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Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome

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ClinicalTrials.gov Identifier: NCT02521493
Recruitment Status : Recruiting
First Posted : August 13, 2015
Last Update Posted : August 16, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This phase III trial studies response-based chemotherapy in treating newly diagnosed acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Response-based chemotherapy separates patients into different risk groups and treats them according to how they respond to the first course of treatment (Induction I). Response-based treatment may be effective in treating acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome while reducing the side effects.

Condition or disease Intervention/treatment Phase
Blasts 5 Percent or More of Bone Marrow Nucleated Cells Childhood Acute Myeloid Leukemia Childhood Myelodysplastic Syndrome Cytopenia Down Syndrome Myeloid Leukemia Associated With Down Syndrome Myeloproliferative Neoplasm Trisomy 21 Trisomy 21 Mosaicism Drug: Asparaginase Drug: Asparaginase Erwinia chrysanthemi Drug: Cytarabine Drug: Daunorubicin Hydrochloride Drug: Etoposide Other: Laboratory Biomarker Analysis Drug: Mitoxantrone Hydrochloride Drug: Thioguanine Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 256 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome
Actual Study Start Date : November 23, 2015
Estimated Primary Completion Date : March 31, 2022


Arm Intervention/treatment
Experimental: Arm A (standard risk)

INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days.

INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days.

INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days.

INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days.

Drug: Cytarabine
Given IT and IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • Cloridrato de Daunorubicina
  • Daunoblastin
  • Daunoblastina
  • Daunoblastine
  • Daunomycin Hydrochloride
  • Daunomycin, hydrochloride
  • Daunorubicin.HCl
  • Daunorubicini Hydrochloridum
  • FI-6339
  • Ondena
  • RP-13057
  • Rubidomycin Hydrochloride
  • Rubilem

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Thioguanine
Given PO
Other Names:
  • 2-Amino 6MP
  • 2-Amino-1,7-dihydro-6H-purine-6-thione
  • 2-Amino-6-mercaptopurine
  • 2-Amino-6-purinethiol
  • 2-Aminopurin-6-thiol
  • 2-Aminopurine-6(1H)-thione
  • 2-Aminopurine-6-thiol
  • 2-Mercapto-6-aminopurine
  • 6-Amino-2-mercaptopurine
  • 6-Mercapto-2-aminopurine
  • 6-Mercaptoguanine
  • 6-TG
  • 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI)
  • BW 5071
  • Lanvis
  • Tabloid
  • Tioguanin
  • Tioguanine
  • Wellcome U3B
  • WR-1141
  • X 27

Experimental: Arm B (high risk)

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days.

INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days.

INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi IM or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.

Drug: Asparaginase
Given IM or IV
Other Names:
  • ASP-1
  • Asparaginase II
  • Asparaginase-E.Coli
  • Colaspase
  • Elspar
  • Kidrolase
  • L-Asnase
  • L-ASP
  • L-Asparaginase
  • L-Asparagine amidohydrolase
  • Laspar
  • Lcf-ASP
  • Leucogen
  • Leunase
  • MK-965
  • Paronal
  • Re-82-TAD-15
  • Serasa
  • Spectrila

Drug: Asparaginase Erwinia chrysanthemi
Given IM or IV
Other Names:
  • Crisantaspasum
  • Cristantaspase
  • Erwinase
  • Erwinaze
  • L-asparginase (Erwinia )

Drug: Cytarabine
Given IT and IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Dihydroxyanthracenedione Dihydrochloride
  • Mitoxantrone Dihydrochloride
  • Mitoxantroni Hydrochloridum
  • Mitozantrone Hydrochloride
  • Mitroxone
  • Neotalem
  • Novantrone
  • Onkotrone
  • Pralifan




Primary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: At 2 years ]
    The Kaplan-Meier method will be used to estimate 2-year EFS from the end of Induction I along with 95% log-minus-log transformed confidence limits separately for high risk and standard risk patients at end of Induction I.


Other Outcome Measures:
  1. Average total number of days per patient spent on protocol therapy [ Time Frame: 6 months ]
    A two-sample t-test will be used to compare average number of days per patient spent on protocol therapy for standard risk patients.

  2. Early death rates [ Time Frame: 1 month ]
  3. Overall survival [ Time Frame: Up to at least 10 years ]
  4. Treatment related mortality [ Time Frame: 6 months ]
  5. Relapse risk [ Time Frame: Up to at least 10 years ]
  6. Percentage of patients experiencing grade 3 or higher toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: 6 months ]
  7. Time to count recovery [ Time Frame: 6 months ]
  8. Duration of hospitalization [ Time Frame: 6 months ]
    Two-sample t-test will be used to compare average number of days of hospitalization per patient for standard risk patients.

  9. Infection rates [ Time Frame: 6 months ]


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Ages Eligible for Study:   91 Days to 3 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have constitutional trisomy 21 (Down syndrome) or trisomy 21 mosaicism (by karyotype or fluorescence in situ hybridization [FISH])
  • Patient has one of the following:

    • Patients has previously untreated de novo AML and meets the criteria for AML with >= 20% bone marrow blasts as set out in the World Health Organization (WHO) Myeloid Neoplasm classification

      • Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive; in cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis
    • Patients has cytopenias and/or bone marrow blasts but does not meet the criteria for the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20% marrow blasts and meets the criteria for a diagnosis of myelodysplastic syndrome (MDS)
    • Patients has a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention), who:
    • Are > 8 weeks since resolution of transient myeloproliferative disease (TMD) with >= 5% blasts, OR
    • Patients who have an increasing blast count (>= 5%) in serial bone marrow aspirates performed at least 4 weeks apart
  • Children who have previously received chemotherapy, radiation therapy or any anti-leukemic therapy are not eligible for this protocol, with the exception of cytarabine for the treatment of TMD
  • There are no minimal organ function requirements for enrollment on this study

    • Note: Previous cardiac repair with sufficient cardiac function is not an exclusion criteria
  • Each patient?s parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human subjects research must be met

Exclusion Criteria:

  • Patients with promyelocytic leukemia (French-American-British [FAB] M3)
  • Prior therapy

    • Patients =< 30 days from the last dose of cytarabine used for treatment of TMD

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02521493


  Show 173 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jason Berman Children's Oncology Group

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02521493     History of Changes
Other Study ID Numbers: AAML1531
NCI-2015-00324 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
s16-01673
AAML1531
AAML1531 ( Other Identifier: Childrens Oncology Group )
AAML1531 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: August 13, 2015    Key Record Dates
Last Update Posted: August 16, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Down Syndrome
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Trisomy
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Aneuploidy
Chromosome Aberrations
Chromosome Duplication
Etoposide
Podophyllotoxin
Mitoxantrone