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

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:

1. Evaluate the safety and toxicity of high dose Vitamin C

2. 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:

1. 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.

2. Evaluate the pharmacokinetic profile (PK) of Vitamin C as hypomethylating or
demethylating agent

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

1. Platelets ≥20,000/μL

2. Absolute neutrophil count ≥ 500/μL

3. Bilirubin < 1.5 x institutional upper limit of normal (ULN) or < 3 x ULN in
patients with Gilbert's disease or liver involvement

4. Serum albumin ≥ 2.0 g/dL

5. 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

6. 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:

1. 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

2. 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