Background: BBI608 is an oral first-in-class cancer stemness inhibitor of Stat3. Potent anti-tumor activity was observed in vitro and in vivo,in mono- and combination therapy. In a phase I study, BBI608 monotherapy was generally well tolerated at 500 mg BID with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was performed to determine RP2D, safety, tolerability, and preliminary anti-cancer activity of BBI608 in combination with FOLFIRI with or without bevacizumab. BBI608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m² bolus with 2400 mg/m², irinotecan 180 mg/m², and leucovorin 400 mg/m²infusion) with or without bevacizumab 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 9 pts were enrolled with 4 pts receiving FOLFIRI and 5 pts receiving FOLFIRI with bevacizumab in combination with BBI608. All pts were pretreated with ≥ 1 line and 67% (6/9) of pts with ≥ 4 prior lines of therapy. Combination treatment was well tolerated with no dose-limiting toxicity and safety profile similar to that of each regimen individually, with no difference in safety observed with addition of bevacizumab. Most common adverse events included grade 1 and 2 diarrhea, abdominal cramps, nausea, vomiting and anorexia. Grade 3 diarrhea was observed in 2 pts, and resolved with a brief BBI608 dose holiday or dose reduction to 160 mg BID and anti-diarrheal medications, respectively. Additionally, self-resolving grade 3 fatigue lasting 4-8 days was observed in 2 pts. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 9 of 9 evaluable pts (100%) with 1 PR (44% regression) and 8 SD with tumor size reduction (25%, 23%, 17%, 16%, 14%, 14%, 4% and 2%, respectively). The median progression free survival was 23.7 weeks with SD of ≥ 6 months in (33.3%) 3/9 pts. Conclusions: This phase Ib study demonstrated that BBI608 at 240 mg BID can be safely combined with FOLFIRI with and without bevacizumab. Encouraging anti-tumor activity was observed in pts with advanced and heavily pretreated CRC. Clinical trial information: NCT02024607