CPI-613 (Devimistat) in Combination With Chemoradiation in Patients With Pancreatic Adenocarcinoma

Inclusion Criteria: 1. Age ≥ 18 years. 2. Pathologically confirmed (histologic or cytologic) adenocarcinoma of the pancreas. 3. Patients should have an inoperable disease (locally advanced, oligometastatic, or medically inoperable) and, based on the review of the institutional pancreatic tumor board, should otherwise benefit from chemoradiation for definitive local control of the primary tumor. 4. Patients with and without regional adenopathy are eligible. 5. History/physical examination, including a collection of weight and vital signs, within 30 days prior to treatment. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 14 days of study entry. 7. Imaging requirements are to include 1. Diagnostic abdominal/pelvic CT with IV contrast or abdominopelvic magnetic resonance (MR) scan with perfusion and diffusion-weighted sequences within 45 days prior to study entry. 2. Chest CT scan or X-ray within 45 days prior to study entry. 3. Radiation treatment planning abdominal CT. A recommended abdominal MR will be done as a simulation (SIM) scan with interpretation. The CT SIM will not be done with interpretation. Positron emission tomography (PET) scan and MRI are both optional but encouraged. Abdominal MR scans for staging and radiation planning and follow-up are optional but encouraged. 8. Heme Onc (Chem 24) and cancer antigen 19-9/ carcinoembryonic antigen (CEA) within 30 days prior to treatment, as follows: 1. Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3. 2. Platelets ≥ 100,000 cells/mm3. 3. Hemoglobin ≥ 8.0g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin ≥ 8.0 g/dl is acceptable). 4. Not on hemodialysis. 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \<4x the upper limit of normal. 6. Total bilirubin \<2x the upper normal mg/dL (higher levels are acceptable if Gilbert Syndrome is suspected clinically). 9. Negative serum pregnancy test (if applicable). 10. Ability to position for radiation therapy. 11. Pregnancy It is not known what effects this treatment has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below. Female patients must meet one of the following: * Postmenopausal for at least one year before the screening visit, or * Surgically sterile, or * If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through three months after the last dose of study drug, and * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, or * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable contraception methods.) Male patients, even if surgically sterilized (i.e., status postvasectomy), must agree to one of the following: * Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose, or * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, or * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) 12. Ability to understand a written informed consent document, and the willingness to sign it. Exclusion Criteria: 1. Prior invasive malignancy (except nonmelanomatous skin cancer, noninvasive breast cancer \[ductal carcinoma in situ\], or prostate cancer under active surveillance). Other malignancies are allowed if the patient has been disease free for a minimum of two years. 2. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields. 3. Any major surgery within 28 days prior to study entry, except colonic stent placement, intestinal diversion without resection, exploratory laparotomy and laparoscopy or vascular access insertion. 4. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during the course of the study and for women three months after study therapy is completed and for men six months after study therapy is completed. This exclusion is necessary because the treatment involved in this study may be significantly teratogenic. 5. Life expectancy less than two months. 6. Severe, active co-morbidity, defined as follows: * Any unresolved bowel or bile duct obstruction, or * Symptomatic myocardial ischemia, or * uncontrolled clinically significant conduction abnormalities (e.g., ventricular tachycardia on antiarrhythmics is excluded and first-degree atrioventricular (AV) block or asymptomatic left anterior fascicular block (LAFB) / right bundle branch block (RBBB) will not be excluded), or * Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose * Any active uncontrolled bleeding or patients with a bleeding diathesis. 7. Serious psychiatric illness (e.g., depression, psychosis) or medical conditions that in the opinion of investigator could interfere with treatment. 8. Concurrent therapy with approved or investigational anticancer therapeutics other that what is stipulated by the protocol. 9. Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus (HCV) RNA or HBsAg (HBV surface antigen). 10. Known to be HIV seropositive and on anti-HIV drugs because of the unknown interactions between these drugs and the study agents.