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

Publication Date:
2018-05-02
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
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autor Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
beschreibung 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 AACR . See related commentary by Costa and Bosch, p. 2029
citation_standardnr 6248664
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-05-02
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/9/2050?rss=1
search_space articles
shingle_author_1 Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
shingle_author_2 Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
shingle_author_3 Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
shingle_author_4 Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
shingle_catch_all_1 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
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 AACR . See related commentary by Costa and Bosch, p. 2029
Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 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
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 AACR . See related commentary by Costa and Bosch, p. 2029
Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 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
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 AACR . See related commentary by Costa and Bosch, p. 2029
Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 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
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 AACR . See related commentary by Costa and Bosch, p. 2029
Banerji, U., Dean, E. J., Perez-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., Foxley, A., Lawrence, P., Lindemann, J. P. O., Maudsley, R., Pass, M., Rowlands, V., Rugman, P., Schiavon, G., Yates, J., Schellens, J. H. M.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 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
shingle_title_2 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
shingle_title_3 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
shingle_title_4 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
timestamp 2025-06-30T23:34:39.542Z
titel 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
titel_suche 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
topic WW-YZ
uid ipn_articles_6248664