Early Intervention in High Risk CCUS

This is an open-label, multicenter pilot study testing the feasibility and safety of early pharmacologic intervention, decitabine/cedazuridine, in participants with higher-risk clonal cytopenia of unknown significance (CCUS).

The U.S. Food and Drug Administration (FDA) has not approved DEC/CED for CCUS but it has been approved for other uses.

The research study procedures include screening for eligibility, in-clinic treatment visits, electrocardiograms, echocardiograms, bone marrow biopsies, and blood tests.

Participants who choose to enroll in the intervention cohort will receive the oral drug for 1 year and will continue in a post-treatment observation period for 2 years after treatment. Participants in both groups will each participate in the study for 3 years total.

It is expected that the study will continue to enroll up to 108 participants in total or until there are 30 participants enrolled in the early intervention cohort, whichever occurs first.

Astex Oncology is funding this research study by providing the drug Decitabine/cedazuridine.

Inclusion criteria

• Age ≥18 years.
• Unexplained cytopenia(s) for at least 4 months (at least two separate labs within 4 months including at time of screening must meet this criteria). Cytopenia(s) defined as the presence of ≥ 1 of the following:

• Hemoglobin (Hgb) <12 g/dL for women and <13g/dL for men
• Absolute neutrophil count (ANC) < 1.8 × 109/L*
• Platelet count (Plt) <150 × 109/L *Patients known to have a Duffy-null genotype must have anemia (Hgb < 12g/dL for women, Hgb <13g/dL for men) and/or thrombocytopenia (Plt < 150 × 109/L) to be eligible for this study.

• 1 pathogenic variant detected in any myeloid driver gene with a VAF of at least 0.02 (2%) identified by local next generation sequencing (NGS) of peripheral blood or bone marrow sample within 3 months from screening bone marrow biopsy.
• Participants must have a high risk score per the Clonal Hematopoiesis Risk Calculator (CHRS). See APPENDIX C for calculation.
• Screening bone marrow biopsy must not be diagnostic of any overt hematologic malignancy by morphologic assessment and must be consistent with a diagnosis of clonal cytopenia of unknown significance (CCUS) as determined by multi-institutional hematopathology review.
• ECOG performance status 0-2 (see Appendix A).
• Participants must meet the following organ function as defined below:

• Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤3x upper limit of normal (ULN).
• Serum total bilirubin <1.5x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis or Gilbert's syndrome. In these cases, approval from the study Sponsor-Investigator is required.
• Creatinine clearance greater than 40 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation.
• Ability to understand and the willingness to sign a written informed consent document.
• For participants of the early pharmacologic intervention cohort: women of childbearing potential must use highly effective contraception during treatment for at least 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose.

Exclusion criteria

• Concurrent primary malignancy requiring active cytotoxic chemotherapy and/or ionizing radiation therapy.
• Known inherited bone marrow failure disorder and/or germline predisposition to hematologic malignancy.
• Receipt of anti-cancer therapy including any cytotoxic chemotherapy, ionizing radiation therapy, immunomodulatory agents such as lenalidomide, and targeted anti-cancer therapies including PARP inhibitors within the last 6 months. Patients with complete surgical resection of a tumor are not excluded from this study.
• Anti-cancer therapy, including any cytotoxic chemotherapy, ionizing radiation therapy, immunomodulatory agents such as lenalidomide and targeted agents such as PARP inhibitors, planned in the next 6 months. Patients on hormonal adjuvant therapy for nonmetastatic breast and prostate cancer or other minimally-myelosuppressive maintenance therapies for non-metastatic cancer may be eligible at the discretion of the study PI.
• Diagnosis of MDS, MPN, CMML, AML or any other hematolymphoid malignancy in the patient's lifetime. This includes individuals with MDS-defining chromosomal abnormalities identified via conventional karyotype or FISH.
• Presence of a concurrent hematologic malignancy precursor state, such as smoldering multiple myeloma (SMM), and smoldering Waldenstrom's macroglobulinemia.
• Presence of an early-stage hematologic precursor state-such as monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B cell lymphocytosis (MBL).
• Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
• Recent (within 3 months) vaccination with any live attenuated vaccine or vaccination with live attenuated vaccine planned during the next 15 months. *Live attenuated vaccines include measles, mumps, rubella (MMR combined vaccine), rotavirus, smallpox, chickenpox, and yellow fever.
• Laboratory evidence indicative of clinically significant red cell hemolysis.
• Hypersplenism and/or evidence of portal hypertension on physical exam or imaging.
• Pregnant or lactating.