Gliosarcoma, MGMT-Unmethylated Glioblastoma
Conditions
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.
Detailed description
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.
Interventions
Undergo contrast-enhanced brain MRI
BIOLOGICALIpilimumab
Given IV
BIOLOGICALNivolumab
Given IV
DEVICENovoTTF-100A Device
Wear Optune device
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
RADIATIONRadiation Therapy
Undergo radiation therapy
DRUGTemozolomide
Given PO
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) (Phase II) | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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 at 2 Years | 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 | 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) at Six Months (Patient Reported Outcomes) | Up to 2 years | The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score is the average of the subscale items, given that a specified minimum numbers of items were completed. |
| Neurocognitive Function (NCF) | Up to 2 years | — |
| Selected Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Items | Up to 2 years | 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). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAndrew B Lassman
NRG Oncology
Participant flow
Pre-assignment details
Screening required central pathology review confirmation of glioblastoma histology and unmethylated MGMT promotor status in order to proceed to randomization. Of 374 patients registered, 159 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Contrast-enhanced Magnetic Resonance Imaging: Undergo contrast-enhanced brain MRI
NovoTTF-100A Device: Wear Optune device
Quality-of-Life Assessment: Ancillary studies
Questionnaire Administration: Ancillary studies
Radiation Therapy: Undergo radiation therapy
Temozolomide: Given PO | 80 |
| 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.
Contrast-enhanced Magnetic Resonance Imaging: Undergo contrast-enhanced brain MRI
Ipilimumab: Given IV
Nivolumab: Given IV
Quality-of-Life Assessment: Ancillary studies
Questionnaire Administration: Ancillary studies
Radiation Therapy: Undergo radiation therapy | 79 |
| Total | 159 |
Baseline characteristics
| Characteristic | Arm I (Radiation Therapy, Temozolomide) | Total | Arm II (Radiation Therapy, Ipilimumab, Nivolumab) |
|---|---|---|---|
| Age, Continuous | 59.5 years | 60 years | 61 years |
| Age, Customized ≤ 49 | 15 Participants | 24 Participants | 9 Participants |
| Age, Customized 50 -59 | 25 Participants | 52 Participants | 27 Participants |
| Age, Customized 60 -69 | 30 Participants | 57 Participants | 27 Participants |
| Age, Customized ≥ 70 | 10 Participants | 26 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 16 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 142 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Extent of resection Biopsy | 1 Participants | 1 Participants | 0 Participants |
| Extent of resection Subtotal | 28 Participants | 55 Participants | 27 Participants |
| Extent of resection Total (gross) | 51 Participants | 103 Participants | 52 Participants |
| Intent to use Optune No | 42 Participants | 83 Participants | 41 Participants |
| Intent to use Optune Yes | 38 Participants | 76 Participants | 38 Participants |
| Karnofsky performance status (KPS) 100 | 9 Participants | 24 Participants | 15 Participants |
| Karnofsky performance status (KPS) 70 | 10 Participants | 16 Participants | 6 Participants |
| Karnofsky performance status (KPS) 80 | 24 Participants | 46 Participants | 22 Participants |
| Karnofsky performance status (KPS) 90 | 37 Participants | 73 Participants | 36 Participants |
| Neurologic function Minor symptoms | 44 Participants | 71 Participants | 27 Participants |
| Neurologic function Moderate symptoms (fully active) | 11 Participants | 21 Participants | 10 Participants |
| Neurologic function Moderate symptoms (required assistance) | 3 Participants | 8 Participants | 5 Participants |
| Neurologic function No symptoms | 22 Participants | 59 Participants | 37 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) White | 71 Participants | 140 Participants | 69 Participants |
| Recursive partitioning analysis (RPA) class III | 9 Participants | 16 Participants | 7 Participants |
| Recursive partitioning analysis (RPA) class IV | 58 Participants | 116 Participants | 58 Participants |
| Recursive partitioning analysis (RPA) class V | 13 Participants | 27 Participants | 14 Participants |
| Sex: Female, Male Female | 26 Participants | 54 Participants | 28 Participants |
| Sex: Female, Male Male | 54 Participants | 105 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 80 | 37 / 79 |
| other Total, other adverse events | 70 / 74 | 70 / 78 |
| serious Total, serious adverse events | 29 / 74 | 45 / 78 |
Outcome results
Primary
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.
Time frame: From randomization to date of death or last known follow-up. Maximum follow-up time was 19.3 months.
Population: Study did not continue to the Phase III component.
Primary
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.
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.
Population: Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Radiation Therapy, Temozolomide) | Progression-free Survival (PFS) (Phase II) | 8.5 months |
| Arm II (Radiation Therapy, Ipilimumab, Nivolumab) | Progression-free Survival (PFS) (Phase II) | 7.7 months |
Comparison: For the phase II endpoint, observation of 100 PFS events among the 150 randomized patients (from both arms) provides 95% statistical power to detect an improvement in median PFS from 5.7 months in the control arm to 9.7 months in the experimental arm, corresponding to a hazard reduction of 42% (hazard ratio 0.58) at one-sided significance level of 0.15 (and 87% power for hazard ratio of 0.65 at this same alpha).p-value: 0.9695% CI: [0.98, 2.21]Log Rank
Secondary
Change in MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) at Six Months (Patient Reported Outcomes)
The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score is the average of the subscale items, given that a specified minimum numbers of items were completed.
Time frame: Up to 2 years
Secondary
Neurocognitive Function (NCF)
Time frame: Up to 2 years
Secondary
Number of Participants by Highest Grade Adverse Event Reported
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.
Time frame: From randomization to date of last known follow-up. Maximum follow-up time was 19.3 months.
Population: Randomized participants who started protocol treatment and were assessed for adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Radiation Therapy, Temozolomide) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 19 Participants |
| Arm I (Radiation Therapy, Temozolomide) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 9 Participants |
| Arm I (Radiation Therapy, Temozolomide) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 38 Participants |
| Arm I (Radiation Therapy, Temozolomide) | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 0 Participants |
| Arm I (Radiation Therapy, Temozolomide) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 6 Participants |
| Arm II (Radiation Therapy, Ipilimumab, Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 4 Participants |
| Arm II (Radiation Therapy, Ipilimumab, Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 1 Participants |
| Arm II (Radiation Therapy, Ipilimumab, Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 21 Participants |
| Arm II (Radiation Therapy, Ipilimumab, Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 38 Participants |
| Arm II (Radiation Therapy, Ipilimumab, Nivolumab) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 10 Participants |
Secondary
Overall Survival at 2 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.
Time frame: From randomization to two years
Population: Study did not continue to the Phase III component.
Secondary
PFS for the Entire Cohort (Phase II/III)
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.
Time frame: From randomization to date of progression, death, or last known follow-up. Maximum follow-up time was 19.3 months.
Population: Study did not continue to the Phase III component.
Secondary
Selected Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Items
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).
Time frame: Up to 2 years
Other Pre-specified
MGMT Protein Expression
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.
Time frame: Up to 4 years
Other Pre-specified
OS (if the Study Discontinues in Phase II)
Time frame: At the end of phase II of study
Other Pre-specified
Tumor Biomarker Analyses
Will assess PD-L1 expression and mutational burden expression specifically.
Time frame: Up to 4 years