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

This is an open label, Phase Ib 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. The primary objectives phase 1 study is to establish safety and confirm a steady level of Vitamin C on ≥1 mM in > 75% of the patients is achieved. 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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Vitamin C

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ariana Budhu; Phone Number: 212-263-4644; Email: Ariana.budhu@nyulangone.org

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine -Sylvester Cancer Center
  • New York
    • New York, New York, United States, 10016
      • New York University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• 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 currently receiving or who previously received Hydroxyurea, Erythrocyte stimulating agents (ESA), or granulocyte colony stimulating factors (G-CSF) are allowed to participate in the study.

Exclusion Criteria:

• Concurrent hypomethylation agent usage; the last dose of treatment must be ≥4 weeks before the start of the Vitamin C infusion
• Myeloblast count ≥20% in peripheral blood or bone marrow aspirate
• Major surgery within 2 weeks prior to first dose of study drug
• Allogeneic stem cell transplant
• Any previous chemotherapy agent other than hypomethylating agents (e.g., Venetoclax)
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin C 50 g; Patients will receive Vitamin C as a continuous intravenous infusion (CIVI) of 50 grams (g) daily over 24 hours for 5 days for total of 250 grams over 5 days up.	Drug: Vitamin C; All patients will receive at least 1 cycle of treatment (4 weeks) of Vitamin C as a continuous intravenous infusion (CIVI). Patients with clinical benefit (CR, PR, or SD) then will undergo a second 4-week cycle of treatment. Patients to receive a maximum of 16 weeks of treatment (4 cycles). If a patient progress after receiving a cycle of treatment then the patient will be withdrawn from the study. Patients will be maintained on 1 gram oral Vitamin C daily from the end of the CIVI until the beginning of the next cycle (from day 6 till 28).; Other Names: ascorbic acid; ascorbate
Experimental: Vitamin C 75 g; Patients will receive Vitamin C as a continuous intravenous infusion (CIVI) of 75 grams (g) daily over 24 hours for 5 days for total of 375 grams over 5 days.	Drug: Vitamin C; All patients will receive at least 1 cycle of treatment (4 weeks) of Vitamin C as a continuous intravenous infusion (CIVI). Patients with clinical benefit (CR, PR, or SD) then will undergo a second 4-week cycle of treatment. Patients to receive a maximum of 16 weeks of treatment (4 cycles). If a patient progress after receiving a cycle of treatment then the patient will be withdrawn from the study. Patients will be maintained on 1 gram oral Vitamin C daily from the end of the CIVI until the beginning of the next cycle (from day 6 till 28).; Other Names: ascorbic acid; ascorbate
Experimental: Vitamin C 100 g; Patients will receive Vitamin C as a continuous intravenous infusion (CIVI) of 100 grams (g) daily over 24 hours for 5 days for total of 500 grams over 5 days.	Drug: Vitamin C; All patients will receive at least 1 cycle of treatment (4 weeks) of Vitamin C as a continuous intravenous infusion (CIVI). Patients with clinical benefit (CR, PR, or SD) then will undergo a second 4-week cycle of treatment. Patients to receive a maximum of 16 weeks of treatment (4 cycles). If a patient progress after receiving a cycle of treatment then the patient will be withdrawn from the study. Patients will be maintained on 1 gram oral Vitamin C daily from the end of the CIVI until the beginning of the next cycle (from day 6 till 28).; Other Names: ascorbic acid; ascorbate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Experienced a Dose Limiting Toxicity (DLT)	DLT is defined as grade 3 or higher of any duration or as a Grade ≥2 adverse event (AE) that persists for ≥96 hours with the exception of Grade ≥ 2 AEs clearly related to the underlying MDS	Week 16

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: Perlmutter Cancer Center
• Investigators: Principal Investigator: Mohammad M Abdul Hay, MD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Actual): November 6, 2022
• Study Completion (Actual): May 16, 2023

Study Registration Dates

• First Submitted: February 8, 2018
• First Submitted That Met QC Criteria: February 8, 2018
• First Posted (Actual): February 15, 2018

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: ASCORBIC ACID
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 17-00978

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No