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

• ClinicalTrials.gov Identifier: NCT02521493
• Recruitment Status: Active, not recruiting
• First Posted: August 13, 2015
• Last Update Posted: March 30, 2023
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: August 10, 2015
• First Posted Date: August 13, 2015
• Last Update Posted Date: March 30, 2023
• Actual Study Start Date: November 23, 2015
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (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: Response-Based Chemotherapy in Treating Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome in Younger Patients With Down Syndrome
• Official Title: 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 in case of relapse.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Myeloid Leukemia
• Down Syndrome
• Myelodysplastic Syndrome
• Myeloid Leukemia Associated With Down Syndrome
• Myeloproliferative Neoplasm

Intervention

• 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 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 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

• 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 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 Hydrochloride

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 14, 2020): 312
• Original Estimated Enrollment (submitted: August 12, 2015): 256
• Estimated Study Completion Date: June 30, 2024
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

Eligibility 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:

  • 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)

  • For patients who do not meet criteria for AML or MDS as outlined above; patient has a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention and:

    • Is > 8 weeks since resolution of transient myeloproliferative disease (TMD) with >= 5% blasts, OR
    • Has 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

• Sexes Eligible for Study: All

• Ages: 91 Days to 3 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, Saudi Arabia, United States

Administrative Information

• NCT Number: NCT02521493
• Other Study ID Numbers: AAML1531; NCI-2015-00324 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); AAML1531; s16-01673; AAML1531 ( Other Identifier: Children's Oncology Group ); AAML1531 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jason N Berman; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: March 2023