A Multi-center, Open-label, Dose Escalation and Expansion, Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) Characteristic of SYHA1815 in Subjects With Unresectable Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 97
- 试验地点
- 1
- 主要终点
- Number of participants with Dose-limiting Toxicities
研究概览
简要总结
This is a multi-center, open-label, dose escalation and expansion, phase I study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) characteristics, preliminary efficacy of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors. Once the expected effective dose is identified, the dose expansion study will be started to further evaluate the safety, clinical activity and PK profile of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors.
详细描述
This is a multi-center, open-label, dose escalation and expansion, phase I study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) characteristics, preliminary efficacy of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors. The dose escalation study will include six dose cohorts starting at 2 mg/day. Once the expected effective dose is identified, the dose expansion study will be started to further evaluate the safety, clinical activity and PK profile of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female subjects aged 18 to 75 years (inclusive)；
- •Histologically or cytologically confirmed diagnosis of unresectable locally advanced or metastatic solid tumors (thyroid cancer, non-small cell lung cancer, gastric cancer [including gastroesophageal junction cancer], colorectal cancer, pancreatic cancer, soft tissue sarcoma, etc.), failure of standard treatment (disease progression or intolerance), or no alternative standard treatment or refusal of standard treatment;
- •The subjects included in the dose expansion study should provide written biomarker test reports or tumor tissue samples to the central laboratory;
- •The time interval between the last dose of anti-tumor drug and the first administration of SHYA1815 must meet the following conditions: ≥ 4 weeks for cytotoxic drugs, PD-1 / PD-L1, cellular immunotherapy; ≥2 weeks for oral molecular targeted drug therapy; ≥4 weeks for radiotherapy (≥ 2 weeks for palliative local radiotherapy for pain relief), and had recovered from the toxicities of radiotherapy; ≥2 weeks for anticancer Traditional Chinese medicine or Chinese patent medicine;
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
- •Life expectancy ≥ 12 weeks;
- •At least one measurable lesion according to RECIST 1.1 at the screening phase;
- •The organ function level and related laboratory values of the subjects must meet the following requirements within 7 days before the first dose of study drug (not receiving blood transfusion within 14 days before the first administration):
- •Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelet count ≥ 75 × 10^9/L /L; Hemoglobin ≥ 90 g / L; the values of blood phosphorus and calcium are in normal range;
- •Blood biochemistry: serum total bilirubin ≤ 1.5× upper limit of normal value (ULN); AST / ALT ≤ 3 ×ULN (≤ 5 ×ULN for liver metastasis); Serum creatinine ≤ 1.5 × ULN;
- •Coagulation: Internationally standardized ratio (INR) or prothrombin time (PT) ≤ 1.5×ULN, activated partial thrombin time (APTT) ≤ 1.5×ULN;
- •For women of childbearing potential: the serum pregnancy test within 7 days before the first administration must be negative, and female subjects are willing to take adequate contraceptive measures during the treatment period and for at least 3 months after the last dose of the study drug. Male subjects must agree to take contraceptive measures (non-drug or instrumental contraception) from the beginning of the study to at least 3 months after the last dose of study drug;
- •Voluntarily participate in the study and sign the informed consent form.
