Evaluation of a nonbiologic nanoparticle form of paclitaxel in metastatic pancreatic cancer.

Abstract

e15076 Background: The (nab-Pac)/Gemcitabine (Gem) combination has recently been shown to impart a significant survival advantage over Gem alone in patients with metastatic pancreatic cancer. The goal of this study was to define a non-biologic, nanoparticle paclitaxel (NBN-Pac) which has a similar toxicity profile and utilizes the same albumin-mediated transport mechanism. Herein, we report in vitro, preclinical and phase I clinical results for this NBN-Pac in metastatic pancreatic cancer. Methods: In vitro drug cytotoxicity was measured as mean IC50 values following a 72-h exposure in four pancreatic cell lines (MIA Paca-2 and Capan-1 and multi-drug resistant cell lines PANC-1 and ASPC-1). In vivo anti-tumor activities were assessed in xenografted MIA PaCa-2 and PANC-1 models in nude mice treated with three i.v. doses of NBN-Pac (20, 50 mg/kg) and Taxol (20 mg/kg) on days 0, 3, and 6 (q3dx3), and twelve i.v. doses of Gem (140 mg/kg) on every 3 days (q3dx12). A phase I clinical trial (N=18) was conducted to determine the MTD and the recommended phase II dose of the combination therapy with NBN-Pac (220-300 mg/m2, q3w) and Gem (1250 mg/m2) as primary endpoints in first line treatment of subjects with advanced pancreatic cancer. Reduction in the plasma levels of CA19-9 was measured as a PD biomarker. Results: The mean IC50 value of NBN-Pac in four pancreatic cell lines was approximately 30-fold lower than that of Gem. NBN-Pac formulation (50 mg/kg) produced superior anti-tumor activity in the two xenograft models tested over Taxol and Gem at clinically equivalent doses. Our phase I trial established the MTD of this NBN-Pac formulation as 300mg/m2. Moreover, 5 out of 16 subjects (31.3%) were CR or PR with 95% exact confidence interval of (11.0%, 58.7%). The median PFS time was 5.6 month (95% C.I = 2.9). The median OS time could not be estimated as the survival rate did not fall below 50%. Other safety variables revealed no significant abnormality that may have affected the result of the study. Conclusions: NBN-Paclitaxel formulation has superior anti-tumor activity vs. Taxol and Gem in in vitro toxicity assays, preclinical models of pancreatic cancer, as well in a phase I clinical study in patients with advanced pancreatic cancer.