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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03422094
Recruitment Status : Active, not recruiting
First Posted : February 5, 2018
Last Update Posted : June 2, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE January 29, 2018
First Posted Date  ICMJE February 5, 2018
Last Update Posted Date June 2, 2020
Actual Study Start Date  ICMJE October 31, 2018
Actual Primary Completion Date May 25, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • 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 ]
    • 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.
  • Feasibility of generating a personalized neoantigen peptide vaccine as measured by the ability to identify candidate tumor-specific neoantigens [ Time Frame: From time of resection to 4 weeks post-radiation therapy (approximately 14 weeks) ]
  • Feasibility of generating a personalized neoantigen peptide vaccine as measured by the the ability to manufacture a neoantigen-based synthetic long peptide vaccine [ Time Frame: From time of resection to 4 weeks post-radiation therapy (approximately 14 weeks) ]
  • Feasibility of generating a personalized neoantigen peptide vaccine as measured by the ability to administer the vaccine to a patient at 4 weeks post-completion of radiotherapy [ Time Frame: From time of resection to 4 weeks post-radiation therapy (approximately 14 weeks) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Number of high quality candidate neoantigens present in patients with newly diagnosed glioblastoma [ Time Frame: Up to 2 weeks post sequencing ]
    High quality neoantigens will be defined as those that meet criteria for inclusion in a vaccine
  • Progression-free (PFS) survival rate [ Time Frame: 6 months ]
  • Overall survival (OS) rate [ Time Frame: 12 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoantigen-based Personalized Vaccine Combined With Immune Checkpoint Blockade Therapy in Patients With Newly Diagnosed, Unmethylated Glioblastoma
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Biological: NeoVax
    At each vaccination time point, patients will receive up to 20 synthetic long peptides co-administered with 1.5 mg of poly-ICLC divided into a maximum of four injections (pools). Each pool (of vaccine + poly IC:LC) will be administered to one of the four limbs (right axilla, left axilla, right inguina, left inguina) by subcutaneous injection.
    Other Name: Synthetic long peptides plus poly-ICLC
  • Biological: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Name: Opdivo
  • Biological: Ipilimumab
    Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
    Other Name: Yervoy
  • Procedure: Research blood draw
    -Baseline, cycle 2 day 1, cycle 4 day 1, and time of progression or discontinuation of treatment
  • Procedure: Leukapheresis for research
    -Baseline, cycle 4 day 1, and time of progression or discontinuation of treatment
Study Arms  ICMJE
  • Experimental: Cohort A: NeoVax+Nivolumab (start at time of progression)
    • NeoVax 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
    Interventions:
    • Biological: NeoVax
    • Biological: Nivolumab
    • Procedure: Research blood draw
    • Procedure: Leukapheresis for research
  • Experimental: Cohort B: NeoVax+Nivolumab (start with Cycle 2)
    • NeoVax 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)
    Interventions:
    • Biological: NeoVax
    • Biological: Nivolumab
    • Procedure: Research blood draw
    • Procedure: Leukapheresis for research
  • Experimental: Cohort C: NeoVax + Nivolumab (start with Cycle 1)
    • NeoVax 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)
    Interventions:
    • Biological: NeoVax
    • Biological: Nivolumab
    • Procedure: Research blood draw
    • Procedure: Leukapheresis for research
  • Experimental: Cohort D: NeoVax+Ipilimumab+Nivolumab (start with Cycle 3)
    • NeoVax 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
    Interventions:
    • Biological: NeoVax
    • Biological: Nivolumab
    • Biological: Ipilimumab
    • Procedure: Research blood draw
    • Procedure: Leukapheresis for research
  • Experimental: Cohort E: NeoVax+Ipilimumab+Nivolumab (day 1&15 each cycle)
    • NeoVax 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
    Interventions:
    • Biological: NeoVax
    • Biological: Nivolumab
    • Biological: Ipilimumab
    • Procedure: Research blood draw
    • Procedure: Leukapheresis for research
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 28, 2020)
3
Original Estimated Enrollment  ICMJE
 (submitted: January 29, 2018)
30
Estimated Study Completion Date  ICMJE February 26, 2021
Actual Primary Completion Date May 25, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03422094
Other Study ID Numbers  ICMJE 201804195
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Gavin Dunn, M.D., Ph.D. Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP