Phase I Trial Integrating HLA-Haploidentical Anti-CD19 CAR T Cells With Post-Transplantation Cyclophosphamide-Based HLA-Haploidentical Hematopoietic Cell Transplantation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 155
- 试验地点
- 1
- 主要终点
- Identify the safety of anti-CD19 CAR T-cell therapy in combination with HLA-haploidentical HCT in participants with high risk CD19+ hematologic malignancies
研究概览
简要总结
Background:
High-risk blood cancers (leukemias and lymphomas) often come back after treatment, and many cannot be cured with chemotherapy alone. These cancers may be treated and potentially cured in 2 ways: (1) Bone marrow transplant (allogeneic hematopoietic cell transplantation, or alloHCT) gives immune and blood stem cells from a donor. These new cells can attack the cancer and also grow into healthy blood. (2) Chimeric antigen receptor (CAR) T-cell therapy takes immune cells and changes them in a lab to better recognize and target certain cancers. But these 2 treatments are not usually given at the same time.
Objective:
To test alloHCT and CAR-T cell therapy, used together, in people with high-risk blood cancers.
Eligibility:
People aged 18 to 75 years with an aggressive blood cancer that has a protein on the surface called CD19. A healthy related donor aged 12 years or older is also needed; this donor may be a parent or child or may be some siblings or even extended family members, but has to be half-matched at something called the HLA (human leukocyte antigen).
Design:
Participants will be screened. They will have imaging scans, blood tests, and tests of their heart and lung function. They will have eye and dental exams. They may have fluid drawn from around their spinal cord (spinal tap) and tissue taken from inside a bone (bone marrow biopsy).
Healthy donors will provide bone marrow, immune cells, and about 9 tablespoons of blood for both the recipient s treatment and for research. They will also provide stool, saliva, and oral swabs just for research.
Recipient participants will stay in the hospital for 4 to 6 weeks. They will be given drugs over 6 days to prepare for the cell therapies. Both the donor bone marrow cells and CAR-T-cells will be given through a tube inserted into a vein. They will receive drugs to reduce complications after the treatments.
Participants will remain within a 1-hour drive of the hospital for 2 to 3 months after they leave the hospital. They will have frequent visits during that time. They will continue to have periodic follow-up visits for 5 years.
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详细描述
Background:
- High-risk hematologic malignancies generally are incurable without an allogeneic hematopoietic cell transplant (HCT), but even with HCT they are at high-risk of relapse and poor overall survival.
- Chimeric-antigen-receptor (CAR) T-cell therapy can offer a high remission rate for relapsed or refractory B-cell malignancies but is not curative in the majority of patients.
- Currently, these two therapies (HCT and CAR-T cells) are used individually or sequentially, with HCT being used as consolidation or salvage post-CAR-T cells or CART cells being used to treat post-HCT relapse.
- Allogeneic CAR-T cells may be given to treat post-transplant relapse, but have not been used early post-transplant due to potential increased risk of graft-versus-host disease (GVHD).
- Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic GVHD and the immunosuppressive burden after HCT, including allowing LAhaploidentical HCT to be performed safely and routinely worldwide.
- In pre-clinical major histocompatibility complex (MHC)-haploidentical HCT models, CAR-T cells can be given on day 0 or day +5 (before or early after PTCy) and exert potent anti-tumor effects without impairing PTCy s efficacy in preventing GVHD. Administration of CAR-T cells on day +9 or +14 was ineffective in eradicating leukemia.
- In our preclinical models, administration of CAR-T cells on day 0 (prior to PTCy) surprisingly led to better anti-tumor efficacy than when given on day +5, associated with better early expansion, less CD4+ CAR-T cells with a regulatory phenotype, more activated CD4+ CAR-T cells, and more cytotoxic CD8+ CAR-T cells.
- The premise for the clinical application is that the CAR-T cells given in conjunction with or early post-transplant would induce an initial deep remission, while the polyclonal allogeneic T cells contained in the HCT would eliminate escape clones and promote longterm cure.
- The direct integration of CAR-T cells with PTCy-based HCT has the potential to provide synergistic reduction of relapse, reduce the duration of treatment, and allow CAR-T cells to persist post-transplant.
Objectives:
- To identify the safety of donor-derived HLA-haploidentical anti-CD19 CAR-T cells that can be given in combination with PTCy-based HLA-haploidentical allogeneic HCT in participants who have high-risk CD19-expressing hematologic malignancies (Phase I -dose escalation).
- To estimate 1 year relapse and survival outcomes at the maximum tolerated dose (MTD) (Phase I - dose expansion)
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA - Recipient
- •Participants with high or very high-risk hematologic malignancies, as defined by the revised Disease Risk Index (DRI), or malignancy that remains persistently MRD+ (by flow cytometry, cytogenetics, FISH, PCR, or NGS) on most recently assessed disease specimen (within 2 months of initiating conditioning).
- •Hematologic malignancy must be CD19+ (uniform expression on immunohistochemistry or >= 80% on flow cytometry) as confirmed by CD19 IHC assay (BT51E) or flow cytometry (BD QuantiBRITE(TM) Beads PE Fluorescence Quantitation Kit). (Participants do not have to have refused or lack access to commercial anti-CD19 CAR-T-cell therapies since this study focuses on the integration of CAR-T cells and HCT and not specifically the CAR-T cells themselves; furthermore the construct used to manufacture this product is the same as used in a current commercial product, but developed from a new batch and with a similar but not identical manufacturing process.)
- •Karnofsky >= 60%.
