Clinical Trials /

A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations

NCT04293562

Description:

This phase III trial compares standard chemotherapy to therapy with CPX-351 and/or gilteritinib for patients with newly diagnosed acute myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as daunorubicin, cytarabine, and gemtuzumab ozogamicin, 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. CPX-351 is made up of daunorubicin and cytarabine and is made in a way that makes the drugs stay in the bone marrow longer and could be less likely to cause heart problems than traditional anthracycline drugs, a common class of chemotherapy drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene called FLT3. Genes are pieces of DNA (molecules that carry instructions for development, functioning, growth and reproduction) inside each cell that tell the cell what to do and when to grow and divide. FLT3 plays an important role in the normal making of blood cells. This gene can have permanent changes that cause it to function abnormally by making cancer cells grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with standard chemotherapy may work better in treating patients with acute myeloid leukemia compared to standard chemotherapy alone.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations
  • Official Title: A Phase 3 Randomized Trial for Patients With De Novo AML Comparing Standard Therapy Including Gemtuzumab Ozogamicin (GO) to CPX-351 With GO, and the Addition of the FLT3 Inhibitor Gilteritinib for Patients With FLT3 Mutations

Clinical Trial IDs

  • ORG STUDY ID: AAML1831
  • SECONDARY ID: NCI-2020-00546
  • SECONDARY ID: AAML1831
  • SECONDARY ID: AAML1831
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04293562

Conditions

  • Acute Myeloid Leukemia

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 A Low Risk Group 1
Asparaginase Erwinia chrysanthemiCrisantaspase, Crisantaspasum, Erwinase, Erwinaze, L-asparginase (Erwinia )Arm A Low Risk Group 1
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 High Risk Group
DaunorubicinDaunomycin, Daunorrubicina, DNR, Leukaemomycin C, Rubidomycin, RUBOMYCIN CArm A High Risk Group
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 High Risk Group
Dexrazoxane2, 6-Piperazinedione, 4,4''-propylenedi-, (P)- (8CI), 2,6-Piperazinedione, 4, 4''-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI), ADR-529, ICRF-187, Razoxane (+)-form, Soluble ICRF (L-isomer)Arm A High Risk Group
Dexrazoxane HydrochlorideCardioxane, Totect, ZinecardArm A High Risk Group
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Arm A High Risk Group
Gemtuzumab OzogamicinCalicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676Arm A High Risk Group
GilteritinibASP-2215, ASP2215, XospataArm AC High Risk Group
Gilteritinib FumarateASP-2215 Hemifumarate, ASP2215 Hemifumarate, Gilteritinib Hemifumarate, XospataArm AC High Risk Group
Liposome-encapsulated Daunorubicin-CytarabineCPX-351, Cytarabine-Daunorubicin Liposome for Injection, Liposomal AraC-Daunorubicin CPX-351, Liposomal Cytarabine-Daunorubicin, Liposome-encapsulated Combination of Daunorubicin and Cytarabine, VyxeosArm B High Risk Group
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Arm A High Risk Group
MitoxantroneDihydroxyanthracenedione, MitozantroneArm A Low Risk Group 2
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanArm A Low Risk Group 2
Therapeutic HydrocortisoneAeroseb-HC, Barseb HC, Barseb-HC, Cetacort, Cort-Dome, Cortef, Cortenema, Cortifan, Cortisol, Cortispray, Cortril, Dermacort, Domolene, Eldecort, Hautosone, Heb-Cort, Hydrocortisone, Hydrocortone, Hytone, Komed-HC, Nutracort, Proctocort, RectoidArm A High Risk Group

Purpose

This phase III trial compares standard chemotherapy to therapy with CPX-351 and/or gilteritinib for patients with newly diagnosed acute myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as daunorubicin, cytarabine, and gemtuzumab ozogamicin, 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. CPX-351 is made up of daunorubicin and cytarabine and is made in a way that makes the drugs stay in the bone marrow longer and could be less likely to cause heart problems than traditional anthracycline drugs, a common class of chemotherapy drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene called FLT3. FLT3 plays an important role in the normal making of blood cells. This gene can have permanent changes that cause it to function abnormally by making cancer cells grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells grow. Giving CPX-351 and/or gilteritinib with standard chemotherapy may work better in treating patients with acute myeloid leukemia compared to standard chemotherapy alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare event-free survival (EFS) in children with de novo acute myeloid leukemia (AML)
      without FLT3 mutations who are randomly assigned to standard induction therapy on Arm A with
      daunorubicin, cytarabine (DA) and gemtuzumab ozogamicin (GO) versus Arm B with
      liposome-encapsulated daunorubicin-cytarabine (CPX-351) and GO.

