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. Serum or urine pregnancy test for women of childbearing potential 5. Free T4/TSH 10.8 Followup Period Visits (every 2 months +/- 14 days) Patients will be seen and evaluated by a physician every 2 months during the follow -up period. They will undergo standard of care serial imaging as per Section 10.5, blood work (CBC, CMP, Free T4/TSH), and a history and physical examination. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 37 of 51 11.1 TOXICITIES/SIDE EFFECTS Expected toxicities from SBRT are highly dependent on location of the radiated lesion. Some of these toxicities may include fatigue, dermatitis, pneumonitis, esophagitis, chest wall pain, nausea, vomiting. In very rare cases, patients may experience b r a c h i a l plexopathy, myelitis, bronchial damage, vascular damage, pericarditis, and/or hepatitis. Primary toxicities of concern include radiation pneumonitis. Grade 2 and 3 pulmonary toxicity may be observed in 10% and 3% of patients, respectively. Other grade 2 –4 toxicities included chest wall pain in 20%, fatigue in 15-20%, esophagitis in 5-10%, and skin toxicity in 5-10% of patients. Inferior thoracic lesions may have an increased risk of liver, bowel, and kidney injury. Possible short and long-term toxicities from avelumab include thyroid dysfunction requiring thyroid hormone replacement, adrenal crisis, liver function test abnormalities, pneumonitis, rash, diarrhea, and colitis. In a Phase 1b study of avelumab in patients with mesothelioma, treatment -related adverse events occurred in 41 of 53 patients (77.4%). The most common (>10%) were infusion- related reactions (20 [37.7%]), fatigue (8 [15.1%]), chills (8 [15.1%]), and pyrexia (6 [11.3%]), all of which were grades 1/2. Grade ≥ 3 treatment - related adverse events occurred in 4 patients (7.5%). This included colitis, decreased lymphocytes, and increased GGT or CPK. There were no treatment -related deaths. 11.2 Safety Monitoring Subjects will be evaluated for occurrence of AEs at each visit. Events will be characterized and reported as described below. Safety will also be monitored by performing physical exams and routine laboratory procedures. Extended safety follow- up: o Given the potential risk for delayed immune -related toxicities, safety follow- up must be performed up to 90 days after the last dose of avelumab administration. o The extended safety follow -up beyond 30 days after last study drug administration may be performed either via a site visit or via a telephone call with subsequent site visit requested in case any concerns noted during the telephone call. These visits are included in section 10.0 11.1.1 A d v e r s e Events and Serious Adverse Events Definitions of AEs, non-serious AEs, and serious adverse events (SAEs), as well as reporting guidelines are provided below. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 38 of 51 Definition of Adverse Event and Non-Serious Adverse Event The following definition of AE will be used for the study: “any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to medicinal (investigational) product.” This definition includes any abnormalities or anomalies that were not seen at baseline or which worsened during the course of the study, if present at baseline. A “non- serious” adverse event is any event that does not meet the definition of “serious adverse event” as presented, below. Reporting and Treating Non-Serious Events It is the responsibility of the investigator to perform regular assessments for AEs. Subjects willl be regularly queried about the occurrence of any AEs and w i l l be monitored throughout the study for reactions to study drug and/or study procedures. The investigator and clinical staff will record all AEs, whether volunteered by or elicited from the subject, at any time during a subject ’s participation in the study. Abnormal laboratory findings (e.g., hematology, comprehensive metabolic panel) or other abnormal assessments (e.g., vital signs) will be recorded as AEs if they are judged as clinically significant by the investigator. All subjects experiencing an AE will be evaluated by the investigator and monitored until resolution of the events or until the investigator deems the event clinically stable and/or at an acceptable level. Unless the event requires hospitalization (SAE), medical treatment will be provided to the subjects at the unit and treatment medication and/or medical procedures will be provided per the treating- investigator “s clinical discretion. All clinically significant AEs, including clinically significant laboratory abnormalities, will be followed until resolution. AEs meeting the definition of SAEs require special reporting in addition to documentation in the CRDB as described below. All AEs, including clinically significant laboratory and assessment abnormalities will be recorded according to “Common Terminology Criteria for Adverse Events” V4.0 (CTCAE) and must be recorded in the CRDB. Events occurring prior to initiation of first dose should be recorded on the Medical History page of the CRDB. Any AE occurring after initiation of first dose of study drug should be recorded on the Adverse Event page of the CRDB. AEs should be recorded in the CRDB using the medical terminology found in the source documentation. Whenever possible, diagnoses should be given when signs and s y m p t o m s are due to a common etiology. It is the investigator’s responsibility to provide his/her assessment of the relationship of the event to the study drug and the severity of the event using the following scales: • Relationship Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 39 of 51 o Unrelated: The AE is clearly attributable to a concurrent illness, concurrent medication, clinical state, or environmental factor other than the investigative agent. o Unlikely: The occurrence of the AE does not follow the study in a temporal sequence and/or based upon available subject information, e.g., medical history, disease process, known pharmacology of drug, a relationship between the drug and AE is u n l i k e l y . o Possible: The AE follows a reasonable temporal sequence from the time of study drug administration, but it is possible that other factors; e.g., subject ’s clinical state or concomitant mediations, environmental factors, or the drug’s pharmacology, may have caused the AE . o Probable: The AE follows a reasonable temporal sequence from the time of study drug administration, follows a known