A Study to Evaluate the Safety and Efficacy of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Participants With High Grade Primary Central Nervous System (CNS) Malignancies (CheckMate 908)

Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Subjects With High Grade Primary CNS Malignancies

The purpose of this study is to determine the safety and effectiveness of nivolumab alone and in combination with ipilimumab in pediatric patients with high grade primary central nervous system (CNS) malignancies.

Study Overview

• Status: Completed
• Conditions: Various Advanced Cancer
• Intervention / Treatment: Biological: Nivolumab; Biological: Ipilimumab

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 2

Expanded Access

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Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Local Institution - 0022
  • Queensland
    • Sth Brisbane, Queensland, Australia, 4101
      • Local Institution - 0035
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Local Institution
    • Parkville, Victoria, Australia, 3052
      • Local Institution - 0034
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Local Institution - 0033
• Brazil
  • Sao Paulo, Brazil, 04023-062
    • Local Institution - 0049
  • Sao Paulo, Brazil, 08270-070
    • Local Institution - 0050
  • RIO Grande DO SUL
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90035-074
      • Local Institution - 0052
  • Sao Paulo
    • Barretos, Sao Paulo, Brazil, 14784-400
      • Local Institution - 0051
    • Ribeirao Preto, Sao Paulo, Brazil, 14048-900
      • Local Institution - 0053
• Canada
  • Quebec, Canada, G1V 4G2
    • Local Institution - 0002
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Local Institution - 0021
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Local Institution - 0001
• France
  • Angers, France, 49100
    • Local Institution - 0028
  • Bordeaux Cedex, France, 33076
    • Local Institution - 0029
  • Lille, France, 59000
    • Local Institution - 0027
  • Lyon, France, 69008
    • Local Institution - 0025
  • Marseille, France, 13385 cedex 05
    • Local Institution - 0024
  • Paris, France, 75231 cedex 5
    • Local Institution - 0023
  • VIillejuif, France, 94805 CEDEX
    • Local Institution - 0026
  • Vandoeuvre les Nancy, France, 54500
    • Local Institution - 0064
• Germany
  • Essen, Germany, 45147
    • Local Institution - 0060
  • Hamburg, Germany, 20246
    • Local Institution - 0061
  • Heidelberg, Germany, 69120
    • Local Institution - 0063
  • Wuerzburg, Germany, 97080
    • Local Institution - 0062
• Hong Kong
  • Hong Kong, Hong Kong, 852
    • Local Institution - 0018
• Israel
  • Haifa, Israel, 3109601
    • Local Institution - 0059
  • Ramat Gan, Israel, 5266202
    • Local Institution - 0058
• Netherlands
  • Rotterdam, Netherlands, 3015 GJ
    • Local Institution - 0007
  • Utrecht, Netherlands, 3584 EA
    • Local Institution - 0008
• Norway
  • Oslo, Norway, 0027
    • Local Institution - 0067
• Poland
  • Warszawa, Poland, 04-730
    • Local Institution - 0047
• Russian Federation
  • Moscow, Russian Federation, 117997
    • Local Institution - 0048
• Spain
  • Esplugues de Llobregat, Spain, 08950
    • Local Institution - 0037
  • Madrid, Spain, 28009
    • Local Institution - 0038
  • Valencia, Spain, 46026
    • Local Institution - 0036
• Sweden
  • Solna, Sweden, 171 76
    • Local Institution - 0065
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, WC1N 3JH
      • Local Institution - 0010
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L12 2AP
      • Local Institution - 0013
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NEI 4LP
      • Local Institution - 0015
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Local Institution - 0057
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Local Institution - 0016
  • Florida
    • Gainesville, Florida, United States, 32611
      • Local Institution - 0046
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Local Institution - 0011
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Local Institution - 0005
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0043
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Local Institution - 0044
  • New York
    • New York, New York, United States, 10021
      • Local Institution - 0004
    • New York, New York, United States, 10032
      • Local Institution - 0017
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Local Institution - 0066
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Local Institution
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Local Institution - 0012
  • Texas
    • Houston, Texas, United States, 77030
      • Local Institution - 0042

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must have received standard of care therapy, and there must be no potentially-curative treatment available, in one of the following cohorts:
• A newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) that has been treated with radiation therapy (RT) but no chemotherapy
• A histologically confirmed recurrent or progressive non-brainstem High Grade Glioma (HGG) previously treated with surgical resection and RT
• A histologically confirmed medulloblastoma that has relapsed or is resistant to at least one line of prior therapy including surgery, RT, and chemotherapy
• A histologically confirmed ependymoma that has relapsed or is resistant to at least one line of prior therapy including surgical resection and RT
• A histologically-confirmed high grade CNS malignancy "other than above" which is recurrent or progressive after at least one line of prior therapy
• Lansky play score (LPS) for ≤ 16 years of age or Karnofsky performance scale (KPS) for > 16 years of age assessed within two weeks of enrollment must be >= 60
• A tumor sample must be available for submission to central laboratory (not required for DIPG)

