A Phase 1 Study to Evaluate the Safety, Tolerability, Preliminary Efficacy, and Pharmacokinetic Characterization of KQ-2003 for Patients With Relapsed/Refractory POEMS Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 21
- 试验地点
- 2
- 主要终点
- Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
This is a multicenter, open-label, dose-escalation/expansion phase 1 study to evaluate the safety, tolerability, pharmacokinetic/pharmacodynamic characteristics and determine the recommended dose of KQ-2003 CAR T-cells for patients with Relapsed/Refractory POEMS Syndrome
详细描述
The study included the phase 1a dose escalation study and the phase 1b cohort extension study. The phase 1a study is an open, dose-escalation design with 3 dose groups according to the "3+3" dose escalation rule: low dose group (0.5×10^6 CAR T cells/kg), medium dose group (1.0×10^6 CAR T cells/kg), high dose group (2.0×10^6 CAR T cells/kg). After initial confirmation of maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), a phase 1b cohort extension study will be conducted.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years old, male or female;
- •Diagnosis of POEMS syndrome with relapsed or refractory disease;
- •Eastern Cooperative Oncology Group (ECOG) Performance ≤2 ;
- •Adequate venous access for the apheresis of peripheral blood mononuclear cell;
- •Vascular Endothelial Growth Factor (VEGF) ≥1200ng/L；
- •Overall Neuropathy Limitations Scale (ONLS) ≥ 1;
- •Adequate organ function;
- •Able and willing to comply with the study protocol and follow-up plan, and sign the informed consent form in writing.
排除标准
- •Subjects who had previously received BCMA-CD19 dual-target CAR-T cell products or autologous stem cell transplantation within 12 weeks before the collection of peripheral blood mononuclear cells;
- •Known allergy or hypersensitivity reactions to cyclophosphamide, fludarabine, dimethyl sulfoxide (DMSO), CD19, or BCMA-targeted drugs;
- •Received any treatment that might influence the activity of CAR-T cells prior to the collection of peripheral blood mononuclear cells;
- •Have history of vaccination within the 4 weeks preceding the collection of peripheral blood mononuclear cells;
- •Have tested positive for cytomegalovirus and/or mycobacterium tuberculosis, or had any uncontrolled active infection within 14 days prior to the collection of peripheral blood mononuclear cells;
- •Subjects infected with active HBV or HCV, HIV, syphilis;
- •Subjects with known central nervous system disease, for example, seizure disorders, clinically significant cerebral ischemia/hemorrhage, dementia);
- •Subjects currently experiencing active autoimmune diseases; Diagnosed with immunodeficiency or receiving any other form of immunosuppressive therapy within 7 days prior to enrollment in this study;
- •Subjects with active bleeding or VTE events (such as pulmonary embolism or deep vein thrombosis) require anticoagulation;
- •Have following severe diseases: unstable angina, cerebrovascular accident or transient ischemic attack, myocardial infarction , New York Heart Association (NYHA) Class ≥ III, congestive heart failure, poorly controlled severe arrhythmias or other cardiac diseases requiring mechanical support; subjects with known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal; subjects with known moderate or severe persistent asthma, or a history of asthma within the past 2 years, or currently having any category of uncontrolled asthma; subjects requiring oxygen to maintain adequate oxygen saturation; subjects with hypertension whose blood pressure cannot be lowered to the following range despite treatment with two or more antihypertensive medications;
- •Have active malignancies;
- •Have any non-hematologic toxicity resulting from prior treatments that cannot be restored to ≤ grade 1 or baseline, excluding alopecia and grade 2 neuropathy;
- •Subjects had participated in other clinical trials and used its investigational drugs within the 3 months prior to the collection of peripheral blood mononuclear cells;
- •History of alcohol abuse, drug addiction, substance abuse, or mental illness within the past year;
- •Pregnant or lactating women;
- •Any situation that the investigator believes may increase the risk of subjects or interfere with the results of clinical trials
结局指标
主要结局
Recommended Phase 2 Dose (RP2D)
时间窗: Through study completion, an average of 1 year
To determine after all subjects in the Phase 1 dose-escalation study completed DLT observation
Maximum Tolerated Dose (MTD)
时间窗: Within 28 days of receiving KQ-2003 CAR T-cells transfusion therapy
At least 6 subjects in the MTD dose group must complete the DLT assessment.
Number of patients with dose-limiting toxicity (DLT)
时间窗: Within 28 days of receiving KQ-2003 CAR T-cells transfusion therapy
For DLT evaluation, severity (grade) is classified according to common terminology criteria for adverse events version 5.0 (CTCAE v5.0).
Adverse Event
时间窗: Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1)
Safety will be assessed by adverse events (AEs), which include clinically significant abnormalities identified during a medical test (e.g. laboratory tests, electrocardiogram, vital signs, physical examinations). AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) and their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).
次要结局
- Response rate of critical organs(Through study completion, an average of 2 years)
- Hematologic response(Through study completion, an average of 2 years)
- Levels of IL-2(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Levels of IL-10(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Overall survival (OS)(Through study completion, an average of 2 years)
- Levels of IL-6(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- CD3+T lymphocyte count(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- CD4+T lymphocyte count(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Response of serum vascular endothelial growth factor level(VEGF)(Through study completion, an average of 2 years)
- Response of positron emission tomography-scan (PET-CT)(Through study completion, an average of 2 years)
- Disease-free survival (DFS)(Through study completion, an average of 2 years)
- Levels of IFN-γ(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- CD19+B lymphocyte count(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- CD20+B lymphocyte count(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- CD8+T lymphocyte count(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- ADA(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Complete response rate (CRR)(Through study completion, an average of 2 years)
- Maximum concentration (Cmax)(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Time to maximum plasma concentration (Tmax)(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Levels of TNF-α(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Levels of C-reactive protein (CRP)(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))
- Levels of ferritin(Minimum 2 years after KQ-2003 CAR T-cells infusion (Day 1))