Asia-wide, Multicenter Open-label, Phase II Non-randomised Study Involving Children With Down Syndrome Under 21 Year-old With Newly Diagnosed, Treatment naïve Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 60
- 试验地点
- 10
- 主要终点
- Event Free Survival
研究概览
简要总结
To evaluate the outcome of a prednisolone and low dose methotrexate based protocol in Down syndrome children with ALL (DS-ALL) in an Asia-wide study. The treatment protocol was modified based upon backbone of Taiwan Pediatric Oncology Group (TPOG)-ALL protocol in which risk classification will be guided by level of flow minimal residual disease (MRD) instead.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 20 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Down syndrome diagnosed clinically or cytogenetically (including Mosaic Down)
- •Newly diagnosed ALL according to WHO 2016 classification.
- •Age < 21 years old at time of enrollment.
- •ECOG performance status (PS) score of 0-
- •Written informed consent obtained from legally acceptable representatives.
排除标准
- •Second malignancy.
- •Philadelphia positive ALL.
- •Mature B-ALL.
- •Mixed phenotype acute leukemia.
- •Any previous treatment with cytotoxic chemotherapy excluding treatment for TAM or radiation therapy. Patient pre-treated with short term steroid (< 7 days of duration within last 1 month prior to treatment start) can be enrolled into this study.
- •Renal dysfunction with creatinine >2x upper limit of normal (ULN). Patients whose creatinine has improved to <2x ULN before treatment commencement can enrol subject to discretion of site PI.
- •Liver dysfunction with direct bilirubin > 5x ULN.
- •Any serious uncontrolled medical condition or impending end organ dysfunction that would impair the ability of the subject to receive protocol therapy, including:
- •History of coronary arterial disease, cardiomyopathy, heart failure, arrhythmia (other than sinus arrhythmia) or severe cardiac malformation which with residual abnormalities or requires further major corrective surgery within 2 years.
- •Ongoing uncontrolled hypertension.
- •Ongoing uncontrolled diabetes mellitus.
- •Ongoing uncontrolled infection.
- •History of congenital or acquired immunodeficiency including HIV infection.
- •History of interstitial pneumonia, pulmonary fibrosis, bronchiectasis or severe pulmonary emphysema.
- •CNS hemorrhage.
- •Psychiatric disorder.
- •Other concurrent active neoplasms.
- •Pregnant or lactating women.
- •Doubtful compliance or ability to complete study therapy due to financial, social, familial or geographic reason, or in the judgement of site investigator.
研究组 & 干预措施
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: E-coli L-asparaginase (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: E-coli L-asparaginase (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Daunorubicin (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Prednisolone (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Vincristine (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Epirubicin (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: 6-Mercaptopurine (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Hydrocortisone (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Methotrexate (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Cyclophosphamide (Drug)
SR
Standard Risk (SR) :
CNS 3 or CNS 2 regardless of response OR Time-point #1 (Day 15 induction) Flow MRD ≥ 1% (treatment will not be de-escalated even MRD <0.01% by TP#2) OR Time-point #2 (Day 1 IDMTX/MP of Consolidation) ≥0.01%
SR strategy:
All SR patient will have to receive two doses of anthracycline and 12 L-asparaginase doses during induction except those who are escalated to SR at time point 2 when MRD ≥0.01%.
During the first year of maintenance phase (48 weeks; 4x12 weeks blocks), cyclophosphamide and cytarabine bolus will be administered at 4 weekly interval.
干预措施: Cytarabine (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: Prednisolone (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: Daunorubicin (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: Vincristine (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: Epirubicin (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: 6-Mercaptopurine (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: Methotrexate (Drug)
LR
Low Risk (LR):
Time-point #1 (Day 15 induction) Flow MRD <1% AND Time-point #2 (Day 1 IDMTX/MP of Consolidation) <0.01% AND CNS 1 only
LR strategy:
For LR patients, one dose of anthracycline and 3 doses of L-asparaginase will be omitted during induction.
Following re-induction I, interim maintenance and additional block of re-induction ie. re-induction II prior to maintenance phase will be omitted for LR patients.
干预措施: Hydrocortisone (Drug)
结局指标
主要结局
Event Free Survival
时间窗: Up to 5 years
Percentage of patients who are event free at 5 years.
次要结局
- Flow MRD at day 15(At day 15 of induction therapy)
- Overall survival(Up to 5 years)
- Disease free survival(Up to 5 years)
- Induction failure(5 weeks)
- Complete remission rate(5 weeks)
- Cumulative incidence of relapse(Up to 5 years)
- Incidence of treatment-related adverse events(Up to 10 years)