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A Phase 1, First-In-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, 2 in Patients with Advanced Solid Tumors

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A Phase 1, First-In-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, 2 in Patients with Advanced Solid Tumors Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 A Phase 1, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, 2 in Patients With Advanced Solid Tumors 3 Afshin Dowlati,1 Gordana Vlahovic,2 Ronald Natale,3 Erik Rasmussen,4 Indrajeet Singh,4 4 Yuying C. Hwang,4,* John Rossi,4,* Michael B. Bass,4,* Gregory Friberg,4 Cheryl A. 5 Pickett4 6 1Case Western Reserve University and University Hospitals Seidman Cancer Center, 7 Cleveland, OH, USA; 2Duke University Medical Center, Durham, NC, USA; 3Cedars 8 Sinai Medical Center, Los Angeles, CA, USA; 4Amgen Inc., Thousand Oaks, CA, USA 9 *Affiliation at the time the research was conducted 10 Running title: AMG 780 in Patients With Advanced Solid Tumors 11 Keywords: angiogenesis, angiopoietin axis, targeted therapy, Tie2 12 receptor, dose escalation 13 Financial support: This study was supported by Amgen Inc. 14 Address correspondence to: Afshin Dowlati, UH Case Medical Center, Department of 15 Medicine—Hematology and Oncology; 11100 Euclid 16 Avenue, Cleveland, OH 44106; Phone: +1-216-844-1228; 17 Fax: +1-216-844-5234; Email: 18 [email protected] 19 Conflicts of interest: Erik Rasmussen, Indrajeet Singh, Gregory Friberg, and 20 Cheryl A. Pickett are employees of and stockholders in 21 Amgen Inc. Yuying C. Hwang, John Rossi, and Michael B. 22 Bass were employees of and stockholders in Amgen Inc. at 23 the time this research was conducted. Afshin Dowlati, 24 Gordana Vlahovic, and Ronald Natale have no conflicts to 25 declare. 26 Previous presentation: The results of this study have not been previously published 27 or submitted for publication elsewhere. The results were 28 presented in part as a poster at the American Society of 1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 Clinical Oncology 50th Annual Meeting, Chicago, IL, May 30 2 to June 3, 2014. 3 Target journal: Clinical Cancer Research 4 Word count: 4071/5000 5 Figures/tables: 3/3 6 Clinical trial registration: ClinicalTrials.gov, NCT01137552 7 2 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 Abstract 2 Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, 3 and pharmacodynamics of AMG 780, a monoclonal antibody designed to inhibit the interaction 4 between angiopoietin-1 and -2 and the Tie2 receptor. 5 Experimental Design: This was a phase 1 dose-escalation study of patients with advanced 6 solid tumors refractory to standard treatment without previous antiangiogenic treatment. 7 AMG 780 was administered by intravenous infusion every 2 weeks (Q2W) in doses from 0.1 to 8 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse 9 events (AEs), and pharmacokinetics. Secondary endpoints included tumor response, changes 10 in tumor volume and vascularity, and anti–AMG 780 antibody formation. 11 Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs 12 (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no maximum- 13 tolerated dose was reached. Pharmacokinetics of AMG 780 were dose proportional; median 14 terminal elimination half-life was 8 to 13 days. No anti−AMG 780 antibodies were detected. At 15 week 5, 6/16 evaluable patients had a >20% decrease in volume transfer constant (Ktrans), 16 suggesting reduced capillary blood flow/permeability. The most frequent AEs were 17 hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue 18 (27%). Among 35 evaluable patients, none had an objective response; eight achieved stable 19 disease. 20 Conclusions: AMG 780 could be administered at doses up to 30 mg/kg Q2W in patients with 21 advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. 22 AEs were in line with toxicity associated with antiangiopoietin treatment. 