Clonal Cytopenia of Undetermined Significance, Myelodysplastic Syndrome
Conditions
Keywords
Lower Risk Myelodysplastic Syndromes
Brief summary
This is an open-label, phase 2 study for lower risk MDS and high risk CCUS patients who are transfusion independent. There will be two cohorts enrolled at the same time to measure the effect of nicotinamide riboside and pterostilbene at different doses. The primary goals of the study are: * to assess if study drug improves cytopenias in patients * to determine safety of the study drug in patients
Detailed description
This is an open label, Phase 2 study for lower risk MDS and high risk CCUS patients who are transfusion independent. Ten subjects will be accrued in this protocol in two cohorts. The first five subjects in cohort 1 will be given nicotinamide riboside and pterostilbene 250mg-50mg daily for a year. The second cohort will have five subjects and nicotinamide riboside and pterostilbene will be given 250mg-50mg twice daily for a year. The two cohorts can enroll concurrently. Study visits will be every 90 days. Two bone marrow biopsies will be performed, one at the time of screening and one after 180 days of therapy. The bone marrow biopsy at 180 days will serve to assess responses such as changes in variant allele frequencies, as well as correlative studies.
Interventions
DRUGNicotinamide Riboside
Nicotinamide riboside is an orally administered dietary supplement and a vitamin B3 derivative that serves as a precursor to nicotinamide adenine dinucleotide (NAD+).
DRUGPterostilbene
Pterostilbene is an orally administered dietary supplement and a naturally occurring polyphenol structurally related to resveratrol.
Sponsors
University of Colorado, Denver
Cancer League of Colorado
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed procedures. * Stated willingness to comply with all study procedures and be available for the duration of the study. * Be a male or female aged ≥ 18 years of age. * For persons of reproductive potential, use of highly effective method(s) of contraception. * Subject must have confirmation of high risk CCUS (defined by CHRS score) or the diagnosis of MDS in the lower risk category as defined by IPSS-M less than 0. * Patients must have ECOG of ≤ 2 * Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula. * Subject must have adequate liver function as demonstrated by: * aspartate aminotransferase (AST) ≤ 3.0 × ULN * alanine aminotransferase (ALT) ≤ 3.0 × ULN * Unless due to Gilbert's syndrome, patients must have a total bilirubin ≤ 3 × ULN. * Subject is informed that consumption of the following fruits is prohibited 3 days prior to the initiation of study treatment and throughout participation: grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit.
Exclusion criteria
* Subject is known to be positive for HIV with uncontrolled disease. HIV testing is not required. * Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV may participate. * Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to: * Significant active cardiac disease within the previous 6 months including: New York Heart Association heart failure \> class 2, unstable angina, or myocardial infarction. * Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia. * Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. This includes history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease (e.g. sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity. * Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Uncontrolled is defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment. * Subject has a history of other malignancies prior to study entry, with the exception of: * Adequately treated in situ carcinoma of the breast or cervix uteri * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin * Prostate cancer not requiring therapy beyond hormonal therapy * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent * Any subject who is transfusion dependent and a candidate for MDS therapy such as erythroid stimulating agents, thrombopoietin receptor agonists, Lusparercept, Imetelstat or hypomethylating agents. * Pregnant or breast-feeding females. A pregnancy test will be obtained at the time of screening if applicable. * Known or suspected hypersensitivity to nicotinamide riboside and pterostilbene.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary Efficacy: Cytopenia Improvement | 24 weeks | To assess efficacy of nicotinamide riboside and pterostilbene supplementation by assessing whether it increased hemoglobin by 1g/dL in 24 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety Information Collection | From enrollment to 30 days after last dose of study drug, approximately 390 days. | To determine the safety of nicotinamide riboside and pterostilbene in patients with CCUS and MDS via AE and SAE collection throughout study. Frequency and proportion of specific AEs will be calculated for the entire cohort, as well as for each individual dosing cohort. |
| Additional Efficacy Outcomes - Platelet and Neutrophil Response | From start of study drug to end of treatment, approximately 360 days. | -To assess platelet response and neutrophil response. Platelet response will be defined as an increase of at least 30 x 109/L or an increase from \< 20 x 109/L to \> 20 x 109/L. Neutrophil response will be defined as an increase of at least 100% and an absolute increase of at least 0.5 x 109/L. |
| Additional Efficacy Outcomes - Decrease in Variant Allele Frequency | From start of study drug to end of treatment, approximately 360 days. | -To assess decrease in variant allele frequency by 50%. Secondary end points will include decrease in variant allele frequency by 50%, and platelet and neutrophil response. |
Countries
United States
Contacts
CONTACTDerek Schatz
PRINCIPAL_INVESTIGATORMaria Amaya, PhD MD
University of Colorado, Denver
Outcome results
None listed