NCT00369317 · CITED IN SOURCE DOCUMENTS

Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2022-01-28

This phase III trial is studying how well combination chemotherapy works in treating young patients with Down syndrome and acute myeloid leukemia or myelodysplastic syndromes. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-free Survival (EFS) at 3 Years

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outcome · POSTED

Overall Survival (OS) at 3 Years

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outcome · POSTED

Induction Remission Rate

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outcome · POSTED

Percentage of Patients Experiencing Grade 3 or 4 Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

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outcome · POSTED

Prevalence of Leukemia Phenotype of DS Patients < 4 Years of Age at Diagnosis by Flow Cytometry

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outcome · POSTED

Prevalence of of GATA1 Mutations of DS Patients < 4 Years of Age at Diagnosis

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outcome · POSTED

Proportions of Patients in Morphologic Remission With Positive MRD by Flow Cytometry

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outcome · POSTED

Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program

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outcome · POSTED

Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program

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outcome · POSTED

Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program

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outcome · POSTED

Gene Expression Profiles by Microarrays

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Diagnosis DS or DS mosaicism by karyotype or chromosomal analysis * Diagnosis of myelodysplastic syndromes (MDS) with \< 30% blasts or acute myeloid leukemia (AML) * Newly diagnosed disease * Patients with a history of transient myeloproliferative disorder (TMD) are eligible provided the patient is diagnosed with AML or MDS at \> 90 days of age AND meets either of the following criteria: * At least 30% blasts in the bone marrow regardless of time since resolution of TMD * More than 8 weeks since resolution of TMD with ≥ 5% blasts in the bone marrow * Immunophenotype required for study entry * No promyelocytic leukemia * Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST or ALT \< 2.5 times ULN * Creatinine adjusted according to age as follows: * No greater than 0.4 mg/dL (≤ 5 months) * No greater than 0.5 mg/dL (6 months -11 months) * No greater than 0.6 mg/dL (1 year-23 months) * No greater than 0.8 mg/dL (2 years-5 years) * No greater than 1.0 mg/dL (6 years-9 years) * No greater than 1.2 mg/dL (10 years-12 years) * No greater than 1.4 mg/dL (13 years and over \[female\]) * No greater than 1.5 mg/dL (13 years to 15 years \[male\]) * No greater than 1.7 mg/dL (16 years and over \[male\]) * Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min * No evidence of dyspnea at rest * No exercise intolerance * Pulse oximetry \> 94% * No prior chemotherapy, radiotherapy, or any antileukemic therapy * Intrathecal cytarabine therapy given at diagnosis allowed * Prior therapy for TMD allowed
healthy Volunteers: false
maximum Age: 4 Years
sex: ALL
std Ages: CHILD

Treatment arms and interventions

arm Groups

description
INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
intervention Names
Drug: asparaginase
Drug: daunorubicin hydrochloride
Drug: cytarabine
Drug: thioguanine
Drug: etoposide
Other: laboratory biomarker analysis
label
Treatment (combination chemotherapy)
type
EXPERIMENTAL

interventions

arm Group Labels
Treatment (combination chemotherapy)
description
Given IM
name
asparaginase
other Names
ASNase
Colaspase
Crasnitin
Elspar
L-ASP
type
DRUG
arm Group Labels
Treatment (combination chemotherapy)
description
Given IV
name
daunorubicin hydrochloride
other Names
Cerubidin
Cerubidine
daunomycin hydrochloride
daunorubicin
RP-13057
type
DRUG
arm Group Labels
Treatment (combination chemotherapy)
description
Given IV or IT
name
cytarabine
other Names
ARA-C
arabinofuranosylcytosine
arabinosylcytosine
Cytosar-U
cytosine arabinoside
type
DRUG
arm Group Labels
Treatment (combination chemotherapy)
description
Given orally
name
thioguanine
other Names
6-TG
type
DRUG
arm Group Labels
Treatment (combination chemotherapy)
description
Given IV
name
etoposide
other Names
EPEG
VP-16
VP-16-213
type
DRUG
arm Group Labels
Treatment (combination chemotherapy)
description
Correlative studies
name
laboratory biomarker analysis
type
OTHER

Study design

allocation

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 205
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

measure
Event-free Survival (EFS) at 3 Years
time Frame
Time from study entry to induction failure, relapse, or death assessed at 3 years.
measure
Overall Survival (OS) at 3 Years
time Frame
Time from study entry to death, assessed at 3 years.

