An Investigational Immuno-therapy Study of Nivolumab Compared to Temozolomide, Each Given With Radiation Therapy, for Newly-diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate 498)

• ClinicalTrials.gov Identifier: NCT02617589
• Recruitment Status: Completed
• First Posted: December 1, 2015
• Results First Posted: February 3, 2021
• Last Update Posted: March 28, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief Summary:

The purpose of this study is to evaluate patients with glioblastoma that is MGMT-unmethylated (the MGMT gene is not altered by a chemical change). Patients will receive Nivolumab every two weeks in addition to radiation therapy, and then every four weeks. They will be compared to patients receiving standard therapy with temozolomide in addition to radiation therapy.

Condition or disease	Intervention/treatment	Phase
Brain Cancer	Drug: Nivolumab; Drug: Temozolomide; Radiation: Radiotherapy	Phase 3

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 560 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination With Radiation Therapy in Newly Diagnosed Adult Subjects With Unmethylated MGMT (Tumor O-6-methylguanine DNA Methyltransferase) Glioblastoma (CheckMate 498: CHECKpoint Pathway and Nivolumab Clinical Trial Evaluation 498)
• Actual Study Start Date: March 1, 2016
• Actual Primary Completion Date: January 17, 2019
• Actual Study Completion Date: March 4, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nivolumab + Radiotherapy Arm; Nivolumab IV infusion + Radiotherapy dose as specified	Drug: Nivolumab; Radiation: Radiotherapy
Active Comparator: Temozolomide + Radiotherapy Arm; Temozolomide + Radiotherapy dose as specified	Drug: Temozolomide; Radiation: Radiotherapy

Outcome Measures

Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: up to 3 years ]
   OS is defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date.

Secondary Outcome Measures :

1. Kaplan-Meier Plot of Progression Free Survival [ Time Frame: From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years) ]
   PFS was defined as the time from randomization to the date of the first documented tumor progression or death due to any cause. Participants who did not have disease progression or who did not die were censored at the date of last tumor assessment. Participants who did not have any on study tumor assessment and did not have tumor progression or die were censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported progression were censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. Participants who had surgical resection post start of study treatment were censored at the last tumor assessment date prior to initiation of surgical resection. PFS was determined by investigator reported response based on the Radiologic Assessment in Neuro-Oncology criteria.
2. Overall Survival Rate at 24 Months [ Time Frame: At 24 Months ]
   The overall survival (OS) rate of (nivolumab + radiation therapy) and (temozolomide + radiation therapy) estimated as Kaplan-Meier probability of survival at 24 months. OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date.
3. Overall Survival in Tumor Mutational Burden (TMB) High Population [ Time Frame: From randomization to the date of death due to any cause (up to approximately 6 years) ]
   OS in all randomized participants that are tumor mutational burden high. OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date.
4. Progression Free Survival in Tumor Mutational Burden (TMB) High Population [ Time Frame: From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years) ]
   PFS in all randomized participants that are tumor mutational burden high. PFS was defined as the time from randomization to the date of the first documented tumor progression or death due to any cause. Participants who did not have disease progression or who did not die were censored at the date of last tumor assessment. Participants who did not have any on study tumor assessment and did not have tumor progression or die were censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported progression were censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. Participants who had surgical resection post start of study treatment were censored at the last tumor assessment date prior to initiation of surgical resection. PFS was determined by investigator reported response based on the Radiologic Assessment in Neuro-Oncology criteria.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Males and Females, age ≥ 18 years old
• Newly-diagnosed brain cancer or tumor called glioblastoma or GBM
• Tumor test result shows MGMT unmethylated type
• Karnofsky performance status of ≥ 70 (able to care for self)

Exclusion Criteria:

• Prior treatment for GBM (other than surgical resection)
• Any known tumor outside of the brain
• Recurrent or secondary GBM
• Active known or suspected autoimmune disease
• Biopsy with less than 20% of tumor removed

Other protocol-defined inclusion/exclusion criteria apply

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294-3410

United States, Arizona

Local Institution - 0083

Phoenix, Arizona, United States, 85013

United States, California

Cedars Sinai Medical Center

Los Angeles, California, United States, 90048

Local Institution - 0019

Los Angeles, California, United States, 90095-1769

Sutter Institute For Medical Research

Sacramento, California, United States, 95816

Sharp Memorial Hospital

San Diego, California, United States, 92123

The Regents of the University of California, San Francisco

San Francisco, California, United States, 94143-0372

United States, Connecticut

Yale Cancer Center

New Haven, Connecticut, United States, 06520

United States, District of Columbia

Georgetown University Medical Center

Washington, District of Columbia, United States, 20007

United States, Florida

University Of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, United States, 33136

Moffitt Cancer Center

Tampa, Florida, United States, 33612

United States, Georgia

Emory University - Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Illinois

The University Of Chicago

Chicago, Illinois, United States, 60637

United States, Kansas

University Of Kansas Medical Center

Westwood, Kansas, United States, 66205

United States, Kentucky

Norton Cancer Institute

Louisville, Kentucky, United States, 40202

United States, Maryland

Johns Hopkins University School Of Medicine

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

Massachusetts General Hospital

Boston, Massachusetts, United States, 02215

United States, Michigan

Local Institution - 0006

Detroit, Michigan, United States, 48202

United States, Missouri

Washington University School OF Medicine-Siteman Cancer Center

Saint Louis, Missouri, United States, 63110

United States, New Jersey

JFK Medical Center

Edison, New Jersey, United States, 08820

Local Institution - 0064

Hackensack, New Jersey, United States, 07601

United States, New York

Columbia University Medical Center (Cumc)

New York, New York, United States, 10032

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Levine Cancer Institute

Charlotte, North Carolina, United States, 28204

Preston Robert Tisch Brain Tumor Center at Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Local Institution - 0010

Cleveland, Ohio, United States, 44195

Local Institution - 0095

Columbus, Ohio, United States, 43210

United States, Pennsylvania

Local Institution - 0132

Allentown, Pennsylvania, United States, 18103

Local Institution - 0007

Philadelphia, Pennsylvania, United States, 19107

United States, South Carolina

Medical University Of South Carolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Local Institution - 0090

Chattanooga, Tennessee, United States, 37404

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

University Of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390-8852

University Of Texas Md Anderson Cancer Ctr

Houston, Texas, United States, 77030

United States, Utah

Local Institution - 0068

Salt Lake City, Utah, United States, 84112

United States, Washington

Swedish Neuroscience Institute

Seattle, Washington, United States, 98122

Australia, New South Wales

Royal North Shore Hospital

St. Leonards, New South Wales, Australia, 2065

Australia, Victoria

Local Institution - 0003

Heidelberg, Victoria, Australia, 3084

Local Institution - 0004

Prahran, Victoria, Australia, 3181

Australia, Western Australia

Local Institution - 0001

Nedlands, Western Australia, Australia, 6009

Australia

Local Institution - 0002

New South Wales, Australia, 2170

Austria

Local Institution - 0061

Linz, Austria, 4020

Local Institution - 0060

Vienna, Austria, 1090

Belgium

Universitair Ziekenhuis Brussel

Brussels, Belgium, 1090

Cliniques Universitaires Saint-Luc

Bruxelles, Belgium, 1200

Uz Leuven

Leuven, Belgium, 3000

Canada, British Columbia

BC Cancer - Vancouver

Vancouver, British Columbia, Canada, V5Z 4E6

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada, H3A 2B4

Denmark

Local Institution

Copenhagen, Denmark, 2100

Local Institution

Odense, Denmark, 5000

France

Local Institution - 0032

Bron Cedex, France, 69677

Local Institution

Lille Cedex, France, 59037

Local Institution - 0024

Marseille, France, 13005

Local Institution - 0101

Nancy, France, 54035

Local Institution - 0038

Paris cedex 13, France, 75651

Local Institution - 0023

Paris, France, 75010

Centre Eugene Marquis

Rennes, France, 35000

Local Institution - 0106

Toulouse, France, 31100

Germany

Local Institution - 0051

Bonn, Germany, 53105

Local Institution - 0072

Erlangen, Germany, 91054

Local Institution - 0049

Frankfurt am Main, Germany, 60528

Local Institution - 0073

Freiburg, Germany, 79106

Local Institution - 0054

Hamburg, Germany, 20246

Local Institution - 0052

Heidelberg, Germany, 69120

Local Institution - 0139

Koeln, Germany, 50937

Local Institution - 0050

Muenster, Germany, 48149

Local Institution - 0138

Munich, Germany, 81675

Local Institution - 0055

Regensburg, Germany, 93053

Local Institution - 0056

Tuebingen, Germany, 72076

Israel

Local Institution - 0096

Petach Tikva, Israel, 49100

Local Institution - 0097

Tel Aviv, Israel, 64239

Italy

Local Institution - 0076

Bologna, Italy, 40139

Local Institution - 0079

Milano, Italy, 20133

Local Institution - 0126

Padova, Italy, 35128

Local Institution - 0135

Rozzano (milano), Italy, 20089

Local Institution - 0078

Siena, Italy, 53100

Local Institution - 0077

Torino, Italy, 10126

Japan

Local Institution - 0115

Nagoya-shi, Aichi, Japan, 4668560

Local Institution - 0125

Chiba-shi, Chiba, Japan, 2608677

Local Institution - 0123

Hiroshima-Shi, Hiroshima, Japan, 7348551

Local Institution - 0122

Sapporo-shi, Hokkaido, Japan, 0608648

Local Institution - 0129

Kobe, Hyogo, Japan, 6500017

Local Institution - 0111

Tsukuba-shi, Ibaraki, Japan, 3058576

Local Institution - 0121

Kanazawa-shi, Ishikawa, Japan, 9200934

Local Institution - 0131

Kagoshima-shi, Kagoshima, Japan, 8908520

Local Institution - 0133

Sagamihara-shi, Kanagawa, Japan, 2520375

Local Institution - 0119

Kumamoto-shi, Kumamoto, Japan, 8608556

Local Institution - 0117

Kyoto-shi, Kyoto, Japan, 606-8507

Local Institution - 0116

Kyoto-shi, Kyoto, Japan, 6128555

Local Institution - 0134

Okayama-shi, Okayama, Japan, 7008558

Local Institution

Hirakata-shi, Osaka, Japan, 5731191

Local Institution - 0130

Suita-shi, Osaka, Japan, 565-0871

Local Institution - 0113

Hidaka, Saitama, Japan, 350-1298

Local Institution - 0128

Bunkyo-ku, Tokyo, Japan, 1138655

Local Institution - 0114

Chuo-ku, Tokyo, Japan, 1040045

Local Institution - 0118

Mitaka-shi, Tokyo, Japan, 181-8611

Local Institution - 0110

Yamagata-shi, Yamagata, Japan, 9909585

Local Institution - 0112

Tokyo, Japan, 1628666

Netherlands

NKI AVL

Amsterdam, Netherlands, 1066 CX

Universitair Medisch Centrum Groningen

Groningen, Netherlands, 9713 AP

Erasmus Mc

Rotterdam, Netherlands, 3015 CE

Local Institution - 0063

Utrecht, Netherlands, 3584CX

Norway

Local Institution

Oslo, Norway, 0379

Poland

Local Institution - 0080

Gdansk, Poland, 80952

Local Institution - 0081

Warszawa, Poland, 02-781

Russian Federation

Local Institution - 0070

Moscow, Russian Federation, 105229

Local Institution - 0105

Moscow, Russian Federation, 115478

Spain

Local Institution

Badalona-Barcelona, Spain, 08916

Local Institution

Barcelona, Spain, 08035

Local Institution - 0028

Barcelona, Spain, 08036

Local Institution - 0029

Madrid, Spain, 28007

Local Institution

Madrid, Spain, 28041

Local Institution

Santiago De Compostela, Spain, 15706

Local Institution - 0025

Valencia, Spain, 46014

Sweden

Local Institution

Lund, Sweden, 221 85

Local Institution

Solna, Sweden, 171 64

Switzerland

Local Institution - 0059

Geneve, Switzerland, 1211

Local Institution - 0057

Lausanne, Switzerland, 1011

Local Institution - 0053

Zuerich, Switzerland, 8091

United Kingdom

University College Hospital

London, Greater London, United Kingdom, NW1 2PG

Christie Hospital Nhs Found. Trust

Manchester, Greater Manchester, United Kingdom, M20 4BX

Royal Marsden Hospital

Sutton, Surrey, United Kingdom, SM2 5PT

Beaston West of Scotland Cancer Centre

Glasgow, United Kingdom, G12 0YN

Sponsors and Collaborators

Bristol-Myers Squibb

Ono Pharmaceutical Co. Ltd

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:

Study Protocol  [PDF] November 15, 2017

Statistical Analysis Plan  [PDF] February 8, 2019

More Information

Additional Information:

BMS Clinical Trial Information 

BMS Clinical Trial Patient Recruiting 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02617589
• Other Study ID Numbers: CA209-498; 2015-003739-37 ( EudraCT Number )
• First Posted: December 1, 2015
• Results First Posted: February 3, 2021
• Last Update Posted: March 28, 2023
• Last Verified: March 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Glioblastoma; Brain Neoplasms; 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; Nivolumab; Temozolomide; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents