Background: BB608 (aka Napabucasin, BBI-608) is an oral first-in-class cancer stemness inhibitor targeting Stat3-driven gene transcription. Anti-tumor activity was observed in vitro and in vivo. BB608 showed safety and encouraging signs of anti-cancer activity in phase I/II studies. Methods: A phase Ib extension multi-center study in pts with advanced CRC was undertaken to confirm the RP2D and signs of anti-cancer activity of BB608 in combination with FOLFIRI +/- Bev. BB608 was administered continuously 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/m² infusion) +/- Bev 5 mg/kg, administered bi-weekly until disease progression, unacceptable toxicity, or other discontinuation criterion. Results: 46 pretreated CRC pts who had failed an average of > 2 prior lines of therapy were enrolled; including 20 pts (43.5%) previously progressed on FOLFIRI +/- Bev. Of the 46 pts, 14 received FOLFIRI and 32 FOLFIRI with Bev in combination with BB608. There was no dose-limiting or unexpected toxicity or significant pharmacokinetic interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. Grade 3 AEs observed in 15 pts included diarrhea (9), fatigue (3), dehydration/hyponatremia (1), hypokalemia (1) and burning in rectum (1) resolved with dose reduction and/or supportive care. Disease control (PR+SD) was observed in 37 of 40 evaluable pts (93%), with partial response (PR) in 11 pts (28%) (RECIST 1.1 30-65% regression), and stable disease with tumor regression in 21 pts (53%). Among 19 pts who had progressed on FOLFIRI +/- Bev previously and were evaluable for tumor assessment, disease control (PR+SD) was observed in 17 pts (90%), tumor regression was observed in 15 pts (80%) of which 6 pts achieved PR (32%). Conclusions: This phase Ib extension study confirmed that BB608 can be safely combined with FOLFIRI +/- Bev, and shows encouraging signs of anti-tumor activity in CRC pts, including pts who had previously progressed on FOLFIRI +/- Bev. Clinical trial information: NCT02024607