*Local guidelines, or e.g. ESC guidelines (https:/ /www.escardio.org/Guidelines/Clinica l - Practice -Guidelines) or AHA guidelines (http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t= 1001) Renal ir AEs Grade of Creatinine Increased (NCI-CTCAE v4) Management Follow -up Grade 1 Creatinine increased > ULN to 1.5 x ULN Continue avelumab therapy Continue renal function monitoring If worsens: Treat as Grade 2 to 3 or 4. Grade 2 to 3 Creatinine increased > 1.5 and ≤ 6 x ULN Withhold avelumab therapy Increase frequencyof monitoring to every 3 days 1.0 to 2.0 mg/kg/day prednisone or equivalent. Add prophylactic antibiotics for opportunistic infections Consider renal biopsy If returns to Grade ≤1: Taper steroids over at least 1 month, and resume avelumab therapy following steroids taper. If worsens: Treat as Grade 4. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 31 of 51 Grade 4 Creatinine increased > 6 x ULN Permanentlydiscontinue avelumab therapy Monitor creatinine daily 1.0 to 2.0 mg/kg/day prednisone or equivalent. Add prophylactic antibiotics for opportunistic infections Consider renal biopsy Nephrologyconsult f returns to Grade ≤1: Taper steroids over at least 1 month. Other irAEs (not described above) Grade of other ir AEs (NCI-CTCAE v4) Management Follow -up Grade 2 or Grade 3 clinical signs or symptoms suggestive of a potential irAE Withhold avelumab therapy pending clinical investigation If irAE is ruled out, manage as appropriate according to the diagnosis and consider re-starting avelumab therapy If irAE is confirmed, treat as Grade 2 or 3 irAE. Grade 2 irAE or first occurrence of Grade 3 irAE Withhold avelumab therapy 1.0 to 2.0 mg/kg/day prednisone or equivalent Add prophylactic antibiotics for opportunistic infections Specialty consult as appropriate If improves to Grade ≤ 1: Taper steroids over at least 1 month and resume avelumab therapy following steroids taper. Recurrence of same Grade 3 irAEs Permanentlydiscontinue avelumab therapy 1.0 to 2.0 mg/kg/day prednisone or equivalent Add prophylactic antibiotics for opportunistic infections Specialty consult as appropriate If improves to Grade ≤ 1: Taper steroids over at least 1 month. Grade 4 Permanentlydiscontinue avelumab therapy 1.0 to 2.0 mg/kg/day prednisone or equivalent and/or other immunosuppressant as needed Add prophylactic antibiotics for opportunistic infections Specialty consult. If improves to Grade ≤ 1: Taper steroids over at least 1 month Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks for reasons other than hormonal replacement for adrenal insufficiency Persistent Grade 2 or 3 irAE lasting 12 weeks or longer Permanentlydiscontinue avelumab therapy Specialty consult Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 32 of 51 Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B -type natriuretic peptide; CK-MB=creatine kinase MB; CT= computed tomography; FSH=follicle -stimulating hormone; GH=growth hormone; IGF-1=insulin -like growth factor 1; irAE=immune -related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute -Common TerminologyCriteria for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid -stimulating hormone; ULN=upper limit of normal. 9.6 Management of Radiation Side Effects Toxicities related to SBRT will be managed according to institutional supportive care guidelines. 10.1 EVALUATION DURING TREATMENT/INTERVENTION A calendar is presented below. Further explanation of each visit is provided after the table. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 33 of 51 Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 34 of 51 Study Calendar Visit Screening 1 2 3 4 5 6 7 8 9 10 11- EOT End of Treatment Visit6 Treatment C1 C2 SBRT5 C3/2 Wks Post - SBRT C4 C5 C6 C7 C8/2M Post- SBRT C9 to EOT Days (approx.) -45 1 15 29 43 57 71 85 99 113 Week of Treatment 1 3 5 7 9 11 13 15 17 19 – EOT 30 days and 90 days after last Avelumab Visit Window -45 days +/- 3 days +/- 7 days +/- 7 days +/- 3 days +/- 3 days +/- 3 days +/- 3 days +/- 7 days +/- 3 days +/- 14 days Informed Consent, Demographics X Medical History, Physical Examination1 X X X X X X X X X X (Every Cycle) X Recording of Adverse Events X X X X X X X X X (Every Cycle) X FDG-PET Scan X X (Prior to biopsy) CT chest, abdomen, pelvis2 X X X X (q2 months post SBRT into follow - up period) DW/DCE – MR (unless contraindicated) X X (Prior to biopsy) 12-lead EKG X Serum or urine pregnancy test3 X X CBC, CMP X X X X X X X X X X X Free T4/TSH X X X X8 X Serology4 X Research Blood Tests X X X X Tumor Biopsies X9 X 1 Including height, weight, vital signs (temperature, pulse rate, respiration rate, blood pressure), and performance status (Karnofsky). Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 35 of 51 2 Pref erably with contrast. The companion CT scan from the FDG -PET scan may fulfill this requirement. 3 For all women of childbearing potential (serum pregnancy test within two weeks or urine pregnancy test within 24 hours of starting avelumab) 4 HepBsAg, HepBcAb and hepatitis C antibody (negative test acceptable prior to screening period) within 30 days prior to starting a v e l u m a b . 5 Patient simulated for radiation treatment no later than 20 days after Cycle 1, Day 1. 6 90 Day Short -term Follow- up Visit can be conducted over the phone by a RN, NP, or MD. If any concern arises, the patient will be called in for a follow- up visit within 5 calendar days for appropriate assessments (as per the investigator ’s medical judgment). 7 The research blood test should occur within 3 days prior to Avelumab Administration. 8 Free T4/TSH will be performed at cycle 12 and every 4 cycles until EOT. 9 Standard of Care biopsy, for irradiated lesion and non-irradiated lesion. Biopsy will collect 4 cores, 1 core will be treated with formalin, will be sent to pathology and the remaining 3 cores will be fresh frozen and sent for research, per lesion. 10.2 Pre-Treatment As Per Section 8.0 10.3 At Every Cycle (+/- 3 days) 1. History and physical examination, including height, weight, vital signs (temperature, pulse rate, respiration rate, blood pressure), and performance status ( Karnofsky) 2. Report side effects 3. CBC with differential and platelet count, CMP (including Na, Cl, BUN, Creatinine, K, CO2, glucose, AST, ALT, alkaline phosphatase, total bilirubin, calcium, albumin, and total protein) 4. Treatment with avelumab 5. Free T4/TSH (every 4 cycles) 10.4 Two weeks after Irradiation (+/- 7 days) 1. Repeat biopsy of initially biopsied irradiated lesion and the unirradiated lesion (biopsy to be core needle biopsy up to 4 cores, preferably 18-gauge or larger, specified prior to biopsy, permanently fixed, managed by CSP Correlative Science Program) 2. FDG-PET scan (must be completed prior to biopsy) 3. DW/DCE-MRI with contrast of the lesion to irradiated (must be completed prior to biopsy) as described in Section 8.0 to be completed in the MSKCC Department of Radiation Oncology. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 36 of 51 4. Research blood tests 10.5 Research Blood Tests Baseline, at cycle 2s of avelumab, at cycle 3, and 2 months after completing irradiation. Specimens should be collected prior to drug administration. Four (4) tubes of blood are to be collected in BD Vacutainer® CPT™ Cell Preparation Tubes with Sodium Heparin. Each tube should contain approximately 10 cc of blood. Tubes will be processed as follows: 1) Tubes will be inverted several times immediately after collection. For serum tubes, blood will be allowed to clot for 30 minutes in a tube rack 2) Adhesive labels identifying patient ID, MRN, and date of collection must be attached to each tube 3) Time and date will be completed on the requisition form 4) All collected tubes and forms are placed in a biohazard Ziplock bag at room temperature with protective padding 5) Specimens are sent and p r o c e s s i n g will be performed according to institutional practice in the Immune Monitoring Facility (IMF). 10.6 Serial Imaging CT of the chest, abdomen, and pelvis, preferably with contrast, will be performed every 2 months after completing SBRT (+/- 14 days) through the follow -up period. 10.7 End of treatment visits at 30 and 90 days after last avelumab (+/-14 days) 1. History and physical examination, including height, weight, vital signs (temperature, pulse rate, respiration rate, blood pressure), and performance status ( Karnofsky) 2.