Clinical Trials /

Neoantigen-based Personalized Vaccine Combined With Immune Checkpoint Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma

NCT03422094

Description:

This is a single institution, open-label, multi-arm, pilot study assessing the safety, feasibility, and immunogenicity of a personalized neoantigen-based vaccine plus poly-ICLC (NeoVax) combined with immune checkpoint inhibitors in subjects with newly diagnosed, unmethylated glioblastoma.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Neoantigen-based Personalized Vaccine Combined With Immune Checkpoint Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma
  • Official Title: A Pilot Study to Assess the Safety, Feasibility, and Immunogenicity of a Neoantigen-based Personalized Vaccine Combined With Immune Checkpoint Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 17-x441
  • NCT ID: NCT03422094

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
NeoVaxSynthetic long peptides plus poly-ICLCCohort A: NeoVax+Nivolumab (start at time of progression)
NivolumabOpdivoCohort A: NeoVax+Nivolumab (start at time of progression)
IpilimumabYervoyCohort D: NeoVax+Ipilimumab+Nivolumab (start with Cycle 3)

Purpose

This is a single institution, open-label, multi-arm, pilot study assessing the safety, feasibility, and immunogenicity of a personalized neoantigen-based vaccine plus poly-ICLC (NeoVax) combined with immune checkpoint inhibitors in subjects with newly diagnosed, unmethylated glioblastoma.

Trial Arms

NameTypeDescriptionInterventions
Cohort A: NeoVax+Nivolumab (start at time of progression)ExperimentalNeoVax given on Days 1, 8, 15, and 22 of Cycle 1 (priming phase), and then on Day 1 of each subsequent cycle (boosting phase) Nivolumab 480 mg i.v. given on Day 1 of each cycle beginning at time of progression
    Cohort B: NeoVax+Nivolumab (start with Cycle 2)ExperimentalNeoVax given on Days 1, 8, 15, and 22 of Cycle 1 (priming phase), and then on Day 1 of each subsequent cycle (boosting phase) Nivolumab 480 mg i.v. given on Day 1 of each cycle beginning with Cycle 2 (start of boosting phase)
      Cohort C: NeoVax + Nivolumab (start with Cycle 1)ExperimentalNeoVax given on Days 1, 8, 15, and 22 of Cycle 1 (priming phase), and then on Day 1 of each subsequent cycle (boosting phase) Nivolumab 480 mg i.v. given on Day 1 of Cycle 1 (priming phase), and then on Day 1 of each subsequent cycle (boosting phase)
        Cohort D: NeoVax+Ipilimumab+Nivolumab (start with Cycle 3)ExperimentalNeoVax given on Days 1, 8, 15, and 22 of Cycle 1 (priming phase), and then on Day 1 of each subsequent cycle (boosting phase) Ipilimumab 1 mg/kg i.v. given on Days 1 and 22 of Cycle 1 (priming phase) Nivolumab 480 mg i.v. given on Day 1 of Cycle 3 and then on Day 1 of each subsequent cycle
          Cohort E: NeoVax+Ipilimumab+Nivolumab (day 1&15 each cycle)ExperimentalNeoVax given on Days 1, 8, 15, and 22 of Cycle 1 (priming phase), and then on Day 1 of each subsequent cycle (boosting phase) Ipilimumab 1 mg/kg i.v. given every 6 weeks beginning on Day 1 of Cycle 1 (C1D1, C2D15, C4D1, C5D15, C7D1, C8D15 …) Nivolumab 3 mg/kg i.v. given on Days 1 and 15 of each cycle (q2w) beginning on Day 1 of Cycle 1

            Eligibility Criteria

                    Inclusion Criteria:
            
                      -  Newly diagnosed histologically confirmed unmethylated glioblastoma multiforme (WHO
                         grade IV). Patients with secondary glioblastoma, in particular those who are IDH1 or
                         IDH2 mutant, will not be excluded. Unmethylated MGMT must be confirmed by a PCR-based
                         assay.
            
                      -  Patients who had craniotomy with biopsy, subtotal resection, total gross resection, or
                         re-resection will be permitted.
            
                      -  Consented 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.
            
