1. 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.
- Author
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Hidalgo M, Martinez-Garcia M, Le Tourneau C, Massard C, Garralda E, Boni V, Taus A, Albanell J, Sablin MP, Alt M, Bahleda R, Varga A, Boetsch C, Franjkovic I, Heil F, Lahr A, Lechner K, Morel A, Nayak T, Rossomanno S, Smart K, Stubenrauch K, and Krieter O
- Subjects
- Adult, Aged, Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized, Colonic Neoplasms metabolism, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Kidney Neoplasms metabolism, Male, Maximum Tolerated Dose, Middle Aged, Neovascularization, Pathologic drug therapy, Antibodies, Monoclonal pharmacology, Colonic Neoplasms drug therapy, Kidney Neoplasms drug therapy, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vesicular Transport Proteins antagonists & inhibitors
- 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 K
TRANS (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 ., (©2017 American Association for Cancer Research.)- Published
- 2018
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