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Published on: January 7, 2019
First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with
Klaus Mross1, Heike Richly2, Richard Fischer3
1Klinik für Tumorbiologie, Albert-Ludwigs Universität, Freiburg, Germany.
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.
Trial Registration:
ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257.
Insights
PRS-050, a novel Anticalin targeting vascular endothelial growth factor A (VEGF-A), demonstrated good tolerability in a phase I trial. The recommended dose for further studies was established based on safety and pharmacokinetic data.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- PRS-050 is a novel Anticalin engineered from human tear lipocalin.
- It is designed to target and antagonize vascular endothelial growth factor A (VEGF-A).
Purpose of the Study:
- To evaluate the safety and tolerability of PRS-050 in a first-in-human phase I trial.
- To determine the recommended dose for phase II studies.
Main Methods:
- A nonrandomized, first-in-human phase I trial was conducted.
- Patients with advanced solid tumors received escalating doses of PRS-050 (0.1–10 mg/kg IV).
- The primary endpoint was safety, with pharmacokinetic and pharmacodynamic assessments.
Main Results:
- Twenty-six patients were enrolled; 25 were evaluable. The maximum tolerated dose was not reached.
- Common adverse events included chills, fatigue, hypertension, and nausea.
- PRS-050 exhibited dose-proportional pharmacokinetics and effectively engaged VEGF-A, reducing free VEGF-A levels and matrix metalloproteinase 2.
Conclusions:
- PRS-050 was well-tolerated up to 10 mg/kg.
- A dose of 5 mg/kg every 2 weeks is recommended for phase II studies based on safety, pharmacokinetic, and pharmacodynamic data.
