dc.contributor.author | Banerji, U | |
dc.contributor.author | Dean, EJ | |
dc.contributor.author | Pérez-Fidalgo, JA | |
dc.contributor.author | Batist, G | |
dc.contributor.author | Bedard, PL | |
dc.contributor.author | You, B | |
dc.contributor.author | Westin, SN | |
dc.contributor.author | Kabos, P | |
dc.contributor.author | Garrett, MD | |
dc.contributor.author | Tall, M | |
dc.contributor.author | Ambrose, H | |
dc.contributor.author | Barrett, JC | |
dc.contributor.author | Carr, TH | |
dc.contributor.author | Cheung, SYA | |
dc.contributor.author | Corcoran, C | |
dc.contributor.author | Cullberg, M | |
dc.contributor.author | Davies, BR | |
dc.contributor.author | de Bruin, EC | |
dc.contributor.author | Elvin, P | |
dc.contributor.author | Foxley, A | |
dc.contributor.author | Lawrence, P | |
dc.contributor.author | Lindemann, JPO | |
dc.contributor.author | Maudsley, R | |
dc.contributor.author | Pass, M | |
dc.contributor.author | Rowlands, V | |
dc.contributor.author | Rugman, P | |
dc.contributor.author | Schiavon, G | |
dc.contributor.author | Yates, J | |
dc.contributor.author | Schellens, JHM | |
dc.date.accessioned | 2017-11-01T15:01:57Z | |
dc.date.issued | 2017-10-24 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (9), pp. 2050 - 2059 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/890 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-17-2260 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 2050 - 2059 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Breast Neoplasms | |
dc.subject | Genital Neoplasms, Female | |
dc.subject | Neoplasm Metastasis | |
dc.subject | Pyrimidines | |
dc.subject | Pyrroles | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Neoplasm Staging | |
dc.subject | Treatment Outcome | |
dc.subject | Area Under Curve | |
dc.subject | Mutation | |
dc.subject | Adult | |
dc.subject | Aged | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | Class I Phosphatidylinositol 3-Kinases | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Biomarkers, Tumor | |
dc.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. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-10-19 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-17-2260 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 9 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 24 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Medicine Drug Development Unit (de Bono) | |
dc.contributor.icrauthor | Banerji, Udai | |