4 ) 12. Tumor biopsy for confirmation of either progressive or metastatic disease completed as standard of care of two lesions, a lesion to be irradiated and a lesion to be un- irradiated. Biopsy to be core needle biopsy up to 4 cores, 1 core to be sent to pathology and 3 cores to be sent to lab for research for each site, preferably 18- gauge or larger, specified prior to biopsy, permanently fixed, managed by CSP, Correlative Science Program. 9.0 TREATMENT/INTERVENTION PLAN Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 20 of 51 Version: 2/26/16 9.1 Dosing Instructions and Schedule 9.1.1 Avelumab Dosing Instructions and Schedule One cycle of avelumab is definedas two weeks. Administration of avelumabw i l l commence after completion of pre-treatment procedures. Patients will receive avelumab 10mg/kg as an IV infusion Q2W. In order to mitigate infusion related reactions, a premedication with an antihistamine and with acetaminophen 30 to 60 minutes prior to each dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500- 650 mg acetaminophen IV or oral). The treating oncologist may use equivalent or similar medications as available at their dis c r etion . Two cycles will be given before starting radiation therapy. After 2 cycles of avelumab, a short course of SBRT (after the end of Cycle 2 and before Cycle 3, Day 1) will be delivered to a portion of MPM that is symptomatic or at risk of causing symptoms. Avelumab treatment continues during and after RT for up to two years or until disease progression. Avelumab may be continued after disease progression at the discretion of the investigator if criteria in section 4.2 are met. The first day of dosing is considered Day 1 of the cycle. Day 1 of Cycle 1 is considered the date of first dose and is used to determine the maximum 24 months of treatment. Trial treatment should be administered on Day 1 of each cycle. Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. All trial treatments will be administered on an outpatient basis. 9.1.2 SBRT Dosing Instructions and Schedule SBRT will be administered after 2 cycles of avelumab are complete, with fractionation and schedule at the discretion of the treating radiation oncologist. The radiation dose and organ dose constraints will be in accordance with standard institutional guidelines (see appendix 1). Avelumab and SBRT should not be delivered on the same day. SBRT may be delayed up to 6 weeks for immunotherapy toxicity management. If the patient is unable to receive radiation within the 6 weeks, they will be removed from protocol and r eplac ed . Patients will be treated on an outpatient basis. Patients will be evaluated by the radiation oncology team and then undergo simulation for 3D-CRT, IMRT, or VMAT, the choice of which is determined by the radiation oncologist. Each patient will be positioned in a custom immobilization and undergo a CT scan (slice spacing 2-2.5 mm, depending on the scanner) for treatment planning. The radiation oncologist will delineate the gross tumor volume (GTV) on the planning scan. If clinically indicated for lesions within the chest, only, the 4D-CT scan will be used to account for respiratory motion. Target volumes: The definitions of volumes will be in accordance with the 1999 ICRU report #62. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 21 of 51 Definition of the gross tumor volume (GTV): The volume determined to clinically correspond with the area require ing palliation will constitute the GTV. Definition of the internal target volume (ITV): For patients who undergo 4DCT simulation, only: an ITV will be created based on the 4D- CT scan to account for all respiratory motion throughout the respiratory cycle, thus resulting in a motion-inclusive ITV. Definition of the clinical target volume (CTV): The CTV will be defined as the ITV plus typically 0.2cm to account for microscopic tumor extension. Definition of the planning target volume (PTV): The PTV will include the CTV plus a margin of 0.5 cm to account for setup uncertainties. Critical normal tissues in proximity to the irradiated lesion will be contoured. Hypofractionated guidelines based on current MSKCC guidelines will be applied (see appendix 1). Isocenter is at the center of the GTV. Treatment is delivered with 6 or 15 MV photon beams. IMRT/VMAT will use the dynamic multileaf collimator (DMLC or sliding window) technique, on a Varian LINAC. The IMRT optimization algorithm uses an iterative gradient search method to minimize a quadratic objective function that can include terms to impose target dose uniformity, limit normal tissue maximum and mean doses and impose dose- volume constraints. Calculations are performed on a commercial treatment planning system using the analytic anisotropic algorithm (AAA) or Acuros algorithm (Varian EclipseTM). Radiation will be given outpatient Monday to Friday, excluding holidays, until all (< 8) treatments have been completed. If the patient misses a scheduled treatment, this treatment will be added on the end of the initial treatment plan. Each treatment day, the patient will be positioned supine on the treatment table with custom immobilization. Patients are first positioned with the use of skin tattoos and an in-room laser localization system. Patients will then undergo a cone- beam CT prior to each fraction. Refinements in patient positioning are made based on the on-board 3D imaging. Patients will be matched based on the tumor within a 2mm tolerance, which will be approved by the attending radiation oncologist. The radiation treatment will then be administered. All patients will be monitored for gross body movement using intra- fraction motion such as infrared, Align RT or interval KV bone match. 9.2 Monitoring of Dose Administration Subjects will be monitored during avelumab administration and for a minimum of 2 hours after infusion with assessment of vital signs. Subjects will be monitored during avelumab administration and for a minimum of 30 minutes after infusion with assessment of vital signs if there are no infusion related reactions within the first 8 cycles. As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be immediately available, and s t u d y personnel m u s t be trained to recognize and treat anaphylaxis. The study site must have immediate access to Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 22 of 51 emergency resuscitation teams and equipment in addition to the ability to admit subjects to an intensive care unit if necessary. Avelumabshould be administered in a settingthat allows for immediateaccess toan intensive care unit or equivalent environment and administration of therapy for anaphylaxis, such as the ability to implement immediate resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents at the treating oncologist ’s discretion, and oxygen should be available for immediate access. 9.3 Concomitant Medications 9.3.1 Permitted Concomitant Medications Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for those medications identified as “excluded” as listed in Section 9.3.2. 9.3.2 Excluded Concomitant Medications Subjects must be instructed not to take any medications, includingover-the-counter products, without first consulting with the investigator. The following medications are considered exclusionary during the study. The Principal Investigator must be notified if a subject receives any of these during the study. • Any investigational anticancer therapy. • Any concurrent chemotherapy, immunotherapy, or biologic therapy. Concurrent use of hormones for non-cancer -related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. • Immunosuppressive medications including, but not limited to systemic corticosteroids (>10 mg/dayprednisone or equivalent), methotrexate, azathioprine, and tumor necrosis factor alpha (TNF -α) blockers. Use of immunosuppressive medications for the management of investigational product -related AEs, in subjects with contrast allergies is acceptable. In addition, use of inhaled and intranasal corticosteroids is permitted. 9.4 Dose Modification and Discontinuation 9.4.1 Adverse Drug Reactions (ADRs) Requiring Avelumab Discont inuation or Dose Modification Any Grade 4 ADRs require treatment discontinuation with avelumab except for single laboratory values out of normal range that are unlikely related to study treatment as assessed by the investigator, do not have any clinical correlate, and resolve within 7 days with adequate medical management. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 23 of 51 Any Grade 3 ADRs require treatment discontinuation with avelumab except for any of the following: • Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which are controlled with medical management • Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to Grade ≤ 1 • Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) that are unlikely related to study treatment according to the Investigator, do not have any clinical correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management • Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected tumor Any Grade 2 ADR should be managed as follows: • If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may continue. • If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions should not be given on the following cycle. If at the end of the following cycle the event has not resolved to Grade 1, the subject should permanently discontinue treatment with avelumab (except for hormone insufficiencies, that can be managed by replacement therapy; for these hormone insufficiencies, up to 2 subsequent doses may be omitted). • Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that can be managed by replacement therapy) in the same subject, treatment with avelumab will be permanently discontinued. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 24 of 51 9.4.2 Treatment Modification for Symptoms of Infusion- Related Reactions NCI-CTCAE Grade Treatment Modification for Study Drug Grade 1 – mild Mild transient reaction; infusion interruption not indicated; intervention not indicated. Decrease the study drug infusion rate by 50% and monitor closelyfor any worsening. Grade 2 – moderate Therapy or infusion interruption indicated but responds promptlyto symptomatic treatment (for example, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤ 24 hrs. Stop study drug infusion. Resume infusion at 50% of previous rate once infusion- related reaction has resolved or decreased to at least Grade 1 in severity and monitor closelyfor any worsening. Grade 3 or Grade 4 – severe or life-threatening Grade 3: Prolonged (for example, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4: Life-threatening consequences; urgent intervention indicated. Stop the study drug infusion immediatelyand disconnect infusion tubing from the subject. Subjects have to be withdrawn immediatelyfrom study drug treatment and must not receive any further study drug treatment. - Once the avelumab infusion rate has been decreased by50% or interrupted due to an infusion- related reaction, it must remain decreased for all subsequent infusions. - If hypersensitivityreaction occurs, the subject must be treated according to the best available medical practice. IV = intravenous; NCI-CTCAE = National Cancer Institute -Common TerminologyCriteria for Adverse Event; NSAIDs = nonsteroidal anti-inflammatorydrugs. Additional Modifications for Patients with Grade 2 Avelumab Infusion-Related Reactions: In the event of a Grade 2 infusion -related reaction that does not improve or worsens after implementation of the modifications indicated in Section 9.4.2 (including reducing the infusion rate by 50%), the investigator may consider treatment with corticosteroids, and the infusion should not be resumed for that cycle. At the next cycle, the investigator may consider the addition of H2-blocker antihistamines (e.g., famotidine or ranitidine), meperidine, or ibuprofen to the mandatory premedications. Prophylactic steroids are NOT permitted. Management of Avelumab-related Severe Hypersensitivity Reactions and Flu-like Symptoms: Many mAb therapies can induce flu-like symptoms and hypersensitivity reactions, including impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, hypotension, pale/clammy skin, and cyanosis. Avelumab should be administered in a setting that allows for immediate access to an intensive care unit or equivalent environment if required. Patients should be placed on monitors immediately and epinephrine injections and dexamethasone infusions should be available for immediate access. For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable nonsteroidal anti- inflammatory drugs (NSAID) dose (e.g., ibuprofen 600 mg, naproxen sodium 500 mg) Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 25 of 51 may be administered at the investigator ’s discretion 2 hours before and 8 hours after the start of each dose of avelumab IV infusion. Alternative treatments for fever (e.g., paracetamol or ibuprofen) and rigors (e.g., meperidine) may be given to patients at the discretion of the investigator. 9.5 Management of Avelumab Immune -Related Adverse Events Since inhibition of PD-L1 stimulates the immune system, immune -related AEs (irAEs) may occur. Treatment of irAEs is mainlydependent upon severity (NCI-CTC AE grade): Grade 1 to 2: treat symptomaticallyor with moderate dose steroids, more frequent monitoring Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) Grade 3 to 4: treat with high dose corticosteroids Treatment of gastrointestinal, dermatological, pulmonary, hepatic and endocrine irAEs should follow guidelines set forth in the table below. Gastrointestinal irAEs Severity of Diarrhea / Colitis (NCI-CTCAE v4.03) Management Follow -up Grade 1 Diarrhea: < 4 stools/dayover Baseline Colitis: asymptomatic Continue avelumab therapy Symptomatic treatment (for example, loperamide) Close monitoring for worsening symptoms Educate subject to report worsening immediately If worsens: Treat as Grade 2 or 3/4 Grade 2 Diarrhea: 4 to 6 stools per day over Baseline; IV fluids indicated < 24 hours; not interfering with ADL Colitis: abdominal pain; blood in stool Delay avelumab therapy Symptomatic treatment If improves to Grade 1: Resume avelumab therapy If persists > 5 to 7 days or recur: 0.5 to 1.0 mg/kg/day methylprednisolone or equivalent When symptoms improve to Grade 1, taper steroids over at least 1 month, consider prophylactic antibiotics for opportunistic infections, and resume avelumab therapyper protocol. If worsens or persists > 3 to 5 days with oral steroids: Treat as Grade 3 to 4 Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 26 of 51 Grade 3 to 4 Diarrhea (Grade 3): ≥ 7 stools per day over Baseline; incontinence; IV fluids ≥ 24 hrs.; interfering with ADL Colitis (Grade 3): severe abdominal pain, medical intervention indicated, peritoneal signs Grade 4: life-threatening, perforation Discontinue avelumab therapy per protocol 1.0 to 2.0 mg/kg/day methylprednisolone IV or equivalent Add prophylactic antibiotics for opportunistic infections Consider lower endoscopy If improves: Continue steroids until Grade 1, then taper over at least 1 month If persists > 3 