Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

Abstract

Background:CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity.Methods:This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours.Results:Thirty-one patients received CYT997 over 12 dose levels (7–358 mg m−2). Doses up to 202 mg m−2 were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m−2, consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour Ktrans values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of ⩾65 mg m−2. Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles.Conclusions:CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

“…Vascular disrupting agents are a related, but separate, class of compounds that disrupt the existing vasculature in tumors, and promising data have been reported from clinical trials of the more advanced compounds in this class (Anderson et al, 2003;Hande et al, 2006). CYT997 is a structurally novel, orally active VDA discovered in our laboratories (Burns et al, 2009b), which has successfully completed two phase I clinical trials (Francesconi et al, 2009;Lickliter et al, 2010). Preliminary antivascular activity of the compound has been reported (Burns et al, 2009a), and in this article we have described further studies to better understand the vascular disrupting effects of the compound with particular regard to dose and functional activity in in vivo tumor models.…”

Clinical, Pharmacodynamic, and Pharmacokinetic Evaluation of BNC105P: A Phase I Trial of a Novel Vascular Disrupting Agent and Inhibitor of Cancer Cell Proliferation

“…The search continues for validated biomarkers within this compound class. Cell adhesion molecules, von Willebrand factor, and circulating endothelial cells have all been evaluated (10,16,17). Quantitation of polymerized tubulin from PBMCs represents another option for the assessment of PD effect.…”

A perspective on vascular disrupting agents that interact with tubulin: preclinical tumor imaging and biological assessment

“…In many cases simple DCE used small paramagnetic contrast agents, but in other cases larger materials designed to be retained in the vasculature such as macromolecular contrast agent albumin-gadolinium diethylenetriaminepentaacetate (albumin-GdDTPA)136 or SPIOS were used. Diverse tumors have been examined for research in animals (mice and rats) and as part of clinical trials in patients 135. Several investigators have taken the opportunity to use MRI to compare the efficacy of different VDAs 124,137,138.…”

“…A compilation of VDAs currently in human clinical trials that function, in part, through a tubulin mechanism include: CA4P11-13, AVE806214, CA1P15-17, MPC-682718, ABT-75119, TZT-102720, CYT99721,22, MN-02923, NPI-235824, BNC105P25, EPC240726-28, CKD-51629.…”