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

Inclusion Criteria:

1. Written, signed consent for trial participation must be obtained from the patientappropriately in accordance with applicable ICH guidelines and local and regulatoryrequirements prior to the performance of any study specific procedure.
2. Must have histologically confirmed advanced CRC that is metastatic.
3. Must have failed treatment with one regimen containing a fluoropyrimidine, oxaliplatinwith or without bevacizumab for metastatic disease. All patients must have received aminimum of 6 weeks of the first-line regimen that included bevacizumab (ifapplicable), oxaliplatin and a fluoropyrimidine in the same cycle. Treatment failureis defined as radiologic progression during or < 6 months after the last dose offirst-line therapy.
4. FOLFIRI therapy is appropriate for the patient and is recommended by the Investigator.
5. Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans asnecessary to document all sites of disease performed within 21 days prior torandomization. Patients with either measurable disease or non-measurable evaluabledisease are eligible.
6. Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7. Must be ≥ 18 years of age.
8. For male or female patient of child bearing potential: Must agree to use contraceptionor take measures to avoid pregnancy during the study and for 180 days for female andmale patients, of the final FOLFIRI dose. Patients who receive single agentnapabucasin without FOLFIRI must agree to use contraception or take measures to avoidpregnancy during the study and for 30 days for female patients and 90 days for malepatients, of the final napabucasin dose.
9. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancytest within 5 days prior to randomization. The minimum sensitivity of the pregnancytest must be 25 IU/L or equivalent units of HCG.
10. Must have alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal (ULN) [≤ 5 × ULN in presence of liver metastases] within 14 days prior to randomization.
11. Must have hemoglobin (Hgb) ≥ 9.0 g/dL within 14 days prior to randomization. Must nothave required transfusion of red blood cells within 1 week of baseline Hgb assessment.
12. Must have total bilirubin ≤ 1.5 × institutional ULN [≤ 2.0 x ULN in presence of livermetastases] within 14 days prior to randomization.
13. Must have creatinine ≤ 1.5 × institutional ULN or Creatinine Clearance > 50 ml/min (ascalculated by the Cockcroft-Gault equation (Chronic Kidney Disease EpidemiologyCollaboration [CKD-EPI]) within 14 days prior to randomization.
14. Must have absolute neutrophil count ≥ 1.5 x 10^9/L within 14 days prior torandomization.
15. Must have platelet count ≥ 100 x 10^9/L within 14 days prior to randomization. Mustnot have required transfusion of platelets within 1 week of baseline plateletassessment.
16. Patient must have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m^2and body weight of > 40 kg with serum albumin > 3 g/dL.
17. Other baseline laboratory evaluations, listed in Section 6.0, must be done within 14days prior to randomization.
18. Patient must consent to provision of, and Investigator(s) must confirm access to andagree to submit a representative formalin fixed paraffin block of tumor tissue inorder that the specific biomarker assays may be conducted. Submission of the tissue isto occur prior to randomization, unless approved by the Sponsor. Where local centerregulations prohibit submission of blocks of tumor tissue, two 2 mm cores of tumorfrom the block and 10-30 unstained slides of whole sections of representative tumortissue are preferred. Where two 2 mm cores of tumor from the block are unavailable, 10-30 unstained slides of whole sections of representative tumor tissue alone areacceptable. Where no previously resected or biopsied tumor tissue exists or isavailable, on the approval of the Sponsor/designated CRO, the patient may still beconsidered eligible for the study.
19. Patient must consent to provision of a sample of blood in order that the specificcorrelative marker assays may be conducted.
20. Patients must be accessible for treatment and follow-up. Patients registered on thistrial must receive protocol treatment and be followed at the participating center.This implies there must be reasonable geographical limits placed on patients beingconsidered for this trial. Investigators must ensure that the patients randomized onthis trial will be available for complete documentation of the treatment, responseassessment, adverse events, and follow-up.
21. Protocol treatment is to begin within 2 calendar days of patient randomization.
22. The patient is not receiving therapy in a concurrent clinical study and the patientagrees not to participate in other interventional clinical studies during theirparticipation in this trial while on study treatment. Patients participating insurveys or observational studies are eligible to participate in this study.

Exclusion Criteria:

1. Anti-cancer chemotherapy or biologic therapy if administered prior to the firstplanned dose of study medication (napabucasin or FOLFIRI) within period of timeequivalent to the usual cycle length of the regimen. An exception is made for oralfluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10 days since last dosemust be observed prior to the first planned dose of study medication. Standard dose ofbevacizumab (5 mg/kg) may be administered prior to FOLFIRI infusion, per Investigatordecision, for as long as permanent decision to include or exclude bevacizumab is madeprior to patient randomization. Radiotherapy, immunotherapy (including immunotherapyadministered for non-malignant diseaseneoplastic treatment purposes), orinvestigational 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) withpalliative 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 iftreated.
5. Women who are pregnant or breastfeeding. Women should not breastfeed while takingstudy treatment and for 4 weeks after the last dose of napabucasin or while undergoingtreatment with FOLFIRI and for 180 days after the last dose of FOLFIRI.
6. Gastrointestinal disorder(s) which, in the opinion of the Qualified/PrincipalInvestigator, would significantly impede the absorption of an oral agent (e.g.intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastricand 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 activeinfection, clinically significant non-healing or healing wounds, symptomaticcongestive heart failure, unstable angina pectoris, clinically significant cardiacarrhythmia, significant pulmonary disease (shortness of breath at rest or mildexertion), uncontrolled infection or psychiatric illness/social situations that wouldlimit 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 studytreatment.
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 HeartAssociation (NYHA) Class II; active coronary artery disease, myocardialinfarction within 6 months prior to study entry; unevaluated new onset anginawithin 3 months or unstable angina (angina symptoms at rest) or cardiacarrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin arepermitted).
• Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg ordiastolic pressure > 90 mmHg despite optimal medical management) as well as priorhistory of hypertensive crisis or hypertensive encephalopathy.
• History of arterial thrombotic or embolic events (within 6 months prior to studyentry)
• 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 procedureduring the course of the study as well as minor surgical procedure (excludingplacement of a vascular access device or bone marrow biopsy) within 7 days priorto study enrollment
• Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baselineshould 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, orintra-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 humanor humanized recombinant antibodies.

19. Patients with a history of other malignancies except: adequately treated non-melanomaskin cancer, curatively treated in-situ cancer of the cervix, or other solid tumorscuratively treated with no evidence of disease for > 3 years.
20. Any active disease condition which would render the protocol treatment dangerous orimpair the ability of the patient to receive protocol therapy.
21. Any condition (e.g. psychological, geographical, etc.) that does not permit compliancewith the protocol.