A Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia

NCT ID: NCT03164057

Last Updated: 2025-05-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2

Total Enrollment

206 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-06-15

Study Completion Date

2027-06-30

Brief Summary

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The overall aim of this study is to determine if epigenetic priming with a DNA methyltransferase inhibitor (DMTi) prior to chemotherapy blocks is tolerable and carries evidence of a clinical efficacy signal as determined by minimal residual disease (MRD), event-free survival (EFS), and overall survival (OS). Tolerability for each of the agents, as well as total reduction in DNA methylation and outcome assessments will be done to simultaneously obtain preliminary biological and clinical data for each DMTi in parallel.

PRIMARY OBJECTIVES:

* Evaluate the tolerability of five days of epigenetic priming with azacitidine and decitabine as a single agent DMTi prior to standard AML chemotherapy blocks.
* Evaluate the change in genome-wide methylation burden induced by five days of epigenetic priming and the association of post-priming genome-wide methylation burden with event-free survival among pediatric AML patients.

SECONDARY OBJECTIVES

* Describe minimal residual disease levels following Induction I chemotherapy in patients that receive DMTi.
* Estimate the event-free survival and overall survival of patients receiving a DMTi prior to chemotherapy courses.

Detailed Description

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To determine tolerability, priming with DMTi (azacitidine or decitabine) will be limited to Induction I and II during Part 1 of the study. If DMTi treatment is tolerated during Part 1, the investigators will go on to an Expansion Phase (Part 2) that includes DMTi priming prior to all chemotherapy blocks.

Treatment will consist of 5 blocks of conventional chemotherapy: Induction I, Induction II, Intensification I, Intensification II, and Intensification III over approximately 5 months.

RANDOMIZATION: Patients will be randomized to receive one of two DMTi (azacitidine or decitabine) for 5 days prior to Induction I. Intrathecal (ITHMA) treatments will be given right before treatment on this study or on Day 1 of Induction I treatment. Leucovorin will be given 24-30 hours following ITHMA.

INDUCTION I CHEMOTHERAPY: Patients receive cytarabine, daunorubicin, and etoposide.

INDUCTION II CHEMOTHERAPY; Patients receive their assigned DMTi for 5 days followed by fludarabine, cytarabine, G-CSF, and idarubicin.

Patients are then evaluated and assigned to either the low-risk arm, intermediate-risk arm, or the high-risk arm for Intensification therapy.

Patients with ≥ 5% blasts following Induction II will be considered refractory and will go off therapy. The rare high risk patient with an MRD \< 0.1% following Induction I may proceed directly to stem cell transplant (SCT) after Induction II - if a suitable donor is available and the transplant can be performed without delay. MDS patients may proceed to SCT once they have achieved MRD \<0.1% irrespective of the number of chemotherapy courses received.

INTENSIFICATION I CHEMOTHERAPY - LOW-RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive cytarabine and etoposide. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to cytarabine and etoposide.

INTENSIFICATION II CHEMOTHERAPY - LOW RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive mitoxantrone and cytarabine. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine.

INTENSIFICATION I CHEMOTHERAPY - HIGH-RISK AML with a donor: Patients receive mitoxantrone and cytarabine followed by stem cell transplant (SCT). Treatment related AML patients and patients with treatment related MDS who have a donor but are not able to receive a SCT without delay will proceed to HR Intensification III and receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine or erwinia asparaginase and cytarabine.

Treatment related AML patients and treatment related MDS patients that are not able to receive a SCT should go off treatment following Intensification II.

INTENSIFICATION III CHEMOTHERAPY - INTERMEDIATE-RISK AML and HIGH-RISK AML with no donor: Patients receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to erwinia asparaginase and cytarabine.

Conditions

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Acute Myeloid Leukemia Myelodysplastic Syndromes

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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AZA+ADE | AZA+FLAG+Ida | AE | MA

Part 1 Tolerability with AZA - Low Risk

Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and then receive low-risk intensifications I \& II without azacitidine.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide,dexrazoxane, fludarabine, idarubicin, G-CSF, mitoxantrone., ITMHA.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

DAC+ADE | DAC+FLAG+Ida | AE | MA

Part 1 Tolerability with DAC - Low Risk

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive low-risk Intensifications I \& II without decitabine.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, ITMHA.

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

AZA+ADE | AZA+FLAG+Ida+Sor | AZA+AE+Sor | AZA+MA+Sor

Part 2 Dose Expansion with AZA - Low Risk

Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and low- risk Intensifications I \& II. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, ITMHA.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

DAC+ADE | DAC+FLAG+Ida+Sor | DAC+AE+Sor|DAC+MA+Sor

Part 2 Dose Expansion with DAC - Low Risk

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and low-risk Intensifications I \& II. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, ITMHA.

