Clinical Trials /

TET2 Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia With Azacitidine + Ascorbic Acid

NCT03397173

Description:

The purpose of this study is to evaluate the efficacy of treatment with azacitidine (an FDA approved drug for the treatment of MDS) and high dose ascorbic acid in patients with TET2 mutations. This approach is intended to enhance the enzymatic activity of TET2 protein, which in term may help to improve counts and symptoms, related to Myelodysplastic Syndromes and Acute Myeloid Leukemia. This combination is specific to individuals who carry this mutation.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TET2 Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia With Azacitidine + Ascorbic Acid
  • Official Title: Targeting TET2 Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia (AML) With Azacitidine and Ascorbic Acid

Clinical Trial IDs

  • ORG STUDY ID: CASE1917
  • NCT ID: NCT03397173

Conditions

  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
AzacitidineAzacitidine + Ascorbic acid
Ascorbic acidAzacitidine + Ascorbic acid

Purpose

The purpose of this study is to evaluate the efficacy of treatment with azacitidine (an FDA approved drug for the treatment of MDS) and high dose ascorbic acid in patients with TET2 mutations. This approach is intended to enhance the enzymatic activity of TET2 protein, which in term may help to improve counts and symptoms, related to Myelodysplastic Syndromes and Acute Myeloid Leukemia. This combination is specific to individuals who carry this mutation.

Detailed Description

      Primary Endpoint To estimate the overall response rate (ORR) of the combination of standard
      dose azacitidine and oral dose of ascorbic acid in patients with MDS, AML, and MDS /
      Myeloproliferative Neoplasm (MPN) overlap with heterozygous TET2 mutations

      Secondary Endpoints

        1. The safety profile of the combination in the targeted patient population

        2. Response duration

        3. Overall survival of the treated population (compared to matched historical cohort of
           patients treated with single agent Azacitidine)

        4. The identification of biomarkers that predict response to the combination

      Study Design This is an open-label, phase II study that will be conducted at Cleveland
      Clinic, Taussig Cancer Institute.

      Azacitidine will be administered intravenously or subcutaneously at a fixed dose of
      75mg/m2/day for 7 consecutive days, (allowing for weekends, and holidays) of each 28-day
      cycle. Ascorbic acid will be administered orally daily at 1 g/day three days prior to start
      azacitidine and then continues daily for a total of 28 days of each 28 day cycle.
    

Trial Arms

NameTypeDescriptionInterventions
Azacitidine + Ascorbic acidExperimentalAzacitidine will be administered intravenously or subcutaneously at a fixed dose of 75mg/m2/day for 7 consecutive days, (allowing for weekends, and holidays) of each 28-day cycle. Ascorbic acid will be administered orally daily at 1 g/day three days prior to start azacitidine and then continues daily for a total of 28 days of each 28 day cycle.
  • Azacitidine
  • Ascorbic acid

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a confirmed heterozygous TET2 mutations identified by next
             generation targeted deep sequencing.

          -  Patients must have MDS, or MDS/MPN overlap defined by 2016 World Health Organization
             (WHO) criteria. Both newly diagnosed or previously treated MDS or MDS/MPN patients are
             eligible as long as the patient has never received prior treatment with azacitidine or
             decitabine.

          -  Patients with Leukemic/blast phase transformation MPN.

          -  Patient with AML according to 2016 WHO criteria.

               -  Newly diagnosed patients who are ineligible or declined to receive intensive
                  chemotherapy after discussion of risks and benefits of that approach or patients
                  with primary refractory/relapsed AML.

               -  Patients with active central nervous system (CNS) leukemia eligible at the
                  discretion of treating physician.

               -  Relapse/Refractory is defined as at least 1 course of treatment for AML excluding
                  any patients treated with azacitidine or decitabine.

                    -  Patients should be off any prior treatment or line of therapy for 2 weeks
                       prior to start study with the exception of hydrea (Hydroxyurea).

          -  Prior therapy with hydroxyurea, biological or targeted therapy (e.g. flt3 inhibitors,
             other kinase inhibitors) or hematopoietic growth factors is allowed.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3.

          -  Patients must have normal organ and marrow function as defined at the discretion of
             the treating physician and PI.

          -  Women of childbearing potential must have a negative serum or urine pregnancy test
             within 10-14 days prior to enrollment.

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  Patient must be willing to comply with all aspects of the protocol including
             completing the drug diary.

          -  Patient must discontinue any and all use of multivitamin and/or vitamin c medication
             24 hours before first dose of Ascorbic Acid.

        Exclusion Criteria:

          -  Any prior treatment with azacitidine or decitabine.

          -  Patients diagnosed with acute promyelocytic leukemia (APL), AML-M3.

          -  Patients receiving other active treatment for their myeloid malignancy including
             investigational agents with the exception of hydrea for white blood cell control.

          -  Nursing or pregnant women.

          -  History of allergic reactions to either azacitidine or ascorbic acid.

          -  Patients with uncontrolled intercurrent illness including, but not limited to ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements.

          -  Patients with higher risk of bleeding (deemed by the treating physician) or on
             anticoagulation.

          -  Patients who are unwilling or unable to comply with all study requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with response per MDS International Working Group 2006 Criteria
Time Frame:171 Days (6 cycles of 28 days plus 3 day loading period)
Safety Issue:
Description:A binary indicator of overall response, defined as achieving CR, PR, or HI) per 2006 International Working Group (IWG) criteria Responses for MDS patients: Complete Response (CR): Bone marrow: ≤ 5% myeloblasts with normal maturation. Peripheral blood: Hgb ≥ 11 g/dL Platelets ≥ 100 × 109/L Neutrophils ≥ 1.0 × 109/L, Blasts 0% Partial response (PR): All CR criteria if abnormal before treatment except: bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% Hematologic Improvement (HI): (responses must last at least 8 weeks) Erythroid response [HI-E; (if pretreatment Hgb < 11 g/dL)]; Hgb increase by ≥ 1.5 g/dL; Relevant reduction of units of red blood cell (RBC) transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for an Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:171 Days (6 cycles of 28 days plus 3 day loading period)
Safety Issue:
Description:Incidence of adverse events of the combination defined by CTCAE 4.1 criteria. Toxicity will be any drug related Grade 3 or 4 toxicity.
Measure:Response duration
Time Frame:171 Days (6 cycles of 28 days plus 3 day loading period)
Safety Issue:
Description:Response duration to the combination recorded from start of treatment to progression
Measure:Overall survival
Time Frame:171 Days (6 cycles of 28 days plus 3 day loading period)
Safety Issue:
Description:Overall survival measured from start of treatment to death or last follow up

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Azacitidine
  • Ascorbic Acid

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