Clinical Trials /

5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies

NCT04187703

Description:

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.

Related Conditions:
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndrome with Isolated del(5q)
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies
  • Official Title: Proof-Of-Concept Study of Metabolically Optimized, Non-Cytotoxic 5-Azacitidine and Decitabine Epigenetic Therapy for Myeloid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: CASE4919
  • NCT ID: NCT04187703

Conditions

  • Myelodysplastic Syndromes
  • MDS/MPN Crossover Syndromes

Interventions

DrugSynonymsArms
5-azacytidineazacytidine5AZA-alt-DEC
Decitabine5-aza-2'-deoxycytydine5AZA-alt-DEC

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
5AZA-alt-DECExperimentalParticipants 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
  • 5-azacytidine
  • Decitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have myelodysplastic syndrome (MDS) or MDS/myeloproliferative overlap
             disorder with potential sensitivity to Hypomethylating agents (HMA) therapy

               -  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).

                    -  Patient with MDS who are IPSS-R high and very high risk should only be
                       considered if their primary clinician feels that they will not tolerate
                       azacitidine 75mg/m^2 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 Refractory anemia with ringed sideroblasts and essential
                  thrombocytosis (RARS-T), Chronic myelomonocytic leukemia (CMML), Atypical Chronic
                  myeloid leukemia (Atypical CML) (BCR-ABL negative), and myelodysplastic and
                  myeloproliferative overlap syndrome not otherwise specified (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 < 1.5 x 109/L

          -  Patients must have performance status of 60% or greater by Karnofsky Performance
             Status (KPS)

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

        Exclusion Criteria:

          -  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.

          -  Currently pregnant or breast-feeding. Females of child bearing potential (FOCBP) 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 patients with MDS and MDS/MPNs are prone to
                  infections, if patients 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. Patients 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 patient or impair the assessment of
                  study results.

          -  FOCBP 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.

          -  Patients with known active HIV infection, as this will further increase the risk for
             opportunistic infections. However, patients 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) of 5AZA-alt-DEC
Time Frame:Up to 6 months from end of treatment
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Cumulative incidence of response for both CR and overall response
Time Frame:Up to 6 months from end of treatment
Safety Issue:
Description:Cumulative incidence of response for both CR and overall response
Measure:Duration of response (DOR)
Time Frame:Up to 2 years from end of treatment
Safety Issue:
Description:Duration of response (DOR)
Measure:Safety evaluation by tabulation of AEs of grade 3 and higher per CTACE version 5.0
Time Frame:through 30 days after the final dose of study drug
Safety Issue:
Description:Safety evaluation by tabulation of AEs of grade 3 and higher per CTACE version 5.0.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Last Updated

December 3, 2019