ASTX727 (Decitabine/Cedazuridine) and Retifanlimab-dlwr for the Treatment of Advanced/Unresectable Merkel Cell Carcinoma

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent document
• 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. Subjects must be considered unresectable based on the judgment of the treating physician
• Subjects must have progressed on prior PD-1 or PD-L1 inhibitor-based therapy. Progression is defined as the lack of clinical benefit at the investigator’s discretion. Subjects 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
• Evaluable/measurable disease according to Response Evaluation Criteira in Solid Tumors (RECIST) version (v) 1.1 within 28 days of registration
• Up to 2 lines of prior systemic therapy are allowed. Subjects must have progressed on anti-PD1 or anti-PD-L1 based therapy as their most recent line of systemic therapy. Prior treatment with anti-CTLA-4, chemotherapy, or targeted therapy is permitted. Prior treatment with retifanlimab is permitted. * Prior immunotherapy or biologic therapy must be completed at least 28 days prior to registration. * Prior chemotherapy must be completed at least 21 days prior to registration. * The subject must have recovered from all reversible acute toxic effects of prior regimen(s) (other than alopecia) to ≤ grade 1 or baseline. Subjects with chronic controlled immune related endocrinopathies can be enrolled
• Individuals at least 18 years of age at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Predicted life expectancy 3+ months from study registration, as determined by the enrolling physician or protocol designee
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 (obtained within 28 days of registration)
• Platelet ≥ 75,000/mm^3 (obtained within 28 days of registration)
• Hemoglobin (Hgb) ≥ 9.0 g/dL (obtained within 28 days of registration)
• Serum creatinine < 2 x upper limit of normal (ULN) (obtained within 28 days of registration)
• Total bilirubin ≤ 2 × upper limit of normal (ULN) except patients with documented Gilbert’s syndrome who must have a baseline total bilirubin ≤ 3.0 mg/dL (obtained within 28 days of registration)
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN in case of tumor liver involvement (metastasis) (obtained within 28 days of registration)
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN in case of tumor liver involvement (metastasis) (obtained within 28 days of registration)
• Albumin ≥ 75% of lower limit of normal (LLN) (obtained within 28 days of registration)
• Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 7 days prior to registration. The screening pregnancy test should also fall within 7 days of cycle 1 day 1 (C1D1)
• Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from heterosexual activity or use an effective method(s) of contraception. Males able to father a child who are sexually active with female of childbearing potential must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception
• HIV-infected subjects on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. Testing is not required at screening unless mandated by local policy
• Subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Subjects with a history of hepatitis C virus (HCV) infection must have been treated and cured. For subjects with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Testing is not required at screening unless mandated by local policy
• Ability of the subject to understand and comply with study procedures for the entire length of the study, as determined by the enrolling physician or protocol designee

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). Subjects 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. Patients 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. * Note: Subjects must have recovered from all radiation-related toxicities (to grade ≤ 1 or baseline), been successfully weaned off from corticosteroids for this purpose within 1 week prior to registration, and must not have had radiation pneumonitis
• Has symptomatic or uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
• 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. * Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted. * Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate. * Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate. * Brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or study treatment–related standard premedications are permitted
• Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis
• Active infection requiring systemic therapy within 7 days prior to registration
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• History of organ transplant, including allogeneic stem cell transplantation
• Known allergy or hypersensitivity to any component of retifanlimab or formulation components
• Subjects with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial
• Treatment with any investigational drug from a prior clinical trial within 28 days prior to registration
• Has received a live vaccine within 28 days before the planned start of study treatment. Examples of live vaccines include but are not limited to measles, mumps, rubella, varicellazoster (chickenpox), yellow fever, rabies, Bacille Calmette Guerin (BCG), and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines are live, attenuated vaccines and are not allowed