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

NCT03164057 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: AML16NCI-2017-00928
• Study Type: interventional
• Target: 206
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

DNA methyltransferase inhibitors; Acute myeloid leukemia

Outcome Measures

Primary Outcomes (3)

• Proportion of evaluable patients who tolerate five days of single agent DMTi before a standard chemotherapy combination

  Patients will be monitored for grade 4-5 non-hematologic toxic events during these two courses of chemotherapy. Tolerating a course is defined as completing the course without experiencing death or a grade 4 non-hematologic toxicity.

  From enrollment to completion of chemotherapy (up to 8 months after start of therapy)

• Change in genome-wide methylation burden of leukemia cells from diagnosis to after five days of single agent DMTi

  Leukemic cells will be collected from patients at diagnosis and after five days of single agent DMTi. Each sample of leukemic cells will be profiled with a methylation microarray. For each leukemic sample, genome-wide methylation burden (GWMB) will be computed as the sum of methylation values across all markers. For each patient, the change in GWMB will be computed as the day 5 GWMB minus the diagnostic GWMB.

  From diagnosis to completion of five days of single agent DMTi (up to 2 weeks after start of therapy)

• Cox model hazard ratio for association of event-free survival with genome-wide methylation burden

  Patients will be monitored for the events of interest from enrollment for at least three years. EFS will be defined as the time elapsed from enrollment to the first of the following events: death, relapse, resistant disease, or second malignancy. EFS times for subjects who have not experienced these events at the time of analysis will be censored at date of last follow-up. A Cox regression model will be used to evaluate the association of EFS with genome-wide methylation burden observed after completion of five days of single agent decitabine or azacitidine as randomly assigned.

  From diagnosis to the first of the following events: death, relapse, resistant disease, second malignancy, or last follow-up (up to 3 years after completion of therapy)

Secondary Outcomes (3)

• Proportion of MRD-evaluable subjects with detectable minimal residual disease after receiving five days of a single agent DMTi followed by araC+daunorubicin+etoposide.

  MRD will be measured after completion of DMTi+araC+daunorubicin+etoposide (up to 6 weeks after the start of therapy)

• Kaplan-Meier estimate of event-free survival

  From diagnosis to the first of the following events: death, relapse, resistant disease, second malignancy, or last follow-up (up to 3 years after completion of therapy)

• Kaplan-Meier estimate of overall survival

  From diagnosis to the first of the following events: death or last follow-up (up to 3 years after completion of therapy)

Study Arms (16)

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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,

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

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

EXPERIMENTAL

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.

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

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

EXPERIMENTAL

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.

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Biological: Stem Cell Transplant

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

EXPERIMENTAL

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

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Biological: Stem Cell Transplant

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

EXPERIMENTAL

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

Drug: Decitabine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Biological: Stem Cell Transplant

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

EXPERIMENTAL

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.

Drug: Azacitidine; Drug: Cytarabine; Drug: Daunorubicin; Drug: Etoposide; Combination Product: ITMHA; Drug: Idarubicin; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Erwinia asparaginase; Drug: Sorafenib; Drug: G-CSF; Drug: Dexrazoxane; Biological: Stem Cell Transplant

Interventions

Idarubicin DRUG

Given IV.

Also known as: Idamycin PFS®

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

Fludarabine DRUG

Given IV over approximately 30 minutes.

Also known as: Fludara®

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

Mitoxantrone DRUG

Given IV.

Also known as: Novantrone®

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

Erwinia asparaginase DRUG

Given IV or intramuscularly (IM).

Also known as: Asparaginase Erwinia chrysanthemi, Erwinaze®, Crisantaspase®

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

Sorafenib DRUG

Given PO.

Also known as: Nexavar®

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

G-CSF DRUG

Given IV.

Also known as: Neupogen, Filgrastim

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

Azacitidine DRUG

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

Also known as: Vidaza®

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

Decitabine DRUG

Administered intravenously (IV) over approximately one hour.

Also known as: Dacogen®

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

Cytarabine DRUG

Given IV or intrathecally (IT).

Also known as: Ara-C, Cytosar®

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

Daunorubicin DRUG

Given IV.

Also known as: Daunomycin, Cerubidine®

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

Etoposide DRUG

Given IV.

Also known as: Vepesid®, VP-16, Etoposide Phosphate, Etopophos®

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

ITMHA COMBINATION_PRODUCT

Given IT.

Also known as: Intrathecal Triples, Methotrexate/Hydrocortisone/Cytarabine

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

Dexrazoxane DRUG

Given IV immediately before idarubicin administration.

Also known as: Zinecard®

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

Stem Cell Transplant BIOLOGICAL

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

Also known as: SCT

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

Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn DRUG

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

Also known as: Rylaze™, Recombinant Erwinia

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

Eligibility Criteria

• Age: 29 Days - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (10)

Children's Hospital of Central California

Madera, California, 93636, United States

Location

Children's Hospital of Orange County

Orange, California, 92968, United States

Location

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital and Health Center

San Diego, California, 92123, United States

Location

University of Chicago Children's Hospital (Comer)

Chicago, Illinois, 60637, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

Sanford Children's Specialty Clinic

Sioux Falls, South Dakota, 57117, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Azacitidine; Decitabine; Cytarabine; Daunorubicin; Etoposide; etoposide phosphate; Methotrexate; Idarubicin; fludarabine; fludarabine phosphate; Mitoxantrone; asparaginase erwinia chrysanthemi recombinant; Sorafenib; Granulocyte Colony-Stimulating Factor; Filgrastim; Dexrazoxane; Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Anthraquinones; Anthrones; Anthracenes; Quinones; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Razoxane; Diketopiperazines; Piperazines; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Raul C. Ribiero, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2017
• First Posted: May 23, 2017
• Study Start: June 15, 2017
• Primary Completion: September 20, 2025
• Study Completion (Estimated): June 1, 2027
• Last Updated: April 23, 2026

Record last verified: 2026-04

Locations

US (10)