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

NCT ID: NCT03397173

Last Updated: 2021-08-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-16
• Study Completion Date: 2021-01-21

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

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.

Conditions

Myelodysplastic Syndromes; Myeloproliferative Neoplasm; Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

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.

Ascorbic acid

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Case Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Aziz Nazha, MD

Role: PRINCIPAL_INVESTIGATOR

Cleveland Clinic, Case Comprehensive Cancer Center

Locations

Cleveland Clinic, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

CASE1917

Identifier Type: -

Identifier Source: org_study_id