Epigenetic Priming for Acute Myeloid Leukemia

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

206 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Azacitidine, Vidaza, 5-azacytidine, Decitabine, Decitabine, Dacogen, ASTX727 (when combined with cedazuridine) for treating Acute Myeloid Leukemia?

Research shows that azacitidine and decitabine, which are part of the treatment, have been effective in treating acute myeloid leukemia (AML) by reactivating genes that suppress tumors and stopping cancer cell growth. Clinical trials have demonstrated that these drugs can extend survival and delay relapse in AML patients, especially when used in combination with other agents. ^{1 2 3 4 5}

Is epigenetic priming with decitabine safe for humans?

Decitabine, used in epigenetic priming for acute myeloid leukemia, has been shown to be generally safe in humans, with side effects similar to standard chemotherapy. Some studies noted more gastrointestinal issues with longer treatment durations, but overall, it was well tolerated. ^{1 4 6 7 8}

What makes the drug Azacitidine and Decitabine unique for treating acute myeloid leukemia?

This drug combination is unique because it uses 'epigenetic priming' to prepare cancer cells for chemotherapy by altering their DNA methylation, which can reactivate genes that suppress tumors. This approach aims to improve the effectiveness of standard chemotherapy in patients with acute myeloid leukemia. ^{1 4 8 9 10}

What is the purpose of this trial?

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.

Research Team

Raul C. Ribiero, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

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

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.

Written informed consent according to institutional guidelines

Exclusion Criteria

Shwachman syndrome

Pregnant or lactating

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Decitabine. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML). [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Oral Maintenance Drug Forestalls AML Relapse. [2020]

4. Germany pubmed.ncbi.nlm.nih.gov

Decitabine. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

A Phase II Trial of the Double Epigenetic Priming Regimen Including Chidamide and Decitabine for Relapsed/Refractory Acute Myeloid Leukemia. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Decitabine in chronic leukemias. [2019]