NCT06950086招募中1 期
A Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of the CDK2/4/6 Inhibitor TYK-00540 Tablets in Patients With Advanced Solid Tumors
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 180
- 试验地点
- 1
- 主要终点
- Dose Limiting Toxicity (DLT)
研究概览
简要总结
This study is to evaluate the safety, pharmacokinetics, and preliminary antitumor activity of TYK-00540 as monotherapy or combined with fulvestrant in advanced solid tumors.
详细描述
This is an open-label, multi-center, dose-escalation and expansion phase I/II study to evaluate dose limiting toxicities (DLT) and determine the maximum tolerated dose (MTD) in subjects with locally advanced or metastatic solid tumors.
To investigate the pharmacokinetic profile of TYK-00540 and its metabolites after single then multiple doses of TYK-00540 administered orally once daily. To assess preliminary effectiveness. To evaluate the efficacy of TYK-00540 combined with fulvestrant in subjects with ER+/HER2- breast cancer who have relapsed or progressed after treatment with CDK4/6 inhibitors
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Other 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.
- 另有 1 项未显示
排除标准
- •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.).
研究组 & 干预措施
TYK-00540±Fulvestrant
Experimental
TYK-00540• Find the maximum tolerated dose(MTD) and the recommended phase 2 dose (RP2D) of TYK-00540, given orally. • Increased dose cohorts from low dose to MTD, starting at 5mg twicely.
fulvestrant: is in the form of a syringe containing 5ml of an injection solution of 250mg of fulvestrant for injection. The recommended dose is every 28 days, once at a dose of 500mg, and on the 15th day after the initial injection, a loading dose of fulvestrant 500mg id added.
干预措施: TYK-00540 (Drug)
结局指标
主要结局
Dose Limiting Toxicity (DLT)
时间窗: Within 31 days of the first dose
Numbers of participants experiencing AEs which are defined as DLTs classfied by CTCAE
Recommended dose for combination-agent escalation and single-agent expansion (RDE)
时间窗: 1 year
To determine the recommended dose for combination-agent escalation and single-agent expansion agent expansion.
Adverse events (AEs)
时间窗: From Baseline up to 28 days after the end of the treatment
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Objective response rate (ORR)
时间窗: At least 24 weeks
ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
次要结局
- The time to the peak concentration (Tmax)(0 hours (h) (within 30 min before dosing), 0.25 h, 0.5 h , 1 h , 2 h , 3 h, 4 h, 8 h , 12 h, 24 h after dosing)
- Maximum plasma concentration (Cmax)(0 hours (h) (within 30 min before dosing), 0.25 h, 0.5 h , 1 h , 2 h , 3 h, 4 h, 8 h , 12 h, 24 h after dosing)
- Minimum plasma concentration (Cmin)(0 hours (h) (within 30 min before dosing), 0.25 h, 0.5 h , 1 h , 2 h , 3 h, 4 h, 8 h , 12 h, 24 h after dosing)
- Disease Control Rate (DCR)(At least 24 weeks)
研究者
研究点 (1)
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