Study Evaluating Efficacy and Safety of FFX Versus Combination of CPI-613 With mFFX in Patients With Metastatic Adenocarcinoma of the Pancreas
Condition: Pancreatic Cancer Metastatic
MeSH terms: Adenocarcinoma
Intervention: CPI 613, mFolfirinox; Folfirinox
Intervention description: CPI-613: 500mg/m2, IV infusion at a rate of 4mL/min via a central venous port. mFolfirinox: given immediately after CPI-613 administration; Folfirinox
Intervention MeSH terms: Leucovorin; Folic Acid; Oxaliplatin; Irinotecan; Folfirinox; Levoleucovorin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 528.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      A prospective, multicenter, open label, randomized phase III study to evaluate efficacy and
      safety of FFX versus CPI-613 + mFFX in patients with metastatic adenocarcinoma of the
      pancreas with age range of 18 to 75 years
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically or cytologically confirmed metastatic Stage IV adenocarcinoma of the
             pancreas

          2. No prior treatments for stage IV pancreatic adenocarcinoma (prior adjuvant or
             neoadjuvant treatment is allowed provided completed > 6 months prior to disease
             recurrence)

          3. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1

          4. Male and female patients 18 - 75 years of age

          5. Measurable disease determined using guidelines of Response Evaluation Criteria In
             Solid Tumors (RECIST version 1.1)

          6. Expected survival >3 months

          7. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
             sterile) must use accepted highly effective contraceptive methods (abstinence,
             intrauterine device [IUD], oral contraceptive(s), intrauterine hormone releasing
             system (IUS), bilateral tubal occlusion or vasectomized partner) during and for 6
             months after last study dose and must have a negative serum or urine pregnancy test
             within 1 week prior to treatment initiation, at monthly interval (day 1 of every even
             numbered cycle), at the end of systemic exposure, and at 30 days after the systemic
             exposure

          8. Males with female partners (of childbearing potential) and female partners (of child
             bearing potential) with male partners 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

          9. At least 2 weeks must have elapsed from any prior surgery with resolution of any
             sequela for randomization

         10. Laboratory values ≤2 weeks prior to randomization must be:

               -  Adequate hematologic values

                    -  Platelet count ≥100,000 cells/mm3 or ≥100 bil/L;

                    -  Absolute neutrophil count [ANC] ≥1,500 cells/mm3 or ≥1.5 bil/L;

                    -  Hemoglobin ≥9 g/dL or ≥90 g/L)

               -  Adequate hepatic function

                    -  Aspartate aminotransferase [AST/SGOT] ≤3x upper normal limit [UNL] (≤5x UNL
                       if liver metastases present)

                    -  Alanine aminotransferase [ALT/SGPT] ≤3x UNL (≤5x UNL if liver metastases
                       present)

                    -  Bilirubin (≤1.5x UNL); bilirubin ≤ 2.5 x ULN for subjects with Gilbert's
                       syndrome

                    -  Serum albumin > 3.0 g/dL

               -  Adequate renal function serum creatinine clearance CLcr > 30 mL/min).
                  (Cocroft-Gault Formula should be used for CrCl calculation)

               -  Adequate coagulation function • International Normalized Ratio or INR must be
                  <1.5 unless on therapeutic blood thinners)

         11. No evidence of active infection and no serious infection within the past 30 days.

         12. Mentally competent, ability to understand and willingness to sign the informed consent
             form.

        Exclusion Criteria:

          1. Endocrine or acinar pancreatic carcinoma

          2. Known cerebral metastases, central nervous system (CNS), or epidural tumor

          3. Prior treatment with any chemotherapy for metastatic adenocarcinoma of the pancreas

          4. Completion of a gemcitabine-based adjuvant chemotherapy regimen within less than 6
             months at the time of screening.

