Phase 2/3 Study Evaluating Efficacy and Safety of Erythrocytes Encapsulating L-asparaginase (GRASPA)Versus Reference L-asparaginase Treatment in Combination With Standard Polychemotherapy in Patient With First Recurrence of Philadelphia Negative Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 85
- 试验地点
- 27
- 主要终点
- Duration of Asparaginase Activity >100 U/L During Induction
研究概览
简要总结
Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies (A-Abs), which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA improves pharmacokinetics, tolerability and maintain circulating asparaginase activity due to the protective barrier of the erythrocyte membrane.
This study is run to confirm the benefit/risk profile of GRASPA at 150 IU/kg in combination with the COOPRALL regimen in adults and children patients with relapsed ALL, with or without known hypersensitivity to L-asparaginase.
详细描述
This open, randomized international Phase 2/3 study will enrol patients with relapsed ALL. The co-primary endpoints were the duration of asparagine depletion < 2µmol/L and the incidence of asparaginase hypersensitivity during induction. Key secondary endpoints are complete remission (CR), minimal residual disease (MRD), event free survival (EFS) and overall survival (OS).The study was powered to detect 3-fold difference in the incidence of allergic reactions between treatments. patients will be randomized to GRASPA or to Reference L-asparaginase. Patients with history of hypersensitivity to previous L-asparaginase treatment will be treated with GRASPA (exploratory arm)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient from 1 to 55 years old (Children and adolescents from 1 to 17 years/ Adults from 18 to 55 years)
- •Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma) OR Failure to ALL first line treatment (no complete remission obtained)
- •Patient previously treated with free E.Coli L-asparaginase form or pegylated one
- •Performance Status ≤ 2 (WHO score)
- •Patient informed and consent provided (the 2 parents need to consent when children are below 18)
排除标准
- •ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive)
- •Patient with 2nd relapse and over
- •Women of childbearing potential without effective contraception as well as pregnant or breast feeding women
- •Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)/Serum creatinine 2 x ULN unless related to ALL /ALT or AST 5 x ULN unless related to ALL /Pancreatitis history /Other malignancy that ALL / Severe Infection, HIV positive, active hepatitis related to B or C virus infection / Trisomy 21 / Other serious conditions according to investigator's opinion
- •Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0)
- •History of grade 3 transfusional incident
- •Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient
- •Patient under concomitant treatment likely to cause hemolysis
- •Patient undergoing yellow fever vaccination
- •Patient under phenytoin treatment
- •Patient included in previous clinical study less than 6 weeks ago
研究组 & 干预措施
GRASPA
Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL).
GRASPA® administration takes place as below:
- for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity)
- for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)
干预措施: GRASPA (Drug)
reference L-asparaginase
For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL).
•for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks).
NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity)
•for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles).
干预措施: L-asparaginase (Drug)
结局指标
主要结局
Duration of Asparaginase Activity >100 U/L During Induction
时间窗: Induction treatment period (i.e. 28 days)
Co-primary efficacy endpoint: duration in days of asparaginase activity \>100 U/L in whole blood during the induction treatment phase: last available date/time of activity \>100 UI/L before activity drops below 100 U/L - date/time of first activity \>100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.
Allergic Reaction During Induction Phase
时间窗: Induction treatment period (i.e. 28 days)
Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.
次要结局
- Complete Remission (CR)(Induction treatment period (i.e. 28 days))
- Overall Survival (OS)(Overall trial period to 36 months)
- Event Free Survival(Overall trial period to 36 months)