      SECONDARY OBJECTIVES:

      I. To compare overall survival (OS) and rates of end of Induction 1 (EOI1) minimal residual
      disease (MRD) in children with de novo AML without FLT3 mutations who are randomly assigned
      to standard induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B).

      II. To estimate the EFS and rate of EOI1 MRD in FLT3 internal tandem duplication mutation
      positive patients (FLT3/ITD+; as defined by allelic ratio > 0.1) without favorable
      cytomolecular characteristics (NPM1 and/or CEBPA) receiving gilteritinib fumarate
      (gilteritinib) in combination with DA-GO (Arm AC).

      III. To estimate the EFS and rate of EOI1 MRD in patients with non-ITD FLT3 activating
      mutations who receive backbone therapy (DA-GO or CPX-351 and GO) with gilteritinib (Arms AD
      and BD).

      IV. To determine the feasibility of combining gilteritinib and DA-GO or CPX-351 and GO in
      patients with FLT3/ITD mutations (Arm AC/Arm BC/Arm AD/Arm BD).

      V. To compare EOI1 MRD and EFS in patients with FLT3/ITD AML+ (allelic ratio [AR] > 0.1)
      without favorable cytogenetic/molecular characteristics treated with DA-GO-gilteritinib
      versus (vs) CPX-GO-gilteritinib (Arm AC vs Arm BC).

      VI. To compare the incidence of significant left ventricular systolic dysfunction (LVSD) in
      children with de novo AML without FLT3 mutations who are randomly assigned to standard
      induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B).

      VII. To compare the changes in echocardiography-derived measures of cardiac function,
      including left ventricular ejection fraction (EF) and global longitudinal strain (GLS),
      throughout AML therapy in patients with low and high risk AML without FLT3 mutations
      receiving Arm A vs Arm B.

      VIII. Determine if early changes in sensitive echocardiographic measures of cardiac function
      (i.e., post-Induction 1 decline in GLS) and elevations in circulating cardiac biomarkers
      (i.e., cardiac troponin T and N-terminal pro b-type natriuretic peptide) are associated with
      subsequent declines in left ventricular ejection fraction in patients with non-FLT3 mutant
      AML receiving therapy on Arms A or B.

      IX. To compare longitudinal acute changes in neuropsychological functioning and
      neurocognitive late effects between those with central nervous system (CNS) disease and those
      without CNS disease and between those treated with hematopoietic stem cell transplant (HSCT)
      and those treated with chemotherapy only for patients on Arms A and B.

      X. To compare cardiotoxicity measures (EF, GLS, and cardiac biomarkers) in patients receiving
      standard induction with dexrazoxane hydrochloride (dexrazoxane) vs. CPX-351 in the context of
      gilteritinib therapy and explore whether the differential cardiotoxicity across arms varies
      from that observed in non-FLT3 mutant AML without gilteritinib exposure.

      EXPLORATORY OBJECTIVES:

      I. To estimate the EFS and rate of EOI1 MRD in patients with high allelic ratio (HAR)
      FLT3/ITD+ patients, as historically defined by an AR > 0.4, receiving gilteritinib in
      combination with DA-GO (Arm AC with AR > 0.4).

      II. To estimate the EFS and rate of EOI1 MRD in FLT3/ITD+ patients (as defined by allelic
      ratio > 0.1) with NPM1 and/or bZIP CEBPA mutations receiving gilteritinib in combination with
      DA-GO (Arm AC).

      III. Compare the changes in high sensitivity troponin and natriuretic peptide elevations
      throughout AML therapy, as measured at the end of each chemotherapy course, in patients with
      low and high risk AML without FLT3 mutations receiving Arm A vs Arm B.

      IV. Quantify the association of host factors (age, sex, body mass index [BMI], race),
      treatment exposures (cumulative anthracycline dose, anthracycline arm, hematopoietic stem
      cell transplant vs. chemotherapy alone), early declines in GLS, and elevations in cardiac
      biomarkers (cTnT and NT-proBNP) with subsequent LVSD.

      V. Develop a multi-marker risk prediction model incorporating significant host factors,
      treatment exposures, and echocardiographic predictors for the development of LVSD within 1
      year of completing therapy.

