An Investigational Immuno-therapy Study of Temozolomide Plus Radiation Therapy With Nivolumab or Placebo, for Newly Diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate548)

• ClinicalTrials.gov Identifier: NCT02667587
• Recruitment Status: Active, not recruiting
• First Posted: January 29, 2016
• Results First Posted: February 3, 2022
• Last Update Posted: July 19, 2022
• 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-methylated (the MGMT gene is altered by a chemical change). Patients will receive temozolomide plus radiation therapy. They will be compared to patients receiving nivolumab in addition to temozolomide plus radiation therapy.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 716 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 3 Single Blind Study of Temozolomide Plus Radiation Therapy Combined With Nivolumab or Placebo in Newly Diagnosed Adult Subjects With MGMT-Methylated (Tumor O6-methylguanine DNA Methyltransferase) Glioblastoma
• Actual Study Start Date: May 9, 2016
• Actual Primary Completion Date: December 22, 2020
• Estimated Study Completion Date: August 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nivolumab + Temozolomide + Radiotherapy; Nivolumab: specified dose on specified days; IV (intravenous) infusion Temozolomide: 75 mg (milligram)/meter squared daily during Radiotherapy, 4 week treatment break, 150 mg/meter squared Day 1-5 for Cycle 1 and increased to 200 mg/meter squared Day 1-5 for Cycle2-Cycle 6 as tolerated; orally (additional cycles may be permitted with approval of sponsor) Radiotherapy: 2 gray units (joule of radiation energy per kilogram) 5 times per week for 6 weeks	Drug: Nivolumab; Other Names: Opdivo; Nivo; N; BMS-936558; Drug: Temozolomide; Other Names: Temodar; TMZ; Temodal; Temcad; Radiation: Radiotherapy; Other Name: RT
Placebo Comparator: Nivolumab placebo + Temozolomide + Radiotherapy; Nivolumab Placebo: specified dose on specified days; IV infusion Temozolomide: 75 mg/meter squared daily during Radiotherapy, 4 week treatment break, 150 mg/meter squared Day 1-5 for Cycle 1 and increased to 200 mg/meter squared Day 1-5 for Cycle2-Cycle 6 as tolerated; orally (additional cycles may be permitted with approval of sponsor) Radiotherapy: 2 gray units 5x/week x 6 weeks	Drug: Temozolomide; Other Names: Temodar; TMZ; Temodal; Temcad; Radiation: Radiotherapy; Other Name: RT; Other: Nivolumab Placebo

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) Determined by BICR [ Time Frame: From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 4.5 years) ]
   The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by a Blinded Independent Central Review (BICR) assessed based on Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease.
2. Overall Survival (OS) [ Time Frame: From randomization to date of death (up to approximately 4.5 years) ]
   The time from the date of randomization to the date of death. who have not died by the end of the study will be censored to last known date alive. OS is assessed in the randomized population with no corticosteroids at baseline population and in the overall randomized population.

Secondary Outcome Measures :

1. Overall Survival (OS) Rates at 12 Months [ Time Frame: From randomization to 12 months after first dose ]
   Overall Survival (OS) rate is defined as the percentage of participants surviving at 12 months
2. Overall Survival (OS) Rates at 24 Months [ Time Frame: From randomization to 24 months after first dose ]
   Overall Survival (OS) rate is defined as the percentage of participants surviving at 24 months
3. Progression Free Survival (PFS) Based on Investigator Assessment [ Time Frame: From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 4.5 years) ]
   The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by investigator assessment based Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease.

Eligibility Criteria

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

Criteria

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Males and Females, age ≥ 18 years old
• Newly diagnosed brain cancer or tumor called glioblastoma or GBM
• Karnofsky performance status of ≥ 70 (able to take care of self)
• Substantial recovery from surgery resection
• Tumor test result shows MGMT methylated or indeterminate tumor subtype

Exclusion Criteria:

• Biopsy-only of GBM with less than 20% of tumor removed
• 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

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35294-3410

United States, Arizona

Local Institution - 0003

Phoenix, Arizona, United States, 85013

United States, California

Cedars Sinai Medical Center

Los Angeles, California, United States, 90048

UCLA Neuro-Oncology Program

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 University School Of Medicine

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

Local Institution - 0030

Tampa, Florida, United States, 33612

United States, Illinois

Local Institution

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

Local Institution - 0028

Boston, Massachusetts, United States, 02215

Massachusetts General Hospital

Boston, Massachusetts, United States, 02215

United States, Michigan

Local Institution - 0035

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 - 0012

Hackensack, New Jersey, United States, 07601

United States, New York

Columbia University

New York, New York, United States, 10032

Local Institution - 0024

New York, New York, United States, 10065

United States, North Carolina

Local Institution - 0032

Charlotte, North Carolina, United States, 28204

Preston Robert Tisch Brain Tumor Center at Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Pennsylvania

Local Institution - 0098

Allentown, Pennsylvania, United States, 18105

Local Institution - 0016

Philadelphia, Pennsylvania, United States, 19107

United States, South Carolina

Medical University Of South Carolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Erlanger Oncology & Hematology - Univ. of TN

Chattanooga, Tennessee, United States, 37403

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

University Of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390-8852

United States, Utah

Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

United States, Washington

Local Institution - 0005

Seattle, Washington, United States, 98122

Australia, New South Wales

Local Institution

Liverpool, New South Wales, Australia, 2170

Royal North Shore Hospital

St. Leonards, New South Wales, Australia, 2065

Australia, Victoria

Local Institution

Heidelberg, Victoria, Australia, 3084

Local Institution

Prahran, Victoria, Australia, 3181

Australia, Western Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia, 6009

Austria

Local Institution - 0062

Linz, Austria, 4020

Medical University Of Vienna

Vienna, Austria, 1090

Belgium

Local Institution - 0070

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 - 0043

Lille Cedex, France, 59037

Local Institution - 0041

Lyon Cedex 03, France, 69394

Local Institution - 0040

Marseille, France, 13385

Local Institution - 0042

Nancy, France, 54035

Groupe Hospitalier Pitie-Salpetriere

Paris cedex 13, France, 75651

Hopital Saint Louis

Paris, France, 75010

Local Institution - 0044

Rennes Cedex, France, 35042

Local Institution - 0045

Toulouse, France, 31100

Germany

Universitaetsklinikum Bonn

Bonn, Germany, 53127

Uniklinik Erlangen

Erlangen, Germany, 91054

Klinikum Der J. W. Goethe-Universitaet Frankfurt/Main

Frankfurt Am Main, Germany, 60528

Local Institution - 0124

Freiburg, Germany, 79106

Local Institution - 0057

Hamburg, Germany, 20246

Local Institution - 0056

Heidelberg, Germany, 69120

Universitaetsklinikum Koeln

Koeln, Germany, 50937

Universitaetsklinikum Muenster

Muenster, Germany, 48149

Klinikum rechts der Isar der Technischen Universitat Munchen

Munich, Germany, 81675

Universitaetsklinikum Regensburg

Regensburg, Germany, 93053

Universitasklinikum Tubingen

Tuebingen, Germany, 72076

Israel

Local Institution

Petach Tikva, Israel, 49100

Local Institution

Tel Aviv, Israel, 64239

Italy

Local Institution

Bologna, Italy, 40139

Local Institution

Milano, Italy, 20133

Local Institution

Padova, Italy, 35128

Local Institution - 0127

Rozzano (milano), Italy, 20089

Local Institution

Siena, Italy, 53100

Azienda Ospedaliera Citta della Salute e della Scienza

Torino, Italy, 10126

Japan

Local Institution

Nagoya-shi, Aichi, Japan, 4668560

Local Institution

Chiba-shi, Chiba, Japan, 2608677

Local Institution

Hiroshima-Shi, Hiroshima, Japan, 7348551

Local Institution

Sapporo-shi, Hokkaido, Japan, 0608648

Local Institution

Kobe-shi, Hyogo, Japan, 650-0017

Local Institution

Tsukuba-shi, Ibaraki, Japan, 3058576

Local Institution - 0103

Kanazawa-shi, Ishikawa, Japan, 9200934

Local Institution

Kagoshima-shi, Kagoshima, Japan, 8908520

Local Institution

Sagamihara-shi, Kanagawa, Japan, 2520375

Local Institution

Kumamoto-shi, Kumamoto, Japan, 8608556

Local Institution

Kyoto-shi, Kyoto, Japan, 6128555

Local Institution

Okayama-shi, Okayama, Japan, 7008558

Local Institution

Hirakata-shi, Osaka, Japan, 5731191

Local Institution

Suita, Osaka, Japan, 5650871

Local Institution

Hidaka-shi, Saitama, Japan, 3501298

Local Institution - 0114

Bunkyo-ku, Tokyo, Japan, 1138655

Local Institution - 0111

Chuo-ku, Tokyo, Japan, 1040045

Local Institution - 0107

Mitaka-shi, Tokyo, Japan, 181-8611

Local Institution

Shinjuku-ku, Tokyo, Japan, 1628666

Local Institution

Yamagata-shi, Yamagata, Japan, 9909585

Local Institution

Kyoto, Japan, 6068507

Netherlands

Local Institution - 0073

Rotterdam, Zuid-Holland, Netherlands, 3015 GD

NKI AVL

Amsterdam, Netherlands, 1066 CX

Universitair Medisch Centrum Groningen

Groningen, Netherlands, 9713 AP

Local Institution - 0072

Utrecht, Netherlands, 3584 CX

Norway

Local Institution

Oslo, Norway, 0424

Poland

Uniwersyteckie Centrum Kliniczne Klinika Onkologii I Radiote

Gdansk, Poland, 80-214

Klinika Nowotworow Glowy i Szyi

Warszawa, Poland, 02-781

Russian Federation

Local Institution - 0095

Moscow, Russian Federation, 105229

Local Institution

Moscow, Russian Federation, 115478

Spain

Local Institution

Badalona-barcelona, Spain, 08916

Local Institution

Barcelona, Spain, 08035

Local Institution

Barcelona, Spain, 08036

Local Institution - 0077

Madrid, Spain, 28009

Local Institution

Madrid, Spain, 28041

Local Institution

Santiago Compostela, Spain, 15706

Local Institution

Valencia, Spain, 46014

Sweden

Local Institution

Lund, Sweden, 221 85

Local Institution

Solna, Sweden, 171 64

Switzerland

Local Institution - 0065

Geneve, Switzerland, 1211

Local Institution - 0064

Lausanne, Switzerland, 1011

UniversitaetsSpital Zurich

Zuerich, Switzerland, 8091

United Kingdom

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

University College Hospital

London, United Kingdom, NW1 2BU

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] September 2, 2021

Statistical Analysis Plan  [PDF] March 29, 2021

More Information

Additional Information:

BMS Clinical Trial Information 

BMS Clinical Trial Patient Recruiting 

FDA Safety Alerts and Recalls 

Investigator Inquiry Form 

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

Lim M, Weller M, Idbaih A, Steinbach J, Finocchiaro G, Raval RR, Ansstas G, Baehring J, Taylor JW, Honnorat J, Petrecca K, De Vos F, Wick A, Sumrall A, Sahebjam S, Mellinghoff IK, Kinoshita M, Roberts M, Slepetis R, Warad D, Leung D, Lee M, Reardon DA, Omuro A. Phase 3 Trial of Chemoradiotherapy With Temozolomide Plus Nivolumab or Placebo for Newly Diagnosed Glioblastoma With Methylated MGMT Promoter. Neuro Oncol. 2022 May 2. pii: noac116. doi: 10.1093/neuonc/noac116. [Epub ahead of print]

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.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02667587
• Other Study ID Numbers: CA209-548; 2015-004722-34 ( EudraCT Number )
• First Posted: January 29, 2016
• Results First Posted: February 3, 2022
• Last Update Posted: July 19, 2022
• Last Verified: July 2022

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

Additional relevant MeSH terms:

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