Phase I/IIa Trial of Retifanlimab and Difluoromethylornithine (DFMO) in Patients With Progressive High-Grade Glioma
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- Mayo Clinic
- Enrollment
- 33
- Locations
- 1
- Primary Endpoint
- Best tolerable dose level of Difluoromethylornithine (DFMO, or eflornithine) (phase I)
Overview
Brief Summary
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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
Arms & Interventions
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.
Intervention: Biospecimen Collection (Procedure)
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.
Intervention: Lumbar Puncture (Procedure)
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.
Intervention: Tumor Resection (Procedure)
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.
Intervention: Lumbar Puncture (Procedure)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
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.
Intervention: Tumor Resection (Procedure)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
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.
Intervention: Biospecimen Collection (Procedure)
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.
Intervention: Tumor Resection (Procedure)
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.
Intervention: Biospecimen Collection (Procedure)
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.
Intervention: Lumbar Puncture (Procedure)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
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.
Intervention: Retifanlimab (Biological)
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.
Intervention: Eflornithine (Drug)
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.
Intervention: Eflornithine (Drug)
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.
Intervention: Retifanlimab (Biological)
Outcomes
Primary Outcomes
Best tolerable dose level of Difluoromethylornithine (DFMO, or eflornithine) (phase I)
Time Frame: Up to 5 years
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)
Time Frame: From baseline up to 5 years
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.
Secondary Outcomes
- T cell/myeloid cell ratio(From baseline up to 5 years)
- Myeloid cell abundance(Up to 5 years)
- Extracellular cytokines/ chemokines(Up to 5 years)
- Incidence of adverse events (AE)(Up to 5 years)
- Progression free survival (PFS)(Up to 5 years)