Abstract
To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m(2)). The recommended dose level was 16 mg/m(2) and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m(2) and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced.
Highlights
Vascular disruption agents (VDA) cause a rapid occlusion of tumor vasculature, leading to hypoxic stress within the tumor and induction of cell death
Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours
Active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin being observed in peripheral blood mononuclear cells (PBMCs)
Summary
Vascular disruption agents (VDA) cause a rapid occlusion of tumor vasculature, leading to hypoxic stress within the tumor and induction of cell death. Their selective action on tumor vasculature endothelium distinguishes them from other vaso-active agents such as the antiangiogenics. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). There are at least 12 compounds that have been evaluated in the clinic. These agents can be grouped into 2 broad classes: the flavonoids (such as ASA404) and the tubulin-binding agents [2, 3]
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