Neoantigen DNA Vaccine in Pancreatic Cancer Patients Following Surgical Resection and Adjuvant Chemotherapy

Study Overview
=================
Brief Summary
-----------------
This is a phase 1 open-label study to evaluate the safety and immunogenicity of a neoantigen DNA vaccine strategy in pancreatic cancer patients following surgical resection and adjuvant chemotherapy. The neoantigen DNA vaccines will incorporate prioritized neoantigens and personalized mesothelin epitopes and will be administered with an electroporation device. The hypothesis of this study is that neoantigen DNA vaccines will be safe and capable of generating measurable neoantigen-specific CD4 and CD8 T cell responses.

Detailed Description
-----------------
-Subjects will be enrolled within 12 weeks of surgery and standard of care adjuvant chemotherapy will last approximately 12 weeks with an additional 12 weeks of standard of care adjuvant chemotherapy or adjuvant chemoradiation. The first vaccine may be administered following confirmation of disease-free status and within 60 days following date of repeat imaging. From time of enrollment to first vaccine could be up to 45 weeks.

Official Title
-----------------
A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of a Neoantigen DNA Vaccine Strategy in Pancreatic Cancer Patients Following Surgical Resection and Adjuvant Chemotherapy

Conditions
-----------------
Pancreatic Cancer, Pancreas Cancer, Cancer of the Pancreas

Intervention / Treatment
-----------------
* Biological: Personalized neoantigen DNA vaccine
* Device: TDS-IM Electrode Array System
* Procedure: Peripheral blood draws


Participation Criteria
=================
Eligibility Criteria
-----------------
A patient will be eligible for the trial only if ALL of the following criteria apply: Inclusion Criteria: Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma; mixed histology will be included as long as the predominant histology is adenocarcinoma. Completed an R0 or R1 surgical resection as determined by pathology Pathology review demonstrates tumor cellularity no less than 30% in quantities sufficient to obtain 6-8 1mm biopsies from the original FFPE blocks. At least 18 years of age. Life expectancy of > 12 months. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Normal bone marrow and organ function as defined below: white blood cells (WBC) ≥3,000/μL absolute neutrophil count ≥1,500/μL platelets ≥100,000/μL total bilirubin ≤2.5 X institutional upper limit of normal (ULN) AST/ALT≤ 2.5 X institutional upper limit of normal creatinine ≤1.5 X institutional upper limit of normal International Normalized Ratio (INR) and activated partial thromboplastin time (PTT) < 1.5 x ULN provided the patient is not on anticoagulation therapy. Patients who have had a stent placed for biliary obstruction can be included in the study provided serum bilirubin at time of enrollment is within protocol limits. Women of child-bearing 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Able to understand and willing to sign an IRB approved written informed consent document. Patients may be consented prior to receiving adjuvant therapy, or during the course of adjuvant therapy. Adjuvant therapy must meet the following criteria below for enrollment to the trial: Initiation of adjuvant chemotherapy within 12 weeks of surgery Completion of at least 4 months of adjuvant chemotherapy with gemcitabine/capecitabine or similar adjuvant chemotherapy at the discretion of the patient's medical oncologist. Additional chemoradiation therapy as recommended by the patient's medical oncologist. Reimaging within 4 weeks of last dose of chemotherapy demonstrates no evidence of recurrent disease and CA 19-9 is less than 92.5 u/mL Dose modifications and/or delays in adjuvant chemotherapy is at the discretion of the treating physician -There is a 1 week washout prior to Day 1 of vaccine for patients on daily systemic steroids at doses exceeding 10 mg prednisone. Exclusion Criteria: Evidence of neuroendocrine tumor, duodenal adenocarcinoma, or ampullary adenocarcinoma. Received neoadjuvant chemotherapy for their pancreatic adenocarcinoma Evidence of disease recurrence or metastasis following surgical resection at any time prior to the first vaccination administration. Most patients will undergo restaging midway through adjuvant chemotherapy and at the completion of therapy; however, timing of imaging is at the discretion of the patient's medical oncologist. History of other malignancy ≤ 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. Receiving any other investigational agents, or has received an investigational agent within the last 30 days. Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty. Acute or chronic, clinically significant hematologic, pulmonary, cardiovascular, hepatic renal, and/or other functional abnormality that would jeopardize the health and safety of the participant as determined by the investigator based on medical history, physical examination, laboratory values, and/or diagnostic studies. A psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator from the medical history, physical exam, and/or medical record History of syncopal or vasovagal episode as determined by medical record and history in the 12 month period prior to first vaccination administration. Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue for eligible injection sites (left and right medial deltoid region) exceeds 40 mm. Individuals in whom the ability to observe possible local reactions at the eligible injection sites (deltoid region) is, in the opinion of the investigator, unacceptably obscured due to a physical condition or permanent body art. Therapeutic or traumatic metal implant in the skin or muscle of either deltoid region. Any chronic or active neurologic disorder, including seizures and epilepsy, excluding a single febrile seizure as a child. Current use of any electronic stimulation device, such as cardiac demand pacemakers, automatic implantable cardiac defibrillator, nerve stimulators, or deep brain stimulators. Prior or currently active autoimmune disease requiring management with immunosuppression. 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 (e.g., corticosteroids) which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. In the case of asthma or chronic obstructive pulmonary disease taking inhaled corticosteroids that does not require daily systemic corticosteroids is acceptable. Additionally, local acting steroids (topical, inhaled, or intraarticular) will be allowed. Patients on intermittent or short course steroids will be allow if the dose does not exceed 4 mg of dexamethasone (or equivalent) per day for > 7 consecutive days. Any patients receiving steroids should be discussed with the PI to determine if eligible. Pregnant and/or breastfeeding. Known HIV-positive status. These patients are ineligible because of the potential inability to generate an immune response to vaccines.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Personalized neoantigen DNA vaccine<br>Vaccines will be weeks 1, 5, 9, 13, 17, and 21. Vaccines will occur within +/- 1 week with at least 3 weeks between vaccines. All study injections will be given intramuscularly using TDS-IM system. At each vaccination time point, patients will receive 2 injections of the neoantigen DNA vaccine, 1 injection into each deltoid or lateralis. Minimum observation of 30 minutes. Vital signs will be taken at 30-45 minutes post-immunization. The injection sites will be inspected for evidence of local reaction. Follow up on subject well-being will be performed by telephone on the 1st or 2nd day following each injection. -Post-vaccination follow-up visits are at Week 25 ± 7 days and Week 77 ± 14 days. Additional follow-up visits or telephone contact will be scheduled at Week 129 and annually thereafter if the patient is alive and available for follow-up. At intervals throughout the study (both before and after vaccination) subjects will have blood drawn for immunologic assays. | Biological: Personalized neoantigen DNA vaccine<br>* -Personalized polyepitope inserts integrating the prioritized neoantigens and mesothelin epitopes will be designed and then synthesized and cloned into the pING parent vector<br>Device: TDS-IM Electrode Array System<br>* -Ichor Medical Systems<br>Procedure: Peripheral blood draws<br>* -Enrollment, mid adjuvant chemotherapy, end of chemotherapy, week 1, week 5, week 9, week 13, week 17, week 21, week 25, and week 77<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Neoantigen DNA Vaccine as Measured by the Number of Subjects Experiencing Each Type of Treatment-related Adverse Event | Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 Related indicates possibly, probably, or definitely related to the study treatment | Through week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of the Neoantigen DNA Vaccine as Measured by ELISPOT Analysis | Immunogenicity is defined as the number of participants with a neoantigen-specific immune response measured by ELISPOT analysis. A participant is considered a responder if there is a significant increase in the number of neoantigen-specific T cells to at least one neoantigen after vaccination. A significant increase is based on t-test comparing the number of neoantigen-specific T-cells before and after vaccination with p=0.05 for significance. | Through week 77 | 
| Immunogenicity of the Neoantigen DNA Vaccine as Measured by Multiparametric Flow Cytometry |  | Through week 77 |