Abstract LB-452: A phase I, open label, safety, pharmacokinetic and pharmacodynamic dose escalation study of BIND-014 given by IV infusion to patients with advanced or metastatic cancer
Authors: Summa Jason , LoRusso Patricia M. , Eisenberg Peter , Hrkach Jeff , Schnipper Ed , Hoff Daniel Von 
Published: August 2012

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 most non-prostate solid tumors. In preclinical studies, BIND-014 exhibited pharmacological properties substantially differentiated from conventional solvent based docetaxel (sb-DTXL, Taxotere), including enhanced tumor accumulation and tumor growth suppression in murine xenograft models, and PK characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL. This Phase 1 study was designed to evaluate the safety, PK and PD of ascending doses of BIND-014 in patients with advanced or metastatic cancer. Methods: BIND-014 was administered once every three weeks by 1-hour intravenous infusion. Main eligibility criteria: ≥18 years old; advanced or metastatic cancer for which no standard or curative therapy exists; measurable or evaluable disease per RECIST version 1.1.; ECOG performance status 0 or 1; life expectancy &gt; 12 weeks. Starting dose was 3.5 mg/m2. Preliminary Results: To date, doses of 3.5, 7.5, 15, 30, 60 and 75 mg/m2 have been evaluated in 17 pts (7 female/10 male; median age 62 yo). Transient grade 4 neutropenia was observed in 2/7 pts at 60 mg/m2 and 2/3 pts at 75 mg/m2. No febrile neutropenia was observed. Non-hematological toxicities were mild to moderate in severity and were well-managed. Further evaluation of BIND-014 is ongoing. PK based on measurement of total (encapsulated and released) DTXL is distinct from sb-DTXL, dose proportional at all doses studied, and consistent with retention of NPs in the plasma compartment and controlled release of DTXL. Mean CL is 0.3 L/h/m2, Vss is 3.6 L/m2, and t1/2 is 6 h. SD following ≥ 2 cycles of therapy was observed in 1 pt with cholangiocarcinoma at 15 mg/m2, 1 pt with tonsillar cancer at 30 mg/m2, 1 pt with colorectal cancer at 60 mg/m2, 1 pt with anal cancer at 60 mg/m2 (durable response with 9 cy) and 1 pt with pancreatic cancer at 75 mg/m2 and reduced to 60 mg/m2 at cy 2. A confirmed PR by RECIST was observed during cy 1 in a pt with cervical cancer dosed at 75 mg/m2. Preliminary Conclusions: BIND-014 is generally well-tolerated. PK is substantially differentiated from sb-DTXL and preliminary evidence of anti-tumor activity has been observed at low DTLX doses and in tumors in which sb-DTXL has minimal activity. The Phase 1 study is ongoing. The current data support further evaluation in Phase 2 clinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-452. doi:1538-7445.AM2012-LB-452