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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00369317
First received: August 24, 2006
Last updated: April 29, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Childhood Acute Basophilic Leukemia
Childhood Acute Eosinophilic Leukemia
Childhood Acute Erythroleukemia (M6)
Childhood Acute Megakaryocytic Leukemia (M7)
Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)
Childhood Acute Monoblastic Leukemia (M5a)
Childhood Acute Monocytic Leukemia (M5b)
Childhood Acute Myeloblastic Leukemia With Maturation (M2)
Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
Childhood Acute Myelomonocytic Leukemia (M4)
Childhood Myelodysplastic Syndromes
de Novo Myelodysplastic Syndromes
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
Drug: asparaginase
Drug: daunorubicin hydrochloride
Drug: cytarabine
Drug: thioguanine
Drug: etoposide
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Event-free survival (EFS) [ Time Frame: Time from study entry to induction failure, relapse, or death ] [ Designated as safety issue: No ]
  • Overall survival (OS) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Induction remission rate [ Time Frame: End of induction therapy ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Prevalence of leukemia phenotype of DS patients < 4 years of age at diagnosis by flow cytometry [ Time Frame: At baseline and at the end of therapy (intensification) or disease relapse ] [ Designated as safety issue: No ]
    The prevalence of AMkL phenotype will be estimated as the proportion of patients with phenotype data available determined to have the AMkL phenotype. EFS will be estimated for those with and without AMkL using the approach of Kaplan and Meier. Differences in these estimates will be tested for significance using the log-rank statistic test.

  • 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 ] [ Designated as safety issue: No ]
    The prevalence of GATA1 mutations will be estimated as the proportion of patients with phenotype data available determined to have the GATA1 mutations.

  • Proportions of patients in morphologic remission with positive MRD by flow cytometry [ Time Frame: After completion of induction therapy (I, IV) and after completion of intensification therapy ] [ Designated as safety issue: No ]
    Differences in the cumulative incidence of relapse for those with and without MRD will be tested using Gray's test.

  • Cytarabine drug sensitivity by R-Strip (MicroMath) curve fitting program. [ Time Frame: Days 1, 2, 8, and 9 of induction II ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to summarize pharmacokinetic parameters, such as peak plasma concentration, area under the concentration time curve, and half-life of elimination

  • Gene expression profiles by microarrays [ Time Frame: At baseline and at the time of relapse (if available) ] [ Designated as safety issue: No ]
    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.


Enrollment: 205
Study Start Date: March 2007
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (combination chemotherapy)

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.

Drug: asparaginase
Given IM
Other Names:
  • ASNase
  • Colaspase
  • Crasnitin
  • Elspar
  • L-ASP
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Drug: cytarabine
Given IV or IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: thioguanine
Given orally
Other Name: 6-TG
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Other: laboratory biomarker analysis
Correlative studies

  Hide Detailed Description

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 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 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.

  Eligibility

Ages Eligible for Study:   up to 4 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00369317

  Show 97 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Principal Investigator: Jeffrey Taub, MD Children's Oncology Group
  More Information

No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00369317     History of Changes
Other Study ID Numbers: AAML0431, NCI-2009-00318, CDR0000492776, COG-AAML0431, AAML0431, AAML0431, U10CA098543
Study First Received: August 24, 2006
Last Updated: April 29, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasm Metastasis
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Down Syndrome
Leukemia, Monocytic, Acute
Hypereosinophilic Syndrome
Leukemia, Erythroblastic, Acute
Leukemia
Syndrome
Leukemia, Eosinophilic, Acute
Leukemia, Basophilic, Acute
Leukemia, Megakaryoblastic, Acute
Neoplastic Processes
Neoplasms
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities

ClinicalTrials.gov processed this record on September 22, 2014