TSL2109 Capsules in Advanced Solid Tumor Patients: Safety, Tolerability, PK and Preliminary Efficacy

TSL2109 is a novel dual-target inhibitor of Cyclin-Dependent Kinase 4/6-Dualspecificity tyrosine-(Y)-phosphorylation Regulated Kinase 2 (CDK4/6-DYRK2) developed by Jiangsu Tasly Diyee Pharmaceutical Co., Ltd., intended for the treatment of solid tumors. Preclinical studies have demonstrated that TSL2109 selectively targets CDK4/6 and DYRK2, where DYRK2 (Dual-specificity tyrosine-phosphorylation regulated kinase 2) belongs to the CMGC family of the eukaryotic kinome. In vitro treatment of palbociclib-resistant cell lines with TSL2109 induced downregulation of cell cycle-related proteins and downstream ribosomal synthesis regulatory proteins of the DYRK2 signaling pathway, including Regulator of Ribosome Synthesis 1 (RRS1) and Recombinant Cyclin-Dependent Kinase 2 (CDK2), while simultaneously upregulating Recombinant Tumor Protein P53 (p53), thereby exerting synergistic antitumor effects and overcoming resistance to enzalutamide and palbociclib.This product is a selective small-molecule inhibitor of DYRK2 and CDK4/6 based on novel anticancer targets, novel chemical structure, and novel mechanism of action. Selective inhibition of DYRK2 and CDK4/6 can block tumor cell cycle progression independent of hormonal signaling pathways. In vitro and in vivo animal experiments have demonstrated promising efficacy in overcoming resistance to androgen receptor (AR) inhibitors, addressing the unmet clinical need for prostate cancer patients who have progressed following AR inhibitor therapy. Secondly, selective inhibition of DYRK2 can reduce CDK2 activity and block CDK4/6 compensatory mechanisms, with in vitro and in vivo animal experiments showing efficacy in overcoming resistance to CDK4/6 inhibitors. This addresses the treatment challenge for patients with HR+/HER2- advanced breast cancer who have progressed following CDK4/6 inhibitor therapy, providing a novel therapeutic option for HR+/HER2- breast cancer patients. Participants: Dose-Escalation Phase: Patients with advanced solid tumors, with priority given to those with metastatic castration-resistant prostate cancer (mCRPC) and HR+/HER2- advanced breast cancer. Dose-Expansion Phase: Cohort A and/or Cohort C: Metastatic castration-resistant prostate cancer (mCRPC) Cohort B and/or Cohort D: HR+/HER2- advanced breast cancer C0 Treatment Cycle (3 days): Oral administration on the morning of Day 1 under fasting conditions, followed by 72-hour observation. C1 Treatment Cycle (28 days): Multiple doses administered under fasting conditions, with daily dosing (QD) for 3 weeks followed by a 1-week treatment-free interval. If no dose-limiting toxicity (DLT) occurs during the DLT observation period and the investigator determines that continued treatment may provide benefit, the participant may continue receiving study treatment. During subsequent treatment, if the investigator determines based on available safety and efficacy data that increasing the dose may enhance potential benefit for the participant, and the participant has demonstrated good tolerability, the dose level may be escalated to a previously established tolerable dose following discussion between the investigator and sponsor. Treatment may continue until disease progression, intolerable toxicity, or initiation of new antitumor therapy. Dose-Expansion Phase: The same dosing regimen as C1. Missed Dose: Make-up dosing is permitted within 8 hours; if more than 8 hours have elapsed, the missed dose should be skipped. Notes: Participants previously enrolled at dose levels above the maximum tolerated dose (MTD) will have their subsequent doses adjusted to the MTD dose level once the MTD is established. Administered orally under fasting conditions.