.....90 J1790 / Version 7.0/ December 10, 2020 4 1. OBJECTIVES 1.1 Primary Objective To determine the objective response rate (ORR) using Response Evaluation Criteria for Solid Tumors (RECIST 1.1 ) in two cohorts of subjects with previously treated metastatic pancreatic cancer : Arm A treated with cyclophosphamide (CY)/ nivolumab/ipilimumab/ GVAX pancreas vaccine followed by nivolumab/ipilimumab/ CRS -207 and Arm B treated with nivolumab/ipilimumab/CRS -207. 1.2 Secondary Objective 1.2.1 To assess safety and characterize toxicities of each vaccine treatment regimen when combined with anti-PD-1 and anti -CTLA -4 blockade in subjects with metastatic pancreatic adenocarcinoma. 1.3 Exploratory Objectives 1.3.1 To assess the overall survival (OS). 1.3.2 To assess progression free survival (PFS), duration of response (DOR), and time to progression (TTP) by RECIST 1.1. 1.3.3 To measure tumor marker kinetics (CA 19 -9) in subjects receiving treatment and correlate with OS, PFS, and best overall response. 1.3.4 To assess the ORR , PFS, and DOR by immune -related response criteria (irRC) . 1.3.5 To collect peripheral blood mononuclear cells (PBMC) , plasma, and serum to identify potential therapeutic targets , biomarkers and predictors of response (OS, PFS and best overall response) and autoimmune toxicity. • Measure pre - and post-treatment changes in PBMCs including effector, helper, and regulatory T cells, NK cells, monocytes, and macrophages through cell phenotyping analysis and gene expression profiling . • Correlate induction of Listeria monocytogenes (Lm)- and mesothelin antigen -specific T cell responses and changes to the T cell epitope repertoire with OS, PFS , and best overall response . • Correlate telomere length of lymphocytes to help predict response (OS, PFS, and best overall response) . • Correlate the i nduction of anti-thyroglobulin and anti-galectin -3 antibody responses with response (OS, PFS , and best overall response) . J1790 / Version 7.0/ December 10, 2020 5 • Proteomic approaches will be used on pre - and post-treatment sera to identify targets and biomarkers of response (OS, PFS , and best overall response) or toxicity. 1.3.6 To collect archived tissue and pre - and post-treatment biopsies to test for predictors of response (OS, PFS , and best overall response) and future targets for combinatorial therapy. • Immunohistochemistry (IHC) and/or gene expression profiling will be used to compare the nature of tumors and immune infiltrates for responders versus non -responders . • Next -generation sequencing of T cell receptor (TCR) genes may be used to compare the tumor infiltrating T cell repertoire in re sponders and non - responders • Up-regulation of immune inhibitory molecules (such as programmed death - ligand 1 [ PD-L1]) will be evaluated in the pre- and post -treatment samples. • Proteomic approaches to quantify protein expression and activation of specific signaling pathways in tumors from responders vers us non - responders . 1.3.7 To collect stool and oral wash samples pre - and post -treatment to identify candidate gut microbial biomarkers and predictors of response ( OS, PFS and best overall response) • Microbial com munity analysis to correlate gut microbiome composition with response (OS, PFS and best overall response). • Whole metagenome functional profiling analysis via shotgun sequencing to correlate microbiome composition and microbial functions and pathways with response (OS, PFS and best overall response) . 1.4 Study Design This is a multi -center, open -label, randomized , phase 2 study to evaluate the safety and clinical activity of nivolumab and ipilimumab in combination with either sequential administration of CY/GVAX pancreas vaccine followed by CRS -207 (Arm A) or with administration of CRS -207 alone (Arm B) in subjects with metastatic pancreatic adenocarcinoma who have progres sed after at least 1 prior chemotherapy regimen . The primary endpoint of this study is objective response rate (ORR) using RECIST 1.1. Approximately 63 subjects will be enrolled and randomized 1:1 to the two treatment arms to achieve 60 treated subjects (i.e. allowing for 5% loss) . The study will consist of a screening period (within 21 days of first dose), a treatment period per