This phase I/II trial tests the safety, side effects, best dose and how well giving selumetinib with 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 trastuzumab deruxtecan (DS-8201a) 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.

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.

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.

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 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 × ULN in the presence of documented Gilbert's syndrome or liver metastases at baseline) (within 14 days of enrollment)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 5 × ULN in participants with liver metastases (within 14 days of enrollment)

• Serum albumin ≥ 2.5 g/dL (within 14 days of enrollment)

• International Normalized Ratio (INR)/Prothrombin Time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (within 14 days of enrollment)

• Creatine phosphokinase (CPK) ≤ 2.5 × ULN (within 14 days of enrollment)

• Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 (within 14 days of enrollment)

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging, performed at least 6 months after central nervous system (CNS)-directed therapy, shows no evidence of progression

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must undergo a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible, patients must be NYHA Class II or better and have no history of myocardial infarction within 6 months prior to enrollment, no symptomatic congestive heart failure (NYHA Class IIb-IV), and no troponin levels consistent with myocardial infarction (as defined by the manufacturer) within 28 days prior to enrollment

• Patients must have a baseline left ventricular ejection fraction (LVEF) ≥ 50% as measured by echocardiogram (ECHO) or mutilated acquisition scan (MUGA) scan within 28 days before randomization/enrollment

• Patients must be willing to undergo baseline ophthalmic evaluation, including visual acuity and slit-lamp examination

• The effects of selumetinib (AZD6244 hydrogen sulfate) and DS-8201a on the developing human fetus are unknown. For this reason and because MEK inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 7 months (for WOCBP) or 4 months (for men) after completion of drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method

• Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study

• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration

• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

• Patients with prior MEK inhibitor, ERK inhibitor, or HER2-directed therapy treatment
• Patients who have had chemotherapy (including antibody drug therapy, retinoid therapy, hormonal therapy for cancer) within 3 weeks (2 weeks or five half-lives, whichever is longer for small-molecule targeted agents such as 5-fluorouracil-based agents, folinate agents), weekly paclitaxel; 6 weeks for nitrosoureas or mitomycin C
• Patients who have had immunotherapy including monoclonal antibody therapy within 4 weeks
• Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies
• Patients who have had a major surgery within 4 weeks
• Patients with a history of allogeneic organ or stem cell transplant
• Patients who are receiving any other investigational agents or received any other investigational agents within the past 21 days prior to protocol treatment initiation
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib (ADZ6244 hydrogen sulfate) or DS-8201a
• Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment
• Patients with prior use of immunosuppressive medication within 14 days prior to first study dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses less than 10 mg/day of prednisone or equivalent
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Patients with a corrected QT interval (QTc) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)
• Patients with a history of (non-infectious) interstitial lung disease (ILD) that required steroids, presence of ILD that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity, or where suspected ILD cannot be ruled out by imaging at screening. These patients will be excluded because DS-8201a is known to increase the risk of developing ILD and pneumonitis
• Patients with lung-specific, intercurrent, clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months prior to study enrollment, severe asthma, severe chronic obstructive pulmonary disorder (COPD), restrictive lung disease, significant pleural effusion, etc.), and any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), and/or prior pneumonectomy. These patients will be excluded because DS-8201a is known to increase the risk of developing ILD and pneumonitis
• Patients with gastrointestinal conditions which could impair absorption of selumetinib (AZD6244 hydrogen sulfate) or inability to ingest selumetinib (AZD6244 hydrogen sulfate)
• Patients with a history of significant retinal pathology (including but not limited to, retinal vein occlusion, retinal detachment, or macular degeneration) or clinically significant ophthalmic abnormalities that may increase the risk of retinal adverse events
• Active ocular disease requiring systemic therapy or current use of contact lenses that may interfere with ophthalmic evaluations
• Based on pre-clinical and clinical data, DS-8201a and selumetinib (AZD6244 hydrogen sulfate) are associated with ocular toxicity. Patients with clinically significant corneal disease, in the opinion of the investigator, will be excluded from this study
• Patients who have had chest radiation therapy within 4 weeks (2 weeks for palliative stereotactic body radiation therapy). These patients will be excluded because DS-8201a is known to increase the risk of developing pneumonitis
• Patients with spinal cord compression, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Patients that have received a live vaccine within 30 days prior to the first dose of study drug will be excluded. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed
• Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia or peripheral neuropathy) not yet resolved to grade ≤ 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee (e.g., grade 2 chemotherapy-induced neuropathy). Subjects should no longer be symptomatic nor require treatment with corticosteroids or anticonvulsants and must have recovered from the acute toxic effect of radiotherapy
• Patients with ongoing muscle disorders or elevated baseline creatine phosphokinase (CPK) levels suggestive of rhabdomyolysis or myopathy
• Patients currently using high-dose vitamin E supplements exceeding the recommended daily intake (≥ 400 IU/day) or concurrent use of anticoagulants/antiplatelets that may increase bleeding risk, unless clinically indicated and closely monitored
• Pregnant women are excluded from this study because selumetinib (AZD6244 hydrogen sulfate) is a MEK inhibitor agent with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with selumetinib (AZD6244 hydrogen sulfate) breastfeeding should be discontinued if the mother is treated with selumetinib (AZD6244 hydrogen sulfate). These potential risks also apply to treatment with DS-8201a
• Patients who have received prior systemic anticancer therapy, investigational agents, or radiotherapy without completion of an adequate washout period prior to study treatment initiation defined as at least 14 days or > 5 half-lives of the prior agent (whichever is shorter). This applies to therapies with potential overlapping toxicities with DS-8201a or selumetinib (AZD6244 hydrogen sulfate) including but not limited to agents associated with pulmonary toxicity, cytopenias, or gastrointestinal toxicity

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