ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03397173
Recruitment Status : Recruiting
First Posted : January 11, 2018
Last Update Posted : February 8, 2018
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Myeloproliferative Neoplasm Acute Myeloid Leukemia Drug: Azacitidine Drug: Ascorbic acid Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Targeting TET2 Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia (AML) With Azacitidine and Ascorbic Acid
Actual Study Start Date : January 29, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : January 2020


Arm Intervention/treatment
Experimental: Azacitidine + Ascorbic acid
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.
Drug: Azacitidine
Azacitidine will be administered intravenously or subcutaneously at a fixed dose of 75mg/m2/day for 7 consecutive days, allowing interruptions for weekends and holidays within each 28-day cycle. No dose modifications will be permitted during the treatment period.

Drug: Ascorbic acid
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. No dose modifications will be permitted during the treatment period.




Primary Outcome Measures :
  1. 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) ]

    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.


  2. Number of AML patients with response [ Time Frame: 171 Days (6 cycles of 28 days plus 3 day loading period) ]

    Complete Response (CR): Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines, Absolute neutrophil count (ANC) >/= 1.0 X 109/L, platelet count >/= 100 X 109/L, no detectable Auer rods and no extramedulary leukemia.

    Complete Response (CR) with incomplete hematologic recovery (CRi): Responses as in CR but ANC < 1.0 X 109/L.

    Complete Response (CR) with incomplete platelets recovery (CRp): Responses as in CR but platelets < 100 X 109/L.

    Partial response (PR): All CR criteria if abnormal before treatment except: bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5%.



Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 171 Days (6 cycles of 28 days plus 3 day loading period) ]
    Incidence of adverse events of the combination defined by CTCAE 4.1 criteria. Toxicity will be any drug related Grade 3 or 4 toxicity.

  2. Response duration [ Time Frame: 171 Days (6 cycles of 28 days plus 3 day loading period) ]
    Response duration to the combination recorded from start of treatment to progression

  3. Overall survival [ Time Frame: 171 Days (6 cycles of 28 days plus 3 day loading period) ]
    Overall survival measured from start of treatment to death or last follow up



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03397173


Contacts
Contact: Aziz Nazha, MD 216-445-0320 nazhaa@ccf.org

Locations
United States, Ohio
Cleveland Clinic, Taussig Cancer Institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: Aziz Nazha, MD    216-445-0320    nazhaa@ccf.org   
Principal Investigator: Aziz Nazha, MD         
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Aziz Nazha, MD Cleveland Clinic, Taussig Cancer Institute, Case Comprehensive Cancer Center

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03397173     History of Changes
Other Study ID Numbers: CASE1917
First Posted: January 11, 2018    Key Record Dates
Last Update Posted: February 8, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Case Comprehensive Cancer Center:
Azacitidine
Ascorbic Acid

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Ascorbic Acid
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antioxidants
Protective Agents
Physiological Effects of Drugs
Vitamins
Micronutrients
Growth Substances