2. Continuous oxygen use 3. Known history of active TB (Tuberculosis), HIV, and/or Hepatitis B/C 4. Hypersensitivity to avelumab or any of its exci pients 5. Prior monoclonal antibody treatment within 4 weeks prior to study Day 1 or has not recovered (i.e., ≥ Grade 1 at baseline) from adverse events due to agents administered > 4 weeks e a r l i e r . 6. Prior chemotherapy, targeted small molecule therapy, within 4 weeks prior to study Day 1 or has not recovered (i.e., ≥ Grade 1 at baseline) from adverse events due to a previously administered agent (excluding Grade 2 neuropathy). 7. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti- CD137, or anti-Cytotoxic T-lymphocyte- associated antigen -4 (CTLA -4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) within 4 weeks prior to study Day 1 or has not recovered (i.e., ≥ Grade 1 at baseline) from adverse events due to a previously administered agent Study Drug Avelumab; 10mg/kg delivered by IV infusion Study Design This clinical trial will be designed as a single -arm, single -institution safety study at Memorial Sloan Kettering Cancer Center Main Campus and Regional Sites. The main objective is to evaluate the safety of a novel combination of avelumab (anti-PD-L1 mAb) and stereotactic body radiation therapy (SBRT) for advanced malignant pleural and peritoneal mesothelioma (MPM). The treatment will consist of one dose of avelumab every other week as well as a short course of SBRT after the first two doses of avelumab. Avelumab will be continued up to 24 months or until disease progression. To further enhance our current understanding of tumor immunology as well as prognostic biomarkers, we will collect peripheral serum samples before, during and after treatment, and tumor biopsies of the irradiated and an unirradiated lesion (if available) before and after radiation. The safety endpoint of the trial will be assessed based on grade 3 or higher non-hematologic toxicity. We hypothesize that the combination of immunotherapy and SBRT will be safe and well tolerated. Furthermore, we believe that this combination therapy will lead to an increase in tumor -specific T- cells and neoantigen diversity along with a higher T-cell infiltration of irradiated and unirradiated tumor lesions and objective overall responses in lesions both in and outside the radiation field. Accrual is estimated to be 1 patient per month. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 10 of 51 Version: 2/26/16 2.1 OBJECTIVES AND SCIENTIFIC AIMS • The primary objective of this study is to evaluate the safety of avelumab plus SBRT. This study is designed to include both pleural and peritoneal mesothelioma. • The secondary objectives are to assess: o Overall response rate (ORR) using modified RECIST for mesothelioma treated with SBRT and avelumab. o Response of irradiated (in-field) and unirradiated (out-of-field) lesions defined by RECIST 1.1 for extrathoracic disease o Progression- free and overall survival • Exploratory objectives are to evaluate T-cell infiltration and phenotype both in- and outside the irradiated field, serum immune phenotype before and after avelumab plus SBRT, and correlate imaging response (DW/DCE-MRI and PET) with biopsy sample results. 3.0 BACKGROUND AND RATIONALE 3.1 Malignant Mesothelioma Malignan t pleural/peritoneal mesothelioma (MPM) is a cancer commonly associatedwith prior asbestos exposure. The simian virus 40 (SV40) has also been discussed as a potential carcinogen [3, 4] as around 25% of MPM patients have no known asbestos exposure. Pleural mesothelioma, affecting the lining of the lungs, accounts for about 75- 80% of all cases while the peritoneal type, found in the abdomen, is present in 10-15% of mesothelioma patients. While the US incidence appears steady at 3,000 new diagnoses per year, the incidence of mesothelioma continues to increase globally and in some regions is epidemic.[5, 6] MPM is often unresectable at diagnosis and the mean overall survival is only 8-13 months.[7] MPM is almost universally lethal and therapeutic advances have largely plateaued over the past decade. Even with resectable disease, traditional treatments, including multimodality therapy, have a limited and transient impact on the disease. Local recurrences are quite common and cause tremendous morbidity for patients.[8] As there are no FDA-approved therapies for second-line treatment of MPM, an unmet need persists and the bar for therapeutic efficacy in this setting is low. 3.2 Clinical Data on Immunotherapy and Mesothelioma The recent emergence of immunotherapy in cancer provides a new avenue for therapy in MPM. T-cell checkpoint inhibitors like anti-PD-1/anti-PD-L1 and anti-CTLA-4 have shown durable activity and prolonged disease stabilization in solid tumors like melanoma, NSCLC and colorectal cancer even after treatment cessation.