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 overall survival (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.
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.
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.
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 is required; biopsy is
not allowed because it will not provide sufficient tissue for MGMT analysis
- Contrast-enhanced brain MRI within 3 days after surgery
- Magnetic resonance imaging (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
- 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
- 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.)
- 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
- Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achieve
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) >= 50mL/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, central nervous system (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
- Endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids
- 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
