INCLUSION CRITERIA FOR SECOND-LINE THERAPY: Histologically confirmed metastatic adenocarcinoma of the pancreas INCLUSION CRITERIA FOR THIRD-LINE THERAPY: Histologically confirmed metastatic adenocarcinoma of the pancreas Patient has definitive histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. Patients with islet cell or neuroendocrine neoplasms are excluded. Patients must have histologically or cytologically documented advanced or metastatic adenocarcinoma of the pancreas Participants with biopsy-proven adenocarcinoma of the pancreas that is determined to be potentially or borderline resectable by National Comprehensive Cancer Network (NCCN) criteria Histologically or cytologically proven adenocarcinoma of the pancreas Histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the pancreas Histologically confirmed adenocarcinoma of the pancreas or ampulla of Vater; at least the majority of the histopathologic specimen must be identified as adenocarcinoma as opposed to another histologic subtype; in patients with a diagnosis of recurrent disease (based on radiographic progression and/or rising CA- levels) and a history of a biopsy-proven adenocarcinoma of the pancreas or the ampulla of Vater, repeat biopsy of the recurrence site is not required for participation of the trial Diagnosis of ductal adenocarcinoma of the pancreas (PDAC). Patients with histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas Histologically or cytologically confirmed newly diagnosed treatment-naive metastatic adenocarcinoma of the pancreas with metastatic disease diagnosed no more than weeks prior to enrollment Histologically or cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease and without evidence of disease progression on treatment For Part II (Arm C): Patients can have either locally advanced or metastatic pancreas adenocarcinoma; up to two prior treatment regimens are permissible (excluding a prior PARP inhibitor) for either localized or metastatic pancreas adenocarcinoma; prior combined chemotherapy and radiotherapy is permissible provided the patient has measurable disease outside the radiation port; prior therapy must have been completed at least weeks prior to starting study therapy Histologically-proven invasive adenocarcinoma of the pancreas Have a newly diagnosed, biopsy-proven adenocarcinoma of the head, neck and uncinate of the pancreas, and is a candidate for a pancreaticoduodenectomy; if the biopsy is not sufficient for diagnosis, the patient can be considered to meet eligibility if the study team agrees that clinically the patients tumor is suspected to be adenocarcinoma Subjects must have histologically or cytologically confirmed adenocarcinoma of the pancreas Adenocarcinoma of the pancreas Histologically or cytologically proven adenocarcinoma of the pancreas (within the last days) Arm : histologically or cytologically confirmed adenocarcinoma of the pancreas that is locally advanced or metastatic Pathologically confirmed adenocarcinoma of the pancreas Histologically and/or cytologically confirmed adenocarcinoma of the pancreas, clinical stage T-, N-, M Patients must have pathologically confirmed adenocarcinoma of the pancreas Subjects with biopsy-proven potentially resectable or borderline adenocarcinoma of the pancreas as determined by National Comprehensive Cancer Network (NCCN) criteria Histologically or cytologically confirmed adenocarcinoma of the pancreas Histologically proven adenocarcinoma of the pancreas Histologic or cytological diagnosis of recurrent or metastatic pancreas adenocarcinoma (PCA) who present for first line chemotherapy treatment Histologically or cytologically proven adenocarcinoma of the pancreas that has been resected with a close (< .mm) or positive margin based on surgical and pathological findings Cohort (MTD) only: metastatic adenocarcinoma of the pancreas; prior systemic treatment for metastatic disease is allowed COHORT II (MTD): metastatic adenocarcinoma of the pancreas and tumor amenable to biopsies; prior systemic treatment for metastatic disease is allowed Have histologically proven adenocarcinoma of the pancreas; patients with mixed histology will be excluded PHASE II: Patients must have histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas with no prior systemic therapy for metastatic disease Histologically or cytologically proven diagnosis of adenocarcinoma of the pancreas prior to registration Subject has a definitive histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas. Subjects with islet cell neoplasms are excluded. Metastatic adenocarcinoma of the pancreas. Patients with islet cell neoplasms are not eligible. adenocarcinoma of the pancreas, Histologically confirmed adenocarcinoma of the pancreas that has been documented to be resectable