This phase I/II trial tests the safety, side effects best dose and effect of retifanlimab with or without difluoromethylornithine (DFMO) for the treatment of high grade gliomas that are growing, spreading, or getting worse (progressive). Immunotherapy with monoclonal antibodies, such as retifanlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. DFMO is in a class of medications called ornithine decarboxylase (ODC) inhibitors. It works by blocking the action of a substance that signals tumor cells to multiply. This helps stop or slow the spread of tumor cells. Giving retifanlimab with or without DFMO mat be safe, tolerable and/or effective in treating patients with progressive high grade glioma.
Age ≥ 18 years
Glioblastoma, IDH-wild type (WT)
Grade 3 or 4 IDH1/2 mutant astrocytoma or
Grade 3 oligodendroglioma
Pregnant persons
Nursing persons
Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception
ongoing or active infection (e.g., pneumonia, sepsis, etc.) requiring systemic therapy
Sequential
Biospecimen Collection
Procedure/SurgeryUndergo blood and CSF collection
Eflornithine
DrugGiven PO
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Retifanlimab
Biological/VaccineGiven IV
Tumor Resection
Procedure/SurgeryUndergo resection surgery
Best tolerable dose level of Difluoromethylornithine (DFMO, or eflornithine) (phase I)
Will use a modified Bayesian Optimal Interval phase I/II (BOIN12) trial design to identify a dose level that is tolerable and has sufficient/optimal pharmacodynamic effects \[e.g., maximum tolerated dose (MTD)\]. Will evaluate toxicity up front to determine dose levels that have acceptable tolerability. Both dose limiting toxicity and pharmacodynamic activity will be used to identify the best dose to bring forward for the phase IIa portion.
Change in T cell/myeloid cell ratio (phase IIa)
Will use a log2 transformation of this percentage measure. Will summarize this within each of the treatment arms, and will compare these measures between arms using a two-sample t-test or a nonparametric Wilcoxon rank sum test if not sufficiently normally distributed.
T cell/myeloid cell ratio
Will use a two-sample t-test or the nonparametric Wilcoxon rank sum test to evaluate whether the combination of eflornithine (DFMO) and retifanlimab increases the average increase in the T cell/myeloid cell ratio versus with retifanlimab alone.
Myeloid cell abundance
Will use a two-sample t-test or the nonparametric Wilcoxon rank sum test to evaluate if the combination of DFMO and retifanlimab increases the average increase in the T cell/myeloid cell ratio versus with retifanlimab alone.
Extracellular cytokines/ chemokines
Will evaluate concentrations of pro-inflammatory cytokines/chemokines, CSCL9 and CCL5 in tissue and in cerebrospinal fluid (CSF), and how these correspond or correlate to each other.
Incidence of adverse events (AE)
Assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number, type, and grade of adverse events will be summarized for each treatment arm.
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