Back to resultsTET2 Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia With Azacitidine + Ascorbic Acid
Primary Purpose
Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Acute Myeloid Leukemia
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Azacitidine
Ascorbic acid
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring 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.
Sites / Locations
- Cleveland Clinic, Case Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Azacitidine + Ascorbic acid
Arm Description
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.
Outcomes
Primary Outcome Measures
Number of patients with response per MDS International Working Group 2006 Criteria
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.
Number of AML patients with response
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
Incidence of adverse events
Incidence of adverse events of the combination defined by CTCAE 4.1 criteria. Toxicity will be any drug related Grade 3 or 4 toxicity.
Response duration
Response duration to the combination recorded from start of treatment to progression
Overall survival
Overall survival measured from start of treatment to death or last follow up
Full Information
NCT ID
NCT03397173
First Posted
January 5, 2018
Last Updated
August 4, 2021
Sponsor
Case Comprehensive Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT03397173
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
March 16, 2018 (Actual)
Primary Completion Date
January 3, 2021 (Actual)
Study Completion Date
January 21, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Case Comprehensive Cancer Center
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
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
The safety profile of the combination in the targeted patient population
Response duration
Overall survival of the treated population (compared to matched historical cohort of patients treated with single agent Azacitidine)
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Acute Myeloid Leukemia
Keywords
Azacitidine, Ascorbic Acid
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Azacitidine + Ascorbic acid
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ascorbic acid
Intervention Description
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 Measure Information:
Title
Number of patients with response per MDS International Working Group 2006 Criteria
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.
Time Frame
171 Days (6 cycles of 28 days plus 3 day loading period)
Title
Number of AML patients with response
Description
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%.
Time Frame
171 Days (6 cycles of 28 days plus 3 day loading period)
Secondary Outcome Measure Information:
Title
Incidence of adverse events
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.
Time Frame
171 Days (6 cycles of 28 days plus 3 day loading period)
Title
Response duration
Description
Response duration to the combination recorded from start of treatment to progression
Time Frame
171 Days (6 cycles of 28 days plus 3 day loading period)
Title
Overall survival
Description
Overall survival measured from start of treatment to death or last follow up
Time Frame
Up to 1 year from end of treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aziz Nazha, MD
Organizational Affiliation
Cleveland Clinic, Case Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cleveland Clinic, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
12. IPD Sharing Statement
Learn more about this trial
TET2 Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia With Azacitidine + Ascorbic Acid
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