Overview

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

Status:
Recruiting
Trial end date:
2024-08-23
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 2/Phase 3
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
Collaborator:
NRG Oncology
Treatments:
Ipilimumab
Nivolumab
Temozolomide
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 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