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First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors

Authors :
Elena Garralda
Christophe Le Tourneau
Angelika Lahr
Katharina Lechner
Christophe Massard
Valentina Boni
Christophe Boetsch
Marie-Paule Sablin
Manuel Hidalgo
Kay-Gunnar Stubenrauch
Joan Albanell
Maria Martinez-Garcia
Marie Alt
Rastilav Bahleda
Izolda Franjkovic
Tapan K. Nayak
Florian Heil
Anthony Morel
Andreea Varga
Álvaro Taus
Oliver Krieter
Simona Rossomanno
Kevin Smart
Source :
Clinical Cancer Research. 24:1536-1545
Publication Year :
2018
Publisher :
American Association for Cancer Research (AACR), 2018.

Abstract

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb 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 biweekly (3–30 mg/kg) or weekly (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 biweekly 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 weekly than biweekly dosing. A MTD 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 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Conclusions: Biweekly 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 antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536–45. ©2017 AACR.

Details

ISSN :
15573265 and 10780432
Volume :
24
Database :
OpenAIRE
Journal :
Clinical Cancer Research
Accession number :
edsair.doi.dedup.....d74d22bc32864b46916d4ffbf1b2319b
Full Text :
https://doi.org/10.1158/1078-0432.ccr-17-1588