by standardized radiographic criteria by a pancreatic surgeon Histological diagnosis of adenocarcinoma of the pancreas Histological documentation of primary adenocarcinoma of the pancreas Patients must have histologically or cytologically confirmed carcinoma of the pancreas; most cases will be adenocarcinoma; cases with undifferentiated or poorly differentiated carcinoma will also be eligible Histologically or cytologically confirmed locally advanced adenocarcinoma of the pancreas that is considered unresectable or borderline resectable based on institutional standardized criteria of unresectability or medical inoperability; patients with and without regional adenopathy are eligible Have histologically- or cytologically-proven adenocarcinoma of the pancreas; patients with mixed histology will be excluded Previously untreated, apparently resectable, adenocarcinoma of the pancreas at registration A histological diagnosis of adenocarcinoma of the pancreas confirmed by pathology. Resectable primary tumor of the head, body or tail of the pancreas defined as a visible mass in the pancreas and: Lipase < . x the upper limit of normal (except for participants with adenocarcinoma of the pancreas) Prior systemic therapy for pancreas cancer Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas; patients who have not undergone biopsy but have highly suspected adenocarcinoma of the pancreas with borderline resectable features on imaging study may also be eligible for study and undergo the pretreatment biopsy as per protocol; the biopsy must confirm adenocarcinoma of the pancreas to continue on study; biopsy is required within days of starting therapy Histologically or cytologically proven diagnosis of metastatic ductal adenocarcinoma of the pancreas. Histologically or cytologically confirmed adenocarcinoma of the pancreas. Advanced adenocarcinoma of the pancreas that is inoperable or metastatic. Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. A histological diagnosis of adenocarcinoma of the pancreas confirmed by pathology. Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the pancreas with immunohistochemistry (IHC) evidence of guanylyl cyclase C (GCC) expression indicated by an H-score of or greater. Treatment with or more prior chemotherapies for advanced or metastatic adenocarcinoma of the pancreas. Histologically or cytologically confirmed adenocarcinoma of the pancreas. Advanced adenocarcinoma of the pancreas that is inoperable or metastatic. Histologically or cytologically confirmed adenocarcinoma of the pancreas Patient has histologically or cytologically confirmed localized adenocarcinoma of the pancreas including tumors in the pancreatic head, uncinate process, neck, body and tail that are potentially resectable by pancreatico-duodenectomy (Kausch-Whipple procedure); patients with islet cell or other neuroendocrine neoplasms are excluded Patient has histologically or cytologically confirmed borderline resectable adenocarcinoma of the pancreas; patients with islet cell or other neuroendocrine neoplasms are excluded Histologically documented Stage IV ductal adenocarcinoma of the pancreas Prior adjuvant therapy for the treatment of ductal adenocarcinoma of the pancreas Histologically documented Stage IV ductal adenocarcinoma of the pancreas Prior adjuvant therapy for the treatment of ductal adenocarcinoma of the pancreas Histologically or cytologically proven adenocarcinoma of the pancreas; if the patient has mixed tumor with predominant adenocarcinoma pathology, they can be enrolled Have histologically proven malignant adenocarcinoma of the pancreas; measurable disease is not required, mixed histology is not allowed; subjects must have metastatic disease Patients with a documented (histologically- or cytologically-proven) epithelial cell/adenocarcinoma of the pancreas that is relapsed, locally advanced, or metastatic. Have histologically proven malignant adenocarcinoma of the pancreas; measurable disease is not required. (Subjects with mixed histology will be included if the predominant component is adenocarcinoma. Subjects must have metastatic disease.) Prior chemotherapy or radiation therapy of any kind for treatment of pancreas adenocarcinoma Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas Histologically or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting All patients with metastatic pancreas cancer will be eligible Patients who have tumors other than metastatic pancreas cancer Previous partial or complete resection of the pancreas for adenocarcinoma Histologically confirmed adenocarcinoma of the pancreas Presence of suspicious lesion of the pancreas consistent with pancreatic adenocarcinoma; cytological confirmation is not required No prior therapy for pancreas cancer is allowed*