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

Abstract

Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.Experimental Design: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation.Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (K trans ), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease.Conclusions: AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment.

A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors

“…With the caveat of limitations of cross-trial comparisons, these data are similar to findings reported in clinical trials of other inhibitors of Ang1 and Ang2, where fatigue and peripheral edema were also the most common clinical toxicities (25,26). With the exception of fatigue, there were no obvious dose-related patterns in the occurrence or severity of treatment-related AEs.…”

“…Apart from the caveat of cross-trial comparisons, a mechanistic explanation of selective inhibition of Ang2 without Ang1 inhibition may account for the lack of proteinuria seen with nesvacumab (29)(30)(31), unlike the proteinuria grade ! 3 reported with the Ang1/Ang2 inhibitors trebananib and AMG780 (25,26), Except for one patient with vena cava thrombosis, occurring in the context of progressive retroperitoneal disease, there were no other thrombotic events. Reversible CNS abnormalities seen on MRI in 3 patients were atypical in their clinical and radiologic appearance from those seen with other antiangiogenic agents (32,33).…”

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

“…High blood pressure appeared to be dose dependent and predominantly driven by the systemic vanucizumab-mediated VEGF-A inhibition. Across clinical studies, the frequency of G3/4 hypertension is 9%-32% with bevacizumab monotherapy (21)(22)(23)(24)(25) but 6% for single-agent Ang-1/2 antagonists (26)(27)(28)(29)(30)(31)(32)(33). Moreover, hypertension rates with bevacizumab treatment did not increase by concurrent inhibition of the Ang/ Tie-2 signaling pathway in patients with metastatic breast cancer [39%-40% (G!3: 18%-23%) compared with 38% (G!3: 19%) without concurrent Ang/Tie-2 inhibition; ref.…”

“…Altered glomerular permeability with leakage of large proteins into the urine appears to be a direct result of VEGF-A and Ang-2 inhibition. Proteinuria is a common side effect of bevacizumab with an overall incidence (all grades) of 20% (37) and has been reported in 14% of patients treated with agents targeting the Ang/Tie2 pathway (28). Simultaneous inhibition of VEGF-A and Ang-2 with vanucizumab did not increase the rate or grade of proteinuria.…”

“…Simultaneous inhibition of VEGF-A and Ang-2 with vanucizumab did not increase the rate or grade of proteinuria. Although the exact mechanism by which edema might occur is unclear, dual, nonselective Ang-1 and Ang-2 inhibition frequently induces edema formation in up to 30% of patients (27,28). In preclinical models, Ang-1 acts as an antipermeability factor and protects adult vessels from leaking (38).…”