Nivolumab, Ipilimumab and Chemoradiation in Pancreatic Cancer.

Inclusion Criteria:

• Signed informed consent

• Subjects must have signed and dated an IRB/IEC approved written informedconsent form in accordance with regulatory and institutional guidelines. Thismust be obtained before the performance of any protocol related procedures thatare not part of normal subject care

• Subjects must be willing and able to comply with scheduled visits, treatmentschedule, laboratory testing, and other requirements of the study

• Histological or cytological confirmation of locally advanced or metastaticpancreatic carcinoma prior to entering this study

• No prior chemotherapy regimens received for PC

• Age 18 years or older

• Life expectancy greater than 6 months

• ECOG/WHO Performance Status (PS) 0-1

• All participants will be required to undergo mandatory pre- and on-treatmentbiopsies at acceptable clinical risk as judged by the investigator. An archivalpre-treatment sample is acceptable

• Patients must have normal organ and marrow function as defined below:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L

• Platelet count ≥ 100 x 10⁹/L

• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert'sSyndrome must have a total bilirubin ≤ 50 mmol/L)

• AST/ALT ≤ 5 x ULN

• Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min (using the Cockcroft-Gaultformula)

• Women of child bearing potential (WOCBP) must use method(s) of contraception asindicated in Appendix 3. For a teratogenic study drug and/or when there isinsufficient information to assess teratogenicity (preclinical studies have not beendone), a highly effective method(s) of contraception (failure rate of less than 1%per year) is required. The individual methods of contraception and duration shouldbe determined in consultation with the investigator. WOCBP must follow instructionsfor birth control when the half-life of the investigational drug is greater than 24hours, contraception should be continued for a period of 30 days plus the timerequired for the investigational drug to undergo five half-lives. The half-life ofnivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP shouldtherefore use an adequate method to avoid pregnancy for 23 weeks (30 days plus thetime required for nivolumab to undergo five half-lives) after the last dose ofinvestigational drug

• Men who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year (Appendix 3). The investigator shall reviewcontraception methods and the time period that contraception must be followed. Menthat are sexually active with WOCBP must follow instructions for birth control whenthe half-life of the investigational drug is greater than 24 hours, contraceptionshould be continued for a period of 90 days plus the time required for theinvestigational drug to undergo five half-lives. The half-life of nivolumab is up to 25 days. Men who are sexually active with WOCBP must continue contraception for 31weeks (90 days plus the time required for nivolumab to undergo five half-lives)after the last dose of investigational drug. Women who are not of childbearingpotential (ie, who are postmenopausal or surgically sterile as well as azoospermicmen do not require contraception

• Subjects must have signed and dated a BIOPAC approved written informed consent formin accordance with regulatory and institutional guidelines

Exclusion Criteria:

• Metastatic disease

• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, oranti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cellco-stimulation or checkpoint pathways

• Any serious or uncontrolled medical disorder that, in the opinion of theinvestigator, may increase the risk associated with study participation or studydrug administration, impair the ability of the subject to receive protocol therapy,or interfere with the interpretation of study results

• Participants with active, known or suspected autoimmune disease. Participants withvitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmunecondition only requiring hormone replacement, psoriasis not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare permitted to enroll.

• Participants with a condition requiring systemic treatment with eithercorticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressivemedications. Inhaled or topical steroids and adrenal replacement doses > 10 mg dailyprednisone equivalents are permitted in the absence of active autoimmune disease.

• Patients should be excluded if they have known history of testing positive for humanimmunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

• Allergies and adverse drug reaction

• History of allergy to study drug components

• History of severe hypersensitivity reaction to any monoclonal antibody

• WOCBP who are pregnant or breastfeeding