                      -  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 institutional upper limit of normal (IULN)
            
                           -  AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
            
                           -  Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with
                              creatinine levels above institutional normal
            
                      -  Systemic corticosteroid therapy is permitted provided dosing is no greater than 4 mg
                         per day (dexamethasone or equivalent) on the day of vaccine administration.
            
                      -  Bevacizumab will be allowed if given for symptomatic control of vasogenic edema and to
                         avoid high dose of corticosteroids.
            
                      -  Women of childbearing potential and men must agree to use adequate contraception
                         (hormonal or barrier method of birth control, abstinence) prior to study entry and for
                         the duration of study participation, including at least 5 months (for women of
                         childbearing potential) and at least 7 months (for men) after last dose of study drug.
                         Should a woman become pregnant or suspect she is pregnant while participating in this
                         study, she must inform her treating physician immediately.
            
                      -  Ability to understand and willingness to sign an IRB approved written informed consent
                         document (or that of legally authorized representative, if applicable).
            
                    Exclusion Criteria:
            
                      -  As this study aims to assess the immunogenicity of various vaccine plus adjuvant
                         combinations, 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.
            
                      -  Receiving any other investigational agents within 4 weeks of beginning study
                         treatment.
            
                      -  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 poly-ICLC or other agents used in the study.
            
                      -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
                         infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
                         arrhythmia, or psychiatric illness/social situations that would limit compliance with
                         study requirements.
            
                      -  History of pre-existing immunodeficiency disorder or autoimmune condition requiring
                         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 clinically significant increased intracranial pressure (e.g. impending
                         herniation) or hemorrhage, uncontrolled seizures, or requirement for immediate
                         palliative treatment.
            
                      -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
                         pregnancy test within 7 days of first dose of vaccine.
                  
            Maximum Eligible Age:N/A
            Minimum Eligible Age:18 Years
            Eligible Gender:All
            Healthy Volunteers:No

            Primary Outcome Measures

            Measure:Safety and tolerability of regimen as measured by a <= 33% dose-limiting toxicity (DLT) rate for a given cohort
            Time Frame:Up to 90 days after start of treatment
            Safety Issue:
            Description:The DLT observation period is 60 days after C1D1 for patients enrolled to Cohorts A, C, and D and is 90 days after C1D1 for patients enrolled to Cohorts B and E. DLT is defined as any grade 3 or greater event that occurs during the DLT observation period that is considered at least possibly related to the study treatment.

            Secondary Outcome Measures

            Measure:Immunogenicity of a personalized neoantigen peptide vaccine as measured by the ability to generate a measurable neoantigen-specific T cell response in vaccinated patients
            Time Frame:Week 4 post-vaccination
            Safety Issue:
            Description:
            Measure:Immunogenicity of a personalized neoantigen peptide vaccine as measured by the ability to generate a measurable neoantigen-specific T cell response in vaccinated patients
            Time Frame:Week 16 post-vaccination
            Safety Issue:
            Description:
            Measure:Immunogenicity of a personalized neoantigen peptide vaccine as measured by the number of individual neoantigens per number of neoantigens vaccinated against, with which a measurable T cell-specific response
            Time Frame:Week 4 post-vaccination
            Safety Issue:
            Description:
            Measure:Immunogenicity of a personalized neoantigen peptide vaccine as measured by the number of individual neoantigens per number of neoantigens vaccinated against, with which a measurable T cell-specific response
            Time Frame:Week 16 post-vaccination
            Safety Issue:
            Description:
            Measure:Number of high quality candidate neoantigens present in patients with newly diagnosed glioblastoma
            Time Frame:Up to 2 weeks post sequencing
            Safety Issue:
            Description:High quality neoantigens will be defined as those that meet criteria for inclusion in a vaccine
            Measure:Progression-free (PFS) survival rate
            Time Frame:6 months
            Safety Issue:
            Description:
            Measure:Overall survival (OS) rate
            Time Frame:12 months
            Safety Issue:
            Description:

            Details

            Phase:Phase 1
            Primary Purpose:Interventional
            Overall Status:Not yet recruiting
            Lead Sponsor:Washington University School of Medicine

            Last Updated

            April 10, 2018