Immune Checkpoint Inhibition in Combination With Radiation Therapy in Pancreatic Cancer or Biliary Tract Cancer Patients

Inclusion Criteria: * Signed informed consent * Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care * Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study * Histopathological confirmation of pancreatic adenocarcinoma or BTC prior to entering this study OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are consistent with a diagnosis of PC or BTC * At least one measurable primary in-situ (or locally-recurrent) or metastatic tumor must be present and, in the opinion of radiation oncologist, be amenable to RT as planned in the protocol and at least one additional metastatic tumor that will not undergo RT and which is measurable according to RECIST 1.1 criteria. Both lesions must be accessible for image-guided percutaneous biopsy * There is no upper limit on the number of prior chemotherapy regimens received. Patients must have received and failed or intolerance to at least one line of prior systemic chemotherapy with gemcitabine or platinum-containing regimens for unresectable and/or metastatic PC or BTC * Age \> 18 years and older * Life expectancy greater than 3 months * ECOG/WHO Performance Status (PS) 0-1 * Patients must have normal organ and marrow function as defined below: * White blood cell count (WBC) ≥ 2 x 10⁹/L * Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L * Hemoglobin ≥ 5,6 mmol/l * Platelet count ≥ 100 x 10⁹/L * Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin \< 3.0 mg/dL) * ASAT/ALAT ≤ 3 x ULN ( \< 5 x ULN if known liver metastasis) * PP ≥ 40 or INR ≤ 1.5 * Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min (using the Cockcroft-Gault formula) * Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated per protocol. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. * WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab * Women must not be breastfeeding * Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Men who are sexually active with WOCBP must continue contraception for 31 weeks (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 childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception * Subjects must have signed and dated a BIOPAC IRB/IEC approved written informed consent form and patients with BTC must have signed and dated a CHOCA in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care Exclusion Criteria: * Malignant ascites that is clinically detectable by physical examination or is symptomatic. Evidence of radiographic ascites that is not clinically significant will not be exclusion criteria * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways * No chemotherapy, radiotherapy, or major surgery within the last 2 weeks prior to entering the study * Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results * Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger * Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection * Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease * As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab- and ipilimumab containing regimen * Patients should be excluded if they have known history of testing positive for human immunodeficiency 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 * Women with a positive pregnancy test at enrollment or prior to administration of study medication * Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for \[lowest minimum is 4 weeks or more\] after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration