10 3.2 Malignant Mesothelioma .............................................................................................................. 10 3.3 Clinical Data on Immunotherapy and Mesothelioma ................................................................ 10 3.4 Preclinical and Clinical Data on Radiation Therapy and Immunotherapy ............................ 12 3.5 Avelumab ................................................................................................................................. 12 3.6 SBRT ............................................................................................................................. 13 3.7 Rationale for Study Design ................................................................................................ 14 4.1 OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................... 14 4.2 Design ................................................................................................................................ 14 4.3 Intervention .................................................................................................................................... 14 4.4 Estimated Duration of Subject Participation ........................................................................... 15 5.1 THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 15 5.2 SBRT ............................................................................................................................. 15 5.3 Avelumab ................................................................................................................................. 15 6.1 CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................... 16 6.2 Subject Inclusion Criteria ......................................................................................................... 16 6.3 Subject Exclusion Criteria ....................................................................................................... 16 7.0 RECRUITMENT PLAN ....................................................................................................... 18 8.0 PRETREATMENT EVALUATION ...................................................................................... 19 9.1 TREATMENT/INTERVENTION PLAN ............................................................................... 19 9.2 Dosing Instructions and Schedule .......................................................................................... 20 9.2.1 Avelumab Dosing Instructions and Schedule ................................................................. 20 9.2.2 SBRT Dosing Instructions and Schedule ........................................................................ 20 9.3 Monitoring of Dose Administration .............................................................................................. 21 9.4 Concomitant Medications ................................................................................................................. 22 9.4.1 Permitted Concomitant Medications ...................................................................................... 22 9.4.2 Excluded Concomitant Medications ................................................................................... 22 9.5 Dose Modification and Discontinuation .................................................................................. 22 9.5.1 Adverse Drug Reactions (ADRs) Requiring Avelumab Discontinuation or Dose Modification ............................................................................................................................................ 22 Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 6 of 51 9.5.2 Treatment Modification for Symptoms of Infusion- Related Reactions ............................. 24 9.6 Management of Avelumab Immune -Related Adverse Events ................................................... 25 9.7 Management of Radiation Side Effects ................................................................................... 32 10.1 EVALUATION DURING TREATMENT/INTERVENTION ...................................................... 32 A calendar is presented below. Further explanation of each visit is provided after the table .......... 32 10.2 Pre-Treatment ...................................................................................................................... 34 10.3 At Every Cycle (+/- 3 days) .............................................................................................. 34 10.4 Two weeks after Irradiation (+/- 7 days) ............................................................................ 34 10.5 Research Blood Tests .............................................................................................................. 35 10.6 Serial Imaging ........................................................................................................................... 35 10.7 End of treatment visits at 30 and 90 days after last avelumab (+/-14 days) ...................... 35 11.1 TOXICITIES/SIDE EFFECTS ......................................................................................................... 36 11.2 Safety Monitoring ............................................................................................................................. 36 11.1.1 Adverse Events and Serious Adverse Events ....................................................................... 36 12.0 CRITERIAFOR THERAPEUTIC RESPONSE/OUTCOME ASSESS MENT........................... 39 13.0 CRITERIA FOR REMOVAL FROM STUDY .................................................................................. 42 14.0 BIOSTATISTICS ............................................................................................................... 42 15.1 RESEA RCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 43 15.2 Research Participant Registration ........................................................................................... 43 15.3 Randomization ......................................................................................................................... 44 16.1 DAT AM ANAGEMENT ISSUES ......................................................................................... 44 16.2 Quality Assurance ............................................................................................................... 44 16.3 Data and Safety Monitoring ......................................................................................................... 44 17.1 PROTECTION OF HUMAN SUBJECTS .................................................................................... 46 17.2 Privacy ................................................................................................................................ 46 17.3 Serious Adverse Event (SAE) Reporting ................................................................................. 47 17.2.1 S A E Reporting to Study Sponsor / Drug Supplier ............................................................ 48 18.0 INFORMED CONSENT PROCEDURES ........................................................................................ 49 19.0 REFERENCES .................................................................................................................................