Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 First-in-human phase I study of single-agent vanucizumab, a first-in- class bi-specific anti-angiopoietin-2/anti-VEGF antibody, in adult patients with advanced solid tumors Manuel Hidalgo1,2*; Maria Martinez Garcia3*; Christophe Le Tourneau4; Christophe Massard5; Elena Garralda2; Valentina Boni2; Alvaro Taus3; Joan Albanell3; Marie-Paule Sablin4; Marie Alt4; Ratislav Bahleda5; Andrea Varga5; Christophe Boetsch6; Izolda Franjkovic7; Florian Heil7; Angelika Lahr7; Katharina Lechner7; Anthony Morel6; Tapan Nayak6; Simona Rossomanno6; Kevin Smart8; Kay Stubenrauch7; Oliver Krieter7. *Joint first authors 1Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. 2START Madrid-CIOCC, HM Sanchinarro.3Medical Oncology Department, Hospital del Mar. Barcelona, Spain.4Department of Medical Oncology, Institut Curie, Saint-Cloud & Paris.5Department of Drug Development, Gustave Roussy, Villejuif, France.6Roche Innovation Center Basel, Basel, Switzerland.7Roche Innovation Center Munich, Penzberg, Germany.8Roche Innovation Centre Welwyn, Welwyn Garden City, United Kingdom. Running title: Phase I study of vanucizumab Keywords: Vanucizumab, RG7221, RO5520985, VEGF-A, Ang-2 Corresponding authors: 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 Manuel Hidalgo, Chief, Division Hematology Oncology, Director, Rosenberg Clinical Cancer Center, Beth Israel Deaconess Medical Center, Member of the Faculty of Medicine, Harvard Medical School, 330 Brookline Avenue - KS207, Boston, MA 02215, USA. Phone: 1 (0) 617-667-3173; Fax: 1(0) 617-667- 0130; Email: [email protected]. Maria Martinez Garcia, Medical Oncology Department, Hospital del Mar, Passeig Maritim 25-29, 08003 Barcelona, Spain. Phone: +34 93 248 3862; Email: [email protected]. Disclosure of Potential Conflicts of Interest: M.M Garcia reports receiving travel, accommodation or expenses from Amgen, Roche, and Celgene. C. Massard reports acting as an advisory board member, speaker and investigator for Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Orion, Pfizer, and Roche. J. Albanell reports receiving honoraria, and travel, accommodation or expenses from Roche and Amgen, and consulting fees from Roche, Amgen, and Pfizer. M.-P. Sablin reports receiving travel, accommodation or expenses from Boehringer. M. Alt reports receiving honoraria from Merck. C. Boetsch, A. Morel, and T. Nayak are employees and shareholders of F. Hoffman La Roche. I Franjkovic and A. Lahr are employees of Roche Diagnostics GmbH. F. Heil is an employee of Roche Diagnostics GmbH and holds stocks in Roche. K. Lechner is an employee and shareholder of Roche Diagnostics GmbH, and has an ownership interest (including patents) in Roche Diagnostics GmbH. S. Rossomanno and K. Subenrauch are employees of Roche. O. Krieter is an employee and shareholder of Roche, and has an ownership interest 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 (including patents) in Roche. K. Smart is an employee and shareholder of Roche Products Ltd. No potential conflicts of interest were disclosed by the other authors. Word count: 3370 (Clin Cancer Res word limit for original articles: 5000 words) Number of figures/tables: 3/3 (Clin Cancer Res limit: 6 in total) Supplementary materials: Methodology, 3 tables, 1 figure 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 Translational Relevance Treatment of cancer by targeting VEGF-A with bevacizumab has been extensively validated in the clinic. However, not all tumors respond to VEGF-A blockade and escape mechanisms due to overlapping and compensatory pathways can limit the full potential of antiangiogenic agents. Angiopoietin-2 (Ang-2) and VEGF-A have complementary roles in regulating tumor angiogenesis and metastasis, suggesting that dual pathway inhibition is necessary to improve treatment outcomes. Vanucizumab is an investigational, first-in-class, bi-specific IgG1-like monoclonal antibody using CrossMab technology that simultaneously blocks VEGF-A and Ang-2 from interacting with their receptors. This first-in-human study demonstrated an acceptable safety and tolerability profile for vanucizumab in patients with advanced solid tumors. A maximum tolerated dose was not reached with either vanucizumab schedule (weekly/bi-weekly) tested at the highest dose (30 mg/kg). Vanucizumab also demonstrated consistent pharmacokinetic and pharmacodynamic effects, and showed encouraging signs of anti- tumor activity that support further evaluation of vanucizumab in clinical trials. 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 Abstract 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. 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 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. 6 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/1078-0432.CCR-17-1588 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hidalgo et al. Clin Cancer Res submission 2017 Introduction Targeting angiogenesis is an attractive therapeutic approach in many cancers (1). Several inhibitors of the VEGF receptor (VEGFR) and family of ligands are approved, including the anti-VEGF-A monoclonal antibody (mAb) bevacizumab; the anti-VEGFR2 mAb ramucirumab; the dual VEGF-A/placenta growth factor (PlGF) inhibitor aflibercept; and the tyrosine kinase inhibitors sunitinib, sorafenib, pazopanib, regorafenib, and axitinib. Bevacizumab plus chemotherapy prolongs patient survival in many cancers compared with chemotherapy alone (2). However, patients who respond to VEGF/VEGFR inhibition invariably develop resistance due to activation of compensatory angiogenic signaling pathways (3). Resistance to VEGF-targeted therapies may be partly mediated by Angiopoietin-1 and 2 (Ang-1 and Ang-2), the functional ligands