This is a single arm, open-label study of CPI-613 in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic cancer never treated with systemic chemotherapy.

The primary specific aim of the study is to establish the maximum tolerated dose (MTD) of CPI-613 when given in combination with gemcitabine/nab-paclitaxel for patients with locally advanced or metastatic pancreatic cancer.

Inclusion Criteria:

1. Histologically or cytologically documented and measurable stage III or IV pancreatic adenocarcinoma.

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

3. First line treatment for patients diagnosed with metastatic disease

4. First line treatment for patients with locally advanced pancreatic cancer who have not been treated with systemic therapies. Prior treatment with chemoradiation is allowed if 4 or more weeks have passed from completion of chemo-radiotherapy.

5. Expected survival > 3 months.

6. Women of child-bearing potential must use accepted contraceptive methods (abstinence, intrauterine device, oral contraceptive, or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation.

7. Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists.

8. Laboratory values ≤2 weeks must be:

   A. Adequate hematologic (platelet count ≥ 100,000 cells/mm^3 or ≥ 100 bil/L; absolute neutrophil count [ANC] ≥ 1500 cells/mm3 or ≥1.5 bil/L; and hemoglobin ≥ 9 g/dL or ≥ 90 g/L).

   B. Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤ 3x upper normal limit [UNL], alanine aminotransferase [ALT/SGPT] ≤ 3x UNL (≤ 5x UNL if liver metastases present), Total bilirubin ≤ 1.5x ULN C. Adequate renal function (serum creatinine ≤ 2.0 mg/dL or 177 μmol/L). D. Adequate coagulation (International Normalized Ratio or INR must be ≤ 1.5), unless the patient receives anticoagulation treatment in which case the INR should be within the therapeutic level, not higher than 3.5 E. Albumin > 2.5 g/dL

9. No evidence of active infection and no serious infection within the past month.

10. Mentally competent, ability to understand and willingness to sign the informed consent form.

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Exclusion Criteria:

1. Unwilling or unable to follow protocol requirements. Endocrine or acinar pancreatic carcinoma

2. Known cerebral metastases, central nervous system (CNS), or epidural tumor

3. Prior treatment with any systemic chemotherapy for metastatic adenocarcinoma of the pancreas or for stage III (locally advanced) adenocarcinoma

4. Presence of clinically significant abdominal ascites

5. 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.

6. Serious medical illness that would potentially increase patients' risk for toxicity.

7. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease).

8. Pregnant women, or women of child-bearing potential not using reliable means of contraception (because the teratogenic potential of CPI-613 is unknown).

9. Lactating females.

10. Fertile men unwilling to practice contraceptive methods during the study period.

11. Life expectancy less than 3 months.

12. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients.

13. Unwilling or unable to follow protocol requirements.

14. 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.

15. Patients with a history of myocardial infarction that is <3 months prior to registration.

16. Evidence of active infection, or serious infection within the past month.

17. Patients with known HIV infection.

18. Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment. Steroid use for contrast induced allergy or other supportive care indication is allowed

19. Requirement for immediate palliative treatment of any kind including surgery.

20. Any other malignancy within last 3 years

21. History of interstitial lung disease, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis

22. Peripheral neuropathy grades 2 or higher

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There is no plan to make individual data available to other researchers