A phase I study investigating AZD8186, a potent and selective inhibitor of PI3Kβ/δ, in patients with advanced solid tumors Journal Article
| Authors: | Choudhury, A. D.; Higano, C. S.; de Bono, J. S.; Cook, N.; Rathkopf, D. E.; Wisinski, K. B.; Martin-Liberal, J.; Linch, M.; Heath, E. I.; Baird, R. D.; García-Carbacho, 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. |
| Article Title: | A phase I study investigating AZD8186, a potent and selective inhibitor of PI3Kβ/δ, in patients with advanced solid tumors |
| 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: (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. © 2022 The Authors; Published by the American Association for Cancer Research |
| Keywords: | adult; controlled study; treatment response; aged; unclassified drug; major clinical study; prednisone; clinical trial; drug tolerability; fatigue; advanced cancer; diarrhea; drug safety; hypophosphatemia; side effect; antineoplastic agent; prostate specific antigen; enzyme inhibition; anemia; nausea; vomiting; antineoplastic combined chemotherapy protocols; carcinoma, non-small-cell lung; lung neoplasms; drug dose escalation; pneumonia; prostate-specific antigen; prostatic neoplasms; lung tumor; alanine aminotransferase; aspartate aminotransferase; cause of death; hypokalemia; maculopapular rash; population research; dosage schedule comparison; multicenter study; prostate tumor; chromones; sepsis; colitis; drug blood level; phase 1 clinical trial; aniline compounds; abiraterone acetate; drug half life; platelet count; drug elimination; phosphatidylinositol 3 kinase inhibitor; non small cell lung cancer; triple negative breast cancer; aniline derivative; chromone derivative; humans; human; male; female; article; metastatic castration resistant prostate cancer; azd 8186; vistusertib; azd8186; alcohol withdrawal syndrome; squamous non small cell lung cancer |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 11 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-06-01 |
| Start Page: | 2257 |
| End Page: | 2269 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-3087 |
| PUBMED: | 35247924 |
| PROVIDER: | scopus |
| PMCID: | PMC9662946 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2022 -- Source: Scopus |
