Killer Cells Against Relapsed/Refractory Myeloid Acute Leukemia (KARMA): a Clinical Trial Evaluating the Safety and Efficacy of Expanded, Universal Donor Natural Killer Cells for Treatment of Relapsed/Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Rate of dose limiting toxicities
研究概览
简要总结
This is a phase I/II dose escalation study designed to determine the safety and estimate the efficacy of UD-NK cells combined with FLA chemotherapy in patients age 1-24.99 with relapsed or refractory acute myeloid leukemia.
PRIMARY OBJECTIVE:
I. To determine the safety and recommended phase II dose of adoptive NK cell therapy using UD-NK cells in pediatric and young adult patients with relapsed/refractory AML.
SECONDARY OBJECTIVES:
I. To estimate the efficacy of UD- NK cells with FLA chemotherapy in pediatric and young adult patients with relapsed/refractory AML.
EXPLORATORY OBJECTIVES:
I. To determine the immunophenotype and function of UD-NK cells
II. To characterize in vivo expansion of UD-NK cells
III. To determine the persistence of UD-NK cells
Six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.
详细描述
The treatment plan consists of Fludarabine/Cytarabine chemotherapy followed by six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.
In this study the first NK cell infusion is referred as day zero (D0), treatment plan activities prior or after D0 are denominated as day minus (D-) or day plus (D+).
FLA will be give as follows: Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2000 mg/ m2/day (days -6 to day -2)
Six doses of UD-NK cells will be given thrice weekly for two weeks beginning day 0. NK cell administration schedule may vary and doses may be given from day 0 to 21. A minimum of 2 days between NK cell doses is required. Patients must meet eligibility criteria for NK cell infusion as described in the protocol.
Patients will be eligible to receive a second cycle of chemotherapy for the following reasons:
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
- 1 Year 至 24 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with relapsed or primary refractory AML, including:
- •Patients with relapsed AML (Any patient in first or subsequent relapse are eligible. Patients with relapse after HSCT are eligible)
- •Primary refractory AML defined as failure to achieve a complete response after 2 cycles of induction chemotherapy, including persistent MRD positivity
- •Patients with isolated CNS or extramedullary disease are eligible Note: a response monitoring plan must be developed a priori for subjects with extramedullary disease
- •Patient age 1-24.99 years old
- •Negative serum test to rule out pregnancy within 2 weeks prior to enrollment in females of childbearing potential
- •o Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator for 6 months after the last dose of chemotherapy and/or NK cell infusion
- •Negative serology for human immunodeficiency virus (HIV)
- •Both males and females and members of all races and ethnic groups are eligible
- •Organ function requirements:
- •Renal function: Creatinine ≤ 2 mg/dl OR creatinine clearance > 60 ml/min/1.73m
- •Liver function: Total bilirubin ≤ 2 mg/dl (unless Gilbert's syndrome), AST and ALT ≤ 5 times the upper limit of normal (unless related to leukemic involvement). Upper limit of normal should be determined by the institutional defined normal laboratory range.
- •Cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥20%. May be eligible after cardiology clearance if qualitatively normal function or repeat measures are normal.
- •CNS: Patients with seizure disorder may be eligible if seizures well controlled
- •All prior treatment related non-hematologic toxicities must have resolved to ≤ Grade 2 prior to enrollment unless granted approval by study PI and/or Co-Is.
- •All patients and/or their legal guardians must be able to understand and willing to sign a written informed consent document
排除标准
- •AML directed therapies in the 2 weeks prior to beginning treatment on this protocol (except for hydroxyurea)
- •o Note: There is no waiting period required for patients having received intrathecal cytarabine, methotrexate and/or hydrocortisone
- •Patients on immunosuppressive therapy
- •o Patients must be off of all systemic immunosuppressive therapy for at least 2 weeks prior to enrollment with no evidence of recurrent GVHD
- •Patients with a history of donor lymphocyte infusion or cellular therapy within the last 30 days are not eligible for this study
- •Allogeneic SCT < 3 months prior to study enrollment
- •Any comorbidities that in the opinion of the investigator will preclude receiving study therapy
- •Performance status: Karnofsky or Lansky Performance Scale (PS) < 50
- •Uncontrolled infection, defined as an infection which has not resolved or does not show evidence of significant resolution after initiating appropriate therapy
- •o Asymptomatic viremia such as CMV, HPV, BK virus, HCV, etc. is NOT considered as an exclusion criterion
- •Uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease
- •History of autoimmune disease
- •Active GVHD at the time of enrollment
- •Patients with a history of adoptive cell therapy are excluded unless at least 30 days from infusion and with evidence of recovery of normal hematopoiesis (ANC ≥ 500/μL, platelet count ≥ 50,000/μL).
研究组 & 干预措施
Treatment
Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2000 mg/ m2/day (days -6 to day -2)
Six doses of universal donor IL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks starting on day 0. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.
干预措施: Universal Donor Natural Killer Cells (Biological)
结局指标
主要结局
Rate of dose limiting toxicities
时间窗: Up to 56 days after the first NK cell infusion
Incidence and severity of adverse events
时间窗: Up to 56 days after the first NK cell infusion
次要结局
- Minimal Residual Disease (MRD) negative response rate by flow cytometry(At the end of Cycle 1 and Cycle 2 (each cycle is 28 days))
- CR rate after first cycle(At the end of Cycle 1 (each cycle is 28 days))
- Relapse free survival and overall survival(1 year)
- Median duration of remission for patients who do not go onto transplant(1 year)
- Incidence of infectious complications(1 year)
- Percentage of patients receiving this regimen who are rendered transplant-eligible(1 year)
- Median time to neutrophil and platelet count recovery(1 year)