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dc.contributor.authorHamilton, E. P.
dc.contributor.authorOliveira, M.
dc.contributor.authorBanerji, U.
dc.contributor.authorHernando, C.
dc.contributor.authorGarcia-Corbacho, J.
dc.contributor.authorArmstrong, Anne C
dc.contributor.authorCiruelos, E.
dc.contributor.authorPatel, M. R.
dc.contributor.authorIncorvati, J.
dc.contributor.authorTwelves, C.
dc.contributor.authorBrier, T.
dc.contributor.authorCarroll, D.
dc.contributor.authorFox, S.
dc.contributor.authorKlinowska, T.
dc.contributor.authorLindemann, J. P. O.
dc.contributor.authorMather, R.
dc.contributor.authorMaudsley, R.
dc.contributor.authorMcGuinness, S.
dc.contributor.authorSykes, A.
dc.contributor.authorBaird, R.
dc.date.accessioned2020-11-16T07:49:09Z
dc.date.available2020-11-16T07:49:09Z
dc.date.issued2020en
dc.identifier.citationHamilton EP, Oliveira M, Banerji U, Hernando C, Garcia-Corbacho J, Armstrong AC, et al. A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer Journal of Clinical Oncology. 2020;38(15)en
dc.identifier.urihttp://hdl.handle.net/10541/623387
dc.description.abstractBackground: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown antitumor efficacy in a range of preclinical models of breast cancer. Methods: SERENA-1 (NCT03616587) is an ongoing Phase 1, open-label study in pre- and post-menopausal women, after ?1 endocrine therapy and ?2 prior chemotherapies for ER+ HER2- advanced breast cancer (ABC). The primary objective is to determine the safety and tolerability of AZD9833 once daily (QD), with dose-limiting toxicities (DLTs) in 28d defining the maximum tolerated dose. Secondary objectives include pharmacokinetics and anti-tumor response. Pharmacodynamic (PD) analysis includes ER modulation in paired tumor biopsies and ctDNA dynamic changes. Results: At 20 January 2020: 60 patients were treated (median prior therapies 5 (1–9); prior fulvestrant (Fv) 82%; prior CDK4/6i 68%) across five doses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 450 mg QD n=10. AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12h. Treatment-related AEs experienced by ?10% of patients were visual disturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patients experienced DLTs: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and a combination of G2 visual disturbance, G2 headache and G2 gait disturbance (450 mg). DLTs resolved with dose reduction. No G4 or 5 AEs were reported. Efficacy data are presented in the table below; objective response rate (ORR) and clinical benefit rate (CBR) at 24 weeks. Clinical trial information: NCT03616587. ER signalling pathway modulation was observed in all dose cohorts. In patients where clinical responses occurred and paired biopsies obtained, 98% reduction in Ki67 was measured. Updated data will be presented. Conclusions: AZD9833 has an encouraging efficacy and dose-dependent safety profile. Evidence of clinical benefit and target engagement was observed at all dose levels in women with ER+ ABC, including patients pre-treated with CDK4/6i and Fv, and those with ESR1 mutations. A Phase 2 study comparing efficacy and safety of three doses AZD9833 vs Fv is planned (NCT04214288).en
dc.language.isoenen
dc.titleA phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast canceren
dc.typeMeetings and Proceedingsen
dc.contributor.departmentSarah Cannon Research Institute and Tennessee Oncology, Nashville, TNen
dc.identifier.journalJournal of Clinical Oncologyen
dc.description.noteen]


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