Neoantigen-based Personalized DNA Vaccine With Retifanlimab PD-1 Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma

NCT05743595 | Active Not Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: 202307205
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single institution, open-label, multi-arm, phase I study assessing the safety and immunogenicity of a personalized neoantigen-based personalized DNA vaccine combined with PD-1 blockade therapy in subjects with newly diagnosed, MGMT promoter unmethylated glioblastoma (GBM). Immune checkpoint blockade, specifically those targeting the PD-1/PD-L1 pathways, has shown efficacy in multiple solid and hematologic malignancies. Furthermore, as has been demonstrated in metastatic melanoma, combining PD-1/PD-L1 blockade with other immune checkpoint inhibitors has shown improved objective response rates, though there is a significant increase in serious immune-related adverse events. As such, current trials are exploring different doses, administration schedules, and immune checkpoint agents. One alternative approach, however, is to introduce a tumor-directed therapy such as a personalized neoantigen vaccine combined with these immune modulating agents (i.e. immune checkpoint blocking antibodies) to maximize the tumor-specific response but minimize the toxicity associated with increasing non-specific systemic immune activation by generating a potent and focused neoantigen specific immune response. This study will test the hypothesis that a personalized neoantigen DNA vaccine in combination with concurrent administration of immune checkpoint blockade therapy will enhance the magnitude and breadth of neoantigen-specific T cell responses while maintaining an acceptable safety profile. The overall goal of this study is to identify the optimal vaccine plus adjuvant platform that can be tested in a subsequent phase II study to determine the efficacy of a personalized neoantigen vaccine approach in patients with GBM.

Conditions

Unmethylated Glioblastoma

Keywords

glioblastoma; neoantigen vaccine; PD-1 blockade; unmethylated MGMT

Outcome Measures

Primary Outcomes (1)

• Safety as measured by treatment-related dose-limiting toxicity (DLT) rate related to vaccination

  * Safety will be defined as a \< 33% treatment-related DLT rate related to vaccination alone or in combination with retifanlimab, by the end of the DLT observation period for a given cohort. * A DLT will be defined as any grade 3 toxicity or greater according to CTCAE v5 considered at least possibly related to study treatment (exceptions are listed in the protocol). * The DLT observation period begins with date of first vaccine administration and continues for 30 days from administration of first dose of retifanlimab. For patients in Cohort A, this is Day 87 (first dose of retifanlimab is given with vaccine Dose 3 on Day 57), and for patients in Cohort B, this is Day 30 (first dose of retifanlimab is given with vaccine Dose 1 on Day 1).

  Through completion of DLT observation period for all enrolled subjects (estimated to be up to 12 months and 87 days)

Secondary Outcomes (9)

• Number of high-quality candidate neoantigens in patients enrolled in the study

  Through completion of vaccine manufacture for all enrolled subjects (estimated to be 15 months)

• Progression-free survival (PFS)

  At 6 months

• Overall survival (OS)

  At 12 months

• Objective response rate (ORR)

  Through completion of treatment (estimated to be 12 months)

• Immunogenicity as measured by the number of subjects in a cohort who develop at least one demonstrable neoantigen CD8 T cell response by day 71 after administration of the first dose of vaccine

  Day 71 after first vaccine dose

Study Arms (2)

Cohort A: Personalized neoantigen DNA vaccine + retifanlimab

EXPERIMENTAL

* Cohort A will receive the personalized neoantigen DNA vaccine via electroporation mediated IM injection alone during the first two priming doses, then concurrently with retifanlimab during the subsequent boosting doses (Doses 3 through 6) * The personalized neoantigen DNA vaccine will be given once every 28 days for up to 6 doses. Retifanlimab is given at a fixed dose of 500 mg every 28 days. * Patients may receive up to 6 doses of personalized neoantigen DNA vaccine and up to 12 months total of retifanlimab

Biological: Personalized Neoantigen DNA vaccine; Biological: Retifanlimab; Device: TDS-IM v 2.0 electroporation device

Cohort B: Personalized neoantigen DNA vaccine + retifanlimab

EXPERIMENTAL

* Cohort B will receive the personalized neoantigen DNA vaccine via electroporation mediated IM injection plus concurrent retifanlimab beginning with Dose 1 and continuing for a total of 6 doses. * The personalized neoantigen DNA vaccine will be given once every 28 days for up to 6 doses. Retifanlimab is given at a fixed dose of 500 mg every 28 days. * Patients may receive up to 6 doses of personalized neoantigen DNA vaccine and up to 12 months total of retifanlimab

Biological: Personalized Neoantigen DNA vaccine; Biological: Retifanlimab; Device: TDS-IM v 2.0 electroporation device

Interventions

Personalized Neoantigen DNA vaccine BIOLOGICAL

The sites of immunization may be rotated for each of the immunizations.