response pattern of the medication class, and cannot be reasonably explained by other fac tor s . o Definite: The AE follows a reasonable temporal sequence from the time of study drug administration, follows a known response pattern of the medication class, is a commonly associated AE, and is certainly explained by the study intervention. • Severity The severity of all adverse events should be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) V4.0. For those adverse events not listed in the CTCAE, the following grading system should be e m p l o y e d : o Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily tolerated and no interference with subject’s daily activities o Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with subject’s usual activities, but still acceptable o Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable interference with the subject’s daily activities, unac c eptab le o Life-threatening (CTCAE Grade 4): Life-threatening or disabling AE o Death (CTCAE Grade 5): Death- related AE. Definition of Serious Adverse Event The following definition of SAE applies for the study: “a serious AE means any AE occurring at any dose that results in any of the following outcomes: death, a life- threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, a congenital anomaly/birth defect, or overdose of study drug. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered a serious AE when, based upon appropriate medical judgment, they may jeopardize the subject, or the subject may require medical or surgical intervention to prevent one of the outcomes listed in this definition. A life-threatening AE is any AE that places the subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred (e.g., it does not include a reaction Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 40 of 51 that, had it occurred in a more severe form, might have caused death).” Refer to section 17.2 for “Reporting and Treating Serious Adverse Events.” Pregnancies Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 120 days of completing the trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All subjects and femalepartners of male subjects who becomepregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported within 5 calendar days to the MSKCC Safety Office and within 2 working days to Pfizer Safety (Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322, OR USA.AEReporting@pfizer.com specifying Protocol, Subject, Site/PI, and SAE/Onset). 12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT For the purposes of this study, patients will be evaluated for response every 2 months after completing SBRT (approximately 8 weeks, or every 4 cycles). Modified RECIST for mesothelioma and RECIST 1.1 criteria will be used [22]. CT scan of the chest, abdomen, and pelvis will be used for response assessment. The companion CT from an integrated PET/CT examination is suitable for this requirement. As part of the secondary endpoints, progression- free and overall survival will be recorded. Progression- free survival is defined as the length of time from the start of active treatment (avelumab) until removal from study due to progressive disease (defined by modified RECIST 1.1) or death. Removal from study due to toxicity will be counted as censoring. Overall survival is defined as the length of time from the start of active treatment until d e a t h . Modified RECIST for Mesothelioma [23, 24] The modified RECIST criteria for mesothelioma use unidimensional measurements of tumor thickness perpendicular to the chest wall or mediastinum. In our protocol, the irradiated lesion is not required to be intrathoracic. This is measured on CT scan in 2 sites at 3 different levels at least 1cm apart. At reassessment, the thickness must be measured at the same position and level. Exhaustive documentation of non-measurable lesions are not required. The sum of tumor diameters is used to measure response. Definitions of Overall Response Complete Response (CR) Disappearance of all target lesions who no evidence of tumor elsewhere. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 40 of 51 Version: 2/26/16 Partial Response (PR) At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) Response neither meeting the criteria of CR, PR or PD Progressive Disease (PD) At least a 20% increase in the sum of diameters of tumor measurements over the nadir measurement, or appearance of one or more new lesions. RECIST 1.1 Evaluation of target lesions Complete Response (CR) Disappearance of all target lesions Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Evaluation of non-target lesions Complete Response (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non- pathological in size (<10mm short axis). Non-CR/Non -PD Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) Unequivocal progression (see comments below) of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression). Time point response: patients with target (+/- non-target) disease Target lesions Non-target lesions New lesions Overall response CR CR No CR CR Non-CR/non -PD No PR CR Not evaluated No PR PR Non-PD or not all evaluated No PR SD Non-PD or not all evaluated No SD Not all evaluated Non-PD No NE Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 42 of 51 PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD NE = inevaluable 13.1 CRITERIAFOR REMOVAL FROM STUDY Patients should permanently discontinue treatment with avelumab for the reasons enumerated in Section 9 or in the event of: • Intolerable adverse events (e.g. CTCAE v4.0 grade 3 or 4) that cannot be managed by dose modification or delay • Further dose modification or delay considered necessary but not allowed per protocol section 9.4 • Pregnancy1 • Withdrawal of informed consent2 • If the treating physician determines that it is in the best interest of the patient to stop study drug • Non-compliance with the defined treatment plan Patients will be removed from study after treatment ends in the event of: • Death • Pregnancy1 • Withdrawal of informed consent2 • Non-compliance with the defined follow up studies 1Pregnancy: In case of a patient or the patient’s partner becoming pregnant during the trial the investigational drug has to be immediately stopped and the patients must be followed- up until birth or other termination of the pregnancy. Repeat counseling on birth defect risk must be offered. 