CD83 CAR T in Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase I Trial
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicity (DLT)
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of genetically engineered cells (CD83 chimeric antigen receptor [CAR] T cells) in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or has not responded to previous treatment (refractory). CD83 is a protein that is found on AML blasts. Blasts are abnormal immature white blood cells that can multiply uncontrollably: filling up the bone marrow and preventing the production of other cells important for survival. CD83 CAR T cells represent a new cell therapy to eliminate AML blasts, while avoiding the risk for graft versus host disease (GVHD) after stem cell transplant to replace bone marrow or, tumor toxicity like myeloid aplasia where the body's own immune system causes damage to the bone marrow stem cells. Therefore, human CD83 CAR T cells are a promising cell-based approach to preventing two critical complications of stem-cell transplant - GVHD and relapse. Giving CD83 CAR T cells may be safe, tolerable, and/or effective in treating patients with relapsed or refractory AML.
详细描述
PRIMARY OBJECTIVE:
I. To evaluate the safety and determine the maximal tolerated dose (MTD) of autologous anti-CD83 CAR T-cells (CD83 CAR T cells) administered as a single infusion to refractory/relapsed acute myeloid leukemia (AML) patients.
SECONDARY OBJECTIVES:
I. To observe and record activity against AML. II. To evaluate response for AML using 2022 European Leukemia Net (ELN) criteria.
III. To evaluate progression-free and overall survival after CAR T cell infusion.
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
- •Age ≥ 18 years old.
- •Karnofsky performance status score ≥ 70%.
- •Relapsed or refractory AML based upon ELN 2022 criteria.
- •Creatinine clearance: ≥ 40 mL/min (Cockroft-Gault).
- •Total bilirubin: ≤ 2mg/dL except for patients with Gilbert's syndrome, hemolysis, or related to disease.
- •Aspartate aminotransferase (AST) and alanine transaminase (ALT) < 3.0 x upper limit of normal (ULN).
- •Left ventricular (LV) ejection fraction: > 45% and be free of symptomatic congestive heart failure or uncontrolled arrhythmia.
- •Oxygen (O2) saturation: ≥ 92% on room air without needs for supplemental O
- •Absolute lymphocyte count: ≥ 0.2 x 10^9/L, HCT of ≥ 27% and platelets of ≥ 20 x 10^9/L. Transfusion support is allowed to meet HCT and platelet parameters prior to apheresis.
- •Life expectancy ≥12 weeks from the time of enrollment, per clinical judgment.
- •Negative serum pregnancy test in females of child-bearing potential (FOCBP). FOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
- •If history of allogeneic HCT, must have completed transplant at least 3 months prior, be off immunosuppression, including ruxolitinib, at least 2 weeks prior to apheresis, and have no evidence of GVHD requiring treatment at enrollment.
- •Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for 12 months following duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
- •Participants must be considered preliminarily eligible for an allogeneic hematopoietic cell transplantation, with potential donors identified per a transplant and cellular therapy consult at Roswell Park Comprehensive Cancer Center.
- •Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure.
排除标准
- •Concomitant systemic glucocorticoid use at a dose equivalent to > 10 mg daily prednisone at the time of apheresis and/or within 4 weeks of CD83 CAR T infusion for any reasons other than GVHD.
- •Diagnosis of acute promyelocytic leukemia (APL; AML M3 by French-American-British [FAB] classification).
- •Active central nervous system (CNS) leukemia; patients with history of CNS leukemia in complete response (CR) are eligible.
- •Patients enrolled in another investigational therapy protocol for their disease within 14 days or 5 half-lives prior to leukapheresis, whichever is shorter.
- •Patients requiring agents or any treatments other than hydroxyurea, single agent cytarbine,hypomethylating agents with or without ventoclax and/or targeted agents (i.e., FLT3, IDH2 or IDH1 inhibitors) to control blast counts within 14 days or 5 half-lives (whichever is shorter) prior to lymphodepletion.
- •Ongoing uncontrolled serious infection, pulmonary disease or psycho/social concerns.
- •HIV seropositivity or active hepatitis B or C infection within (defined by positive polymerase chain reaction [PCR]) 4 weeks of enrollment.
- •Other active malignancy within 2 years of study entry, except for basal cell cancer of skin, cervical cancer treated surgically with curative intent or localized prostate cancer managed with observational approach.
- •Active grade II-IV acute GVHD in patients with relapsed AML after HCT requiring treatment.
- •Prior solid organ transplant.
- •Active autoimmune disease requiring immunosuppressive therapy.
- •Pregnant or nursing female participants.
- •Unwilling or unable to follow protocol requirements.
- •Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug.
研究组 & 干预措施
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Questionnaire Administration (Other)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Leukapheresis (Procedure)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Computed Tomography (Procedure)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Lumbar Puncture (Procedure)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Autologous Anti-CD83 CAR T-cells (Drug)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Echocardiography (Procedure)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Fludarabine Phosphate (Drug)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Hydroxyurea (Drug)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Cyclophosphamide (Drug)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Chest Radiography (Procedure)
Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells)
Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.
干预措施: Biospecimen Collection (Procedure)
结局指标
主要结局
Incidence of dose-limiting toxicity (DLT)
时间窗: Up to 28 days
Will be defined as any adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) version (v)5. Cytokine release syndrome(CRS)/immune effector cell-associated neurotoxicity syndrome will be graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Guidelines. The DLTs will be summarized by dose level using frequencies and relative frequencies. Will employ the Bayesian optimal interval design to find the maximal tolerated dose (MTD). The target DLT rate for the MTD is = 0.33.
次要结局
- Objective response(At 28 days and 1 year)
- Time to treatment related adverse event(From treatment initiation until a treatment related adverse event, 12 months post infusion, or last follow-up, assessed up to 1 year)
- Overall survival(From treatment initiation until death due to any cause or last follow-up, assessed up to 1 year)
- Progression-free survival(From treatment initiation until disease progression/relapse, death due to any cause, subsequent treatment (censored), or last follow-up, assessed up to 1 year)
- Hematologic recovery(At 28 days)
- Time to hematologic recovery(From treatment initiation until hematologic recovery or last follow-up, assessed up to 1 year)
- Acute graft-versus-host disease (GVHD)(Up to 6 weeks)
- Time to GVHD(From treatment initiation until grade II-IV GVHD, 6 weeks post infusion, or last follow-up, assessed up to 1 year)
- Treatment-related adverse events(Up to 12 months)
- Number of peripheral blood chimeric antigen receptor (CAR) T cells(Up to 1 year)