5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies

NCT04187703 | Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: CASE4919
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Myelodysplastic Syndromes; MDS/MPN Crossover Syndromes

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR) of 5AZA-alt-DEC

  Overall response rate (ORR) of 5AZA-alt-DEC including: Complete Response (CR) Partial Response (PR) Hematologic improvement (HI), with HI criteria specifically as defined by IWG criteria Therefore, the overall response rate (ORR) = CR + PR + HI

  Up to 6 months from end of treatment

Secondary Outcomes (3)

• Cumulative incidence of response for both CR and overall response

  Up to 6 months from end of treatment

• Duration of response (DOR)

  Up to 2 years from end of treatment

• Safety evaluation by tabulation of all AEs and SAEs per CTACE version 5.0

  through 30 days after the final dose of study drug

Other Outcomes (6)

• Correlation of clinical response IWG criteria with disease biological phenotype

  Up to 2 years from end of treatment

• Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by quantitative immunofluorescence

  Up to 2 years from end of treatment

• Correlation of predicted DNMT1 depletion with clinically assessed DNMT1 depletion as evaluated by flow cytometry

  Up to 2 years from end of treatment

Study Arms (1)

5AZA-alt-DEC

EXPERIMENTAL

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

Drug: 5-azacytidine; Drug: Decitabine

Interventions

5-azacytidine DRUG

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

Also known as: azacytidine

5AZA-alt-DEC

Decitabine DRUG

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

Also known as: 5-aza-2'-deoxycytydine

5AZA-alt-DEC

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Benjamin Tomlinson: lead

Study Sites (1)

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

Cleveland, Ohio, 44106, United States

RECRUITING

Related Publications (1)

• 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

  BACKGROUND

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Azacitidine; Decitabine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; 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

Study Officials

• Benjamin H Tomlinson, Tomlinson

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

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Benjamin Tomlinson, MD

CONTACT

216-844-0139; benjamin.tomlinson@uhhospitals.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: December 3, 2019
• First Posted: December 5, 2019
• Study Start: November 16, 2020
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 9, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: Beginning 3 months and ending 5 years following article publication
• Access Criteria: Investigators who provide a methodologically sound proposal for use of requested data

Locations

US (1)