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

Study Overview
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Brief Summary
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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
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Allocation: Randomized (Cohorts 1, 2 and Part B of 1c/1d), Non-Randomized (Cohorts 1b, and Part A of 1c/1d)

Official Title
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A Randomized Phase 3 Open Label Study of Nivolumab Versus Bevacizumab and Multiple Phase 1 Safety Cohorts of Nivolumab or Nivolumab in Combination With Ipilimumab Across Different Lines of Glioblastoma

Conditions
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Recurrent Glioblastoma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Bevacizumab
* Biological: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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 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)

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm N:Nivolumab<br>Cohort 1, 1c, 1d and 2: Nivolumab specified dose on specified days | Biological: Nivolumab<br>* specified dose on specified days<br>* Other names: BMS-936558;|
| Experimental: Arm N + I:Nivolumab + Ipilimumab<br>Cohort 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 | Biological: Nivolumab<br>* specified dose on specified days<br>* Other names: BMS-936558;Biological: Ipilimumab<br>* specified dose on specified days<br>* Other names: Yervoy;|
| Active Comparator: Arm B: Bevacizumab<br>Cohort 2: Bevacizumab specified dose on specified days | Biological: Bevacizumab<br>* specified dose on specified days<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Doses | 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 | Includes events reported between first dose and 30 days after last dose of study therapy (up to 3 doses, up to approximately 2 months) | 
| Percentage of Participants With Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d | 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 | From first dose to 30 days post last dose (up to approximately 34 months). | 
| Percentage of Participants With Serious Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d | 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 | From first dose to 30 days post last dose (up to approximately 34 months). | 
| Percentage of Participants With Specific Laboratory Abnormalities in Liver Tests in Cohorts 1, 1b, 1c and 1d | 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. | From first dose to 30 days post last dose (up to approximately 34 months). | 
| Percentage of Participants With Specific Laboratory Abnormalities in Thyroid Tests in Cohorts 1, 1b, 1c and 1d | 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. | From first dose to 30 days post last dose (up to approximately 34 months). | 
| Overall Survival (OS) for Cohort 2 | 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. | Time between the date of randomization and the date of death due to any cause (up to 17Jun2019, approximately 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) at 12 Months for Cohort 2 | 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. | From randomization to 12 months following randomization | 
| Overall Survival (OS) for Cohorts 1c and 1d | 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. | Time between the date of randomization and the date of death due to any cause (up to 17Jun2019, approximately 5 years) | 
| Progression Free Survival (PFS) for Cohort 2 | 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. | Time from randomization to the date of the first documented tumor progression or death due to any cause (up to 17Jun2019, approximately 5 years) | 
| Objective Response Rate (ORR) for Cohort 2 | 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. | Time from randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 31 months) |