Clinical Trial Finder

Inclusion Criteria:

• - Biopsy proven Merkel cell carcinoma which is unresectable or metastatic, stage III or IV.

• - Prior first-line treatment with aPD1 monotherapy (defined as at least one dose of pembrolizumab, avelumab, nivolumab, etc.) with evidence of progression of disease ≥10 weeks after starting therapy, in the absence of significant clinical deterioration.

• - Patients with clinical deterioration during aPD1 monotherapy are eligible ≥6 weeks after starting aPD1 therapy.

• - Criteria for clinical deterioration to be determined and agreed upon by treating physician and Principal Investigator.

• - All detectable sites of MCC are amenable to comprehensive ablative radiation therapy in opinion of treating radiation oncologist and principal investigator.

• - ≥18 years of age.

• - Performance status ≤2 on the Eastern Cooperative Oncology Group Performance Scale.

• - Able to provide valid written informed consent.

• - Normal organ and marrow function.

• - Hematologic: Lymphocyte count ≥800/mm^3, neutrophil count ≥1500/mm^3, platelet count ≥75,000/mm^3, leukocyte count ≥3000/mm^3, hemoglobin ≥9 g/dL.

• - Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal, unless Gilbert's syndrome; aspartate transaminase and alanine transaminase ≤ 2.5 times the upper limit of normal (in the absence of hepatobiliary metastases); ≤ 3.0 times the upper limit of normal (in the presence of hepatobiliary metastases) - Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula.

Exclusion Criteria:

• - Prior systemic therapy for MCC other than first-line aPD1 monotherapy (ie, chemotherapy) - Pregnancy or breastfeeding.

• - Adverse events due to prior cancer therapy which are grade 3 or higher and have not resolved.

°Patients with prior grade 3 or higher immune related adverse events are not eligible, even if they have resolved.

• - Prior severe hypersensitivity reaction (CTCAE version 5.0 grade ≥3) to avelumab.

• - Prior radiotherapy which precludes the ability to safely deliver comprehensive ablative radiation therapy in the opinion of the treating radiation oncologist and principal investigator.

°Institutional guidelines for reirradiation will be used when making this determination.

• - Known central nervous system metastases.

• - Known clinically significant cardiovascular disease, defined as: - Stroke or myocardial infarction within 6 months of first dose of avelumab.

• - Symptomatic congestive heart failure (New York Heart Association Class 2 or higher) - Serious arrhythmia requiring anti-arrhythmic agents.

• - Known Human Immunodeficiency Virus infection.

• - Known Hepatitis B or C infection requiring ongoing treatment.

• - Vaccination within 4 weeks of first dose of avelumab.

°Inactivated vaccines are permissible.

• - Iatrogenic immunosuppression with daily systemic corticosteroid equivalent of >10 mg of prednisone.

• - Active autoimmune disease that may cause clinical deterioration during immunotherapy.

°Including, but not limited to:

• - Inflammatory bowel disease or immune colitis.

• - Immune mediated pneumonitis or pulmonary fibrosis.

• - History of solid organ or hematopoietic transplant.

• - Active infection requiring systemic therapy.

• - Active suicidal ideation or behavior.

• - Comorbid or diagnostic abnormalities which would interfere with interpretation of study results.

- Known hematopoietic cancer or dysfunction (i.e., leukemia, lymphoma) - Known non-MCC solid tumor with known metastasis or estimated risk of metastasis >20% within 3 months

Arms

Experimental: Avelumab and Radiation Therapy

Will receive avelumab at the FDA approved dose and schedule of 800 mg IV over 60 minutes every 2 weeks (+/- 3 days) until treatment intolerance or disease progression occurs or 2 years of study therapy have been administered; standard of care Avelumab therapy after 2 years is permitted. Comprehensive Ablative Radiation Therapy (CART) will be initiated between the first and second dose of Avelumab. Comprehensive ablative radiation therapy will be given according to guidelines.

Interventions

Drug: - Avelumab

Avelumab 800 mg given intravenously over 60 minutes every 2 weeks (+/- 3 days)

Radiation: - Comprehensive Ablative Radiation Therapy

Comprehensive ablative radiation therapy 24 Gy in 3 fractions every 2-3 days