2Consent withdrawal: in case a patient withdraws his/her consent for taking drug, it is of utmost importance for the robustness and integrity of the trial results that his/her safety data are recorded until the end of the 52 weeks period. Thus, all patients will be asked to follow their visit schedule until 52 weeks. Patients who discontinue from this trial are not allowed to be reenrolled in this trial. Patients who discontinue medication within the first two weeks (during the washout period) will be replaced. For the patients who stopped trial before enrollment, their data will be part of the description of the screening population. 14.0 BIOSTATISTICS Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 43 of 51 The primary endpoint, the safety of a combination of avelumab and SBRT, will be defined based on the rate of any grade 3 or higher non-hematologic toxicity within the first 3 months after SBRT (for the rest of the section this will be referred to as AE). A two-stage stopping rule will be used to protect patients‟ safety. If 3 or more among the first 13 patients develop AEs, then the trial will be stopped and declared unsafe. Otherwise, an additional 14 patients will be enrolled and treated. If, among the total 27 patients, 5 or more patients are observed to have AEs, then the trial will also be declared unsafe. This stopping rule has a power of 80% declaring the true AE rate of 0.1 or lower safe, and a type 1 error rate (alpha) of 5% declaring true AE rate of 0.3 or higher safe. For secondary endpoints, the overall response and the irradiated lesion and non-irradiated lesion response rates (4 months from start date of the combined therapy) based on RECIST 1.1 response criteria will be summarized by sample proportions and their confidence intervals. PFS and OS will be evaluated by Kaplan -Meier method. For the exploratory objectives, we will evaluate changes of T-cell infiltration and serum immunophenotype at baseline and after SBRT + immunotherapy both in- and outside the irradiated field. The former is measured as numerical values so we will use Wilcoxonsigned - rank test. The latter is categorical so we will tabulate it and employ the marginal homogeneity test. Due to the expected small sample size, results will be interpreted cautiously. The imaging studies using DWI-MRI and DCE- MRI, and FDG-PET will be correlated with biopsy results by McNemar ’s tests . 15.1 RESEA RCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 15.2 Research Participant Registration Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. Obtain informed consent, by following procedures defined in section entitled Informed Consent Procedures. During the registration process registering individuals will be required to complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether or not the participant is eligible to enroll in the study. Study staff are responsible for ensuring that all institutional requirements necessary to enroll a participant to the study have been completed. All participants must be registered through the Clinical Trials Management System (CTMS) at Memorial Sloan -Kettering Cancer Center. The completed signature page of the written consent/verbal script and a completed Eligibility Checklist and other relevant documents must be uploaded to CTMS. See related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 15.3 Randomization Not applicable in this study. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 44 of 51 16.1 DAT A M ANAGEMENT ISSUES A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities of the CRC include project compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study team. The data collected for this study will be entered into a secured database (Medidata Rave) at Memorial Sloan -Kettering Cancer Center. Source documentation will be available to support the computerized patient record. 16.2 Quality Assurance Routine data quality reports will be generated to assess missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow -up will be monitored periodically throughout the study period and potential problems will be brought to the attention of the study team for discussion and action. Random -sample data quality and protocol compliance audits may be conducted by the study team, at a minimum of two times per year, or more frequently if i n d i c a t e d . 16.3 Data and Safety Monitoring The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM Plan where applicable. The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by the National Cancer Institute in August 2018. The plans address the new policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials. ” There are several different mechanisms by which clinical studies are monitored for data safety and quality. At a departmental/PI level, there exist procedures for quality control by the research team(s). Institutional processes in place for quality assurance include protocol monitoring, complianceand data verification audits, staff education on clinical research QA, and two institutional committees that are responsible for monitoring the activities of our clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Deputy Physician -in-Chief of Clinical Research. The degree of monitoring required will be determined based on level of risk and documented. The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials. The DSMB/C have oversight over the following trials: · MSK Investigator -Initiated Trials (IITs; MSK as sponsor) · External studies where MSK is the data coordinating center Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 45 of 51 · Low risk studies identified as requiring DSMB/C review The DSMC will initiate review following the enrollment of the first participant, or by the end of the year one if no accruals, and will continue for the study lifecycle until there are no participants under active therapy and the protocol has closed to accrual. The DSMB will initiate review once the protocol is open to accrual. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 46 of 51 17.1 PROTECTION OF HUMAN SUBJECTS Participation in this trial is voluntary. All patients will be required to sign a statement of informed consent, which must conform to IRB guidelines. Inclusion of Women and Minorities: Memorial Sloan -Kettering Cancer Center has filed forms HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 680 (age discrimination); we also take due notice of the NIH policy concerning inclusion of women and minorities in clinical research populations. Patients of all races, both male and female, will be accepted into the protocol.