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Childhood Acute Basophilic LeukemiaPhase 3NCT00369317

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

A Phase 3 study testing asparaginase, daunorubicin hydrochloride and cytarabine in people with Childhood Acute Basophilic Leukemia and Childhood Acute Eosinophilic Leukemia, run by Children's Oncology Group at 97 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages Up to 4 years
What is being tested?
asparaginase, daunorubicin hydrochloride and cytarabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
205 participants
Where
97 sitesin 4 countries
Study dates
Mar 2007to 31 Dec 2021
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 4 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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
Show all 28Show fewer
  • 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

Who cannot join

None listed.

Trial locations and contacts

97 sites in 4 countries.

97 sites in 4 countries

United States88 sites

  • Children's Hospital Medical Center of Akron

    Akron, Ohio, 44308

  • C S Mott Children's Hospital

    Ann Arbor, Michigan, 48109

  • Children's Healthcare of Atlanta - Egleston

    Atlanta, Georgia, 30322

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Sinai Hospital of Baltimore

    Baltimore, Maryland, 21215

  • Johns Hopkins University-Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • Eastern Maine Medical Center

    Bangor, Maine, 04401

  • Walter Reed National Military Medical Center

    Bethesda, Maryland, 20889-5600

  • Saint Luke's Mountain States Tumor Institute

    Boise, Idaho, 83712

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • University of Vermont

    Burlington, Vermont, 05401

  • University of North Carolina

    Chapel Hill, North Carolina, 27599

  • Carolinas Medical Center

    Charlotte, North Carolina, 28203

  • Lurie Children's Hospital-Chicago

    Chicago, Illinois, 60614

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Palmetto Health Richland

    Columbia, South Carolina, 29203

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • Wayne State University-Karmanos Cancer Institute

    Detroit, Michigan, 48201

  • Saint John Hospital and Medical Center

    Detroit, Michigan, 48236

  • Southern California Permanente Medical Group

    Downey, California, 90242

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Sanford Medical Center-Fargo

    Fargo, North Dakota, 58122

  • Hurley Medical Center

    Flint, Michigan, 48502

  • Broward Health Medical Center

    Fort Lauderdale, Florida, 33316

  • Cook Children's Medical Center

    Fort Worth, Texas, 76104

  • Helen DeVos Children's Hospital at Spectrum Health

    Grand Rapids, Michigan, 49503

  • Hackensack University Medical Center

    Hackensack, New Jersey, 07601

  • Penn State Hershey Children's Hospital

    Hershey, Pennsylvania, 17033

  • Memorial Healthcare System - Joe DiMaggio Children's Hospital

    Hollywood, Florida, 33021

  • University of Hawaii

    Honolulu, Hawaii, 96813

  • Baylor College of Medicine

    Houston, Texas, 77030

  • Indiana University Medical Center

    Indianapolis, Indiana, 46202

  • Riley Hospital for Children

    Indianapolis, Indiana, 46202

  • Saint Vincent Hospital and Health Services

    Indianapolis, Indiana, 46260

  • University of Mississippi Medical Center

    Jackson, Mississippi, 39216

  • Nemours Children's Clinic - Jacksonville

    Jacksonville, Florida, 32207-8426

  • The Childrens Mercy Hospital

    Kansas City, Missouri, 64108

  • Nevada Cancer Research Foundation CCOP

    Las Vegas, Nevada, 89106

  • Miller Children's Hospital

    Long Beach, California, 90806

  • Children's Hospital Los Angeles

    Los Angeles, California, 90027

  • Kosair Children's Hospital

    Louisville, Kentucky, 40202

  • Covenant Children's Hospital

    Lubbock, Texas, 79410

  • Children's Hospital Central California

    Madera, California, 93636-8762

  • Loyola University Medical Center

    Maywood, Illinois, 60153

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Midwest Children's Cancer Center

    Milwaukee, Wisconsin, 53226

  • Children's Hospitals and Clinics of Minnesota - Minneapolis

    Minneapolis, Minnesota, 55404

  • University of Minnesota Medical Center-Fairview

    Minneapolis, Minnesota, 55455

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Saint Peter's University Hospital

    New Brunswick, New Jersey, 08901

  • UMDNJ - Robert Wood Johnson University Hospital

    New Brunswick, New Jersey, 08903

  • Tulane University Health Sciences Center

    New Orleans, Louisiana, 70112

  • Columbia University Medical Center

    New York, New York, 10032

  • Memorial Sloan-Kettering Cancer Center

    New York, New York, 10065

  • Newark Beth Israel Medical Center

    Newark, New Jersey, 07112

  • Childrens Hospital-King's Daughters

    Norfolk, Virginia, 23507

  • Children's Hospital and Research Center at Oakland

    Oakland, California, 94609-1809

  • Kaiser Permanente-Oakland

    Oakland, California, 94611

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

  • Children's Hospital and Medical Center of Omaha

    Omaha, Nebraska, 68114

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • Childrens Hospital of Orange County

    Orange, California, 92868-3874

  • Florida Hospital

    Orlando, Florida, 32803

  • Lucile Packard Children's Hospital Stanford University

    Palo Alto, California, 94304

  • Advocate Lutheran General Hospital.

