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

Phase 3
Completed
Conditions
Recurrent Glioblastoma
Interventions
Biological: Nivolumab
Biological: Bevacizumab
Biological: 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
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
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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)
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Arm N + I:Nivolumab + IpilimumabNivolumabCohort 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:NivolumabNivolumabCohort 1, 1c, 1d and 2: Nivolumab specified dose on specified days
Arm B: BevacizumabBevacizumabCohort 2: Bevacizumab specified dose on specified days
Arm N + I:Nivolumab + IpilimumabIpilimumabCohort 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
NameTimeMethod
Percentage of Participants With Specific Laboratory Abnormalities in Thyroid Tests in Cohorts 1, 1b, 1c and 1dFrom 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 DosesIncludes 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 1dFrom 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 1dFrom 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 1dFrom 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 2Time 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
NameTimeMethod
Overall Survival (OS) at 12 Months for Cohort 2From 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 1dTime 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 2Time 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 2Time 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

🇨🇭

Zuerich, Switzerland

UniversitaetsSpital Zurich

🇨🇭

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)

🇨🇭

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

🇨🇭

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

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