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)

• ClinicalTrials.gov Identifier: NCT03130959
• Recruitment Status: Completed
• First Posted: April 27, 2017
• Results First Posted: April 1, 2021
• Last Update Posted: August 9, 2022
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: April 5, 2017
• First Posted Date: April 27, 2017
• Results First Submitted Date: March 3, 2021
• Results First Posted Date: April 1, 2021
• Last Update Posted Date: August 9, 2022
• Actual Study Start Date: June 12, 2017
• Actual Primary Completion Date: March 10, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 14, 2022)

• Number of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: up to 6 weeks post-dosing ]
  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).
• Number of Safety Lead-In Participants With Serious Adverse Events (SAEs) [ Time Frame: up to 6 weeks post-dosing ]
  The number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.
• Number of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation [ Time Frame: From first dose to 30 days post-last dose (up to approximately 6 weeks) ]
  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.
• Overall Survival (OS), Cohort 1 Only [ Time Frame: up to approximately 42 months ]
  Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.
• Progression-Free Survival (PFS), Cohorts 2-4 [ Time Frame: up to approximately 42 months ]
  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-Free Survival (PFS), Cohort 5 Only [ Time Frame: up to approximately 42 months ]
  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.

Original Primary Outcome Measures (submitted: April 24, 2017)

• Incidence of dose limiting toxicity (DLT) [ Time Frame: Approximately 6 weeks ]
  Safety and tolerability
• Incidence of serious adverse events (SAEs) [ Time Frame: Approximately 6 weeks ]
  Safety and tolerability
• Incidence of adverse events (AEs) [ Time Frame: Approximately 6 weeks ]
  Safety and tolerability
• Overall Survival (OS) [ Time Frame: Approximately 3 years ]
  Diffuse Intrinsic Pontine Glioma (DIPG).
• Progression Free Survival (PFS) [ Time Frame: Approximately 2 years ]
  All other tumor types.

Current Secondary Outcome Measures (submitted: July 14, 2022)

• Progression-Free Survival (PFS), Cohort 1 Only [ Time Frame: From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months) ]
  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
• Overall Survival at 12 Months (OS12), Cohorts 1-4 [ Time Frame: From first dose to up to 12 months after first dose ]
  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.
• Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5 [ Time Frame: From first dose to up to 6 months after first dose ]
  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
• Overall Survival (OS), Cohorts 2-5 [ Time Frame: From first dose to the date of death (up to approximately 55 months) ]
  Overall survival (OS) is defined as the time between date of first dose and the date of death for Cohorts 2-5.
• Number of Treated Participants With Adverse Events (AEs) [ Time Frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months) ]
  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.
• Number of Treated Participants With Serious Adverse Events (SAEs) [ Time Frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months) ]
  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.
• Number of Treated Participants With Drug-Related Adverse Events [ Time Frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months) ]
  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.
• Number of Treated Participants With Adverse Events Leading to Discontinuation [ Time Frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months) ]
  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.
• Number of Treated Participant Deaths [ Time Frame: From first dose to the date of death (up to approximately 55 months) ]
  The number of treated participants who died during the course of the study.
• Number of Treated Participant With Laboratory Abnormalities - Liver [ Time Frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months) ]
  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)
• Number of Treated Participant With Laboratory Abnormalities - Thyroid [ Time Frame: From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months) ]
  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)

Original Secondary Outcome Measures (submitted: April 24, 2017)

• Incidence of AEs [ Time Frame: Approximately 3 years ]
  Safety
• Incidence of SAEs [ Time Frame: Approximately 3 years ]
  Safety
• Incidence of laboratory abnormalities [ Time Frame: Approximately 3 years ]
  Safety
• Progression Free Survival (PFS) [ Time Frame: 18 months to 24 months ]
  Diffuse Intrinsic Pontine Glioma (DIPG)
• Overall Survival [ Time Frame: Approximately 12 months ]
  Diffuse Intrinsic Pontine Glioma (DIPG). Overall Survival at 12 month point (OS(12)).
• Progression Free Survival [ Time Frame: Approximately 6 months ]
  High Grade Glioma (HGG), Medulloblastoma, Ependymoma, and other high-grade CNS tumors. At 6 months (PFS(6)).
• Overall Survival (OS) [ Time Frame: Approximately 3 years ]
  High Grade Glioma (HGG), Medulloblastoma, Ependymoma, and other high-grade CNS tumors.
• Overall Survival [ Time Frame: Approximately 12 months ]
  High Grade Glioma (HGG), Medulloblastoma, Ependymoma. At 12 month point (OS(12)).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: Phase Ib /II Clinical Trial of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Subjects With High Grade Primary CNS Malignancies
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Various Advanced Cancer

Intervention

• Biological: Nivolumab
  Specified dose on specified days
  Other Name: Opdivo, BMS-936558
• Biological: Ipilimumab
  Specified dose on specified days
  Other Name: Yervoy, BMS-734016

Study Arms

• Experimental: Module A
  Intervention: Biological: Nivolumab
• Experimental: Module B
  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 26, 2021): 166
• Original Estimated Enrollment (submitted: April 24, 2017): 170
• Actual Study Completion Date: January 17, 2022
• Actual Primary Completion Date: March 10, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, France, Germany, Hong Kong, Israel, Netherlands, Norway, Poland, Russian Federation, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT03130959
• Other Study ID Numbers: CA209-908; 2016-004441-82 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Bristol-Myers Squibb
• Verification Date: July 2022