Background: Napabucasin (BBI-608, BB608) is a first-in-class cancer stemness inhibitor targeting the STAT3 pathway that has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a dose escalation study, BB608 plus weekly paclitaxel was well tolerated in patients (pts) with advanced solid tumors. RP2D expansion included accrual of pts with platinum resistant ovarian cancer (PROC). Methods: Pts with advanced epithelial ovarian, fallopian, or peritoneal cancer who have progressed on a prior taxane-based regimen and who were platinum resistant or refractory were enrolled. BB608 240-480 mg twice daily was administered orally with paclitaxel 80 mg/m2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a disease control rate (DCR) of 60% to 80%. DCR is the proportion with stable disease (SD) at least 8 weeks or ,partial (PR) or complete response (CR) per RECIST 1.1. Results: 56 pts were enrolled after a median 4 prior lines of therapy, including prior taxanes (92% paclitaxel only, 4% docetaxel only, 4% both). Treatment was tolerated without dose-limiting toxicity or unexpected adverse events (AE). Grade 3 AE included rapidly-reversible diarrhea (18%), vomiting (7%), abdominal pain (7%), nausea (5%), dehydration and fatigue ( < 4% each). 80% of pts with grade 3 AE continued study at a reduced dose. In evaluable pts (n = 40), DCR was 68%, tumor regression occurred in 40%, and ORR (PR+CR) was 25%, including 1 with CR. Prior to being evaluated, 2 pts withdrew due to neuropathy, 6 for other AE, 5 for deterioration, 2 for noncompliance, and 1 for MI (unrelated). In the intent to treat (ITT) pts (n = 56), DCR was 48%, ORR was 18%, median progression free survival was 15 weeks and median overall survival was 38 weeks. In pts with up to 2 prior lines of therapy (n = 11), ORR was 45%. Conclusions: BB608 can be safely combined with weekly paclitaxel with acceptable tolerability in pts with heavily pretreated PROC who have progressed on prior taxane-based regimens. Complete and partial response, durable disease control, and prolonged progression free survival and overall survival have been observed in this population, warranting further clinical study. Clinical trial information: NCT01325441.