A Phase 1 Study to Evaluate BAFFR-Targeting CAR T Cells for Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Incidence of adverse events
研究概览
简要总结
This phase I trial tests the safety and side effects of B-cell activating factor receptor (BAFFR) chimeric antigen receptor (CAR) T cells and how well they work in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) and B-cell lymphoblastic lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR T-cell therapy, such as BAFFR-CAR T cells, is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving BAFFR-CAR T cells may be safe, tolerable and/or effective in treating patients with relapsed or refractory B-cell ALL and B-cell lymphoblastic lymphoma.
详细描述
PRIMARY OBJECTIVE:
I. Assess the safety of administering autologous BAFFR-targeting CAR T cells (BAFFR[EQ]BBζ/EGFRt T cells) (also known as [aka], BAFFR-CAR T cells).
SECONDARY OBJECTIVES:
I. Evaluate the ability of BAFFR-CAR T cells to mediate clinical response in participants with B-ALL.
II. Evaluate the level of residual disease in participants who achieve remission after BAFFR-CAR T cell treatment.
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
- •Documented informed consent of the participant and/or legally authorized representative
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies
- •If unavailable, exceptions may be granted with study principal investigator (PI) approval
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) ≤ 2
- •Life expectancy ≥ 16 weeks
- •Histologically confirmed B-ALL or B-cell lymphoblastic lymphoma
- •Relapsed/refractory disease. Minimal residual disease (MRD) relapse is allowed
- •Evidence of tumor expressing BAFF-R at any level either by flow or immunohistochemistry
- •Recovered to ≤ grade 1 from the acute toxic effects (except alopecia and peripheral neuropathy) of prior anti-cancer therapy
- •No known contraindications to leukapheresis, steroids or tocilizumab
- •Ineligible for or failed prior CD19-targeted immunotherapy (e.g., blinatumomab or CD19-CAR T cells)
- •For participants who had prior CD19-CAR T cell therapy:
- •At least 90-days has elapsed since participant received last CD19-CAR T cell therapy AND
- •Persistence of prior CD19-CAR T cells must be evaluated and found to be < 5% prior to leukapheresis procedure
- •Note: Participants who have undergone stem cell transplantation (at least 100 days prior to enrollment) after the last CD19-CAR T cell therapy, are considered eligible and do not need to meet the above criteria
- •Participants with central nervous system (CNS) involvement by leukemia (CNS2 and asymptomatic CNS3) may be considered eligible after discussions with the study team
- •Total serum bilirubin ≤ upper limit of normal (ULN) (unless has Gilbert's disease or related to liver involvement by leukemia, then ≤ 3.0)
- •Aspartate aminotransferase (AST) ≤ ULN, unless related to liver involvement by ALL, then ≤ 3.0
- •Alanine aminotransferase (ALT) ≤ ULN, unless related to liver involvement by ALL, then ≤ 3.0
- •Creatinine clearance of ≥ 40 mL/min per 24-hour urine test or the Cockcroft-Gault formula
- •Left ventricular ejection fraction (LVEF) ≥ 50%
- •Oxygen (O2) saturation ≥ 92% on room air
- •Seronegative for HIV quantitative polymerase chain reaction (qPCR), hepatitis C virus (HCV), and active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR])
- •If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed OR
- •If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. The viral load must be undetectable
- •Meets other institutional and federal requirements for infectious disease titer requirements
- •Note Infectious disease testing to be performed within 28 days prior to start of protocol therapy
- •Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test
- •If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- •QuantiFERON-tuberculosis (TB) Gold or equivalent
- •Results do not impact patient eligibility; however, the test must be initiated prior to enrollment
- •Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy
- •Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
- •A complete liver evaluation (which includes ultrasound elastography, MRI of the liver and a hepatology consult) may be done if needed based on PI's recommendation
排除标准
- •Autologous/allogeneic stem cell transplant within 100 days at the time of enrollment
- •Immunosuppressant medications within 1 month prior to protocol enrollment
- •Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. Physiologic replacement of steroids (prednisone ≤ 7.5 mg /day or equivalent) is allowed
- •Auto-immune disease or active graft-versus-host disease (GvHD) within 3 months prior to protocol enrollment requiring systemic immunosuppressant therapy
- •Class III/IV cardiovascular disability according to the New York Heart Association (NYHA) Classification
- •Subjects with clinically significant arrhythmia or arrhythmias not stable on medical management within 2 weeks of enrollment
- •Any abnormal liver enzyme levels (as defined by grade 1 elevation from ULN in ALT, AST, and bilirubin levels) at time of enrollment, unless they are abnormal due to liver involvement by leukemia per the treating physician's discretion
- •Subjects with a known history or prior diagnosis of uncontrolled central nervous system (CNS) disorders such as optic neuritis or other immunologic or inflammatory disease affecting the CNS, including uncontrolled seizure disorder
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
- •Known significant bleeding disorders (e.g., severe von Willebrand's disease) or hemophilia
- •History of venous occlusive disease (VOD), or GvHD
- •Subjects with a history of the following GvHD may still be included in the study:
- •Resolved grade 2 or less steroid-sensitive acute skin GvHD
- •Grade 1 gastrointestinal (GI)-GvHD developed within 100 days post prior alloHCT
- •Limited chronic GVHD
- •History of stroke or intracranial hemorrhage within 6 months of enrollment
- •History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for ≥ 2 years
- •Clinically significant uncontrolled illness
- •Active systemic uncontrolled infection
- •Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
- •Females only: Pregnant or breastfeeding
- •Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures
- •Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
研究组 & 干预措施
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Autologous BAFFR-targeting CAR T Cells (Biological)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Bridge Therapy (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Chest Radiography (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Computed Tomography (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Echocardiography Test (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Leukapheresis (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Ultrasonographic Elastography (Procedure)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Fludarabine (Drug)
Treatment (BAFFR-CAR T cells)
Patients undergo leukapheresis and may receive bridging therapy per treating physician discretion. Patients then receive lymphodepletion therapy with cyclophosphamide IV and fludarabine IV on days -5 to -3 and BAFFR-CAR T cells IV over 10-15 minutes on day 0. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, chest x-ray, and PET/CT or CT throughout the study. Additionally, patients may also undergo liver ultrasonographic elastography at screening at discretion of investigator and brain MRI or CT, CSF specimen collection, and ECHO or MUGA throughout the study.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Incidence of adverse events
时间窗: Up to 28 days after chimeric antigen receptor (CAR) T cells
Will be graded using Common Terminology Criteria for Adverse Events version 5.0, American Society for Transplantation and Cellular Therapy Consensus Criteria on Cytokine Release Syndrome/Neurotoxicity, graft-versus-host disease (GVHD) criteria, and Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome identification and grading. Will be summarized by organ involved, severity, time of onset, and attribution.
Dose-limiting toxicity
时间窗: From the start of CAR T infusion up to 28 days
Will be described individually.
次要结局
- Severity of GVHD in recipients of prior allogeneic hematopoietic stem cell transplantation(Within 8 weeks after T cell infusion)
- Disease response rate(At 4 weeks)
- Minimal residual disease negative rate(At 4 weeks)
- Duration of B-cell aplasia(Up to 15 years)
- Progression-free survival(From T cell infusion to the first observation of disease relapse/progression or death from any cause, whichever occurs first, assessed up to 15 years)
- Overall survival(From T cell infusion to death from any cause, assessed up to 15 years)