5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies

NCT ID: NCT04187703

Last Updated: 2025-04-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-16
• Study Completion Date: 2026-12-01

Brief Summary

Another term for myelodysplastic syndrome is bone marrow failure. The bone marrow is where components of blood such as red cells, platelets and white cells are made. In bone marrow failure, the ability for bone marrow to make these cells is decreased. In myelodysplastic syndrome, this decreased bone marrow function is believed to result from abnormalities that prevent the normal maturation process by which bone marrow cells develop into red blood cells, white blood cells and platelets. In myelodysplastic syndrome, these abnormal bone marrow cells occupy space in the bone marrow and prevent the function of remaining normal bone marrow cells.

One approach to treating the abnormal growth of immature cells is to give chemotherapy which damages DNA within these cells and causes their death. Unfortunately, such therapy has side-effects, since even normal cells can be affected by the treatment. Both 5-azacitidine (5AZA) and decitabine (DEC) are FDA-approved to treat MDS. In this study, 5AZA and DEC will be administered using an alternating low doses schedule in an attempt to overcome the known mechanisms of resistance to the administration of 5AZA or DEC as single agents caused by automatic adaptive shifts in DNA metabolism.

Detailed Description

This will be a single arm, open label pilot study of 5AZA-alt-DEC. Participants will be treated for a minimum of 24 weeks in the absence of clear evidence of progressive disease. Participants who have any response will be permitted to continue treatment until relapse or progression of disease that is not sensitive to protocol defined dose escalation.

The primary objective of this study is to determine Overall Response Rate (ORR) of 5AZA-alt-DEC. The combined response endpoint will include complete response (CR), partial response (PR), and hematologic improvement (HI), with HI criteria specifically as defined by IWG criteria

The secondary endpoints of this study include:

• Cumulative incidence of response for both CR and overall response
• Duration of response (DOR)
• Safety evaluation by tabulation of adverse events of grade 3 and higher

Correlative endpoints include:

• Correlation of DNMT1 depletion with clinical response criteria
• Correlation of clinical response with disease biological phenotype measured by morphology and cytogenetics
• Exploratory measurements of pyrimidine metabolism pre-treatment and on-therapy

Conditions

Myelodysplastic Syndromes; MDS/MPN Crossover Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

5AZA-alt-DEC

Participants will be treated for a minimum of 24 weeks in the absence of clear evidence of progressive disease. Patients who have any response will be permitted to continue treatment until relapse or progression of disease that is not sensitive to protocol defined dose escalation.

Treatments will include:

5-azacytidine (50mg/m^2) Day 1 every week

Decitabine (5mg/m^2) Day 4 every week

Weeks 1-8 will be an induction phase, and weeks 9+ will be a long-term treatment phase

Group Type: EXPERIMENTAL

5-azacytidine

Intervention Type: DRUG

5-azacytidine 50 mg/m\^2 Day 1 every week ± G-CSF \~5 µg/kg (300µg vs 480µg)

Decitabine

Intervention Type: DRUG

Decitabine 5 mg/m\^2 Day 4 every week ± G-CSF \~5 µg/kg (300µg vs 480µg)

Interventions

5-azacytidine

5-azacytidine 50 mg/m\^2 Day 1 every week ± G-CSF \~5 µg/kg (300µg vs 480µg)

Intervention Type: DRUG

Decitabine

Decitabine 5 mg/m\^2 Day 4 every week ± G-CSF \~5 µg/kg (300µg vs 480µg)

Intervention Type: DRUG

Other Intervention Names

azacytidine; 5-aza-2'-deoxycytydine

Eligibility Criteria

Inclusion Criteria

• Participants must have MDS or MDS/myeloproliferative overlap disorder with potential sensitivity to HMA therapy, defined as prior published evidence of response to HMA

• Myelodysplastic Syndromes:

• As classified by hematopathology review of WHO categories, myelodysplastic/myeloproliferative neoplasm unclassifiable, refractory anemia with ring sideroblasts and thrombocytosis, refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multi-lineage dysplasia (RCMD), refractory anemia with excess blasts (RAEB), myelodysplastic syndrome with isolated del(5q), myelodysplastic syndrome unclassifiable (MDS-U).
• Participant with MDS who are IPSS-R high and very high risk or IPSS intermediate 2 risk and higher are excluded given proven overall survival benefit in higher risk MDS from AZA-001 with this treatment
• Myelodysplastic/myeloproliferative neoplasm overlap disorders ---MDS/MPN crossover syndromes with limited evidence of extramedullary hematopoiesis (may not have palpable splenomegaly) and reticulin fibrosis of grade 1 or less without evidence of progression to accelerated phase. These may include but may not be limited to RARS-T, CMML, Atypical CML (BCR-ABL negative), and MDS/MPN NOS
• Indication for HMA therapy: Symptomatic anemia OR thrombocytopenia with a platelet count of <100 x 109/L OR transfusion dependence for red-cells OR transfusion dependence for platelets OR absolute neutrophil count < 1.0 x 109/L

--Participants with lower risk MDS must have must have failed or have contraindications to available therapies (e.g. lenalidomide, epoetin if indicated for symptomatic anemia and/or transfusion dependence of red cells) known to be effective for treatment of their disease

• Participants must have performance status of 60% or greater by Karnofsky Performance Status (KPS)
• Must have adequate end organ function defined as:

• AST and ALT < 3× the upper limit of normal (ULN)
• Bilirubin ≤ 1.5× the ULN. If elevated bilirubin is due to impaired conjugation (e.g Gilbert's disease or concomitant medication) or disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN

Exclusion Criteria

• Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures.

• MDS with IPSS-R high or very high risk, or IPSS intermediate-2 or high risk disease
• Prior Treatment with azacitidine, decitabine or investigational HMA therapy with overlapping mechanism of action (e.g. guadecitibine)
• No other disease directed therapy, save for hydroxyurea, including experimental or investigational drug therapy for 14 days prior to study entry.
• Toxicity (grade 2 or higher) from prior therapies including chemotherapy, targeted therapy, immunotherapy, experimental therapy, radiation or surgery must be resolved to grade 1 or less.
• Currently pregnant or breast-feeding. Females of child bearing (FOCBP) potential must have negative serum pregnancy test within 72 hours from treatment start. (NOTE: FOCBP is any biologic female, regardless of sexual or gender orientation, having undergone tubal ligation, or remaining celibate by choice, who has not undergone a documented hysterectomy or bilateral oophorectomy or has had a menses any time in the preceding 12 months (therefore not naturally post-menopausal for > 12 months)
• Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates. This includes, but is not limited to:

• Ongoing or active infection. As participants with MDS and MDS/MPNs are prone to infections, if participants are actively being treated with appropriate antibiotics or antifungal therapy with clinical evidence of infection control, then they will be considered eligible for study.
• Uncontrolled concurrent malignancy
• Congestive heart failure of NYHA class III/IV. Participants with compensated heart failure are permitted.
• Unstable angina pectoris
• New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are permitted
• Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD score ≥21)
• Psychiatric illness/social situations that would limit compliance with study requirements.
• Any other prior or ongoing condition, in the opinion of the investigator, that could adversely affect the safety of the participant or impair the assessment of study results.
• WOCBP and males that are unwilling to agree to use dual contraceptive measures (i.e., hormonal or barrier method of birth control; abstinence, condom) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately
• Sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of 5AZA-alt-DEC.
• Participants with known active HIV infection, as this will further increase the risk for opportunistic infections. However, participants with chronic HIV with undetectable viral load by PCR, without opportunistic infection, and on a stable regimen of antiretroviral therapy would be eligible.
• Known allergy or hypersensitivity to any component of azacitidine or decitabine formulations

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Benjamin Tomlinson

OTHER

Sponsor Role: lead

Responsible Party

Benjamin Tomlinson

MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Benjamin H Tomlinson, Tomlinson

Role: PRINCIPAL_INVESTIGATOR

Cleveland Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Locations

Cleveland Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Benjamin Tomlinson, MD

Role: CONTACT

benjamin.tomlinson@uhhospitals.org

216-844-0139

Facility Contacts

Benjamin Tomlinson

Role: primary

benjamin.tomlinson@uhhospitals.org

+1 216-844-0139

References

Xiaorong Gu, Rita Tohme, Benjamin K. Tomlinson, Lisa Durkin, Caroline Schuerger, Asmaa M Zidan, Tomas Radivoyevitch, Hetty E. Carraway, Ronald Sobecks, Betty K. Hamilton, Alan Lichtin, MD, Jaroslaw P. Maciejewski, Yogenthiran Saunthararajah; Feedback Responses of the Pyrimidine Metabolism Network Mediate Resistance to Decitabine and 5-Azacytidine. Blood2019; 134 (Supplement_1): 537. doi: https://doi.org/10.1182/blood-2019-125823

Reference Type: BACKGROUND

Other Identifiers

CASE4919

Identifier Type: -

Identifier Source: org_study_id