Trial of Devimistat in Combination With Modified FOLFIRINOX in Patients With Metastatic Adenocarcinoma of the Pancreas

A Multicenter Open-Label Dose Optimization Trial of Devimistat in Combination With Modified FOLFIRINOX in Patients With Metastatic Adenocarcinoma of the Pancreas

This protocol will enroll patients with metastatic pancreatic cancer to receive modified FOLFIRINOX plus devimistat. Patients will be enrolled with 1:1 randomization between Dose Escalation Cohort and Cohort A until required 20 patients have been enrolled on Cohort A following which randomization will end and patients will be enrolled without randomization to Dose Escalation Cohort and then subsequently to Cohort B.

Eligibility Criteria:

• Histologically or cytologically confirmed metastatic stage IV adenocarcinoma of the pancreas
• No prior systemic treatment for advanced pancreatic adenocarcinoma. Prior adjuvant or neoadjuvant treatment is allowed provided it completed ≥ 6 months prior to disease recurrence. Palliative radiation therapy is allowed provided it completed ≥ 2 weeks prior to starting trial therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
• Age 18 years or greater
• Measurable disease determined using guidelines of Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must agree to use acceptable highly effective contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive(s), intrauterine hormone releasing system (IUS), bilateral tubal occlusion or vasectomized partner) starting at screening, during the study, and for 9 months after last study dose and must have a negative serum or urine pregnancy test during screening.
• Males with female partners (of childbearing potential) must agree to use double barrier contraceptive measure (a combination of male condom with either cap, diaphragm or sponge with spermicide) in addition to oral contraception, or avoidance of intercourse during the study and for 6 months after last study dose is received.
• At least 4 weeks from major surgery with resolution of any sequela to date of enrollment
• Laboratory values ≤2 weeks during screening must be: Platelet count ≥ 100,000 cells/mm3, Absolute neutrophil count ≥ 1500 cells/mm3, Hemoglobin > 9 g/dL, AST/ALT ≤ 3x upper limit of normal [ULN], or (≤ 5x ULN if liver metastasis present), Bilirubin ≤ 1.5x ULN, or (≤ 2.5 x ULN for subjects with Gilbert's syndrome), Albumin > 3 g/dL, Serum creatinine clearance CrCl > 30 mL/min per Cockcroft-Gault Formula, INR <1.5 unless on anticoagulants
• No evidence of active infection and no serious infection within the past 30 days. Patient must have completed antibiotic course.
• Mentally competent, ability to understand and willingness to sign the informed consent form and follow protocol requirements
• No known central nervous system metastasis or epidural tumor
• No known hypersensitivity to devimistat, platinum-based drugs, FOLFIRINOX treatment or any of their excipients
• Patients must not have received any other investigational systemic agent for any indication within the past 2 weeks prior to initiation of devimistat treatment
• No active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., Hemophilia A)
• Female patients must not be pregnant, have a positive pregnancy test, breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 9 months after the last dose of study treatment.
• Male patients must be willing to abstain from donating sperm during treatment and for 6 months after completion of study treatment
• No active heart disease including but not limited to myocardial infarction that is <3 months prior to registration, symptomatic congestive heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris
• No prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cancer, localized prostate cancer (Gleason score <8), or adequately treated cancer from which the patient has been disease-free for at least 3 years prior to registration.
• Patients must not be using strong CYP3A4 inducers or inhibitors (as listed in Appendix II: CYP3A4 Inducers or Inhibitors)
• No marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 470 milliseconds (ms) (CTCAE grade 1) using Fridericia's QT correction formula (i.e. QTcF); or history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome).
• Patients must not have known reduced UGT1A1 or DPD activity.