Study of TYK-00540 Tablets in Patients With Advanced Solid Tumors

Inclusion criteria

• Age ≥18 years, gender requirements:
• Monotherapy dose-escalation phase: No gender restriction.
• Combination dose-selection phase: No gender restriction.
• Monotherapy and combination expansion phases:
• Cohort A-1: Females only.
• ther cohorts: No gender restriction.
• Monotherapy Dose-Escalation Phase:
• Histologically or cytologically confirmed locally advanced/metastatic solid tumors with no standard treatment available, failure of/intolerance to standard treatment, or refusal of standard treatment.
• Monotherapy Dose-Expansion Phase:
• Cohort A-1: Histologically or cytologically confirmed advanced platinum-resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer:
• Platinum resistance defined as: Disease recurrence/progression \<6 months after completion of prior platinum-based chemotherapy (≥4 cycles) or progression during initial/recurrent treatment.
• Disease recurrence/progression requires:
• Objective radiographic progression; OR
• Persistent CA125 elevation (confirmed after 1 week) with clinical symptoms or signs of progression.
• 3 prior lines of chemotherapy for recurrent/metastatic disease, with ≤1 systemic therapy after platinum resistance.
• Cohort A-2: HR+/HER2- advanced breast cancer with confirmed resistance to CDK4/6 inhibitors (≥1 documented instance).
• Combination Dose-Selection Phase:
• HR+/HER2- advanced breast cancer with confirmed resistance to CDK4/6 inhibitors (≥1 documented instance).
• Combination Dose-Expansion Phase:
• Cohort B-1: HR+/HER2- advanced breast cancer with prior endocrine therapy resistance and either:
• No prior CDK4/6 inhibitor treatment; OR
• CDK4/6 inhibitor-treated in the adjuvant setting with recurrence \>1 year after completion (no confirmed resistance).
• Cohort B-2: HR+/HER2- advanced breast cancer with progression during/after endocrine + CDK4/6 inhibitor therapy:
• For adjuvant CDK4/6 inhibitor resistance: Recurrence during or ≤1 year after treatment;
• ≥1 documented CDK4/6 inhibitor resistance.
• Note for Cohorts A-2, Combination Dose-Selection, and Combination Expansion Phases:
• 2 prior endocrine therapy regimens for recurrent/metastatic disease (adjuvant endocrine therapy leading to recurrence within 1 month of completion counts as 1 regimen).
• 1 prior chemotherapy or ADC regimen for recurrent/metastatic disease.
• Prior CDK4/6 inhibitor use:
• Duration ≥6 months;
• Adjuvant CDK4/6 inhibitor use with progression \>1 year after completion does not count as resistance;
• Switching CDK4/6 inhibitors due to intolerance is permitted.
• For female patients in Combination Phases:
• Meet ≥1 of the following:
• Bilateral oophorectomy;
• Age ≥60 years;
• Age \<60 years with natural menopause ≥12 months (without chemotherapy, tamoxifen, toremifene, or ovarian suppression in the past year), confirmed by postmenopausal FSH and estradiol levels;
• Age \<60 years on tamoxifen/toremifene with postmenopausal FSH and estradiol levels.
• Non-postmenopausal patients must use LHRH agonists/antagonists throughout the study.
• Baseline Lesions:
• Monotherapy dose-escalation: Extracranial evaluable/measurable lesions.
• Combination phases: Extracranial measurable lesions (RECIST 1.1).
• ECOG performance status 0-1, no deterioration within 2 weeks prior to first dose (Appendix II).
• Life expectancy ≥3 months.
• Adequate Organ Function:
• Liver:TBIL ≤1.5×ULN, ALT/AST ≤2.5×ULN (≤5×ULN for liver metastases; ≤3×ULN for combination with fulvestrant).
• Kidney:Serum creatinine ≤1.5×ULN, creatinine clearance ≥50 mL/min (Cockcroft-Gault formula, Appendix III).
• Hematology:Platelets ≥90×10\^9/L, ANC ≥1.5×10\^9/L, Hb ≥90 g/L (without transfusion/G-CSF within 2 weeks).
• Cardiac:LVEF ≥50% (echocardiogram), QTcF \<470 ms. Coagulation:INR ≤1.5, APTT ≤1.5×ULN (without anticoagulation).
• Contraception:Females of childbearing potential: Negative pregnancy test and commitment to highly effective contraception/abstinence from screening until 6 months post-treatment (Appendix IV).Males: Commitment to contraception/abstinence during the same period.For fulvestrant combination: Contraception until 1 year after last dose.
• Voluntary signed ICF (or by legal guardian) and willingness to comply with study procedures.

Exclusion criteria

• Known hypersensitivity to any excipient of TYK-00540 or contraindication to fulvestrant (for Combination Dose-Selection and Combination Expansion Phases).
• Prior/concurrent therapies:
• Systemic anticancer therapies within 28 days prior to first dose: chemotherapy, large-molecule targeted therapy, immunotherapy.
• Endocrine therapy, small-molecule targeted therapy, or fluorouracil-based oral agents within 14 days prior to first dose.
• Nitrosoureas or mitomycin within 6 weeks prior to first dose. Anticancer herbal medicine or traditional Chinese medicine within 7 days prior to first dose.
• Local radiotherapy (e.g., thoracic/rib) or palliative radiotherapy for bone metastases within 7 days prior to first dose.
• Major surgery (excluding minor procedures, e.g., appendectomy, tumor biopsy) within 4 weeks prior to first dose.
• Proton pump inhibitor (PPI) use within 7 days prior to first dose or during the study.
• Concurrent use of medications known to prolong QTc interval or induce torsades de pointes (Appendix V).
• Participation in other interventional clinical trials within 28 days prior to first dose (non-interventional trials excluded).
• Prior allogeneic bone marrow transplantation. For Combination Phases: prior use of fulvestrant, other SERDs, or SERCAs.
• History of other malignancies, except:Cured basal cell carcinoma, squamous cell carcinoma, cervical carcinoma in situ, thyroid papillary carcinoma, ductal carcinoma in situ of the breast, or malignancies with disease-free survival \>3 years.
• Residual toxicity from prior therapy \>Grade 1 (except alopecia or platinum-related neuropathy).
• Central nervous system (CNS) disease:Primary CNS tumors, CNS metastases with prior local treatment failure, or newly diagnosed CNS metastases.Exception: Asymptomatic, stable CNS metastases (no steroids/CNS-specific treatment ≥14 days, radiologically confirmed stability at screening).
• Spinal cord compression caused by tumor.
• Visceral crisis.
• Clinically uncontrolled pleural effusion, ascites, or pericardial effusion requiring repeated drainage/medical intervention (within 14 days prior to first dose).
• Clinically significant ECG abnormalities at baseline (e.g., QTc ≥470 ms, complete LBBB, acute/indeterminate-age myocardial infarction, ST-T changes suggesting ischemia, second-/third-degree AV block, severe bradycardia/tachycardia).
• Cardiovascular events within 6 months:Myocardial infarction, long QT syndrome, torsades de pointes, arrhythmias (sustained ventricular tachycardia/fibrillation), severe conduction defects (e.g., bifascicular block, third-degree AV block), unstable angina, coronary/peripheral bypass, symptomatic CHF (NYHA Class III/IV), stroke, TIA, symptomatic pulmonary embolism, or clinically significant thromboembolism.Persistent NCI CTCAE ≥Grade 2 arrhythmia, atrial fibrillation (asymptomatic atrial fibrillation ≥Grade 2).
• Exception: Patients with cardiac pacemakers/devices and QTcF \>470 ms may be eligible after discussion with the medical monitor.
• Unstable or uncontrolled medical conditions affecting safety/compliance, including:Uncontrolled hypertension (systolic BP \>160 mmHg and/or diastolic BP \>100 mmHg).Uncontrolled diabetes, active bleeding, ocular disease, severe psychiatric/neurological/cardiovascular/respiratory disorders.
• Active/uncontrolled infections or immunodeficiencies:Active HBV (HBsAg-positive with HBV DNA ≥2000 copies/mL \[or 500 IU/mL\]).Active HCV (HCV antibody-positive with HCV RNA-positive).HIV-positive.Exception: Asymptomatic chronic HBV/HCV carriers.
• Lung disease:Radiation pneumonitis requiring steroids, interstitial lung disease (ILD)/pneumonitis (active or drug-induced), acute/progressive pulmonary fibrosis, or high-risk factors for ILD per investigator judgment.
• Clinically significant gastrointestinal disorders affecting drug absorption (e.g., dysphagia, uncontrolled vomiting, active ulcers, inflammatory bowel disease, chronic diarrhea, bowel obstruction, chronic PPI-dependent conditions).
• Hypercoagulability with thromboembolic events within 6 months (e.g., stroke, DVT, pulmonary embolism).
• Pregnancy, lactation.
• The investigator concluded that the patient was not suitable to participate in the study (such as not conforming to the most beneficial treatment for the patient, patient compliance, etc.).