All-Trans Retinoic Acid (ATRA) Plus PD-1 Inhibition in Recurrent IDH-Mutant Glioma

NCT05345002 | Recruiting Phase 2 FDA Drug

• 1 other identifier: UPCC 02322
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase II study of the combination of All-Trans Retinonic Acid (ATRA) and PD-1 inhibition (Retifanlimab) in patient with recurrent IDH-mutant glioma. The Sponsor-Investigator hypothesizes that the proposed regimen will be safe and stimulate a robust anti-tumor immune response.

Conditions

Glioma; IDH Mutation; Astrocytoma; Oligodendroglioma

Outcome Measures

Primary Outcomes (1)

• Objective radiographic response (ORR)

  Objective radiographic response (ORR), as measured by modified Response Assessment in Neuro-Oncology (RANO) criteria. ). The response is classified as Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD).

  26 months

Secondary Outcomes (3)

• Incidence of Treatment-Emergent Adverse Events as assessed by NCI CTCAE v 5.0

  25 months

• Progression Free Survival

  84 months

• Overall survival

  84 months

Study Arms (4)

Arm A (failed prior TMZ + one other alkylating chemotherapy)

EXPERIMENTAL

Subjects in Arm A are alkylator-refractory and at high risk for progression of disease, have failed temozolmide and another alkylating agent. Subjects in Arm A will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Drug: Retifanlimab; Drug: All-trans retinoic acid

Arm B (failed only one prior alkylating chemotherapy)

EXPERIMENTAL

Subject in Arm B are patients who have failed only one prior alkylating chemotherapy regimen and have gone at least 12 months since the last treatment. Subjects in Arm B will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Drug: Retifanlimab; Drug: All-trans retinoic acid

Arm C (surgical arm, ATRA alone pre-operatively)

EXPERIMENTAL

Subject in Arm C will receive ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery, then undergo surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Drug: Retifanlimab; Drug: All-trans retinoic acid

Arm D (surgical arm, ATRA + retifanlimab pre-operatively)

EXPERIMENTAL

Subject in Arm D will receive the combination of ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery plus a 500mg IV dose of retifanlimab 14 days prior to the date of surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Drug: Retifanlimab; Drug: All-trans retinoic acid

Interventions

Retifanlimab DRUG

Administered 500mg IV on day 1 of every 28-day cycle, continued until disease progression, unacceptable toxicity, or 2 years from the first dose of study medication, whichever occurs first.

Arm A (failed prior TMZ + one other alkylating chemotherapy); Arm B (failed only one prior alkylating chemotherapy); Arm C (surgical arm, ATRA alone pre-operatively); Arm D (surgical arm, ATRA + retifanlimab pre-operatively)

All-trans retinoic acid DRUG

All-trans retinoic acid (ATRA) 45mg/m2 orally in two equally divided doses on days 1-14 of each 28-day cycle, continued until disease progression, unacceptable toxicity, or 2 years from the first dose of study medication, whichever occurs first.

Arm A (failed prior TMZ + one other alkylating chemotherapy); Arm B (failed only one prior alkylating chemotherapy); Arm C (surgical arm, ATRA alone pre-operatively); Arm D (surgical arm, ATRA + retifanlimab pre-operatively)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Prior histopathologically proven diagnosis of astrocytoma (grade 2-4) or oligodendroglioma (grade 2-3) according to the World Health Organization (WHO) 2021 Classification System that is progressive or recurrent following at least one prior alkylating chemotherapy regimen (i.e., temozolomide and/or lomustine), +/- radiation therapy
• Patient's tumor must have a known mutation in IDH1 or IDH2. IDH1/2 mutation status must be confirmed by DNA sequencing and could have been performed in any CLIA/CAP-certified laboratory. IDH1/2 mutational testing could have been performed on patient's tumor either at initial diagnosis or on a subsequent recurrent tumor.
• Safety Run-In and Phase 2 (Arm A and Arm B) patients:
• All Safety Run-In and Phase 2 patients: patients with any contrast-enhancing tumor must have measurable disease per RANO criteria (defined by at least 1cmx1cm of contrast-enhancing tumor). Patients with exclusively non-enhancing tumors must have least a 25% increase in bi-dimensional product of FLAIR signal abnormality (measurable disease) compared to the patient's best MRI scan (smallest bi-dimensional product of FLAIR signal abnormality) obtained following completion of the patient's most recent line of therapy
• Safety Run-In: Must have failed temozolomide OR another alkylator (e.g. lomustine, procarbazine, carmustine). May have failed an unlimited number of prior systemic regimens, +/- prior radiotherapy.
• Arm A: Must have failed temozolomide AND another alkylator (e.g. lomustine, procarbazine, carmustine). May have failed an unlimited number of prior systemic regimens, +/- prior radiotherapy.
• Arm B: Must have failed temozolomide OR another alkylator (maximum one prior chemotherapy regimen) +/- prior radiotherapy, AND must have gone at least 12 months since last treatment (chemotherapy or radiotherapy).
• Surgical patients (Arm C and Arm D):
• Must have clinical indication for surgical resection of the suspected recurrent/progressive tumor, as determined by patient's care providers; measurable disease is not required
• aminolevulinic acid (5-ALA) is not allowed for intraoperative tumor visualization due to the photosensitizing agent interaction with ATRA
• Patient may have had an unlimited number of relapses and prior therapy regimens
• Patients must be able to undergo MRI of the brain with gadolinium. Patients must be maintained on a stable or decreased dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI.
• Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
• weeks from completion of radiation
• weeks from a nitrosourea cytotoxic chemotherapy

You may not qualify if:

• Any of the following would exclude the subject from participation in the study:
• Diffuse leptomeningeal disease
• Patients who have received bevacizumab within the last 3 months are ineligible
• Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of midline shift)
• Use of any immunosuppressive medication other than steroids, including but not limited to antimetabolites, calcineurin inhibitors, and/or anti-TNF agents within six months of start of study drug
• Prior diagnosis of immunodeficiency
• Prior solid organ or bone marrow transplantation
• Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (\> 10 mg/day of prednisone or equivalent).
• Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted.
• Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate.
• Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate.
• Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedications are permitted.
• EXCEPTIONS: Patients with the following autoimmune diseases may participate: type I diabetes mellitus, hypothyroidism only requiring hormone replacement, Grave's disease that is previously treated with thyroidectomy or radioiodine, celiac disease with symptoms controlled with a gluten-free diet.
• Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis.
• Immune related toxicity during prior checkpoint inhibitor therapy for which permanent discontinuation of therapy was recommended (per product label or consensus guidelines) or any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (with the exception of endocrinopathy that is well controlled on replacement hormones).

Sponsors & Collaborators

• Stephen Bagley, MD, MSCE: lead
• Incyte Corporation: collaborator
• Abramson Cancer Center at Penn Medicine: collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

MeSH Terms

Conditions

Glioma; Astrocytoma; Oligodendroglioma

Interventions

Tretinoin

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Study Officials

• Stephen Bagley, MD MSCE

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: The study has a Safety Run-In, a Phase 2 Portion with Arm A and Arm B and a Surgical Portion with Arm C and Arm D. .

Study Record Dates

• First Submitted: April 19, 2022
• First Posted: April 25, 2022
• Study Start: November 16, 2022
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)