ASIA Down Syndrome Acute Lymphoblastic Leukemia 2016

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Down Syndrome, Acute Lymphoblastic Leukemia, Childhood Cancer

Intervention / Treatment
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* Drug: Daunorubicin
* Drug: Prednisolone
* Drug: Vincristine
* Drug: Epirubicin
* Drug: E-coli L-asparaginase
* Drug: 6-Mercaptopurine
* Drug: Methotrexate
* Drug: Hydrocortisone
* Drug: Cytarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 0-2. Written informed consent obtained from legally acceptable representatives. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: risk stratification-directed chemotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SR<br>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. | Drug: Daunorubicin<br>* Given IV<br>* Other names: DNR;Drug: Prednisolone<br>* Given PO or IV<br>* Other names: Pred;Drug: Vincristine<br>* Given IV<br>* Other names: VCR;Drug: Epirubicin<br>* Given IV<br>* Other names: EPI;Drug: E-coli L-asparaginase<br>* Given IM or IV<br>* Other names: E-coli L-Asp;Drug: 6-Mercaptopurine<br>* Given PO<br>* Other names: 6-MP;Drug: Methotrexate<br>* Given IV, PO or IT<br>* Other names: MTX;Drug: Hydrocortisone<br>* Given IT<br>Drug: Cytarabine<br>* Given IV, IT or SC<br>* Other names: Ara-C;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Cy;|
| Experimental: LR<br>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. | Drug: Daunorubicin<br>* Given IV<br>* Other names: DNR;Drug: Prednisolone<br>* Given PO or IV<br>* Other names: Pred;Drug: Vincristine<br>* Given IV<br>* Other names: VCR;Drug: Epirubicin<br>* Given IV<br>* Other names: EPI;Drug: E-coli L-asparaginase<br>* Given IM or IV<br>* Other names: E-coli L-Asp;Drug: 6-Mercaptopurine<br>* Given PO<br>* Other names: 6-MP;Drug: Methotrexate<br>* Given IV, PO or IT<br>* Other names: MTX;Drug: Hydrocortisone<br>* Given IT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Percentage of patients who are event free at 5 years. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Percentage of patients who survive at 5 years. | Up to 5 years | 
| Disease free survival | Percentage of patients who are leukemia free at 5 years. | Up to 5 years | 
| Induction failure | Percentage of patients who had failed induction. | 5 weeks | 
| Complete remission rate | Percentage of patients who had achieved complete remission at the end of induction. | 5 weeks | 
| Cumulative incidence of relapse |  | Up to 5 years | 
| Incidence of treatment-related adverse events | Incidence of treatment-related infectious and metabolic complications (throughout various phases of study therapy) and secondary neoplasms. | Up to 10 years | 
| Flow MRD at day 15 | To assess the prognostic value flow MRD level during induction for DS-ALL. | At day 15 of induction therapy |