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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 : October 22, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE August 10, 2015
First Posted Date  ICMJE August 13, 2015
Last Update Posted Date October 22, 2019
Actual Study Start Date  ICMJE November 23, 2015
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 5, 2019)
Event-free survival probability at 2 years [ Time Frame: At 2 years ]
The Kaplan-Meier method will be used to estimate 2-year event-free survival (EFS) from the end of Induction I along with 95% log-minus-log transformed confidence limits. EFS is defined as the time from the end of Induction I to failure to achieve remission at the end of Induction II, relapse, occurrence of a second malignancy, or death.
Original Primary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
EFS [ Time Frame: 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.
Change History Complete list of historical versions of study NCT02521493 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
  • Average total number of days per patient spent on protocol therapy [ Time Frame: Up to at least 10 years ]
  • Duration of hospitalization [ Time Frame: Up to at least 10 years ]
  • Early death rates [ Time Frame: Up to at least 10 years ]
  • Infection rates [ Time Frame: Up to at least 10 years ]
  • Overall survival [ Time Frame: Up to at least 10 years ]
  • 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: Up to at least 10 years ]
  • Relapse risk [ Time Frame: Up to at least 10 years ]
  • Time to count recovery [ Time Frame: Up to at least 10 years ]
  • Treatment related mortality [ Time Frame: Up to at least 10 years ]
Current Other Pre-specified Outcome Measures
 (submitted: October 21, 2019)
  • Mean length on protocol therapy [ Time Frame: 6 months ]
    The mean number of days patients spent on protocol therapy.
  • Proportion of patients with an early death [ Time Frame: 1 month ]
    The proportion of patients experiencing an early death in the first month.
  • Overall survival probability at 2 years. [ Time Frame: 2 years ]
    The Kaplan-Meier method will be used to estimate 2-year Overall Survival (OS) from the end of Induction I along with 95% log-minus-log transformed confidence limits. OS is defined as the time from the end of Induction I to death.
  • Proportion with treatment related mortality [ Time Frame: 6 months ]
    The proportion of patients experiencing a treatment related death will be reported along with a corresponding confidence interval.
  • Proportion of patients experiencing a relapse risk [ Time Frame: 2 years ]
    The proportion of patients experiencing a relapse after achieving remission will be reported along with a corresponding confidence interval.
  • Percentage of patients experiencing grade 3 or adverse events [ Time Frame: 6 months ]
    The percentage of patients experiencing grade 3 or higher toxicity will be reported, where adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
  • Mean time to absolute neutrophil count (ANC) recovery [ Time Frame: 6 months ]
    The mean time to recovery of ANC to at least 1000/uL will be reported.
  • Mean duration of hospitalization [ Time Frame: 6 months ]
    Mean number of days patients are hospitalized.
  • Proportion of patients with at least 1 infection [ Time Frame: 6 months ]
    The proportion of patients having at least one infection will be reported.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome
Official Title  ICMJE Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome
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.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the 2-year event-free-survival (EFS) for children with standard risk Down syndrome (DS) acute myeloid leukemia (AML) (minimal residual disease [MRD]-negative after one cycle of induction therapy) after elimination of high dose (HD) Ara-C (cytarabine) from the treatment regimen.

II. To determine the 2-year EFS for children with high risk DS AML (MRD-positive after one cycle of induction therapy) after intensification of treatment equivalent to that used for high risk AML in children without DS.

EXPLORATORY OBJECTIVES:

I. To compare the feasibility and analytical characteristics of flow cytometry, polymerase chain reaction (PCR) and targeted error-corrected sequencing of GATA binding protein 1 (globin transcription factor 1) (GATA1) mutations as methods to detect MRD in DS AML.

II. To establish a DS AML cell bank of viably frozen bone marrow samples collected at the end of induction and corresponding non-tumor deoxyribonucleic acid (DNA) samples collected at end of Induction 1.

OUTLINE:

INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and intravenously (IV) continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine orally (PO) twice daily (BID) on days 1-4. Induction I continues for a minimum of 28 days.

Patients are assigned to 1 of 2 treatment arms based on their MRD status after completion of Induction I.

ARM A (STANDARD RISK) (Closed to accrual and treatment with amendment #4A 01/07/2019):

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.

ARM B (HIGH RISK):

INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours every 12 (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 (E. carotovora) intramuscularly (IM) or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days.

After completion of study treatment, patients are followed up at 1 month, monthly for 12 months, every 3 months for 12 months, every 6 months for 3 years, annually for 10 years, and then at relapse.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Down Syndrome
  • Myelodysplastic Syndrome
  • Myeloid Leukemia Associated With Down Syndrome
  • Myeloproliferative Neoplasm
Intervention  ICMJE
  • 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:
    • Crisantaspase
    • Crisantaspasum
    • 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
  • Drug: Daunorubicin
    Given IV
    Other Names:
    • DAUNOMYCIN
    • Daunorrubicina
    • DNR
    • Leukaemomycin C
    • Rubidomycin
    • RUBOMYCIN C
  • 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
    • VP 16-213
    • VP-16
    • VP-16-213
    • VP16
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mitoxantrone
    Given IV
    Other Names:
    • Dihydroxyanthracenedione
    • Mitozantrone
  • Drug: Mitoxantrone Hydrochloride
    Given IV
    Other Names:
    • CL 232315
    • DHAD
    • DHAQ
    • Dihydroxyanthracenedione Dihydrochloride
    • Mitoxantrone Dihydrochloride
    • Mitoxantroni Hydrochloridum
    • Mitozantrone Hydrochloride
    • Mitroxone
    • Neotalem
    • Novantrone
    • Onkotrone
    • Pralifan
  • 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-Aminopurine-6-thiol Hemihydrate
    • 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
    • Thioguanine Hemihydrate
    • Thioguanine Hydrate
    • Tioguanin
    • Tioguanine
    • Wellcome U3B
    • WR-1141
    • X 27
Study Arms  ICMJE
  • 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.

    (This arm is closed to accrual and treatment with amendment #4A 01/07/2019)

    Interventions:
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Daunorubicin Hydrochloride
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Drug: Thioguanine
  • 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.

    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Drug: Cytarabine
    • Other: Laboratory Biomarker Analysis
    • Drug: Mitoxantrone
    • Drug: Mitoxantrone Hydrochloride
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 12, 2015)
256
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

    • Patient 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
    • Patient 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)
    • Patient 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 91 Days to 3 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   Saudi Arabia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02521493
Other Study ID Numbers  ICMJE AAML1531
NCI-2015-00324 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AAML1531
s16-01673
AAML1531 ( Other Identifier: Childrens Oncology Group )
AAML1531 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Jason N Berman Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP