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

Information source: Children's Oncology Group
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: 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

Intervention: asparaginase (Drug); daunorubicin hydrochloride (Drug); cytarabine (Drug); thioguanine (Drug); etoposide (Drug); laboratory biomarker analysis (Other)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Jeffrey Taub, MD, Principal Investigator, Affiliation: Children's Oncology Group

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.

Clinical Details

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

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Event-free Survival (EFS) at 3 Years

Overall Survival (OS) at 3 Years

Secondary outcome:

Induction Remission Rate

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

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

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

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

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

Gene Expression Profiles by Microarrays

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.

Eligibility

Minimum age: N/A. Maximum age: 4 Years. Gender(s): Both.

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

Locations and Contacts

San Jorge Children's Hospital, Santurce 00912, Puerto Rico

Phoenix Childrens Hospital, Phoenix, Arizona 85016, United States

British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada

Southern California Permanente Medical Group, Downey, California 90242, United States

Miller Children's Hospital, Long Beach, California 90806, United States

Children's Hospital Los Angeles, Los Angeles, California 90027, United States

Children's Hospital Central California, Madera, California 93636-8762, United States

Children's Hospital and Research Center at Oakland, Oakland, California 94609-1809, United States

Kaiser Permanente-Oakland, Oakland, California 94611, United States

Childrens Hospital of Orange County, Orange, California 92868-3874, United States

Lucile Packard Children's Hospital Stanford University, Palo Alto, California 94304, United States

Rady Children's Hospital - San Diego, San Diego, California 92123, United States

University of California San Francisco Medical Center-Parnassus, San Francisco, California 94143, United States

Children's Hospital Colorado, Aurora, Colorado 80045, United States

Alfred I duPont Hospital for Children, Wilmington, Delaware 19803, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

Lombardi Comprehensive Cancer Center at Georgetown University, Washington, District of Columbia 20057, United States

Broward Health Medical Center, Fort Lauderdale, Florida 33316, United States

Memorial Healthcare System - Joe DiMaggio Children's Hospital, Hollywood, Florida 33021, United States

Nemours Children's Clinic - Jacksonville, Jacksonville, Florida 32207-8426, United States

Florida Hospital, Orlando, Florida 32803, United States

All Children's Hospital, Saint Petersburg, Florida 33701, United States

Children's Healthcare of Atlanta - Egleston, Atlanta, Georgia 30322, United States

University of Hawaii, Honolulu, Hawaii 96813, United States

Saint Luke's Mountain States Tumor Institute, Boise, Idaho 83712, United States

Lurie Children's Hospital-Chicago, Chicago, Illinois 60614, United States

Loyola University Medical Center, Maywood, Illinois 60153, United States

Advocate Lutheran General Hospital., Park Ridge, Illinois 60068, United States

Saint Jude Midwest Affiliate, Peoria, Illinois 61602, United States

Southern Illinois University, Springfield, Illinois 62702, United States

Indiana University Medical Center, Indianapolis, Indiana 46202, United States

Riley Hospital for Children, Indianapolis, Indiana 46202, United States

Saint Vincent Hospital and Health Services, Indianapolis, Indiana 46260, United States

Kosair Children's Hospital, Louisville, Kentucky 40202, United States

Tulane University Health Sciences Center, New Orleans, Louisiana 70112, United States

Eastern Maine Medical Center, Bangor, Maine 04401, United States

CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada

Johns Hopkins University-Sidney Kimmel Cancer Center, Baltimore, Maryland 21287, United States

Sinai Hospital of Baltimore, Baltimore, Maryland 21215, United States

Walter Reed National Military Medical Center, Bethesda, Maryland 20889-5600, United States

C S Mott Children's Hospital, Ann Arbor, Michigan 48109, United States

Saint John Hospital and Medical Center, Detroit, Michigan 48236, United States

Wayne State University-Karmanos Cancer Institute, Detroit, Michigan 48201, United States

Hurley Medical Center, Flint, Michigan 48502, United States

Helen DeVos Children's Hospital at Spectrum Health, Grand Rapids, Michigan 49503, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

University of Minnesota Medical Center-Fairview, Minneapolis, Minnesota 55455, United States

University of Mississippi Medical Center, Jackson, Mississippi 39216, United States

The Childrens Mercy Hospital, Kansas City, Missouri 64108, United States

Children's Hospital and Medical Center of Omaha, Omaha, Nebraska 68114, United States

University of Nebraska Medical Center, Omaha, Nebraska 68198, United States

Nevada Cancer Research Foundation CCOP, Las Vegas, Nevada 89106, United States

Hackensack University Medical Center, Hackensack, New Jersey 07601, United States

Saint Peter's University Hospital, New Brunswick, New Jersey 08901, United States

UMDNJ - Robert Wood Johnson University Hospital, New Brunswick, New Jersey 08903, United States

Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States

Roswell Park Cancer Institute, Buffalo, New York 14263, United States

Columbia University Medical Center, New York, New York 10032, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States

University of Rochester, Rochester, New York 14642, United States

State University of New York Upstate Medical University, Syracuse, New York 13210, United States

Ny Cancer%, Valhalla, New York 10595, United States

Janeway Child Health Centre, Saint John's, Newfoundland and Labrador A1B 3V6, Canada

University of North Carolina, Chapel Hill, North Carolina 27599, United States

Carolinas Medical Center, Charlotte, North Carolina 28203, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Sanford Medical Center-Fargo, Fargo, North Dakota 58122, United States

Children's Hospital Medical Center of Akron, Akron, Ohio 44308, United States

Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States

Nationwide Children's Hospital, Columbus, Ohio 43205, United States

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States

Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston, Ontario K7L 5P9, Canada

Children's Hospital, London, Ontario N6A 5W9, Canada

Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Legacy Emanuel Hospital and Health Center, Portland, Oregon 97227, United States

Oregon Health and Science University, Portland, Oregon 97239, United States

Penn State Hershey Children's Hospital, Hershey, Pennsylvania 17033, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Saint Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134, United States

Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, United States

Rhode Island Hospital, Providence, Rhode Island 02903, United States

Palmetto Health Richland, Columbia, South Carolina 29203, United States

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States

University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States

Cook Children's Medical Center, Fort Worth, Texas 76104, United States

Baylor College of Medicine, Houston, Texas 77030, United States

Covenant Children's Hospital, Lubbock, Texas 79410, United States

University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, United States

Primary Children's Hospital, Salt Lake City, Utah 84113, United States

University of Vermont, Burlington, Vermont 05401, United States

Childrens Hospital-King's Daughters, Norfolk, Virginia 23507, United States

Seattle Children's Hospital, Seattle, Washington 98105, United States

Mary Bridge Children's Hospital and Health Center, Tacoma, Washington 98405, United States

Princess Margaret Hospital for Children, Perth, Western Australia 6008, Australia

Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: March 2007
Last updated: February 10, 2015

Page last updated: August 23, 2015

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