Clinical Trials

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas.
• No prior treatments for stage IV pancreatic adenocarcinoma (prior adjuvant or neoadjuvant treatment is allowed provided completed > 6 months prior to disease recurrence).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1.
• Male and female patients, 18 - 75 years of age.
• Measurable disease determined using guidelines of Response Evaluation Criteria In Solid Tumors (RECIST version 1.1).
• Expected survival > 3 months.
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted 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 of the study and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation, at the end of systemic exposure and between the cycles if the menstrual period is delayed by over 30 days. 
• Adult subjects of child bearing potential must agree to use double barrier contraceptive measure, oral contraception or avoidance of intercourse during the study and for 6 months after last study dose is received.
• At least 2 weeks must have elapsed from any prior surgery with resolution of any sequela for randomization.
• Laboratory values ≤ 2 weeks prior to randomization must be: 
  • Adequate hematologic values: 
    • Platelet count ≥ 100,000 cells/mm^3 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] Alanine aminotransferase [ALT/SGPT] ≤ 3x UNL (≤ 5x UNL if liver metastases present) Bilirubin ≤ 1.5x UNL); does not apply to subjects with Gilbert's syndrome Serum albumin > 3.0 g/dL.
  • Adequate renal function: 
    • Serum creatinine clearance CLcr > 30 mL/min).
  • Adequate coagulation function: 
    • International Normalized Ratio or INR must be <1.5 unless on therapeutic blood thinners) 
  • Bilirubin less than or equal to 1.5x UNL:
    • Bilirubin  ≤ 2.5 x ULN for subjects with Gilbert's syndrome.
• No evidence of active infection and no serious infection within the past 30 days.
• Mentally competent, ability to understand and willingness to sign the informed consent form.

Exclusion Criteria:

• Endocrine or acinar pancreatic carcinoma.
• Known cerebral metastases, central nervous system (CNS), or epidural tumor.
• Prior treatment with any chemotherapy for metastatic adenocarcinoma of the pancreas.
• Completion of a gemcitabine-based adjuvant chemotherapy regimen within less than 6 months at the time of screening. 
• Receipt of neoadjuvant or adjuvant FOLFIRINOX therapy.
• Presence of clinically significant abdominal ascites.
• 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 CPI-613 treatment.
• Serious medical illness that would potentially increase patients' risk for toxicity.
• Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease).
• NAP.
• Lactating females.
• Fertile men unwilling to practice contraceptive methods during the study period.
• Life expectancy less than 3 months.
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients.
• Unwilling or unable to follow protocol requirements.
• 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.
• Patients with a history of myocardial infarction that is <3 months prior to registration.
• Evidence of active infection, or serious infection within the past 30 days. 
• Patients with known HIV infection.
• Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment (steroids given for supportive care or in response to allergic reactions are allowed at any time).
• Requirement for immediate palliative treatment of any kind including surgery.
• No 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.
• Unwilling or unable to avoid the concomitant use of strong CYP3A4 inducers or inhibitors during treatment with irinotecan.
• 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).
• A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of long QT syndrome).
• The use of concomitant medications that prolong the QT/QTc intervals are excluded at screening and C1D1.
• 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.
• 5FU/ Fluorouracil
  • 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 < 2x10^9/l and/or platelet count of <100x10^9l.
  • 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.