TPS9592 Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive human skin cancer often caused by the Merkel cell polyomavirus or extended exposure to sunlight. Since the approvals of avelumab globally and subsequently pembrolizumab (US only), anti–PD–(L)1 antibody therapies have become the standard of care for advanced/metastatic MCC patients in recent years. Still, a significant proportion of MCC patients do not respond to or relapse on anti–PD–(L)1 antibody monotherapy. Recent preclinical data suggest that the small molecule, selective class I histone deacetylase inhibitor (HDACi) domatinostat can overcome critical mechanisms of MCC resistance to checkpoint inhibitors. These escape mechanisms include the epigenetic downregulation of the antigen processing and presentation machinery, hence treatment with domatinostat is thought to favorably modulate the tumor environment allowing a reintroduction of anti–PD–(L)1 therapy for an improved and sustained clinical benefit. Methods: The study is a phase II, multicenter, single arm clinical trial of the orally administered HDACi domatinostat in combination with the anti–PD–(L)1 antibody avelumab for patients with advanced unresectable/metastatic MCC that are progressing on previous anti–PD–(L)1 therapy. ClinicalTrials.gov Identifier: NCT04393753. Key Inclusion Criteria are: histologically confirmed MCC, an ECOG performance status ≤ 1, MCC in an advanced, unresectable stage III or metastatic stage IV, and progressing on previous anti–PD–(L)1 antibody monotherapy within the last 12 weeks before planned first administration of study medication. Key Exclusion Criteria are: history of serious anti–PD–(L)1 therapy related adverse reactions prohibiting further avelumab treatment, more than one line of previous systemic anti neoplastic therapy other than anti–PD–(L)1 antibody monotherapy (excluded: palliative radiation therapy of single lesions within 2 weeks before planned administration of study medication), significant active or chronic disease (infections, immunodeficiencies, cardiovascular, psychiatric disorders). A total of 40 patients will be enrolled in up to 46 clinical study sites in Europe and USA. Anti-tumor activity will be primarily assessed by the objective response rate according to RECIST v1.1 as an exploratory analysis. Secondary objectives include additional efficacy assessments, safety, quality of life and pharmacokinetics of domatinostat in combination with avelumab. Correlative aims include evaluating biomarkers for association with clinical benefit. The first patient was enrolled on Oct. 16, 2020, 21 of 46 clinical sites are active and 4 out of 40 planned patients have been enrolled as of Feb. 15, 2021. Clinical trial information: NCT04393753.