    Park Ridge, Illinois, 60068

  • Saint Jude Midwest Affiliate

    Peoria, Illinois, 61602

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Saint Christopher's Hospital for Children

    Philadelphia, Pennsylvania, 19134

  • Phoenix Childrens Hospital

    Phoenix, Arizona, 85016

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15224

  • Legacy Emanuel Hospital and Health Center

    Portland, Oregon, 97227

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • Rhode Island Hospital

    Providence, Rhode Island, 02903

  • University of Rochester

    Rochester, New York, 14642

  • Primary Children's Hospital

    Salt Lake City, Utah, 84113

  • University of Texas Health Science Center at San Antonio

    San Antonio, Texas, 78229-3900

  • Rady Children's Hospital - San Diego

    San Diego, California, 92123

  • University of California San Francisco Medical Center-Parnassus

    San Francisco, California, 94143

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Southern Illinois University

    Springfield, Illinois, 62702

  • All Children's Hospital

    St. Petersburg, Florida, 33701

  • State University of New York Upstate Medical University

    Syracuse, New York, 13210

  • Mary Bridge Children's Hospital and Health Center

    Tacoma, Washington, 98405

  • Ny Cancer%

    Valhalla, New York, 10595

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

  • Lombardi Comprehensive Cancer Center at Georgetown University

    Washington D.C., District of Columbia, 20057

  • Alfred I duPont Hospital for Children

    Wilmington, Delaware, 19803

Other trials in United States

Canada7 sites

  • Cancer Centre of Southeastern Ontario at Kingston General Hospital

    Kingston, Ontario, K7L 5P9

  • Children's Hospital

    London, Ontario, N6A 5W9

  • Children's Hospital of Eastern Ontario

    Ottawa, Ontario, K1H 8L1

  • Janeway Child Health Centre

    St. John's, Newfoundland and Labrador, A1B 3V6

  • Hospital for Sick Children

    Toronto, Ontario, M5G 1X8

  • British Columbia Children's Hospital

    Vancouver, British Columbia, V6H 3V4

  • CancerCare Manitoba

    Winnipeg, Manitoba, R3E 0V9

Other trials in Canada

Australia1 site

  • Princess Margaret Hospital for Children

    Perth, Western Australia, 6008

Other trials in Australia

Puerto Rico1 site

  • San Jorge Children's Hospital

    Santurce, 00912

Other trials in Puerto Rico

About this study

Official title: The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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.

Being tested
asparaginase, daunorubicin hydrochloride, cytarabine, thioguanine, etoposide
Medical subject headings
Leukemia, Eosinophilic, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • asparaginaseDrug

    Also called ASNase, Colaspase, Crasnitin, Elspar

    Given IM

  • daunorubicin hydrochlorideDrug

    Also called Cerubidin, Cerubidine, daunomycin hydrochloride, daunorubicin

    Given IV

  • cytarabineDrug

    Also called ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U

    Given IV or IT

  • thioguanineDrug

    Also called 6-TG

    Given orally

  • etoposideDrug

    Also called EPEG, VP-16, VP-16-213

    Given IV

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT00369317
Study groupRoleWhat they receive
Treatment (combination chemotherapy)ExperimentalINDUCTION 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.
Receives: Drug: asparaginase; Drug: daunorubicin hydrochloride; Drug: cytarabine; Drug: thioguanine; Drug: etoposide; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Event-free Survival (EFS) at 3 Years

    Measured: Time from study entry to induction failure, relapse, or death assessed at 3 years.

  2. Overall Survival (OS) at 3 Years

    Measured: Time from study entry to death, assessed at 3 years.

Secondary outcomes (9)

  1. Induction Remission Rate

    Proportion of participants with a remission after four courses of Induction therapy.

    Measured: End of induction therapy (day 112)

  2. 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

    Proportion of participants with at least one grade 3 or higher adverse event during therapy.

    Measured: From the beginning of induction therapy to the end of intensification therapy

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

    Proportion of participants having megakaryoblastic subtype (AMkL) phenotype among patients with phenotype data available.

    Measured: At the start of therapy

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

    Proportion of participants having GATA1 mutation among patients with phenotype data available.

    Measured: At baseline and at the end of therapy (intensification) or disease relapse

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

    Proportion of participants in complete remission by morphology and with positive MRD by flow cytometry among patients having evaluable remission and MRD assessment.

    Measured: After Induction I therapy (day 28 from start of therapy)

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

    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.

    Measured: Days 1, 2, 8, and 9 of induction II

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

    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.

    Measured: Days 1, 2, 8, and 9 of induction II

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

    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.

    Measured: Days 1, 2, 8, and 9 of induction II

  9. Gene Expression Profiles by Microarrays

    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.

    Measured: At baseline and at the time of relapse (if available)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Aug 2006 (estimated)
  2. Study startMar 2007
  3. Primary completion1 Dec 2013
  4. Study completion31 Dec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
205 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00369317
Sponsor's protocol ID
AAML0431
Other IDs
NCI-2009-00318, CDR0000492776, COG-AAML0431, AAML0431, U10CA098543
Status last verified
Mar 2021
First submitted
24 Aug 2006
Last updated
28 Jan 2022
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 28389462

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing asparaginase, daunorubicin hydrochloride and cytarabine in people with Childhood Acute Basophilic Leukemia and Childhood Acute Eosinophilic Leukemia, run by Children's Oncology Group at 97 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 97 sites in United States, Canada, Australia, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Jan 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event-free Survival (EFS) at 3 Years (time frame: Time from study entry to induction failure, relapse, or death assessed at 3 years.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00369317, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2022.

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