Exclusion Criteria:

• An active, known, or suspected autoimmune disease
• A concurrent condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of start of study treatment
• Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

Other protocol defined inclusion/exclusion criteria apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module A	Biological: Nivolumab; Specified dose on specified days; Other Names: Opdivo, BMS-936558
Experimental: Module B	Biological: Nivolumab; Specified dose on specified days; Other Names: Opdivo, BMS-936558; Biological: Ipilimumab; Specified dose on specified days; Other Names: Yervoy, BMS-734016

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)	A dose-limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of study treatment. A participant was considered evaluable for a DLT if study treatment was delayed > 2 weeks or was discontinued due to a related Adverse Event (AE), or if planned study treatment (3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was administered and safety evaluation after 6 weeks on study is available to the study steering committee (SSC).	up to 6 weeks post-dosing
Number of Safety Lead-In Participants With Serious Adverse Events (SAEs)	The number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.	up to 6 weeks post-dosing
Number of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation	The number of Safety Lead-In Participants who experienced an Adverse Event (AE) during the course of the study that lead to discontinuation of study therapy.	From first dose to 30 days post-last dose (up to approximately 6 weeks)
Overall Survival (OS), Cohort 1 Only	Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.	up to approximately 42 months
Progression-Free Survival (PFS), Cohorts 2-4	Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.	up to approximately 42 months
Progression-Free Survival (PFS), Cohort 5 Only	Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.	up to approximately 42 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS), Cohort 1 Only	Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Progression is defined as: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement; Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor; Failure to return for evaluation as a result of death or deteriorating condition; Clear progression of non-measurable disease	From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months)
Overall Survival at 12 Months (OS12), Cohorts 1-4	Overall survival at 12 months (OS12) is defined as the percentage of participants who are alive at 12 months, measured as the survival rate at 12 months from Kaplan-Meier product limit cumulative probability.	From first dose to up to 12 months after first dose
Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5	Progression-free survival at 6 months (PFS6) is defined as the percentage of participants who are progression free and alive at 6 months following first dose date, measured as the survival rate at 6 months from Kaplan-Meier product limit cumulative probability of progression free. Progression is defined as: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement; Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor; Failure to return for evaluation as a result of death or deteriorating condition; Clear progression of non-measurable disease	From first dose to up to 6 months after first dose
Overall Survival (OS), Cohorts 2-5	Overall survival (OS) is defined as the time between date of first dose and the date of death for Cohorts 2-5.	From first dose to the date of death (up to approximately 55 months)
Number of Treated Participants With Adverse Events (AEs)	The number of treated participants who experienced an Adverse Event (AE) during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.	From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
Number of Treated Participants With Serious Adverse Events (SAEs)	The number of treated participants who experienced a Serious Adverse Event (SAE) during the course of the study. SAE is defined as any untoward medical occurrence that, at any dose: Results in death; Is life-threatening; Requires inpatient hospitalization or causes prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; Is an important medical event Note: The reporting timeframe of the SAEs for this Outcome Measure (first dose to 30 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the AE section of the results form (first dose to 100 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.	From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
Number of Treated Participants With Drug-Related Adverse Events	The number of treated participants who experienced a Drug-Related Adverse Event during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.	From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
Number of Treated Participants With Adverse Events Leading to Discontinuation	The number of treated participants who experienced an Adverse Event leading to discontinuation during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.	From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
Number of Treated Participant Deaths	The number of treated participants who died during the course of the study.	From first dose to the date of death (up to approximately 55 months)
Number of Treated Participant With Laboratory Abnormalities - Liver	The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Units per Liter (U/L) Results reported in International System of Units (SI)	From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
Number of Treated Participant With Laboratory Abnormalities - Thyroid	The number of treated participants who experienced a laboratory abnormality of the thyroid during the course of the study. Free T3 (FT3) Free T4 (FT4) Thyroid stimulating hormone (TSH) Lower Limit of Normal (LLN) Upper limit of normal (ULN) Milliunits per Liter (mlU/L) Results reported in International System of Units (SI)	From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2017
• Primary Completion (Actual): March 10, 2020
• Study Completion (Actual): January 17, 2022

Study Registration Dates

• First Submitted: April 5, 2017
• First Submitted That Met QC Criteria: April 24, 2017
• First Posted (Actual): April 27, 2017

Study Record Updates

• Last Update Posted (Actual): August 9, 2022
• Last Update Submitted That Met QC Criteria: July 14, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: CA209-908; 2016-004441-82 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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