American Association for Cancer Research
10780432ccr171588-sup-184271_2_supp_4383881_pz71fp.docx (810.82 kB)

Supplementary Methods, Supplementary References, Supplementary Figure 1, Supplementary Tables 1-3 from 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

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posted on 2023-03-31, 19:49 authored by Manuel Hidalgo, Maria Martinez-Garcia, Christophe Le Tourneau, Christophe Massard, Elena Garralda, Valentina Boni, Alvaro Taus, Joan Albanell, Marie-Paule Sablin, Marie Alt, Ratislav Bahleda, Andrea Varga, Christophe Boetsch, Izolda Franjkovic, Florian Heil, Angelika Lahr, Katharina Lechner, Anthony Morel, Tapan Nayak, Simona Rossomanno, Kevin Smart, Kay Stubenrauch, Oliver Krieter

Supplementary Table S1. Criteria for defining dose-limiting toxicities; Supplementary Table S2. Plasma pharmacokinetic parameters of vanucizumab on Cycles 1 and 4 following bi-weekly administration of ascending doses of vanucizumab; Supplementary Table S3. Plasma pharmacokinetic parameters of vanucizumab on Cycles 1 and 4 following weekly administration of ascending doses of vanucizumab.


F. Hoffmann-La Roche Ltd



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.

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