A Phase II Trial of Tisagenlecleucel in First-line High-risk (HR) Pediatric and Young Adult Patients With B-cell Acute Lymphoblastic Leukemia (B-ALL) Who Are Minimal Residual Disease (MRD) Positive at the End of Consolidation (EOC) Therapy

Novartis Pharmaceuticals79 个研究点分布在 3 个国家目标入组 121 人2019年6月24日

适应症B-Cell Acute Lymphoblastic Leukemia

干预措施CTL019

概览

阶段: 2 期
干预措施: CTL019
疾病 / 适应症: B-Cell Acute Lymphoblastic Leukemia
发起方: Novartis Pharmaceuticals
入组人数: 121
试验地点: 79
主要终点: Disease Free Survival (DFS) rate without censoring for new anticancer therapy, including Stem Cell Transplantation (SCT) while in remission
状态: 进行中（未招募）
最后更新: 15天前

概览研究者入排标准研究组 & 干预措施结局指标研究点相似试验

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 tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who received first-line treatment and are EOC MRD positive. The study will have the following sequential phases: screening, pre-treatment, treatment & follow-up, and survival. After tisagenlecleucel infusion, patient will have assessments performed more frequently in the first month and then at Day 29, then every 3 months for the first year, every 6 months for the second year, then yearly until the end of the study. Efficacy and safety will be assessed at study visits and as clinically indicated throughout the study. The study is expected to end in approximately 8 years after first patient first treatment (FPFT). A post-study long term follow-up safety will continue under a separate protocol per health authority guidelines.

注册库

clinicaltrials.gov

开始日期

2019年6月24日

结束日期

2027年10月19日

最后更新

15天前

研究类型

Interventional

研究设计

Single Group

性别

All

研究者

发起方

Novartis Pharmaceuticals

责任方

Sponsor

入排标准

入选标准

•CD19 expressing B-cell Acute Lymphoblastic Leukemia
•De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC. EOC bone marrow MRD will be collected prior to screening and will be assessed by multi-parameter flow cytometry using central laboratory analysis.
•Age 1 to 25 years at the time of screening
•Lansky (age \< 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60%
•Adequate organ function during the screening period:
•A. Renal function based on age/gender B. ALT ≤ 5 times ULN for age C. AST ≤ 5 times ULN for age D. Total bilirubin \< 2 mg/dL (for Gilbert's Syndrome subjects total bilirubin \< 4 mg/dL)
•E. Adequate pulmonary function defined as:
•no or mild dyspnea (≤ Grade 1)
•oxygen saturation of \> 90% on room air F. Adequate cardiac function defined as LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram or MUGA within 6 weeks of screening
•Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3 blocks of standard chemotherapy for first-line B-ALL, defined as 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance with high-dose methotrexate.

排除标准

•M3 marrow at the completion of 1st line induction therapy
•M2 or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy or evidence of disease progression in the peripheral blood or new extramedullary disease prior to enrollment. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia at the time of screening.
•Philadelphia chromosome positive ALL
•Hypodiploid: less than 44 chromosomes and/or DNA index \< 0.81, or other clear evidence of a hypodiploid clone
•Prior tyrosine kinase inhibitor therapy
•Subjects with concomitant genetic syndromes associated with bone marrow failure states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Subjects with Down syndrome will not be excluded.
•Subjects with Burkitt's lymphoma/leukemia (i.e. subjects with mature B-ALL, leukemia with B-cell \[sIg positive and kappa or lambda restricted positivity\] ALL, with FAB L3 morphology and /or a MYC translocation)
•Has had treatment with any prior anti-CD19 therapy
•Treatment with any prior gene or engineered T cell therapy
•Other protocol-defined inclusion/exclusion may apply.

