Myelodysplastic Syndromes
Conditions
Keywords
Vitamin C, Ascorbate, Myelodysplastic Syndrome, AIMS
Brief summary
This is an open-label, phase II clinical trial with safety run-in evaluating the safety, tolerability, and efficacy of IV HDA in combination with azacitidine for participants with MDS.
Detailed description
This Phase II clinical trial investigates the combination of high-dose intravenous ascorbate (vitamin C) with azacitidine in adults with higher-risk myelodysplastic syndrome (MDS). The study includes a small safety run-in followed by an efficacy phase, enrolling a total of 38 participants. It aims to determine whether adding high-dose ascorbate can safely enhance the therapeutic response to azacitidine, a standard hypomethylating agent used in MDS treatment.
Interventions
Ascorbate, or vitamin C, is a water-soluble vitamin with antioxidant properties that also functions as a cofactor for several enzymatic reactions, including collagen synthesis and the activity of dioxygenase enzymes involved in DNA and histone demethylation
DRUGAzacitidine
Azacitidine is a pyrimidine nucleoside analog of cytidine that incorporates into RNA and DNA, inhibiting DNA methyltransferase and leading to global DNA hypomethylation
Sponsors
Prajwal Dhakal
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years. * Diagnosis of myelodysplastic syndrome (MDS) requiring treatment with a hypomethylating agent (HMA). * Higher-risk MDS per the Molecular International Prognostic Scoring System (IPSS-M) - Moderate High, High, or Very High risk categories. * No prior MDS-directed therapy, except: ≤ 1 prior cycle of azacitidine, decitabine, or oral decitabine-cedazuridine; or prior use of ESA, luspatercept, or imetelstat. Prior hydroxyurea use is allowed but continuation beyond Cycle 1 requires PI approval. * ECOG performance status 0-2. * Adequate organ function: Creatinine clearance \>45 mL/min; total bilirubin ≤1.5 × ULN; ALT and AST ≤3 × ULN. * Ability to provide written informed consent. * Willingness to comply with study visits, treatment, and contraception requirements. * Negative pregnancy test for women of childbearing potential at screening.
Exclusion criteria
* MDS with isolated del(5q) eligible for lenalidomide therapy. * MDS/MPN overlap syndromes other than MDS. * Known hypersensitivity or allergy to ascorbate or azacitidine. * Pregnant or nursing individuals. * Inability or unwillingness to use adequate contraception. * Uncontrolled intercurrent illness including active infection, recent myocardial infarction (≤6 months), uncontrolled heart failure or arrhythmia, pulmonary edema, unstable angina, or significant psychiatric illness. * Renal disease requiring dialysis, diabetic nephropathy, renal transplant recipients, or history of oxalate nephropathy. * Paroxysmal nocturnal hemoglobinuria. * Uncontrolled HIV infection (patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible). * G6PD deficiency. * Use of warfarin (due to potential interaction with high-dose ascorbate). * Diabetic patients using fingerstick or continuous glucose monitors to adjust insulin doses (ascorbate can cause false readings). * Concurrent active malignancy, except adequately treated nonmelanoma skin cancer or curatively treated in situ cancers with \>2 years disease-free. * Systemic immunosuppressive therapy with prednisone ≥20 mg/day (or equivalent), except for inhaled or topical steroids. * Primary hemochromatosis or transfusion-related iron overload (ferritin \>1000 ng/mL).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | At the end of Cycle 1 (each cycle is 28 days) | Assess the safety and tolerability of intravenous (IV) high-dose ascorbate (HDA) in combination with azacitidine. |
| Treatment Efficacy | At the end of Cycle 4 (each cycle is 28 days) | Proportion of participants achieving a complete response (CR) or partial response (PR) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From treatment initiation until death from any cause or up to 24 months, whichever comes first | Time from treatment initiation to death from any cause. |
| Event-Free Survival (EFS) | From treatment initiation until disease progression, disease relapse, treatment failure, or death from any cause, whichever came first, assessed up to 24 months | Time from treatment initiation to progression, relapse, treatment failure, or death. |
| Transfusion Requirements | At baseline, assessed throughout the treatment up to the end of cycle 4 (each cycle is 28 days) | Changes in red blood cell and platelet transfusion needs during treatment. |
| Hematologic Parameters | At baseline, assessed throughout the treatment up to the end of cycle 4 (each cycle is 28 days) | Changes in hemoglobin, platelet, and neutrophil counts. |
| Composite Complete Response (cCR) Rate | At the end of cycle 4 (each cycle is 28 days) | Proportion of participants achieving CR, CRh, CRL, or CR-equivalent per IWG 2023 criteria. |
| Overall Response Rate (ORR) | At the end of cycle 4 (each cycle is 28 days) | Proportion of participants achieving CR, CRh, CRL, PR, or hematologic improvement (HI) per IWG 2023 criteria after four treatment cycles |
| Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | At baseline, at the end of cycle 4, every 3 months after the end of cycle 4 up to 24 months (each cycle is 28 days) | HRQOL will be assessed using the EORTC QLQ-C30 questionnaire. This outcome measure will evaluate participants' overall quality of life, functional status, and symptom burden at various time points throughout the study. Scoring Range: 0 to 100 for each scale. Functioning Scales: Higher scores = better functioning. Symptom Scales: Higher scores = worse symptoms. Global Health Status/QOL Scale: Higher scores = better overall QOL. |
| Health-Related Quality of Life (HRQOL) using EuroQol (EQ-5D-5L) questionnaire | At baseline, at the end of cycle 4, every 3 month after end of cycle 4 up to 24 months (each cycle is 28 days) | HRQOL will be assessed using the EQ-5D-5L questionnaire, which uses a descriptive system and a visual analogue scale. The descriptive system will evaluate participants' mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scoring range: 11111 to 55555. Higher scores= worse problems. The visual analog scale asks patients to rate their current health on a scale of 0 to 100. Higher scores= better health status. |
Countries
United States
Contacts
CONTACTPrajwal Dhakal, MD
PRINCIPAL_INVESTIGATORPrajwal Dhakal, MD
University of Iowa
Outcome results
None listed