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

Jason Lickliter, Alessandra Francesconi, Gregg Smith, Matthew Burge, Alan Coulthard, Stephen Rose, Mark Griffin, Robert Milne, Jennifer McCarron, Trina Yeadon, Andrew Frederick Wilks, Annette Cubitt, David Wyld, Paul Vasey

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25 Citations (Scopus)

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 K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=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.
Original languageEnglish
Pages (from-to)597 - 606
Number of pages10
JournalBritish Journal of Cancer
Volume103
Issue number5
DOIs
Publication statusPublished - 2010

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