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

This phase I/II trial tests the safety, side effects, best dose and how well giving selumetinib with trastuzumab deruxtecan (DS-8201a) works for the treatment of pancreatic ductal adenocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced), that cannot be removed by surgery (unresectable) or that has spread from where it first started (primary site) to other places in the body (metastatic). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. DS-8201a is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Giving selumetinib with DS-8201a may be safe, tolerable and/or effective in treating patients with advanced, unresectable or metastatic 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.

Procedure: Biospecimen Collection. Undergo blood sample collection

Procedure: Diagnostic Imaging Testing. Undergo diagnostic imaging

Procedure: Echocardiography Test. Undergo echocardiography

Procedure: Multigated Acquisition Scan. Undergo MUGA scan

Drug: Selumetinib. Given PO

Biological: Trastuzumab Deruxtecan. Given IV

Treatment (Selumetinib and DS-8201a) (experimental): Patients receive selumetinib PO BID on days 1-21 of each cycle and DS-8201a 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 MUGA scan, diagnostic imaging and blood sample collection throughout the study.

Occurrence of dose limiting toxicities (DLTs) (dose escalation phase). Will provide the number and proportion of DLTs provide and 95% confidence intervals. Time frame: From baseline up to day 21.

HER2 expression status (dose escalation phase). Will be evaluated descriptively during the dose escalation phase with respect to safety, tolerability and preliminary antitumor activity. Time frame: Up to 1 year.

Overall response rate (phase II). Defined as confirmed responses by Response Evaluation Criteria in Solid Tumors version (v) 1.1. A confirmed response requires documentation of a complete response (CR) or partial response (PR) on a subsequent imaging assessment performed at least ≥ 4 weeks after the initial response is observed. Time frame: Up to 1 year.

Incidence of adverse events. Time frame: Up to 1 year.

Biochemical response. Time frame: Up to 1 year.

Time to response. Time frame: From the first dose of study treatment to the first documentation of a confirmed objective response, up to 1 year.

Duration of response. Time frame: From the first documentation of confirmed objective response (CR or PR) to the date of first documented disease progression or death, up to 1 year.

Disease control rate. Time frame: Up to 1 year.

Clinical benefit rate. Time frame: Up to 1 year.

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 use of selumetinib (AZD6244 hydrogen sulfate) in combination with DS-8201a (trastuzumab deruxtecan) in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 70%). Regardless of performance status, enrollment should be based on the judgment of the treating physician that the patient will be able to be safely treated with the proposed therapeutic intervention * Hemoglobin ≥ 9 g/dL (within 14 days of enrollment) * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment * Leukocytes ≥ 3,000/mcL (within 14 days of enrollment) * Absolute neutrophil count ≥ 1,500/mcL (within 14 days of enrollment) * No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment * Platelets ≥ 100,000/mcL (within 14 days of enrollment) * Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), (\< 3 × …

Enrollment: 31 participants (estimated).