Phase I, pharmacokinetic, and pharmacodynamic evaluation of BNC105P, a novel anticancer agent that is both a vascular disrupting agent (VDA) and an inhibitor of cancer cell proliferation

Abstract

e14512 Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of < 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2. [Table: see text] [Table: see text]