Modulation of Stem Cell Differentiation in Individuals With High Risk Clonal Haematopoiesis

Official title

A Multi-centre, Double-blind, Placebo-controlled Randomised Phase II Trial to Evaluate the Effect of Low Dose Decitabine and Tetrahydrouridine in Individuals With High-risk Clonal Haematopoiesis

Overview

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

• Drug Oral Decitabine and Tetrahydrouridine
  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
• Drug Matched Placebo (Capsules)
  Placebo capsules will be administered on the same schedule and dosing frequency to the active drug

Primary outcome measures

• Change in variant allele fraction (VAF) in peripheral blood mononuclear cells (PBMC) at the completion of 24 weeks of treatment. [Time frame: End of Treatment (Week 24)]

Secondary outcome measures (8)

• 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 [Time frame: End of Treatment (Week 24)]
• Number and proportion of participants completing planned 24 weeks of treatment. [Time frame: End of Treatment (Week 24)]
• Number and proportion of participants with cytopenia response [Time frame: End of Treatment (Week 24) and Follow Up 1 (Week 48)]
• Duration of cytopenia response [Time frame: End of Treatment (Week 24) and Follow Up Visit 1 (Week 48)]
• Changes in VAF in subgroups defined by cytopenias and baseline mutations [Time frame: 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)]
• Changes in peripheral blood VAF [Time frame: 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)]
• Changes in the levels of inflammatory cytokines between treatment groups in peripheral blood and bone marrow. [Time frame: 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)]
• Changes in bone marrow (BM) VAF [Time frame: Screening, End of Treatment (Week 24)]

Eligibility criteria

Inclusion criteria

• Age ≥ 60 and ≤ 85 years old
• 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

• CH driver mutation variant allele fraction (VAF) of ≥ 10%
• For participants living with HIV:

• Receiving and adherent to suppressive antiretroviral therapy for at least 12 months
• CD4+T cell count ≥ 0.35 x 109/L
• 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:

• 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
• Refrain from donating eggs or sperm during the same period
• 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

• 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
• Significant active cardiac disease within the previous 6 months, including:

• New York Heart Association (NYHA) class III or IV congestive heart failure
• Unstable angina or angina requiring surgical or medical intervention
• Myocardial infarction
• New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are permitted
• Active systemic infections:

• Infection with ongoing signs/symptoms related to the infection without improvement despite appropriate anti-infectives
• 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)
• 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
• 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:

• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system)
• Known hypersensitivity to trial drugs or their constituents
• Currently enrolled in the treatment phase of an interventional investigational trial.
• Pregnant or breast-feeding individuals
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Australia · 3 centers

• Canberra Health Services — Canberra
• Prince of Wales Hospital — Randwick
• Westmead Hospital — Westmead

Identifiers

NCT: NCT07435636 · 24-CH-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