Efficacy of Hypomethylating Agents vs. Intensive Chemotherapy in Acute Myeloid Leukemia Using 5hmC as a Blood-Based Minimal Residual Disease Marker

NCT07060001 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: PRO00038056 (HMCC-HM24-001)
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

This is a therapeutic intervention trial evaluating the clinical utility of a novel blood-based epigenetic biomarker-genome-wide 5-hydroxymethylcytosine (5hmC) in cell-free DNA (cfDNA)-for assessing measurable residual disease (MRD) in patients with newly diagnosed acute myeloid leukemia (AML). The study compares the efficacy of hypomethylating agent (HMA)-based therapy versus intensive induction chemotherapy, using the 5hmC biomarker to guide post-induction treatment decisions. Approximately 112 adult patients will be enrolled and assigned to treatment arms based on a stratified sampling scheme. Blood samples will be collected at defined intervals to assess MRD status. Primary endpoints include minimal residual disease (MRD) negativity rate, duration of remission, event-free survival (EFS), and overall survival (OS).

Conditions

Acute Myeloid Leukemia (AML); Acute Myeloid Leukaemia (AML)

Keywords

AML; Leukemia; Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (4)

• 5hmC Minimal Residual Disease Rates

  cfDNA 5hmC-MRD negativity and positivity rates at the time of morphologic remission.

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

• Duration of Remission (DoR) Based on 5hmC-MRD Status

  Time from initial treatment to disease relapse or progression, stratified by 5-hydroxymethylcytosine minimal residual disease (5hmC-MRD) status (positive vs. negative). This measure evaluates the impact of 5hmC-MRD on the sustainability of remission.

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

• Event-Free Survival (EFS) by 5hmC-MRD Status

  Time from treatment initiation to the occurrence of any treatment failure event, including relapse, progression, or death from any cause, compared between patients with positive and negative 5hmC-MRD. This outcome assesses the prognostic value of 5hmC-MRD in predicting treatment durability.

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

• Overall Survival (OS) in Relation to 5hmC-MRD

  Time from diagnosis or treatment start to death from any cause, analyzed by 5hmC-MRD status. This outcome measure determines whether 5hmC-MRD positivity is associated with reduced overall survival.

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

Secondary Outcomes (4)

• MRD Positivity Rate Across Detection Methods

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

• Duration of Remission (DoR) in MRD-Positive and MRD-Negative Patients by Method

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

• Event-Free Survival by MRD Detection Method

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

• Overall Survival by MRD Detection Method

  From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

Study Arms (2)

HMA- Based Treatment Arm

ACTIVE COMPARATOR

Azacitidine or Decitabine with or without Venetoclax (HMA-based treatment): * Venetoclax is a BCL-2 inhibitor FDA Approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine or low-dose cytarabine in. * Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours. * Azacitidine can be given as a sub-cutaneous injection or intravenously. In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.

Diagnostic Test: 5hmC Biomarker; Drug: Venetoclax; Drug: Decitabine 20 mg/m²/day for 5 days; Drug: Azacitidine (AZA)

Intensive Chemotherapy Arm

ACTIVE COMPARATOR

Cytarabine with Anthracycline (standard intensive induction therapy): * Cytarabine is FDA approved chemotherapy (pyrimidine analog) infusion that is frequently used with other drug such as anthracycline to treat acute myeloid leukemia, acute lymphoblastic leukemia. Common side effects include low counts, immune suppression, nausea, neutropenic fever. * Anthracyclines are chemotherapy infusions which topoisomerase II inhibition. Other than having side effects similar to cytarabine, it may cause weakening of heart pumping function few years later. Both of these medications may cause a temporary loss of hair in some people. After treatment with cytarabine has ended, normal hair growth should return.

Diagnostic Test: 5hmC Biomarker; Drug: Cytarabine (Ara-C); Drug: Anthracycline

Interventions

5hmC Biomarker DIAGNOSTIC_TEST

The 5hmC marker will be used to determine treatment modality post-induction therapy. After Week 4 of standard-of-care therapy (either HMA-based treatment or intensive induction chemotherapy), 5hmC biomarker testing will be performed. If MRD is positive, patients will continue the same standard-of-care treatment or crossover to the other arm of the study. If MRD is negative, patients will proceed with consolidation (either HSCT or continue on same treatment). For patients receiving HMA-based treatment, blood samples will be collected ± 5 days before and after 4 and 12 weeks of therapy. For patients receiving intensive chemotherapy blood samples will be collected ± 5 days before and after 4 and 12 weeks of therapy.

HMA- Based Treatment Arm; Intensive Chemotherapy Arm

Venetoclax DRUG

Venetoclax is a BCL-2 inhibitor FDA Approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine or low-dose cytarabine.

HMA- Based Treatment Arm

Decitabine 20 mg/m²/day for 5 days DRUG

Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours.

HMA- Based Treatment Arm

Azacitidine (AZA) DRUG

Azacitidine can be given as a sub-cutaneous injection or intravenously.

HMA- Based Treatment Arm

Cytarabine (Ara-C) DRUG

Cytarabine is FDA approved chemotherapy (pyrimidine analog) infusion that is frequently used with other drug such as anthracycline to treat acute myeloid leukemia, acute lymphoblastic leukemia. Common side effects include low counts, immune suppression, nausea, neutropenic fever.

Intensive Chemotherapy Arm

Anthracycline DRUG

Anthracyclines are chemotherapy infusions which topoisomerase II inhibition. Other than having side effects similar to cytarabine, it may cause weakening of heart pumping function few years later. Both of these medications may cause a temporary loss of hair in some people. After treatment with cytarabine has ended, normal hair growth should return.

Intensive Chemotherapy Arm

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient (or legally acceptable representative if applicable) provides written informed consent for the trial. Spanish speaking patients will be included and translation services will be provided as needed.
• Male or female, 18 years of age or older, on the day of informed consent signing.
• Newly diagnosed de novo AML
• \. Expected life expectancy of at least 6 months 6. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations. 7. Women with childbearing potential and men should practice at least one of the following methods of birth control throughout the study and for 6 for women and 3 months for men after the last dose of study therapy:
• Total abstinence from sexual intercourse (periodic abstinence not acceptable);
• Surgically sterile partner(s) including vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
• Practicing 2 effective methods of contraception (at least 1 highly effective, method of contraception \[See Appendix 4\]). WOCBP should only be included after a confirmed negative serum pregnancy test.

You may not qualify if:

• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks of trial treatment administration.
• The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Confirmed positive pregnancy test in WOCBP.

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead

Study Sites (1)

Houston Methodist Neal Cancer Center

Houston, Texas, 77030, United States

Location

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MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

venetoclax; Decitabine; Azacitidine; Cytarabine; Anthracyclines

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Arabinonucleosides; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Shilpan Shah, MD

  Houston Methodist Neal Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Danielle Sewell

CONTACT

3462382674; dmsewall@houstonmethodist.org

Titilayo Olubajo

CONTACT

7133639803; tolubajo@houstonmethodist.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2025
• First Posted: July 11, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029
• Last Updated: March 6, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)