排除标准
- •The previous anti-tumor or surgical treatment history with any of the following conditions:
- •Received the treatment of other intervention clinical studies with 4 weeks before the first dose of study drug;
- •Had undergone major surgery within 4 weeks before the first dose of study drug or had not fully recovered from any previous invasive operation;
- •Prior treatment of RET/FGFR inhibitors or small molecular kinase inhibitors with RET/FGFR as the main targets;
- •Any unresolved toxicities from prior anti-tumor therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1, except for alopecia, pigmentation, previous chemotherapy-related neurotoxicity (≤ grade 2) and other adverse reactions judged no safety risk by the investigators;
- •Subjects with symptomatic brain metastasis or meningeal metastasis, spinal cord compression or mental disorder, and asymptomatic brain metastasis can be enrolled (there is no disease progress within at least 4 weeks after radiotherapy and/or no neurological symptoms after surgical resection, and glucocorticoids, anticonvulsant drugs and mannitol are not required);
- •Impaired cardiac function or clinically significant cardiovascular and cerebrovascular diseases, including any of the following:
- •History of myocardial infarction, congestive heart failure (NYHA grade ≥ grade III), and unstable angina pectoris within 6 months prior to screening;
- •Cerebrovascular disease occurred within 6 months before screening (except for transient ischemic attack (TIA), lacunar infarction with no clinical significance);
- •Severe uncontrollable arrhythmia requiring medical treatment;
- •Electrocardiogram (ECG) examination, female QTc interval>470 milliseconds (ms), male QTc interval>450 milliseconds (ms) according to Fridericia formula;
- •The left ventricular ejection fraction is less than 50% according to cardiac ultrasound examination;
- •History of active bleeding within 6 months before screening;
- •Any serious or uncontrollable disease, and not suitable for this study as determined by the investigator;
- •Any uncontrollable active infection that will prevent the subjects from receiving the study drug within 2 weeks prior to the first dose of study drug;
- •HIV positive, HCV positive with HCV RNA quantity higher than the upper limit of normal value in the research center;
- •Active hepatitis B infection, with the HBV DNA quantity higher than the upper limit of normal value of the research center;
- •A history of any other malignant tumors within 5 years (except for effectively controlled non-melanoma skin basal cell carcinoma, cervical carcinoma in situ, and other malignant tumors that have been effectively controlled without treatment in the past 5 years;
- •Subjects who have taken potent inhibitors and inducers of CYP3A4 liver metabolic enzymes within 2 weeks before the first administration and still need to continue to use such drugs;
- •Women who are breastfeeding;
- •Concomitant disease or condition that may interfere with the conduct of the trial, or that would pose an unacceptable risk to the subject in this trial in the opinion of the investigator.
研究组 & 干预措施
Dose Escalation Cohort
Six dose levels will be tested. The dose-limiting toxicity (DLT) will be assessed from the first administration of SYHA1815 to the end of the first cycle (28 days).
干预措施: SYHA1815 (Drug)
cohort Expansion Cohort
Once the expected effective dose is determined, four expansion cohorts will be started to further evaluate the safety, clinical activity and PK profile of SYHA1815.
干预措施: SYHA1815 (Drug)
结局指标
主要结局
Number of participants with Dose-limiting Toxicities
时间窗: Baseline through 28 days after the first dose of study drug
Number of participants with Dose-limiting Toxicities
Incidence of adverse events and SAEs
时间窗: Up to 3 years
Incidence of adverse events and SAEs defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0).
Clinically significant changes from baseline in vital signs examination
时间窗: Up to 3 years
Clinically significant changes from baseline in vital signs examination
Clinically significant changes from baseline in physical examination
时间窗: Up to 3 years
Clinically significant changes from baseline in physical examination
Clinically significant changes from baseline in routine blood test
时间窗: Up to 3 years
Clinically significant changes from baseline in routine blood test
Clinically significant changes from baseline in blood biochemistry test
时间窗: Up to 3 years
Clinically significant changes from baseline in blood biochemistry test
Clinically significant changes from baseline in routine urine test
时间窗: Up to 3 years
Clinically significant changes from baseline in routine urine test
Clinically significant changes from baseline in coagulation function test
时间窗: Up to 3 years
Clinically significant changes from baseline in coagulation function test
Clinically significant changes from baseline in 12-lead electrocardiogram (ECG)
时间窗: Up to 3 years
Clinically significant changes from baseline in 12-lead electrocardiogram (ECG)
次要结局
- Objective Response Rate (ORR)(Up to 3 years)
- Disease control rate (DCR)(Up to 3 years)
- Duration of response (DOR)(Up to 3 years)
- Progression free survival (PFS)(Up to 3 years)
- Time to maximum plasma concentration (Tmax)(Up to 3 years)
- Terminal disposition rate constant (λz)(Up to 3 years)
- Apparent total clearance of the drug from plasma after oral administration (CL/F)(Up to 3 years)
- Apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F)(Up to 3 years)
- Change from baseline in serum phosphate(Up to 3 years)
- Serum carcinoembryonic antigen (CEA)(Up to 3 years)
- Fibroblast growth factor 23 (FGF23)(Up to 3 years)
- Calcitonin (thyroid cancer detection only)(Up to 3 years)
- Vascular endothelial growth factor receptor 2 (sVEGFR2)(Up to 3 years)
- Potential population who benefit from the study drug(Up to 3 years)
- Correlation between the changes of RET/FGFR gene and efficacy(Up to 3 years)
- Maximum Plasma Concentration (Cmax)(Up to 3 years)
- Plasma half-life (T1/2)(Up to 3 years)
- Area under the plasma concentration-time curve from time 0 to time t (AUC0-t)(Up to 3 years)
- Area under the plasma concentration-time curve from time 0 to infinity (AUCinf)(Up to 3 years)