BBI608/Gemcitabine/Nab-Paclitaxel in Metastatic Pancreatic Ductal Adenocarcinoma
BBI608 is an oral first-in-class cancer stemness inhibitor that works by blocking STAT3-mediated transcription of cancer stemness genes.1 Potent anticancer stem-cell activity was observed in vitro and in vivo, in monotherapy and combination therapy. In phase 1 studies, BBI608 was generally well-tolerated with encouraging signs of antitumor activity.1 Shahda and colleagues reported on a phase 1b open-label, multicenter study in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) that assessed the recommended phase 2 dose (RP2D), safety, tolerability, and preliminary anticancer activity of BBI608 when administered in combination with gemcitabine (GEM) and nab-paclitaxel (nab-PTX); secondary objectives included the pharmacokinetic profile and pharmacodynamics of BBI-608, and preliminary antitumor activity of the 3-drug combination.2
BBI608 was administered at 240 mg twice daily in combination with GEM 125 mg/m2 and nab-PTX 1000 mg/m2 administered weekly for 3 of every 4 weeks until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. A total of 31 patients with histologically or cytologically confirmed mPDAC were enrolled and received BBI608 in combination with GEM and nab-PTX for a total sum of 83 study cycles. Twenty-five (81%) of 31 patients were treatment-naïve and 6 (19%) patients had received 1 prior line of systemic therapy. The most common adverse events included grade 1 diarrhea, abdominal pain, nausea, and fatigue; no grade 3 adverse events were noted. Combination treatment was well-tolerated with no dose-limiting toxicity observed and a safety profile similar to that of each agent individually. One patient experienced a grade 3 event of dehydration related to protocol therapy that resolved with hydration.
Of the 8 patients enrolled in the RP2D determination portion of the study, 7 patients were evaluable for response; disease control (partial remission [PR] + stable disease [SD]) was observed in all 7 patients (100%). Prolonged tumor regression (≥24 weeks) was observed in 6 (86%) of 7 patients with 3 PR (41%, 38%, and 33% tumor regression) and 3 SD (26%, 21%, and 20% tumor regression). The median progression-free survival was 7.8 months with PR or SD of >6 months in 6 of 8 patients (75%). The authors concluded that BBI608 at 240 mg twice daily can be safely combined with GEM and nab-PTX, with no new adverse events and no evidence of pharmacokinetic interaction. Moreover, this combination demonstrates encouraging antitumor activity with durable responses in patients with mPDAC.
- Hubbard JM, et al. ASCO 2015. Abstract 3616.
- Shahda S, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 284.