NCT04396860|CompletedPhase 2ResultsFDA Drug

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

A Randomized Phase II/III Open-Label Study of Ipilimumab and Nivolumab Versus Temozolomide in Patients With Newly Diagnosed MGMT (Tumor O-6-Methylguanine DNA Methyltransferase) Unmethylated Glioblastoma

National Cancer Institute (NCI)ClinicalTrials.gov

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3 other identifiers

NCI-2020-03404NRG-BN007U10CA180868

Study Type

interventional

Target

159

Locations

1 country

Sites

285

Timeline

RegisteredMay 2020

StartedSep 2020

CompletionDec 2025

Brief Summary

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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

159

participants targeted

Target at P75+ for phase_2

Timeline

Completed

Started Sep 2020

Longer than P75 for phase_2

Geographic Reach

1 country

285 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

5.3 years study duration

First Submitted

Initial submission to the registry

May 20, 2020

Completed

1 day until next milestone

First Posted

Study publicly available on registry

May 21, 2020

Completed

3 months until next milestone

Study Start

First participant enrolled

September 1, 2020

Completed

2.4 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 13, 2023

Completed

1.3 years until next milestone

Results Posted

Study results publicly available

May 1, 2024

Completed

1.6 years until next milestone

Study Completion

Last participant's last visit for all outcomes

December 23, 2025

Completed

Last Updated

April 22, 2026

Status Verified

April 1, 2026

Enrollment Period

2.4 years

First QC Date

May 20, 2020

Results QC Date

April 9, 2024

Last Update Submit

April 6, 2026

Conditions

Gliosarcoma MGMT-Unmethylated Glioblastoma

Outcome Measures

Primary Outcomes (2)

Progression-free Survival (PFS) (Phase II)
Disease progression was confirmed by central review and defined using an adaptation of the Response Assessment in Neuro-Oncology criteria (Wen et al, J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15) with modification such that the first MRI performed following completion of radiotherapy is the baseline MRI for determination of radiographic disease. Progression-free survival time is defined as time from randomization to the date of first progression, death, or the last progression assessment with no documented progression (censored). Progression-free survival rates were estimated using the Kaplan-Meier method.
From randomization to date of progression, death, or last known follow-up, whichever occurs first. Maximum follow-up time was 19.3 months.
Overall Survival (OS) (Phase III)
Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates were to be estimated by the Kaplan-Meier method.
From randomization to date of death or last known follow-up. Maximum follow-up time was 19.3 months.

Secondary Outcomes (6)

PFS for the Entire Cohort (Phase II/III)
From randomization to date of progression, death, or last known follow-up. Maximum follow-up time was 19.3 months.
Overall Survival at 2 Years
From randomization to two years
Number of Participants by Highest Grade Adverse Event Reported
From randomization to date of last known follow-up. Maximum follow-up time was 19.3 months.
Change in MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) at Six Months (Patient Reported Outcomes)
Up to 2 years
Neurocognitive Function (NCF)
Up to 2 years
+1 more secondary outcomes

Other Outcomes (3)

OS (if the Study Discontinues in Phase II)
At the end of phase II of study
Tumor Biomarker Analyses
Up to 4 years
MGMT Protein Expression
Up to 4 years

Study Arms (2)

Arm I (radiation therapy, temozolomide)

ACTIVE COMPARATOR

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.

Procedure: Contrast-enhanced Magnetic Resonance ImagingDevice: NovoTTF-100A DeviceOther: Quality-of-Life AssessmentOther: Questionnaire AdministrationRadiation: Radiation TherapyDrug: Temozolomide

Arm II (radiation therapy, ipilimumab, nivolumab)

EXPERIMENTAL

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.

Procedure: Contrast-enhanced Magnetic Resonance ImagingBiological: IpilimumabBiological: NivolumabOther: Quality-of-Life AssessmentOther: Questionnaire AdministrationRadiation: Radiation Therapy

Interventions

IpilimumabBIOLOGICAL

Given IV

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016, Ipilimumab Biosimilar CS1002, MDX 010, MDX-010, MDX-CTLA4, MDX010, Yervoy

Arm II (radiation therapy, ipilimumab, nivolumab)

Contrast-enhanced Magnetic Resonance ImagingPROCEDURE

Undergo contrast-enhanced brain MRI

Also known as: CONTRAST ENHANCED MRI, Contrast-enhanced MRI, MRI With Contrast

Arm I (radiation therapy, temozolomide)Arm II (radiation therapy, ipilimumab, nivolumab)

NivolumabBIOLOGICAL

Given IV

Also known as: ABP 206, BCD-263, BMS 936558, BMS-936558, BMS936558, CMAB819, MDX 1106, MDX-1106, MDX1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar BCD-263, Nivolumab Biosimilar CMAB819, ONO 4538, ONO-4538, ONO4538, Opdivo

Arm II (radiation therapy, ipilimumab, nivolumab)

NovoTTF-100A DeviceDEVICE

Wear Optune device

Also known as: NovoTTF-100A, NovoTTF-100A System, NovoTTF-100A system (Optune), NovoTTFields, NovoTumor Treatment Fields, Optune, Optune Device

Arm I (radiation therapy, temozolomide)

Quality-of-Life AssessmentOTHER

Ancillary studies

Also known as: Quality of Life Assessment

Arm I (radiation therapy, temozolomide)Arm II (radiation therapy, ipilimumab, nivolumab)

Questionnaire AdministrationOTHER

Ancillary studies

Arm I (radiation therapy, temozolomide)Arm II (radiation therapy, ipilimumab, nivolumab)

Radiation TherapyRADIATION

Undergo radiation therapy

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Arm I (radiation therapy, temozolomide)Arm II (radiation therapy, ipilimumab, nivolumab)

TemozolomideDRUG

Given PO

Also known as: CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temizole, Temodal, Temodar, Temomedac, TMZ

Arm I (radiation therapy, temozolomide)

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

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
D 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
+17 more criteria

You may not qualify if:

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;
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:
+7 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

National Cancer Institute (NCI)lead
NRG Oncologycollaborator

Study Sites (285)

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233, United States

Location

University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

Kaiser Permanente-Anaheim

Anaheim, California, 92806, United States

Location

Sutter Auburn Faith Hospital

Auburn, California, 95602, United States

Location

Sutter Cancer Centers Radiation Oncology Services-Auburn

Auburn, California, 95603, United States

Location

John Muir Medical Center-Concord

Concord, California, 94520, United States

Location

UC San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

Loma Linda University Medical Center

Loma Linda, California, 92354, United States

Location

Kaiser Permanente Los Angeles Medical Center

Los Angeles, California, 90027, United States

Location

Cedars Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Kaiser Permanente-Ontario

Ontario, California, 91761, United States

Location

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

Sutter Cancer Centers Radiation Oncology Services-Roseville

Roseville, California, 95661, United States

Location

Sutter Roseville Medical Center

Roseville, California, 95661, United States

Location

Sutter Medical Center Sacramento

Sacramento, California, 95816, United States

Location

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

Torrance Memorial Physician Network - Cancer Care

Torrance, California, 90505, United States

Location

Torrance Memorial Medical Center

Torrance, California, 90509, United States

Location

John Muir Medical Center-Walnut Creek

Walnut Creek, California, 94598, United States

Location

Penrose-Saint Francis Healthcare

Colorado Springs, Colorado, 80907, United States

Location

AdventHealth Porter

Denver, Colorado, 80210, United States

Location

AdventHealth Littleton

Littleton, Colorado, 80122, United States

Location

AdventHealth Parker

Parker, Colorado, 80138, United States

Location

Hartford Hospital

Hartford, Connecticut, 06102, United States

Location

The Hospital of Central Connecticut

New Britain, Connecticut, 06050, United States

Location

Beebe Medical Center

Lewes, Delaware, 19958, United States

Location

Beebe South Coastal Health Campus

Millville, Delaware, 19967, United States

Location

Delaware Clinical and Laboratory Physicians PA

Newark, Delaware, 19713, United States

Location

Helen F Graham Cancer Center

Newark, Delaware, 19713, United States

Location

Medical Oncology Hematology Consultants PA

Newark, Delaware, 19713, United States

Location

Christiana Care Health System-Christiana Hospital

Newark, Delaware, 19718, United States

Location

Beebe Health Campus

Rehoboth Beach, Delaware, 19971, United States

Location

Baptist MD Anderson Cancer Center

Jacksonville, Florida, 32207, United States

Location

AdventHealth Orlando

Orlando, Florida, 32803, United States

Location

Augusta University Medical Center

Augusta, Georgia, 30912, United States

Location

Memorial Health University Medical Center

Savannah, Georgia, 31404, United States

Location

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

Savannah, Georgia, 31405, United States

Location

Lewis Hall Singletary Oncology Center

Thomasville, Georgia, 31792, United States

Location

Hawaii Cancer Care Inc - Waterfront Plaza