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    First-in-human phase i study of MP0250, a first-in-class DARPin drug candidate targeting VEGF and HGF, in patients with advanced solid tumors

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    Authors
    Baird, R. D.
    Linossi, C.
    Middleton, M.
    Lord, S.
    Harris, A.
    Rodón, J.
    Zitt, C.
    Fiedler, U.
    Dawson, K. M.
    Leupin, N.
    Stumpp, M. T.
    Harstrick, A.
    Azaro, A.
    Fischer, Stefanie C
    Omlin, A.
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    Affiliation
    University of Cambridge, Cambridge, United Kingdom.
    Issue Date
    2020
    
    Metadata
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    Abstract
    Purpose: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. Patients and methods: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. Results: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. Conclusion: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.
    Citation
    Baird RD, Linossi C, Middleton M, Lord S, Harris A, Rodon J, et al. First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors. J Clin Oncol. 2020:JCO2000596.
    Journal
    Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/623660
    DOI
    10.1200/jco.20.00596
    PubMed ID
    33301375
    Additional Links
    https://dx.doi.org/10.1200/jco.20.00596
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1200/jco.20.00596
    Scopus Count
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    All Paterson Institute for Cancer Research

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