ASIA Down Syndrome Acute Lymphoblastic Leukemia 2016

Sponsor

National Hospital Organization Nagoya Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03286634

Collaborator

(none)

Enrollment

Locations

Arms

191.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Down Syndrome Acute Lymphoblastic Leukemia Childhood Cancer	Drug: Daunorubicin Drug: Prednisolone Drug: Vincristine Drug: Epirubicin Drug: E-coli L-asparaginase Drug: 6-Mercaptopurine Drug: Methotrexate Drug: Hydrocortisone Drug: Cytarabine Drug: Cyclophosphamide	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

risk stratification-directed chemotherapyrisk stratification-directed chemotherapy

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 18, 2017

Anticipated Primary Completion Date :

Mar 31, 2028

Anticipated Study Completion Date :

Mar 31, 2033

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Daunorubicin Given IV Other Names: DNR Drug: Prednisolone Given PO or IV Other Names: Pred Drug: Vincristine Given IV Other Names: VCR Drug: Epirubicin Given IV Other Names: EPI Drug: E-coli L-asparaginase Given IM or IV Other Names: E-coli L-Asp Drug: 6-Mercaptopurine Given PO Other Names: 6-MP Drug: Methotrexate Given IV, PO or IT Other Names: MTX Drug: Hydrocortisone Given IT Drug: Cytarabine Given IV, IT or SC Other Names: Ara-C Drug: Cyclophosphamide Given IV Other Names: Cy
Experimental: 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.	Drug: Daunorubicin Given IV Other Names: DNR Drug: Prednisolone Given PO or IV Other Names: Pred Drug: Vincristine Given IV Other Names: VCR Drug: Epirubicin Given IV Other Names: EPI Drug: E-coli L-asparaginase Given IM or IV Other Names: E-coli L-Asp Drug: 6-Mercaptopurine Given PO Other Names: 6-MP Drug: Methotrexate Given IV, PO or IT Other Names: MTX Drug: Hydrocortisone Given IT

Arm

Intervention/Treatment

Experimental: 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.

Drug: Daunorubicin

Given IV

Other Names:

DNR

Drug: Prednisolone

Given PO or IV

Other Names:

Pred

Drug: Vincristine

Given IV

Other Names:

VCR

Drug: Epirubicin

Given IV

Other Names:

EPI

Drug: E-coli L-asparaginase

Given IM or IV

Other Names:

E-coli L-Asp

Drug: 6-Mercaptopurine

Given PO

Other Names:

6-MP

Drug: Methotrexate

Given IV, PO or IT

Other Names:

MTX

Drug: Hydrocortisone

Given IT

Drug: Cytarabine

Given IV, IT or SC

Other Names:

Ara-C

Drug: Cyclophosphamide

Given IV

Other Names:

Experimental: 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.

Drug: Daunorubicin

Given IV

Other Names:

DNR

Drug: Prednisolone

Given PO or IV

Other Names:

Pred

Drug: Vincristine

Given IV

Other Names:

VCR

Drug: Epirubicin

Given IV

Other Names:

EPI

Drug: E-coli L-asparaginase

Given IM or IV

Other Names:

E-coli L-Asp

Drug: 6-Mercaptopurine

Given PO

Other Names:

6-MP

Drug: Methotrexate

Given IV, PO or IT

Other Names:

MTX

Drug: Hydrocortisone

Given IT

Outcome Measures

Primary Outcome Measures

Event Free Survival [Up to 5 years]
Percentage of patients who are event free at 5 years.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 20 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Prince of Wales Hospital	Shatin	New Territories	Hong Kong
2	Kagoshima University Hospital	Kagoshima		Japan	890-8544
3	University of Malaya Medical Centre	Kuala Lumpur		Malaysia	59100
4	Subang Jaya Medical Centre	Subang Jaya		Malaysia	47500
5	National University Hospital	Singapore		Singapore	119074
6	KK Women's and Children's Hospital	Singapore		Singapore	229899
7	National Taiwan University Children's Hospital	Taipei		Taiwan	100
8	Mackay Memorial Hospital	Taipei		Taiwan	10449
9	Chang Gung Memorial Hopsital, Linkou	Taoyuan		Taiwan	333
10	Siriraj Hospital Mahidol University	Bangkok		Thailand	10700