A Single-Arm Multicenter Phase II Study Preceded by Dose Evaluation to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab (MT103) in Pediatric and Adolescent Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 93
- 试验地点
- 50
- 主要终点
- Phase I: Number of Participants With Dose-limiting Toxicities (DLTs)
研究概览
简要总结
The purpose of this study is to determine the dose of the bispecific T cell engager blinatumomab (MT103) in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and to assess whether this dose of blinatumomab is effective.
详细描述
Childhood acute lymphoblastic leukemia (ALL) is a type of cancer of the blood and bone marrow in which the bone marrow makes too many abnormal immature lymphocytes.
Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against cluster of differentiation (CD)19 expressing cells.
The purpose of this study is to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of escalating doses of blinatumomab in pediatric and adolescent patients with relapsed/refractory B-precursor ALL, to select a dose and to investigate the efficacy and safety of that dose of blinatumomab in the above-mentioned patient population.
The phase 1 part of the study included the evaluation of four dose levels of blinatumomab with comprehensive PK/PD assessments and was separated in 2 parts:
- Phase 1 dose evaluation/escalation part to define the recommended phase 2 dose of blinatumomab in patients aged 2 to 17 years
- Phase 1 PK expansion part in patients aged < 18 years to further assess PK/PD at the recommended phase 2 dose. In this part additional participants were enrolled to ensure that 6 patients in each of the 2 older age groups (2-6 and 7-17 years) were analyzed for PK before recruitment of infants < 2 years of age began.
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 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Morphologic evidence of B-precursor ALL with > 25% blasts in bone marrow (M3) at study enrolment
- •Age less than 18 years at enrollment
- •Relapsed/refractory disease:
- •Second or later bone marrow relapse,
- •Any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or
- •Refractory to other treatments: Patients in first relapse must have failed to achieve a CR following full standard reinduction chemotherapy regimen of at least 4 weeks duration. Patients who have not achieved a first remission must have failed a full standard induction regimen
- •Karnofsky performance status more than or equal to 50% for patients more than or equal to 16 years and Lansky Performance Status (LPS) of more than or equal to 50% for patients less than 16 years
- •Organ function requirements: All patients must have adequate renal and liver functions
排除标准
- •Active acute or extensive chronic graft-versus-host disease (GvHD)
- •Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment
- •Evidence for current central nervous system (CNS) involvement by ALL (CNS 2, CNS 3) or testicular involvement by ALL
- •History of relevant CNS pathology or current relevant CNS pathology
- •History of autoimmune disease with potential CNS involvement or current autoimmune disease
- •Any HSCT within 3 months prior to blinatumomab treatment
- •Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (except for intrathecal chemotherapy and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids)
- •Chemotherapy related toxicities that haven't resolved to less than or equal to Grade 2
- •Radiotherapy within 2 weeks prior to blinatumomab treatment
- •Immunotherapy (e.g. rituximab, alemtuzumab) within 6 weeks prior to blinatumomab treatment
- •Any investigational product within 4 weeks prior to study entry
- •Previous treatment with blinatumomab
- •Active severe infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
- •Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)
结局指标
主要结局
Phase I: Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: Cycle 1, 28 days
The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities.
Percentage of Participants With Complete Remission in the First Two Cycles
时间窗: Cycles 1 and 2 (12 weeks)
Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as * M1 bone marrow (bone marrow blasts \< 5%) * No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts.
次要结局
- Time to Hematological Relapse (Duration of Response)(Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.)
- Overall Survival(Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.6 months for phase 2.)
- Number of Participants With Adverse Events(From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days)
- Steady State Concentration of Blinatumomab(Cycles 1 and 2 during the IV infusion on day 3 (at least 48 hours after start of infusion) and days 8, 15 and 22 (steady state) and day 29 at End of Infusion (EoI) and 2, 4, and 8 hours after EoI for ages ≥ 2 years.)
- Relapse-free Survival(Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.)
- Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant During Blinatumomab Induced Remission(Up to the data cut-off date of 12 January 2015; Maximum duration on study was 24 months in phase 1 and 15 months for phase 2.)
- Number of Participants Who Developed Anti-blinatumomab Antibodies(Predose up until 30 days after last dose of study medication; median treatment duration was 28 days.)
- Serum Cytokine Peak Levels(Cycle 1 and 2 day 1 (prior to infusion, 2 and 6 hours after infusion start), day 2 and day 3.)