An Investigational Immuno-therapy Study of Nivolumab Compared to Temozolomide, Each Given With Radiation Therapy, for Newly-diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate patients with glioblastoma that is MGMT-unmethylated (the MGMT gene is not altered by a chemical change). Patients will receive Nivolumab every two weeks in addition to radiation therapy, and then every four weeks. They will be compared to patients receiving standard therapy with temozolomide in addition to radiation therapy.

Official Title
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A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination With Radiation Therapy in Newly Diagnosed Adult Subjects With Unmethylated MGMT (Tumor O-6-methylguanine DNA Methyltransferase) Glioblastoma (CheckMate 498: CHECKpoint Pathway and Nivolumab Clinical Trial Evaluation 498)

Conditions
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Brain Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Temozolomide
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females, age ≥ 18 years old Newly-diagnosed brain cancer or tumor called glioblastoma or GBM Tumor test result shows MGMT unmethylated type Karnofsky performance status of ≥ 70 (able to care for self) Exclusion Criteria: Prior treatment for GBM (other than surgical resection) Any known tumor outside of the brain Recurrent or secondary GBM Active known or suspected autoimmune disease Biopsy with less than 20% of tumor removed Other protocol-defined inclusion/exclusion criteria apply

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: Nivolumab + Radiotherapy Arm<br>Nivolumab IV infusion + Radiotherapy dose as specified | Drug: Nivolumab<br> <br> Radiation: Radiotherapy<br> <br> |
| Active Comparator: Temozolomide + Radiotherapy Arm<br>Temozolomide + Radiotherapy dose as specified | Drug: Temozolomide<br> <br> Radiation: Radiotherapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Plot of Progression Free Survival | PFS was defined as the time from randomization to the date of the first documented tumor progression or death due to any cause. Participants who did not have disease progression or who did not die were censored at the date of last tumor assessment. Participants who did not have any on study tumor assessment and did not have tumor progression or die were censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported progression were censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. Participants who had surgical resection post start of study treatment were censored at the last tumor assessment date prior to initiation of surgical resection. PFS was determined by investigator reported response based on the Radiologic Assessment in Neuro-Oncology criteria. | From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years) | 
| Overall Survival Rate at 24 Months | The overall survival (OS) rate of (nivolumab + radiation therapy) and (temozolomide + radiation therapy) estimated as Kaplan-Meier probability of survival at 24 months. OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date. | At 24 Months | 
| Overall Survival in Tumor Mutational Burden (TMB) High Population | OS in all randomized participants that are tumor mutational burden high. OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date. | From randomization to the date of death due to any cause (up to approximately 6 years) | 
| Progression Free Survival in Tumor Mutational Burden (TMB) High Population | PFS in all randomized participants that are tumor mutational burden high. PFS was defined as the time from randomization to the date of the first documented tumor progression or death due to any cause. Participants who did not have disease progression or who did not die were censored at the date of last tumor assessment. Participants who did not have any on study tumor assessment and did not have tumor progression or die were censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported progression were censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. Participants who had surgical resection post start of study treatment were censored at the last tumor assessment date prior to initiation of surgical resection. PFS was determined by investigator reported response based on the Radiologic Assessment in Neuro-Oncology criteria. | From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years) |