Abstract P6-12-03: A phase I study of AZD9496, a novel oral, selective estrogen receptor degrader (SERD) in women with estrogen receptor positive, HER-2 negative advanced breast cancer (ABC)
Authors: Hamilton E , Patel M , Armstrong A , Baird R , Jhaveri K , Hoch M , Morgan S , Dowdall T , Schiavon G , Klinowska T , Weir H , Bujac S , Nash T , Im S-A 
Published: March 2017

Abstract
Background AZD9496 is a potent orally bioavailable ER antagonist and degrader that has shown antitumor efficacy in a range of preclinical xenograft models including ESR1wild-type tamoxifen-resistant and long term estrogen deprived models and an ESR1 mutant model.
Methods This is a phase I, open label global multicenter study in women with ER+ HER2–ve BC either metastatic or locoregionally recurrent, not amenable to treatment with curative intent. Patients are post-menopausal, or pre-menopausal women receiving LHRH agonist therapy, with disease progression after ≥6 months endocrine therapy for ER+ BC (no limit on number of prior endocrine therapies; ≤2 prior chemotherapies in advanced setting). The primary objective is to determine the safety and tolerability of AZD9496. Cohorts of 3-6 patients received daily oral therapy and dose limiting toxicities (DLTs) occurring in cycle 1 (28 days) were assessed. Patients are dosed until MTD (defined as ≤1/6 patients with a DLT) or maximum feasible dose (MFD) is reached. Key secondary objectives include determination of single and multiple dose pharmacokinetics (PK), and preliminary antitumor efficacy. ER target modulation by protein and gene expression is evaluated in circulating tumor cells and paired tumor biopsies.
In addition to the dose escalation phase, expansion cohort(s) in patients with or without ESR1 mutations can be enrolled to examine the safety, tolerability, PK and biological activity of AZD9496 further.
Results Preliminary data as of 30th April 2016: 45 patients (median age 62 (range 41-83); 38 post-menopausal, 7 pre/perimenopausal; visceral metastases 76%, prior fulvestrant 25/45) received AZD9496 in 7 dose escalation cohorts: 20mg QD n=4, 40mg BID n=6, 80mg BID n=5, 150mg BID n=6, 250mg BID n=6, 400mg BID n=6, 600mg BID n=6 and also a 250mg BID expansion cohort n=6. The majority of adverse events (AEs) were grade 1 or 2; the most common treatment-related AEs (≥10%) have been diarrhoea (33%), fatigue (27%), nausea (22%), upper abdominal pain (13%) and increased liver function tests (13%). Six patients had treatment-related grade 3 AEs, 5 of which were manageable with dose interruption +/- dose reduction. Specifically, three had DLTs: grade 3 increased AST/ALT/GGT-150mg BID, serious adverse reaction (SAR) leading to withdrawal; grade 3 diarrhoea and grade 3 increased AST/ALT/GGT-400mg BID, SAR, manageable with dose reductions; grade 3 diarrhoea 600mg BID, manageable with dose reduction. The MTD/MFD has not been reached.
Following the first dose up to 400mg the AZD9496 exposure increased in reasonable proportion to increasing dose. At 600mg a more than dose-proportional increase in exposure was observed. Evidence of reduced ER and Ki67 has been observed in on-study biopsies at 150mg BID and above. 10 subjects received treatment for &gt;3-&lt;6 months (5 ongoing, 5 discontinued),4 subjects &gt;6-&lt;12 months (3 ongoing, 1 discontinued), 3 subjects ≥1 year (2 ongoing, 1 discontinued).
Conclusions AZD9496 has a tolerable safety profile, evidence of PD biomarker modulation and prolonged stabilisation of disease in women with heavily pre-treated ER+ve ABC.
Citation Format: Hamilton E, Patel M, Armstrong A, Baird R, Jhaveri K, Hoch M, Morgan S, Dowdall T, Schiavon G, Klinowska T, Weir H, Bujac S, Nash T, Im S-A. A phase I study of AZD9496, a novel oral, selective estrogen receptor degrader (SERD) in women with estrogen receptor positive, HER-2 negative advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-03.