Abstract A070: A phase 1/2a, open-label, dose-escalation study of EC-18 in patients with metastatic breast cancer for the prevention of chemotherapy-induced neutropenia

Abstract

Abstract Background/Aim: Chemotherapy-induced neutropenia (CIN) is the major dose-limiting toxicity of systemic cancer chemotherapy leading to dose reductions, treatment delays or treatment early termination, which may compromise treatment outcome. EC-18 is a synthetic, orally available and lipid-based small molecular compound (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol). EC-18 prevents CIN by attenuating neutrophil extravasation via down-regulation of adhesion molecules, pro-inflammatory cytokines & chemokines (Cell & Bioscience 2019;9:4). The aim of this study is to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary activity of EC-18 for CIN (NCT03104595). Methods: A standard 3+3 design was used. EC-18 (softgel capsule) was administered on Day 1 through Day 21 to patients with metastatic breast cancer receiving combined doxorubicin and cyclophosphamide (AC regimen) in four dose-escalation cohorts (500mg/day, 1,000mg/day, 1,500mg/day, 2,000mg/day, respectively) with 3 subjects per each cohort. The first cohort was treated at a starting dose (500mg/day) and the subsequent cohorts were sequentially treated at increasing doses levels. PK was assessed on Day 1 and Day 15 in the first cycle of chemotherapy. Results: EC-18 was shown to be well tolerated in all participants and none of the subjects experienced drug-related severe adverse events or adverse events leading to discontinuation of treatment. Dose-limiting toxicity (DLT) did not occur and maximum-tolerated dose (MTD) was not determined accordingly. The baseline-adjusted absolute neutrophil count (ANC) of the patients showed a tendency to improve the neutrophil decline with increasing doses of EC-18 during the course of the study. With increasing dosage amount of EC-18, the time period (day) for the recovery of neutropenia from nadir to ANC > 500/mm3 showed a tendency to become shorter proportionally; 4.0 days in 500mg/day, 3.7 days in 1,000mg/day, 3.0 days in 1,500mg/day and 2.3 days in 2,000mg/day, respectively. In the PK outcomes, the plasma exposure on 500-2000 mg was observed in a dose-dependent manner. No plasma accumulation by the repeated dosing was observed based on the PK results of Day 1 and 15. The PK analysis and simulation suggested that the higher dose than 2000 mg would reach a systemic steady-state. Conclusion: EC-18 is safe and well tolerated. Studies in patients clearly demonstrated pharmacokinetics. Preliminary results suggest EC-18 has the potential to prevent and treat chemotherapy-induced neutropenia. Further dose-expansion cohorts trial is planned to explore a maximum tolerated dose and determine an efficacious dose for phase 2 clinical trial. Citation Format: Sung-Bae Kim, Myung-Hwan Kim. A phase 1/2a, open-label, dose-escalation study of EC-18 in patients with metastatic breast cancer for the prevention of chemotherapy-induced neutropenia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A070. doi:10.1158/1535-7163.TARG-19-A070