Phase 1, Open Label, Dose Escalation Study to Evaluate the Safety, Expansion, Persistence, and Preliminary Clinical Activity of Autologous CD64 CAR T Cells in Patients With Relapsed and/or Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (HR-MDS)
概览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
概览
简要总结
This is a Phase 1, open label, dose-escalation study to evaluate the safety, expansion, persistence, and preliminary clinical activity of lentivirally transduced autologous T cells expressing anti-CD64 chimeric antigen receptors (CAR) expressing tandem CD3ζ and 4-1BB (CD3ζ/4-1BB) costimulatory domains in subjects with refractory or relapsed (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). This CAR T cell product will be referred to as "CD64 CAR T" which is CD64 directed, autologous, genetically modified CAR T cells. The primary objective identify the safety profile and maximum tolerated dose (MTD) of CD64 CAR T in subjects with R/R AML or MDS as determined by the defined DLTs using a standard Bayesian Optimal Interval (BOIN) design.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥ 18 years of age.
- •Subjects must have one of the following diagnoses per the International Consensus Classification (ICC) 2022 criteria:
- •Acute Myeloid Leukemia (AML).
- •Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML).
- •MDS with excess blasts (MDS-EB).
- •Refractory OR relapsed AML, MDS/AML, or MDS-EB, defined as:
- •a. Refractory disease i. Lack of at least PR after a minimum of 1 cycle of a hypomethylating agent (HMA) and venetoclax (Ven) combination (Ven/HMA) OR; ii. Lack of CRMRD- after a minimum of 3 cycles of Ven/HMA (MRD defined as ≥ 0.1% blasts by multi-parameter flow cytometry).
- •b. Relapsed disease i. Recurrence of \> 5% blasts in the bone marrow by morphology OR; ii. ≥ 0.1% blasts by multi-parameter flow cytometry when a previous bone marrow aspirate demonstrated MRD-negativity OR; iii. ≥ 0.1% blasts by multi-parameter flow cytometry ≥ 6 months post-allogeneic stem cell transplant AND no active graft-versus-host disease (GVHD) requiring immunosuppressive therapy.
- •Subjects must have received at least one prior line of therapy, including at least one line of therapy containing Ven.
- •Documentation of CD64 expression on myeloid blasts by flow cytometry after the most recent relapse, as determined by standardized and validated multiparameter flow cytometry assay (Hematologics, Inc., Seattle, WA).
排除标准
- •Subjects with Acute Promyelocytic Leukemia (APL) with t(15;17)
- •Receipt of previous chemotherapy for AML or MDS, as follows:
- •a. Prior to apheresis, the following washout periods apply: i. Hydroxyurea: 1 day ii. Hypomethylating agent and/or venetoclax: 7 days iii. Small molecule targeted therapy (including tyrosine kinase inhibitors): 3 half-lives or 7 days, whichever is shorter.
- •iv. Immune checkpoint inhibitors or other immunological agents: 5 half-lives or 28 days, whichever is shorter.
- •v. Investigational products: 5 half-lives or 28 days, whichever is shorter. vi. Any other systemic chemotherapy: 14 days vii. Allogeneic stem cell transplantation: 180 days viii. Donor lymphocyte infusion (DLI): 60 days ix. Craniospinal or total body radiation: 42 days b. After apheresis and prior to lymphodepletion, no treatment for AML and MDS is permitted, with the exception of bridging hydroxyurea with a washout period of 1 day prior to the start of the lymphodepletion regimen.
- •Concurrent use of systemic steroids or immunosuppressant medications. Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is not exclusionary.
- •Previous treatment with investigational gene or cell therapy (including CAR therapy).
- •Signs or symptoms indicative of CNS leukemia involvement. A CNS evaluation should be performed if CNS involvement is suspected to rule out CNS leukemia involvement.
- •Pregnant or lactating (nursing) women.
- •Known HIV infection or active Hepatitis B or Hepatitis C infection.
研究组 & 干预措施
Relapsed and/or Refractory AML and HR-MDS
Patients with relapsed and/or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (HR-MDS) will receive lymphodepleting chemotherapy followed by infusion of CD64 CAR T-cells, starting at dose level 1.
干预措施: CD64 CAR T Cells (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: Day 0 through Day 42
MTD will be established from the DLTs, which will be considered from the time of CD64 CAR T infusion (Day 0) through Day 42 after the subject's last infusion. A DLT is a treatment-emergent adverse event, or a clinically significant abnormal laboratory value, observed during the DLT observation period.
次要结局
- Manufacturability - Product Release Failure(Day 0 (Infusion))
- Manufacturability - Dose Failures(Day 0 (Infusion))
- Efficacy - Overall Response Rate (ORR)(Day 28, Month 3, and Month 6)
- Efficacy - Overall Survival(Up to 12 months post infusion)
- Efficacy - Progression Free Survival (PFS)(From treatment to end of study)
- Efficacy - Duration of Response (DOR)(From treatment to end of study)
- Efficacy - Need for Rescue Allogenic Stem Cell Transplant(From treatment to early termination for transplant)