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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

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ClinicalTrials.gov Identifier: NCT04293562
Recruitment Status : Recruiting
First Posted : March 3, 2020
Last Update Posted : March 19, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE February 18, 2020
First Posted Date  ICMJE March 3, 2020
Last Update Posted Date March 19, 2021
Actual Study Start Date  ICMJE July 20, 2020
Estimated Primary Completion Date September 30, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 2, 2020)
Event-free survival (EFS) [ Time Frame: Up to 3 years ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2020)
  • Overall survival (OS) [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
  • Proportion of patients positive for minimal residual disease (MRD+) [ Time Frame: Up to 4 weeks ]
    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.
  • Proportion of patients who died during protocol therapy [ Time Frame: Up to 2 years ]
    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.
  • Relapse rate [ Time Frame: Up to 3 years ]
    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.
  • Treatment-related mortality rate (TRM) [ Time Frame: Up to 3 years ]
    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.
  • Incidence of adverse events [ Time Frame: Up to 2 years ]
    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).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2020)
  • Overall survival (OS) [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
  • Proportion of patients minimal residual disease positive (MRD+) [ Time Frame: Up to 4 weeks ]
    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.
  • Proportion of patients who died during protocol therapy [ Time Frame: Up to 2 years ]
    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.
  • Relapse rate [ Time Frame: Up to 3 years ]
    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.
  • Treatment-related mortality rate (TRM) [ Time Frame: Up to 3 years ]
    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.
  • Incidence of adverse events [ Time Frame: Up to 2 years ]
    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).
Current Other Pre-specified Outcome Measures
 (submitted: March 2, 2020)
  • Course duration [ Time Frame: Up to 2 years ]
    Median and range of the length of course duration will be determined.
  • Length of hospitalization [ Time Frame: Up to 2 years ]
    Median and range of the length of hospitalization time during protocol therapy will be determined.
  • Time to count recovery [ Time Frame: Up to 2 years ]
    Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery in days where deaths are competing events.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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.
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) (DA-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 or via nasogastric (NG) or gastronomy (G) tube daily 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 or via NG or G tube daily 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 or via NG or G tube daily 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 or via NG or G tube daily 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 or via NG or G tube daily 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 or via NG or G tube daily 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 or via NG or G tube daily 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 or via NG or G tube daily 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 10-37 (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 years 4-10. Patients who undergo HSCT are also followed up at 30, 100, and 180 days, 9 months, and 1 year post-HSCT.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia
Intervention  ICMJE
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo allogeneic HSCT
    Other Names:
    • Allogeneic
    • Allogeneic Hematopoietic Cell Transplantation
    • Allogeneic Stem Cell Transplantation
    • HSC
    • HSCT
    • Stem Cell Transplantation, Allogeneic
  • 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 )
  • Behavioral: Cogstate Assessment Battery
    Ancillary studies
  • Drug: Cytarabine
    Given IV or IT
    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: Dexrazoxane Hydrochloride
    Given IV
    Other Names:
    • Cardioxane
    • Totect
    • Zinecard
  • 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
  • Drug: Gemtuzumab Ozogamicin
    Given IV
    Other Names:
    • Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody
    • CDP-771
    • CMA-676
    • gemtuzumab
    • hP67.6-Calicheamicin
    • Mylotarg
    • WAY-CMA-676
  • Drug: Gilteritinib Fumarate
    Given PO or via NG or G tube
    Other Names:
    • ASP-2215 Hemifumarate
    • ASP2215 Hemifumarate
    • Gilteritinib Hemifumarate
    • Xospata
  • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    Given IV
    Other Names:
    • CPX-351
    • Cytarabine-Daunorubicin Liposome for Injection
    • Daunorubicin and Cytarabine (Liposomal)
    • Liposomal AraC-Daunorubicin CPX-351
    • Liposomal Cytarabine-Daunorubicin
    • Liposome-encapsulated Combination of Daunorubicin and Cytarabine
    • Vyxeos
  • Drug: Methotrexate
    Given IT
    Other Names:
    • Abitrexate
    • 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-19039
  • 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: Therapeutic Hydrocortisone
    Given IT
    Other Names:
    • Aeroseb-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
    • Rectoid
Study Arms  ICMJE
  • Experimental: Arm A High Risk Group
    Arm A High Risk Group: See Detailed Description.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm A Low Risk Group 1
    Arm A Low Risk Group 1: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm A Low Risk Group 2
    Arm A Low Risk Group 2: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Methotrexate
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm AC High Risk Group
    Arm AC High Risk Group: See Detailed Description.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm AC Low Risk Group 2
    Arm AC Low Risk Group 2: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Methotrexate
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm AD High Risk Group
    Arm AD High Risk Group: See Detailed Description.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm AD Low Risk Group 2
    Arm AD Low Risk Group 2: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Methotrexate
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm B High Risk Group
    Arm B High Risk Group: See Detailed Description.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm B Low Risk Group 1
    Arm B Low Risk Group 1: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm B Low Risk Group 2
    Arm B Low Risk Group 2: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm BC High Risk Group
    Arm BC High Risk Group: See Detailed Description.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm BC Low Risk Group 2
    Arm BC Low Risk Group 2: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm BD High Risk Group
    Arm BD High Risk Group: See Detailed Description.
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Therapeutic Hydrocortisone
  • Experimental: Arm BD Low Risk Group 2
    Arm BD Low Risk Group 2: See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • Drug: Asparaginase Erwinia chrysanthemi
    • Behavioral: Cogstate Assessment Battery
    • Drug: Cytarabine
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Etoposide
    • Drug: Gemtuzumab Ozogamicin
    • Drug: Gilteritinib Fumarate
    • Drug: Liposome-encapsulated Daunorubicin-Cytarabine
    • Drug: Methotrexate
    • Drug: Mitoxantrone Hydrochloride
    • Drug: Therapeutic Hydrocortisone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 2, 2020)
1400
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2027
Estimated Primary Completion Date September 30, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • Patients must be less than 22 years of age at the time of study enrollment
  • 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 (sample 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
  • All patients and/or their 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 studies must be met.

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 22 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04293562
Other Study ID Numbers  ICMJE AAML1831
NCI-2020-00546 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AAML1831 ( Other Identifier: Children's Oncology Group )
AAML1831 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Todd M Cooper Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date February 2021

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