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 Foxley

Peter 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

Clinical Pharmacology and Trials, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom. [email protected].
Medical Oncology (Drug Development), University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom.
Department of Oncology and Hematology, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, CIBERONC, Valencia, Spain.
Department of Oncology, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Canada.
Department of Medical Oncology, The Princess Margaret Cancer Centre, Toronto, Canada.
Medical Oncology Department, Institut de Cancérologie des Hospices Civils de Lyon, CITOHL, Université Lyon 1, Lyon, France.
Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado.
School of Biosciences, University of Kent, Canterbury, United Kingdom.
Clinical PD Biomarker Group, The Institute of Cancer Research, Sutton, United Kingdom.
IMED, AstraZeneca, Cambridge, United Kingdom.
IMED, AstraZeneca, Waltham, Massachusetts.

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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SDG 3 Good Health and Well-being

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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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