A Randomized Trial Comparing CD3/CD19 Depleted or CD3 Depleted/CD56 Selected Haploidentical Donor Natural Killer (NK) Cell Based Therapy in Older Adults With Acute Myelogenous Leukemia in First Complete Remission
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Disease-Free Survival
研究概览
简要总结
This is a phase II trial designed to test the safety and efficacy (disease free survival [DFS]) of related donor HLA-haploidentical NK-cell based therapy for the treatment of acute myelogenous leukemia (AML). The natural killer (NK) cell product will be given to patients 60 years and older who are in a first complete remission after 1 or 2 courses of standard AML induction. After a preparative regimen of cyclophosphamide and fludarabine, patients will receive a single infusion of either CD3-/CD19- NK cells or CD3-/CD56+ NK cells followed by a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion.
详细描述
The trial will use a single-stage design and will take place in two parts. The first part will support the selection of the better NK cell product as measured by in vivo NK cell expansion. Successful in vivo NK cell expansion is defined as 40% donor DNA and 40% of lymphocytes are NK cells at day 7 post infusion OR 20% donor DNA and 20% of lymphocytes are NK cells at day 14 post infusion.
Part 1: 1:1 randomization with 10 patients per cohort to either:
- CD3-/CD19- NK cell product or
- CD3-/CD56+ purified NK cell product The product with better NK cell expansion will be used for the rest of the trial. If the results and safety profile are equivalent, the CD56+ selection approach will be used. If neither approach results in successful NK cell expansion, the trial will be stopped and the platform redesigned.
Part 2: complete the trial by enrolling an additional 26 patients using the product deemed successful during part 1 to estimate the primary endpoint (DFS at 12 months)
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of acute myelogenous leukemia (except acute promyelocytic leukemia) in a first complete remission (CR1) and meet the following criteria:
- •Meets the definition of complete remission by morphologic criteria including <5% blasts in a moderately cellular (> 20% cellularity) or cellular marrow.
- •Complete remission (CR) was achieved after no more than 2 cycles of standard induction chemotherapy. Early re-induction therapy based on residual disease on a day 14 bone marrow (BM) will count as a 2nd cycle. Prior therapy with demethylating agents (i.e. azacitidine) is allowed, but patients must have attained CR after standard cytotoxic therapy (defined as absolute neutrophil count (ANC) > 1000 cells/μL, platelets > 100 x 10^9/L)
- •No more than 3 months have lapsed from attainment of CR1
- •No acute myelogenous leukemia (AML) consolidation therapy administered prior to enrollment
- •Not a candidate for allogeneic stem cell transplantation
- •≥ 60 years of age
- •Karnofsky performance status ≥ 70%
- •Available related HLA haploidentical natural killer (NK) cell donor (sibling, offspring, or offspring of an HLA identical sibling) by at least Class I serologic typing at the A&B locus (donor age 18-75 years)
- •At least 30 days since last dose of chemotherapy
- •Adequate organ function within 14 days of enrollment defined as:
- •Creatinine: ≤ 2.0 mg/dL
- •Hepatic: aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) < 5 x upper limit of institutional normal (ULN)
- •Pulmonary: oxygen saturation ≥ 90% on room air
- •Cardiac: left ventricular ejection fraction (LVEF) by echocardiogram (ECHO or MUGA) ≥ 40%, no uncontrolled angina, uncontrolled atrial or ventricular arrhythmias, or evidence of acute ischemia or active conduction system abnormalities (rate controlled a-fib is not an exclusion)
- •Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the NK cell infusion (excluding preparative regimen pre-meds)
- •Voluntary written consent
排除标准
- •Biphenotypic acute leukemia
- •New progressive pulmonary infiltrates on screening chest x-ray or chest Computed Tomography scan that has not been evaluated with bronchoscopy (when feasible). Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections).
