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:

Suspended

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:

          -  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

               -  As azacitidine and decitabine have little renal metabolism, and have proven
                  safety even in dialysis participants, renal function is not an inclusion or
                  exclusion criteria

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

        Exclusion Criteria:

          -  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
      
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 all AEs and SAEs 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 all AEs and SAEs per CTACE version 5.0

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Suspended
Lead Sponsor:Benjamin Tomlinson

Last Updated

March 17, 2021