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Testing the Use of the Immunotherapy Drugs Ipilimumab and Nivolumab Plus Radiation Therapy Compared to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Unmethylated Glioblastoma

Study Purpose

This phase II/III trial compares the usual treatment with radiation therapy and temozolomide to radiation therapy in combination with 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. Temozolomide, may not work as well for the treatment of tumors that have the unmethylated MGMT. Immunotherapy with monoclonal antibodies called immune checkpoint inhibitors, 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. It is possible that immune checkpoint inhibitors may work better at time of first diagnosis as opposed to when tumor comes back. Giving radiation therapy with ipilimumab and nivolumab may lengthen the time without brain tumor returning or growing and may extend patients' life compared to usual treatment with radiation therapy and temozolomide.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- PRIOR TO STEP 1 REGISTRATION: - No known IDH mutation.

(If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered)

- Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin & eosin (H&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status.

Note that tissue for central pathology review and central MGMT assessment must be received by the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 23. If tissue cannot be received by postoperative calendar day 23, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 6 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue. Note: In the event of an additional tumor resection(s), tissue must be received within 23 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection. Surgical resection (partial or complete) is required; a limited biopsy is not allowed because it will not provide sufficient tissue for MGMT analysis.

- Note: The central pathology review and central MGMT results determine eligibility.

Therefore, patients may be offered the opportunity to consent REGARDLESS of local pathology and MGMT results, and consent can occur BEFORE local pathology interpretation is finalized and BEFORE local MGMT testing is conducted.

- Contrast-enhanced brain MRI within 3 days after surgery.

- MRI with Axial T2 weighted FLAIR {preferred} or T2 turbo spin echo (TSE)/fast spin echo (FSE) and 3-dimensional (3D) contrast-enhanced T1 sequences are required.

- 3D pre contrast-enhanced T1 sequences are strongly suggested.

- Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must be willing to use an adequate method of contraception hormonal or barrier method of birth control; or abstinence during and after treatment.

- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

- PRIOR TO STEP 2 REGISTRATION: - Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review.

- Note: diagnoses of "Molecular glioblastoma" per the Consortium to Inform Molecular and Practical Approaches to Central Nervous System (CNS) Tumor Taxonomy (c-IMPACT-NOW) criteria or "CNS grade 4" per the World Health Organization (WHO) 2021 criteria are NOT relevant.

- MGMT promoter without methylation confirmed by central pathology review.

Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or methylated MGMT promoter are excluded.

- Note: central pathology review and central MGMT results determine eligibility; local pathology or MGMT results cannot be used for eligibility/randomization.

- Note: patients with methylated MGMT may be considered for enrollment on NRG-BN011.

- 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). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at step 2.)

- Note: this test is not being performed in real time as part of central review and will not be provided to sites from a centrally performed test.

- History/physical examination within 28 days prior to step 2 registration.

- Karnofsky Performance Status (KPS) >= 70 within 28 days prior to step 2 registration.

- Neurologic function assessment within 28 days prior to step 2 registration.

- Age >= 18 years.

- Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable) (within 7 days prior to step 2 registration) - Leukocytes >= 2,000/mm^3 (within 7 days prior to step 2 registration) - Absolute neutrophil count >= 1,500/mm^3 (within 7 days prior to step 2 registration) - Platelets >= 100,000/mm^3 (within 7 days prior to step 2 registration) - Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN) (within 7 days prior to step 2 registration) - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (within 7 days prior to step 2 registration) - Alanine transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 7 days prior to step 2 registration) - Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (within 7 days prior to step 2 registration) - For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- For women of childbearing potential (WOCBP), negative serum or urine pregnancy test within 7 days prior to step 2 registration.

Note that it may need to be repeated if not also within 3 days prior to treatment start.

- Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.

Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes.

Exclusion Criteria:

- Prior therapy for tumor except for resection.

For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitial thermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, gamma knife, cyber knife, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery;

- Note that 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent.

- Current or planned treatment with any other investigational agents for the study cancer.

- Definitive clinical or radiologic evidence of metastatic disease outside the brain.

- Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years.

- Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields.

- Pregnancy and nursing females due to the potential teratogenic effects and potential risk for adverse events in nursing infants.

- History of severe hypersensitivity reaction to any monoclonal antibody.

