The goal of this clinical trial is to learn if ASTX727 can be combined with retifanlimab to treat Merkel cell cancer. It will also learn about the safety of combining these drugs. The main questions it aims to answer are:

• Can the combination shrink cancer and lower the chance of the cancer growing or spreading?
• Is the combination better than standard of care for Merkel cell cancer?

Participants will:

• Take oral ASTX727 and retifanlimab through a vein in the arm for about 2 years.
• Visit the clinic once every 2 weeks for checkups and tests

This study is being done to see if combining ASTX727 (decitabine/cedazuridine) with retifanlimab-dlwr is safe and confers clinical benefit in patients with advanced Merkel cell carcinoma who have progressed on anti-PD-(L)1 inhibitor therapy.

Inclusion Criteria:

• Individuals age ≥ 18 years at the time of consent
• ECOG Performance Status of 0-2
• Histological or cytological evidence/confirmation of Merkel cell carcinoma (MCC)
• Must have unresectable stage III/IV MCC per American Joint Committee on Cancer (AJCC) 8th edition. Participants must be considered unresectable based on the judgment of the treating physician
• Participants must have progressed on prior programmed cell death protein-1 (PD-1) or programmed death-ligand 1(PD-L1) inhibitor-based therapy. Participants must have received at least 2 doses of anti-PD-1 or anti-PD-L1 inhibitor. Relapsed/refractory disease from prior adjuvant PD-1 or PD-L1 inhibitor is permitted. Prior treatment with retifanlimab is permitted.
• Demonstrate adequate organ and marrow function; all screening labs to be obtained within 28 days prior to registration

Exclusion Criteria:

• Prior treatment with a hypomethylating agent (HMA) (e.g., azacitidine, decitabine, guadecitabine)
• History of clinically significant intolerance, hypersensitivity, or treatment discontinuation of an anti-PD-1 or anti-PD-L1 inhibitor due to grade 3 or greater immune-related adverse events (irAEs). Participants who are able to be successfully rechallenged with anti-PD-(L)1 inhibitor without recurrence of grade 3 or greater irAEs are permitted on study. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study drug(s) may be included (e.g. hearing loss, hypothyroidism, adrenal insufficiency, type 1 diabetes, or other endocrinopathies) after consultation with the sponsor investigator
• Palliative radiation therapy administered within 1 week before the first dose of study treatment or radiation therapy in the thoracic region that is > 30 Gy within 6 months before the first dose of study treatment
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration
• Active infection requiring systemic therapy within 7 days prior to registration

Researchers must have local IRB approval for their study that is to include study of the biospecimens and accompanying data. Release of biospecimens to non-UW researchers will be performed according to all UW regulatory policies. Tissue (including blood) specimen as part of this research will be primarily stored at UW and may be sent to an outside lab/facility to achieve the objectives of the study. No study data or patient health information will be shared with a third party.

Researchers who are doing biomedical research may apply to the PI for access to blood and tissue (no patient identifiers on tubes or slides). Only de-identified information will be released with the specimens