Abstract 565TiP
Background
Most patients with ER+/HER2- breast cancer are diagnosed at an early stage, receive adjuvant endocrine therapy (ET), and have a good prognosis. However, a subset relapses while on or after adjuvant ET and are placed on first-line ET. After initially responding, they however will progress. These patients account for the majority of breast cancer-related deaths. Fulvestrant, currently the only approved drug that binds and selectively degrades the ER, shows significant anti-tumor activity following ET failure. While effective, it is limited by its poor pharmacological properties, with administration via intramuscular injection leading to sub-optimal exposure and injection-related adverse events such as pain and ecchymosis; in addition, caution is advised when treating patients with bleeding disorders, thrombocytopenia or receiving anticoagulants. ZN-c5 is a novel and potentially potent SERD with oral bioavailability, which demonstrated activity in estrogen-dependent tumor models. Combination therapy of fulvestrant or letrozole with palbociclib, a CDK4/6 inhibitor, significantly improved progression-free survival compared to ET alone in phase 3 trials.
Trial design
This phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics, and anti-tumor activity of ZN-c5 alone and in combination with palbociclib. The primary objectives are to determine maximum tolerated doses and recommended phase 2 doses by standard 3+3 dose escalation in phase 1 and preliminary anti-tumor efficacy in phase 2. Subjects are adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) with advanced and incurable adenocarcinoma of the breast, ER+/HER2- disease, and appropriate protocol-specified prior therapy. ZN-c5 is taken orally once or twice daily until disease progression or unacceptable toxicity. Palbociclib is administered per the approved dosing schedule. Biomarkers and pharmacodynamic effects of therapy will be explored. Subject recruitment is ongoing.
Clinical trial identification
NCT03560531.
Editorial acknowledgement
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
V. Abramson: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Daiichi-Sankyo; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Eli Lilly; Non-Financial Interests, Personal, Member: ASCO. H.M. Linden: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Eisai. J. Mortimer: Financial Interests, Personal, Invited Speaker: Puma; Financial Interests, Personal, Invited Speaker: Mesoblast; Financial Interests, Personal, Invited Speaker: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: Incyte; Financial Interests, Personal, Invited Speaker: Novartis. J. Nangia: Financial Interests, Institutional, Research Grant: Paxman Coolers Ltd. R. Layman: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Institutional, Research Grant: Zentalis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Celcuity. J. Suarez: 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. P. Chalasani: Financial Interests, Personal, Advisory Board: Zentalis Parmaceuticals; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer. All other authors have declared no conflicts of interest.