Cohort A: Personalized neoantigen DNA vaccine + retifanlimab; Cohort B: Personalized neoantigen DNA vaccine + retifanlimab

Retifanlimab BIOLOGICAL

Retifanlimab will be supplied by Incyte.

Also known as: INCMGA00012, MGA012

Cohort A: Personalized neoantigen DNA vaccine + retifanlimab; Cohort B: Personalized neoantigen DNA vaccine + retifanlimab

TDS-IM v 2.0 electroporation device DEVICE

Each DNA vaccination will be 1 mL vaccine administered intramuscularly using an integrated electroporation administration system

Cohort A: Personalized neoantigen DNA vaccine + retifanlimab; Cohort B: Personalized neoantigen DNA vaccine + retifanlimab

Eligibility Criteria

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

You may qualify if:

• Newly diagnosed histologically or molecularly consistent with WHO grade IV high grade glioma, IDH wildtype.
• Patients who had prior craniotomy with biopsy, subtotal resection, total gross resection, or re-resection will be permitted.
• Consent to genome sequencing and dbGaP-based data sharing and has provided or will provide germline (PBMC) and tumor DNA/RNA samples of adequate quality for sequencing. (Acquisition of specimens for sequencing and the sequencing itself may be done as part of routine care or another research project.)
• At least 18 years of age.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
• Confirmed MGMT promoter unmethylated glioblastoma multiforme. Patients with secondary glioblastoma, in particular those who are IDH1 or IDH2 mutant, will not be excluded. High grade gliomas with molecular features of glioblastoma will be included. MGMT promoter methylation status must be determined by a standard PCR-based assay.
• Note: While tissue sequencing can begin prior to confirmation of MGMT promotor status, the manufacturing process will not begin until MGMT promotor is confirmed as unmethylated.
• Personalized neoantigen DNA vaccine manufactured for administration.
• Karnofsky performance status ≥ 60%
• Normal bone marrow and organ function as defined below:
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
• Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal

You may not qualify if:

• As this study aims to assess the immunogenicity of a personalized neoantigen DNA vaccine in combination with checkpoint blockade, no prior immunotherapy will be permitted.
• Inadequate tissue acquisition to allow for neoantigen screening.
• No candidate neoantigen identified during screening.
• A history of other malignancy ≤ 3 years previous with the exception of non-melanoma skin cancer, any in situ cancer that has been successfully resected and cured, treated superficial bladder cancer, or any early-stage solid tumor that was successfully resected without need for adjuvant radiation or chemotherapy.
• Known allergy, or history of serious adverse reaction to, vaccines such as anaphylaxis, hives, or respiratory difficulty.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to any agents used in the study.
• History of immunodeficiency disorder or autoimmune condition requiring active immunosuppressive therapy. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines.
• Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM injections.
• Presence of a cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located ipsilateral to the intended deltoid injection site (unless deemed acceptable by a Cardiologist).
• Presence of any metal implants or implantable medical device within the electroporation area.
• Any active uncontrolled neurologic disorder, including seizures and epilepsy.
• Recurrent known vasovagal-related syncopal episodes resulting in loss of consciousness.
• Individuals in whom skin pinch thickness for all eligible injection sites exceeds 50 mm.
• Individuals in whom the ability to observe possible local reactions at the eligible injection sites is, in the opinion of the investigator, unacceptably obscured due to a physical condition or permanent body art.
• History of organ transplant, including allogeneic stem cell transplantation.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Incyte Corporation: collaborator
• PapiVax Biotech, Inc.: collaborator
• The Foundation for Barnes-Jewish Hospital: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Glioblastoma

Condition Hierarchy (Ancestors)

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

Study Officials

• Tanner M Johanns, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 14, 2023
• First Posted: February 24, 2023
• Study Start: October 27, 2023
• Primary Completion: April 7, 2026
• Study Completion (Estimated): March 9, 2029
• Last Updated: May 4, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share

Locations

US (1)