- •Uncontrolled bacterial, fungal, or viral infections including human immunodeficiency virus (HIV) - chronic asymptomatic viral hepatitis is allowed
- •Pleural effusion large enough to be detectable on chest x-ray
- •Known hypersensitivity to one or more of the study agents
- •Donor Selection:
- •Related donor (sibling, offspring, or offspring of an HLA identical sibling) 18-75 years of age
- •At least 40 kilograms
- •In general good health as determined by the medical provider
- •Negative for hepatitis and HIV on donor viral screen
- •HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus
- •Not pregnant
- •Voluntary written consent
研究组 & 干预措施
Patients Using CD3-/CD19- NK cell product
Patients receive the apheresis product (collected day -1: enriched for NK cells using the CliniMACS® CD3 and CD19 Reagent System in combination with the large-scale tubing set (Miltenyi Biotec) to simultaneously deplete CD3+ cells to remove T-lymphocytes and deplete CD19+ cells to remove B-lymphocytes (CD3-/CD19- natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: CD3-/CD19- natural killer cells (Biological)
Patients Using CD3-/CD19- NK cell product
Patients receive the apheresis product (collected day -1: enriched for NK cells using the CliniMACS® CD3 and CD19 Reagent System in combination with the large-scale tubing set (Miltenyi Biotec) to simultaneously deplete CD3+ cells to remove T-lymphocytes and deplete CD19+ cells to remove B-lymphocytes (CD3-/CD19- natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: CliniMACS® CD3 and CD19 Reagent System (Device)
Patients Using CD3-/CD19- NK cell product
Patients receive the apheresis product (collected day -1: enriched for NK cells using the CliniMACS® CD3 and CD19 Reagent System in combination with the large-scale tubing set (Miltenyi Biotec) to simultaneously deplete CD3+ cells to remove T-lymphocytes and deplete CD19+ cells to remove B-lymphocytes (CD3-/CD19- natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: Cyclophosphamide (Drug)
Patients Using CD3-/CD19- NK cell product
Patients receive the apheresis product (collected day -1: enriched for NK cells using the CliniMACS® CD3 and CD19 Reagent System in combination with the large-scale tubing set (Miltenyi Biotec) to simultaneously deplete CD3+ cells to remove T-lymphocytes and deplete CD19+ cells to remove B-lymphocytes (CD3-/CD19- natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: Fludarabine (Drug)
Patients Using CD3-/CD19- NK cell product
Patients receive the apheresis product (collected day -1: enriched for NK cells using the CliniMACS® CD3 and CD19 Reagent System in combination with the large-scale tubing set (Miltenyi Biotec) to simultaneously deplete CD3+ cells to remove T-lymphocytes and deplete CD19+ cells to remove B-lymphocytes (CD3-/CD19- natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: Aldesleukin (Drug)
Patients Using CD3-/CD56+ purified NK cell product
Patients receive the apheresis product (collected day -1): purified for NK cells using the CliniMACS® CD3 Reagent System (Miltenyi Biotec) in combination with the large-scale tubing set to deplete CD3+ cells and then use the CliniMACS® CD56 Reagent System to enrich CD56+ NK cells (CD3-CD56+ natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: CD3-CD56+ natural killer cells (Biological)
Patients Using CD3-/CD56+ purified NK cell product
Patients receive the apheresis product (collected day -1): purified for NK cells using the CliniMACS® CD3 Reagent System (Miltenyi Biotec) in combination with the large-scale tubing set to deplete CD3+ cells and then use the CliniMACS® CD56 Reagent System to enrich CD56+ NK cells (CD3-CD56+ natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: CliniMACS® CD3 and CD19 Reagent System (Device)
Patients Using CD3-/CD56+ purified NK cell product
Patients receive the apheresis product (collected day -1): purified for NK cells using the CliniMACS® CD3 Reagent System (Miltenyi Biotec) in combination with the large-scale tubing set to deplete CD3+ cells and then use the CliniMACS® CD56 Reagent System to enrich CD56+ NK cells (CD3-CD56+ natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: CliniMACS® CD56 Reagent System (Device)
Patients Using CD3-/CD56+ purified NK cell product
Patients receive the apheresis product (collected day -1): purified for NK cells using the CliniMACS® CD3 Reagent System (Miltenyi Biotec) in combination with the large-scale tubing set to deplete CD3+ cells and then use the CliniMACS® CD56 Reagent System to enrich CD56+ NK cells (CD3-CD56+ natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: Cyclophosphamide (Drug)
Patients Using CD3-/CD56+ purified NK cell product
Patients receive the apheresis product (collected day -1): purified for NK cells using the CliniMACS® CD3 Reagent System (Miltenyi Biotec) in combination with the large-scale tubing set to deplete CD3+ cells and then use the CliniMACS® CD56 Reagent System to enrich CD56+ NK cells (CD3-CD56+ natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: Fludarabine (Drug)
Patients Using CD3-/CD56+ purified NK cell product
Patients receive the apheresis product (collected day -1): purified for NK cells using the CliniMACS® CD3 Reagent System (Miltenyi Biotec) in combination with the large-scale tubing set to deplete CD3+ cells and then use the CliniMACS® CD56 Reagent System to enrich CD56+ NK cells (CD3-CD56+ natural killer cells). Patients will also receive Cyclophosphamide, Fludarabine and Aldesleukin.
干预措施: Aldesleukin (Drug)
结局指标
主要结局
Disease-Free Survival
时间窗: 1 Year
the length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.
次要结局
- Incidence of Infusional Toxicities(Day 100)
- Incidence of Chronic Graft-Versus-Host Disease (GVHD)(1 Year)
- Incidence of Acute Graft-Versus-Host Disease (GVHD)(Day 100)
- Treatment-Related Mortality(Day 100, 1 Year and 2 Years)
- Overall Survival(1 Year and 2 Years)
- Disease-Free Survival(2 Years)