Zunsemetinib with mFOLFIRINOX for the Treatment of Advanced or Metastatic Pancreatic Ductal Adenocarcinoma

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
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Absolute neutrophil count ≥ 1.5 K/cumm
• Platelets ≥ 100 K/cumm without transfusion within 2 weeks prior to cycle 1 day 1 (C1D1)
• Hemoglobin ≥ 9.0 g/dL without transfusion within 2 weeks prior to C1D1
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [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 electrocardiogram (EKG) with Fridericia's corrected QT interval (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 institutional review board (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, and drugs with QT prolonging potential, within 5 half-lives of C1D1
• Known brain metastases or central nervous system (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 antiretroviral therapy (ART) according to Department of Health and Human Services (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