Αρχειοθήκη ιστολογίου

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Πέμπτη 7 Δεκεμβρίου 2017

First-in-human phase I study of single-agent vanucizumab, a first-in-class bi-specific anti-Ang-2/anti-VEGF antibody, in adult patients with advanced solid tumors

Purpose: Vanucizumab is an investigational anti-angiogenic, first-in-class, bi-specific monoclonal antibody targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating bi-weekly (q2w; 3-30 mg/kg) or weekly (qw; 10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally-located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg q2w dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related Grade ≥3 toxicities. Toxicity was generally higher with qw than q2w dosing. A maximum tolerated dose of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced-MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2000 mg q2w dose (phamacokinetically equivalent to 30 mg/kg q2w) was recommended for further investigation. Conclusion: Bi-weekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging anti-tumor activity in this heterogeneous population.



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