A Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia
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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. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03164057 |
|
Recruitment Status :
Active, not recruiting
First Posted : May 23, 2017
Last Update Posted : November 1, 2022
|
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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.
| 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 Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 206 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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: G-CSF Given IV.
Other Names:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: G-CSF Given IV.
Other Names:
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, asparaginase erwinia chrysanthemi (recombinant)-rywn, 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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
Drug: Dexrazoxane Given IV immediately before idarubicin administration.
Other Name: Zinecard® Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).
Other Names:
|
|
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, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA. |
Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen® Drug: Cytarabine Given IV or intrathecally (IT).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
Drug: Dexrazoxane Given IV immediately before idarubicin administration.
Other Name: Zinecard® Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).
Other Names:
|
|
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
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, asparaginase erwinia chrysanthemi (recombinant)-rywn, 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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
Drug: Dexrazoxane Given IV immediately before idarubicin administration.
Other Name: Zinecard® Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).
Other Names:
|
|
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, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA. |
Drug: Decitabine
Administered intravenously (IV) over approximately one hour.
Other Name: Dacogen® Drug: Cytarabine Given IV or intrathecally (IT).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
Drug: Dexrazoxane Given IV immediately before idarubicin administration.
Other Name: Zinecard® Drug: Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).
Other Names:
|
|
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
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:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Combination Product: ITMHA Given IT.
Other Names:
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:
Drug: Sorafenib Given PO.
Other Name: Nexavar® Drug: G-CSF Given IV.
Other Names:
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 |
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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.
| Ages Eligible for Study: | 29 Days to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
INCLUSION CRITERIA:
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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.
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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.
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
| United States, California | |
| Children's Hospital of Central California | |
| Madera, California, United States, 93636 | |
| Children's Hospital of Orange County | |
| Orange, California, United States, 92968 | |
| Lucile Packard Children's Hospital Stanford University | |
| Palo Alto, California, United States, 94304 | |
| Rady Children's Hospital and Health Center | |
| San Diego, California, United States, 92123 | |
| United States, Illinois | |
| University of Chicago Children's Hospital (Comer) | |
| Chicago, Illinois, United States, 60637 | |
| United States, Indiana | |
| Riley Hospital for Children | |
| Indianapolis, Indiana, United States, 46202 | |
| United States, Massachusetts | |
| Dana-Farber Cancer Institute | |
| Boston, Massachusetts, United States, 02215 | |
| United States, Michigan | |
| Children's Hospital of Michigan | |
| Detroit, Michigan, United States, 48201 | |
| United States, North Dakota | |
| Sanford Roger Maris Cancer Center | |
| Fargo, North Dakota, United States, 58122 | |
| United States, South Dakota | |
| Sanford Children's Specialty Clinic | |
| Sioux Falls, South Dakota, United States, 57117 | |
| United States, Tennessee | |
| St. Jude Children's Research Hospital | |
| Memphis, Tennessee, United States, 38105 | |
| United States, Texas | |
| Cook Children's Medical Center | |
| Fort Worth, Texas, United States, 76104 | |
| Principal Investigator: | Jeffrey E. Rubnitz, MD, PhD | St. Jude Children's Research Hospital |
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT03164057 |
| 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: | November 1, 2022 |
| Last Verified: | October 2022 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
|
DNA methyltransferase inhibitors Acute myeloid leukemia |
|
Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Myelodysplastic Syndromes Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases Cytarabine Hydrocortisone Methotrexate Azacitidine Decitabine Fludarabine Etoposide |
Etoposide phosphate Sorafenib Daunorubicin Asparaginase Mitoxantrone Idarubicin Dexrazoxane Razoxane Asparaginase erwinia chrysanthemi, recombinant-rywn Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Physiological Effects of Drugs Antimetabolites, Antineoplastic Antimetabolites |