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

Secondary Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00369317
• Other study ID #: AAML0431
• Secondary ID: NCI-2009-00318CD
• Status: Completed
• Phase: Phase 3
• Start date: March 2007
• Est. completion date: December 31, 2021

Study information

• Verified date: March 2021
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 205
• Est. completion date: December 31, 2021
• Est. primary completion date: December 1, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 4 Years

Eligibility

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

Related Conditions & MeSH terms

• 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
• Down Syndrome
• Hypereosinophilic Syndrome
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Megakaryoblastic, Acute
• Leukemia, Monocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Myelodysplastic Syndromes
• Neoplasm Metastasis
• Preleukemia
• Secondary Acute Myeloid Leukemia
• Secondary Myelodysplastic Syndromes
• Syndrome
• Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Intervention

Drug:
• asparaginase
Given IM
• daunorubicin hydrochloride
Given IV
• cytarabine
Given IV or IT
• thioguanine
Given orally
• etoposide
Given IV

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	Children's Hospital	London	Ontario
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Puerto Rico	San Jorge Children's Hospital	Santurce
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University-Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont	Burlington	Vermont
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Wayne State University-Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Sanford Medical Center-Fargo	Fargo	North Dakota
United States	Hurley Medical Center	Flint	Michigan
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	Memorial Healthcare System - Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	University of Hawaii	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University Medical Center	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Services	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Miller Children's Hospital	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	Children's Hospital Central California	Madera	California
United States	Loyola University Medical Center	Maywood	Illinois
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Childrens Hospital of Orange County	Orange	California
United States	Florida Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Advocate Lutheran General Hospital.	Park Ridge	Illinois
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	University of Rochester	Rochester	New York
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	University of California San Francisco Medical Center-Parnassus	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Southern Illinois University	Springfield	Illinois
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Ny Cancer%	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free Survival (EFS) at 3 Years		Time from study entry to induction failure, relapse, or death assessed at 3 years.
Primary	Overall Survival (OS) at 3 Years		Time from study entry to death, assessed at 3 years.
Secondary	Induction Remission Rate	Proportion of participants with a remission after four courses of Induction therapy.	End of induction therapy (day 112)
Secondary	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.	From the beginning of induction therapy to the end of intensification therapy
Secondary	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.	At the start of therapy
Secondary	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.	At baseline and at the end of therapy (intensification) or disease relapse
Secondary	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.	After Induction I therapy (day 28 from start of therapy)
Secondary	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.	Days 1, 2, 8, and 9 of induction II
Secondary	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.	Days 1, 2, 8, and 9 of induction II
Secondary	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.	Days 1, 2, 8, and 9 of induction II
Secondary	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.	At baseline and at the time of relapse (if available)

External Links

•   Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive