MK2 Inhibitor in Combination With mFOLFIRINOX for Untreated Metastatic Pancreatic Ductal Adenocarcinoma

Phase I Trial of MK2 Inhibitor in Combination With mFOLFIRINOX for Untreated Metastatic Pancreatic Ductal Adenocarcinoma

The investigators hypothesize that MK2 inhibition may improve efficacy of mFOLFIRINOX chemotherapy for patients with pancreatic ductal adenocarcinoma (PDAC).

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer; Cancer of the Pancreas; Metastatic Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: Zunsemetinib; Drug: mFOLFIRINOX

• Study Type: Interventional
• Enrollment (Estimated): 51
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Moh'd Khushman, M.D.; Phone Number: 314-273-3564; Email: mkhushman@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Sub-Investigator: Olivia Aranha, M.D., Ph.D.
      • Sub-Investigator: Nikolaos Trikalinos, M.D.
      • Sub-Investigator: Patrick Grierson, M.D., Ph.D.
      • Sub-Investigator: Kian-Huat Lim, M.D., Ph.D.
      • Sub-Investigator: Esther Lu, Ph.D.
      • Sub-Investigator: Rama Suresh, M.D.
      • Sub-Investigator: Benjamin Tan, M.D.
      • Contact: Moh'd Khushman, M.D.; Phone Number: 314-273-3564; Email: mkhushman@wustl.edu
      • Principal Investigator: Moh'd Khushman, M.D.
      • Sub-Investigator: Nikolaos Andreatos, M.D.
      • Sub-Investigator: Ramon Jin, M.D., Ph.D.
      • Sub-Investigator: Max Wattenberg, M.D.
      • Sub-Investigator: Chunjie Li, M.D., Ph.D.
      • Sub-Investigator: Mark O'Hara, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed pancreatic ductal adenocarcinoma with no prior systemic treatment for advanced or metastatic disease. Patients with mixed cytology in their tumors such as adeno-squamous, mixed neuroendocrine-carcinoma are permitted if the portion of adenocarcinoma is predominant. Prior adjuvant/neoadjuvant therapy (including FOLFIRINOX or mFOLFIRINOX regimens) is allowed if progression occurred ≥ 12 months from the last dose of that therapy. A biopsy is not required to confirm advanced or metastatic disease.
• Dose escalation: Diagnosis of advanced inoperable or metastatic disease, where mFOLFIRINOX (or classical FOLFIRINOX) is deemed a suitable option per the treating physician.
• Dose expansion: Diagnosis of metastatic disease, where mFOLFIRINOX (or classical FOLFIRINOX) is deemed a suitable option per the treating physician.
• Measurable disease by RECIST 1.1.
• At least 18 years of age
• ECOG performance status ≤ 1.

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm without transfusion within 2 weeks prior to C1D1
  • Hemoglobin ≥ 9.0 g/dL without transfusion within 2 weeks prior to C1D1
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN
  • Creatinine clearance > 50 mL/min by Cockcroft-Gault
• Baseline EKG with QTcF ≤ 460 ms.
• Women of childbearing potential and men who are heterosexually active must agree to use adequate contraception as specified in the protocol. Contraception should continue for 1 month following last dose of zunsemetinib, 6 months following last dose of irinotecan, 9 months following last dose of oxaliplatin, and/or 3 months following last dose of fluorouracil. Should a woman (or the female partner of a male participant) become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• A history of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of metastatic pancreatic cancer.
• History of allogeneic organ or stem cell transplant.
• Currently receiving any other investigational agents, or receipt of an investigational agent within 2 weeks or 5 half-lives of the agent, whichever is shorter.
• Receipt of strong and moderate CYP3A4 and CYP2C8 inhibitors (including grapefruit), strong and moderate CYP3A and CYP2C8 inducers (see Appendices H and I), and drugs with QT prolonging potential within 5 half-lives of cycle 1 day 1.
• Known brain metastases or CNS involvement, because brain metastases are often associated with poor functional status, shortened life expectancy and risk of toxicity.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to zunsemetinib, or other agents used in the study.
• Clinically significant neuropathy ≥ grade 2.
• Presence of interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity.
• Gastrointestinal conditions which could prevent absorption of zunsemetinib, in the opinion of the treating physician.
• Inability to swallow pills.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia .
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 7 days of C1D1.
• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
• Major surgery within 28 days prior to C1D1. Major surgery refers to any surgical procedure that involves general or regional anesthesia, involves extensive resecting or altering of body parts, carries a higher risk of complications, or requires long recovery times. Central line placement is allowed.
• Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of C1D1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation phase (zunsemetinib + mFOLFIRNOX); The dose of zunsemetinib will be determined by the dose level assigned and will be taken by mouth either once or twice daily depending on assigned dose level. mFOLFIRINOX will be 85 mg/m^2 of oxaliplatin intravenous (IV) on day 1 of each cycle, 150 mg/m^2 of irinotecan IV on day 1 of each cycle, 400 mg/m^2 of leucovorin IV on day 1 of each cycle, and 2400 mg/m^2 continuous infusion starting on day 1 of each cycle and continuing for 46 hours. Each cycle is 2 weeks in length.	Drug: Zunsemetinib; Patients should take zunsemetinib approximately 12 hours apart (if twice daily dosing) or 24 hours apart (if once daily dosing) at the same time(s) every day, with 8 oz of water.; Other Names: ATI-450; Drug: mFOLFIRINOX; Includes oxaliplatin, irinotecan, leucovorin, and 5-FU.
Experimental: Dose expansion phase (zunsemetinib + mFOLFIRNOX); The dose of zunsemetinib will be determined during the dose escalation phase of the trial. mFOLFIRINOX will be 85 mg/m^2 of oxaliplatin intravenous (IV) on day 1 of each cycle, 150 mg/m^2 of irinotecan IV on day 1 of each cycle, 400 mg/m^2 of leucovorin IV on day 1 of each cycle, and 2400 mg/m^2 continuous infusion starting on day 1 of each cycle and continuing for 46 hours. Each cycle is 2 weeks in length.	Drug: Zunsemetinib; Patients should take zunsemetinib approximately 12 hours apart (if twice daily dosing) or 24 hours apart (if once daily dosing) at the same time(s) every day, with 8 oz of water.; Other Names: ATI-450; Drug: mFOLFIRINOX; Includes oxaliplatin, irinotecan, leucovorin, and 5-FU.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Recommended phase II dose (RP2D) of zunsemetinib in combination with mFOLFIRINOX (Dose Escalation Only)	Completion of 2 cycles (each cycle is 2 weeks - estimated to be 4 weeks)
Number of participants with dose-limiting toxicities (DLTs) (Dose Escalation only)	Completion of 2 cycles (each cycle is 2 weeks - estimated to be 4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events by types	Graded by CTCAE v5.	From start of treatment through 30 days after last zunsemetinib dose (estimated to be 13 months)
Progression-free rate (PFR) (only for those treated at RP2D)	Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and/or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.	At 6 months
Disease control rate (DCR) (only for those treated at RP2D)	DCR is defined as the number of participants with complete response, partial response, or stable disease) per RECIST 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	Through completion of treatment (estimated to be 12 months)
Overall response rate (ORR) (only for those treated at RP2D)	ORR = defined as number of participants with complete response or partial response by RECIST 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Through completion of treatment (estimated to be 12 months)
Progression-free survival (PFS) (only for those treated at RP2D)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and/or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.	Through completion of follow-up (estimated to be 3 years)
Overall survival (OS) (only for those treated at RP2D)	OS is defined as the duration of time from start of treatment to time of death from any cause.	Through completion of follow-up (estimated to be 3 years)
CA19-9 response rate (only for those treated at RP2D)		Through completion of treatment (estimated to be 12 months)
Change in plasma concentration of zunsemetinib and its metabolites		Cycle 1 day 1 (each cycle is 2 weeks), cycle 2 day 1 (each cycle is 2 weeks), cycle 3 day 1 (each cycle is 2 weeks), cycle 4 day 1 (each cycle is 2 weeks), and end of treatment (estimated to be 12 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); Aclaris Therapeutics, Inc.
• Investigators: Principal Investigator: Moh'd Khushman, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): May 31, 2030

Study Registration Dates

• First Submitted: October 15, 2024
• First Submitted That Met QC Criteria: October 17, 2024
• First Posted (Actual): October 18, 2024

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Pancreatic cancer; FOLFIRINOX; Zunsemetinib
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms
• Other Study ID Numbers: 202502144; P50CA272213 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual patient data that underlie the results reported in the article, after deidentification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Researchers who can provide a methodologically sound proposal may direct the proposal to the Principal Investigator at mkhushman@wustl.edu. To gain access, researchers will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No