Safety and Efficacy of Expanded KIR-HLA Mismatched Natural Killer Cell Immunotherapy (AdaptNK) for High-Risk Myeloid Diseases as Bridge to Allogeneic Hematopoietic Stem Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD)
研究概览
简要总结
This is a multi-institutional Phase I/II study of an allogeneic KIR-HLA mismatched NK cell infusion (AdaptNK) and a short course of subcutaneous interleukin-2 (IL-2) administered after lymphodepleting chemotherapy [cyclophosphamide (CY)/fludarabine (FLU)] in patients with relapsed or refractory acute myelogenous leukemia (AML). AdaptNK is a natural killer (NK) cell product that is enriched for NK cells with an "adaptive", or human cytomegalovirus (CMV)-induced, phenotype.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •18-74 years with Karnofsky score ≥ 70%
- •75 years and older: KPS ≥ 70%, HCT-CI < 5 (excluding history of solid tumor), AND not frail by Fried frailty criteria (see Appendix III)
- •HLA type C1/C1 or C2/C2
- •Note: For easy determination, the definition of HLA-C ligand group assigments is included below:
- •HLA-C1 group alleles are defined as HLA-C01, C03, C07, C08, C12, C14, C16 HLA-C2 group alleles are defined as HLA-C02, C04, C05, C06, C15, C17, C18
- •adequate liver, renal, pulmonary and cardiac function
- •ability to be off glucocorticoids and other immunosuppressive medications indicated for acute or chronic GVHD for at least 28 days prior to the AdaptNK cell infusion
- •There must be sufficient time between the most recent therapy and the screening bone marrow as delineated below:
- •anti-leukemic systemic cytotoxic chemotherapy - 2 weeks
- •Targeted anti-leukemic agents (FLT-3, IDH, menin inhibitors) - 3 half-lives of the medication
- •Radiotherapy - 1 week
- •donor lymphocyte infusions - 6 weeks
- •hematopoietic growth factors (filgrastim, TPO agonists, EPO) - 1 week
- •biologic therapy (monoclonal antibodies, T-cell engagers) - 2 weeks
- •Immune effector cellular therapy - 4 weeks
- •Intrathecal chemotherapy for treatment of active CNS leukemia - there must be at least two CSF samples negative for leukemia separated by one week before enrollment.
- •WBC shall be < 25,000 before infusion. Hydroxyurea is permitted until day -3 to control excess blast proliferation. No other systemic treatment is allowed after the screening bone marrow is performed for inclusion in protocol
- •All prior treatment related toxicities should have resolved to ≤ grade 1 prior to study enrollment
- •agrees to use of adequate contraception from study enrollment to 4 months after cell infusion
- •voluntary written consent
排除标准
- •Myeloid neoplasms with known or strongly suspected germline background, except DDX41, TP53, or RUNX
- •Acute promyelocytic leukemia (APL)
- •myocardial infarction (MI) within previous 6 months of study enrollment
- •pregnant or breastfeeding
- •Active CNS involvement with AML
- •new or progressive pulmonary infiltrates
- •active autoimmune disease requiring immunosuppressive therapy
- •Preexisting inflammatory disease requiring immunosuppressive therapy
- •history of severe asthma and currently on chronic systemic medications
- •HIV-1/2 positivity or hepatitis C/B
- •active systemic infections requiring anti-infective treatment
- •received any investigational agent within the 14 days before the start of study treatment (1st dose of fludarabine)
- •Patients with second malignancies are excluded if they have required systemic cytotoxic chemotherapy within 1 year or if they are not in remission
- •Exception: patients that are on stable dosing of hormonal therapy (e.g. aromatase inhibitor or antiandrogen therapy) for active breast or prostate cancer for 1 year are eligible.
- •Patients with excised basal cell or squamous cell carcinoma of the skin are eligible.
- •Patients with excised carcinoma in situ of the cervix or breast are eligible.
- •Patients with untreated T1a or T1b prostate cancer are eligible.
研究组 & 干预措施
Dose Level Cohort 3
2.4 - 3 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: AdaptNK (Biological)
Dose Level Cohort 3
2.4 - 3 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Fludarabine (Drug)
Dose Level Cohort 3
2.4 - 3 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Cyclophosphamide (Drug)
Dose Level Cohort -1
Safety dose level. < 1 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: AdaptNK (Biological)
Dose Level Cohort 1
2.4 - 3 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: AdaptNK (Biological)
Dose Level Cohort 2
0.8 - 1 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: AdaptNK (Biological)
Dose Level Cohort 3
2.4 - 3 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: IL-2 (Drug)
Dose Level Cohort -1
Safety dose level. < 1 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Fludarabine (Drug)
Dose Level Cohort -1
Safety dose level. < 1 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Cyclophosphamide (Drug)
Dose Level Cohort -1
Safety dose level. < 1 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: IL-2 (Drug)
Dose Level Cohort 1
2.4 - 3 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Fludarabine (Drug)
Dose Level Cohort 1
2.4 - 3 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Cyclophosphamide (Drug)
Dose Level Cohort 1
2.4 - 3 x 10^8 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: IL-2 (Drug)
Dose Level Cohort 2
0.8 - 1 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Fludarabine (Drug)
Dose Level Cohort 2
0.8 - 1 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: Cyclophosphamide (Drug)
Dose Level Cohort 2
0.8 - 1 x 10^9 Total Nucleated Cells (TNC) of AdaptNK product administered intravenously (IV).
干预措施: IL-2 (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD)
时间窗: 1 year
The primary objective of the study is to assess the safety and determine the maximum tolerated dose (MTD) of AdaptNK administered as a single infusion intravenously (IV) to KIR-HLA mismatched patients with relapsed or refractory AML.
次要结局
- Safety of AdaptNK(Day 42)
- Objective response (OR)(Day 42)