the table below , and a follow -up period. J1790 / Version 7.0 / December 10, 2020 6 Table 1: Treatment Schedule TREATMENT SCHEDULE Arm CY Nivolumab Ipilimumab GVAX CRS - 207 A Day 1, Cycles 1, 2 Day 1, Cycles 1, 2, 3, 4, 5, 6 Day 1, Cycles 1, 3, 5 Day 2, Cycles 1, 2 Day 2, Cycles 3, 4, 5, 6 B None Day 1, Cycles 1, 2, 3, 4, 5, 6 Day 1, Cycles 1, 3, 5 None Day 2, Cycles 1, 2, 3, 4, 5, 6 Subjects on both arms will receive treatment every 3 weeks for 6 cycles of treatment within a course . A course of treatment will be 18 weeks and courses can be repeated. The treatment schedule for Arms A and B can be found in Table 1 . Subjects will come to the clinic for dosing an d/ or assessments on Days 1 and 2 of each cycle and additional days for safety and immune monitoring follow - up per the study schedules in Section 10 . No dose escalation s or reduction s are allowed. E nrol lment will continue until 6 0 subje cts have received at least one dose of study treatment. It is estimated that 5% of the subjects will not receive treatment , so approximately 63 subjects will be randomized to achieve 30 treated subjects in Arm A and 30 treated subjects in Arm B . I f the investigator assesses a drug - related toxicity ( that requires discontinuation ) to be related to an individual component of the treatment schedule , dosing for that study drug alone may be discontinued while dosing is delayed until the subject meets cri teria to resume treatment of the other study drugs . The relationship to the discontinued study drug should be well documented in the source documents and permission from the Protocol Chair needs to be obtained prior to continuation with the other study dru gs . The proportion of treated subjects with unacceptable toxicity will be monitored using a Bayesian stopping guideline within each treatment arm separately . Once the first 12 participants have been randomized (6 in each group), a ccrual will be suspended until the toxicity levels have been determined to be acceptable in both arm s (i.e. confirmation that less than 3 subjects experience unacceptable toxicities during the first 4 weeks of treatment ) . Then, the remaining participants will be enrolled and moni tored routinely . Complete unacceptable toxicity criteria can be found in Section 5.7 . At the investigator’s discretion, subjects may receive additional courses of the assigned treatment regimen if they are clinically stable and meet dosing eligibility cr iteria. All subjects may continue in the treatment period up to a maximum of 2 years, or until discontinuation due to unacceptable toxicity, lack of clinical benefit as determined by the investigator, subject withdrawal, or termination of the study by IND S ponsor. Subjects that begin a new course prior to the 2 year cut - off may complete that course prior to coming off study. Subjects may continue on treatment with radiographic disease progression if subject is clinically stable and investigator believes the treatment is providing benefit. Criteria for removal from treatment are found in Section 5.1 0 . S ubjects will return to the study site 28 (±7) days after the final administration of study treatment for an end - of - treatment (EO T ) evaluation. Subjects who are still J1790 / Version 7.0/ December 10, 2020 7 receiving treatment at the time of study close may complete the current treatment course and the EOT evaluation prior to transitioning to long -term follow -up. Subjects wi ll be considered in the treatment period until 28 days after the last dose of study drug . Blood cultures through a peripheral vein and also through a central line (if applicable) will be collected to monitor for the presence of CRS -207 per Section 5.13 . After completion of treatment and EOT assessment s, all subjects , including those who did not receive treatment, will continue to be followed every three months (+/ - 2 weeks) by telephone, e - mail, or optional clinic visit until death, withdrawal of consent, or closure of study . Subjects will also be contacted at 100 days (+14 day reporting window) from the last dose of nivolumab / ipilimumab or 28 days (+7 day reporting window) from the last dose of cyclophosphamide, GVAX, or CRS -207 if the subject never rece ived nivolumab /ipilimumab or is no longer receiving nivolumab /ipilimumab due to toxicity , whichever reporting period is longer . Information on survival and new cancer therapies will be collected. In addition, all subjects that received at least one dose of CRS -207 will be monitored for CRS -207 infection for one year per Section 5.13 . All subjects who discontinue study treatment should continue to be monitored for disease status by radiologic imaging every two months (+/ - 2 weeks) until: 1) the start of a new antineoplastic therapy (information of the new cancer therapy will be collected), 2) disease progression, 3 ) death , 4) withdrawal of consent, or 5) the close of the study , whichever occurs first. All subjects will be followed after their l ast dose of study drug for the development of adverse events (AEs ) and serious adverse events (SAEs) as described in Section 7.5.1 . The primary analysis will be conducted when all treated subjects have documented response or progression by RECIST 1.1, or have discontinued the study . Information on survival may continue to be gathered for supplementary analyses after the completion of the primary analysis. At the conclusion of the study, all remaining subjects will be offered enrollment in a long -term follow - up study and continue to be followed for survival. 2. BACKGROUND 2.1 Study Disease Despite decades of basic and clinical research, effective therapy for the treatment of patients with pancreatic ductal adenocarcinoma (PAC) remains one of the grea test unmet clinical needs in oncology today. Currently, PAC accounts for approximately 7% of all cancer -related mortality and has the lowest 5 -year survival rate among all cancer types in the United States . PAC is currently the 4th leading cause of death from cancer in the U.S. with estimates in 2016 for 53,070 people diagnosed and about 41,780 dying from the disease1. Worldwide it will claim more than 300,000 lives this year2. It is projected that by 2030, pancreatic cancer will become the second leading cause of cancer -related death in the US3. Most patients are initially diagnosed with advanced disease that is inoperable with median survival of less th an 1 year. Patients with advanced disease are usually treated with chemotherapy, with the intent of prolonging survival and palliating symptoms (pain, weight loss and decrease in performance status). From 1997, gemcitabine was the standard chemotherapy for advanced pancreatic cancer after demonstrating a significant improvement in survival compared to 5 - J1790 / Version 7.0/ December 10, 2020 8 fluorouracil (5 -FU)4. Median survival was 5.65 months for gemcitabine -treated patients and 4 .41 months for 5 -FU treated patients, while overall tumor response rates were 5.4% and 0%, respectively. Until recently, only erlotinib, an oral epidermal growth factor (EGF) inhibitor, was shown in a Phase 3 study to modestly improve median OS in combination with gemcitabine over gemcitabine alone (6.24 months for the doublet versus 5.91 months for gemcitabine alone) without a significant difference in ORR between the treatments5. In 2011, a Phase 2/3 trial conducted by a French consortium study group demonstrated FOLFIRINOX, a combined regimen of oxaliplatin, irinotecan, fluorouracil, and leucovorin significantly increased survival in patients with pancreatic cancer over gemcitabine alone. Median OS was 11.1 months versus 6.8 months for each treatment, respectively (hazard ratio [HR] for death, 0.57; 95% confidenc e interval [CI], 0.45 to 0.73; p < 0.001). The ORR was also increased to 31.6% from 9.4% ( p < 0.001). Adverse events were increased in the FOLFIRINOX group and 5.4% of patients in this group experienced febrile neutropenia6. Although FOLFIRINOX represents an efficacious regimen in pancreatic cancer, there are still concerns about its potential toxicity and it is being reserved for the most fit patients. In the MPACT ( Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, nab-paclitaxel combined with gemcitabine demonstrated a statistica lly significant and clinically meaningful median OS of 8.5 versus 6.7 months (HR 0.72, p < 0.0001 including a 59% increase in one -year survival (35% versus 22%, p=0.0002) and demonstrated double the rate of survival at two years (9% versus 