TY - JOUR
T1 - A 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
AU - Banerji, Udai
AU - Dean, Emma J.
AU - Alejandro Perez-Fidalgo, J.
AU - Batist, Gerald
AU - Bedard, Philippe L.
AU - You, Benoit
AU - Westin, Shannon N.
AU - Kabos, Peter
AU - Garrett, Michelle D.
AU - Tall, Mathew
AU - Ambrose, Helen
AU - Carl Barrett, J.
AU - Hedley Carr, T.
AU - Amy Cheung, S. Y.
AU - Corcoran, Claire
AU - Cullberg, Marie
AU - Davies, Barry R.
AU - de Bruin, Elza C.
AU - Elvin, Paul
AU - Foxley, Andrew
AU - Lawrence, Peter
AU - Lindemann, Justin P.O.
AU - Maudsley, Rhiannon
AU - Pass, Martin
AU - Rowlands, Vicky
AU - Rugman, Paul
AU - Schiavon, Gaia
AU - Yates, James
AU - Schellens, Jan H.M.
N1 - Funding Information:
This study (Study 1; NCT01226316) was sponsored by AstraZeneca. AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). We thank James Sherwood (Astra-Zeneca) for performing the Sequenom analysis and acknowledge infrastructural funding from CRUK and ECMC (ICR/RMH/Christie), as well as NIHR BRC (ICR/RMH) funding, for UK sites. We thank all the investigators and site staff, with special thanks to the patients and families. Medical writing assistance was provided by Andrew Jones (PhD from Mudskipper Business Ltd.) funded by AstraZeneca.
Funding Information:
U. Banerji reports receiving commercial research grants from AstraZeneca. E. J. Dean is currently an employee of AstraZeneca. J.A. Pérez-Fidalgo reports receiving speakers bureau honoraria from AstraZeneca, Pfizer, and Roche. S.N. Westin is a consultant/advisory board member for AstraZeneca, Clovis, and Medivation. P. Kabos is a consultant/advisory board member for Eli Lilly. C. Corcoran, M. Cullberg, B.R. Davies, P. Elvin, and M. Pass hold ownership interest (including patents) in AstraZeneca. J.H.M. Schellens holds ownership interest (including patents) in Modra Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
Prior presentation: This study (Study 1, Astra Zeneca study D3610C00001; NCT01226316)was presented in part at the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO; abstract number 2541) and at the 2015 ASCO Meeting(abstract number 2500). This study (Study 1; NCT01226316) was sponsored by AstraZeneca. AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). We thank James Sherwood (AstraZeneca) for performing the Sequenom analysis and acknowledge infrastructural funding from CRUK and ECMC (ICR/RMH/Christie), as well as NIHR BRC (ICR/RMH) funding, for UK sites. We thank all the investigators and site staff, with special thanks to the patients and families. Medical writing assistance was provided by Andrew Jones (PhD from Mudskipper Business Ltd.) funded by AstraZeneca.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Purpose: 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 ¼ 47), 4/7 (n ¼ 21), and 2/7 (n ¼ 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.
AB - Purpose: 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 ¼ 47), 4/7 (n ¼ 21), and 2/7 (n ¼ 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.
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U2 - 10.1158/1078-0432.CCR-17-2260
DO - 10.1158/1078-0432.CCR-17-2260
M3 - Article
C2 - 29066505
AN - SCOPUS:85045540606
SN - 1078-0432
VL - 24
SP - 2050
EP - 2059
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -