Clinical trial NCT00369317: Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes
Official title: The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: 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
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-08-29
Enrollment: 205
Sex: ALL
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Event-free Survival (EFS) at 3 Years
timeFrame: Time from study entry to induction failure, relapse, or death assessed at 3 years.
measure: Overall Survival (OS) at 3 Years
timeFrame: Time from study entry to death, assessed at 3 years.
Secondary outcomes:
measure: Induction Remission Rate
timeFrame: End of induction therapy (day 112)
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
timeFrame: From the beginning of induction therapy to the end of intensification therapy
measure: Prevalence of Leukemia Phenotype of DS Patients < 4 Years of Age at Diagnosis by Flow Cytometry
timeFrame: At the start of therapy
measure: Prevalence of of GATA1 Mutations of DS Patients < 4 Years of Age at Diagnosis
timeFrame: At baseline and at the end of therapy (intensification) or disease relapse
measure: Proportions of Patients in Morphologic Remission With Positive MRD by Flow Cytometry
timeFrame: After Induction I therapy (day 28 from start of therapy)
measure: Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
timeFrame: Days 1, 2, 8, and 9 of induction II
measure: Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
timeFrame: Days 1, 2, 8, and 9 of induction II
measure: Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
timeFrame: Days 1, 2, 8, and 9 of induction II
measure: Gene Expression Profiles by Microarrays
timeFrame: At baseline and at the time of relapse (if available)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Long Beach
country: United States
facility: Miller Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Oakland
country: United States
facility: Kaiser Permanente-Oakland
state: California
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Broward Health Medical Center
state: Florida
city: Hollywood
country: United States
facility: Memorial Healthcare System - Joe DiMaggio Children's Hospital
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic - Jacksonville
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Boise
country: United States
facility: Saint Luke's Mountain States Tumor Institute
state: Idaho
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Lutheran General Hospital.
state: Illinois
city: Peoria
country: United States
facility: Saint Jude Midwest Affiliate
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Hospital and Health Services
state: Indiana
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University-Sidney Kimmel Cancer Center
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Detroit
country: United States
facility: Wayne State University-Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital at Spectrum Health
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center of Omaha
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Saint Peter's University Hospital
state: New Jersey
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson University Hospital
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Valhalla
country: United States
facility: Ny Cancer%
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Fargo
country: United States
facility: Sanford Medical Center-Fargo
state: North Dakota
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Legacy Emanuel Hospital and Health Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Saint Christopher's Hospital for Children
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Columbia
country: United States
facility: Palmetto Health Richland
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Lubbock
country: United States
facility: Covenant Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Norfolk
country: United States
facility: Childrens Hospital-King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: Mary Bridge Children's Hospital and Health Center
state: Washington
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Saint John's
country: Canada
facility: Janeway Child Health Centre
state: Newfoundland and Labrador
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: Children's Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Santurce
country: Puerto Rico
facility: San Jorge Children's Hospital
Study officials:
affiliation: Children's Oncology Group
name: Jeffrey Taub, MD
role: PRINCIPAL_INVESTIGATOR
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.