CRS-207, Nivolumab, and Ipilimumab with or without A Vaccine (GVAX Pancreas Vaccine) and Cyclophosphamide in Treating Patients with Metastatic Pancreatic Ductal Cancer

Inclusion Criteria

• Have histologically- or cytologically-proven ductal adenocarcinoma of the pancreas. Patients with mixed histology (> 30% non-adenocarcinoma component) will be excluded
• Have metastatic disease
• 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
• 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
• 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)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Life expectancy of greater than 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Lymphocyte count >= 800/mcL
• Platelets >= 100 x 10^3/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
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x ULN
• Alkaline phosphatase =< 5.0 x ULN
• Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min
• Albumin >= 3.0 g/dL
• 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 must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total of 5 months post treatment completion * Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion * At least one barrier method of contraception must be employed by all sexually active patients (male and female), regardless of other methods, to prevent the transfer of body fluids
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

• Patient has a known history or evidence of brain metastases
• Patient who has had chemotherapy, radiation, or biological cancer therapy within 14 days prior to the first dose of study drug
• Patient has received an investigational agent or used an investigational device within 28 days of the first dose of study drug
• Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study
• Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
• Patients who have received any prophylactic vaccine within 14 days of first dose of study drug (7 days for the COVID vaccine) or received a live vaccine within 30 days of planned start of study therapy
• Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibodies
• Have used any systemic steroids within 14 days of study treatment
• Use more than 2 g/day of acetaminophen
• Patients on immunosuppressive agents (e.g., TNF pathway inhibitors, PI3 kinase inhibitors) within 7 days of study treatment
• Patients receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration. Use of such agents while on study is also prohibited
• Patient has a known allergy to both penicillin and sulfa
• History of severe hypersensitivity reaction to any monoclonal antibody
• Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other component of GVAX pancreas vaccine or CRS-207 (e.g., glycerol)
• Have current or prior history of infection or clinically significant adverse events (AEs) associated with an exogenous implant(s) or device(s) that has not and cannot be easily removed
• Subjects who have implanted medical devices that pose high risks for colonization and cannot be easily removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic screw[s], metal plate[s]) if infection occurs. Other common devices such as venous access devices (e.g., Port-a-Cath or Mediport) may be permitted as well as arterial and venous stents and dental and breast implants
• Evidence of clinical ascites. Trace or small amounts of radiographic ascites may be approved by the protocol chair
• Have clinically significant and/or malignant pleural effusion (pleural effusions that are not clinically significant are allowed, defined as no more than 25% fluid level of the corresponding hemithorax and stable fluid level [non-progressive] over at least 6 weeks documented radiographically)
• Have had a new pulmonary embolism, extremity deep venous thromboembolism, or portal vein thrombosis within 2 months of study enrollment (any thrombosis within 2 months of study enrollment may be approved by the protocol chair)
• 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
• Subjects with active, known or suspected autoimmune disease. Subjects with Graves or Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Instances where loss of the graft is not a clinical concern (such as dental bone grafts or skin grafts placed only to promote skin growth) can be approved by the protocol chair. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded
• All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE], version 4.03) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long-lasting sequelae, such as neuropathy after chemotherapy, are permitted to enroll
• Have received a diagnosis of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (patients who are hepatitis C antibody positive may be enrolled if they are confirmed with negative viral load at screening)
• Patient has a pulse oximetry of < 92% on room air
• Patient is on supplemental home oxygen
• Patient has an unhealed surgical wound or ulcer, or a bone fracture considered non-healing
• Patient has clinically significant heart disease (such as uncontrolled angina, myocardial infarction within the last 3 months or congestive heart failure of New York Heart Association III or IV)
• Patient has valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis
• Have insufficient peripheral venous access to permit completion of the study dosing and compliance with study phlebotomy regimen
• Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
• Patient is unwilling or unable to follow the study schedule for any reason
• Patient is pregnant or breastfeeding
• Have rapidly progressing disease, as judged by the investigator (e.g., rapid progression through prior treatment[s])