A Study of Napabucasin (BBI-608) in Combination With FOLFIRI in Adult Patients With Previously Treated Metastatic Colorectal Cancer

Exclusion Criteria

• •1. Anti-cancer chemotherapy or biologic therapy if administered prior to the first planned dose of study medication (napabucasin or FOLFIRI) within period of time equivalent to the usual cycle length of the regimen. An exception is made for oral fluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10 days since last dose must be observed prior to the first planned dose of study medication. Standard dose of bevacizumab (5 mg/kg) may be administered prior to FOLFIRI infusion, per Investigator decision, for as long as permanent decision to include or exclude bevacizumab is made prior to patient randomization. Radiotherapy, immunotherapy (including immunotherapy administered for non-malignant diseaseneoplastic treatment purposes), or investigational agents within four weeks of first planned dose of study medication, with the exception of a single dose of radiation up to 8 Gy (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.
• •2. More than one prior chemotherapy regimen administered in the metastatic setting.
• •3. Major surgery within 4 weeks prior to randomization.
• •4. Patients with any known brain or leptomeningeal metastases are excluded, even if treated.
• •5. Women who are pregnant or breastfeeding. Women should not breastfeed while taking study treatment and for 4 weeks after the last dose of napabucasin or while undergoing treatment with FOLFIRI and for 180 days after the last dose of FOLFIRI.
• •6. Gastrointestinal disorder(s) which, in the opinion of the Qualified/Principal Investigator, would significantly impede the absorption of an oral agent (e.g. intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection).
• •7. Unable or unwilling to swallow napabucasin capsules daily.
• •8. Prior treatment with napabucasin.
• •9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
• •10. Known hypersensitivity to 5-fluorouracil/leucovorin
• •11. Known dihydropyrimidine dehydrogenase (DPD) deficiency
• •12. Known hypersensitivity to irinotecan
• •13. Chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis)
• •14. Patients receiving treatment with St. John's wort or Phenytoin.
• •15. Patients who plan to receive yellow fever vaccine during the course of the study treatment.
• •16. Abnormal glucuronidation of bilirubin, known Gilbert's syndrome
• •17. Patients with QTc interval \> 470 milliseconds
• •18. For patients to be treated with a regimen containing bevacizumab:
• •* History of cardiac disease: congestive heart failure (CHF) \> New York Heart Association (NYHA) Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
• •* Current uncontrolled hypertension (systolic blood pressure \[BP\] \> 150 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management) as well as prior history of hypertensive crisis or hypertensive encephalopathy.
• •* History of arterial thrombotic or embolic events (within 6 months prior to study entry)
• •* Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease)
• •* Evidence of bleeding diathesis or clinically significant coagulopathy
• •* Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28 days, or anticipation of the need for major surgical procedure during the course of the study as well as minor surgical procedure (excluding placement of a vascular access device or bone marrow biopsy) within 7 days prior to study enrollment
• •* Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
• •* History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months
• •* Ongoing serious, non-healing wound, ulcer, or bone fracture
• •* Known hypersensitivity to any component of bevacizumab
• •* History of reversible posterior leukoencephalopathy syndrome (RPLS)
• •* History of hypersensitivity to Chinese hamster ovary (CHO) cells or other human or humanized recombinant antibodies.
• •19. Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for \> 3 years.
• •20. Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
• •21. Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.