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.
Age ≥ 60 and ≤ 85 years old
CH driver mutation variant allele fraction (VAF) of ≥ 10%
Receiving and adherent to suppressive antiretroviral therapy for at least 12 months
CD4+T cell count ≥ 0.35 x 109/L
ANC < 0.5 x109/L
Serum AST (Aspartate transaminase) or ALT (Alanine aminotransaminase) > 3 times of upper limit of normal
Calculated or measured creatinine clearance ≤ 50 mL/min
New York Heart Association (NYHA) class III or IV congestive heart failure
Parallel
Oral Decitabine and Tetrahydrouridine
DrugAfter 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
Matched Placebo (Capsules)
DrugPlacebo capsules will be administered on the same schedule and dosing frequency to the active drug
Change in variant allele fraction (VAF) in peripheral blood mononuclear cells (PBMC) at the completion of 24 weeks of treatment.
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)
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
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.
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
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
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
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Clinical Hub for Interventional Research (CHOIR)
Lead sponsor
Medical Research Future Fund
Collaborator
Australian National University
Collaborator
University of Auckland, New Zealand
Collaborator
Treebough Therapies
Collaborator
The University of New South Wales
Collaborator
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