[9, 10] Although anti-PD-1 treatment alone is currently being studied (clinicaltrials.gov NCT02399371) and has shown impressive preliminary results,[11] our proposal to combine PD-1 inhibition with radiation Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 11 of 51 therapy is a novel approach in MPM. There is already high-quality emerging evidence of activity of immunotherapy in MPM. Kindler et al. reported on anti-CTLA- 4 therapy as second- or third-line treatment of unresectable MPM at ASCO 2016. There was previous activity of tremelimumab shown in pre- treated MPM patients (Calabro et al., Lancet Oncology 2013). These were the results of the double- blind, placebocontrolled DETERMINE study. Patients whoprogressed after 1 or 2 lines of prior therapy were randomized 2:1 to 10mg/kg q4 weeks for 7 doses, then q12 weeks to tremelimumab versus placebo. The primary endpoint was overall survival. 572 total patients were randomized, stratified by EORTC status, line of therapy, and anatomic site. There was no statistically significant difference in overall survival (median 7.7 vs 7.3 months, p=0.408). Anti-PD-1/PD -L1 agents have shown some significant promise. At the 2015 AACR, Alley et al. presented the mesothelioma results of the KEYNOTE- 028 trial, a non-randomized multi- cohort phase IB study of pembrolizumab for PD-L1 positive solid advanced tumors. In this cohort of 38 patients (out of 84 screened), each had > 1% PD-L1 expression in tumor cells or PD-L1-positive stromal bands. The primary endpoint was safety, tolerability, and preliminary efficacy. 88% had received at least one line of prior therapy, most of which was a platinum - based agent in combination with pemetrexed. Treatment was pembrolizumab 10mg/kg every 2 weeks for up to 2 years, or until confirmed progression of disease. 60% of patients experienced a drug- related adverse event, although only 12% (3 patients) experienced grade 3 or higher toxicity. No patients discontinued therapy due to drug- related events. There was a 76% disease control rate, which was remarkable (24% overall response rate, with 52% stable disease). Given this significant response rate and potential for additional improvement, the role of immunotherapy, particularly with PD-L1 inhibitors is certainly warranted. Data on safety and early efficacy information on avelumab in mesothelioma were first presented at the ASCO 2016 Annual Meeting by Hassan et al. 53 patients with unresectable pleural or peritoneal mesothelioma were recruited. These patients had progressed after a platinum -pemetrexed -containing regimen and were unselected for PD- L1 expression. They were treated with avelumab 10 mg/kg IV every 2 weeks until progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST 1.1). Patients were followed for a median of 46 weeks. The overall response rate was 9.4% (5 partial responses; 95% CI: 3.1, 20.7) and an additional 4 were ongoing. Stable disease was observed in 25 patients (47.2%). This yielded a disease control rate of 56.6%. Median progression- free survival was 17.1 weeks (95% CI: 6.1, 30.1), and PFS rate at 24 weeks was 38.4% (95% CI: 23.3, 53.4). 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. These data indicate that avelumab has a reasonable toxicity profile and favorable activity in a PD-L1 unselected population. We note that this study was in an unselected cohort of patients. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 12 of 51 Additionally, Calabro et al. are studying a combination of tremelimumab and durvalumab, an anti-PDL1 agent, in patients with MPM in the NIBIT -MESO -1 study, introduced at ASCO 2016. 3.3 Preclinical and Clinical Data on Radiation Therapy and Immunotherapy Radiation therapy, in addition to being highly effective in local tumor control, has been observed to show anti-tumor effects in non-irradiated sites when combined with immunotherapy, first described in MSKCC‟s department of radiation oncology.[12] The mechanisms of this so called “abscopal effect” have yet to be fully e x p l a i n e d . Nevertheless, a growing body of evidence suggests that the effect can be attributed to antigen exposure by the cells killed by ionizing radiation, leading to an activation of the immune system through an enhanced repertoire of T-cell receptors (TCRs) in tumor infiltrating lymphocytes (TILs)[13, 14] and to an induc tionof proinflammatory cytokines.[15] Results from both preclinical and clinical trials highlight the potential synergy of radiation and immunotherapy. In a proof -of principle trial, 41 patients with solid tumors received chemoradiation for two sites of disease as well as GM-CSF (granulocyte- macrophage colony stimulating factor) injections. Of those patients, 26.8% (11) showed objective responses in a third, untreated lesion.[1] Interleukin- 2 (IL-2)-based immunotherapy has been used as a treatment for melanoma and renal cancer for many years. Its historical response rate of 16% in melanoma has however been significantly improved to 71% (CI = 95%, 29-96%) by combining it with stereotactic body radiation therapy ( SBRT).[16] There are no results yet for clinical trials evaluating combined RT and anti PD-L1 therapy, but RT and anti-CTLA4 treatment has been tested in patients with melanoma and other cancers. Unirradiated lesions showed partial response and stable disease (each in 18% of patients) for a group of 22 melanoma patients treated with ipilimumab (CTLA -4 inhibitor) and RT to an index target.[14] Consequent mouse trials revealed that a partial immunity against RT and anti-CTLA- 4 had developed after the treatment and that this phenomenon could be evaded by inhibiting PD-L1 or PD-1.[14] Survival in mice with GL261 gliomas was significantly higher after treatment with RT and anti-PD-1 compared to the control, RT only and anti-PD-1 only groups (p<.001, median survival 52, 26, 27 and 30 days respectively).[17] In a phase I/II study of patients with metastatic castrate -resistant prostate cancer, the combination of ipilimumab (anti-CTLA -4) and RT showed promising tumor response results and a manageable toxicity profile.[18] 3.4 Avelumab Avelumab (initially known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to engage the innate immune system and may induce antibody - dependent cell-mediated cytotoxicity (ADCC). Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 13 of 51 Preclinical data are extensive in the potency of avelumab. Avelumab has the ability to lyse a range of human tumor cells in the presence of peripheral blood mononuclear cells (PBMC) or natural killer (NK) effectors. IFN-γ is able to enhanc etumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis. Purified NK cells are potent effectors for avelumab. Finally, similar levels of avelumab -mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients.[19] Avelumab was found to have significant activity in a preclinical model of bladder cancer. MB49 murine tumor cells formed multifocal, superficial tumors on the mucosal wall of the bladder, similar to human transitional cell bladder tumors. Administration of avelumab resulted in antitumor effects and subsequently improved overall survival. Both were abrogated by selective in vivo depletion of CD4 or CD8 T cells. These findings suggest that in this murine bladder tumor model, interruption of the immune suppressive PD-1/PD - L1 complex using avelumab releases an adaptive immune response that significantly reduces tumor growth.[20] Given the existing data on anti-solid tumor effectiveness of blocking PD 1/PD -L1 interaction, avelumab was rapidly translated into clinical trials under the JAVELIN clinical trial program. An umbrella study, JAVELIN Solid Tumor (Online, available https://clinicaltrials.gov/ct2/show/NCT01772004 ), sought to evaluate safety and efficacy of avelumab in metastatic and locally advanced solid malignancies. 3.5 SBRT Stereotactic body radiotherapy (SBRT) represents a significant innovation in clinical radiation oncology. [21] SBRT allows the delivery of ablative radiation with relative sparing of high- dose to normal tissue. SBRT has been extensively studied in lung, pancreas, liver, and prostate cancers, and has also been used to ablate bone metastases. Local control exceeds 90% in spine and lung lesions. In palliation of previously irradiated or radioresistant bone metastases, SBRT can provide durable pain control. SBRT offers an excellent treatment for local management of metastatic or progressive lesions. SBRT is already offered in the routine management of early stage inoperable non-small cell lung cancers and associated with high local control and low t o x i c i t y . MSKCC already has extensive experience treating MPM with radiation. Rimner et al. treated 67 patients with definitive or adjuvant pleural intensity -modulated radiation therapy.[8] Actuarial in-field failure rates at 1- and 2-years was 56% and 74% respectively. Distant failures occurred in 48% of patients. The predominant form of failure was local in- field failures, suggesting that dose- escalated radiation, as offered by SBRT, may improve local control without increasing dose -limiting lung toxicity. In addition, a significant number of patients had distant failures, suggesting there is a significant opportunity to improve systemic therapy. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 14 of 51 3.6 Rationale for Study Design In this context of promising preclinical and clinical results, compelling evidence supports our proposal to study treatment of stage IV malignant mesothelioma with combination anti- PD- L1 and SBRT. With this trial we will accomplish several things: 1) determine the overall response rate of combining checkpoint inhibition with radiation therapy with additional information on local control of both targeted and non-targeted disease; 2) confirm the safety of combined radiation therapy and anti-PD-L1 therapy; 3) determine the role of biomarkers to predict response to this type of therapy; and 4) expand our understanding of the mechanism of the abscopal effect. Since it is challenging to fully treat the diffuse pleural disease involved with MPM with local therapies, MPM is an excellent disease in which to study and answer these questions. If effective, this paradigm has thepotentialtotransform thestandard treatment of unresectable MPM. Furthermore, by examining a variety of biomarkers we will greatly expand the currently limited knowledge of predictive and influential biological factors in radiation and immunotherapy to support the optimization of individualized cancer care. 4.1 OVERVIEW OF STUDY DESIGN/INTERVENTION 4.2 Design This is a single -arm, two-stage study that will be conducted at Memorial Sloan Kettering Cancer Center Main Campus and regional sites. 