CCUS Clonal Cytopenia of Undetermined Significance, Clonal Cytopenia of Uncertain Significance, Clonal Hematopoiesis
Conditions
Keywords
MOSAIC, CH, Modulation of stem cell differentiation, CCUS, persistent cytopenia, clonal hematopoiesis, clonal haematopoiesis, Clonal Cytopenia of Uncertain Significance
Brief summary
Clonal hematopoiesis (CH) is characterized by the overproduction of blood cells derived from a single hematopoietic stem and progenitor cell (HSPC) harboring certain somatic mutations. It is linked to serious outcomes, including cardiovascular disease, myeloid neoplasm (MN), and increased mortality. Clonal Cytopenia of Uncertain Significance (CCUS) is a CH subtype characterized by associated persistent cytopenia. It affects approximately 10 % of people over 70 and is the most advanced precursor state with the highest risk of progressing to MN. There is an unmet need to determine whether modifying CH can prevent adverse outcomes. Current blood cancer therapies are too toxic for precursor conditions like CH. MOSAIC is a randomized double-blind placebo-controlled trial that will test a novel low-dose oral epigenetic therapy-decitabine with tetrahydrouridine (Dec+THU) in CCUS. It has shown targeted, non-cytotoxic reversal of common CH mutations in preclinical and early-phase studies. The goal is to develop a safe and effective therapy in CCUS that restores normal blood cell production and prevents progression.
Interventions
After randomization, participants will receive oral combination capsules containing decitabine (Dec) (2.5 mg) and tetrahydrouridine (THU) (125 mg) minitablets, or matched placebo. Trial medication will be dispensed on Day 1 of each cycle and taken once weekly (Days 1, 8, 15, 22) for 24 weeks. Dosing of Dec+THU will follow weight-based dosing at 0.2mg/kg and 10mg/kg respectively. This is a phase II, multicenter, double-blind, placebo-controlled randomized trial
Placebo capsules will be administered on the same schedule and dosing frequency to the active drug
Sponsors
Clinical Hub for Interventional Research (CHOIR)
Medical Research Future Fund
Australian National University
University of Auckland, New Zealand
Treebough Therapies
The University of New South Wales
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 60 and ≤ 85 years old 2. Clonal Cytopenia of Uncertain Significance (CCUS), defined by all of the following: a. Persistent cytopenia, present on at least two occasions, at least four months apart, with no other cause identified: i. Hemoglobin (Hb) \< 120 g/L in people born female, and \< 130 g/L in people born male ii. Platelet count \< 150 x 109/L iii. Absolute Neutrophil Count (ANC) \< 1.8 x109/L b. Clonal hematopoiesis (CH) driver mutation confirmed by custom gene panel mutation analysis c. absence of features diagnostic for defined myeloid neoplasm (MN) on bone marrow examination 3. CH driver mutation variant allele fraction (VAF) of ≥ 10% 4. For participants living with HIV: 1. Receiving and adherent to suppressive antiretroviral therapy for at least 12 months 2. CD4+T cell count ≥ 0.35 x 109/L 3. HIV viral load \< 50 copies/mL 6\. Performance status by Eastern Cooperative Oncology Group (ECOG) Criteria of 0 or 1 7. For participants who are of childbearing potential, or whose partners are of childbearing potential: 1. Agreement to use at least two highly effective (per Clinical Trial Facilitation Group) contraceptive methods throughout the course of the trial, and for 6 months following the last dose of trial drug 2. Refrain from donating eggs or sperm during the same period 3. Confirmation of a negative serum pregnancy test at screening and at the beginning of each treatment cycle visit (for female participants of childbearing potential) 8. Provision of signed written informed consent document prior to any trial-related assessments or procedures being carried out
Exclusion criteria
1. ANC \< 0.5 x109/L 2. Serum AST (Aspartate transaminase) or ALT (Alanine aminotransaminase) \> 3 times of upper limit of normal 3. Calculated or measured creatinine clearance ≤ 50 mL/min 4. Significant active cardiac disease within the previous 6 months, including: 1. New York Heart Association (NYHA) class III or IV congestive heart failure 2. Unstable angina or angina requiring surgical or medical intervention 3. Myocardial infarction 4. New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are permitted 5. Active systemic infections: 1. Infection with ongoing signs/symptoms related to the infection without improvement despite appropriate anti-infectives 2. Active Hepatitis B infection (HBV) (defined as HBsAg positive, or HBcAb positive and measurable HBV DNA; participants who are HBcAb positive must have HBV DNA assayed during screening) 3. Active Hepatitis C Virus (HCV) will be ineligible if there is clinical hepatic dysfunction or other systemic manifestations of HCV disease, or if the hepatic eligibility parameters above are not met. Consideration should be given to curative HCV therapy prior to enrolment in consultation with HCV clinician 6. Any history of hematological or solid malignancy in previous the 5 years unless the participant has been free of disease for ≥ 36 months. However, participants with the following history/concurrent conditions are not excluded: 1. Basal or squamous cell carcinoma of the skin 2. Carcinoma in situ of the cervix 3. Carcinoma in situ of the breast 4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system) 7. Known hypersensitivity to trial drugs or their constituents 8. Currently enrolled in the treatment phase of an interventional investigational trial. 