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

The Washington University

Status and phase: Begins enrollment in 1 month; Phase 1

Conditions: Metastatic Pancreatic Ductal Adenocarcinoma; Cancer of the Pancreas; Pancreatic Cancer

Treatments: Drug: mFOLFIRINOX; Drug: Zunsemetinib

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT06648434

24-x291

P50CA272213 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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

Enrollment: 51 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically or cytologically confirmed pancreatic ductal adenocarcinoma with no prior systemic treatment. Patients with mixed cytology in their tumors such as adeno-squamous, mixed neuroendocrine-carcinoma are permitted if the portion of adenocarcinoma is predominant.

• 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 and up to 75 years of age (inclusive). FOLFIRINOX or mFOLFIRINOX carries excessive risks of toxicities for advanced aged patients. In the original study of FOLFIRINOX versus gemcitabine1, patients above the age of 75 years were excluded.

• ECOG performance status ≤ 1.

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9.0 g/dL
  • 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 ≤ 1.5 x IULN or 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 (for women) or 3 months (for men) after the end of treatment. Should a woman 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

• Prior receipt of FOLFIRINOX or mFOLFIRINOX regimen for pancreatic cancer in the adjuvant/neoadjuvant setting.
• 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.
• Currently receiving or have received 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 the agent.
• 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.
• Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of C1D1.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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51 participants in 2 patient groups

Dose escalation phase (zunsemetinib + mFOLFIRNOX)

Experimental group

Description:

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.

Treatment:

Drug: Zunsemetinib

Drug: mFOLFIRINOX

Dose expansion phase (zunsemetinib + mFOLFIRNOX)

Experimental group

Description:

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.

Treatment:

Drug: Zunsemetinib

Drug: mFOLFIRINOX