secondary Outcomes

description
Proportion of participants with a remission after four courses of Induction therapy.
measure
Induction Remission Rate
time Frame
End of induction therapy (day 112)
description
Proportion of participants with at least one grade 3 or higher adverse event during therapy.
measure
Percentage of Patients Experiencing Grade 3 or 4 Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
time Frame
From the beginning of induction therapy to the end of intensification therapy
description
Proportion of participants having megakaryoblastic subtype (AMkL) phenotype among patients with phenotype data available.
measure
Prevalence of Leukemia Phenotype of DS Patients < 4 Years of Age at Diagnosis by Flow Cytometry
time Frame
At the start of therapy
description
Proportion of participants having GATA1 mutation among patients with phenotype data available.
measure
Prevalence of of GATA1 Mutations of DS Patients < 4 Years of Age at Diagnosis
time Frame
At baseline and at the end of therapy (intensification) or disease relapse
description
Proportion of participants in complete remission by morphology and with positive MRD by flow cytometry among patients having evaluable remission and MRD assessment.
measure
Proportions of Patients in Morphologic Remission With Positive MRD by Flow Cytometry
time Frame
After Induction I therapy (day 28 from start of therapy)
description
Mean and standard deviation of peak plasma concentration. Specimen draws were performed only with dose 1, day 1 of induction II of AraC. First sample drawn pre-infusion, then drawn 30 mins prior to the end of the infusion, and then drawn for 6 time periods post infusion up to 8 hours post infusion (and before the 2nd dose of AraC). Results are based from these multiple time points on Day 1 of Induction II only.
measure
Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
time Frame
Days 1, 2, 8, and 9 of induction II
description
Mean and standard deviation of area under the concentration time curve. Specimen draws were performed only with dose 1, day 1 of induction II of AraC. First sample drawn pre-infusion, then drawn 30 mins prior to the end of the infusion, and then drawn for 6 time periods post infusion up to 8 hours post infusion (and before the 2nd dose of AraC). Results are based from these multiple time points on Day 1 of Induction II only.
measure
Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
time Frame
Days 1, 2, 8, and 9 of induction II
description
Mean and standard deviation of half-life of elimination. Specimen draws were performed only with dose 1, day 1 of induction II of AraC. First sample drawn pre-infusion, then drawn 30 mins prior to the end of the infusion, and then drawn for 6 time periods post infusion up to 8 hours post infusion (and before the 2nd dose of AraC). Results are based from these multiple time points on Day 1 of Induction II only.
measure
Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
time Frame
Days 1, 2, 8, and 9 of induction II
description
A hierarchical clustering algorithm is used to assemble the genes into a dendrogram or tree structure with branches containing genes with similar patterns of expression. This ordered representation can be graphically displayed with colors that reflect the qualitative and quantitative relationships of the expressed genes.
measure
Gene Expression Profiles by Microarrays
time Frame
At baseline and at the time of relapse (if available)

Full study description

brief Summary: This phase III trial is studying how well combination chemotherapy works in treating young patients with Down syndrome and acute myeloid leukemia or myelodysplastic syndromes. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.
detailed Description: PRIMARY OBJECTIVES: I. Determine the event-free survival (EFS) and overall survival rates in pediatric patients with Down syndrome (DS) and acute myeloid leukemia AML or myelodysplastic syndromes MDS treated with induction therapy comprising cytarabine, daunorubicin hydrochloride, thioguanine, and asparaginase followed by intensification therapy comprising cytarabine and etoposide. II. Determine if the EFS rate in these patients can be increased with an intensified course of cytarabine therapy during induction therapy, compared to the EFS rate of patients in protocol COG-A2971. III. Determine if the number of intrathecal chemotherapy treatments can be reduced in these patients. IV. Determine if the total cumulative anthracycline dose can be reduced in these patients. SECONDARY OBJECTIVES: I. Determine the type and degree of treatment-related toxicity in these patients. II. Determine the prevalence of leukemia phenotype and globin transcription factor 1 (GATA1) mutations of DS patients \< 4 years of age at diagnosis. III. Determine the relationship of GATA1 mutations with leukemia phenotype and EFS rates of DS patients \< 4 years of age at diagnosis. IV. Determine the relationship of minimal residual disease monitored by flow cytometry and remission status during and after completion of therapy based on bone marrow morphology. V. Examine parameters of in vitro drug sensitivity and in vivo Ara-C pharmacokinetics. VI. Examine gene expression profiles by microarrays and the relationship to leukemia phenotype and outcome. VII. Examine the relationship of functional polymorphisms in phase I and phase II detoxification genes and DNA repair pathways that may modify susceptibility to leukemia and outcome of therapy in DS children. VIII. Assess the effect of karyotypic abnormalities on survival. IX. Establish a DS leukemia cell bank for future biological studies. OUTLINE: This is a nonrandomized, multicenter study. INDUCTION THERAPY: Patients undergo 4 courses of induction therapy. Each course is 28 days. COURSE I: Patients receive intrathecal (IT) cytarabine on day 1\* and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously over 96 hours, and oral thioguanine twice daily on days 1-4. NOTE: \*Patients with Central Nervous System (CNS) disease receive cytarabine IT twice weekly for up to 6 doses; patients with persistent CNS leukemia after 6 doses of IT cytarabine are removed from the study. COURSE II: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course 1. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course 1. Induction therapy continues in the absence of disease progression or unacceptable toxicity. Patients with partial response, relapsed, or refractory disease after completion of course 4 are taken off study. Patients achieving complete response proceed to intensification therapy. INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for 5 years and then annually thereafter.

Source references

references

citation
Taub JW, Berman JN, Hitzler JK, Sorrell AD, Lacayo NJ, Mast K, Head D, Raimondi S, Hirsch B, Ge Y, Gerbing RB, Wang YC, Alonzo TA, Campana D, Coustan-Smith E, Mathew P, Gamis AS. Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood. 2017 Jun 22;129(25):3304-3313. doi: 10.1182/blood-2017-01-764324. Epub 2017 Apr 7.
pmid
28389462
type
DERIVED