Phase 1 Study of Lentivirally Transduced T Cells Engineered to Contain Anti-CD123 Linked to TCRζ and 4-1BB Signaling Domains in Pediatric Subjects With Refractory or Relapsed Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Evaluate the safety of CART123 in AML subjects
研究概览
简要总结
Phase 1 open-label study to evaluate the safety of intravenously administered, lentivirally transduced T cells expressing anti-CD123 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in pediatric subjects with relapsed/refractory Acute Myeloid Leukemia (AML).
详细描述
This is a Phase 1 study designed to evaluate the safety, feasibility, and preliminary efficacy of CART123 cells in pediatric subjects with relapsed/refractory Acute Myeloid Leukemia (AML). The study was originally designed to evaluate these primary endpoints at a single CART123 dose level (2x106 CART123 cells/kg). This dose level was selected based on experience in an adult trial using this investigational product in relapsed/refractory AML patients (NCT03766126).
As of Protocol Amendment V6, the study design has been converted into a 3+3 dose escalation design in order to further explore the safety of CART123 cells in the target disease population, and determine a maximum tolerated dose (MTD). The initial dose level (2x106 CART123 cells/kg) will be retrospectively identified as Dose Level 1 (DL1), and up to two new dose levels of CART123 cells will now be evaluated as follows:
- Dose Level 1 (DL1): 2x106 CART123 cells/kg
o <DL1 Fully Enrolled as of Protocol Amendment V6>
- Dose Level 2 (DL2): 5x106 CART123 cells/kg
- Dose Level 3 (DL3): 1x107 CART123 cells/kg
Dose Level 1 (DL1) was fully evaluated as of Protocol Amendment V6. Dose Level 2 (DL2) and Dose Level 3 (DL3) will be evaluated as follows:
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 29 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients ≥ 1 and ≤ 29 years of age at time of consent.
- •AML in second or greater relapse, post-transplant relapse, or chemotherapy-refractory disease. Specifically:
- •Second or greater relapse defined as flow cytometric confirmation of myeloid leukemia of at least 0.1% after second documented complete remission; OR
- •Any detectable disease post-allogeneic transplant with flow cytometric confirmation (MRD) of myeloid leukemia of at least 0.1% (as confirmed by Hematologics); OR
- •Refractory disease, defined as persistent bone marrow involvement with >5% blasts after two courses of induction chemotherapy for patients at initial presentation or >5% bone marrow blasts after one course of re-induction chemotherapy for patients who have relapsed after previously achieving a CR.
- •Subjects must have a suitable stem cell donor identified with projected ability to proceed to transplant within 6-8 weeks of CART123 infusion.
- •Adequate organ function defined as:
- •A serum creatinine based on age/gender
- •Adequate liver function
- •i. ALT ≤ 5 x ULN
- •ii. Total bilirubin ≤ 3 x ULN
- •iii. ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to AML infiltration of the liver.
- •c. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and < Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator
- •d. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO, or adequate ventricular function documented by a scan or a cardiologist. In cases where quantitative assessment of LVSF/LVEF is not possible, a statement by the cardiologist that the ECHO shows qualitatively normal ventricular function will suffice.
- •Adequate performance status defined as Lansky or Karnofsky score ≥ 50
- •Signed informed consent must be obtained.
- •No contraindications for leukapheresis (unless apheresis product previously acquired).
- •Subjects of reproductive potential must agree to use acceptable birth control methods.
排除标准
- •Pregnant or lactating (nursing) women.
- •Patients with relapsed AML with t(15:17).
- •Patients < 6 months from alloHSCT.
- •HIV infection.
- •Active hepatitis B or hepatitis C infection.
- •Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy
- •Patients requiring chronic treatment with systemic steroids or immunosuppressant medications. Low-dose physiologic replacement therapy with corticosteroids, topical steroids and inhaled steroids are acceptable. For additional details regarding use of steroids and immunosuppressant medications (including washout requirements prior to CAR T cell administration).
- •Any uncontrolled active medical disorder that would preclude participation as outlined.
- •Uncontrolled active infection
- •Subjects with CNS3 disease that is progressive on therapy or with CNS parenchymal lesions that may increase the risk of CNS toxicity. Subjects with adequately treated CNS leukemia are eligible.
- •Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
- •Patients with any prior history of myeloproliferative neoplasm.
- •Patients with somatic JAK2 V617F mutation by PCR or next generation sequencing.
研究组 & 干预措施
Treatment Arm
CART123 cells; cyclophosphamide; fludarabine
干预措施: CART123 cells; cyclophosphamide; fludarabine (Biological)
结局指标
主要结局
Evaluate the safety of CART123 in AML subjects
时间窗: 5 Years
* Occurrence of adverse events that are possibly, probably, or definitely related to CART123 cells * Occurrence of dose-limiting toxicities (DLTs) and determination of Maximum Tolerated Dose (MTD)
次要结局
- Evaluate study feasibility(15 Years)
- Evaluate the need for rescue alloHCT(15 Years)
- Evaluate manufacturing feasibility(15 Years)
- Describe preliminary efficacy(15 Years)