A phase Ib extension study of cancer stemness inhibitor BB608 (napabucasin) in combination with gemcitabine and nab-paclitaxel (nab-PTX) in patients (pts) with metastatic pancreatic cancer.

4128 Background: BB608 (aka napabucasin, BBI-608) is an oral first-in-class cancer stemness inhibitor that works by targeting Stat3-driven gene transcription. Preclinical anti-tumor activity was observed in vitro and in vivo. BB608 has shown clinical safety and encouraging signs of anti-cancer activity in multiple cancer types in phase I/II studies. Methods: A phase Ib extension, open label, multi-center study in pts with metastatic pancreatic ductal adenocarcinoma (mPDAC) was undertaken to confirm the RP2D, PK profile and signs of anticancer activity of BB608 in combination with gemcitabine and nab-PTX. BB608 was administered at 240 mg BID in combination with gemcitabine 1000 mg/m2 and nab-PTX 125 mg/m2 administered weekly for 3 out every 4 weeks until progression of disease, unacceptable toxicity, or other discontinuation criterion. Results: Of 37 pts enrolled, 31 (84%) were treatment-naïve and 6 (16%) received neoadjuvant systemic therapy. There were no dose-limiting or unexpected toxicities. Most common adverse events (AE's) related to BB608 included grade 1 diarrhea, abdominal pain, nausea, and fatigue with grade 3 adverse events observed in 6 pts: 1 pt (diarrhea), 1 pt (dehydration), 3 pts (fatigue, hypokalemia) and 1 pt (hyponatremia). No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 27 of 29 evaluable pts (93%), with 23 pts (79.3%) with tumor regression of which 10 pts (34.5%) achieved PR (RECIST 1.1: 33 - 78% regression). Of the 8 pts who were non-evaluable for treatment response, 3 stopped treatment due to clinical progression, 1 due to non-compliance, and 4 withdrew consent. Among 37 pts enrolled (intent-to-treat), disease control (PR+SD) was observed in 27 pts (73%), with tumor regression observed in 23 pts (62.2%) of which 10 pts achieved PR (27%). Conclusions: This phase Ib extension study confirmed that BB608 can be combined with gemcitabine and nab-PTX and shows encouraging signs of anti-tumor activity in pts with pancreatic cancer. Clinical trial information: NCT02231723.