Retifanlimab With or Without Difluoromethylornithine for the Treatment of Progressive High Grade Gliomas

Phase I/IIa Trial of Retifanlimab and Difluoromethylornithine (DFMO) in Patients With Progressive High-Grade Glioma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Malignant Glioma; Diffuse Astrocytoma; Anaplastic Oligodendroglioma; Astrocytoma, IDH-Mutant, Grade 3; Glioblastoma, IDH-Wildtype; Astrocytoma, IDH-Mutant, Grade 4
• Intervention / Treatment: Procedure: Lumbar Puncture; Procedure: Magnetic Resonance Imaging; Biological: Retifanlimab; Drug: Eflornithine; Procedure: Tumor Resection; Procedure: Biospecimen Collection

• Study Type: Interventional
• Enrollment (Estimated): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Terence C. Burns, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years

• Diagnosis of high-grade glioma, including any of the following:

  • Glioblastoma, IDH-wild type (WT)
  • Grade 3 or 4 IDH1/2 mutant astrocytoma or
  • Grade 3 oligodendroglioma
  • Any prior grade 2 astrocytoma or oligodendroglioma that is suspected to have recurred at a higher grade
  • Other high-grade glioma
• Plan for surgical resection as part of routine clinical care
• Radiographic disease progression, with or without tissue confirmation
• Measurable disease

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 and Karnofsky Performance Status (KPS) ≥ 60

  • NOTE: PS must be assessed (again) within 7 days prior to first dose of study drug
• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 15 days prior to registration)
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to registration)
• Platelet count ≥ 100,000/mm^3 (obtained ≤ 15 days prior to registration)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 15 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 15 days prior to registration)
• Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula (obtained ≤ 15 days prior to registration)
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only
• Provide written informed consent for the current study
• Willing to provide consent for the Neuro-oncology biorepository (IRB 12-003458) for archiving of tissue, cerebrospinal fluid (CSF), and/or blood samples
• Ability to complete forms by themselves or with assistance
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception

• Uncontrolled intercurrent illness that by the judgement of the investigator would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the regimens including, but not limited to:

  • ongoing or active infection (e.g., pneumonia, sepsis, etc.) requiring systemic therapy
  • current diagnosis or previous history of immune-related (non-infectious) pneumonitis or interstitial lung disease that requires or required steroids
  • active autoimmune disease that required systemic treatment other than replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids) ≤ 2 years prior to registration
  • symptomatic congestive heart failure
  • unstable angina pectoris
  • psychiatric illness/social situations that would limit compliance with study requirements (e.g., drug addiction)
  • concurrent active Hepatitis B (defined as hepatitis B surface antigen [HBsAg] positive and/or detectable hepatitis B virus [HBV] deoxyribonucleic acid [DNA]) and Hepatitis C virus (defined as anti-hepatitis C virus [HCV] antibody [Ab] positive and detectable HCV ribonucleic acid [RNA]) infection

EXCEPTIONS:

• Patients with evidence of hepatitis B virus (HBV) infection (HBsAg positive) must have completed at least 4 weeks of HBV antiviral therapy, and the HBV viral load must be undetectable at the time of registration

• Patients with a history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load. Patients must have completed curative anti-viral treatment ≥ 4 weeks prior to registration.

  • NOTE: Patients without symptoms or prior history do not require testing prior to registration

    • Co-morbid systemic illnesses or other severe concurrent disease that would make the patient inappropriate for entry into the study or interfere with proper assessment of safety and toxicity
    • History of myocardial infarction ≤ 6 months prior to registration or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
    • Active autoimmune disease that has required systemic treatment (other than replacement therapy) ≤ 1 year prior to registration
    • History of allogeneic stem cell transplant
    • Receiving any other investigational agent with therapeutic intent
    • Participants who are unable to swallow the DFMO solution or who are at risk for impaired absorption of oral medication.

