Myelodysplastic Syndromes
Conditions
Keywords
ASCORBIC ACID
Brief summary
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.
Interventions
DRUGVitamin 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 If a patient progress after receiving a cycle of treatment then the patient will be withdrawn from the study.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).
Sponsors
Perlmutter New York University Cancer Center
NYU Langone Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3 dose-escalation cohorts in a 3+3 design. One subject at a time will be enrolled into the first cohort until the first dose level cohort is completed and all patients treated successfully for one cycle.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) | Week 16 | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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). | 1 |
| 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.
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). | 3 |
| 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.
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). | 0 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Progression of Disease | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Vitamin C 50 g | Vitamin C 75 g | Total | Vitamin C 100 g |
|---|---|---|---|---|
| Age, Continuous | 73 years STANDARD_DEVIATION 0 | 76 years STANDARD_DEVIATION 2.49 | 74 years STANDARD_DEVIATION 2.49 | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 3 Participants | — |
| Region of Enrollment United States | 1 participants | 3 participants | 4 participants | — |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 3 | 0 / 0 |
| other Total, other adverse events | 1 / 1 | 3 / 3 | 0 / 0 |
| serious Total, serious adverse events | 1 / 1 | 0 / 3 | 0 / 0 |
Outcome results
Primary
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
Time frame: Week 16
Population: No patients were enrolled into the Vitamin C 100 g arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C 50 g | Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
| Vitamin C 75 g | Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
| Vitamin C 100 g | Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |