A Phase I/II Clinical Trial Testing the Safety and Feasibility of IL-21- Expanded Natural Killer Cells for the Induction of Relapsed/Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Maximum Tolerated Dose (MTD) of membrane-bound interleukin 21 (mbIL21)-Expanded Haploidentical NK Cells After Induction Chemotherapy with Fludarabine, Cytarabine, and Granulocyte-colony stimulating factor (G-CSF).
研究概览
简要总结
Relapsed acute myeloblastic leukemia (AML) requires remission prior to allogeneic Hematopoietic Stem Cell Transplant (HSCT) for optimal survival, but is a disease with poor response to chemotherapy. Human leukocyte antigen (HLA) haploidentical, Natural killer (NK) enriched peripheral blood cell infusions have shown safety in patients with poor prognosis AML. Though not powered for such an assessment, this trial showed a promising but not statistically significant trend in remission rate. NK cell therapy was limited by small numbers of NK cells attainable through leukapheresis. We have now demonstrated that large numbers of NK cells can be propagated ex vivo from a small volume blood draw, obviating the need for donor leukapheresis. The purpose of this trial is to determine the feasibility and maximum tolerated dose of expanded NK cells and estimate the toxicity of treating relapsed/refractory AML with fludarabine + high-dose cytarabine + G-CSF (FLAG) chemotherapy followed by haploidentical expanded natural killer (NK) cells.
The first NK cell dosing cohort will be well below the currently-established safe dose of pheresis-derived NK cells, as expanded NK cells may have increased toxicity because of their activated phenotype. In order to avoid accruing patients at suboptimal doses, a dose escalation schema based on the principles of an accelerated titration design is used in this study to allow expeditious advancement up to the current safe dose of NK cells.
详细描述
While growing the NK cells from the blood in the lab, mismatched T cells may also grow, which can cause a reaction against normal tissue called graft-vs-host disease (GvHD). In the lab, the T cells will be removed from the cell product using special magnets and antibody-coated magnetic beads. The drug aldesleukin (interleukin-2) is then added to the NK cells to improve their function. The aldesleukin will be washed out of the cell product before it is given to you.
The NK cells will be donated from a family member who has a certain genetic type in their blood called HLA that partly matches yours.
If you agree to take part in this study, you will be assigned to a dose level of NK cells based on when you joined this study. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue for up to 6 dose levels or until the highest tolerable dose of NK cells is found. One (1) to 10 participants will be treated in each dose level.
The day you receive the first NK cell infusion is called Day 0. The days before you receive your NK cell infusion are called minus days (D-). The days after you receive the NK cell infusion are called plus days (D+).
Study Drug Administration:
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
- 2 Years 至 59 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Obtained within 30 days prior to beginning the lymphodepleting conditioning regimen, unless otherwise specified.
- •Patients with relapsed AML, including Canadian Neurological Scale (CNS) disease or previous hematopoietic stem cell transplantation, which has failed remission to at least one cycle of standard or experimental reinduction chemotherapy, or primary refractory AML (primary AML that has failed remission to at least two cycles of induction therapy)
- •Availability of a haploidentical family peripheral blood donor selected for best possible killer cell inhibitory receptor (KIR) reactivity.
- •Patient age between 2 and 59 years, inclusive.
- •Patient must have recovered from the treatment-related toxicities of prior cytotoxic agents received in the 4 weeks prior to beginning treatment on this protocol, with the exception of cytopenias resulting from persistent disease, and alopecia.
- •"Zubrod" performance scale ≤ 2 or "Lansky" scale ≥
- •Adequate renal function defined as:
- •Serum creatinine ≤2 mg/dL for adults.
- •Serum creatinine ≤2 mg/dL or ≤2 times upper limit of normal (ULN) for age (whichever is less) for children.
- •Or, if serum creatinine does not meet above criteria, patient will be eligible if 24h creatinine clearance ≥60 mL/min/1.73m
- •Adequate liver function, defined as: Total bilirubin ≤2 mg/dL and serum glutamate pyruvate transaminase(SGPT) (ALT) ≤2.5 x ULN for age (unless Gilbert's disease or abnormal liver function due to primary disease).
- •Pulmonary symptoms controlled by medication and pulse oximetry ≥ 92% room air.
- •New York Heart Association classification < III
- •Negative serum test to rule out pregnancy within 2 weeks prior to registration in females of childbearing potential (non childbearing potential defined as premenarchal, greater than one year post-menopausal, or surgically sterilized).
- •Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator.
- •Negative serology for human immunodeficiency virus (HIV).
排除标准
- •Failed attaining remission with any previous FLAG therapy.
- •Investigational therapies in the 4 weeks prior to beginning treatment on this protocol.
- •Congestive heart failure <6 months prior to screening
- •Unstable angina pectoris <6 months prior to screening
- •Myocardial infarction <6 months prior to screening
研究组 & 干预措施
NK Cells + Chemotherapy Starting
Starting on Day -7, G-CSF daily by vein until post nadir of absolute neutrophil counts (ANC) are equal or over 1000. Day -6 to Day -2 Fludarabine administrated by vein at 30 mg/m^2. Four hours later Cytarabine administrated by vein at 2 g/m^2. Natural killer (NK) cell infusion Days 0 to 14 for 6 doses total. The first group of participants receive lowest dose level. Each new group receives a higher dose than the group before it, if no intolerable side effects were seen. This will continue for up to 6 dose levels or until the highest tolerable dose of NK cells is found. One (1) to 10 participants will be treated in each dose level.
NK Cell infusion on Days 0 to 14 for 6 doses total according to dose escalation schema.
干预措施: NK Cells + Chemotherapy Starting (Biological)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of membrane-bound interleukin 21 (mbIL21)-Expanded Haploidentical NK Cells After Induction Chemotherapy with Fludarabine, Cytarabine, and Granulocyte-colony stimulating factor (G-CSF).
时间窗: 28 days
Maximum tolerated dose defined as highest dose studied in which 6 patients have been treated and at most 2 patients with dose-limiting toxicities (DLTs) observed. A dose-limiting toxicity (DLT) is defined as: Acute severe (grade 3 or 4) infusional allergic reaction related to the NK cells infusion. Prolonged cytopenia beyond D+28. If neutropenia is still present at day 28, that will trigger the designation of prolonged neutropenia as a DLT. If neutrophil counts have recovered by day 28, then no DLT will have occurred. In either case, the status of neutrophil recovery beyond day 28 will not change the designation of DLT or No DLT made at day 28. Acute GvHD overall grade 3 or 4. Severe (grade 3 or 4) unexpected toxicity related to the NK cell infusion.
次要结局
- Complete Remission (CR) Assessment Following Infusion of the NK Cells(Baseline up to Day 56)
- Donor NK-Cell Expansion(28 days)