Abstract 564TiP
Background
Hormone receptor+/HER2- breast cancer is the most common subset of breast cancer. Despite the availability of first-line endocrine therapy, one-third of patients diagnosed with early-stage disease experience disease recurrence. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in this population, intramuscular injection is inconvenient, associated with injection-site reactions, and precludes achievement of higher and potentially more efficacious exposures. Combinations of a SERD with CDK4/6 inhibitors like abemaciclib have demonstrated efficacy in large, randomized trials in women with advanced ER+/HER2- breast cancer after endocrine therapy failure. ZN-c5 is a novel, potentially potent, orally bioavailable SERD with demonstrated activity in estrogen-dependent tumor models and a well-tolerated clinical safety profile.
Trial design
This phase 1b, open-label, multicenter study is evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ZN-c5 in combination with abemaciclib. The primary objective is to determine the maximum tolerated dose and recommended phase 2 dose. Subjects are adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) women with advanced adenocarcinoma of the breast and ER+/HER2- disease; they may have received 1 prior hormonal-based therapy but no prior chemotherapy or CDK4/6 inhibitors. Study drug treatment is administered orally and continuously in repeated 28-day cycles until disease progression or unacceptable toxicity. In Cycle 1, subjects receive abemaciclib as of Day 1 and ZN-c5 as of Day 8. In subsequent cycles, both study drugs are taken as of Day 1. Cohorts of subjects are being sequentially enrolled at several dose levels of ZN-c5, based on a modified 3+3 design; the initial dose level of 50 mg was well tolerated in the first-in-human study of ZN-c5. For all cohorts, the dose of abemaciclib is 150 mg BID. Correlations between biomarkers and clinical outcomes will be explored. Subject recruitment is ongoing.
Clinical trial identification
NCT04514159.
Editorial acknowledgement
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
G.P. Keogh: Non-Financial Interests, Personal, Member: ASCO. B. Jackson: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Suster: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Ptaszynski: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. All other authors have declared no conflicts of interest.