Abstract PS12-15: Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC)
Authors: Majid Oneeb , Xiao Jianjun Alan , Sahmoud Tarek , Yasuda Sanae , Cantagallo Lisa , Hamilton Erika P , Pluard Timothy , Juric Dejan , Gualberto Antonio , Husseiin Ziad 
Published: February 2021

Abstract
RATIONALE: Addition of CDK 4/6 inhibitors to endocrine therapy has become standard for patients (pts) with ER+ and HER2- BC with improvements in overall survival. However, acquired resistance to front-line therapy is inevitable, and response to later-line therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα). H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). METHODS: PK samples in phase I were obtained at day 1 and day 15 of cycle 1 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose) and sparse PK samples were collected in the phase II part of the trial. For pts enrolled in the food effect sub-study of phase II, plasma samples were collected during cycle 1 on day 15 and day 22 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose). Nonlinear mixed effect model (NONMEM) was applied for development of population PK models to fit H3B-6545 plasma concentration data with NONMEM® version 7.4 software. R was used for data management, visualization and statistical summaries. RESULTS: This phase I-II trial enrolled 47 pts in phase I part and 83 pts in the phase II part at the recommended phase II dose of 450 mg QD as of May 15, 2020. The 1180 plasma concentrations of H3B-6545 from a total of 103 pts at doses of 100-600 mg available as of January 15, 2020 were included in this analysis, with the following characteristics [n or (median, min-max) unit]: race (n=91/5/1/6 for White/Black/Asian/others), age (62.5, 31-81) yrs, body weight (79.5, 49-140) Kg, BMI (26.9, 17.6-45.6) Kg/m2, albumin (40, 29-52) g/dL, ALP (88.5, 39-917) IU/L, ALT (28, 10-193) IU/L, AST (36.5, 13-259) IU/L, bilirubin (8.6, 1.7-25.7) µM and creatinine clearance (112, 49.5-389) mL/min. The median number of prior therapy in the metastatic setting was 3 (range: 1 - 10). Out of 103 patients, 32 pts received treatment with a single high-fat meal to test food effect on PK over a randomized crossover design. H3B-6545 plasma concentrations were best described with a one compartment disposition PK model, plus a combined first- and zero-order parallel absorption and lag time. The estimated apparent clearance (CL/F) and volume of distribution (V/F) were 31 L/h and 422 L, respectively, with a typical terminal half-life of about 10 hours. H3B-6545 was absorbed fast, with a typical tmax of about 4 hours. A moderate to high variability (40-60%) was identified in major PK parameters (CL/F, V/F, bioavailability [F1]). A high-fat meal increased bioavailability by approximately 45% and prolonged tmax, roughly from 4 hours to 6 hours post dose. No significant effect was identified from other covariates: age, body weight, race, albumin, AST, ALP, ALT, bilirubin and creatinine clearance. CONCLUSIONS: H3B-6545 PK profiles in breast cancer patients were well described by a one-compartment disposition model with no significant effect of demographics, liver and renal function. When administered with a high fat meal, H3B-6545 exposure was modestly increased.
Citation Format: Oneeb Majid, Jianjun Alan Xiao, Tarek Sahmoud, Sanae Yasuda, Lisa Cantagallo, Erika P Hamilton, Timothy Pluard, Dejan Juric, Antonio Gualberto, Ziad Husseiin. Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-15.