First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors

• Published in: PloS one 2013-12, Vol.8 (12), p.e83232
• Main Authors: Mross, Klaus, Richly, Heike, Fischer, Richard, Scharr, Dirk, Büchert, Martin, Stern, Angelika, Gille, Hendrik, Audoly, Laurent P, Scheulen, Max E
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - pharmacokinetics; Antibodies; Biological products; Cancer; Chills; Clinical trials; Dose-Response Relationship, Drug; Endothelium; Fatigue; Female; Fever; Humans; Hypertension; Immunoglobulins; Infusion; Kinases; Ligands; Lipocalin; Lipocalin 1; Lipocalins - administration & dosage; Lipocalins - adverse effects; Lipocalins - pharmacokinetics; Matrix metalloproteinase; Matrix Metalloproteinase 2 - blood; Metalloproteinase; Metastasis; Middle Aged; Nausea; Neoplasms - blood; Neoplasms - drug therapy; Patients; Permeability; Pharmacodynamics; Pharmacokinetics; Pharmacology; Polyethylene glycol; Polypeptides; Product development; Proteins; Reduction (metal working); Solid tumors; Target recognition; Tearing; Time Factors; Toxicity; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - blood
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0083232

To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti-PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug's activity. PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257.