9. Pregnant or breast-feeding individuals 10. Any condition not already outlined above which, in the opinion of the Principal Investigator, would place the participant at risk if they participated or would jeopardize adherence, follow up, or confound the ability to interpret trial data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in variant allele fraction (VAF) in peripheral blood mononuclear cells (PBMC) at the completion of 24 weeks of treatment. | End of Treatment (Week 24) | Change in variant allele fraction (VAF) in peripheral blood mononuclear cells (PBMC), at the completion of 24 weeks of treatment, will be used to compare the evolution of clonal cytopenia of undetermined significance (CCUS) in individuals with CCUS and associated clinically significant cytopenia receiving Dec+THU compared with those receiving placebo, by intention-to-treat analysis. VAF will be assessed by capture sequencing using the Auckland Myeloid Gene Panel V4 (AMGPV4) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and proportion of participants: a) experiencing Grade 3, 4 and 5 adverse events (AE) b) discontinuing treatment due to AEs or Serious Adverse Events (SAEs) c) living with HIV maintaining HIV Viral Load (VL) suppression | End of Treatment (Week 24) | The safety profile of Dec+THU treatment will be evaluated at the end of 24 weeks of treatment. Each cycle is 28 days. |
| Number and proportion of participants completing planned 24 weeks of treatment. | End of Treatment (Week 24) | The feasibility of Dec+THU treatment will be evaluated by number and proportion of participants completing planned 24 weeks of treatment |
| Number and proportion of participants with cytopenia response | End of Treatment (Week 24) and Follow Up 1 (Week 48) | Participant cytopenia response will be assessed and measured according to the 2018 International Working Group (IWG) criteria with comparison between the Dec+THU treatment group and the placebo group |
| Duration of cytopenia response | End of Treatment (Week 24) and Follow Up Visit 1 (Week 48) | Duration of cytopenia response will be assessed and measured according to the 2018 International Working Group (IWG) criteria with comparison between the Dec+THU treatment group and the placebo group |
| Changes in VAF in subgroups defined by cytopenias and baseline mutations | Baseline (Week 0), at the start of Cycle 4 Day 1 (Week 12) (each cycle is 28 days), End of Treatment (Week 24), Follow Up Visit 1 (Week 48) and Follow Up Visit 2 (Week 96) | VAF will be measured to compare changes in VAF in subgroups defined by baseline cytopenias and baseline mutations. DNA extracted from the peripheral blood will be sequenced after NGS library preparation and target-enrichment with a custom capture panel (Agilent Sure Select). Next Generation Sequencing (NGS) will be performed and the number of variant reads at a given position will be used to calculate the VAF. VAF will be a direct measure of the fraction of cells carrying the variant in the sample used for DNA extraction. |
| Changes in peripheral blood VAF | Baseline (Week 0), at the start of Cycle 4 Day 1 (Week 12) (each cycle is 28 days), End of Treatment (Week 24), Follow Up Visit 1 (Week 48), Follow Up Visit 2 (Week 96) | Peripheral blood VAF will be measured at timepoints to compare changes in VAF between the Dec+THU treatment group and placebo group DNA extracted from the peripheral blood will be sequenced after NGS library preparation and target-enrichment with a custom capture panel (Agilent Sure Select). Next Generation Sequencing (NGS) will be performed and the number of variant reads at a given position will be used to calculate the VAF. VAF will be a direct measure of the fraction of cells carrying the variant in the sample used for DNA extraction. |
| Changes in the levels of inflammatory cytokines between treatment groups in peripheral blood and bone marrow. | Baseline (Week 0), at the start of Cycle 4 Day 1 (Week 12) (each cycle is 24 weeks), End of Treatment (Week 24), Follow Up Visit 1 (Week 48), Follow Up Visit 2 (Week 96) | Inflammatory cytokine profile changes will be compared between the Dec+THU treatment group and placebo group in peripheral blood and bone marrow. Serum and plasma will be extracted from participant bone marrow and peripheral blood samples for quantifying inflammatory cytokines levels to compare inflammatory cytokines profile changes between the treatment groups. |
| Changes in bone marrow (BM) VAF | Screening, End of Treatment (Week 24) | This comparison will be made by measuring bone marrow VAF to determine if there are any changes between treatments groups at screening and end of treatment. DNA extracted from the bone marrow will be sequenced after NGS library preparation and target-enrichment with a custom capture panel (Agilent Sure Select). Next Generation Sequencing (NGS) will be performed and the number of variant reads at a given position will be used to calculate the VAF. VAF will be a direct measure of the fraction of cells carrying the variant in the sample used for DNA extraction. |
Countries
Australia
Contacts
CONTACTProfessor Mark Polizzotto
Outcome results
None listed