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

Inclusion Criteria

• Signed written informed consent
• A histologically confirmed solid tumor of the gastrointestinal tract including
• 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 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (as determined by Cockcroft-Gault equation).
• Absolute neutrophil count ≥ 1.5 x 10^9/L.
• Platelets ≥100 x 10^9/L.
• Life expectancy estimated at ≥3 months.

Exclusion Criteria

• Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of the first dose of BBI608.
• Major surgery within 4 weeks prior to first dose.
• 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.
• Pregnant or breastfeeding.
• Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
• Unable or unwilling to swallow BBI608 capsules daily.
• Prior treatment with BBI608.
• Uncontrolled intercurrent illness
• For patients to be treated with a regimen containing 5-fluorouracil/leucovorin:
• Known hypersensitivity to 5-fluorouracil/leucovorin
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• For patients to be treated with a regimen containing capecitabine:
• Known hypersensitivity to capecitabine
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
• For patients to be treated with a regimen containing oxaliplatin:
• Neurosensory neuropathy ≥ grade 2 at baseline
• Known hypersensitivity to oxaliplatin or other platinum containing compounds
• For patients to be treated with a regimen containing irinotecan:
• Known hypersensitivity to irinotecan
• Abnormal glucuronidation of bilirubin
• For patients to be treated with a regimen containing bevacizumab:
• Current uncontrolled hypertension as well as prior history of hypertensive crisis or hypertensive encephalopathy
• 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
• History of arterial thrombotic or embolic events (within 6 months prior to study entry)
• Significant vascular disease
• Evidence of bleeding diathesis or clinically significant coagulopathy
• 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
• Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+.
• 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 rev