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.

Trial registration: ClinicalTrials.gov NCT01141257 https://ichgcp.net/clinical-trials-registry/NCT01141257.

Conflict of interest statement

Competing Interests: This study was sponsored by Pieris AG, the employer of HG and LPA. AS is affiliated to Stern Consult. There is a pending patent (PCT/EP2012/072406) relating to this study: "Novel uses of VEGF antagonists", inventors HG and LPA. KM and MES have received a travel grant from Pieris AG, and AS and MES have consulted for Pieris AG. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Patient disposition.

Patients who completed the single treatment and repeated weekly dosing period were specified to have completed as scheduled. aA fourth patient was enrolled by mistake. bOne patient was treated with the wrong dose of study medication. cWithdrawal of consent. dDisease progression. eThe patient erroneously treated with wrong dose of study medication was withdrawn (same patient as in footnote b). fPatient went to primary care physician for further visits. gAdverse event. N=total number of patients; n=number of patients in the subgroup.

Figure 2. Free PRS-050 drug levels are in excess of VEGF-A/PRS-050 complex concentrations.

Molar plasma concentrations of unbound PRS-050 (red, right Y-axis) and VEGF-A/PRS-050 complex (blue, left Y-axis) in patients treated with 1.5 mg/kg PRS-050 (n = 6) ±SD.

Figure 3. Changes in level of serum MMP-2 after treatment with a single dose of PRS-050.

Note that dose levels are depicted according to dosing cohort (±SE).