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

NCT02521493

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: AAML1531
  • SECONDARY ID: NCI-2015-00324
  • SECONDARY ID: s16-01673
  • SECONDARY ID: AAML1531
  • SECONDARY ID: AAML1531
  • SECONDARY ID: AAML1531
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02521493

Conditions

  • 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

Interventions

DrugSynonymsArms
AsparaginaseASP-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, SpectrilaArm B (high risk)
Asparaginase Erwinia chrysanthemiCrisantaspasum, Cristantaspase, Erwinase, Erwinaze, L-asparginase (Erwinia )Arm B (high risk)
Cytarabine.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-28453Arm A (standard risk)
Daunorubicin HydrochlorideCerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, RubilemArm A (standard risk)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Arm A (standard risk)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanArm B (high risk)
Thioguanine2-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 27Arm A (standard risk)

Purpose

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 determine the extent to which elimination of HD Ara-C from the treatment of standard
      risk DS AML decreases adverse events and resource utilization.

      II. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in
      a significant decrease in the number of days per patient spent on protocol therapy compared
      to predecessor study AAML0431.

      III. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results
      in a significant decrease in the average number of days of hospitalization per patient
      compared to predecessor studies AAML0431 and A2971.

      IV. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in
      a significant decrease in the number (per patient) and rate (per duration of treatment) of
      sterile site infections compared to the predecessor study AAML0431.

      V. To determine if elimination of HD Ara-C from treatment of standard risk DS AML results in
      a significant decrease of resource utilization by AML treatment compared to the predecessor
      study AAML0431.

      VI. 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.

      VII. 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):

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (standard risk)ExperimentalINDUCTION 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.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
  • Thioguanine
Arm B (high risk)ExperimentalINDUCTION 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.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Mitoxantrone Hydrochloride

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:

               -  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
      
Maximum Eligible Age:3 Years
Minimum Eligible Age:91 Days
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame:At 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

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