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

AZA+ADE | AZA+FLAG+Ida | AE | MA | Asp+AraC

Part 1 Tolerability with AZA - Intermediate Risk

Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and then receive intermediate risk Intensifications I, II \& III without azacitidine.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, erwinia asparaginase, ITMHA,

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

DAC+ADE | DAC+FLAG+Ida | AE | MA | Asp+AraC

Part 1 Tolerability with DAC - Intermediate Risk

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive intermediate-risk Intensifications I, II \& III without decitabine.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, erwinia asparaginase, ITMHA.

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

AZA| +ADE | +FLAG+Ida+Sor| +AE+Sor| +MA+Sor| +Asp+AraC+Sor

Part 2 Dose Expansion with AZA - Intermediate-Risk

Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and intermediate-risk Intensification I, II, and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

Intervention Type DRUG

May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).

DAC|+ADE | +FLAG+Ida+Sor | +AE+Sor | +MA+Sor | +Asp+AraC+Sor

Part 2 Dose Expansion with DAC - Intermediate-Risk

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and intermediate-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

Intervention Type DRUG

May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).

AZA+ADE | AZA+FLAG-Ida+Sor | AE | MA+Sor | Asp+AraC+Sor

Part 1 Tolerability with AZA - High Risk (no donor)

Patients are randomized to receive 5 days of single agent azacitidine as part of Induction I \& II and high-risk intensifications I, II \& III without azacitidine. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, ITMHA.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

DAC+ADE | DAC+FLAG+Ida+Sor | AE | MA+Sor | Asp+AraC+Sor

Part 1 Tolerability with DAC - High Risk (no donor)

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive high-risk Intensifications I, II \& III without decitabine. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, ITMHA.

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

AZA | + ADE | +FLAG+Ida+Sor| +AE+Sor | +MA+Sor | +Asp+AraC+Sor

Part 2 Dose Expansion with AZA - High Risk (no donor)

Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and high-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

Intervention Type DRUG

May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).

DAC |+ADE |+FLAG+Ida+Sor |+AE+Sor|+MA+Sor|+Asp+AraC+Sor

Part 2 Dose Expansion with DAC - High Risk (no donor)

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and high-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

Intervention Type DRUG

May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).

AZA+ADE | AZA+FLAG+Ida+Sor | MA+Sor | Asp+AraC+Sor

Part 1 Tolerability with AZA- High Risk (with donor)

Patients are randomized to receive 5 days of single agent azacitidine as part of Induction I Induction II and high-risk Intensifications I or high risk intensification III without azacitidine. Patients will proceed to stem cell transplant. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations.

Interventions: azacitidine cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Stem Cell Transplant

Intervention Type BIOLOGICAL

The transplant protocol will depend on the patient's donor and transplant physician's preference.

DAC+ADE | DAC+FLAG+Ida+Sor | MA+Sor | Asp+AraC+Sor

Part 1 Tolerability with DAC - High Risk (with donor)

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive high-risk Intensifications I or high risk intensification III without decitabine. Patients will proceed to stem cell transplant. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Stem Cell Transplant

Intervention Type BIOLOGICAL

The transplant protocol will depend on the patient's donor and transplant physician's preference.

DAC |+ADE|+FLAG+Ida+Sor|+MA+Sor|+Asp+AraC+Sor

Part 2 Dose Expansion with DAC - High Risk (with donor)

Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and high-risk Intensifications I or high risk intensification III. Patients will proceed to stem cell transplant. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy.

Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant

Group Type EXPERIMENTAL

Decitabine

Intervention Type DRUG

Administered intravenously (IV) over approximately one hour.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Stem Cell Transplant

Intervention Type BIOLOGICAL

The transplant protocol will depend on the patient's donor and transplant physician's preference.

AZA |+ADE|+FLAG+Ida+Sor|+MA+Sor|+Asp+AraC+Sor

Part 2 Dose Expansion with AZA - High Risk (with donor)

Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and high-risk Intensification I or high risk intensification III. Patients will proceed to stem cell transplant. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy.

Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G-CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Cytarabine

Intervention Type DRUG

Given IV or intrathecally (IT).

Daunorubicin

Intervention Type DRUG

Given IV.

Etoposide

Intervention Type DRUG

Given IV.

ITMHA

Intervention Type COMBINATION_PRODUCT

Given IT.

Idarubicin

Intervention Type DRUG

Given IV.

Fludarabine

Intervention Type DRUG

Given IV over approximately 30 minutes.

Mitoxantrone

Intervention Type DRUG

Given IV.

Erwinia asparaginase

Intervention Type DRUG

Given IV or intramuscularly (IM).

Sorafenib

Intervention Type DRUG

Given PO.

G-CSF

Intervention Type DRUG

Given IV.

Dexrazoxane

Intervention Type DRUG

Given IV immediately before idarubicin administration.

Stem Cell Transplant

Intervention Type BIOLOGICAL

The transplant protocol will depend on the patient's donor and transplant physician's preference.

Interventions

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Azacitidine

Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.

Intervention Type DRUG

Decitabine

Administered intravenously (IV) over approximately one hour.

Intervention Type DRUG

Cytarabine

Given IV or intrathecally (IT).

Intervention Type DRUG

Daunorubicin

Given IV.

Intervention Type DRUG

Etoposide

Given IV.

Intervention Type DRUG

ITMHA

Given IT.

Intervention Type COMBINATION_PRODUCT

Idarubicin

Given IV.

Intervention Type DRUG

Fludarabine

Given IV over approximately 30 minutes.

Intervention Type DRUG

Mitoxantrone

Given IV.

Intervention Type DRUG

Erwinia asparaginase

Given IV or intramuscularly (IM).

Intervention Type DRUG

Sorafenib

Given PO.

Intervention Type DRUG

G-CSF

Given IV.

Intervention Type DRUG

Dexrazoxane

Given IV immediately before idarubicin administration.

Intervention Type DRUG

Stem Cell Transplant

The transplant protocol will depend on the patient's donor and transplant physician's preference.

Intervention Type BIOLOGICAL

Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).

Intervention Type DRUG

Other Intervention Names

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Vidaza® Dacogen® Ara-C Cytosar® Daunomycin Cerubidine® Vepesid® VP-16 Etoposide Phosphate Etopophos® Intrathecal Triples Methotrexate/Hydrocortisone/Cytarabine Idamycin PFS® Fludara® Novantrone® Asparaginase Erwinia chrysanthemi Erwinaze® Crisantaspase® Nexavar® Neupogen Filgrastim Zinecard® SCT Rylaze™ Recombinant Erwinia

Eligibility Criteria

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Inclusion Criteria

* Diagnostic criteria: Patients must have one of the following diagnoses:

* Acute myeloid leukemia fulfilling the criteria of the WHO Classification (see Appendix I), or
* \>5% but \< 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality \[e.g., t(8;21), inv(16), t(9;11)\], or
* Myeloid sarcoma (also referred to as extramedullary myeloid tumor, granulocytic sarcoma, or chloroma), with or without evidence of a leukemia process in the bone marrow or peripheral blood, with confirmation of myeloid differentiation, or
* High grade myelodysplastic syndrome (MDS) with greater than 5% blasts, or
* Patients with treatment related myeloid neoplasms including AML and MDS, provided their cumulative anthracycline dose has not exceeded 230 mg/m2 doxorubicin equivalents.
* Other criteria - Patients must meet all the following criteria:

* Age \> 28 days and \< 22 years at time of study entry inclusive, and
* No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (100-200 mg/m2 per day for one week or less for hyperleukocytosis), and
* Written informed consent according to institutional guidelines, and
* Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment, and
* Male and female participants of reproductive potential must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria

* Down syndrome
* Acute promyelocytic leukemia (APL)
* BCR-ABL1 chronic myeloid leukemia in blast crisis (CML-BC)
* Juvenile myelomonocytic leukemia (JMML)
* Fanconi anemia (FA)
* Kostmann syndrome
* Shwachman syndrome
* Other bone marrow failure syndromes or low grade (\<5% bone marrow blasts) MDS.
* Use of concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
* Use of investigational agents within 30 days or any anticancer therapy for this malignancy within 2 weeks before study entry with the exception of IT therapy, hydroxyurea, or low-dose cytarabine as specified in the protocol document. The patient must have recovered from all acute toxicities from any previous therapy.
* Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
* Pregnant or lactating.
* Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
* Prior chemotherapy, with the exception of hydroxyurea or low-dose cytarabine as specified in the protocol document. The patient must have recovered from all acute toxicities from any previous therapy.
* Patients with treatment related myeloid neoplasms with cumulative anthracyclines greater than 230 mg/m2 doxorubicin equivalents.
Minimum Eligible Age

29 Days

Maximum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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St. Jude Children's Research Hospital

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Raul C. Ribiero, MD

Role: PRINCIPAL_INVESTIGATOR

St. Jude Children's Research Hospital

Locations

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Children's Hospital of Central California

Madera, California, United States

Site Status

Children's Hospital of Orange County

Orange, California, United States

Site Status

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Site Status

Rady Children's Hospital and Health Center

San Diego, California, United States

Site Status

University of Chicago Children's Hospital (Comer)

Chicago, Illinois, United States

Site Status

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status

Children's Hospital of Michigan

Detroit, Michigan, United States

Site Status

Sanford Children's Specialty Clinic

Sioux Falls, South Dakota, United States

Site Status

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Site Status

Cook Children's Medical Center

Fort Worth, Texas, United States

Site Status

Countries

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United States

Related Links

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http://www.stjude.org

St. Jude Children's Research Hospital

http://www.stjude.org/protocols

Clinical Trials Open at St. Jude

Other Identifiers

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NCI-2017-00928

Identifier Type: REGISTRY

Identifier Source: secondary_id

AML16

Identifier Type: -

Identifier Source: org_study_id

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