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DNA Methyltransferase Inhibitor

Epigenetic Priming for Acute Myeloid Leukemia

Phase 2

Waitlist Available

Led By Raul C. Ribiero, MD

Research Sponsored by St. Jude Children's Research Hospital

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age > 28 days and < 22 years at time of study entry inclusive

Patients must have one of the following diagnoses: Acute myeloid leukemia fulfilling the criteria of the WHO Classification, 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 with confirmation of myeloid differentiation, or High grade myelodysplastic syndrome with greater than 5% blasts, or Patients with treatment related myeloid neoplasms with cumulative anthracycline dose not exceeding 230 mg/m2 doxorubicin equivalents

Must not have

Patients with treatment related myeloid neoplasms with cumulative anthracyclines greater than 230 mg/m2 doxorubicin equivalents

Acute promyelocytic leukemia (APL)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from diagnosis to completion of five days of single agent dmti (up to 2 weeks after start of therapy)

Awards & highlights

All Individual Drugs Already Approved

No Placebo-Only Group

Summary

This trial is studying how well giving azacitidine or decitabine before standard chemotherapy works in treating patients with acute myeloid leukemia.

Who is the study for?

This trial is for patients under 22 years old with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome, without prior treatment except possibly one dose of intrathecal therapy and certain emergency treatments. They must not have Down syndrome, certain other leukemias or bone marrow syndromes, uncontrolled infections, or be pregnant.

What is being tested?

The study tests if using drugs called azacitidine and decitabine (DMTis) before standard chemotherapy can help treat acute myeloid leukemia in young patients. It checks the safety of this approach and whether it affects disease markers and survival rates.

What are the potential side effects?

Possible side effects include reactions to the drugs such as nausea, fatigue, blood count changes leading to increased infection risk, liver issues, and potential allergic reactions. The exact side effects will vary depending on individual patient responses.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am between 1 month and 22 years old.

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I have a specific type of blood cancer or condition as per WHO guidelines.

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I am a woman who can have children and I have a negative pregnancy test from the last 2 weeks.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have a blood disorder from treatment and received high doses of a specific chemotherapy.

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I have been diagnosed with acute promyelocytic leukemia.

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I have an ongoing infection that is not under control.

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I have been diagnosed with juvenile myelomonocytic leukemia.

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I have Fanconi anemia.

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I have been diagnosed with Kostmann syndrome.

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I have a bone marrow failure syndrome or mild MDS.

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I am not using any cancer treatments not allowed by the study.

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My condition is chronic myeloid leukemia in blast crisis.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from diagnosis to completion of five days of single agent dmti (up to 2 weeks after start of therapy)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from diagnosis to completion of five days of single agent dmti (up to 2 weeks after start of therapy)

This trial's timeline: 3 weeks for screening, Varies for treatment, and from diagnosis to completion of five days of single agent dmti (up to 2 weeks after start of therapy) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

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

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

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

Secondary study objectives

Kaplan-Meier estimate of event-free survival

Kaplan-Meier estimate of overall survival

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

Side effects data

From 2010 Phase 2 & 3 trial • 135 Patients • NCT00176904

40%

Death

Auto recovery

Primary graft failure

100%

80%

60%

40%

20%

Study treatment Arm

Patients Treated With Stem Cell Transplant

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

16Treatment groups

Experimental Treatment

Part 2 Dose Expansion with DAC - Intermediate-Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and intermediate-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group II: DAC+ADE | DAC+FLAG+Ida+Sor | MA+Sor | Asp+AraC+SorExperimental Treatment13 Interventions

Part 1 Tolerability with DAC - High Risk (with donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive high-risk Intensifications I or high risk intensification III without decitabine. Patients will proceed to stem cell transplant. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant

Group III: DAC+ADE | DAC+FLAG+Ida+Sor | DAC+AE+Sor|DAC+MA+SorExperimental Treatment11 Interventions

Part 2 Dose Expansion with DAC - Low Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and low-risk Intensifications I \& II. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, ITMHA.

Group IV: DAC+ADE | DAC+FLAG+Ida+Sor | AE | MA+Sor | Asp+AraC+SorExperimental Treatment12 Interventions

Part 1 Tolerability with DAC - High Risk (no donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive high-risk Intensifications I, II \& III without decitabine. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, ITMHA.

Group V: DAC+ADE | DAC+FLAG+Ida | AE | MA | Asp+AraCExperimental Treatment11 Interventions

Part 1 Tolerability with DAC - Intermediate Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive intermediate-risk Intensifications I, II \& III without decitabine. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, erwinia asparaginase, ITMHA.

Group VI: DAC+ADE | DAC+FLAG+Ida | AE | MAExperimental Treatment10 Interventions

Part 1 Tolerability with DAC - Low Risk Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and then receive low-risk Intensifications I \& II without decitabine. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, ITMHA.

Group VII: DAC |+ADE|+FLAG+Ida+Sor|+MA+Sor|+Asp+AraC+SorExperimental Treatment13 Interventions

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

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.

Part 2 Dose Expansion with AZA - Intermediate-Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and intermediate-risk Intensification I, II, and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group X: AZA+ADE | AZA+FLAG-Ida+Sor | AE | MA+Sor | Asp+AraC+SorExperimental Treatment12 Interventions

Part 1 Tolerability with AZA - High Risk (no donor) Patients are randomized to receive 5 days of single agent azacitidine as part of Induction I \& II and high-risk intensifications I, II \& III without azacitidine. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, ITMHA.

Group XI: AZA+ADE | AZA+FLAG+Ida+Sor | MA+Sor | Asp+AraC+SorExperimental Treatment13 Interventions

Part 1 Tolerability with AZA- High Risk (with donor) Patients are randomized to receive 5 days of single agent azacitidine as part of Induction I Induction II and high-risk Intensifications I or high risk intensification III without azacitidine. Patients will proceed to stem cell transplant. Sorafenib is limited to patients with FLT3-ITD+/NUP98-NSD1+ or FLT3-ITD+/WT1mut somatic mutations. Interventions: azacitidine cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, sorafenib, ITMHA, erwinia asparaginase, stem cell transplant.

Group XII: AZA+ADE | AZA+FLAG+Ida+Sor | AZA+AE+Sor | AZA+MA+SorExperimental Treatment11 Interventions

Part 2 Dose Expansion with AZA - Low Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and low- risk Intensifications I \& II. Sorafenib will be given to patients with FLT3-ITD. For these patients, AZA will be limited to the first two courses of Induction chemotherapy. They will not receive AZA with Intensification therapy. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, ITMHA.

Group XIII: AZA+ADE | AZA+FLAG+Ida | AE | MA | Asp+AraCExperimental Treatment11 Interventions

Part 1 Tolerability with AZA - Intermediate Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and then receive intermediate risk Intensifications I, II \& III without azacitidine. Interventions: azacitidine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, mitoxantrone, erwinia asparaginase, ITMHA,

Group XIV: AZA+ADE | AZA+FLAG+Ida | AE | MAExperimental Treatment10 Interventions

Part 1 Tolerability with AZA - Low Risk Patients are randomized to receive 5 days of single agent azacitidine as part of Inductions I \& II and then receive low-risk intensifications I \& II without azacitidine. Interventions: azacitidine, cytarabine, daunorubicin, etoposide,dexrazoxane, fludarabine, idarubicin, G-CSF, mitoxantrone., ITMHA.

Group XV: AZA |+ADE|+FLAG+Ida+Sor|+MA+Sor|+Asp+AraC+SorExperimental Treatment13 Interventions

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.

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Decitabine

2004

Completed Phase 3

~1680

G-CSF

2014

Completed Phase 4

~1610