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dc.contributor.authorBanerji, U
dc.contributor.authorDean, Emma J
dc.contributor.authorPérez-Fidalgo, J
dc.contributor.authorBatist, G
dc.contributor.authorBedard, P
dc.contributor.authorYou, B
dc.contributor.authorWestin, S
dc.contributor.authorKabos, P
dc.contributor.authorGarrett, M
dc.contributor.authorTall, M
dc.contributor.authorAmbrose, H
dc.contributor.authorBarrett, J
dc.contributor.authorCarr, T
dc.contributor.authorCheung, S
dc.contributor.authorCorcoran, C
dc.contributor.authorCullberg, M
dc.contributor.authorDavies, B
dc.contributor.authorde Bruin, E
dc.contributor.authorElvin, P
dc.contributor.authorFoxley, A
dc.contributor.authorLawrence, P
dc.contributor.authorLindemann, J
dc.contributor.authorMaudsley, R
dc.contributor.authorPass, M
dc.contributor.authorRowlands, V
dc.contributor.authorRugman, P
dc.contributor.authorSchiavon, G
dc.contributor.authorYates, J
dc.contributor.authorSchellens, J
dc.date.accessioned2018-06-27T19:51:43Z
dc.date.available2018-06-27T19:51:43Z
dc.date.issued2018-05-01
dc.identifier.citationA phase I open-label study to identify a dosing regimen of the pan- AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA -mutated breast and gynecologic cancers. 2018, 24(9): 2050-2059 Clin Cancer Resen
dc.identifier.issn1078-0432
dc.identifier.pmid29066505
dc.identifier.doi10.1158/1078-0432.CCR-17-2260
dc.identifier.urihttp://hdl.handle.net/10541/621052
dc.description.abstractPurpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050-9. ©2017 AACRSee related commentary by Costa and Bosch, p. 2029.
dc.language.isoenen
dc.rightsArchived with thanks to Clinical cancer research : an official journal of the American Association for Cancer Researchen
dc.titleA phase I open-label study to identify a dosing regimen of the pan- AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA -mutated breast and gynecologic cancers.en
dc.typeArticleen
dc.contributor.departmentClinical Pharmacology and Trials, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Londonen
dc.identifier.journalClinical Cancer Researchen
html.description.abstractPurpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050-9. ©2017 AACRSee related commentary by Costa and Bosch, p. 2029.


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