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab, nivolumab, or temozolomide.

- On any dose of any systemically administered (oral, rectal, intravenous) corticosteroid within 3 days prior to step 2 registration.

Inhaled, topical, and ocular corticosteroids are allowed without limitation but must be recorded. Note that treatment with systemically administered corticosteroid after initiating study treatment is allowed as needed.

- Patients with known immune impairment who may be unable to respond to anti-CTLA 4 antibody.

- History of interstitial lung disease including but not limited to sarcoidosis or pneumonitis.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, defined as New York Heart Association functional classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, are excluded, as are patients on active immunosuppressive therapy.

These include but are not limited to: patients with a history of immune-related neurologic disease, CNS or motor neuropathy, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as autoimmune vasculitis [e.g., Wegener's Granulomatosis]), systemic lupus erythematosus (SLE), connective tissue diseases (e.g., systemic progressive sclerosis), scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome, Hashimoto's thyroiditis, autoimmune hepatitis are excluded because of the risk of recurrence or exacerbation of disease.

- Exceptions: patients with a history of the following conditions are not excluded, unless receiving active immunosuppressive therapy: - Vitiligo.

- Type I diabetes.

- Rheumatoid arthritis and other arthropathies.

- Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA) - Anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

- Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation are also excluded.

- Current or planned therapy with warfarin

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04396860
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2/Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	National Cancer Institute (NCI)
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Andrew B Lassman
Principal Investigator Affiliation	NRG Oncology
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	NIH, Other
Overall Status	Active, not recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Gliosarcoma, MGMT-Unmethylated Glioblastoma

Additional Details

PRIMARY OBJECTIVES:

I. To determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs progression-free survival (PFS) versus adding temozolomide to radiotherapy in patients with newly diagnosed glioblastoma (GBM) without MGMT promoter methylation.

(Phase II)

II. To determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs overall survival (OS) versus adding temozolomide to radiotherapy in patients with newly diagnosed GBM without MGMT promoter methylation.

(Phase III) SECONDARY OBJECTIVES:

I. To determine if adding ipilimumab and nivolumab to radiotherapy significantly prolongs PFS versus adding temozolomide to radiotherapy in patients with newly diagnosed GBM without MGMT promoter methylation for the phase III part of the study.

II. To determine if adding ipilimumab and nivolumab to radiotherapy significantly increases the 2-year OS rate versus adding temozolomide to radiotherapy in patients with newly diagnosed GBM without MGMT promoter methylation.

III. To evaluate the safety of adding ipilimumab and nivolumab to radiotherapy via comparative frequency between arms of specific adverse events of interest and frequency summaries for all adverse event types.

IV. To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus adding temozolomide to radiotherapy on patient reported outcomes (PROs), as measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in patients with newly diagnosed GBM without MGMT promoter methylation.

V. To evaluate the effect of adding ipilimumab and nivolumab to radiotherapy versus adding temozolomide to radiotherapy on selected Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) items in patients with newly diagnosed GBM without MGMT promoter methylation.

VI. To evaluate the impact of adding ipilimumab and nivolumab to radiotherapy versus adding temozolomide to radiotherapy on neurocognitive function (NCF) in patients with newly diagnosed GBM without MGMT promoter methylation.

EXPLORATORY OBJECTIVES:

I. To explore biomarkers in pre-treatment archival tumor tissue that may predict efficacy of ipilimumab and nivolumab as measured by OS, PFS, and 2-year OS rate, such as but not limited to: Ia.

PDL1 expression; Ib. Mutational burden.

II. To explore (in the two treatment separately) whether the MGMT protein expression correlates with clinical outcomes including OS, PFS, and 2-year OS rate.

III. To evaluate if MGMT protein expression may be predictive of differential treatment effects between the two treatment arms.

OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients undergo radiation therapy for 5 days per week (Monday-Friday) for a total of 30 fractions over 6 weeks and simultaneously receive temozolomide orally (PO) daily for 6 weeks. After radiation, patients may wear the Optune device at the discretion of the patient and their treating physician. Beginning 1 month after radiation therapy, patients receive temozolomide on days 1-5. Treatment repeats every 28 days for up to 12 cycles at the discretion of the treating investigator in the absence of disease progression or unacceptable toxicity. Patients also undergo contrast-enhanced brain magnetic resonance imaging (MRI) throughout the trial. ARM 2: Patients undergo radiation therapy for 5 days per week (Monday-Friday) for a total of 30 fractions over 6 weeks. Starting on the first day of radiation, patients also receive ipilimumab intravenously (IV) over 90 minutes once every 4 weeks (Q4W) for 4 doses and nivolumab IV over 30 minutes every 2 weeks until disease progression. Patients also undergo contrast-enhanced brain MRI throughout the trial. After completion of study treatment, patients are followed up every 3 months for year 1, then every 4 months for year 2, and then every 6 months thereafter.

Arms & Interventions

Arms

Active Comparator: Arm I (radiation therapy, temozolomide)

Patients undergo radiation therapy for 5 days per week (Monday-Friday) for a total of 30 fractions over 6 weeks and simultaneously receive temozolomide PO daily for 6 weeks. After radiation, patients may wear the Optune device at the discretion of the patient and their treating physician. Beginning 1 month after radiation therapy, patients receive temozolomide on days 1-5. Treatment repeats every 28 days for up to 12 cycles at the discretion of the treating investigator in the absence of disease progression or unacceptable toxicity. Patients also undergo contrast-enhanced brain MRI throughout the trial.

Experimental: Arm II (radiation therapy, ipilimumab, nivolumab)

Patients undergo radiation therapy for 5 days per week (Monday-Friday) for a total of 30 fractions over 6 weeks. Starting on the first day of radiation, patients also receive ipilimumab IV over 90 minutes Q4W for 4 doses and nivolumab IV over 30 minutes every 2 weeks until disease progression. Patients also undergo contrast-enhanced brain MRI throughout the trial.

Interventions

Procedure: - Contrast-enhanced Magnetic Resonance Imaging

Undergo contrast-enhanced brain MRI

Biological: - Ipilimumab

Given IV

Biological: - Nivolumab

Given IV

Device: - NovoTTF-100A Device

Wear Optune device

Other: - Quality-of-Life Assessment

Ancillary studies

Other: - Questionnaire Administration

Ancillary studies

Radiation: - Radiation Therapy

Undergo radiation therapy

Drug: - Temozolomide

Given PO

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Birmingham 4049979, Alabama 4829764

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University of Alabama at Birmingham Cancer Center

Birmingham 4049979, Alabama 4829764, 35233

Little Rock 4119403, Arkansas 4099753

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University of Arkansas for Medical Sciences

Little Rock 4119403, Arkansas 4099753, 72205

Kaiser Permanente-Anaheim, Anaheim 5323810, California 5332921

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Kaiser Permanente-Anaheim

Anaheim 5323810, California 5332921, 92806

Sutter Auburn Faith Hospital, Auburn 5325223, California 5332921

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Sutter Auburn Faith Hospital

Auburn 5325223, California 5332921, 95602

Auburn 5325223, California 5332921

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Sutter Cancer Centers Radiation Oncology Services-Auburn

Auburn 5325223, California 5332921, 95603

John Muir Medical Center-Concord, Concord 5339111, California 5332921

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John Muir Medical Center-Concord

Concord 5339111, California 5332921, 94520

UC San Diego Moores Cancer Center, La Jolla 5363943, California 5332921

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UC San Diego Moores Cancer Center

La Jolla 5363943, California 5332921, 92093

Loma Linda University Medical Center, Loma Linda 5367696, California 5332921

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Loma Linda University Medical Center

Loma Linda 5367696, California 5332921, 92354

Los Angeles 5368361, California 5332921

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Kaiser Permanente Los Angeles Medical Center

Los Angeles 5368361, California 5332921, 90027

Cedars Sinai Medical Center, Los Angeles 5368361, California 5332921

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Cedars Sinai Medical Center

Los Angeles 5368361, California 5332921, 90048

Kaiser Permanente-Ontario, Ontario 5379439, California 5332921

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Kaiser Permanente-Ontario

Ontario 5379439, California 5332921, 91761

Orange 5379513, California 5332921

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UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange 5379513, California 5332921, 92868

Roseville 5388881, California 5332921

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Address

Sutter Cancer Centers Radiation Oncology Services-Roseville

Roseville 5388881, California 5332921, 95661

Sutter Roseville Medical Center, Roseville 5388881, California 5332921

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Sutter Roseville Medical Center

