Clinical Trial: NCT02521493 - My Cancer Genome

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
Myeloid Leukemia Associated with Down Syndrome
Myeloid Proliferations Associated with Down Syndrome
Transient Abnormal Myelopoiesis Associated with Down Syndrome

Recruiting Status:

Recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT02521493

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: AAML1531
SECONDARY ID: s16-01673
SECONDARY ID: AAML1531
SECONDARY ID: AAML1531
SECONDARY ID: U10CA180886
NCT ID: NCT02521493

Conditions

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

Interventions

Drug	Synonyms	Arms
Asparaginase	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	Arm B (high risk)
Asparaginase Erwinia chrysanthemi	Crisantaspase, Crisantaspasum, 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-28453	Arm A (standard risk)
Daunorubicin Hydrochloride	Cerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, Rubilem	Arm A (standard risk)
Etoposide	Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16	Arm A (standard risk)
Mitoxantrone Hydrochloride	CL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, Pralifan	Arm B (high risk)
Thioguanine	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	Arm A (standard risk)

Purpose

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.

Trial Arms

Name	Type	Description	Interventions
Arm A (standard risk)	Experimental	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)	Cytarabine Daunorubicin Hydrochloride Etoposide Thioguanine
Arm B (high risk)	Experimental	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.	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:

               -  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

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

Primary Outcome Measures

Measure:	Event-free survival probability at 2 years
Time Frame:	At 2 years
Safety Issue:
Description:	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.

Details

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

Last Updated

August 25, 2021

Clinical Trials /

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