Testing the Combination of Anti-Cancer Drugs, Selumetinib and DS-8201a, for Advanced Pancreatic Ductal Adenocarcinoma

Inclusion Criteria: * Review of eligibility criteria by the study principal investigator (PI) is required prior to enrollment * Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas * Patients must have unresectable or metastatic disease with KRAS mutation per Next Generation Sequencing (NGS) tumor testing and HER2 immunohistochemistry (IHC) positivity (2+ or above for dose escalation and per decision rule for phase II), as determined by a Clinical Laboratory Improvement Act (CLIA)-certified kit using gastric cancer criteria * Patients must have measurable disease that can fulfill Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria * Patients must have exposure to at least one line of systemic chemotherapy for metastatic or unresectable PDAC (for both escalation and phase II cohorts) or a documented patient decision to forego therapy that has an otherwise proven survival advantage (for escalation cohort only) * Patients who have received prior topoisomerase inhibitors including irinotecan and nanoliposomal irinotecan will be eligible for this study * Only 1 prior line of therapy for metastatic or unresectable PDAC will be allowed for patients in the phase II cohort. Adjuvant or neoadjuvant therapy does not count, assuming it was completed \> 6 months prior to the start of systemic therapy for metastatic or unresectable disease * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the …