This phase II trial studies the effect of immunotherapy drugs (ipilimumab and nivolumab) in treating patients with glioma that has come back (recurrent) and carries a high number of mutations (mutational burden). Cancer is caused by changes (mutations) to genes that control the way cells function. Tumors with high number of mutations may respond well to immunotherapy. Immunotherapy with monoclonal antibodies 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. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma with high number of mutations from growing or spreading compared to usual care (surgery or chemotherapy).

PRIMARY OBJECTIVE:

I. To determine whether the combination of ipilimumab and nivolumab increases the tumor response rate assessed by modified Response Assessment in Neuro-Oncology (RANO) Criteria in patients with hypermutated recurrent glioblastoma.

SECONDARY OBJECTIVES:

I. Estimate the overall survival distribution, median survival, and one-year survival rate of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and nivolumab.

II. Estimate the progression-free survival distribution and median progression-free survival of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and nivolumab.

III. Determine the adverse event profile of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and nivolumab.

EXPLORATORY OBJECTIVES:

I. Test whether PD-L1 or immunologic infiltrate in the tumor microenvironment are associated with objective tumor response, overall survival, progression-free survival, tumor mutational burden, or rates of grade 3 or higher adverse events.

II. Test whether MGMT status, microsatellite instability (MSI) status, mutational signatures, or amount of tumor mutational burden (TMB) including germline analysis are associated with objective tumor response, overall survival, progression-free survival, or rates of grade 3 or higher adverse events.

III. Evaluate associations between exome and transcriptome gene levels with objective tumor response, overall survival, progression-free survival, rates of grade 3 or higher adverse events.

IV. Evaluate associations between the gut microbiome and objective tumor response.

V. Response rate using immunotherapy (i)RANO.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients without disease progression are followed every 8 weeks until disease progression, then every 3 months for up to 3 years. Patients with disease progression after completion of study treatment are followed every 3 months for up to 3 years.

Inclusion Criteria:

• PRE-REGISTRATION ELIGIBILITY CRITERIA:

• Histologically confirmed glioblastoma (World Health Organization [WHO] grade IV) presenting at first or second recurrence including secondary glioblastoma

  • Glioblastoma IDH-wildtype central nervous system (CNS) WHO grade 4

    • Diffuse, astrocytic glioma IDH-wildtype with one or more of the following histological or genetic features: microvascular proliferation, necrosis, TERT promoter mutation, EGFR gene amplification, +7/-10 chromosome copy-number changes

  • Astrocytoma, IDH-mutant CNS WHO grade 4

    • Diffuse astrocytic glioma IDH-mutant (with frequent ATRX and/or TP53 mutation and absence of 1p/19q codeletion), with necrosis and/or microvascular proliferation or one with lower grade histological features displaying homozygous deletion of CDKN2A and/or CDKN2B

  • NOTE: The eligibility criteria were changed to include the new diagnostic language from the WHO 2021 pathology classification change. The above diagnoses therefore reflect the change and include the entities that were previously eligible but now carry updated pathologic classification

• Presence of measurable disease, as defined by a bidimensionally measurable lesion on magnetic resonance imaging (MRI) with a minimum diameter of 10 mm in both dimensions, prior to resection or biopsy of recurrent tumor

• Tissue available from surgical resection or biopsy of recurrent tumor =< 28 days prior to pre-registration, or planned surgery or biopsy of recurrent tumor =< 28 days after pre-registration

• Does not require > 4 mg dexamethasone beyond the perioperative period defined as the time =< 2 weeks after surgical procedure

• No active autoimmune disease or history of autoimmune disease

  • These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, 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 should be excluded because of the risk of recurrence or exacerbation of disease
  • Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with 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

• No prior treatment with checkpoint blockade therapies (anti-CTLA4, anti-PD1/PD-L1) or bevacizumab

• No prior treatment with laser ablation at the time of recurrent tumor tissue sampling. Patients who have previously undergone laser ablation >= 4 months prior to recurrent tumor tissue sampling can be included

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Able to undergo brain MRI with contrast

• Absolute neutrophil count >= 1500/mm^3

• Platelet count >= 100,000/mm^3

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

  • If Gilbert syndrome, then total bilirubin =< 3 x ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x ULN

• Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)

• History of active malignancy (outside of the patient's glioblastoma) that has required treatment within the previous 2 years. Participant with prior history of in situ cancer or basal or squamous cell skin cancer are eligible

• REGISTRATION ELIGIBILITY CRITERIA: Tissue obtained from biopsy or resection at first or second recurrence exhibits TMB >= 10 on FoundationOne CDx testing

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