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

  • Clin Cancer Res. 2018 Apr 1;24(7):1536-1545. doi: 10.1158/1078-0432.CCR-17-1588.
Manuel Hidalgo  1  2 ,  Maria Martinez-Garcia  3 ,  Christophe Le Tourneau  4 ,  Christophe Massard  5 ,  Elena Garralda  2 ,  Valentina Boni  2 ,  Alvaro Taus  6 ,  Joan Albanell  6 ,  Marie-Paule Sablin  4 ,  Marie Alt  4 ,  Ratislav Bahleda  5 ,  Andrea Varga  5 ,  Christophe Boetsch  7 ,  Izolda Franjkovic  8 ,  Florian Heil  8 ,  Angelika Lahr  8 ,  Katharina Lechner  8 ,  Anthony Morel  7 ,  Tapan Nayak  7 ,  Simona Rossomanno  7 ,  Kevin Smart  9 ,  Kay Stubenrauch  8 ,  Oliver Krieter  8
Affiliations
  • 1. Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. [email protected] [email protected].
  • 2. START Madrid-CIOCC, HM Sanchinarro, Madrid, Spain.
  • 3. Medical Oncology Department, Hospital del Mar., Barcelona, Spain. [email protected] [email protected].
  • 4. Department of Medical Oncology, Institut Curie, Saint-Cloud and Paris, France.
  • 5. Department of Drug Development, Gustave Roussy, Villejuif, France.
  • 6. Medical Oncology Department, Hospital del Mar., Barcelona, Spain.
  • 7. Roche Innovation Center Basel, Basel, Switzerland.
  • 8. Roche Innovation Center Munich, Penzberg, Germany.
  • 9. Roche Innovation Center Welwyn, Welwyn Garden City, United Kingdom.
PMID: 29217526 DOI: 10.1158/1078-0432.CCR-17-1588
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.

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