Abstract
The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity.
Highlights
Vascular disrupting agents (VDA) show varying degrees of success in the clinical setting
Prior presentation: Interim results of this study have been published in part in ref. [8], and at the 100th Annual Meeting of the American Association of Cancer Research, 2009; the 45th Annual Meeting of the American Society of Clinical Oncology, 2009; 7th International Symposium on Targeted Anticancer Therapies 2009; and 10th International Symposium on Targeted Anticancer Therapies 2012
The current study describes the first clinical evaluation of this combretastatin analog when administered as monotherapy in patients with advanced solid tumors
Summary
Vascular disrupting agents (VDA) show varying degrees of success in the clinical setting. Ombrabulin (AVE8062, AC7700) is an analog of the water-soluble VDA combretastatin A4 phosphate (CA4P). These drugs act by disrupting the architecture of established tumor blood vessels following binding to the colchicine site of tubulin, inhibiting polymerization, and resulting in reorganization of the cytoskeleton and changes in cell shape [1, 2]. Restriction of tumor blood perfusion and decreased interstitial fluid pressure occur rapidly; in mice this has been reported as early as 15 minutes after ombrabulin infusion, peaking after 6 hours with permanent widespread tumor necrosis after 24 hours [5]. As with other VDAs, perfusion changes seen in normal tissues were largely reversible [6], Phase I Pharmacokinetic/Pharmacodynamic of the Vascular Disrupting Agent Ombrabulin
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