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

Study Overview
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Brief Summary
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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.

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

Conditions
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Various Advanced Cancer

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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) |