CompletedNCT04396860ClinicalTrials.gov record

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

Gliosarcoma · MGMT-Unmethylated Glioblastoma

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THE QUICK READ

What this study involves

The registry does not currently label this study as recruiting. Ask about its status before planning a screening visit.

Study type: Interventional
Phase: Phase 2 / Phase 3
Age range: 18 years - Not specified
Sex eligible: All sexes
Healthy volunteers: Not accepted
Participants: 159 Actual

These are starting points, not an eligibility decision. The research team must review the full requirements.

About the research

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.

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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.

Who may be able to participate?

The list below is the sponsor’s full registry wording. It can include conditions, prior treatment, test results and other requirements. A match in search does not mean you qualify.

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

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Treatment, groups and participation

The registry may describe treatments and study duration without a complete visit calendar. Ask the study team for the exact schedule, procedures, risks, costs and alternatives. Keep your usual care plan unless your treating clinician tells you otherwise.

Assignment: Random assignment
Masking: No masking

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.

Procedure: Contrast-enhanced Magnetic Resonance Imaging · Device: NovoTTF-100A Device · Other: Quality-of-Life Assessment · Other: Questionnaire Administration · Radiation: Radiation Therapy · Drug: Temozolomide

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.

Procedure: Contrast-enhanced Magnetic Resonance Imaging · Biological: Ipilimumab · Biological: Nivolumab · Other: Quality-of-Life Assessment · Other: Questionnaire Administration · Radiation: Radiation Therapy

Contrast-enhanced Magnetic Resonance Imaging PROCEDURE

Undergo contrast-enhanced brain MRI

Ipilimumab BIOLOGICAL

Given IV

Nivolumab BIOLOGICAL

Given IV

NovoTTF-100A Device DEVICE

Wear Optune device

Quality-of-Life Assessment OTHER

Ancillary studies

Questionnaire Administration OTHER

Ancillary studies

Radiation Therapy RADIATION

Undergo radiation therapy

Temozolomide DRUG

Given PO

Prepare your questions

What researchers are measuring

Outcome measures describe what is being studied. They are not proof that a treatment works.

Primary measures

Progression-free Survival (PFS) (Phase II)

Time frame: From randomization to date of progression, death, or last known follow-up, whichever occurs first. Maximum follow-up time was 19.3 months.

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.

Overall Survival (OS) (Phase III)

Time frame: From randomization to date of death or last known follow-up. Maximum follow-up time was 19.3 months.

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.

Secondary measures

PFS for the Entire Cohort (Phase II/III)

Time frame: 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

Time frame: From randomization to two years

Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Two-year survival rates were to be estimated by the Kaplan-Meier method.

Number of Participants by Highest Grade Adverse Event Reported

Time frame: From randomization to date of last known follow-up. Maximum follow-up time was 19.3 months.

Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.

Change in MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) Symptom Severity at Six Months (Patient Reported Outcomes)

Time frame: Baseline and six months

The MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Symptom Severity subscale is a patient-reported outcome measure that assesses the severity of symptoms experienced by patients with brain tumors over the previous 24 hours. Possible subscale scores range from 0 to 10, with higher scores indicating a worse outcome. The change score was calculated as the 6-month value minus the baseline value. A negative change reflects improvement at 6 months and a positive change reflects decline at 6 months.

Time to Neurocognitive Failure

Time frame: From randomization to date of failure, disease progression, death, or last known follow-up whichever occurred first. Maximum follow-up time was 55.0 months.

Neurocognitive failure is defined as the first instance of neurocognitive decline in any of six assessments, as determined by the reliable change index: Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) part A, TMT part B, and Controlled Oral Word Association (COWA). Failure time is defined as time from randomization to failure, disease progression or death (competing events), or last follow-up (censored). Neurocognitive failure rates and median failure times are estimated using the cumulative incidence method. Participants with no baseline or no follow-up neurocognitive function data were censored at day 1.

Number of Participants With Most Severe Response for Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) at 6 Months

Time frame: Six months

Questions refer to the participants' experiences for the past 7 days of a given symptom in terms of frequency (never, rarely, occasionally, frequently, almost constantly), severity (none, mild, moderate, severe, very severe), interference with usual or daily activities (not at all, a little bit, somewhat, quite a bit, very much). The last response of each of the lists is the most severe response.

Other measures

OS (if the Study Discontinues in Phase II)

Time frame: At the end of phase II of study

Not reported in this registry record.

Tumor Biomarker Analyses

Time frame: Up to 4 years

Will assess PD-L1 expression and mutational burden expression specifically.

MGMT Protein Expression

Time frame: Up to 4 years

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.

Results are posted in the registry.

Review the complete result tables and limitations in the official record.

Open official results ↗

Research locations (285)

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Find a location in this study

285 locations

University of Alabama at Birmingham Cancer CenterBirmingham, Alabama, United StatesStatus unknown