A Phase I Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Injection in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
研究概览
简要总结
The primary objective is to assess the safety and tolerability of JS-001 in subjects with various advanced or recurrent malignancies, including solid tumors and lymphomas, and to evaluate its preliminary efficacy.
The secondary objectives are to: 1) characterize the single-dose and multi-dose pharmacokinetic (PK) profile of JS-001, 2) characterize the immunogenicity of JS-001; 3) assess the dose-efficacy relationship of JS-001 single agent, and 4) preliminarily evaluate biomarkers associated with the efficacy of JS-001.
The exploratory objectives include to evaluate the consistency between biomarker detection results of archived tissue and fresh frozen tissue, and to assess the consistency of response using various response criteria (such as irRC, WHO, RECIST and irRECIST).
详细描述
OVERVIEW This is a Phase 1, open-label, dose-escalation study of JS-001, a humanized monoclonal IgG4 antibody targeting the Programmed Death -1 (PD-1). It is estimated that 18-36 subjects with advanced or recurrent solid tumors or lymphomas will be enrolled in the dose-escalation study.
A 3+3 design will be utilized for this Phase 1 study. Three dose levels are planned and include: 1, 3, 10 mg/kg/dose. Each of the 3 dose levels will use 2 dose schedules: single dose, and repeated doses every 2 weeks. Subjects will be assigned to a dose schedule in the order of study entry.
The study will be the traditional 3 + 3 design with 3 or 6 subjects treated at this dose level and at all subsequent dose levels depending upon the incidence of DLTs. If no DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at the next higher dose level. If 1 of 3 subjects in a cohort experiences a DLT, that cohort will be expanded to 6 subjects. If only 1 of the 6 subjects has a DLT, then the next cohort of 3 subjects will be treated at the next higher dose level. If 2 or more DLTs occur within a cohort, then that dose level will be above the MTD (the highest dose where no more than 1 of 6 subjects has experienced a DLT), and the previous lower (tolerated) dose level will be considered the MTD.
A DLT is defined as a Grade 3 drug-related adverse event occurring within 28 days after previous dose (excluding tumor flare defined as local pain, irritation, or rash localized at sites of known or suspected tumor or a transient Grade 3 infusion adverse event) using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 in a single dose cohort.
Tumor response will be evaluated using immune-related response criteria (irRC), , Response Evaluation Criteria in Solid Tumors (RECIST 1.1), , and International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphomas (for lymphomas only).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing to sign Informed Consent;
- •Re-entry into the study is allowed with a second informed consent;
- •Willing to provide blood sample for biomarker analysis(mandatory). The tissue sample is optional;
- •A diagnosis of an advanced malignant tumor confirmed by histology or cytology;
- •No standard of care for the patient;
- •At least 1 measurable lesion;
- •Aged 18-65 years;
- •Anticipated life expectancy of at least 3 months;
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
- •i) At least 4 weeks elapsed since receiving systemic chemotherapy, at least 6 weeks since receiving mitomycin or nitrosoureas, and at least 2 weeks since receiving a tyrosine kinase inhibitor;
- •At least 4 weeks elapsed since receiving definite radiotherapy, and at least 2 weeks since receiving palliative radiotherapy;
- •At least 2 weeks since the last dose of systemic steroid therapy (>10 mg/day prednisone or equivalent);
- •At least 4 weeks since receiving anti-cancer biotherapy;
- •Recovered from previous treatment related adverse reaction;
- •willing to use an acceptable contraceptive method;
- •A negative pregnancy test for female subjects of childbearing potential;
排除标准
- •Active central nervous system (CNS) metastases and/or carcinomatous meningitis;
- •Known history of another primary solid tumor, unless the participant has undergone potentially curative therapy with no evidence of that disease for 2 years, or underwent successful definitive resection of basal or squamous cell carcinoma of the skin, or in situ cervical cancer;
- •Active, known or suspected autoimmune disease;
- •Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2,or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies;
- •Significant medical disease;
- •Active infection;
- •Active tuberculosis or history of tuberculosis with one year;
- •Infection of Human immunodeficiency virus (HIV);
- •A complication requiring immune-suppression;
- •Received a live vaccine within 4 weeks prior to first dose of study drug
- •pleural or abdominal effusion with symptoms;
- •Drug or alcohol abuse (for subjects in the pharmacokinetic cohorts) ;
- •evidence of interstitial lung disease;
- •Active hepatitis B or C, or with significant risk of hepatitis reactivation;
- •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to monoclonal antibodies or drugs chemically related to the study drug. History of serious hypersensitivity reaction or serious hepatotoxicity related to any drug.
研究组 & 干预措施
Expanded cohort 1
The subjects of expanded cohort 1 will use repeated doses every 2 weeks like multiple dose cohorts
干预措施: JS001 (Biological)
Expanded cohort 2
The subjects of expanded cohort 2 will use repeated doses every 2 weeks like multiple dose cohorts
干预措施: JS001 (Biological)
Dose Escalation Cohort
JS001
干预措施: JS001 (Biological)
结局指标
主要结局
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
时间窗: 154 days
次要结局
- correlation analysis of PD-L1 expression of tumor and ORR(154 days)