Phase 1 Trial of Autologous CD123-Directed CAR T-Cells (CART123) as Monotherapy or in Combination With Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Evaluate the Safety of CART123
研究概览
简要总结
This study is designed to evaluate the safety and effectiveness of CART123 cells either alone or when combined with ruxolitinib in pediatric and young adult subjects with relapsed or refractory AML. Subjects will be enrolled into one of two treatment cohorts: subjects who will receive CART123 alone (Cohort A) or subjects who will receive CART123 in combination with ruxolitinib (Cohort B).
详细描述
This trial will be conducted at the Children's Hospital of Philadelphia with CART123 infusions occurring in an outpatient setting with close follow-up. Approximately 18 subjects will be treated on Cohort A and 12 patients treated on Cohort B.
Cohort A will consist of a dose escalation of CART123 cells administered intravenously on Day 0 after lymphodepleting chemotherapy. Subjects enrolled on Cohort A will receive a standard regimen of fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (500 mg/m2/day x 2 days). There is the most experience with the use of this regimen in facilitating adoptive immunotherapy in completed and ongoing pediatric CART trials.
Cohort B will consist of a fixed dose of CART123 cells (2x10^6 CART123 cells/kg) to be administered intravenously on Day 0 in combination with age and BSA-based dosing of ruxolitinib given orally from the start of lymphodepleting chemotherapy until Day -2 and again from Day+7 to Day+13. Subjects enrolled on Cohort B will receive the regimen fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (1000 mg/m2/day x 3 days). This regimen of enhanced lymphodepletion has been employed with other investigational CAR T-cell therapies with the goal of improving CAR T-cell expansion. There is no dose escalation of CART123 cells or ruxolitinib on this cohort, but a dose de-escalation of ruxolitinib is planned in the event of unacceptable toxicity defined by dose de-escalation rules.
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
- 0 Years 至 29 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Age at time of consent: Cohort A: 0-29 years. Cohort B: 1-29 years (Note: the first subject at each dose level of Cohort B must be ≥12 years old)
- •2. Subjects with AML in second or greater relapse, post-transplant relapse, or with chemotherapy-refractory disease. Specifically:
- •Second or greater relapse defined as bone marrow flow cytometric confirmation of myeloid leukemia of at least 0.1% or development of extramedullary disease by imaging or biopsy after second documented complete remission; OR
- •Any detectable disease post-allogeneic transplant with bone marrow flow cytometric confirmation of myeloid leukemia of at least 0.1% or development of extramedullary disease by imaging or biopsy; OR
- •Refractory disease, defined as: Persistent bone marrow involvement with ≥0.1% disease by flow cytometry or persistent extramedullary disease by imaging or biopsy after two courses of induction chemotherapy for patients at initial presentation, ≥ 0.1% bone marrow disease by flow cytometry or persistent extramedullary disease by imaging or biopsy after one course of induction chemotherapy for patients who have relapsed after previously achieving a CR , and ≥ 0.1% bone marrow disease by flow cytometry or persistent extramedullary disease by imaging or biopsy after one course of AML-directed chemotherapy for those with myeloid lineage switch.
- •3. Subjects must have an identified stem cell donor with the ability to proceed rapidly to transplant following CART123 treatment if indicated.
- •4. Adequate organ function defined as:
- •Serum creatinine based on age/gender.
- •Adequate liver function: ALT ≤ 500 U/L, Bilirubin ≤3x the upper limit of normal, and 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.
- •Must have a minimum level of pulmonary reserve defined as ≤Grade 1 dyspnea and <Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia if necessary) if PFTs are clinically appropriate as determined by the treating investigator.
- •Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or another scan.
- •5. Adequate performance status defined as Lansky or Karnofsky performance score ≥
- •6. Subjects of reproductive potential must agree to use acceptable birth control methods.
排除标准
- •1. Active hepatitis B or active hepatitis C
- •2. HIV infection
- •3. Active acute or chronic GVHD requiring systemic therapy
- •4. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
- •5. CNS disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
- •6. Pregnant or nursing (lactating) subjects.
- •7. Uncontrolled active infection
研究组 & 干预措施
Cohort B
In Cohort B, the treatment regimen will consist of lymphodepleting chemotherapy and ruxolitinib followed by a fixed dose of CART123 cells and age and body surface area-adjusted dose of ruxolitinib. Subjects enrolled on Cohort B will receive the regimen fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (1000 mg/m2/day x 3 days).
干预措施: Ruxolitinib (JAKAVI®) (Drug)
Cohort A
In Cohort A, the treatment regimen will consist of lymphodepleting chemotherapy followed by CART123 infusion with planned dose escalation. Subjects enrolled on Cohort A will receive a standard regimen of fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (500 mg/m2/day x 2 days).
干预措施: Anti-CD123 LV redirected T cells (CART123) (Biological)
Cohort B
In Cohort B, the treatment regimen will consist of lymphodepleting chemotherapy and ruxolitinib followed by a fixed dose of CART123 cells and age and body surface area-adjusted dose of ruxolitinib. Subjects enrolled on Cohort B will receive the regimen fludarabine (30 mg/m2/day x 4 days) and cyclophosphamide (1000 mg/m2/day x 3 days).
干预措施: Anti-CD123 LV redirected T cells (CART123) (Biological)
结局指标
主要结局
Evaluate the Safety of CART123
时间窗: 5 years
Frequency of Adverse events will be measured by evaluating the frequency and severity of treatment related adverse events following administration of CART123
Safety of CART123 in combination with Ruxolitinib
时间窗: 5 Years
Frequency of Adverse events will be measured by evaluating the frequency and severity of treatment related adverse events following administration of CART123 and Ruxolitinib
Determine Maximum Tolerated Dose of CART123
时间窗: 5 years
The Maximum Tolerated Dose will be determined by measuring the incidence of dose limiting toxicities following administration of the CART123 product.
次要结局
- Determine Feasibility of CART123 Treatment(5 years)
- Determine feasibility of combination treatment with CART123 and ruxolitinib(5 years)
- Determine the Preliminary Efficacy of CART123(5 years)
- Determine the Preliminary Efficacy of CART123 + Ruxolitinib(5 years)
- Evaluate the need for rescue stem cell transplant following treatment with CART123 or CART123 with Ruxolitinib(5 years)
研究者
Stephan Grupp MD PhD
Chief, Cell Therapy and Transplant Section Director, Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy Medical Director, Cell and Gene Therapy Lab
Children's Hospital of Philadelphia