Phase I evaluation of CYT997, a novel cytotoxic and vascular-disrupting agent, in patients with advanced cancer

Abstract

3504 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. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytopia Research Pty Ltd Cytopia Research Pty Ltd Cytopia Research Pty Ltd Cytopia Research