Abstract A212: First in human phase I study of PRS-050 (Angiocal), a VEGF-A targeting anticalin, in patients with advanced solid tumors: Results of a dose escalation study.
Authors: Mross K. , Fischer R. , Richly H. , Scharr D. , Buechert M. , Stern A. , Hoth D. , Gille H. , Audoly L.P. , Scheulen M.E. 
Published: June 2012

Abstract
Background: Anticalins are a new class of therapeutic small protein (20kDa) antibody mimetics based on human lipocalins which can be engineered to bind key molecules involved in tumor progression with high affinity and specificity. PRS-050 (40kDa PEGylated Anticalin) targets VEGF-A. The first clinical trial of this putative therapeutic drug is reported.
Methods: This Phase I study is a dose-escalation trial in patients with solid tumors according to the 3+3 escalation scheme investigating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of PRS-050 given via a 5–20 min iv infusion/bolus on days 1, 22, 29, 36, and 43 and in 2-weeks intervals thereafter until toxicity or tumor progression. PK was assessed after the first administration. Anti-PRS-050 antibodies and PD markers including target engagement (PRS-050:VEGF-A complex), free plasma VEGF-A, serum MMP-2 levels, and DCE-MRI were assessed repetitively. Tumor response was evaluated at day 43 according to RECIST.
Results: Twenty-six patients (pts) with progressive solid tumors were enrolled and treated with doses ranging from 0.1 to 10 mg/kg. Tumor types included CRC (46%), malignant melanoma (12%), and pancreatic cancer (8%). The median treatment duration was 43 days (min. 1, max. 251). Drug-related adverse events (AEs) of all grades reported in &gt;20% of pts were chills (46%, G3 4%), fever (23%, G3 4%), hypertension (39%, G3 12%), which were responsive to pretreatment with steroids, antipyretics, and/or H1/H2 blockers, or antihypertensive medication. DLT's include 1 G3 hypertension at 1.5mg/kg and 1 G3 infusion reaction at 10mg/kg. As a result, infusion time was increased to 2 hrs in 4 pts and there was no further infusion reaction. There was one nonfatal intestinal perforation after dose 9. Anti-PRS-050 antibodies were not detected at day 43 (21 pts) or at day 71 (16 pts). PRS-050 showed a dose-dependent increase in exposure up to 10 mg/kg with a terminal half-life of 6 days. No patient achieved an objective response (PR/CR). Stable disease was observed in 9 pts with the longest duration, to date, of 8.5 months in a patient with melanoma. Free VEGF-A levels were detectable at baseline in 8/22 pts, becoming undetectable after 15 min subsequent to the infusion of PRS-050, and remained so for 21 days. PRS-050:VEGF-A complex formation was detectable for up to 3 weeks at all dose levels (22/22 pts) including pts with no detectable free VEGF-A at baseline. Furthermore, circulating MMP-2 levels and changes in the DCE-MRI response at day 2 suggest an anti-angiogenic effect.
Conclusions: PRS-050 a small selective high affinity antibody mimetics is well-tolerated when administered with premedication as a 2 hour infusion at doses up to 10mg/kg. No formally defined MTD was reached. The recommended dose of PRS-050 for phase II is 6 mg/kg every 2 weeks, with premedication and 2 hour infusion time, based on results in preclinical xenograft models, preclinical and clinical PK/PD data of this phase I study. Most important, the drug demonstrates the intended PD effects and is ready for Phase II studies in patients with solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A212.