MK2 Inhibitor In Combination With MFOLFIRINOX For Untreated Metastatic Pancreatic Ductal Adenocarcinoma

Study Overview

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).

N/A

Metastatic Pancreatic Ductal Adenocarcinoma
Pancreatic Cancer
Cancer of the Pancreas

DRUG: Zunsemetinib
DRUG: mFOLFIRINOX

202502144
P50CA272213 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2024-10-15	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-07-01
First Submitted that Met QC Criteria 2024-10-17	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-07-02
First Posted (ACTUAL) 2024-10-18	Results First Posted N/A	Last Verified 2025-07

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

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	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. 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 I	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. DRUG: mFOLFIRINOX Includes oxaliplatin, irinotecan, leucovorin, and 5-FU.

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

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.

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 I

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.

DRUG: mFOLFIRINOX

Includes oxaliplatin, irinotecan, leucovorin, and 5-FU.

Primary Outcome Measures	Measure Description	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	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)

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Moh'd Khushman, M.D.

Phone Number: 314-273-3564

Email: mkhushman@wustl.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.
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).

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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)
Aclaris Therapeutics, Inc.

Investigators

PRINCIPAL_INVESTIGATOR: Moh'd Khushman, M.D., Washington University School of Medicine

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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