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    A phase I study investigating AZD8186, a potent and selective inhibitor of PI3Kβ/δ, in patients with advanced solid tumors

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    Authors
    Choudhury, A. D.
    Higano, C. S.
    de Bono, J. S.
    Cook, Natalie
    Rathkopf, D. E.
    Wisinski, K. B.
    Martin-Liberal, J.
    Linch, M.
    Heath, E. I.
    Baird, R. D.
    Garcia-Corbacho, J.
    Quintela-Fandino, M.
    Barry, S. T.
    de Bruin, E. C.
    Colebrook, S.
    Hawkins, G.
    Klinowska, T.
    Maroj, B.
    Moorthy, G.
    Mortimer, P. G.
    Moschetta, M.
    Nikolaou, M.
    Sainsbury, L.
    Shapiro, G. I.
    Siu, L. L.
    Hansen, A. R.
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    Affiliation
    Dana-Farber Cancer Institute, Boston, MA, United States. University of Washington, United States. Institute of Cancer Research, Sutton, United Kingdom. Christie NHS Foundation Trust and the University of Manchester, Manchester, United Kingdom. Memorial Sloan Kettering Cancer Center, New York, New York, United States. University of Wisconsin Carbone Cancer Center, Madison, Wi, United States. Catalan Institute of Oncology (ICO) Hospitalet, Barcelona, Spain. University College London Cancer Institute, London, United Kingdom. Karmanos Cancer Center, Detroit, MI, United States. Cancer Research UK Cambridge Centre, Cambridge, United Kingdom. Hospital Clinic Barcelona / IDIBAPs, Barcelona, Cataluña, Spain. Spanish National Cancer Research Centre, Madrid, Madrid, Spain. AstraZeneca (United Kingdom), Cambridge, United Kingdom. AstraZeneca (Australia), Cambridge, United Kingdom. AstraZeneca (United States), Waltham, United States. AstraZeneca (United Kingdom), Boston, MA, United Kingdom. Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. Princess Margaret Hospital, Toronto, ON, Canada.
    Issue Date
    2022
    
    Metadata
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    Abstract
    Purpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients and methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non-small-cell lung cancer. The study comprised four arms: 1) AZD8186 monotherapy dose-finding; 2) monotherapy dose-expansion; 3) AZD8186/abiraterone acetate (with prednisone); and 4) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics, pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60 mg twice daily (BID; 5 days on, 2 days off [5:2]) and 120 mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The pharmacokinetics of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited anti-tumor activity by imaging and, in prostate cancer, PSA reduction. Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of anti-tumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kb-pathway-dependent cancers.
    Citation
    Choudhury AD, Higano CS, de Bono JS, Cook N, Rathkopf DE, Wisinski KB, et al. A phase I study investigating AZD8186, a potent and selective inhibitor of PI3Kβ/δ, in patients with advanced solid tumors. Clin Cancer Res. 2022.
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/625120
    DOI
    10.1158/1078-0432.Ccr-21-3087
    PubMed ID
    35247924
    Additional Links
    https://dx.doi.org/10.1158/1078-0432.Ccr-21-3087
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.Ccr-21-3087
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