Abstract LB-203: A phase I study of BIND-014, a PSMA-targeted nanoparticle containing docetaxel, in patients with refractory solid tumors.
Authors: Von Hoff Daniel D. , Mita Monica , Eisenberg Peter , LoRusso Patricia , Weiss Glen , Sachdev Jasgit , Mita Alain , Low Susan , Hrkach Jeff , Summa Jason , Berk Gregory , Ramanathan Ramesh 
Published: August 2014

Abstract
Background: BIND-014 is a novel, targeted, polymeric nanoparticle (NP) containing docetaxel (DTXL). BIND-014 is targeted to prostate-specific membrane antigen (PSMA), a tumor antigen expressed on prostate cancer cells and on the neovasculature of many non-prostate solid tumors. In preclinical studies, BIND-014 exhibited pharmacological properties substantially different from docetaxel (Taxotere®), including enhanced tumor accumulation and tumor growth suppression in murine xenograft models, and pharmacokinetics (PK) characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL. This phase I study evaluates the safety, tolerability, maximum tolerated dose (MTD), and PK of BIND-014 administered once every 21 days.
Methods: Patients (pts) with advanced solid tumors, adequate organ function and ECOG 0-1 were enrolled. BIND-014 was administered on day 1 of a 21-day cycle (Q3W). Single patient (pt) cohorts were enrolled until grade (gr) 2 toxicity was observed, then adjusted to standard 3x3 design. Doses from 3.5-75 mg/m2 were evaluated. Plasma samples were collected for BIND-014 PK analysis.
Results: Thirty pts were enrolled, 28 were evaluable for toxicity, and 2 were replaced due to disease progression in cycle 1. Demographics: 16M/14F; median age 62 yrs (range 29 to 82). Prior lines of chemotherapy: median 3 (range 0 to 8). Tumor types: non-small cell lung (NSCLC, 6); hepatobiliary (HB, 5); head and neck (H&N, 3); prostate (CRPC, 2); and other solid tumors (14). BIND-014 demonstrates dose-linear PK that is differentiated from docetaxel and characterized by prolonged circulation. Dose limiting toxicities of gr 3 fatigue in 1 pt and gr 4 neutropenia lasting 5 days in 1 pt occurred at 75 mg/m2; MTD on this schedule and in this patient population was determined to be 60 mg/m2. The most common drug-related toxicities included gr 1-4 neutropenia, gr 1-2 alopecia, gr 1-2 anemia, gr 1-2 diarrhea, gr 1-2 dehydration, gr 1-2 fatigue, and gr 1-2 vomiting. All observed toxicities were docetaxel-associated, and several common docetaxel toxicities were mild or absent including nail changes, neuropathy, and mucositis. Confirmed partial responses were observed in 3 pts (cervix, NSCLC, HB). Stable disease lasting &gt; 4 cycles was observed in 5 pts, including CRPC (1), HB (1), pancreatic (1), H&N (1), and anal (1).
Conclusions: BIND-014 was well tolerated with predictable and manageable toxicity. The MTD on the Q3W schedule was 60 mg/m2. The PK profile of BIND-014 is differentiated from docetaxel. Activity is noted in multiple tumors including cervical, HB, NSCLC and CRPC. Final phase I data will be presented. Phase II trials with BIND-014 have been initiated.
Citation Format: Daniel D. Von Hoff, Monica Mita, Peter Eisenberg, Patricia LoRusso, Glen Weiss, Jasgit Sachdev, Alain Mita, Susan Low, Jeff Hrkach, Jason Summa, Gregory Berk, Ramesh Ramanathan. A phase I study of BIND-014, a PSMA-targeted nanoparticle containing docetaxel, in patients with refractory solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2013-LB-203