Epigenetic Priming for Acute Myeloid Leukemia

Not currently recruiting at 11 trial locations

Overseen By Jeffrey E. Rubnitz, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Investigational agents

Disqualifiers: Down syndrome, APL, CML-BC, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether epigenetic priming with azacitidine or decitabine before chemotherapy benefits people with acute myeloid leukemia (AML). The goal is to determine the safety of this approach and its impact on outcomes like survival rates and disease control. Participants will be randomly assigned to different treatment groups to compare effects. This trial targets patients with AML or related conditions who have not undergone extensive prior treatment. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that you cannot use other chemotherapy, radiation, or immunotherapy during the study. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that azacitidine is generally well-tolerated by patients with various conditions. In studies, about 60.5% of patients treated with azacitidine experienced side effects, such as low levels of neutrophils, a type of white blood cell, which can increase the risk of infections. However, no unexpected safety issues have been reported when azacitidine is combined with other treatments.

For decitabine, less specific information is available. Generally, when a treatment reaches this stage of clinical trials, existing safety data suggests it is reasonably well-tolerated in humans. However, due to limited data on decitabine, participants should discuss potential side effects with their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments Azacitidine and Decitabine for acute myeloid leukemia (AML) because they work uniquely by modifying the gene expression through epigenetic changes. Unlike traditional chemotherapy that directly kills cancer cells, these treatments target the DNA methylation process to reactivate tumor suppressor genes, potentially making cancer cells more sensitive to other therapies. Additionally, when combined with sorafenib, these treatments target specific genetic mutations like FLT3-ITD, offering a more tailored and potentially effective approach for patients with these mutations. This innovative strategy could lead to better outcomes and fewer side effects compared to conventional treatments.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that azacitidine (AZA), one of the treatments in this trial, may help treat acute myeloid leukemia (AML). In certain studies, azacitidine has successfully helped high-risk AML patients live longer. For instance, one study found that after 12 months, 88.2% of patients were still alive, and 85.5% had not experienced a return of the disease. Another study demonstrated that taking 75 mg/m² of azacitidine daily for seven days was effective for high-risk patients.

Decitabine (DAC), another treatment option in this trial, is also under study for AML. Although less detailed information exists about decitabine compared to azacitidine, it works by altering DNA to slow cancer cell growth. This suggests it could be beneficial when combined with chemotherapy. Both treatments in this trial aim to reduce cancer and help AML patients live longer. ^{6 7 8 9 10}

Who Is on the Research Team?

Raul C. Ribiero, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Written informed consent according to institutional guidelines

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

I've only had one dose of intrathecal therapy or short-term low-dose treatment for my cancer.

Exclusion Criteria

Shwachman syndrome

Pregnant or lactating

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Epigenetic Priming

Participants receive 5 days of single agent DMTi (azacitidine or decitabine) prior to chemotherapy blocks

1 week

Induction Chemotherapy

Participants receive Induction I and II chemotherapy with cytarabine, daunorubicin, etoposide, and other agents

8 weeks

Intensification Chemotherapy

Participants receive Intensification I, II, and III chemotherapy based on risk stratification

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Decitabine

Trial Overview

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.

How Is the Trial Designed?

Group I: DAC|+ADE | +FLAG+Ida+Sor | +AE+Sor | +MA+Sor | +Asp+AraC+Sor Experimental Treatment 13 Interventions

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+Sor Experimental Treatment 13 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+Sor Experimental Treatment 11 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+Sor Experimental Treatment 12 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+AraC Experimental Treatment 11 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 | MA Experimental Treatment 10 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+Sor Experimental Treatment 13 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

Group VIII: DAC |+ADE |+FLAG+Ida+Sor |+AE+Sor|+MA+Sor|+Asp+AraC+Sor Experimental Treatment 13 Interventions

Part 2 Dose Expansion with DAC - High Risk (no donor) Patients are randomized to receive 5 days of single agent decitabine as part of Inductions I \& II and high-risk Intensifications I, II and III. Sorafenib will be given to patients with FLT3-ITD. For these patients, DAC will be limited to the first two courses of Induction chemotherapy. They will not receive DAC with Intensification therapy. Interventions: decitabine, cytarabine, daunorubicin, etoposide, dexrazoxane, fludarabine, idarubicin, G- CSF, sorafenib, mitoxantrone, erwinia asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, ITMHA.

Group IX: AZA| +ADE | +FLAG+Ida+Sor| +AE+Sor| +MA+Sor| +Asp+AraC+Sor Experimental Treatment 13 Interventions

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+Sor Experimental Treatment 12 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+Sor Experimental Treatment 13 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+Sor Experimental Treatment 11 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+AraC Experimental Treatment 11 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 | MA Experimental Treatment 10 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+Sor Experimental Treatment 13 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.

Group XVI: AZA | + ADE | +FLAG+Ida+Sor| +AE+Sor | +MA+Sor | +Asp+AraC+Sor Experimental Treatment 13 Interventions

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.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Published Research Related to This Trial

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

The optimal biologic dose (OBD) of decitabine for treating acute myeloid leukemia (AML) was determined to be 20 mg/m²/day, which showed limited nonhematologic toxicity and promising clinical activity, with a response rate of 44% among 25 patients.

Combining decitabine with valproic acid (VA) resulted in dose-limiting encephalopathy at lower doses of VA, indicating safety concerns, while the clinical responses were similar whether patients received decitabine alone or in combination with VA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. Blum, W., Klisovic, RB., Hackanson, B., et al.[2019]

Citations

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Clinical Utility of Azacitidine in the Management of Acute ...

The data suggest that oral AZA maintenance is an effective maintenance strategy to prolong survival in high-risk as well as favorable-risk AML ...

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Real-World Treatment Patterns and Outcomes with Oral ...

At 12 mo, estimated OS and rwRFS rates from Oral-AZA initiation were 88.2% (standard error [SE], 2.3) and 85.5% (SE, 2.5), respectively. Median ...

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sciencedirect.com

sciencedirect.com/science/article/pii/S2213048916300486

Clinical outcomes of AML patients treated with Azacitidine ...

The AZA-001 phase III trial has demonstrated effectiveness of azacitidine (AZA) in a dose of 75 mg/m2 daily for 7 consecutive days in patients with high-risk ...

4.

nature.com

nature.com/articles/s41375-025-02730-3

Outcomes of patients treated with venetoclax plus ...

The 5-year relative survival of patients with AML is ~32%, and survival rates are dependent on age at diagnosis. Patients <50 years of age have ...

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Analysis showed that the overall response rates in the azacitidine plus venetoclax, chemotherapy, and azacitidine monotherapy groups were 38.5%, ...

6.

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pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

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Azacitidine has been reported to prolong survival in MDS patients. Azacitidine has been studied in different dosing schedules and combination therapies with the ...

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ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7012

Updated efficacy and safety data from the AGILE study in ...

IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial ...

8.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2012971

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This confirmatory trial (VIALE-A) was designed to evaluate the efficacy and safety of the azacitidine–venetoclax combination regimen as compared ...

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New Efficacy, Safety Data Presented on BCL-2 Inhibitor ...

All patients who received the regimen reported experiencing treatment-emergent adverse events (AEs). Neutropenia occurred in 60.5% of patients, ...

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Efficacy and safety of venetoclax plus azacitidine for patients ...

Venetoclax (14 days) + azacitidine regimen was well tolerated in patients with treatment-naive HR MDS, with no unexpected safety findings.