- •Participants must have adequate organ and marrow function as defined below:
- •Cardiac ejection fraction >= 45% by 2D echocardiography;
- •Forced expiratory volume-1 (FEV-1) and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of >=50% predicted (this requirement would be waived in participants who are unable to properly perform pulmonary function tests - in such circumstances, participants must have pulse oximetry >=90% on room air and no dyspnea or obvious pulmonary restrictions);
- •Estimated serum creatinine clearance of >= 60 ml/minute/1.73m^2 calculated using eGFR in the clinical lab (participants with estimated serum creatinine clearance less than 60 may have measured creatinine clearance performed and if >= 60 will be considered eligible);
- •Total bilirubin <= 2X the upper limit of normal (participants with documented or suspected Gilbert s are exempt from this requirement);
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 5X the upper limit of normal.
- •At least one available HLA-haploidentical donor
- •Women of child-bearing potential (WOCBP) must agree to use a highly effective method of contraception (hormonal, intrauterine device (IUD), surgical sterilization, abstinence) at the study entry and for 1 year after transplant (restriction period).
- •Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and for 1 year after transplant. We also will recommend men with female partners of childbearing potential to ask female partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization). Men must not freeze or donate sperm within the same period.
- •Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 1 year after transplant.
- •Participants seropositive for human immunodeficiency virus (HIV) not due to intravenous immunoglobulin, must have adequate viral suppression (HIV viral load < 200 viral copies per ml of blood) prior to the beginning of conditioning.
- •For participants seropositive for hepatitis B virus (HBV) core antibody not due to intravenous immunoglobulin, a HBV viral load should be undetectable.
- •Participants seropositive for hepatitis C virus (HCV) not due to intravenous immunoglobulin must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
- •Ability of participant or legally authorized representative (LAR) to understand and the willingness to sign a written informed consent document.
- •Ability and willingness of participant to co-enroll on 20-C-0051: Gene Therapy Follow Up Protocol for Subjects Previously Enrolled in NCI for Immuno-Oncology Studies
- •14 Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH (<60 minutes drive), for a minimum of 100 days after transplant or longer if there are complications. Participants must commit to having an adult caregiver with them during the first 100 days after transplant in case of discharging from the hospital before 100 days.
- •INCLUSION CRITERIA - Donor
- •1. Related donor (age >=12) deemed suitable, eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, bone marrow, and stool for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation.
排除标准
- •Recipient
- •Participants who are receiving any other investigational agents within 3 weeks prior to the beginning of conditioning.
- •Active CNS involvement of primary hematologic malignancy
- •Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is metastatic, relapsed/refractory to treatment, or locally advanced and not amenable to intended curative treatment per standard of care.
- •Prior checkpoint inhibitor therapy within 6 weeks prior to the beginning of conditioning.
- •Prior history of seizure.
- •Uncontrolled infection.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents used in study.
- •Positive beta-HCG serum or urine pregnancy test performed in females of childbearing potential at screening. (A low positive test in a post-menopausal woman may not be exclusionary if deemed not indicative of pregnancy per gynecology.)
- •Uncontrolled intercurrent illness evaluated by medical history, physical exam, EKG, and laboratory testing (e.g., severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance) that would make it unsafe to proceed with transplantation.
- •EXCLUSION CRITERIA - donor
- •1. Pregnancy
研究组 & 干预措施
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: CD19 Flow Cytometry Assay (Device)
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: Sirolimus (Drug)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: Fludarabine (Drug)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: Cyclophosphamide (Drug)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: Sirolimus (Drug)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: Mycophenolate Mofetil (Drug)
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: Total Body Irradiation (Radiation)
Donor
Donors for Arms 1 and 2
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: Mycophenolate Mofetil (Drug)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: mCD19-CAR-CD28-CD3-zeta.(anti-CD19 CAR) retroviral vector-transduced allogeneic peripheral blood lymphocytes (PBL) (Biological)
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: Cyclophosphamide (Drug)
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: Fludarabine (Drug)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: Total Body Irradiation (Radiation)
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: CD19 Immunohistochemical Assay (Device)
Phase I: Dose Expansion
Participants receiving CAR-T cells at MTD
干预措施: mCD19-CAR-CD28-CD3-zeta.(anti-CD19 CAR) retroviral vector-transduced allogeneic peripheral blood lymphocytes (PBL) (Biological)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: CD19 Flow Cytometry Assay (Device)
Phase I: Dose Escalation
Participants receiving CAR-T cells at escalation/de-escalation dose levels to determine MTD
干预措施: CD19 Immunohistochemical Assay (Device)
结局指标
主要结局
Identify the safety of anti-CD19 CAR T-cell therapy in combination with HLA-haploidentical HCT in participants with high risk CD19+ hematologic malignancies
时间窗: 28 days (or 35 days for alternate dose levels)
Determine the fraction of evaluable recipient participants at each dose level who experience a dose-limiting toxicity (DLT).
Estimate the 1 year relapse and survival outcomes at the maximum tolerated dose
时间窗: 1 year
Estimates will be determined using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate for participants treated at the MTD and may be reported individually for the MTD and other dose levels. The results at indicated time points will be reported and may include 95% confidence intervals as appropriate.
次要结局
- Estimate the incidence and severity of CRS and ICANS(100 days)
- Estimate the incidence of Grade II-IV and Grade III-IV acute GVHD at +200 days(200 days)
- Estimate the incidence and severity of chronic GVHD at 1 year(1 year)
- Estimate incidence of primary engraftment failure and kinetics of engraftment(60 days)
- Estimate relapse/progression, non-relapse mortality, progression-free survival, and overall survival at 1 year(1 year)
- Estimate relapse/progression, non-relapse mortality, progression-free survival, and overall survival at 5 years(1 year)