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Sub-category:
Vascular Targeting
Category:
Developmental Therapeutics: Molecular Therapeutics
Meeting:
2008 ASCO Annual Meeting
Session Type and Session Title:
Clinical Science Symposium, Novel Antiangiogenic Mechanisms
Abstract No:
3504
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 3504)
Author(s):
J. Lickliter, A. Francesconi, G. Smith, M. Burge, A. Coulthard, S. Rose, M. Griffin, A. Wilks, D. Wyld, P. Vasey
Abstract:
Background: CYT997 binds α-tubulin, inhibits microtubule assembly and demonstrates potent anti-tumour and vascular- disrupting activity in preclinical models. A phase I dose-finding study in patients with advanced cancer has now been completed. Methods: CYT997 was administered by continuous IV infusion over 24 hours, with doses repeated every 3 weeks. Doses were escalated using a standard phase I design (3 patients per dose level) for patients 1-18; subsequently, an accelerated titration design was used. Pharmacodynamic effects on tumour vasculature were assessed with DCE-MRI scans, circulating endothelial cell (CEC) assays and von Willebrand factor (vWF) plasma levels. Results: 31 patients (M/F: 15/16; median age 57, range 21-75) were treated on study. A total of 99 cycles of CYT997 were administered (median 2/patient, range 1-6) over 12 dose levels (7 - 358 mg/m2). Doses up to 202 mg/m2 were well tolerated. However, dose-limiting toxicities were observed at 269 and 358 mg/m2, consisting of grade-3 prolonged QTc interval (n=2) and grade-4 dyspnea in a patient with a history of thoracic radiation. All toxicities were reversible. PK profiles revealed dose-dependent linear increases in Cmax and AUC values. vWF-antigen plasma levels increased significantly following CYT997 doses of 202 mg/m2 and above (mean 136% of baseline, standard deviation 23%), whereas no increase was observed at lower dose levels (p<.00001). In addition, a marked increase in CD146+ CD31+ 7-AADdim apoptotic CECs was observed in one patient at the highest dose level. DCE-MRI assessments (including histogram analyses) were evaluable in 11 patients who received > 65 mg/m2 of CYT997. Statistically-significant changes in tumour Ktrans values consistent with vascular disruption were observed in 7 of these patients. No objective responses were seen among 22 evaluable patients; however, 17 patients had stable disease for a median of 4 cycles (range 2-6). Conclusions: CYT997 was well tolerated at doses associated with vascular targeting activity. The recommended dose for phase II evaluation is 202 mg/m2.
Abstract Disclosures
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