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

PRIMARY OBJECTIVES: I. To assess dose limiting toxicities (DLTs) and determine the recommended phase 2 dose (RP2D) of the combination of selumetinib (AZD6244 hydrogen sulfate) and DS-8201a (trastuzumab deruxtecan) in patients with pancreatic ductal adenocarcinoma (PDAC). (Escalation phase) II. To assess the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. (Phase II \[expansion phase\]) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate the safety and tolerability of the combination of selumetinib (AZD6244 hydrogen sulfate) and DS-8201a (trastuzumab deruxtecan). III. To determine preliminary signals of efficacy, as measured biochemical (CA 19-9) response, time to response, duration of response, disease control rate, clinical benefit rate, progression free survival (PFS), and overall survival (OS). EXPLORATORY OBJECTIVES: I. To evaluate the pharmacodynamic (PD) effect of selumetinib (AZD6244 hydrogen sulfate) plus DS-8201a (trastuzumab deruxtecan). II. To evaluate the pharmacokinetics (PK) of selumetinib (AZD6244 hydrogen sulfate) plus DS-8201a. III. To explore biomarkers and genomic alterations associated with treatment response. OUTLINE: This is a phase I, dose-escalation study of selumetinib with DS-8201a followed by a phase II study. Patients receive selumetinib orally (PO) twice daily (BID) on days 1-21 of each cycle and DS-8201a intravenously (IV), over 30-90 minutes, on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or multigated acquisition (MUGA) scan, diagnostic imaging and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 12 months.