研究组 & 干预措施

Single dose of CTL019

Based on the subject's weight one of two possible dose ranges will be prepared for the subject: Subjects ≤ 50 kg: 0.2 to 5.0 x 10(6) CAR-positive viable T cells per kg body weight OR Subjects \> 50 kg: 0.1 to 2.5 x 10(8) CAR-positive viable T cells

干预措施: CTL019

结局指标

主要结局

Disease Free Survival (DFS) rate without censoring for new anticancer therapy, including Stem Cell Transplantation (SCT) while in remission

时间窗: 5 years after tisagenlecleucel infusion

DFS is defined as the time from the date of tisagenlecleucel infusion to the date of the first documented morphological relapse, occurrence of secondary malignancy or death due to any cause.

Overall Survival (OS) rate

时间窗: 4 years after tisagenlecleucel

OS is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason.

次要结局

Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies(8 years)
Persistence of CAR (reported as copies/ug) categorized by the time to B-cell recovery (recovery < 3 months, >3 months to < 6months, > 6 months)(8 years)
Cmax; cellular kinetic parameter of tisagenlecleucel(8 years)
Tmax; cellular kinetic parameter of tisagenlecleucel(8 years)
AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel(8 years)
AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel(8 years)
T1/2; cellular kinetic parameter of tisagenlecleucel(8 years)
Clast; cellular kinetic parameter of tisagenlecleucel(8 years)
Tlast; cellular kinetic parameter of tisagenlecleucel(8 years)
Impact of tisagenlecleucel dose on day 29 response(8 years)
AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel(Day 29)
Percentage of patients that have measureable anti-mCAR19 antibodies above patient specific cut-point (reported as a %) pre and post tisagenlecleucel infusion categorized by Day 28 response(8 years)
tisagenlecleucel transgene concentration(8 years)
Expression of tisagenlecleucel(8 years)
Cmax: cellular kinetic parameter of tisagenlecleucel(Day 29)
Tmax: cellular kinetic parameter of tisagenlecleucel(Day 29)
T1/2: cellular kinetic parameter of tisagenlecleucel(Day 29)
Percentage of participants with pre-existing antibodies(8 years)
Percentage of participants who are disease free without allogeneic stem cell transplant (SCT)(12 months after last infusion)
DFS rate with censoring for new anticancer therapy, including SCT, while in remission(5 years)
Percentage of participants achieving MRD negative CR or CRi at Month 3(3 months after the tisagenlecleucel infusion.)
Pediatric Quality of Life (PedsQL)(5 years)
European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y))(5 years)
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test(5 years)
Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test(5 years)
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test(5 years)
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test(5 years)
Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test(5 years)
Percentage of participants who are disease free without allogeneic stem cell transplant (SCT)(12 months after last infusion)
DFS rate with censoring for new anticancer therapy, including SCT, while in remission(5 years)
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test(5 years)
Percentage of participants achieving MRD negative CR or CRi at Month 3(3 months after the tisagenlecleucel infusion.)
European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y))(5 years)
Pediatric Quality of Life (PedsQL)(5 years)
Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test(5 years)
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test(5 years)
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test(5 years)
Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test(5 years)
Percentage of participants with pre-existing antibodies(8 years)
Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies(8 years)
Percentage of patients that have measureable anti-mCAR19 antibodies above patient specific cut-point (reported as a %) pre and post tisagenlecleucel infusion categorized by Day 28 response(8 years)
tisagenlecleucel transgene concentration(8 years)
Expression of tisagenlecleucel(8 years)
Persistence of CAR (reported as copies/ug) categorized by the time to B-cell recovery (recovery < 3 months, >3 months to < 6months, > 6 months)(8 years)
Cmax; cellular kinetic parameter of tisagenlecleucel(8 years)
Tmax; cellular kinetic parameter of tisagenlecleucel(8 years)
AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel(8 years)
AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel(8 years)
T1/2; cellular kinetic parameter of tisagenlecleucel(8 years)
Clast; cellular kinetic parameter of tisagenlecleucel(8 years)
Tlast; cellular kinetic parameter of tisagenlecleucel(8 years)
Impact of tisagenlecleucel dose on day 29 response(8 years)
AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel(Day 29)
Cmax: cellular kinetic parameter of tisagenlecleucel(Day 29)
Tmax: cellular kinetic parameter of tisagenlecleucel(Day 29)
T1/2: cellular kinetic parameter of tisagenlecleucel(Day 29)