Phase I/II Open-label Study Evaluating The Safety And Efficacy of Concomitant Administration of Anti-CD19 CAR T-cell Therapy and Lenalidomide in Refractory/Relapsed Chronic Lymphocytic Leukemia Patients.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Adverse events incidence
研究概览
简要总结
This is a Phase I/II interventional, open-label treatment study designed to evaluate the safety and efficacy of concomitant therapy with anti-CD19 CAR T-cells and Lenalidomide in adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have been pretreated with Ibrutinib for 3 months prior to leukapheresis.
详细描述
Patients receive ibrutinib 420 mg daily for 3 months before CAR T-cell infusion. Obinutuzumab 1000 mg is administered 14 days before leukapheresis to reduce circulating CLL cells. Lymphodepletion consists of fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² on days -5 to -3. In a 3+3 dose-escalation design, patients receive a single infusion of 25 × 10⁶ (DL1), 50 × 10⁶ (DL2), or 100 × 10⁶ (DL3) autologous CD19 CAR T cells. Lenalidomide 10 mg is administered orally on days 0 through 6. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles.
The main purposes of the Phase I part are:
- To preliminarily explore the safety (incidence of CRS, ICANS, HLH, infections, late ICAHT, and cytopenias) and tolerability.
- To explore the pharmacokinetics of CAR-T cells.
The main purposes of the Phase II part are:
- Overall response rate, including complete response (CR) and partial response (PR) rates.
- Progression-free survival rates.
- Overall survival rates.
- MRD negativity rates measured by flow cytometry.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Documented CD19+ CLL or SLL
- •Patients must have failed at least 1 prior regimen
- •Patients must be currently receiving ibrutinib for at least 3 months prior to enrollment in the study and:
- •Not experiencing any ≥ grade 2 non-hematologic ibrutinib-related toxicity
- •ECOG Performance status 0 or 1
- •18 years of age and older
- •Adequate organ system function including:
- •Creatinine < 1.6 mg/dl ALT/AST < 3x upper limit of normal Total Bilirubin <2.0 mg/dl with the exception of patients with Gilbert syndrome; patients with Gilbert syndrome may be included if their total bilirubin is ≥ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN.
- •Have no active GVHD and require no immunosuppression
- •Are more than 6 months from transplant
- •No contraindications for leukapheresis
- •Left Ventricular Ejection fraction >50%
- •Gives informed consent
排除标准
- •CLL patients with known or suspected transformed disease (i.e. Richter's transformation).
- •Pregnant or lactating women.
- •Uncontrolled active infection.
- •Active hepatitis B or hepatitis C infection.
- •Concurrent use of systemic steroids or chronic use of immunosuppressant medications.
- •Any uncontrolled active medical disorder
- •HIV infection.
- •Patients with active CNS involvement with malignancy.
- •Class III/IV cardiovascular disability according to the New York Heart Association Classification.
- •Subjects with clinically apparent arrhythmia or arrhythmias who are not stable
研究组 & 干预措施
Medium dose of antiCD19 CAR T-cell therapy plus Lenalidomide
Phase 1: Phase 1: Determine safety of IL-7/IL-15 expanded 50x10^6 antiCD19 CAR-T cells with concomitant Lenalidomide 10 mg per os days 0-6 in patients with relapsed/refractory CLL. Patients will be enrolled in a 3+3 fashion. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles. 3 patients per cohort.
干预措施: Obinutuzumab Injection [Gazyva] (Biological)
High dose antiCD19 CAR T-cell therapy plus Lenalidomide
Phase 1: Phase 1: Determine safety of IL-7/IL-15 expanded 100x10^6 antiCD19 CAR-T cells with concomitant Lenalidomide 10 mg per os days 0-6 in patients with relapsed/refractory CLL. Patients will be enrolled in a 3+3 fashion. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles. 9 patients per cohort.
干预措施: Lenalidomide (Drug)
High dose antiCD19 CAR T-cell therapy plus Lenalidomide
Phase 1: Phase 1: Determine safety of IL-7/IL-15 expanded 100x10^6 antiCD19 CAR-T cells with concomitant Lenalidomide 10 mg per os days 0-6 in patients with relapsed/refractory CLL. Patients will be enrolled in a 3+3 fashion. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles. 9 patients per cohort.
干预措施: Obinutuzumab Injection [Gazyva] (Biological)
Low dose antiCD19 CAR T-cells plus Lenalidomide
Phase 1: Determine safety of IL-7/IL-15 expanded 25x10^6 antiCD19 CAR-T cells with concomitant Lenalidomide 10 mg per os days 0-6 in patients with relapsed/refractory CLL. Patients will be enrolled in a 3+3 fashion. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles.
3 patients per cohort.
干预措施: Obinutuzumab Injection [Gazyva] (Biological)
Medium dose of antiCD19 CAR T-cell therapy plus Lenalidomide
Phase 1: Phase 1: Determine safety of IL-7/IL-15 expanded 50x10^6 antiCD19 CAR-T cells with concomitant Lenalidomide 10 mg per os days 0-6 in patients with relapsed/refractory CLL. Patients will be enrolled in a 3+3 fashion. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles. 3 patients per cohort.
干预措施: Lenalidomide (Drug)
Low dose antiCD19 CAR T-cells plus Lenalidomide
Phase 1: Determine safety of IL-7/IL-15 expanded 25x10^6 antiCD19 CAR-T cells with concomitant Lenalidomide 10 mg per os days 0-6 in patients with relapsed/refractory CLL. Patients will be enrolled in a 3+3 fashion. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles.
3 patients per cohort.
干预措施: Lenalidomide (Drug)
结局指标
主要结局
Adverse events incidence
时间窗: 24 months
Safety
时间窗: 24 months
* To preliminarily explore the safety (incidence of CRS, ICANS, HLH, infections, late ICAHT, and cytopenias) and tolerability. * To explore the pharmacokinetics of CAR-T cells.
次要结局
- Efficacy(- Overall response rate, including complete response (CR) and partial response (PR) rates. - Progression-free survival rates. - Overall survival rates. - MRD negativity rates measured by flow cytometry.)
研究者
Mikalai Katsin
Chief of Hematology/Oncology department
Vitebsk Regional Clinical Cancer Centre