3 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 Abstract word count: 250 (limit, 250) 2 4 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 Statement of translational relevance 2 Inhibition of angiogenesis can slow tumor growth and improve outcomes for patients with 3 metastatic disease. The angiopoietin axis plays an important role in angiogenesis and is distinct 4 from currently approved angiogenesis inhibitors which target the vascular endothelial growth 5 factor (VEGF) pathway. Several investigational drugs that target the angiopoietin axis are 6 currently in clinical trials. AMG 780 is a monoclonal antibody that binds to angiopoietin-1 and -2 7 (Ang1 and Ang2), preventing their binding to the Tie2 receptor to suppress angiogenesis. In 8 this phase 1 first-in-human study in patients with advanced cancer, AMG 780 was administered 9 once every 2 weeks at doses up to 30 mg/kg, with median terminal elimination half-life ranging 10 from 8 to 13 days and evidence of reduced capillary blood flow. No maximum-tolerated dose 11 was reached. Dosing once every 2 weeks supports both patient convenience and combination 12 with other anticancer regimens. 13 Word count: 142 (limit, 150) 14 5 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 Introduction 2 Angiogenesis, the process of new blood vessel formation, is required for tumor growth 3 and metastatic spread and is regulated by a number of different pathways (1). Vascular 4 endothelial growth factor (VEGF) pathway family members play a critical role in angiogenesis by 5 stimulating proliferation, migration, and survival of endothelial cells (2). The angiopoietin axis is 6 a distinct angiogenic pathway that activates complementary angiogenic processes through 7 binding of the ligands angiopoietin-1 and -2 (Ang1 and Ang2) to the tyrosine kinase receptor 8 Tie2 (1). Ang1 is primarily involved in the maturation and stabilization of blood vessels, 9 whereas Ang2 contributes to vascular remodeling and new vessel sprouting (3-5). Many tumor 10 cells overexpress Ang1, and transcription of Ang2 is significantly upregulated in tumor- 11 associated endothelium (3). Studies have also identified increased levels of Ang2 in the tumor 12 vasculature across various types of tumors; these elevations have been associated with disease 13 progression and poor prognosis (6-9). 14 Inhibition of angiogenesis has been shown to improve outcomes in clinical studies. A 15 number of VEGF pathway inhibitors have been shown to be effective in the treatment of a 16 variety of solid tumor types (10-15). Inhibition of the angiopoietin pathway has been shown to 17 result in tumor growth inhibition in preclinical models, with simultaneous inhibition of Ang1 and 18 Ang2 resulting in greater tumor growth suppression compared with targeting either ligand in 19 isolation (16,17). In early phase clinical studies, treatment with trebananib (AMG 386), a 20 peptibody that inhibits the interaction between Ang1 and Ang2 and the Tie2 receptor (18), 21 showed anticancer activity, reducing tumor size and inducing objective responses in some 22 patients (19-23). In a randomized, double-blind, phase 3 clinical study, trebananib plus weekly 23 paclitaxel prolonged progression-free survival of patients with recurrent ovarian cancer 24 compared with placebo plus paclitaxel (7.2 versus 5.4 months; hazard ratio [HR], 0.66, 95% CI, 6 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. AMG 780 in Patients With Advanced Solid Tumors 1 0.57–0.77, P<0.0001) (24). Adverse events (AEs) occurring with greater frequency in the 2 trebananib group included edema, ascites, pleural effusion, and blurred vision (24). 3 AMG 780 is an investigational, intravenously administered fully human monoclonal 4 immunoglobulin G2 antibody that, like trebananib, binds to Ang1 and Ang2, thereby preventing 5 their interaction with the Tie2 receptor. In mice bearing Colo205 human colorectal cancer 6 xenografts, twice weekly administration of AMG 780 significantly inhibited tumor growth (66%), 7 viable tumor fraction (81%), and tumor endothelial cell proliferation (84%) compared with a 8 control antibody (25). The inhibitory activities of AMG 780 (IC50 [nM]: Ang1, 4.5; Ang2, 0.06) 9 were similar to those of trebananib (IC50 [nM]: Ang1, 3.5; Ang2, 0.03) (25).
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