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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03164057
Recruitment Status : Recruiting
First Posted : May 23, 2017
Last Update Posted : October 8, 2019
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes Drug: Azacitidine 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 Phase 2

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia
Actual Study Start Date : June 15, 2017
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2027


Arm Intervention/treatment
Experimental: 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.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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,

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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, ITMHA.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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, ITMHA.

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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, ITMHA.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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, ITMHA.

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Experimental: 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.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Biological: Stem Cell Transplant
The transplant protocol will depend on the patient's donor and transplant physician's preference.
Other Name: SCT

Experimental: 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

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Biological: Stem Cell Transplant
The transplant protocol will depend on the patient's donor and transplant physician's preference.
Other Name: SCT

Experimental: 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

Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Biological: Stem Cell Transplant
The transplant protocol will depend on the patient's donor and transplant physician's preference.
Other Name: SCT

Experimental: 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.

Drug: Azacitidine
Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
Other Name: Vidaza®

Drug: Cytarabine
Given IV or intrathecally (IT).
Other Names:
  • Ara-C
  • Cytosar®

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • Cerubidine®

Drug: Etoposide
Given IV.
Other Names:
  • Vepesid®
  • VP-16
  • Etoposide Phosphate
  • Etopophos®

Combination Product: ITMHA
Given IT.
Other Names:
  • Intrathecal Triples
  • Methotrexate/Hydrocortisone/Cytarabine

Drug: Idarubicin
Given IV.
Other Name: Idamycin PFS®

Drug: Fludarabine
Given IV over approximately 30 minutes.
Other Name: Fludara®

Drug: Mitoxantrone
Given IV.
Other Name: Novantrone®

Drug: Erwinia asparaginase
Given IV or intramuscularly (IM).
Other Names:
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze®
  • Crisantaspase®

Drug: Sorafenib
Given PO.
Other Name: Nexavar®

Drug: G-CSF
Given IV.
Other Names:
  • Neupogen
  • Filgrastim

Drug: Dexrazoxane
Given IV immediately before idarubicin administration.
Other Name: Zinecard®

Biological: Stem Cell Transplant
The transplant protocol will depend on the patient's donor and transplant physician's preference.
Other Name: SCT




Primary Outcome Measures :
  1. Proportion of evaluable patients who tolerate five days of single agent DMTi before a standard chemotherapy combination [ Time Frame: From enrollment to completion of chemotherapy (up to 8 months after start of therapy) ]
    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.

  2. Change in genome-wide methylation burden of leukemia cells from diagnosis to after five days of single agent DMTi [ Time Frame: From diagnosis to completion of five days of single agent DMTi (up to 2 weeks after start of therapy) ]
    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.

  3. Cox model hazard ratio for association of event-free survival with genome-wide methylation burden [ Time Frame: 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) ]
    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.


Secondary Outcome Measures :
  1. Proportion of MRD-evaluable subjects with detectable minimal residual disease after receiving five days of a single agent DMTi followed by araC+daunorubicin+etoposide. [ Time Frame: MRD will be measured after completion of DMTi+araC+daunorubicin+etoposide (up to 6 weeks after the start of therapy) ]
    Flow cytometry will be used to measure minimal residual disease at diagnosis and after completion of the first course of chemotherapy.

  2. Kaplan-Meier estimate of event-free survival [ Time Frame: 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) ]
    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.

  3. Kaplan-Meier estimate of overall survival [ Time Frame: From diagnosis to the first of the following events: death or last follow-up (up to 3 years after completion of therapy) ]
    Patients will be monitored for death from enrollment for at least three years. Overall survival will be defined as the time elapsed from enrollment to death. OS times for subjects who are living at the time of analysis will be censored at date of last follow-up.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03164057


Contacts
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Contact: Tanja A. Gruber, MD, PhD 866-278-5833 tanja.gruber@stjude.org
Contact: Referral Office 866-278-5833 referralinfo@stjude.org

Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Anna Pawlowska, MD    800-826-4673    apawlowska@coh.org   
Principal Investigator: Anna Pawlowska, MD         
Children's Hospital of Central California Recruiting
Madera, California, United States, 93636
Contact: Faisal Razzaqi, MD    866-353-5437    frazzaqi@valleychildrens.org   
Principal Investigator: Faisal Razzaqi, MD         
Children's Hospital of Orange County Recruiting
Orange, California, United States, 92968
Contact: Jamie Frediani, MD    714-509-4348    jfrediani@choc.org   
Principal Investigator: Jamie Frediani, MD         
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Norman J. Lacayo, MD    650-497-8953    lacayon@stanford.edu   
Principal Investigator: Norman J. Lacayo, MD         
Rady Children's Hospital and Health Center Recruiting
San Diego, California, United States, 92123
Contact: Deborah Schiff, MD    858-966-5983    dschiff@chsd.org   
Principal Investigator: Deborah Schiff, MD         
United States, Illinois
University of Chicago Children's Hospital (Comer) Recruiting
Chicago, Illinois, United States, 60637
Contact: Jennifer McNeer, MD    773-702-5782    jmcneer@peds.bsd.uchicago.edu   
Principal Investigator: Jennifer McNeer, MD         
United States, Indiana
IU Health North Hospital Recruiting
Carmel, Indiana, United States, 46202
Contact: Sandeep Batra, MD    317-278-5632    batras@iu.edu   
Principal Investigator: Sandeep Batra, MD         
Indiana University/Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Sandeep Batra, MD    317-274-2552    batras@iu.edu   
Principal Investigator: Sandeep Batra, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Barbara Degar, MD    617-632-5186    Barbara_Degar@dfci.harvard.edu   
Principal Investigator: Barbara Degar, MD         
United States, Michigan
Children's Hospital of Michigan Recruiting
Detroit, Michigan, United States, 48201
Contact: Meret Henry, MD    301-745-5237    mhenry@med.wayne.edu   
Principal Investigator: Meret Henry, MD         
United States, South Dakota
Sanford Children's Specialty Clinic Recruiting
Sioux Falls, South Dakota, United States, 57117
Contact: KayeLyn Wagner, MD    605-312-1050    kayelyn.wagner@sanfordhealth.org   
Principal Investigator: KayeLyn Wagner, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Tanja A. Gruber, MD, PhD    866-278-5833    tanja.gruber@stjude.org   
Contact: Referral Office    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Tanja A. Gruber, MD, PhD         
United States, Texas
Cook Children's Medical Center Recruiting
Fort Worth, Texas, United States, 76104
Contact: Kenneth M. Heym, MD    682-885-4007    kenneth.heym@cookchildrens.org   
Principal Investigator: Kenneth M. Heym, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
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Principal Investigator: Tanja A. Gruber, MD, PhD St. Jude Children's Research Hospital

Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT03164057     History of Changes
Other Study ID Numbers: AML16
NCI-2017-00928 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: May 23, 2017    Key Record Dates
Last Update Posted: October 8, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Jude Children's Research Hospital:
DNA methyltransferase inhibitors
Acute myeloid leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Cytarabine
Fludarabine phosphate
Azacitidine
Decitabine
Fludarabine
Sorafenib
Etoposide
Etoposide phosphate
Daunorubicin
Mitoxantrone
Idarubicin
Asparaginase
Dexrazoxane
Razoxane
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors