Inclusion Criteria:
* Male or female ≥ 18 years of age and willing and able to provide informed consent
* Previously untreated cytologically or histologically confirmed, at least one measurable lesion via Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of cholangiocarcinoma or pancreatic adenocarcinoma meeting following criteria:
* Cholangiocarcinoma
* Borderline resectable/locally advanced cholangiocarcinoma: to be defined as unresectable disease on evaluation by a hepatobiliary multi-disciplinary tumor board/surgeon based on tumor size/location, vascular involvement, and absence of extrahepatic metastasis.
* Metastatic cholangiocarcinoma: Patients with metastatic cholangiocarcinoma patient who have not received prior systemic therapy
* Pancreatic adenocarcinoma
* Borderline resectable pancreatic adenocarcinoma: There are multiple definitions of borderline resectable pancreatic ductal adenocarcinoma (PDAC). For the purposes of this study, borderline resectable disease will be identified per the National Comprehensive Cancer Network (NCCN) criteria. Per this definition, borderline resectable PDAC is defined as the presence of any one or more of the following on CT:
* An interface between the tumor and superior mesenteric artery (SMA) or celiac axis (CA) measuring \< 180º of the circumference of the vessel wall.
* An interface between the tumor with the common hepatic artery without extension into the celiac axis or hepatic artery bifurcation allowing for safe and complete resection and reconstruction.
* An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring ≥ 180° of the circumference of the vessel wall
* Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
* An interface between the primary tumor and the inferior vena cava (IVC)
* Locally advanced pancreatic adenocarcinoma: Multiple guidelines defining locally advanced PDAC have been developed. For the purposes of this study, locally advanced PDAC cases will be identified per the definition developed by the NCCN. Per this definition, locally advanced PDAC is defined as presence of any one or more of the following on CT:
* Interface between the tumor and SMA or CV measuring \> 180º of the circumference of the vessel wall or solid tumor contact with the CA and aortic involvement.
* Occlusion of the SMV-PV that is not amenable to resection and venous reconstruction
* Metastatic pancreatic adenocarcinoma: Patients with metastatic pancreatic adenocarcinoma who have not received prior systemic therapy
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Absolute neutrophil count (ANC) ≥ 1.5x10\^9/L
* Platelets ≥ 100x10\^9/L
* Hemoglobin ≥ 9 g/dL
* Creatinine clearance (Ccr) ≥ 50 mL/min (as calculated by Modified Cockcroft-Gault formula)
* Serum total bilirubin ≤ 2x upper limit of normal (ULN) or \< 3x ULN if Gilbert's syndrome
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 2.5 X ULN; \< 5x ULN in patients with liver metastases
* Women with no childbearing potential because of surgery or who are at least 1 year postmenopausal (ie, 12 months post last menstrual period) or with menopause confirmed by follicle-stimulating hormone testing, OR
* Women of childbearing potential (defined as any female who has experienced menarche and is not permanently sterile or post-menopausal) must use an effective nonhormonal method of contraception (intrauterine device or intrauterine system; condom or occlusive cap \[diaphragm or cervical or vault caps\] with spermicidal foam or gel or film or cream or suppository; or vasectomized male partner if he is the sole partner of that participant) or practice true abstinence for the duration of the study and for up to 14 months after the last systemic treatment
* Male participants must use an effective method of contraception (condom or occlusive cap \[diaphragm or cervical or vault caps\] with spermicidal foam or gel or film or cream or suppository; or vasectomy) or practice true abstinence as defined throughout the study and for up to 11 months after the systemic treatment
* Immunosuppressive doses of systemic medications, such as corticosteroids or absorbed topical corticosteroids (doses \> 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks (14 days) before study treatment administration. Physiologic doses of corticosteroids (≤ 10 mg/day of prednisone or its equivalent) or short pulses of corticosteroids (≤ 3 days) may be permitted
* Products with known potential to prolong the corrected QT (QTc) interval should be avoided when possible. When able will replace non-prolonging QTc acting drug when available and if medically necessary
* Major surgery as defined by the Investigator must be completed at least 4 weeks before study treatment administration. Participants should have recovered from the surgical procedure prior to the first dose being administered
* Adequate baseline tumor tissue sample for correlative studies
Exclusion Criteria:
* Previous treatment with any of planned study drugs in cholangiocarcinoma, though patients with one cycle of gemcitabine/cisplatin/durvalumab will be considered eligible
* Previous treatment with any of planned study drugs in pancreatic adenocarcinoma, though patients with one cycle of FOLFIRINOX will be considered eligible
* Peripheral neuropathy \> grade 2
* Known status of HIV which is not well-controlled (CD4 \< 300) at the time of study eligibility. Patients with controlled and treated HIV/hepatitis C virus (HCV) and an undetectable viral load are allowed
* Untreated hepatitis B infection; Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection (testing is not mandatory, unless known active or known history of infection or required by local regulation):
* Participants with resolved or treated HCV (ie, HCV antibody positive but undetectable HCV ribonucleic acid \[RNA\]) will not be excluded from this study
* Underlying medical conditions that, in the Investigator's opinion, will make the administration of investigational product (IP)(s) hazardous, including but not limited to:
* Interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis
* Active viral, bacterial, or fungal infections requiring parenteral treatment within 14 days of the initiation of the IP,
* Active infection or antibiotics within 48 hours prior to study screening;
* A condition or unresolved adverse event (AE) from a prior investigational drug that may obscure the interpretation of toxicity determination or AEs,
* History of prior solid-organ transplantation
* Any history of malignancy less than 5 years prior to the time of study eligibility (Patients with history of skin cancers excluding melanoma and cancers with a very low risk of recurrence i.e., low grade prostate cancer, thyroid cancer and low risk cervical cancer will be eligible for participation)
* Serious medical comorbidities such as New York Heart Association Class III/IV cardiac disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12 months
* Known family history or personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least grade 3 (QTc \> 500 ms)
* Screening 12-lead electrocardiogram (ECG), in triplicate, with a measurable QTc interval of \> 450ms
* Known, existing uncontrolled coagulopathy. Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation are eligible IF: they are appropriately anticoagulated and have not had a grade 2 or greater bleeding episode in the 3 weeks before day 1
* Known pregnancy, nursing women or positive pregnancy test. Requirement for women of childbearing potential (WOCBP): Negative serum pregnancy test at screening and serum or urine prior to dosing on cycle 1 day 1, within 24 hours prior to the start of treatment (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]). WOCBP must also have a negative serum or urine pregnancy test every 3 weeks, within 24 hours prior to the start of treatment
* Any condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the investigator
* History of trauma or major surgery within 28 days prior to the first dose of IP
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Any active or documented history of autoimmune disease, including but not limited to inflammatory bowel disease, celiac disease, Wegner syndrome, Hashimoto syndrome, systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 3 years of the first dose of study treatment, except for the following:
* Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, or alopecia not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger.
* Endocrinopathies where the participant is stable on hormone replacement therapy
* History of Hashimoto syndrome within 3 years of the first of study treatment that resolved to hypothyroidism alone
