A Study of BBI608 in Combination With Standard Chemotherapies in Adult Patients With Advanced Gastrointestinal Cancer

Inclusion Criteria: 1. Signed written informed consent 2. A histologically confirmed solid tumor of the gastrointestinal tract including 1. Advanced unresectable, metastatic or recurrent colorectal carcinoma (CRC) for which treatment with FOLFOX6 with or without bevacizumab, FOLFIRI with or without bevacizumab, CAPOX, or regorafenib would be acceptable as determined by the Investigator. FOLFIRI/XELIRI-refractory patients with CRC enrolling on the FOLFIRI study arm must have failed treatment with one FOLFIRI pr XELIRI with or without bevacizumab regimen for unresectable or metastatic disease. Treatment failure is defined as progression of disease (clinical or radiologic) during treatment with FOLFIRI with or without bevacizumab or \< 3 months after the last dose of treatment with FOLFIRI with or without bevacizumab. Patients with CRC enrolling on the regorafenib arm of this study will have previously received at least two previous lines of therapy for advanced colorectal cancer, and will have previously received treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Patients with K-ras wild type tumors enrolling on the regorafenib arm will also have previously received either cetuximab or panitumumab. 2. Hepatocellular carcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator. 3. Pancreatic adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator. 4. Cholangiocarcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator. 5. Gastric, GEJ or esophageal adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator. 3. Patients may be treatment naïve, or may have received standard chemotherapy; including regimens containing a fluoropyrimidine, or oxaliplatin, or irinotecan, or regorafenib, or bevacizumab. 4. ≥18 years of age. 5. Karnofsky performance status score ≥70%. 6. Male or female patients of child-producing potential agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after the last BBI608 dose. 7. Females of childbearing potential have a negative serum pregnancy test. 8. AST level ≤2.5 x ULN and ALT ≤ 2.5 × ULN. For patients with liver metastases, AST ≤3.5 x ULN, and AST ≤3.5 x ULN may be enrolled if agreed upon by the investigator and medical monitor for the sponsor. 9. Hemoglobin ≥10 g/dl. 10. Total bilirubin level ≤1.5 × ULN. 11. Creatinine ≤1.5 x ULN or creatinine clearance \>60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal (as determined by Cockcroft-Gault equation). 12. Absolute neutrophil count ≥ 1.5 x 10\^9/L. 13. Platelets ≥100 x 10\^9/L. 14. Life expectancy estimated at ≥3 months. Exclusion Criteria: 1. Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of the first dose of BBI608. 2. Major surgery within 4 weeks prior to first dose. 3. Any known untreated brain metastases. Treated subjects must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. 4. Pregnant or breastfeeding. 5. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent 6. Unable or unwilling to swallow BBI608 capsules daily. 7. Prior treatment with BBI608. 8. Uncontrolled intercurrent illness 9. For patients to be treated with a regimen containing 5-fluorouracil/leucovorin: 1. Known hypersensitivity to 5-fluorouracil/leucovorin 2. Known dihydropyrimidine dehydrogenase (DPD) deficiency 10. For patients to be treated with a regimen containing capecitabine: 1. Known hypersensitivity to capecitabine 2. Known dihydropyrimidine dehydrogenase (DPD) deficiency 3. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent 11. For patients to be treated with a regimen containing oxaliplatin: 1. Neurosensory neuropathy ≥ grade 2 at baseline 2. Known hypersensitivity to oxaliplatin or other platinum containing compounds 12. For patients to be treated with a regimen containing irinotecan: 1. Known hypersensitivity to irinotecan 2. Abnormal glucuronidation of bilirubin 13. For patients to be treated with a regimen containing bevacizumab: 1. Current uncontrolled hypertension as well as prior history of hypertensive crisis or hypertensive encephalopathy 2. History of cardiac disease: congestive heart failure (CHF) \> 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 or cardiac arrhythmias requiring anti-arrhythmic therapy 3. History of arterial thrombotic or embolic events (within 6 months prior to study entry) 4. Significant vascular disease 5. Evidence of bleeding diathesis or clinically significant coagulopathy 6. Major surgical procedure within 28 days, or anticipation of the need for major surgical procedure during the course of the study as well as minor surgical procedure within 7 days prior to study enrollment 7. Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+. 8. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months 9. Ongoing serious, non-healing wound, ulcer, or bone fracture 10. Known hypersensitivity to any component of bevacizumab 11. History of reversible posterior leukoencephalopathy syndrome (RPLS) 14. For patients to be treated with a regimen containing regorafenib: 1. History of cardiac disease: congestive heart failure (CHF) \> 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 or cardiac arrhythmias requiring anti-arrhythmic therapy 2. Current uncontrolled hypertension 3. Interstitial lung disease with ongoing signs and symptoms at the time of screening 4. History of HIV infection or chronic hepatitis B or C 5. Active clinically serious infections 6. History of arterial or embolic events (within 6 months prior to study entry) 7. Liver cirrhosis ≥ Child-Pugh class B with uncontrolled ascites 8. History of RPLS 9. Ongoing serious, non-healing wound, ulcer, or bone fracture 10. Evidence of bleeding diathesis or a clinically significant coagulopathy 11. Renal failure requiring hemo- or peritoneal dialysis 12. Persistent proteinuria of CTCAE grade 3 (\>3.5g/24 hours) 13. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent 14. Known hypersensitivity to regorafenib