Brain Neoplasms
Conditions
Brief summary
The purpose of this study is to evaluate patients with glioblastoma that is MGMT-methylated (the MGMT gene is altered by a chemical change). Patients will receive temozolomide plus radiation therapy. They will be compared to patients receiving nivolumab in addition to temozolomide plus radiation therapy.
Interventions
Sponsors
Ono Pharmaceutical Co. Ltd
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Males and Females, age ≥ 18 years old * Newly diagnosed brain cancer or tumor called glioblastoma or GBM * Karnofsky performance status of ≥ 70 (able to take care of self) * Substantial recovery from surgery resection * Tumor test result shows MGMT methylated or indeterminate tumor subtype
Exclusion criteria
* Biopsy-only of GBM with less than 20% of tumor removed * 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 Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Determined by BICR | From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 4.5 years) | The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by a Blinded Independent Central Review (BICR) assessed based on Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease. |
| Overall Survival (OS) | From randomization to date of death (up to approximately 4.5 years) | The time from the date of randomization to the date of death. who have not died by the end of the study will be censored to last known date alive. OS is assessed in the randomized population with no corticosteroids at baseline population and in the overall randomized population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Rates at 12 Months | From randomization to 12 months after first dose | Overall Survival (OS) rate is defined as the percentage of participants surviving at 12 months |
| Overall Survival (OS) Rates at 24 Months | From randomization to 24 months after first dose | Overall Survival (OS) rate is defined as the percentage of participants surviving at 24 months |
| Progression Free Survival (PFS) Based on Investigator Assessment | From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 4.5 years) | The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by investigator assessment based Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease. |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
716 participants were randomized into the study, 709 participants received study treatment
Participants by arm
| Arm | Count |
|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab Nivolumab: specified dose on specified days; IV (intravenous) infusion Temozolomide: 75 mg (milligram)/meter squared daily during Radiotherapy, 4 week treatment break, 150 mg/meter squared Day 1-5 for Cycle 1 and increased to 200 mg/meter squared Day 1-5 for Cycle2-Cycle 6 as tolerated; orally (additional cycles may be permitted with approval of sponsor) Radiotherapy: 2 gray units (joule of radiation energy per kilogram) 5 times per week for 6 weeks | 358 |
| Radiotherapy, Temozolomide Plus Placebo Radiotherapy: A total dose of 60 Gy \[Gray (radiotherapy dose)\], in 2 Gy daily fractions on 5 days/week, will be administered in 6 weeks (30 fractions).
Placebo: administered intravenously (IV) as a 30 minute infusion every 2 weeks for 8 doses followed by a 30 minute infusion every 4 weeks beginning after 8 doses
Temozolomide: 75 mg/m2 orally daily during radiation therapy followed by 4 week break then 6 (28-day) cycles temozolomide on Days 1-5 at 150 mg/m2 in Cycle 1 increasing to 200 mg/m2 as tolerated up to 6 cycles. | 358 |
| Total | 716 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| End of Treatment | administrative reason by sponsor | 1 | 29 |
| End of Treatment | Adverse Event Unrelated to Study Drug | 19 | 20 |
| End of Treatment | Death | 2 | 1 |
| End of Treatment | Disease Progression | 193 | 226 |
| End of Treatment | Lost to Follow-up | 1 | 2 |
| End of Treatment | maximum clinical benefit | 4 | 4 |
| End of Treatment | other reasonse | 21 | 10 |
| End of Treatment | participant no longer meets study criteria | 1 | 1 |
| End of Treatment | participant request to discontinue treatment | 33 | 35 |
| End of Treatment | participant withdrew consent | 5 | 6 |
| End of Treatment | poor or non compliant | 0 | 1 |
| End of Treatment | Study Drug Toxicity | 75 | 19 |
| Pre-Treatment | Adverse event unrelated to study drug | 1 | 0 |
| Pre-Treatment | Not reported | 1 | 0 |
| Pre-Treatment | Participant no longer meets study criteria | 2 | 2 |
| Pre-Treatment | Participant withdrew consent | 0 | 1 |
Baseline characteristics
| Characteristic | Radiotherapy, Temozolomide Plus Nivolumab | Radiotherapy, Temozolomide Plus Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.9 Years STANDARD_DEVIATION 12.2 | 58.7 Years STANDARD_DEVIATION 11.4 | 58.3 Years STANDARD_DEVIATION 11.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 11 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 171 Participants | 178 Participants | 349 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 180 Participants | 169 Participants | 349 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 33 Participants | 68 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 17 Participants | 3 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 301 Participants | 318 Participants | 619 Participants |
| Sex: Female, Male Female | 153 Participants | 161 Participants | 314 Participants |
| Sex: Female, Male Male | 205 Participants | 197 Participants | 402 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 263 / 358 | 255 / 358 |
| other Total, other adverse events | 351 / 355 | 343 / 354 |
| serious Total, serious adverse events | 259 / 355 | 217 / 354 |
Outcome results
Primary
Overall Survival (OS)
The time from the date of randomization to the date of death. who have not died by the end of the study will be censored to last known date alive. OS is assessed in the randomized population with no corticosteroids at baseline population and in the overall randomized population.
Time frame: From randomization to date of death (up to approximately 4.5 years)
Population: All randomized participants
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Overall Survival (OS) | All randomized participants | 28.91 Months |
| Radiotherapy, Temozolomide Plus Nivolumab | Overall Survival (OS) | All randomized participants without baseline corticosteroids | 31.34 Months |
| Radiotherapy, Temozolomide Plus Placebo | Overall Survival (OS) | All randomized participants | 32.07 Months |
| Radiotherapy, Temozolomide Plus Placebo | Overall Survival (OS) | All randomized participants without baseline corticosteroids | 32.99 Months |
Comparison: All Randomized No Baseline Corticosteroids Participantsp-value: 0.340296.39% CI: [0.87, 1.43]Log Rank
Comparison: All Randomized Participants95% CI: [0.91, 1.33]
Primary
Progression-free Survival (PFS) Determined by BICR
The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by a Blinded Independent Central Review (BICR) assessed based on Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease.
Time frame: From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 4.5 years)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Progression-free Survival (PFS) Determined by BICR | 10.64 Months |
| Radiotherapy, Temozolomide Plus Placebo | Progression-free Survival (PFS) Determined by BICR | 10.32 Months |
95% CI: [0.9, 1.25]
Secondary
Overall Survival (OS) Rates at 12 Months
Overall Survival (OS) rate is defined as the percentage of participants surviving at 12 months
Time frame: From randomization to 12 months after first dose
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Overall Survival (OS) Rates at 12 Months | 82.7 percentage of participants |
| Radiotherapy, Temozolomide Plus Placebo | Overall Survival (OS) Rates at 12 Months | 87.7 percentage of participants |
Secondary
Overall Survival (OS) Rates at 24 Months
Overall Survival (OS) rate is defined as the percentage of participants surviving at 24 months
Time frame: From randomization to 24 months after first dose
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Overall Survival (OS) Rates at 24 Months | 55.9 percentage of participants |
| Radiotherapy, Temozolomide Plus Placebo | Overall Survival (OS) Rates at 24 Months | 63.3 percentage of participants |
Secondary
Progression Free Survival (PFS) Based on Investigator Assessment
The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by investigator assessment based Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease.
Time frame: From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 4.5 years)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Progression Free Survival (PFS) Based on Investigator Assessment | 14.09 Months |
| Radiotherapy, Temozolomide Plus Placebo | Progression Free Survival (PFS) Based on Investigator Assessment | 15.18 Months |
Post Hoc
Overall Survival (OS) - Extended Collection
The time from the date of randomization to the date of death. who have not died by the end of the study will be censored to last known date alive. OS is assessed in the randomized population with no corticosteroids at baseline population.
Time frame: From randomization to date of death (up to approximately 82 Months)
Population: All randomized participants with no baseline corticosteroids
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Overall Survival (OS) - Extended Collection | 28.94 Months |
| Radiotherapy, Temozolomide Plus Placebo | Overall Survival (OS) - Extended Collection | 31.84 Months |
95% CI: [0.89, 1.26]Log Rank
Post Hoc
Progression-free Survival (PFS) Determined by BICR - Extended Collection
The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by a Blinded Independent Central Review (BICR) assessed based on Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease.
Time frame: From randomization to the date of the first documented tumor progression or death by any cause. (up to approximately 82 Months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiotherapy, Temozolomide Plus Nivolumab | Progression-free Survival (PFS) Determined by BICR - Extended Collection | 9.89 Months |
| Radiotherapy, Temozolomide Plus Placebo | Progression-free Survival (PFS) Determined by BICR - Extended Collection | 10.25 Months |
95% CI: [0.99, 1.4]