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

Multicenter, Dose-Escalation & Dose-Expansion, Single-Arm, Open-Label Phase I Trial: Safety, Tolerability, PK and Preliminary Antitumor Efficacy of TSL2109 Capsules in Advanced Solid Tumor Patients

TSL2109 is a novel CDK4/6-DYRK2 dual-target inhibitor developed by Jiangsu Tasly Diyee Pharmaceutical Co., Ltd. for solid tumor treatment. Preclinical studies confirm its selective targeting of CDK4/6 and DYRK2, a eukaryotic CMGC family kinase.

In palbociclib-resistant cell lines, TSL2109 downregulates cell cycle-related proteins and DYRK2 pathway ribosomal synthesis regulators (RRS1, CDK2), and upregulates p53, thus exerting synergistic antitumor effects and overcoming resistance to enzalutamide and palbociclib.

As a small-molecule inhibitor with novel targets, structure and mechanism, TSL2109 blocks tumor cell cycle progression independently of hormonal signaling. Preclinical studies show it overcomes AR inhibitor resistance, meeting unmet needs for prostate cancer patients progressing after AR inhibitor therapy. It also reduces CDK2 activity and blocks CDK4/6 compensatory mechanisms, reversing resistance to CDK4/6 inhibitors, providing a new option for HR+/HER2- advanced breast cancer patients.

Participants Dose-Escalation Phase: Advanced solid tumor patients, prioritizing metastatic castration-resistant prostate cancer (mCRPC) and HR+/HER2- advanced breast cancer.

Dose-Expansion Phase:

Cohort A/C: mCRPC; Cohort B/D: HR+/HER2- advanced breast cancer. Treatment Regimens C0 Cycle (3 days): Single oral dose on Day 1 morning under fasting, followed by 72-hour observation.

C1 Cycle (28 days): Daily fasting oral dosing (QD) for 3 weeks, then 1-week rest. Participants may continue treatment if no DLT and potential clinical benefit.

Dose escalation to a pre-established tolerable level is allowed per investigator-sponsor agreement if well-tolerated and likely beneficial. Treatment continues until disease progression, intolerable toxicity or new antitumor therapy. The Dose-Expansion Phase uses the same regimen as C1.

Missed Dose: Make-up within 8 hours; skip if delayed over 8 hours. Notes: Once MTD is determined, participants dosed above MTD will be adjusted to MTD. All doses are administered orally under fasting conditions.

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.

Inclusion Criteria:

1. Age ≥18 years.
2. Histologically or cytologically confirmed advanced solid tumors, with failure of prior standard therapy, or no available standard therapy, or currently unsuitable for standard therapy, and not amenable to surgery or radiotherapy with curative intent. Priority will be given to patients with metastatic castration-resistant prostate cancer (mCRPC) and HR+/HER2- advanced breast cancer.
3. (Dose-Escalation Phase) At least one evaluable or measurable tumor lesion per RECIST Version 1.1; (Dose-Expansion Phase) At least one measurable tumor lesion per RECIST Version 1.1 (tumor lesions located in prior radiation fields or other locally treated sites generally do not qualify as measurable lesions unless there is clear progression or persistence three months after radiotherapy).
4. Life expectancy ≥3 months.
5. ECOG performance status score of 0 to 1.

Metastatic Castration-Resistant Prostate Cancer (mCRPC):

Castration status at screening: (1) Currently receiving androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or history of bilateral orchiectomy. (2) Serum total testosterone ≤1.7 nmol/L (50 ng/dL) at screening. Additionally, progression documented by one or more of the following three criteria: ① PSA progression defined as PSA >1 ng/mL with two consecutive increases >50% from baseline at least 1 week apart; ② Soft tissue disease progression per RECIST 1.1; ③ Bone disease progression per PCWG3, defined as two or more new bone lesions on bone scan. Priority will be given to end-line patients who have received prior androgen receptor inhibitors and have received chemotherapy or are chemotherapy-intolerant or chemotherapy-refusing.

HR+/HER2- Breast Cancer:

① Histologically or cytologically confirmed HR-positive, HER2-negative breast cancer (determined from the most recent tumor sample [primary or metastatic] with histological confirmation of HR+/HER2- status. To meet HR+ disease requirements, breast cancer must express estrogen receptor [ER], with or without progesterone receptor co-expression), locally advanced or recurrent/metastatic breast cancer in female patients. ② Prior exposure to CDK4/6 inhibitors (e.g., abemaciclib, palbociclib, etc.).

Exclusion Criteria:

1. Clinically symptomatic central nervous system (CNS) metastases or leptomeningeal metastases, or other evidence indicating uncontrolled CNS or leptomeningeal metastases, judged by the investigator as unsuitable for enrollment.
2. Diagnosis of another invasive malignancy within the past 2 years, except for radically treated non-melanomatous skin cancer or superficial urothelial carcinoma, cutaneous basal cell or squamous cell carcinoma, superficial bladder cancer, prostate carcinoma in situ, papillary thyroid carcinoma, cervical carcinoma in situ, or breast carcinoma in situ.
3. Clinically significant gastrointestinal dysfunction that may affect drug intake, transport, or absorption, such as inability to take oral medications, uncontrolled nausea or vomiting, history of extensive gastrointestinal resection, unresolved recurrent diarrhea, untreated gastric conditions requiring long-term proton pump inhibitor therapy, Crohn's disease, ulcerative colitis, intestinal obstruction, etc.
4. Imaging (CT or MRI) showing tumor invasion of major blood vessels (e.g., aorta, pulmonary arteries/veins, vena cava, etc.) with assessed bleeding risk.
5. Interstitial lung disease, pneumonitis, or pulmonary fibrosis, assessed by the investigator as unsuitable for enrollment.
6. History of deep vein thromboembolism.