Abstract PD5-10: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC)
| العنوان: | Abstract PD5-10: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) |
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| المؤلفون: | J.A. Perez Fidalgo, Luna Liu, Antonio González-Martín, U McCurry, J. Cortés, Margaret A. Gates, Jill Fredrickson, Lars Mueller, Xiaojing Wang, Jennifer O. Lauchle, Ingrid A. Mayer, EP Winer, Roland Morley, Jennifer M. Giltnane, Erika Hamilton, Sravanthi Cheeti, R Villanueva, Lori Friedman, Ander Urruticoechea, Maura N. Dickler, Eric W. Humke, Iris T. Chan, S Milan, Meritxell Bellet, Jill M. Spoerke, M. Martin, Aditya Bardia, Valentina Boni, Ciara Metcalfe, Robert Jinze Li |
| المصدر: | Cancer Research. 78:PD5-10 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.drug_class, business.industry, Estrogen receptor, medicine.disease, Metastatic breast cancer, 03 medical and health sciences, 030104 developmental biology, Breast cancer, Pharmacokinetics, Estrogen, Internal medicine, Pharmacodynamics, medicine, Adverse effect, business, Estrogen receptor alpha |
| الوصف: | Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER+ BC. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that are efficacious against ligand-dependent and ligand-independent, constitutively active ESR1 mutant tumors may be of substantial therapeutic benefit. GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conductedin postmenopausal women with ER+ (HER2-) metastatic BC (progressing ≥ 6 months on endocrine therapy and with ≤ 2 prior chemotherapies in the advanced or metastatic setting) to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-0927. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples (after single dose and at steady state), CT scans, and when feasible, pre and on-study tumor biopsies were obtained Results: From March 16, 2015 to March 17, 2017 patients (pts) with a median age of 53 years (range 44-69) and a median number of prior therapies for MBC 4 (range 1-7) were enrolled at 3 total daily dose levels (600, 1000, 1400 mg) once daily (QD) given orally with fasting (n = 12). Increases in GDC-0927 exposure were approximately dose proportional. Treatment related adverse events (AEs) were all grade 1 or 2. The most common treatment-related AEs were nausea (54%, n = 7), diarrhea (46%, n = 6), elevated aspartate aminotransferase (39%, n = 5) and anemia, constipation, (each 31%, n = 4). Treatment interruption was required for 2 pts due to nausea and vomiting. Of those pts with FES-PET avid disease at baseline (9 of 12), all post-therapy scans showed complete or near complete (> 90%) suppression of FES uptake to background levels, including pts with ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-treatment biopsies. Five of 12 pts (1 at 600 mg and 4 at 1400 mg) were on study ≥ 24 weeks (CBR = 41.6 %) with the best overall response of stable disease with 1 patient (ESR1 mt+ D538G) on study for over 490 days. There were no dose limiting toxicities and no SAEs related to study drug. R2PD was 1400 mg and was selected for single arm dose-expansion which is now complete with last patient enrolled on March 17, 2017. Updated results from dose-escalation and dose-expansion will be presented at the meeting (N = 43). Conclusions: GDC-0927 appears well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated pts with advanced or metastatic ER+ BC, including pts with ESR1 mutations. Citation Format: Dickler MN, Villanueva R, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez-Martin A, Cortes J, Martin M, Giltnane J, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Spoerke JM, Metcalfe C, Liu L, Li R, Morley R, McCurry U, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Bardia A. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-10. |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::b6d1e958cce9b58ebb9ab3905b547b39Test https://doi.org/10.1158/1538-7445.sabcs17-pd5-10Test |
| رقم الانضمام: | edsair.doi...........b6d1e958cce9b58ebb9ab3905b547b39 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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