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

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 a...

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Autores principales: Choudhury, Atish D., Higano, Celestia S., de Bono, Johann S., Cook, Natalie, Rathkopf, Dana E., Wisinski, Kari B., Martin-Liberal, Juan, Linch, Mark, Heath, Elisabeth I., Baird, Richard D., García-Carbacho, Javier, Quintela-Fandino, Miguel, Barry, Simon T., de Bruin, Elza C., Colebrook, Steve, Hawkins, George, Klinowska, Teresa, Maroj, Brijesh, Moorthy, Ganesh, Mortimer, Peter G., Moschetta, Michele, Nikolaou, Myria, Sainsbury, Liz, Shapiro, Geoffrey I., Siu, Lillian L., Hansen, Aaron R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662946/
https://www.ncbi.nlm.nih.gov/pubmed/35247924
http://dx.doi.org/10.1158/1078-0432.CCR-21-3087
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author Choudhury, Atish D.
Higano, Celestia S.
de Bono, Johann S.
Cook, Natalie
Rathkopf, Dana E.
Wisinski, Kari B.
Martin-Liberal, Juan
Linch, Mark
Heath, Elisabeth I.
Baird, Richard D.
García-Carbacho, Javier
Quintela-Fandino, Miguel
Barry, Simon T.
de Bruin, Elza C.
Colebrook, Steve
Hawkins, George
Klinowska, Teresa
Maroj, Brijesh
Moorthy, Ganesh
Mortimer, Peter G.
Moschetta, Michele
Nikolaou, Myria
Sainsbury, Liz
Shapiro, Geoffrey I.
Siu, Lillian L.
Hansen, Aaron R.
author_facet Choudhury, Atish D.
Higano, Celestia S.
de Bono, Johann S.
Cook, Natalie
Rathkopf, Dana E.
Wisinski, Kari B.
Martin-Liberal, Juan
Linch, Mark
Heath, Elisabeth I.
Baird, Richard D.
García-Carbacho, Javier
Quintela-Fandino, Miguel
Barry, Simon T.
de Bruin, Elza C.
Colebrook, Steve
Hawkins, George
Klinowska, Teresa
Maroj, Brijesh
Moorthy, Ganesh
Mortimer, Peter G.
Moschetta, Michele
Nikolaou, Myria
Sainsbury, Liz
Shapiro, Geoffrey I.
Siu, Lillian L.
Hansen, Aaron R.
author_sort Choudhury, Atish D.
collection PubMed
description 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: (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. 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 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. 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 antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.
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spelling pubmed-96629462023-01-05 A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors Choudhury, Atish D. Higano, Celestia S. de Bono, Johann S. Cook, Natalie Rathkopf, Dana E. Wisinski, Kari B. Martin-Liberal, Juan Linch, Mark Heath, Elisabeth I. Baird, Richard D. García-Carbacho, Javier Quintela-Fandino, Miguel Barry, Simon T. de Bruin, Elza C. Colebrook, Steve Hawkins, George Klinowska, Teresa Maroj, Brijesh Moorthy, Ganesh Mortimer, Peter G. Moschetta, Michele Nikolaou, Myria Sainsbury, Liz Shapiro, Geoffrey I. Siu, Lillian L. Hansen, Aaron R. Clin Cancer Res Clinical Trials: Targeted Therapy 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: (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. 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 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. 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 antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers. American Association for Cancer Research 2022-06-01 2022-03-01 /pmc/articles/PMC9662946/ /pubmed/35247924 http://dx.doi.org/10.1158/1078-0432.CCR-21-3087 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Clinical Trials: Targeted Therapy
Choudhury, Atish D.
Higano, Celestia S.
de Bono, Johann S.
Cook, Natalie
Rathkopf, Dana E.
Wisinski, Kari B.
Martin-Liberal, Juan
Linch, Mark
Heath, Elisabeth I.
Baird, Richard D.
García-Carbacho, Javier
Quintela-Fandino, Miguel
Barry, Simon T.
de Bruin, Elza C.
Colebrook, Steve
Hawkins, George
Klinowska, Teresa
Maroj, Brijesh
Moorthy, Ganesh
Mortimer, Peter G.
Moschetta, Michele
Nikolaou, Myria
Sainsbury, Liz
Shapiro, Geoffrey I.
Siu, Lillian L.
Hansen, Aaron R.
A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
title A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
title_full A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
title_fullStr A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
title_full_unstemmed A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
title_short A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
title_sort phase i study investigating azd8186, a potent and selective inhibitor of pi3kβ/δ, in patients with advanced solid tumors
topic Clinical Trials: Targeted Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662946/
https://www.ncbi.nlm.nih.gov/pubmed/35247924
http://dx.doi.org/10.1158/1078-0432.CCR-21-3087
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