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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Glioblastoma

Intervention / Treatment
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* Biological: NeoVax
* Biological: Nivolumab
* Biological: Ipilimumab
* Procedure: Research blood draw
* Procedure: Leukapheresis for research


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: NeoVax+Nivolumab (start at time of progression)<br>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<br>* 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.<br>* Other names: Synthetic long peptides plus poly-ICLC;Biological: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;Procedure: Research blood draw<br>* -Baseline, cycle 2 day 1, cycle 4 day 1, and time of progression or discontinuation of treatment<br>Procedure: Leukapheresis for research<br>* -Baseline, cycle 4 day 1, and time of progression or discontinuation of treatment<br>|
| Experimental: Cohort B: NeoVax+Nivolumab (start with Cycle 2)<br>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<br>* 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.<br>* Other names: Synthetic long peptides plus poly-ICLC;Biological: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;Procedure: Research blood draw<br>* -Baseline, cycle 2 day 1, cycle 4 day 1, and time of progression or discontinuation of treatment<br>Procedure: Leukapheresis for research<br>* -Baseline, cycle 4 day 1, and time of progression or discontinuation of treatment<br>|
| Experimental: Cohort C: NeoVax + Nivolumab (start with Cycle 1)<br>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<br>* 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.<br>* Other names: Synthetic long peptides plus poly-ICLC;Biological: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;Procedure: Research blood draw<br>* -Baseline, cycle 2 day 1, cycle 4 day 1, and time of progression or discontinuation of treatment<br>Procedure: Leukapheresis for research<br>* -Baseline, cycle 4 day 1, and time of progression or discontinuation of treatment<br>|
| Experimental: Cohort D: NeoVax+Ipilimumab+Nivolumab (start with Cycle 3)<br>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<br>* 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.<br>* Other names: Synthetic long peptides plus poly-ICLC;Biological: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)<br>* Other names: Yervoy;Procedure: Research blood draw<br>* -Baseline, cycle 2 day 1, cycle 4 day 1, and time of progression or discontinuation of treatment<br>Procedure: Leukapheresis for research<br>* -Baseline, cycle 4 day 1, and time of progression or discontinuation of treatment<br>|
| Experimental: Cohort E: NeoVax+Ipilimumab+Nivolumab (day 1&15 each cycle)<br>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<br>* 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.<br>* Other names: Synthetic long peptides plus poly-ICLC;Biological: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)<br>* Other names: Yervoy;Procedure: Research blood draw<br>* -Baseline, cycle 2 day 1, cycle 4 day 1, and time of progression or discontinuation of treatment<br>Procedure: Leukapheresis for research<br>* -Baseline, cycle 4 day 1, and time of progression or discontinuation of treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of regimen as measured by a <= 33% dose-limiting toxicity (DLT) rate for a given cohort | 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. | Up to 90 days after start of treatment | 
| Feasibility of generating a personalized neoantigen peptide vaccine as measured by the ability to identify candidate tumor-specific neoantigens |  | 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 |  | 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 |  | From time of resection to 4 weeks post-radiation therapy (approximately 14 weeks) | 

Secondary Outcome Measures

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