4%, p=0.02) as c ompared to gemcitabine alone in previously untreated patients with metastatic pancreatic cancer. nab-/gemcitabine also demonstrated a statistically significant improvement in key secondary endpoints compared to gemcitabine alone, including a 31% reduction in the risk of progression or death with a median PFS of 5.5 versus 3.7 months (HR 0.69, p < 0.0001) and an ORR of 23% compared to 7% (response rate ratio of 3.19, p < 0.0001)7. The MPACT study and regimen formed the basis for full FDA approval in September 2013 for the first-line treat ment of metastatic adenocarcinoma of the pancreas. Nanoliposomal irinotecan in combination with 5 -FU was recently approved for patients with previously treated pancreatic cancer. However, it is unknown if this combination is better than 5 - FU and irinotec an (FOLFIRI) as 5 -FU was the comparator and there was no benefit in patients who previously received irinotecan so the value of this drug is questionable in FOLFIRINOX treated patients8. Therapies for patients with metastatic pancreatic cancer are urgently needed. Novel approaches, such as immunotherapy, hold promise in this very difficult cancer. 2.2 Rationale Therapeutic benefit of immunotherapy in pancreatic cancer remains to be seen. Single agent therapy using vaccines to induce antigen -specific T cells or targeting immune checkpoints such as programmed death -1 (PD -1) or cytotoxic T -lymphocyte associated pro tein-4 (CTLA -4) does not address the complex immunosuppressive mechanisms at play both at the systemic level and in the tumor microenvironment. Effective immunotherapy in pancreatic cancer may require combinations of 2 or more agents to overcome this toler ance. Various combination strategies are being tested in less immunogenic tumors. CTLA -4 or PD -1 inhibition with pancreatic cancer vaccines is currently being studied with GVAX Pancreas (allogeneic pancreatic cancer cells modified to express GM -CSF) and C RS-207 (attenuated Lm expressing the tumor associated J1790 / Version 7.0 / December 10, 2020 9 antigen mesothelin). In each of these studies, there have been a handful of objective responses but in general pancreatic cancer has been refractory to immunotherapy and triplet approaches may be necess ary. Numerous studies are targeting various immune checkpoints and stimulatory agonists but it could possibly be futile without a vaccine to induce infiltration of an inflammatory infiltrate including effector T cells into the tumor. Immunotherapies in P ancreatic Cancer - - Nivolumab - - J1790 / Version 7.0 / December 10, 2020 10 - - - - - Nivolumab Dose Selection – - Ipilimumab J1790 / Version 7.0 / December 10, 2020 11 - - Dual Blockade with Nivolumab and Ipilimumab - - 3. PATIENT SELECTION 3.1 Inclusion Criteria 3.1.1 Age ≥ 18 years. 3.1.2 Have histologically - or cytologically - proven ductal adenocarcinoma of the pancreas. Patients with mixed histology (>30% non - adenocarcinoma component) will be excluded. 3.1.3 Have metastatic disease. J1790 / Version 7.0/ December 10, 2020 12 3.1.4 Have documented radiographic disease progression at the time of study enrollment, after previous systemic chemotherapy given in a neoadjuvant, adjuvant, locally advanced or metastatic setting. 3.1.5 Presence of at least one lesion with measurable disease as defined by 10 mm in longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node by RECIST 1.1. 3.1.6 Patient ’s acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator). 3.1.7 ECOG performance status 0 or 1 (Appendix A ). 3.1.8 Life expectancy of greater than 3 months . 3.1.9 Adequate organ and marrow function as defined below: − Leukocytes ≥ 3,000/mcL − Absolute neutrophil count ≥ 1,500/mcL − Lymphocyte count ≥ 800/mcL − Platelets ≥ 100 × 103/uL − Hemoglobin ≥ 9.0 g/dL − Total bilirubin ≤ upper limit of normal ( ULN ) except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL − AST(SGOT ) and ALT(SGPT) ≤2.0 × ULN − Alkaline phosphatase ≤5.0 × ULN − Creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft -Gault formula below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL − Albumin ≥3.0 g/dL J1790 / Version 7.0/ December 10, 2020 13 3.1.10 Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [ HCG ]). WOCBP is defined in Section 5.9.