A Phase I, Single Arm, Multiple Dose, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KN035 Administered in Subcutaneous Injection as a Single Agent to Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 287
- 试验地点
- 4
- 主要终点
- Incidence of dose limiting toxicities (DLTs) in dose escalation study
研究概览
简要总结
This dose escalation and dose expansion study is to evaluate and characterize the tolerability and safety profile of single agent KN035 in Chinese adult subjects with unresectable advanced carcinoma.
详细描述
Dose escalation study is to evaluate the safety and tolerability of KN035 in advanced and metastatic solid tumor. Six dose levels are planned and include: 0.1, 0.3, 1.0, 2.5, 5, 10 mg/kg/dose. Subjects will be assigned to a dose level in the order of study entry. The first cohort of 1 subject will receive KN035 at 0.1 mg/kg/dose as a subcutaneous (sc) injection every week for a total of 4 injections (Days 1, 8, 15 and 22) in the first 28-day cycle. For the first 2 cohorts (0.1 and 0.3 mg/kg/dose), only one subject will be enrolled in each cohort until 1 subject experiences a ≥ Grade 2 drug-related adverse event in the first cycle, then 2 additional subjects will be enrolled at this cohort. Thereafter, the study will become the traditional 3+3 design with 3 or 6 subjects treated at this dose level and all subsequent dose levels depending upon the incidence of DLTs. However, if no ≥ Grade 2 drug-related adverse event occurs in the first 2 cohorts, starting with cohort 3, the study will become the traditional 3+3 design with 3 or 6 subjects enrolled.
Dose expansion-1 study is planned to conduct in advanced hepatocellular cancer subjects at 2.5 mg/kg and 5 mg/kg dose level, respectively.
Dose expansion-2 study is planned to conduct in advanced solid tumor subjects at 2.5 mg/kg and 5 mg/kg dose level, respectively
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Subject Is currently participating and receiving study therapy or has participated in a study of an investigational agent and receive study therapy within 28 days of the first dose of study drug.
- •Subject has not recovered to CTCAE Grade 1 or better from the adverse events due to cancer therapeutics administered
- •Subject has a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds (ms)), or a history of additional risk factors for torsade de pointes (TdP, e.g., heart failure, hypokalemia, family history of Long QT Syndrome), or is using concomitant medications that prolong the QT/QTc interval.
- •Subject has had antineoplastic therapy within 4 weeks prior to the first dose of study therapy KN
- •Subject is, with one year of the time signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
- •Subjects with symptomatic ascites, pleural effusion or pericardial effusion.
- •Subject is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
- •Subject has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and are off steroids for at least 7 days from first dose of KN
- •Subject has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Subject has Leptomeningeal disease.
- •Subject previously had a severe hypersensitivity reaction to treatment with another mAb.
- •Subject has an active infection (CTCAE≥Grade 2) with 4 weeks of the first dose.
- •Subject is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active hepatitis B (HBV surface antigen positive and HBV DNA ≥ 104 copies/ml)or hepatitis C or tuberculosis (HCV antibody positive and HCV-RNA≥ 103 copies/ml).
- •Subject has received or will receive a live vaccine within 4 weeks prior to the first administration of study drug.
- •Addtional exclusion criteria for dose expansion study:
- •Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
- •The patient accepted any anti-cancer therapy within 28 days prior to the first dose of study drug including surgery, radiotherapy, biotherapy, immunotherapy and/or locoregional therapy (eg: radiofrequency ablation [RFA], percutaneous ethanol [PEI] or acetic acid injection [PAI], cryoablation, high-intensity focused ultrasound [HIFU], transarterial chemoembolization [TACE], transarterial embolization [TAE], etc.)
- •Prior liver transplant or history of hepatic encephalopathy
研究组 & 干预措施
KN035
KN035 is to be injected subcutaneously 0.1mg/kg or 0.3mg/kg or 1mg/kg or 2.5mg/kg or 5mg/kg or 10mg/kg weekly until disease progresses or unacceptable tolerability occurs.
干预措施: KN035 (Drug)
结局指标
主要结局
Incidence of dose limiting toxicities (DLTs) in dose escalation study
时间窗: From screening to up to cycle 1 (28 days)
ORR of HCC patients in dose expansion study
时间窗: Up to 2 approximately years
Percentage of participants with adverse events (AEs), serious adverse events and AEs of special interest
时间窗: From screening to up to 1 months after the last dose of study drug (up to approximately 2 years)
次要结局
- t1/2 of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Peak Plasma Concentration (Cmax) of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Peak Time (Tmax) of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Correlation of tumor response with the PD-L1 expression(Up to 2 approximately years)
- Area under the plasma concentration versus time curve (AUC) of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Plasma clearance (CL) of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Changes of cytokine(From Pre-dose of the first dose to up to 6 months)
- Objective Response Rate (ORR)(Up to 2 approximately years)
- Disease Control Rate (DCR)(Up to 2 approximately years)
- Correlation of the tumor response with the expression of specific gene mutation(Up to 2 approximately years)
- overall survival(Up to 2 approximately years)
- Trough concentration of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Apparent volume of distribution of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Accumulation rate of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Anti-Drug Antibody of KN035 in Chinese patients(From Pre-dose of the first dose to up to cycle 12)
- Changes of lymphocyte Subtyping(From Pre-dose of the first dose to up to cycle 12)
- Progression-Free survival (PFS)(Up to 2 approximately years)
- Duration of Response (DOR)(Up to 2 approximately years)