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
Mené sur 47 patients atteints d'une tumeur solide de stade avancé et réfractaire aux traitements existants, cet essai de phase I évalue la dose maximale tolérée et l'activité clinique du nesvacumab, un anticorps monoclonal anti Ang2
Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) of nesvacumab. Experimental Design: Nesvacumab was administered intravenously every two weeks (Q2W) with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors. Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite and diarrhea (each 10.6%) (all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in alpha-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration. Conclusion: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. Based on cumulative safety, antitumor activity, PK and PD data, the 20 mg/kg dose was determined to be the RP2D.