Donor-Derived Very-Rapid Manufactured CD19-Specific T Cells for Lymphoid Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT)
研究概览
简要总结
This phase I trial investigates the side effects and best dose of CD19 positive (+) specific CAR-T cells in treating patients with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Sometimes researchers change the genetic material in the cells of a patient's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the patient's body. Receiving the T-cell infusion may help to control the disease.
详细描述
PRIMARY OBJECTIVE:
I. To determine the safety and maximum tolerated dose (MTD) of donor-derived genetically modified, CD19-specific T cells expressing mbIL15 and HER1t using the Rapid Personalized Manufacture (RPM) process (autologous CD19-CD8-CD28-CD3zeta-chimeric antigen receptor [CAR]-mbIL15-HER1t T cells [CD19-mbIL15-CAR-T cells]) administered to patients with CD19+ advanced lymphoid malignancies who have previously received an allogeneic hematopoietic stem cell transplantation (HSCT), including haploidentical HSCT.
SECONDARY OBJECTIVES:
I. To demonstrate the feasibility of the RPM process. II. To determine the incidence and grading of cytokine release syndrome (CRS) and neurotoxicity.
III. To determine persistence of genetically modified T cells. IV. To determine if cetuximab can control numbers of infused T cells. V. To screen for the development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t).
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •RECIPIENT: Patients with high risk or relapsed disease who are planning to receive, or have received prior allogeneic HSCT from an human leukocyte antigen (HLA)-matched related, or HLA-mismatched related donor; high risk is defined as patients with acute lymphoblastic leukemia who have delayed clearance of minimal residual disease, Philadelphia (Ph)-like, or complex, 11q23 or hypodiploid karyotype
- •RECIPIENT: Available donor who provided hematopoietic stem-cell (HSC)
- •RECIPIENT: Patients with CD19+ lymphoid malignancies that are refractory to or intolerant of standard treatment (as defined below):
- •B-cell Acute Lymphoblastic Leukemia (ALL)
- •Non-Hodgkin lymphoma (NHL) to include diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B cell lymphoma, mantle cell lymphoma, or transformed follicular lymphoma (TFL) as defined by the World Health Organization 2008 criteria
- •Small lymphocytic lymphoma (SLL)
- •Chronic lymphocytic leukemia (CLL)
- •NOTE: Refractory disease for acute and chronic leukemia is defined by:
- •Presence of > 5% malignant blasts in bone marrow and/or peripheral blood and/or minimal residual disease by flow cytometry or molecular analysis for fusion proteins and/or positive imaging for extra-medullary disease to most recent therapy
- •NOTE: Refractory disease for lymphoma is defined as:
- •Progressive disease or stable disease lasting =< 6 months, as best response to most recent chemotherapy regimen; or disease progression or recurrence =< 12 months after prior ASCT
- •Prior therapy must have included an anti-CD20 monoclonal antibody-containing regimen and an anthracycline-containing chemotherapy regimen
- •For patients with TFL, prior chemotherapy for follicular lymphoma and subsequent refractory disease after transformation to DLBCL
- •At least one measurable lesion according to revised International Working Group (IWG) Response Criteria
- •RECIPIENT: In patients with prior transplant, treatment will begin no earlier than 3 months post-transplant. Enrollment can occur earlier to allow time for donor cell collection
- •RECIPIENT: Karnofsky performance scale > 60
- •RECIPIENT: Patient able to provide written informed consent
- •RECIPIENT: Patient able to provide written informed consent for the long-term follow-up (LTFU) gene therapy study
- •RECIPIENT: Negative human anti-mouse antibody (HAMA)
- •DONOR: HLA-matched related, HLA-mismatched related, including haploidentical donor, or related donor cleared to donate based on Stem Cell Transplantation and Cellular Therapy (SCTCT) standard-of-care (SOC) guidelines
- •DONOR: Negative beta HCG in female of child-bearing potential defined as:
- •Not post-menopausal for 12 months, or
- •No previous surgical sterilization, or
- •Lactating females
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Patient must have measurable disease at the time of treatment
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Not received anti-thymocyte globulin (ATG), Campath, or other T-cell immunosuppressive antibodies or donor-lymphocyte infusion in the 28 days prior to T-cell infusion
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Serum creatinine < 2 x upper limit of normal (ULN)
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x ULN or =< 5 x ULN if documented liver metastases
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Total bilirubin =< 1.5 mg/dL, except in patients with Gilbert's syndrome in whom total bilirubin must be =< 3.0 mg/dL
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Cardiac ejection fraction >= 40%, and no clinically-significant electrocardiogram (ECG) findings
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No clinically significant pleural effusion, baseline oxygen saturation > 90% on room air
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No evidence of grade >= 2 active graft versus host disease (GVHD) using the Center for International Blood and Marrow Transplant Research (CIBMTR) Acute GVHD Grading System or requiring systemic steroid therapy greater than physiologic dosing at time of starting treatment
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Non-hematologic toxicity grade >= 2 (Common Terminology Criteria for Adverse Events [CTCAE] version 5) related to the lymphodepleting chemotherapy until the toxicity has resolved to grade =< 1 and the patient is afebrile
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: No new grade > 2 neurologic, pulmonary, cardiac, gastrointestinal, renal or hepatic (excluding albumin) toxicity
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Serum creatinine < 2 x ULN
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Oxygen saturation > 90% on room air
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Active clinically significant infection within 7-days of study treatment
- •T-CELL INFUSION REQUIREMENTS FOR RECIPIENT: Using an investigational agent
排除标准
- •RECIPIENT: Positive beta human chorionic gonadotropin (HCG) in female of child-bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization or lactating females
- •RECIPIENT: Patients with allergy to mouse products or cetuximab
- •RECIPIENT: Active central nervous system (CNS) disease in patient with history of CNS malignancy
- •RECIPIENT: Positive serology for human immunodeficiency virus (HIV)
- •RECIPIENT: Active hepatitis B or active hepatitis C
- •RECIPIENT: Has received a T-cell product within 6 weeks prior to planned infusion of genetically modified T cells
研究组 & 干预措施
Treatment (fludarabine, cyclophosphamide, CD19 T cell)
CHEMOTHERAPY: Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.
T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.
干预措施: Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells (Biological)
Treatment (fludarabine, cyclophosphamide, CD19 T cell)
CHEMOTHERAPY: Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.
T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.
干预措施: Cyclophosphamide (Drug)
Treatment (fludarabine, cyclophosphamide, CD19 T cell)
CHEMOTHERAPY: Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.
T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) as determined by dose limiting toxicity (DLT)
时间窗: Up to 30 days post-infusion
The MTD is defined as the highest dose at which no more than 1 of 6 patients experiences a DLT. The study will employ a standard 3+3 design to find the MTD of CD19-specific chimeric antigen receptor (CAR) T cell dose.
Incidence of adverse events
时间窗: Up to 15 years
Graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events will be summarized by frequencies and percentages by dose level.
次要结局
- Persistence of genetically modified T cells(Up to 12 months)
- Development of host immune responses against transgenes(Up to 12 months)
- Progression-free survival(From the time of T-cell infusion to date of progression of date of death, assessed up to 12 months)
- Incidence and grading of cytokine release syndrome (CRS)(Up to 12 months)
- Cytokine levels(Up to 12 months)
- Change in numbers of infused T cells(Up to 12 months)
- Homing ability of the infused T cells(Up to 12 months)
- Neurotoxicity(Up to 12 months)
- Overall survival(From the time of T-cell infusion to date of death, assessed up to 12 months)
- Disease response(At days 30 and 100)
- Presence of CD19 negative (-) malignant B cells(Up to 12 months)