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

Official title

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

Overview

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.

Interventions

• Procedure Biospecimen Collection
  Undergo blood and CSF collection
• Drug Eflornithine
  Given PO
• Procedure Lumbar Puncture
  Undergo lumbar puncture
• Procedure Magnetic Resonance Imaging
  Undergo MRI
• Biological Retifanlimab
  Given IV
• Procedure Tumor Resection
  Undergo resection surgery

Primary outcome measures

• Best tolerable dose level of Difluoromethylornithine (DFMO, or eflornithine) (phase I) [Time frame: Up to 5 years]
• Change in T cell/myeloid cell ratio (phase IIa) [Time frame: From baseline up to 5 years]

Secondary outcome measures (5)

• T cell/myeloid cell ratio [Time frame: From baseline up to 5 years]
• Myeloid cell abundance [Time frame: Up to 5 years]
• Extracellular cytokines/ chemokines [Time frame: Up to 5 years]
• Incidence of adverse events (AE) [Time frame: Up to 5 years]
• Progression free survival (PFS) [Time frame: Up to 5 years]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Mayo Clinic in Rochester — Rochester

Identifiers

NCT: NCT07468136 · MC230718 · NCI-2026-01392 · 24-000432 · MC230718

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