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

Udai Banerji; Emma J Dean; J Alejandro Pérez-Fidalgo; Gerald Batist; Philippe L Bedard; Benoit You; Shannon N Westin; Peter Kabos; Michelle D Garrett; Mathew Tall; Helen Ambrose; J Carl Barrett; T Hedley Carr; S Y Amy Cheung; Claire Corcoran; Marie Cullberg; Barry R Davies; Elza C de Bruin; Paul Elvin; Andrew Foxley; Peter Lawrence; Justin P O Lindemann; Rhiannon Maudsley; Martin Pass; Vicky Rowlands; Paul Rugman; Gaia Schiavon; James Yates; Jan H M Schellens

doi:10.1158/1078-0432.CCR-17-2260

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

Udai Banerji^*, Emma J Dean, J Alejandro Pérez-Fidalgo, Gerald Batist, Philippe L Bedard, Benoit You, Shannon N Westin, Peter Kabos, Michelle D Garrett, Mathew Tall, Helen Ambrose, J Carl Barrett, T Hedley Carr, S Y Amy Cheung, Claire Corcoran, Marie Cullberg, Barry R Davies, Elza C de Bruin, Paul Elvin, Andrew FoxleyPeter Lawrence, Justin P O Lindemann, Rhiannon Maudsley, Martin Pass, Vicky Rowlands, Paul Rugman, Gaia Schiavon, James Yates, Jan H M Schellens

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 = 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.

Original language	English
Pages (from-to)	2050-2059
Number of pages	10
Journal	Clinical Cancer Research
Volume	24
Issue number	9
DOIs	https://doi.org/10.1158/1078-0432.CCR-17-2260
Publication status	Published - May 2018

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10.1158/1078-0432.CCR-17-2260

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Banerji, U., Dean, E. J., Pérez-Fidalgo, J. A., Batist, G., Bedard, P. L., You, B., Westin, S. N., Kabos, P., Garrett, M. D., Tall, M., Ambrose, H., Barrett, J. C., Carr, T. H., Cheung, S. Y. A., Corcoran, C., Cullberg, M., Davies, B. R., de Bruin, E. C., Elvin, P., ... Schellens, J. H. M. (2018). 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. Clinical Cancer Research, 24(9), 2050-2059. https://doi.org/10.1158/1078-0432.CCR-17-2260

@article{183fcc49f1244859a82de26e07e02807,

title = "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",

abstract = "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 = 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. {\textcopyright}2017 AACRSee related commentary by Costa and Bosch, p. 2029.",

author = "Udai Banerji and Dean, {Emma J} and P{\'e}rez-Fidalgo, {J Alejandro} and Gerald Batist and Bedard, {Philippe L} and Benoit You and Westin, {Shannon N} and Peter Kabos and Garrett, {Michelle D} and Mathew Tall and Helen Ambrose and Barrett, {J Carl} and Carr, {T Hedley} and Cheung, {S Y Amy} and Claire Corcoran and Marie Cullberg and Davies, {Barry R} and {de Bruin}, {Elza C} and Paul Elvin and Andrew Foxley and Peter Lawrence and Lindemann, {Justin P O} and Rhiannon Maudsley and Martin Pass and Vicky Rowlands and Paul Rugman and Gaia Schiavon and James Yates and Schellens, {Jan H M}",

note = "{\textcopyright}2017 American Association for Cancer Research.",

year = "2018",

month = may,

doi = "10.1158/1078-0432.CCR-17-2260",

language = "English",

volume = "24",

pages = "2050--2059",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "9",

}

Banerji, U, Dean, EJ, Pérez-Fidalgo, JA, Batist, G, Bedard, PL, You, B, Westin, SN, Kabos, P, Garrett, MD, Tall, M, Ambrose, H, Barrett, JC, Carr, TH, Cheung, SYA, Corcoran, C, Cullberg, M, Davies, BR, de Bruin, EC, Elvin, P, Foxley, A, Lawrence, P, Lindemann, JPO, Maudsley, R, Pass, M, Rowlands, V, Rugman, P, Schiavon, G, Yates, J & Schellens, JHM 2018, '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', Clinical Cancer Research, vol. 24, no. 9, pp. 2050-2059. https://doi.org/10.1158/1078-0432.CCR-17-2260

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. / Banerji, Udai; Dean, Emma J; Pérez-Fidalgo, J Alejandro et al.
In: Clinical Cancer Research, Vol. 24, No. 9, 05.2018, p. 2050-2059.

Research output: Contribution to journal › Article › Academic › peer-review

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 - Pérez-Fidalgo, J Alejandro

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 - Barrett, J Carl

AU - Carr, T Hedley

AU - Cheung, S Y Amy

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

PY - 2018/5

Y1 - 2018/5

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 = 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.

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 = 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.

U2 - 10.1158/1078-0432.CCR-17-2260

DO - 10.1158/1078-0432.CCR-17-2260

M3 - Article

C2 - 29066505

SN - 1078-0432

VL - 24

SP - 2050

EP - 2059

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 9

ER -

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

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