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, ormedically inoperable) and, based on the review of the institutional pancreatic tumorboard, should otherwise benefit from chemoradiation for definitive local control ofthe 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 ofstudy entry.

7. Imaging requirements are to include

8. Diagnostic abdominal/pelvic CT with IV contrast or abdominopelvic magneticresonance (MR) scan with perfusion and diffusion-weighted sequences within 45days prior to study entry.

9. Chest CT scan or X-ray within 45 days prior to study entry.

10. Radiation treatment planning abdominal CT. A recommended abdominal MR will bedone as a simulation (SIM) scan with interpretation. The CT SIM will not bedone with interpretation. Positron emission tomography (PET) scan and MRI areboth optional but encouraged. Abdominal MR scans for staging and radiationplanning and follow-up are optional but encouraged.

11. Heme Onc (Chem 24) and cancer antigen 19-9/ carcinoembryonic antigen (CEA) within 30days prior to treatment, as follows:

12. Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3.

13. Platelets ≥ 100,000 cells/mm3.

14. Hemoglobin ≥ 8.0g/dl (Note: the use of transfusion or other intervention toachieve hemoglobin ≥ 8.0 g/dl is acceptable).

15. Not on hemodialysis.

16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <4x theupper limit of normal.

17. Total bilirubin <2x the upper normal mg/dL (higher levels are acceptable ifGilbert Syndrome is suspected clinically).

18. Negative serum pregnancy test (if applicable).

19. Ability to position for radiation therapy.

20. Pregnancy It is not known what effects this treatment has on human pregnancy ordevelopment of the embryo or fetus. Therefore, female patients participating in thisstudy should avoid becoming pregnant, and male patients should avoid impregnating afemale partner. Non-sterilized female patients of reproductive age and male patientsshould use effective methods of contraception through defined periods during andafter 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 methodsof contraception from the time of signing of the informed consent form throughthree months after the last dose of study drug, and

• Must also adhere to the guidelines of any treatment-specific pregnancyprevention program, if applicable, or

• Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are notacceptable contraception methods.) Male patients, even if surgically sterilized (i.e., status postvasectomy), mustagree to one of the following:

• Practice effective barrier contraception during the entire study treatmentperiod and through 90 days after the last study drug dose, or

• Must also adhere to the guidelines of any treatment-specific pregnancyprevention program, if applicable, or

• Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are notacceptable methods of contraception.)

12. Ability to understand a written informed consent document, and the willingness tosign it.

Exclusion Criteria:

1. Prior invasive malignancy (except nonmelanomatous skin cancer, noninvasive breastcancer [ductal carcinoma in situ], or prostate cancer under active surveillance).Other malignancies are allowed if the patient has been disease free for a minimum oftwo years.

2. Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields.

3. Any major surgery within 28 days prior to study entry, except colonic stentplacement, intestinal diversion without resection, exploratory laparotomy andlaparoscopy or vascular access insertion.

4. Pregnancy or women of childbearing potential and men who are sexually active and notwilling/able to use medically acceptable forms of contraception during the course ofthe study and for women three months after study therapy is completed and for mensix months after study therapy is completed. This exclusion is necessary because thetreatment 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., ventriculartachycardia on antiarrhythmics is excluded and first-degree atrioventricular (AV) block or asymptomatic left anterior fascicular block (LAFB) / right bundlebranch block (RBBB) will not be excluded), or

• Uncontrolled active infection requiring parenteral antibiotics, antivirals, orantifungals 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 thatin the opinion of investigator could interfere with treatment.

8. Concurrent therapy with approved or investigational anticancer therapeutics otherthat what is stipulated by the protocol.

9. Known active hepatitis A, B, or C infection; or known to be positive for hepatitis Cvirus (HCV) RNA or HBsAg (HBV surface antigen).

10. Known to be HIV seropositive and on anti-HIV drugs because of the unknowninteractions between these drugs and the study agents.