      VI. To describe the rates of CNS disease utilizing an updated strategy for diagnosing and
      defining CNS disease in pediatric AML.

      VII. To describe the rates of CNS relapse (both isolated CNS and combined bone marrow/CNS)
      when utilizing this updated strategy as well as changing CNS prophylaxis and treatment to
      include triple intrathecal chemotherapy.

      VIII. To describe disease-free survival (DFS) and overall survival (OS) in high risk patients
      based on multi-dimensional flow cytometry detection of measurable residual disease prior to
      hematopoietic stem cell transplant (HSCT).

      IX. To describe plasma metabolomics that may impact efficacy, toxicity, and/or
      pharmacokinetics of allogeneic HSCT.

      X. To estimate the prevalence of non-risk stratifying cytogenetic/molecular variants and
      assess their impact on outcome in childhood AML.

      OUTLINE: Patients are randomized to either Arm A or B and assigned to Arm C or D based on
      FLT3 testing results.

      TREATMENT FOR PATIENTS WITHOUT FLT3 MUTATIONS:

      ARM A LOW RISK GROUP 1:

      INDUCTION 1: Patients receive cytarabine intravenously (IV) over 1-30 minutes every 12 hours
      (Q12H) on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes
      on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1
      receive methotrexate intrathecally (IT), therapeutic hydrocortisone (hydrocortisone) IT, and
      cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT once weekly (QW) starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the cerebral spinal fluid (CSF) is clear of blasts (CNS1
      status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 1 for 6 weeks (may continue into Induction 2).

      INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30
      minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15
      minutes on days 1, 3, and 5.

      INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
      over 90-120 minutes on days 1-5.

      INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
      8, and 9. Patients also receive asparaginase Erwinia chrysanthemi intramuscularly (IM) or IV
      over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9.

      ARM B LOW RISK GROUP 1:

      INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab
      ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90
      minutes on days 1, 3, and 5.

      INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
      over 90-120 minutes on days 1-5.

      INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
      8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9.

      ARM A LOW RISK GROUP 2:

      INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane
      IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and
      gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30
      minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15
      minutes on days 1, 3, and 5.

      INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
      over 90-120 minutes on days 1-5.

      INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and
      dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15
      minutes on days 3-6.

      INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
      8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9.

      ARM B LOW RISK GROUP 2:

      INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab
      ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90
      minutes on days 1, 3, and 5.

      INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
      over 90-120 minutes on days 1-5.

      INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and
      dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15
      minutes on days 3-6.

      INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
      8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9.

      ARM A HIGH RISK GROUP:

      INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane
      IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and
      gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30
      minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15
      minutes on days 1, 3, and 5.

      INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
      over 90-120 minutes on days 1-5.

      HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
      patients undergo allogeneic HSCT.

      ARM B HIGH RISK GROUP:

      INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab
      ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
      starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90
      minutes on days 1, 3, and 5.

      INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
      day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
      over 90-120 minutes on days 1-5.

      HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
      patients undergo allogeneic HSCT.

      TREATMENT FOR PATIENTS WITH FLT3/ITD MUTATIONS (ITD AR > 0.1):

      ARM AC LOW RISK GROUP 2:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
      Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
      (PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
      and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
      11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
      3-6, and gilteritinib PO QD on days 7-34.

      INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
      Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.

      POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
      1-365.

      ARM BC LOW RISK GROUP 2:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
      days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
      the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
      Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
      3-6, and gilteritinib PO QD on days 7-34.

      INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
      Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.

      POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
      1-365.

      ARM AC HIGH RISK GROUP:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
      Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
      (PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
      and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
      11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
      patients undergo allogeneic HSCT.

      POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
      receive gilteritinib PO QD on days 1-365.

      ARM BC HIGH RISK GROUP:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
      days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
      the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
      Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
      patients undergo allogeneic HSCT.

      POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
      receive gilteritinib PO QD on days 1-365.

      TREATMENT FOR NON-ITD FLT3 ACTIVATING MUTATIONS:

      ARM AD LOW RISK GROUP 2:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
      Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
      (PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
      and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
      11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
      3-6, and gilteritinib PO QD on days 7-34.

      INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
      Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.

      POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
      1-365.

      ARM BD LOW RISK GROUP 2:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
      days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
      the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
      Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
      3-6, and gilteritinib PO QD on days 7-34.

      INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
      Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.

      POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
      1-365.

