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A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors.

Authors
  • Choudhury, Atish D1
  • Higano, Celestia S2
  • de Bono, Johann S3
  • Cook, Natalie4
  • Rathkopf, Dana E5
  • Wisinski, Kari B6
  • Martin-Liberal, Juan7
  • Linch, Mark8
  • Heath, Elisabeth I9
  • Baird, Richard D10
  • García-Carbacho, Javier11
  • Quintela-Fandino, Miguel12
  • Barry, Simon T13
  • de Bruin, Elza C13
  • Colebrook, Steve13
  • Hawkins, George13
  • Klinowska, Teresa13
  • Maroj, Brijesh13
  • Moorthy, Ganesh14
  • Mortimer, Peter G13
  • And 6 more
  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Department of Medical Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 3 Drug Development Unit, The Institute of Cancer Research and Royal Marsden, London, United Kingdom. , (United Kingdom)
  • 4 The Christie NHS Foundation Trust and The University of Manchester, Manchester, United Kingdom. , (United Kingdom)
  • 5 Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, New York.
  • 6 Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
  • 7 Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain. , (Spain)
  • 8 University College London (UCL) Cancer Institute and UCL Hospital, London, United Kingdom. , (United Kingdom)
  • 9 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
  • 10 Cancer Research UK Cambridge Center, Cambridge, United Kingdom. , (United Kingdom)
  • 11 Department of Medical Oncology (Hospital Clinic Barcelona)/Translational Genomics and Targeted Therapies in Solid Tumors (IDIBAPS), Barcelona, Spain. , (Spain)
  • 12 Hospital Universitario, Quiron Madrid, Madrid, Spain. , (Spain)
  • 13 Oncology R&D, AstraZeneca, Cambridge, United Kingdom. , (United Kingdom)
  • 14 Clinical Pharmacology & Quantitative Pharmacology (CPQP), Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, Massachusetts.
  • 15 Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. , (Canada)
  • 16 Department of Medicine, University of Toronto, Toronto, Ontario, Canada. , (Canada)
Type
Published Article
Journal
Clinical Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jun 01, 2022
Volume
28
Issue
11
Pages
2257–2269
Identifiers
DOI: 10.1158/1078-0432.CCR-21-3087
PMID: 35247924
Source
Medline
Language
English
License
Unknown

Abstract

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. 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: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. 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 PKs 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 antitumor activity by imaging and, in prostate cancer, PSA reduction. 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 antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway-dependent cancers. ©2022 The Authors; Published by the American Association for Cancer Research.

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