A Pilot Study to Assess the Safety and Immunogenicity of a Neoantigen-based Personalized DNA Vaccine With Retifanlimab PD-1 Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma
Overview
- Phase
- Phase 1
- Intervention
- Personalized Neoantigen DNA vaccine
- Conditions
- Unmethylated Glioblastoma
- Sponsor
- Washington University School of Medicine
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Safety as measured by treatment-related dose-limiting toxicity (DLT) rate related to vaccination
- Status
- Active, not recruiting
- Last Updated
- last month
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Step 1 Inclusion Criteria for Tissue Sequencing:
- •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).
- •Step 2 Inclusion Criteria for Treatment Administration:
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
Cohort A: Personalized neoantigen DNA vaccine + retifanlimab
* 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
Intervention: Personalized Neoantigen DNA vaccine
Cohort A: Personalized neoantigen DNA vaccine + retifanlimab
* 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
Intervention: Retifanlimab
Cohort A: Personalized neoantigen DNA vaccine + retifanlimab
* 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
Intervention: TDS-IM v 2.0 electroporation device
Cohort B: Personalized neoantigen DNA vaccine + retifanlimab
* 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
Intervention: Personalized Neoantigen DNA vaccine
Cohort B: Personalized neoantigen DNA vaccine + retifanlimab
* 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
Intervention: Retifanlimab
Cohort B: Personalized neoantigen DNA vaccine + retifanlimab
* 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
Intervention: TDS-IM v 2.0 electroporation device
Outcomes
Primary Outcomes
Safety as measured by treatment-related dose-limiting toxicity (DLT) rate related to vaccination
Time Frame: Through completion of DLT observation period for all enrolled subjects (estimated to be up to 12 months and 87 days)
* 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).
Secondary Outcomes
- 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)
- 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)
- Overall survival (OS)(At 12 months)
- Immunogenicity as measured by the percentage of neoantigens that elicit a neoantigen-specific CD8 T cell response out of the total number of neoantigens vaccinated against within a cohort(Through progression (up to 36 months))
- Objective response rate (ORR)(Through completion of treatment (estimated to be 12 months))
- Immunogenicity as measured by T-cell phenotype, myeloid derived suppressor cell frequency (MDSC) assessed by flow cytometry(Through progression (up to 36 months))
- Immunogenicity as measured by T cell receptor (TCR) sequencing to assess diversity of clonality and putative antigen specificity(Through progression (up to 36 months))
- Immunogenicity as measured by pro- and anti-inflammatory chemokine analysis and cytokine analysis in plasma as assessed by multiplex ELISA(Through progression (up to 36 months))