Haploidentical Donor NK Cell Adoptive Therapy and Double T Cell Depleted Umbilical Cord Blood Transplantation With Post-Transplant IL-2 Immune Therapy For Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Number of Patients With Neutrophil Engraftment
研究概览
简要总结
RATIONALE: Giving chemotherapy and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving interleukin-2 (IL-2, aldesleukin) after transplant may stimulate the natural killer cells to kill any remaining cancer cells.
PURPOSE: This phase II trial is studying the side effects of giving combination chemotherapy together with total-body irradiation followed by interleukin-2 (IL-2, aldesleukin), and umbilical cord blood transplant and to see how well it works in treating patients with relapsed or refractory acute myeloid leukemia.
详细描述
OBJECTIVES:
Primary
- To determine the rate of neutrophil engraftment and grade III-IV acute graft-versus-host disease (GVHD) following a T cell depleted (TCD) umbilical cord blood (UCB) transplantation without post-transplant immunosuppression followed by administration of interleukin-2 (IL-2, aldesleukin) (every other day) days +3 to +13 to expand NK cells in vivo.
Secondary
- To evaluate the safety of this regimen as assessed by monitoring the rates of graft failure, acute GVHD, and transplant-related mortality (TRM).
- To perform quantitative, phenotypic, and functional assessments of the in vivo expanded UCB-derived NK cells on (day +72).
- To assess clinical disease response (leukemia clearance and complete remission) and survival duration in these patients.
- To evaluate the tolerability of aldesleukin in these patients.
- To evaluate the tolerance of IL-2
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
- — 至 45 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 0 to 45 years who meet one of the following criteria:
- •Primary induction failure defined as no complete remission (CR) after two or three induction cycles (no blast limit).
- •Relapsed acute myeloid leukemia (AML) with low disease burden
- •For patients 19 through 45 years of age: must have less than 10% marrow blasts at time of enrollment for patients who did not receive re-induction or measured at least 28 days from the start of re-induction therapy. Patients who have relapsed more than 12 months following a prior hematopoietic cell transplant (HCT) and did not reach CR following one re-induction cycle but have less than 10% marrow blasts are eligible.
- •For patients 0 through 18 years of age: must have less than 50% marrow blasts after no more than 3 induction attempts
- •CR3 or greater. This will include CRp defined as CR without platelet recovery to 100,000/mcL.
- •CR1 or CR2 with high risk features (therapy induced, prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD), high risk cytogenetic or molecular phenotype) with no available alternate (sibling, URD or UCB) donors.
- •Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and is in remission. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the protocol.
- •Have acceptable organ function within 14 days of enrollment defined as:
- •Renal: creatinine ≤ 2.0 mg/dL (adult patients) or calculated creatinine clearance > 40 ml/min (pediatric patients)
- •Hepatic: bilirubin, AST/ALT, ALP ≤ 5 x upper limit of normal
- •Pulmonary function: DLCOcorr > 50% of normal, (oxygen saturation [>92%] can be used in child where PFT's cannot be obtained)
- •Cardiac: left ventricular ejection fraction ≥ 45%
- •Karnofsky score (adults) > 70% or Lansky score > 50% (pediatrics)
- •Women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment.
- •All patients will be questioned about prior exposure to antibody therapy (including OKT3, rituximab, trastuzumab, and gemtuzumab) without affect to eligibility. Patients with prior exposure will have a blood sample collected for human anti-mouse antibody (HAMA). For patients with no prior antibody therapy exposure, no further action will be taken.
- •Not receiving prednisone or other immunosuppressive medications
- •Voluntary written consent
排除标准
- •Active infection at time of enrollment or documented fungal infection within 3 months
- •Evidence of HIV infection or known HIV positive serology
- •Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
- •If ≤ 18 years old, prior myeloablative transplant within the last 6 months. If > 18 years old prior myeloablative allotransplant or autologous transplant
- •Extensive prior therapy including > 12 months of any alkylator chemotherapy (etoposide >100 mg/m^2 x 5 days, cyclophosphamide >1 gm/m^2 or mitoxantrone >8 gm/m^2) delivered at 3-4 week intervals or > 6 months alkylator therapy (as above) with extensive radiation (determined by Radiation Oncology, e.g. mantle irradiation for Hodgkin's) and/or prior radiation therapy that makes a patient ineligible for total body irradiation (TBI).
- •Criteria for Second Course of IL-2 (begin day +60):
- •No Graft-Versus-Host Disease (GVHD), active infection or any other severe medical co-morbidity
- •Absolute neutrophil count (ANC) > 1000 without growth factor support
- •No grade 4 toxicity (except fevers) attributed to IL-2 during course #1
研究组 & 干预措施
UCBT With Post-Transplant IL-2
Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
干预措施: aldesleukin (Biological)
UCBT With Post-Transplant IL-2
Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
干预措施: cyclophosphamide (Drug)
UCBT With Post-Transplant IL-2
Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
干预措施: fludarabine phosphate (Drug)
UCBT With Post-Transplant IL-2
Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
干预措施: umbilical cord blood transplantation (Procedure)
UCBT With Post-Transplant IL-2
Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
干预措施: total-body irradiation (Radiation)
结局指标
主要结局
Number of Patients With Neutrophil Engraftment
时间窗: Day 42
Number of patient with absolute neutrophils \>500\*10\^8/kg by 42 days post transplant.
Number of Patients With Grade III-IV Acute Graft-Versus-Host (GVHD) Disease
时间窗: Day 100 Post Transplant
Number of patients with Grade III-IV GVHD. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Acute GVHD usually happens within the first 3 months after transplant.
次要结局
- Incidence of Primary Graft Failure(Day 42)
- Number of Patients With Acute Graft-Versus-Host (GVHD) Disease(Day 100 Post Transplant)
- Number of Patients With Transplant-Related Death (TRD)(1 Year Post Transplant)
- Number of Patients With Complete Remission of Disease(Day 100)
- Median Overall Survival(Month 6)
- Number of Patients With Successful Natural Killer Expansion(Day 72 Post Transplant)