Brain Cancer
Conditions
Brief summary
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.
Interventions
DRUGNivolumab
DRUGTemozolomide
RADIATIONRadiotherapy
Sponsors
Ono Pharmaceutical Co. Ltd
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | up to 3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Plot of Progression Free Survival | From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years) | 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. |
| Overall Survival Rate at 24 Months | 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. |
| Overall Survival in Tumor Mutational Burden (TMB) High Population | From randomization to the date of death due to any cause (up to approximately 6 years) | 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. |
| Progression Free Survival in Tumor Mutational Burden (TMB) High Population | From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years) | 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. |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab + Radiation Therapy Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously | 280 |
| Temozolomide + Radiation Therapy Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally | 280 |
| Total | 560 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomization | Participant Withdrew Consent | 1 | 2 |
| Randomization | Request to Discontinue Study Treatment | 1 | 3 |
| Treatment | Adverse Event Unrelated to Study Drug | 16 | 9 |
| Treatment | Death | 1 | 1 |
| Treatment | Disease Progression | 216 | 136 |
| Treatment | Maximum Clinical Benefit | 0 | 2 |
| Treatment | Other Reasons | 3 | 3 |
| Treatment | Participant Request to Discontinue | 12 | 21 |
| Treatment | Participant Withdrew Consent | 2 | 6 |
| Treatment | Poor/Non Compliance | 1 | 1 |
| Treatment | Study Drug Toxicity | 27 | 20 |
Baseline characteristics
| Characteristic | Nivolumab + Radiation Therapy | Temozolomide + Radiation Therapy | Total |
|---|---|---|---|
| Age, Continuous | 58.8 Years STANDARD_DEVIATION 10.8 | 56.5 Years STANDARD_DEVIATION 11.3 | 57.6 Years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 112 Participants | 95 Participants | 207 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 165 Participants | 183 Participants | 348 Participants |
| Race/Ethnicity, Customized Asian | 33 Participants | 28 Participants | 61 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 9 Participants | 21 Participants |
| Race/Ethnicity, Customized White | 231 Participants | 240 Participants | 471 Participants |
| Sex: Female, Male Female | 90 Participants | 105 Participants | 195 Participants |
| Sex: Female, Male Male | 190 Participants | 175 Participants | 365 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 269 / 280 | 253 / 280 |
| other Total, other adverse events | 262 / 278 | 259 / 275 |
| serious Total, serious adverse events | 206 / 278 | 141 / 275 |
Outcome results
Primary
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.
Time frame: up to 3 years
Population: All Randomized Participants: All enrolled Participants who were randomized to any treatment arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Radiation Therapy | Overall Survival (OS) | 13.40 Months |
| Temozolomide + Radiation Therapy | Overall Survival (OS) | 14.88 Months |
p-value: 0.003795% CI: [1.09, 1.58]Log-rank test stratified
Secondary
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.
Time frame: From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years)
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Radiation Therapy | Kaplan-Meier Plot of Progression Free Survival | 6.01 Months |
| Temozolomide + Radiation Therapy | Kaplan-Meier Plot of Progression Free Survival | 6.21 Months |
95% CI: [1.19, 1.71]Log-rank test stratified
Secondary
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.
Time frame: From randomization to the date of death due to any cause (up to approximately 6 years)
Population: Data was not and will never be collected
Secondary
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.
Time frame: At 24 Months
Population: All Randomized Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab + Radiation Therapy | Overall Survival Rate at 24 Months | 10.6 Percentage of participants |
| Temozolomide + Radiation Therapy | Overall Survival Rate at 24 Months | 21.2 Percentage of participants |
Secondary
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.
Time frame: From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years)
Population: Data was not and will never be collected
Post Hoc
Kaplan-Meier Plot of Overall Survival (OS) - Extended Collection
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. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date (assessments were made until March 4, 2022).
Time frame: From randomization to the date of death due to any cause (up to approximately 6 years)
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Radiation Therapy | Kaplan-Meier Plot of Overall Survival (OS) - Extended Collection | 13.34 Months |
| Temozolomide + Radiation Therapy | Kaplan-Meier Plot of Overall Survival (OS) - Extended Collection | 14.92 Months |
p-value: 0.002495% CI: [1.1, 1.55]Log-rank test stratified