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

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ClinicalTrials.gov Identifier: NCT03422094
Recruitment Status : Recruiting
First Posted : February 5, 2018
Last Update Posted : April 8, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Glioblastoma Biological: NeoVax Biological: Nivolumab Biological: Ipilimumab Procedure: Research blood draw Procedure: Leukapheresis for research Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 31, 2018
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : November 30, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
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

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

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)
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

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

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)
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

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

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
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

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
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




Primary Outcome Measures :
  1. 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.

  2. 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) ]
  3. 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) ]
  4. 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) ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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

  6. Progression-free (PFS) survival rate [ Time Frame: 6 months ]
  7. Overall survival (OS) rate [ Time Frame: 12 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03422094


Contacts
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Contact: Gavin Dunn, M.D., Ph.D. (314) 362-3570 gpdunn@wustl.edu
Contact: David J Schwab, CCRP 314-747-9912 dschwab@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Gavin Dunn, M.D., Ph.D.    314-362-3570    gpdunn@wustl.edu   
Contact: David J Schwab, CCRP    314-747-9912    dschwab@wustl.edu   
Principal Investigator: Gavin Dunn, M.D., Ph.D.         
Sub-Investigator: William E Gillanders, M.D.         
Sub-Investigator: Robert Schreiber, Ph.D.         
Sub-Investigator: Tanner M Johanns, M.D., Ph.D.         
Sub-Investigator: Jian Campian, M.D., Ph.D.         
Sub-Investigator: George Annstas, M.D.         
Sub-Investigator: Milan G Chheda, M.D.         
Sub-Investigator: Michael Chicoine, M.D.         
Sub-Investigator: Ralph Dacey, M.D.         
Sub-Investigator: Albert Kim, M.D., Ph.D.         
Sub-Investigator: Keith Rich, M.D.         
Sub-Investigator: Joshua Dowling, M.D.         
Sub-Investigator: Eric Leuthardt, M.D.         
Sub-Investigator: Gregory J Zipfel, M.D.         
Sub-Investigator: Joshua Osbun, M.D.         
Sub-Investigator: Christina Tsien, M.D.         
Sub-Investigator: Jiayi Huang, M.D.         
Sub-Investigator: Malachi Griffith, Ph.D.         
Sub-Investigator: Obi Griffith, Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Bristol-Myers Squibb
Investigators
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Principal Investigator: Gavin Dunn, M.D., Ph.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03422094     History of Changes
Other Study ID Numbers: 201804195
First Posted: February 5, 2018    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nivolumab
Ipilimumab
Vaccines
Poly ICLC
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents
Interferon Inducers