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
| Autor: | Manish R. Patel, Erika Hamilton, Justin P.O. Lindemann, Richard Mather, Danielle Carroll, Tim Brier, Udai Banerji, Javier Garcia-Corbacho, Richard D. Baird, Steven Fox, Chris Twelves, Eva Ciruelos, Rhiannon Maudsley, Sam McGuinness, Teresa Klinowska, Jason Incorvati, Anne C Armstrong, Andy Sykes, Mafalda Oliveira, Cristina Hernando |
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| Přispěvatelé: | Baird, Richard [0000-0001-7071-6483], Apollo - University of Cambridge Repository |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Advanced breast Clinical Trials and Supportive Activities Estrogen receptor 32 Biomedical and Clinical Sciences 6 Evaluation of treatments and therapeutic interventions 03 medical and health sciences 0302 clinical medicine Breast cancer Clinical Research Internal medicine Breast Cancer Dose escalation Medicine Cancer business.industry Antagonist HER2 negative medicine.disease 3211 Oncology and Carcinogenesis 030220 oncology & carcinogenesis 6.1 Pharmaceuticals business 030215 immunology |
| Zdroj: | Publons |
| Popis: | 1024 Background: 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). [Table: see text] |
| Databáze: | OpenAIRE |
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