This phase II/III trial compares the usual treatment with radiation therapy and temozolomide to radiation therapy plus immunotherapy with ipilimumab and nivolumab in treating patients with newly diagnosed MGMT unmethylated glioblastoma. Radiation therapy uses high energy photons to kill tumor and shrink tumors. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving radiation therapy with ipilimumab and nivolumab lengthen the time without brain tumor from returning or growing and extend patients life compared to usual treatment of radiation therapy and chemotherapy.
Name: Ipilimumab
Name: Nivolumab
Name: NovoTTF-100A Device
Name: Quality-of-Life Assessment
Name: Questionnaire Administration
Name: Radiation Therapy
Name: Temozolomide
Description: PFS will be defined as time from randomization to disease progress or death. This analysis will be performed on the intent-to-treat basis. PFS distributions for each treatment group will be estimated via the Kaplan-Meier survival function. Will utilize the "PFS resolution" guidance provided in the ALLIANCE A071102 study, the updated Response Assessment in Neuro-Oncology Criteria (RANO) criteria.
Measure: Progression-free survival (PFS) (Phase II) Time: From randomization to disease progress or death, assessed up to 4 yearsDescription: OS will be defined as time from randomization to death from any cause. Will be performed on the intent-to-treat basis. Overall survival distributions for each treatment group will be estimated via the Kaplan-Meier survival function.
Measure: Overall survival (OS) (Phase III) Time: From randomization to death from any cause, assessed up to 4 yearsDescription: PFS curves will be estimated via the Kaplan-Meier method and a stratified log-rank test.
Measure: PFS for the entire cohort (Phase II/III) Time: At 2 yearDescription: 2-year OS will be compared between treatment arms, to determine whether the proportion surviving to this landmark is increased in the experimental (ipilimumab [ipi] + nivolumab [nivo]) arm. Estimates will be obtained from the Kaplan Meier curves, and a test comparing the proportion surviving with an appropriate variance term that accounts for censoring (Greenwood's formula) will be used.
Measure: OS proportion Time: At 2 yearsDescription: Adverse events (AEs) will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 and Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Measure: Comparative frequency of specific adverse events of interest Time: Up to 4 yearsDescription: Adverse events will be graded according to CTCAE v5.0 and PRO-CTCAE. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. Complementing physician-assessed AEs will be selected PRO-CTCAE symptom items that have demonstrated sensitivity to immunotherapy-related toxicities but do not overlap with MDASI-BT. The following PRO-CTCAE symptom items will be monitored: rash, itching, muscle pain, joint pain, headache, chills, mouth/throat sores, skin dryness, hair loss, cough, taste changes, dizziness, swelling, hot flashes.
Measure: Frequency summaries for all adverse event types Time: Up to 4 yearsDescription: Will be assessed using the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT)-modified. The MDASI-BT consists of 23 symptoms rated on an 11-point ordinal scale (0 to 10) to indicate the presence and severity of the symptom in the last 24 hours, with 0 being "not present" and 10 being "as bad as you can imagine." These interference items include: general activity, mood, work (includes both work outside the home and housework), relations with other people, walking, and enjoyment of life. Complementing MDASI-BT will be selected PRO-CTCAE symptom items that have demonstrated sensitivity to immunotherapy-related toxicities but do not overlap with MDASI-BT.
Measure: Patient reported symptom burden Time: Up to 4 yearsDescription: Will utilize the PRO-CTCAE to assess the following items: abdominal pain, rash, itching, muscle pain, joint pain, pain and swelling at injection site, headache, chills, mouth/throat sores, skin dryness, hair loss, cough, taste changes, dizziness, swelling, and hot flashes.
Measure: Patient-reported toxicity outcomes Time: Up to 4 yearsDescription: Will assess PD-L1 expression and mutational burden expression specifically.
Measure: Tumor biomarker analyses Time: Up to 4 yearsDescription: Will assess the prognostic value of MGMT protein expression (in terms of predicting clinical outcomes such as PFS, OS, and 2-year OS rate) in the two treatment arms, separately. In addition, will evaluate if MGMT protein expression may be predictive of differential treatment effects between the two treatment arms. Correlation methods and survival modeling will be used to address these questions.
Measure: MGMT protein expression Time: Up to 4 yearsAllocation: Randomized
Parallel Assignment
There is one SNP
Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or methylated MGMT promoter are excluded - IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). --- R132H ---