13 patients will be accrued in the first stage and, if proven sufficiently safe, an additional 14 patients will be accrued in a second stage. 4.3 Intervention The main objective is to evaluate the safety of a novel combination of avelumab (anti-PD- L1 mAb) and stereotactic body radiation therapy (SBRT) for end-stage malignant pleural and peritoneal mesothelioma (MPM). The safety endpoint of the trial will be assessed based on grade 3 or higher non- hematologic toxicity. One cycle of avelumab is defined as two weeks. The treatment will consist of one dose of avelumab every other week (Q2W) as well as a short course of SBRT after the first two doses of avelumab. Patients will receive avelumab 10mg/kg as an IV infusion every 2 weeks. Avelumab will be continued up to 24 months or until disease progression. Patients may continue Avelumab after RECIST -defined radiologic progression of disease if the following criteria are met: absence of clinical symptoms or signs indicating clinically significant disease progression; no decline in performance status; absence of rapid disease progression or threat to vital organs or critical anatomical sites [e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord compression] Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 15 of 51 requiring urgent alternative medical intervention; no significant, unacceptable or irreversible toxicities related to study treatment. Patients will be treated with SBRT according to standard image- guided radiation treatment procedures. Patients willhavea CT simulation (including 4DCT scanning if clinically indicated) with 2mm slice thickness and daily cone- beam CT verification of patient setup and tumor position. Patients will be treated in < 8 fractions. To further enhance our current understanding of tumor immunology as well as prognostic biomarkers, we will collect peripheral serum samples before, during and after treatment, and tumor biopsies. 4.4 Estimated Duration of Subject Participation Subjects may be treated with avelumab for up to 24 months. All subjects will be followed for survival and assessed every 2 months as per Section 10 for up to 1 year following completion of avelumab or disease progression unless the Principal Investigator or Pfizer elects to end the study. 5.1 THERAPEUTIC/DIAGNOSTIC AGENTS 5.2 SBRT SBRT will be used to treat a designated lesion that is symptomatic or at risk of causing symptoms. SBRT will be performed with external beam ionizing radiation in accordance with institutional standard practice. 3D conformal radiation therapy (3D-CRT), intensity - modulated radiation therapy (IMRT) or volumetric arc therapy (VMAT) will be used at the discretion of the treating radiation oncologist. Total SBRT dose will be between 30 and 60 Gy in < 8 fractions as per standard of care.. The dose must satisfy institutional guidelines and minimize risk to adjacent organs at risk (see appendix 1 for reference). 5.3 Avelumab Avelumab (also known as MSB0010718C) is a fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to engage the innate immune system and may induce antibody -dependent cell- mediated cytotoxicity (ADCC). Avelumab has previously received Breakthrough Therapy Designation for Merkel cell carcinoma. Avelumab will be provided by Pfizer. Avelumab will be stored, prepared, and administered as per MSKCC guidelines. The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational p r o d u c t in accordance with the protocol and any applicable laws and Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 16 of 51 regulations. Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 6.1 CRITERIA FOR SUBJECT ELIGIBILITY 6.2 Subject Inclusion Criteria 1. Patient willing and able to provide written informed consent for the trial. 2. Patient age ≥ 18 at time of consent. 3. Histologically or cytologically confirmed malignant pleural or peritoneal mesothelioma (MPM). 4. No plans for surgical resection. 5. At least one prior line of systemic therapy. Note: Patients on prior immunotherapy are eligible. 6. At least one targetable lesion appropriate for palliative SBRT and one non-target lesion 7. Karnofsky Performance Score (KPS) ≥ 70% 8. If of childbearing potential, must be willing to use highly effective mode of contraception for at least one month prior, during, and for 2 months after the end of active therapy 9. Adequate organ function, defined as • Absolute Neutrophil Count ≥ 1.5K/mcL. • Platelet count ≥ 100K/mcL. • Adequate renal function as defined by an estimated creatinine clearance > 30 mL/min according to the Cockcroft -Gault formula or serum creatinine ≤ 1.5 x U L N • Hemoglobin > 9g/dL (prior transfusion permitted) • Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) r ange • AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic diseaseto the liver). 10.