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.

  1. Hubbard JM, et al. ASCO 2015. Abstract 3616.
  2. Shahda S, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 284.