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.
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 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
Single group
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Diagnostic Imaging Testing
Procedure/SurgeryUndergo diagnostic imaging
Echocardiography Test
Procedure/SurgeryUndergo echocardiography
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA scan
Selumetinib
DrugGiven PO
Trastuzumab Deruxtecan
Biological/VaccineGiven IV
Occurrence of dose limiting toxicities (DLTs) (dose escalation phase)
Will provide the number and proportion of DLTs provide and 95% confidence intervals.
HER2 expression status (dose escalation phase)
Will be evaluated descriptively during the dose escalation phase with respect to safety, tolerability and preliminary antitumor activity.
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.
Incidence of adverse events
Safety will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v 5.0. Descriptive statistics will summarize the frequency and severity of adverse events and serious adverse events, as well as any dose-limiting toxicities. A Clopper-Pearson exact 95% confidence interval for the proportion of subjects exhibiting DLTs will be calculated.
Biochemical response
Will be evaluated by measuring changes in cancer antigen (CA) 19-9 levels. A predefined percentage decrease from baseline (e.g., ≥ 50%) will define response, and response rates will be reported descriptively along with Clopper-Pearson 95% CIs. Patterns of CA 19-9 change over time may be explored as an exploratory analysis.
Time to response
Duration of response
Selumetinib (AZD6244 hydrogen sulfate) pharmacokinetics (PK)
Will be analyzed with both non-compartmental and nonlinear mixed effects (NLME) approaches, while DS-8201a PK will be analyzed using NLME to determine individual PK parameters.
Immunogenicity
Presence and quantity of anti-drug antibodies (ADA) will be determined.
PK parameters
Determined for both agents, including estimated DS-8201a payload exposures, along with ADA presence and quantity, will be correlated with safety and efficacy outcomes.
Trastuzumab deruxtecan (DS-8201a) clearance
Including a time-varying rate of change, will be estimated for each patient using nonlinear mixed effects. The methods for this will include adopting published PK models and using Bayesian estimation. Will use the likelihood ratio test for decision-making when adding each new parameter, using the objective function value (OFV), which is chi-square distributed, and a cut-off of -3.84 change in OFV, which corresponds to a p-value of 0.05 with one degree of freedom. Once a base model is established, we will also evaluate covariates (e.g., albumin, creatinine clearance, ADA, etc.) using forward addition/backward deletion with p = 0.01 as a cut-off for covariate retention.
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