A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 35
- 主要终点
- Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.
研究概览
简要总结
This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL.
详细描述
This was a initially a one cohort, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL. This main cohort completed enrollment. Two new cohorts were added via an amendment, Cohort 1 for high risk B-cell ALL patients at first relapse, and Cohort 2 for feasibility and safety of CTL019 in high risk B-cell ALL in patients that relapsed <6 months post allo-HSCT. Due to lack of recruitment, Cohort 1 and Cohort 2 halted recruitment. This decision was not related to any safety issue.
The study had the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Primary Follow-up, Secondary Follow-up (if applicable) and Survival Follow-up. The total duration of the study is 5 years from CTL019 cell infusion.
Efficacy analyses were performed only on the Main Cohort (n=79) who were infused with tisagenlecleucel. However, the data on disposition and demographics presented in this section includes all patients enrolled to the study (98) and all infused patients (80) (Main Cohort + Cohort 1). No patients were enrolled in Cohort 2.
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
- — 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relapsed or refractory pediatric B-cell ALL
- •Adequate organ function
- •For relapsed patients, documentation of CD19 tumor expression within 3 months of study entry.
- •Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
- •Life expectancy > 12 weeks.
- •Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening
- •Signed written informed consent and assent forms
- •Must meet the institutional criteria to undergo leukapheresis or have an acceptable, store leukapheresis product
- •Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.
- •Cohort 1 only:
- •First relapse AND hypodiploid cytogenetics OR
- •First relapse AND t(17;19) with defined TCF3-HLF fusion OR
- •First relapse with any cytogenetics provided the relapse occurred ≤ 36 months of initial diagnosis AND MRD at end of reinduction therapy is ≥0.01% by flow cytometry (local assessment)
- •Exclusion Criteria
- •Isolated extra-medullary disease relapse
- •Patients with concomitant genetic syndrome: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.
- •Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)
- •Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
- •Treatment with any prior gene therapy product
- •Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
- •Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
- •Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
- •Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).
- •Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines.
- •Patient has an investigational medicinal product within the last 30 days prior to screening.
- •Pregnant or nursing (lactating) women.
- •Women of child-bearing potential, defined as physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception for at least 12 months after the CTL019 infusion and after CAR T-cells are no longer present by qPCR on two consecutive tests
- •Sexually active males must use a condom during intercourse at least 12 months after the CTL019 infusion after CAR T-cells are no longer present by qPCR on two consecutive tests
排除标准
- 未提供
结局指标
主要结局
Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.
时间窗: during the 3 months after tisagenlecleucel administration
Evaluating the efficacy of tisagenlecleucel therapy from all manufacturing facilities as measured by overall remission rate (ORR) during the 3 months after tisagenlecleucel administration. ORR included complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by an Independent Review Committee assessment. Per response criteria defined by National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH) and International Working Group (IWG) guidelines. CR is defined as: Bone marrow \<5% blasts, Peripheral blood: Neutrophils \>1.0 x 10\^9/L, and Platelets \>100 x 10\^9/L and Circulating blasts \<1% and No evidence of extramedullary disease, at least 7 days transfusion independency. CRi is defined as all the prior criteria being met, except that the following exists: Neutrophils ≤1.0 x 10\^9/L, and/or Platelets ≤100 x 10\^9/L, and/or Platelet and/or neutrophil transfusions ≤7 days before the date of the peripheral blood sample for disease assessment.
次要结局
- Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From US Manufacturing Facility as Per IRC in the Main Cohort Only (Key Secondary)(3 months after tisagenlecleucel administration)
- Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT)(6 months after tisagenlecleucel administration)
- Percentage of Participants Who Achieved CR or CRi and Then Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) While in Remission Prior to Month 6 Resoonse(6 months)
- Site of Involvement of Subsequent Relapse(60 months)
- Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary)(3 months after tisagenlecleucel administration)
- Percentage of Participants With Best Overall Response (BOR) of CR or CRi With MRD Negative Bone Marrow by Flow Cytometry From All Manufacturing Facilities as Per IRC in the Main Cohort Only (Key Secondary)(3 months after tisagenlecleucel administration)
- Event-free Survival Per IRC Assessment(60 months)
- Overall Survival (OS)(60 months)
- Duration of Remission (DOR)(60 months)
- Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment(1 month)
- Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only(3 months)
- Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment(Month 60)
- Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute(Month 3)
- Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion(up to 6 months)
- Relapse-free Survival Per IRC Assessment(60 months)
- Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment(28 days)
- Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment(Month 60)
- Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment(Month 6)
- Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC(60 months)
- Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment(Month 6)
- Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019)(At any time post-baseline, up to a max. of 60 months)
- Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire(Month 3, M6, M12, M24, M60)
- Develop a Score Utilizing Clinical and Biomarker Data and Assess Its Ability for Early Prediction of Cytokine Release Syndrome (CRS)(3 months)
- Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin)(Maximum post-baseline (approx. 60 months))
- Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers)(Maximum post-baseline (approx. 60 months))
- Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC(60 months)
- Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC(0 to 84 days after infusion)
- Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion(Month 3, Month 12, Maximum post-baseline (approx. 60 months))
- Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility(60 months)
- Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From Fraunhofer Institute Manufacturing Facility as Per IRC(3 months)
- Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC(60 months)
- Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire(Month 60)
- Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute(Month 60)