FOLFIRINOX Plus IPI-926 for Advanced Pancreatic Adenocarcinoma

Inclusion Criteria:

1. Histologically-confirmed pancreatic adenocarcinoma
2. Disease that is not operable (locally advanced or metastatic)
3. No prior systemic therapy for their diagnosis (except in adjuvant setting > 6 months previously)
4. ECOG performance score of 0-1
5. At least 18 years of age

6. Evidence of either or both of the following:

   • RECIST-defined measurable disease (lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20mm using conventional techniques or ≥10 mm with spiral CT scan)
   • An elevated serum CA19-9 at baseline ( ≥ 2X ULN)
7. Endobiliary stents, but not percutaneous biliary drains, are permissible.

8. Adequate bone marrow function:

   • ANC ≥ 1500/uL
   • platelet count ≥ 100,000/uL
   • hemoglobin ≥ 9.0 g/dL (may be increased to this level with transfusion as long as there is no evidence of active bleeding)

9. Adequate hepatic function:

   • Total bilirubin ≤ 1.5 X ULN
   • AST (SGOT) ≤ 2.5 X ULN
   • ALT (SGPT) ≤ 2.5 X ULN

10. Adequate renal function as determined by either:

    • Calculated or measured creatinine clearance ≥ 40 mL/min (for calculated creatinine clearance, Cockcroft-Gault equation will be used). The Modified Cockcroft-Gault formula is as follows:

      [140 - age(yrs)] x [actual weight (kg)] / [72 x serum creatinine (mg/dl)] Note: Multiply by a factor of 0.85 if female

    • Serum creatinine ≤ 1.5 X ULN
11. Ability to swallow oral medications
12. All women of child-bearing potential (WCBP), all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control throughout the study. Women of child-bearing potential (defined as being less than 1 year post-menopausal) must have a negative serum or urine β human chorionic gonadotropin (βhCG) pregnancy test; and men and women of reproductive potential must agree to practice an effective method of avoiding pregnancy while receiving study drug and for 30 days after the final dose of study drug. Effective contraception includes use of oral contraceptives with an additional barrier method, double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), Depo-Provera, partner vasectomy, and total abstinence.
13. Ability to understand the nature of this study protocol and give written informed consent
14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Any prior systemic or investigational therapy for metastatic pancreatic cancer. Systemic therapy administered alone or in combination with radiation in the adjuvant setting is permissible as long as it was completed > 6 months prior to the time of study enrollment.
2. Inability to comply with study and/or follow-up procedures.
3. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the investigator, renders the subject at high risk from treatment complications or might affect the interpretation of the results of the study.
4. Presence of central nervous system or brain metastases.
5. Life expectancy < 12 weeks
6. Pregnancy (positive pregnancy test) or lactation.
7. Concurrent active malignancy. The following prior malignancies ARE allowed: adequately treated non-melanoma skin cancer; in situ cervical cancer; localized prostate cancer; or adequately treated Stage I or II cancer for which treatment was completed more than one year ago and from which the patient is currently in complete remission; or any other form of cancer from which the patient has been disease-free for 5 years.
8. Patients with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months.
9. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
10. Known, existing uncontrolled coagulopathy. Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation are eligible IF: they are appropriately anticoagulated and have not had a Grade 2 or greater bleeding episode in the 3 weeks before Day 1. However, as concurrent/pre-existing use of coumadin is not allowed, only low-molecular heparin should be used.
11. Pre-existing sensory neuropathy > grade 1.
12. Major surgery within 4 weeks of the start of study treatment, without complete recovery.
13. Cirrhotic liver disease, ongoing alcohol abuse, or known chronic active or acute hepatitis.
14. Concurrent administration of the medications or foods which are known to inhibit CYP3A activity to a clinically relevant degree (see Appendix 1).
15. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
16. Known hypersensitivity reaction to a sulfonamide.
17. Presence of active infection requiring systemic use of antibiotics within 72 hours of treatment.
18. Known human immunodeficiency virus (HIV) positivity.
19. Known hypersensitivity to IPI-926 or any of the excipients in IPI-926 capsules.
20. Pregnant or lactating women.
21. Any other co-morbid condition(s) that may interfere with study participation which in the judgment of the Investigator would place the patient at undue risk or interfere with the study. Examples include, but are not limited to sepsis, recent significant traumatic injury, and other conditions.