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:

Active, not 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: 201804195
  • 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
  • NeoVax
  • Nivolumab
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)
  • NeoVax
  • Nivolumab
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)
  • NeoVax
  • Nivolumab
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
  • NeoVax
  • Nivolumab
  • Ipilimumab
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
  • NeoVax
  • Nivolumab
  • Ipilimumab

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:Recruiting
Lead Sponsor:Washington University School of Medicine

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