests in Cohorts 1, 1b, 1c and 1d	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.	From first dose to 30 days post last dose (up to approximately 34 months).
Percentage of Participants With Specific Laboratory Abnormalities in Thyroid Tests in Cohorts 1, 1b, 1c and 1d	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.	From first dose to 30 days post last dose (up to approximately 34 months).
Overall Survival (OS) for Cohort 2	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.	Time between the date of randomization and the date of death due to any cause (up to up to 17Jun2019, approximately 5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) at 12 Months for Cohort 2	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.	From randomization to 12 months following randomization
Overall Survival (OS) for Cohorts 1c and 1d	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.	Time between the date of randomization and the date of death due to any cause (up to approximately 10 years and 5 months)
Progression Free Survival (PFS) for Cohort 2	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.	Time from randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 10 years and 5 months)
Objective Response Rate (ORR) for Cohort 2	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.	Time from randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 10 years and 5 months)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Woroniecka K, Fecci PE. Immuno-synergy? Neoantigen vaccines and checkpoint blockade in glioblastoma. Neuro Oncol. 2020 Sep 29;22(9):1233-1234. doi: 10.1093/neuonc/noaa170. No abstract available.
• Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bahr O, Phuphanich S, Sepulveda JM, De Souza P, Sahebjam S, Carleton M, Tatsuoka K, Taitt C, Zwirtes R, Sampson J, Weller M. Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Jul 1;6(7):1003-1010. doi: 10.1001/jamaoncol.2020.1024.
• Stupp R. Drug development for glioma: are we repeating the same mistakes? Lancet Oncol. 2019 Jan;20(1):10-12. doi: 10.1016/S1470-2045(18)30827-1. Epub 2018 Dec 3. No abstract available.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2014
• Primary Completion (Actual): June 17, 2019
• Study Completion (Actual): June 21, 2024

Study Registration Dates

• First Submitted: December 17, 2013
• First Submitted That Met QC Criteria: December 20, 2013
• First Posted (Estimated): December 23, 2013

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: March 17, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Nivolumab; Bevacizumab; Ipilimumab
• Other Study ID Numbers: CA209-143; 2013-003738-34 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No