Abstract 5514: Pharmacokinetics of BIND-014 (docetaxel nanoparticles for injectable suspension) in preclinical species and patients with advanced solid tumors

Background: BIND-014 is a novel, prostate-specific membrane antigen (PSMA)targeted, polymeric nanoparticle-containing docetaxel (DTXL). PSMA is expressed on prostate cancer cells and on vasculature of non-prostate solid tumors. The PK profile of BIND-014 is characterized by reduced CL and V(D). These characteristics together with PSMA targeting, potentially lead to greater tumor uptake and improved activity of BIND-014 compared to conventional solvent-based DTXL (sb-DTXL). In a Phase 1 clinical trial, BIND-014 was well tolerated and displayed multiple clinical response. Methods: Preclinical PK studies were performed in tumor-bearing mice and cynomolgus monkeys. Clinical PK was measured in patients with solid tumors. BIND-014 was administered intravenously and blood samples were collected up to 96 hours post-dose. Plasma was analyzed for total and encapsulated DTXL using LC/MS-MS. PK parameters were determined by non-compartmental analysis. Results: BIND-014 preclinical and clinical PK demonstrated monophasic plasma concentration-time profiles were well differentiated from sb-DTXL. BIND-014 displayed higher Cmax and AUC with reduced CL and V(D) compared to sb-DTXL. In all species, the V(D) of BIND-014 was close to the blood volume. Evaluation of encapsulated DTXL plasma concentrations in patients and cynomolgus monkeys demonstrated means of 91% and 92% of total DTXL, respectively, indicating that most circulating DTXL was encapsulated in nanoparticles. Conclusion: BIND-014 displays a PK profile well differentiated from sb-DTXL and consistent with retention of BIND-014 nanoparticles in the blood compartment and controlled release of DTXL. In contrast, sb-DTXL displays rapid CL and a high V(D). The PK characteristics of BIND-014 are associated with increased intratumoral DTXL concentrations and tumor growth suppression in preclinical models, and may lead to greater efficacy in patients. Preclinical and clinical PK differences between BIND-014 and sb-DTXLTumor bearing mouseCynomolgus monkeysPatients with solid tumorsBIND-014sb-DTXLΔBIND-014sb-DTXLΔBIND-014sb-DTXLΔDose (mg/m2)304060C(max) (μg/mL)100.80.7713065.52.72423.81.515.3AUC(0-t) (μg•h/mL)684.72.1326431.04.1105229.22.8580.4t(½) (h)4.38.80.54.719.40.26.1180.3CL (L/h/m2)0.04414.00.0030.0929.40.010.2210.01V(D) (L/m2)53.353.30.0040.63264.40.0023.61130.03 Citation Format: Jason Summa, Daniel Von Hoff, Jasgit Sachdev, Monica Mita, Patricia LoRusso, Peter Eisenberg, Howard Burris, Lowell Hart, Hagop Youssoufian,