title: First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257.
authors.affiliation: Klinik für Tumorbiologie, Albert-Ludwigs Universität, Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Richly
authors.affiliation: Department of Gastroenterology, University Medical Center, Freiburg, German.
authors.forename: Richard
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Klinik für Tumorbiologie, Albert-Ludwigs Universität, Freiburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Scharr
authors.affiliation: Magnetic Resonance Development and Application Center, University Medical Center, Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Büchert
authors.affiliation: Stern Consult, Basel, Switzerland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Stern
authors.affiliation: Pieris AG, Freising, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Gille
authors.affiliation: Pieris AG, Freising, Germany.
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Audoly
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D054835:Lipocalin 1; D054834:Lipocalins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D054835:Lipocalin 1; D054834:Lipocalins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000596016:angiocal protein; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2