Roseville 5388881, California 5332921, 95661

Sutter Medical Center Sacramento, Sacramento 5389489, California 5332921

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Sutter Medical Center Sacramento

Sacramento 5389489, California 5332921, 95816

Sacramento 5389489, California 5332921

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Address

University of California Davis Comprehensive Cancer Center

Sacramento 5389489, California 5332921, 95817

Torrance 5403022, California 5332921

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Address

Torrance Memorial Physician Network - Cancer Care

Torrance 5403022, California 5332921, 90505

Torrance Memorial Medical Center, Torrance 5403022, California 5332921

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Torrance Memorial Medical Center

Torrance 5403022, California 5332921, 90509

John Muir Medical Center-Walnut Creek, Walnut Creek 5406990, California 5332921

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John Muir Medical Center-Walnut Creek

Walnut Creek 5406990, California 5332921, 94598

Penrose-Saint Francis Healthcare, Colorado Springs 5417598, Colorado 5417618

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Penrose-Saint Francis Healthcare

Colorado Springs 5417598, Colorado 5417618, 80907

AdventHealth Porter, Denver 5419384, Colorado 5417618

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AdventHealth Porter

Denver 5419384, Colorado 5417618, 80210

AdventHealth Littleton, Littleton 5429032, Colorado 5417618

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AdventHealth Littleton

Littleton 5429032, Colorado 5417618, 80122

AdventHealth Parker, Parker 5434006, Colorado 5417618

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AdventHealth Parker

Parker 5434006, Colorado 5417618, 80138

Hartford Hospital, Hartford 4835797, Connecticut 4831725

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Hartford Hospital

Hartford 4835797, Connecticut 4831725, 06102

The Hospital of Central Connecticut, New Britain 4839292, Connecticut 4831725

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The Hospital of Central Connecticut

New Britain 4839292, Connecticut 4831725, 06050

Beebe Medical Center, Lewes 4143354, Delaware 4142224

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Beebe Medical Center

Lewes 4143354, Delaware 4142224, 19958

Beebe South Coastal Health Campus, Millville 4143696, Delaware 4142224

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Beebe South Coastal Health Campus

Millville 4143696, Delaware 4142224, 19967

Newark 4143861, Delaware 4142224

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Delaware Clinical and Laboratory Physicians PA

Newark 4143861, Delaware 4142224, 19713

Helen F Graham Cancer Center, Newark 4143861, Delaware 4142224

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Helen F Graham Cancer Center

Newark 4143861, Delaware 4142224, 19713

Newark 4143861, Delaware 4142224

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Medical Oncology Hematology Consultants PA

Newark 4143861, Delaware 4142224, 19713

Newark 4143861, Delaware 4142224

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Christiana Care Health System-Christiana Hospital

Newark 4143861, Delaware 4142224, 19718

Beebe Health Campus, Rehoboth Beach 4144284, Delaware 4142224

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Beebe Health Campus

Rehoboth Beach 4144284, Delaware 4142224, 19971

Baptist MD Anderson Cancer Center, Jacksonville 4160021, Florida 4155751

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Baptist MD Anderson Cancer Center

Jacksonville 4160021, Florida 4155751, 32207

AdventHealth Orlando, Orlando 4167147, Florida 4155751

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AdventHealth Orlando

Orlando 4167147, Florida 4155751, 32803

Augusta University Medical Center, Augusta 4180531, Georgia 4197000

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Augusta University Medical Center

Augusta 4180531, Georgia 4197000, 30912

Savannah 4221552, Georgia 4197000

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Memorial Health University Medical Center

Savannah 4221552, Georgia 4197000, 31404

Savannah 4221552, Georgia 4197000

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Lewis Cancer and Research Pavilion at Saint Joseph's/Candler

Savannah 4221552, Georgia 4197000, 31405

Lewis Hall Singletary Oncology Center, Thomasville 4226348, Georgia 4197000

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Lewis Hall Singletary Oncology Center

Thomasville 4226348, Georgia 4197000, 31792

Honolulu 5856195, Hawaii 5855797

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Address

Hawaii Cancer Care Inc - Waterfront Plaza