A Phase Ib/IIa Study Evaluating the Safety and Tolerability of Vitamin C in Patients With Intermediate or High Risk Myelodysplastic Syndrome With TET2 Mutations

Study Overview
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Brief Summary
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This is an open label, Phase Ib/IIa study designed to evaluate the safety, toxicity and biological activity of high dose Vitamin C in bone marrow and peripheral blood when administered as therapy to patients with intermediate or high risk myelodysplastic syndrome according to the revised IPSS (international prognostic scoring system) criteria whose disease has a Ten-eleven translocation-2, (TET2) mutation.

Detailed Description
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This study will enroll patients with intermediate or high risk myelodysplastic syndrome. All patients will receive at least 1 cycle of treatment (4 weeks). Patients with clinical benefit (CR,PR, or SD) then will undergo a second 4-week cycle of treatment. The primary objectives of this study are: Evaluate the safety and toxicity of high dose Vitamin C Estimate the proportion of Myelodysplastic syndrome (MDS) patients with Ten-eleven translocation-2, (TET2) mutations who exhibit a biological response defined as maintaing a vtamin C serum concentration of ≥1mM over the treatment cycle. The secondary objectives are: Estimate the clinical efficacy, namely objectiveresponse rate (ORR). [including complete response (CR) and partial response (PR)] duration of response (DOR) and progression-free survival (PFS) as defined in the IWG (International Working Group) response criteria in myelodisplasia. Evaluate the pharmacokinetic profile (PK) of Vitamin C as hypomethylating or demethylating agent

Official Title
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A Phase Ib/IIa Study Evaluating the Safety and Tolerability of Vitamin C in Patients With Intermediate or High Risk Myelodysplastic Syndrome With TET2 Mutations

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: 50 gm CIVI/24 hours x 5 days every 4 week


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed Myelodysplastic Syndrome with positive TET2 mutations (We will test all MDS patients for TET2 mutations using next generation sequencing and only patients with TET2 mutations will be included in our study) Myeloblasts account for less than 20% of leukocytes on peripheral blood and bone marrow aspirate Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix 1) Adequate organ function Platelets ≥20,000/μL Absolute neutrophil count ≥ 500/μL Bilirubin < 1.5 x institutional upper limit of normal (ULN) or < 3 x ULN in patients with Gilbert's disease or liver involvement Serum albumin ≥ 2.0 g/dL Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 institutional ULN or, in the case of liver involvement by the primary disease AST/ALT ≤ 5 x ULN Creatinine≤1.5 x institutional ULN or estimated creatinine clearance of ≥45 mL/min by the Cockcroft-Gault equation or measured creatinine clearance >45 mL/min Females of child bearing potential must have a negative serum pregnancy test with 7 days prior to first dose of treatment and use 2 methods of contraceptives while on treatment Ability to understand and the willingness to sign a written informed consent document Patients already receiving hypomethylating agents will be allowed to enroll on the protocol and receive concurrent treatment with vitamin C. Currently or previously being on hydroxyurea Currently or previously being on erythrocyte stimulating agents (ESA) and granulocyte colony stimulating factors (G-CSF) Patients who have received prior allogeneic stem cell transplant will be permitted to enroll on the protocol Exclusion Criteria: Any cancer-related therapy for the current disease within 2 weeks of screening (all supportive care measures are allowed) Myeloblast count ≥20% in peripheral blood or bone marrow aspirate Major surgery within 2 weeks prior to first dose of study drug Requirement for systemic immunosuppressive therapy (e.g. Graft-versus-Host Disease [GVHD] therapy within 12 weeks before the first dose of study drug) Uncontrolled concurrent serious illness Concurrent malignancy or history of a previous malignancy within 1 year prior to first dose of the current study, unless curatively resected basal, squamous cell carcinoma of the skin, breast ductal/lobular carcinoma in situ or cervical carcinoma in situ. Active infections including hepatitis B carrier status, hepatitis C virus (HCV) infection (patients must have a negative Hep B and Hep C viral load at screening) Known HIV-positive status Any significant medical conditions, laboratory abnormality, or psychiatric illness that would exclude the subject from participation or interfere with study treatment, monitoring and compliance such as: Unstable angina pectoris, symptomatic congestive heart failure (NYHA III or IV), myocardial infarction ≤ 6 months prior to first study drug, clinically significant and uncontrolled cardiac arrhythmia (e.g. atrial fibrillation/flutter ventricular cardiovascular physiology is allowed), cerebrovascular accidents ≤ 6 months before study drug start Severely impaired lung function Serious, systemic infection requiring treatment ≤7 days before the first dose of study drug Any severe, uncontrolled disease or condition which in the investigator's opinion, may put the subject at significant risk, may confound the study results, or impact the subject's participation in the study History of any renal calculi or hyperoxaluria or any other preexisting renal disorder History of G6PD deficiency, hereditary spherocytosis or hemochromatosis Patients on therapeutic or prophylactic anticoagulation will be excluded from enrollment on the protocol. However, patients can remain on the study if they develop a thrombosis that requires therapeutic anticoagulation during the course of protocol therapy Uncontrolled hyponatremia, SIADH, hypokalemia, hyerpkalemia, hypomagnesemia or hypermagnesemia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Absorbic Acid<br>All patients will receive at least 1 cycle of treatment (4 weeks). Patients with clinical benefit (CR,PR, or SD) then will undergo a second 4-week cycle of treatment. | Drug: 50 gm CIVI/24 hours x 5 days every 4 week<br>* Each one ml solution will contain 500 mg ascorbic acid in the addition of disodium edetate 0.25mg, sodium hydroxide 110 mg in water with a pH in the range of 5.5 to 7.0 adjusted with sodium bicarbonate and sodium hydroxide. Vitamin C will be dispensed continuously by a computerized ambulatory drug deliver (CADD) pump, which will bereplaced every 24 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of serum bioavailability of Vitamin C in Myelodysplastic syndrome (MDS) patients with TET2 mutations | Weekly serum anion gap as vitamin C can be associated with elevated anion gapacidosis. If anion gap is elevated (>11mEq/L) then we will hold the study drug for one week and recheck anion gap. If still elevated (>11mEq/L), we will withdraw the patient from the study, If not elevated (≤11mEq/L) we will resume vitamin C treatment. | 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASCORBIC ACID