      ARM AD HIGH RISK GROUP:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
      Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
      (PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
      methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
      continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
      CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
      6 weeks (may continue into Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
      and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
      11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
      patients undergo allogeneic HSCT.

      POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
      receive gilteritinib PO QD on days 1-365.

      ARM BD HIGH RISK GROUP:

      CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
      days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
      days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
      on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
      the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
      hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
      Induction 2).

      INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
      IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
      receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.

      INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
      and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
      and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.

      HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
      patients undergo allogeneic HSCT.

      POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
      receive gilteritinib PO QD on days 1-365.

      NOTE: During Induction 2 or Intensification 2, patients in Arms A and B with left ventricular
      systolic dysfunction receive a replacement course of high-dose cytarabine IV over 3 hours on
      days 1, 2, 8, and 9, and asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
      asparaginase IM or IV over 30 minutes on days 2 and 9. Patients in Arms AC, BC, AD, and BD
      receive treatment as in Arms A and B and also receive gilteritinib PO QD on days 10-37
      (Induction 2) or days 10-30 (Intensification 2).

      All treatment continues in the absence of disease progression or unacceptable toxicity.

      OPTIONAL NEUROCOGNITIVE STUDY:

      Patients may complete the Cogstate assessment battery at the end of Induction 1, at the end
      of therapy, and at 9 and 60 months post-enrollment.

      After completion of study treatment, patients are followed up monthly for 6 months and then
      every other month for 6 months (year 1), every 4 months during year 2, every 6 months during
      year 3, then yearly for 7 years. Patients who undergo HSCT are also followed up at 30, 100,
      and 180 days, 9 months, and 1 year post-HSCT.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A High Risk GroupExperimentalArm A High Risk Group: See Detailed Description.
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm A Low Risk Group 1ExperimentalArm A Low Risk Group 1: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm A Low Risk Group 2ExperimentalArm A Low Risk Group 2: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Methotrexate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Therapeutic Hydrocortisone
Arm AC High Risk GroupExperimentalArm AC High Risk Group: See Detailed Description.
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm AC Low Risk Group 2ExperimentalArm AC Low Risk Group 2: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Methotrexate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Therapeutic Hydrocortisone
Arm AD High Risk GroupExperimentalArm AD High Risk Group: See Detailed Description.
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm AD Low Risk Group 2ExperimentalArm AD Low Risk Group 2: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Daunorubicin
  • Daunorubicin Hydrochloride
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Methotrexate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Therapeutic Hydrocortisone
Arm B High Risk GroupExperimentalArm B High Risk Group: See Detailed Description.
  • Cytarabine
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm B Low Risk Group 1ExperimentalArm B Low Risk Group 1: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm B Low Risk Group 2ExperimentalArm B Low Risk Group 2: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Therapeutic Hydrocortisone
Arm BC High Risk GroupExperimentalArm BC High Risk Group: See Detailed Description.
  • Cytarabine
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm BC Low Risk Group 2ExperimentalArm BC Low Risk Group 2: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Therapeutic Hydrocortisone
Arm BD High Risk GroupExperimentalArm BD High Risk Group: See Detailed Description.
  • Cytarabine
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Therapeutic Hydrocortisone
Arm BD Low Risk Group 2ExperimentalArm BD Low Risk Group 2: See Detailed Description.
  • Asparaginase
  • Asparaginase Erwinia chrysanthemi
  • Cytarabine
  • Dexrazoxane
  • Dexrazoxane Hydrochloride
  • Etoposide
  • Gemtuzumab Ozogamicin
  • Gilteritinib
  • Gilteritinib Fumarate
  • Liposome-encapsulated Daunorubicin-Cytarabine
  • Methotrexate
  • Mitoxantrone
  • Mitoxantrone Hydrochloride
  • Therapeutic Hydrocortisone

Eligibility Criteria

        Inclusion Criteria:

          -  All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part
             A) prior to enrollment and treatment on AAML1831. Submission of diagnostic specimens
             must be done according to the Manual of Procedures). Risk stratification will not be
             possible without the submission of viable samples. Given there are multiple required
             samples, bone marrow acquisition techniques such as frequent repositioning or
             performing bilateral bone marrow testing should be considered to avoid insufficient
             material for required studies. Consider a repeat marrow prior to starting treatment if
             there is insufficient diagnostic material for the required studies

          -  Patient must be newly diagnosed with de novo AML according to the 2016 World Health
             Organization (WHO) classification with or without extramedullary disease

               -  Patient must have 1 of the following:

                    -  >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)

                         -  In cases where extensive fibrosis may result in a dry tap, blast count
                            can be obtained from touch imprints or estimated from an adequate bone
                            marrow core biopsy

                    -  < 20% bone marrow blasts with one or more of the genetic abnormalities
                       (obtained within 14 days prior to enrollment)

                    -  A complete blood count (CBC) documenting the presence of at least 1,000/uL
                       (i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a
                       WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells
                       (blasts) if a bone marrow aspirate or biopsy cannot be performed (performed
                       within 7 days prior to enrollment)

          -  ARM C: Patient must be >= 2 years of age at the time of Late Callback

          -  ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular
             Oncology

          -  ARM C: Patient does not have any congenital long QT syndrome or congenital heart block

          -  ARM C: Females of reproductive potential must agree to use effective contraception
             during treatment and for at least 6 months after the last dose of gilteritinib

          -  ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib
             and for 2 months after the last dose of gilteritinib

          -  ARM C: Males of reproductive potential must agree to use effective contraception
             during treatment and for at least 4 months after the last dose of gilteritinib

          -  ARM D: Patient must be >= 2 years of age at the time of Late Callback

          -  ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating
             mutations as reported by Foundation Medicine

          -  ARM D: Females of reproductive potential must agree to use effective contraception
             during treatment and for at least 6 months after the last dose of gilteritinib

          -  ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib
             and for 2 months after the last dose of gilteritinib

          -  ARM D: Males of reproductive potential must agree to use effective contraception
             during treatment and for at least 4 months after the last dose of gilteritinib

          -  NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who
             transfer to Arm C or Arm D are not eligible

          -  NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment

          -  NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking

          -  NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to
             diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental
             retardation)

          -  NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would
             prevent computer use or recognition of visual test stimuli

        Exclusion Criteria:

          -  Patients with myeloid neoplasms with germline predisposition are not eligible

          -  Fanconi anemia

          -  Shwachman Diamond syndrome

          -  Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21

          -  Any other known bone marrow failure syndrome

          -  Any concurrent malignancy

          -  Juvenile myelomonocytic leukemia (JMML)

          -  Philadelphia chromosome positive AML

          -  Mixed phenotype acute leukemia

          -  Acute promyelocytic leukemia

          -  Acute myeloid leukemia arising from myelodysplasia

          -  Therapy-related myeloid neoplasms

          -  Administration of prior anti-cancer therapy except as outlined below:

               -  Hydroxyurea

               -  All-trans retinoic acid (ATRA)

               -  Corticosteroids (any route)

               -  Intrathecal therapy given at diagnosis

               -  In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be
                  avoided from the time of enrollment until it is determined whether the patient
                  will receive gilteritinib. Patients receiving gilteritinib will be required to
                  avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the
                  study treatment

          -  Female patients who are pregnant since fetal toxicities and teratogenic effects have
             been noted for several of the study drugs. A pregnancy test is required for female
             patients of childbearing potential

          -  Lactating females who plan to breastfeed their infants

          -  Sexually active patients of reproductive potential who have not agreed to use an
             effective contraceptive method for the duration of their study participation

          -  ARM D: Patients with congenital long QT syndrome or congenital heart block are not
             eligible for this treatment arm
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
Measure:Proportion of patients minimal residual disease positive (MRD+)
Time Frame:Up to 4 weeks
Safety Issue:
Description:The proportion of patients MRD+ at end of induction 1 (EOI1) will be estimated as the number of patients MRD+ divided by the number of patients with evaluable EOI1 MRD results along with a corresponding 95% confidence interval determined using a binomial exact method.
Measure:Proportion of patients who died during protocol therapy
Time Frame:Up to 2 years
Safety Issue:
Description:The proportion of patients who died during protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method.
Measure:Relapse rate
Time Frame:Up to 3 years
Safety Issue:
Description:Cumulative incidence estimates will be used to determine the 3 year relapse rate defined as time from study entry to induction failure or relapse where deaths or secondary malignancies are competing events.
Measure:Treatment-related mortality rate (TRM)
Time Frame:Up to 3 years
Safety Issue:
Description:Cumulative incidence estimates will be used to determine the 3 year TRM defined as time from study entry to death where induction failure, relapse or secondary malignancies are competing events.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:The proportion of patients experiencing at least one grade 3 or higher non-hematologic toxicity and infection while on protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method. Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Children's Oncology Group

Last Updated

March 2, 2020