          5. Receipt of neoadjuvant or adjuvant FOLFIRINOX therapy if <6 months prior to disease
             recurrence

          6. Patients with hypersensitivity to devimistat, FFX treatment or any of their excipients

          7. Presence of clinically significant abdominal ascites

          8. Patients receiving any other standard or investigational treatment for their cancer,
             or any other investigational agent for any indication within the past 2 weeks prior to
             initiation of devimistat treatment

          9. Serious medical illness that would potentially increase patients' risk for toxicity

         10. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g.,
             active peptic ulcer disease)

         11. Female patients who are pregnant or breastfeeding or planning to become pregnant or
             breastfeed during treatment and for an additional 6 months after the last dose of
             study treatment

         12. Female patients of childbearing potential with a positive pregnancy test assessed by a
             serum pregnancy test at screening

         13. Female patients of childbearing potential unwilling to use 1 highly effective method
             of contraception during treatment and for 6 months after the last dose of study
             treatment

         14. Male patients with a pregnant partner who are unwilling to practice abstinence or use
             a condom during treatment and for 6 months after completion of study treatment

         15. Male patients unwilling to abstain from donating sperm during treatment and for 6
             months after completion of study treatment

         16. Life expectancy less than 3 months

         17. Any condition or abnormality which may, in the opinion of the investigator, compromise
             the safety of patients

         18. Unwilling or unable to follow protocol requirements

         19. Active heart disease including but not limited to symptomatic congestive heart failure
             (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris,
             or symptomatic myocardial infarction

         20. Patients with a history of myocardial infarction that is <3 months prior to
             registration

         21. Evidence of active infection, or serious infection within the past 30 days.

         22. Patients with known HIV infection

         23. Patients who have received cancer immunotherapy of any type within the past 2 weeks
             prior to initiation of devimistat treatment (steroids given for supportive care or in
             response to allergic reactions are allowed at any time)

         24. Requirement for immediate palliative surgery, radiation or chemotherapy of any kind.
             Stenting for bile duct obstruction and need for pain medications are allowed provided
             all other inclusion criteria are met

         25. Prior malignancy except for the following: adequately treated basal or squamous cell
             skin cancer, in situ cervical cancer, adequately treated cancer from which the patient
             has been disease-free for at least 3 years prior to screening

         26. Unwilling or unable to avoid the concomitant use of strong CYP3A4 inducers or
             inhibitors during treatment with irinotecan

         27. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a
             QTc interval > 480 milliseconds (ms) (CTCAE grade 1) using Fredericia's QT correction
             formula (i.e. QTcF)

         28. A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family
             history of long QT syndrome)

         29. The use of concomitant medications that prolong the QT/QTc intervals

         30. Contraindications to any of the FFX treatment as follows:

        Folinic Acid

          -  Calcium Folinate is contraindicated in patients who have previously shown
             hypersensitivity to folinate or any of the excipients.

          -  Calcium Folinate Injection is contraindicated in the treatment of pernicious anemia or
             other megaloblastic anemias where vitamin B12 is deficient. Its use can lead to an
             apparent response of the hematopoietic system, but neurological damage may occur or
             progress if already present.

          -  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
             deficiency or glucose-galactose malabsorption should not take calcium folinate
             tablets.

        Fluorouracil/5FU

          -  Fluorouracil is contraindicated in patients who have any known hypersensitivity to
             fluorouracil, are seriously debilitated or are suffering from bone marrow depression
             after radiotherapy or treatment with other antineoplastic agents, or who are suffering
             from a potentially serious infection.

          -  Fluorouracil is strictly contraindicated in pregnant or breast-feeding women.

          -  Flourouracil should not be used in the management of non-malignant disease.

          -  Fluorouracil must not be taken or used concomitantly with brivudin, sorivudine and
             analogues. Brivudin, sorivudine and analogues are potent inhibitors of the enzyme
             dihydropyrimidine dehydrogenase (DPD) which degrades fluorouracil

          -  In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD)
             activity

        Oxaliplatin

          -  Oxaliplatin is contraindicated in patients who have a known history of
             hypersensitivity to oxaliplatin or to any of the excipients

          -  are breast-feeding.

          -  have myelosuppression prior to starting first course, as evidenced by baseline
             neutrophils <2x109/l and/or platelet count of <100x109l.

          -  have a peripheral sensitive neuropathy with functional impairment prior to first
             course.

          -  have a severely impaired renal function (creatinine clearance less than 30 ml /min)

        Irinotecan

          -  Chronic inflammatory bowel disease and/or bowel obstruction

          -  History of severe hypersensitivity reactions to Irinotecan hydrochloride trihydrate or
             to any of the excipients

          -  Bilirubin > 3 times the ULN

          -  Severe bone marrow failure.

          -  WHO performance status > 2.

          -  Concomitant use with St John's wort