• NOTE: This restriction includes, but is not limited to, refractory vomiting, gastric resection/bypass, and duodenal/jejunal resection

  • Patients with known hypersensitivity or allergy to DFMO or retifanlimab
  • Contraindication to MRI or administration of gadolinium

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (retifanlimab and DFMO then surgery); Patients receive retifanlimab IV, over 30 minutes on day 1 of cycle 1 and DFMO PO Q8H on days 1-14 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care resection surgery. Patients then receive retifanlimab IV, over 30 minutes, on day 1 of each cycle and DFMO PO Q8H on days 1-14 of each cycle. Cycles repeat every 28 days for 16 additional cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI and blood sample collection throughout the study and may optionally undergo CSF fluid collection with or without lumbar puncture.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Biological: Retifanlimab; Given IV; Other Names: INCMGA00012; INCMGA0012; INCMGA 0012; INCMGA-0012; MGA 012; MGA-012; MGA012; Retifanlimab-dlwr; Zynyz; Procedure: Tumor Resection; Undergo resection surgery; Procedure: Biospecimen Collection; Undergo blood and CSF collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection
Experimental: Group B1 (retifanlimab only then surgery); Patients receive retifanlimab IV, over 30 minutes, on day 1 of cycle 1. Patients then undergo standard of care resection surgery. Patients then receive retifanlimab IV, over 30 minutes, on day 1 of each cycle and DFMO PO Q8H on days 1-14 of each cycle. Cycles repeat every 28 days for 16 additional cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI and blood sample collection throughout the study and may optionally undergo cerebrospinal fluid collection with or without lumbar puncture.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Drug: Eflornithine; Given PO; Other Names: DFMO; Difluoromethylornithine; Alpha-Difluoromethylornithine; Difluromethylornithine; Procedure: Tumor Resection; Undergo resection surgery; Procedure: Biospecimen Collection; Undergo blood and CSF collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection
Experimental: Group B2 (retifanlimab and DFMO then surgery); Patients receive retifanlimab IV, over 30 minutes on day 1 of cycle 1 and DFMO PO Q8H on days 1-14 of cycle 1, in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care resection surgery. Patients then receive retifanlimab IV, over 30 minutes, on day 1 of each cycle and DFMO PO Q8H on days 1-14 of each cycle. Cycles repeat every 28 days for 16 additional cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI and blood sample collection throughout the study and may optionally undergo cerebrospinal fluid collection with or without lumbar puncture.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Biological: Retifanlimab; Given IV; Other Names: INCMGA00012; INCMGA0012; INCMGA 0012; INCMGA-0012; MGA 012; MGA-012; MGA012; Retifanlimab-dlwr; Zynyz; Drug: Eflornithine; Given PO; Other Names: DFMO; Difluoromethylornithine; Alpha-Difluoromethylornithine; Difluromethylornithine; Procedure: Tumor Resection; Undergo resection surgery; Procedure: Biospecimen Collection; Undergo blood and CSF collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 5 years
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.	From baseline up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From baseline up to 5 years
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.	Up to 5 years
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.	Up to 5 years
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.	Up to 5 years
Progression free survival (PFS)	Defined as the time from randomization to the time of documented progression and/or death due to any cause. Will be evaluated based on the Response Assessment in Neuro-Oncology criteria.	Up to 5 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Terence C. Burns, MD, PhD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Estimated): April 24, 2026
• Primary Completion (Estimated): October 25, 2030
• Study Completion (Estimated): October 25, 2030

Study Registration Dates

• First Submitted: March 9, 2026
• First Submitted That Met QC Criteria: March 9, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Lymphoma; Hemic and Lymphatic Diseases; Glioblastoma; Glioma; Lymphoma, Follicular; Astrocytoma; Oligodendroglioma; Amino Acids, Peptides, and Proteins; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Biopsy; Amino Acids; Chemistry Techniques, Analytical; Spectrum Analysis; Amino Acids, Basic; Amino Acids, Diamino; Urologic Surgical Procedures; Urogenital Surgical Procedures; Diagnostic Techniques, Neurological; Ornithine; Eflornithine; Specimen Handling; Magnetic Resonance Spectroscopy; Transurethral Resection of Bladder; Spinal Puncture
• Other Study ID Numbers: MC230718 (Other Identifier: Mayo Clinic in Rochester); NCI-2026-01392 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 24-000432 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No