to 5 days, or recurs after improvement: Add infliximab 5 mg/kg (if no contraindication), Note: Infliximab should not be used in cases of perforation or sepsis Dermatological ir AEs Grade of Rash (NCI-CTCAE v4) Management Follow -up Grade 1 to 2 Covering ≤ 30% body surface area Symptomatic therapy (for example, antihistamines, topical steroids) Continue avelumab therapy If persists > 1 to 2 weeks or recurs: Consider skin biopsy Delay avelumab therapy Consider 0.5 to 1.0 mg/kg/day methylprednisolone IV or oral equivalent. Once improving, taper steroids over at least 1 month, consider prophylactic antibiotics for opportunistic infections, and resume avelumab therapy If worsens: Treat as Grade 3 to 4 Grade 3 to 4 Covering > 30% body surface area; life threatening consequences Delay or discontinue avelumab therapy Consider skin biopsy Dermatologyconsult 1.0 to 2.0 mg/kg/day methylprednisolone IV or IV equivalent If improves to Grade 1: Taper steroids over at least1 month and add prophylactic antibiotics for opportunistic infections Resume avelumab therapy Pulmonary irAEs Grade of Pneumonitis (NCI-CTCAE v4) Management Follow -up Grade 1 Radiographic changes only Consider delayof avelumab therapy Monitor for symptoms every 2 to 3 days Consider Pulmonaryand Infectious Disease consults Re-image at least every 3 weeks If worsens: Treat as Grade 2 or Grade 3 to 4 Grade 2 Mild to moderate new symptoms Delay avelumab therapy Pulmonaryand Infectious Disease consults Monitor symptoms daily, consider hospitalization Re-image every 1 to 3 days If improves: When symptoms return to near Baseline, taper steroids over at least 1 month and then resume Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 27 of 51 1.0 mg/kg/day methyl - prednisolone IV or oral equivalent Consider bronchoscopy, lung biopsy avelumab therapy and consider prophylactic antibiotics If not improving after 2 weeks or worsening: Treat as Grade 3 to 4 Grade 3 to 4 Severe new symptoms; New / worsening hypoxia; life-threatening Discontinue avelumab therapy Hospitalize Pulmonaryand Infectious Disease consults 2 to 4 mg/kg/day methylprednisolone IV or IV equivalent Add prophylactic antibiotics for opportunistic infections Consider bronchoscopy, lung biopsy If improves to Baseline: Taper steroids over at least 6 weeks If not improving after 48 hours or worsening: Add additional immunosuppression (for example, infliximab, cyclophosphamide, IV immunoglobulin, or mycophenolate mofetil) Hepatic irAEs Grade of Liver Test Elevation (NCI-CTCAE v4) Management Follow -up Grade 1 Grade 1 AST or ALT > ULN to 3.0 x ULN and / or total bilirubin > ULN to 1.5 x ULN Continue avelumab therapy Continue liver function monitoring If worsens: Treat as Grade 2 or 3 to 4 Grade 2 AST or ALT > 3.0 to ≤ 5 x ULN and / or total bilirubin > 1.5 to ≤ 3 x ULN Delay avelumab therapy Increase frequencyof monitoring to every 3 days If returns to Baseline: Resume routine monitoring, resume avelumab therapy If elevations persist > 5 to 7 days or worsen: 0.5 to 1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to Grade 1 or Baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for opportunistic infections, and resume avelumab therapy Grade 3 to 4 AST or ALT > 5 x ULN and / or total bilirubin > 3 x ULN Discontinue avelumab therapy Increase frequencyof monitoring to every 1 to 2 days 1.0 to 2.0 mg/kg/day methylprednisolone IV or IV equivalent Add prophylactic antibiotics for opportunistic infections Consult gastroenterologist Consider obtaining MRI/CT scan of liver and liver biopsy If returns to Grade 2: Taper steroids over at least 1 month If does not improve in > 3 to 5 days, worsens or rebounds: Add mycophenolate mofetil 1 gram (g) twice daily If no response within an additional 3 to 5 days, consider other immunosuppressants per local guidelines Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 28 of 51 if clinicallywarranted Endocrine ir AEs Endocrine Disorder Management Follow -up Grade 1 or Grade 2 endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, type I diabetes mellitus) Continue avelumab therapy Endocrinologyconsult if needed Start thyroid hormone replacement therapy(for hypothyroidism), anti-thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal insufficiency) or insulin (for Type I diabetes mellitus) as appropriate. Rule -out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) Continue hormone replacement/suppression and monitoring of endocrine function as appropriate. Grade 3 or Grade 4 endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, type I diabetes mellitus) Withhold avelumab therapy Consider hospitalization Endocrinologyconsult Start thyroid hormone replacement therapy(for hypothyroidism), anti-thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal insufficiency) or insulin (for type I diabetes mellitus) as appropriate. Rule -out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) Resume avelumab once symptoms and/or laboratory tests improve to Grade ≤ 1 (with or without hormone replacem ent/suppression). Continue hormone replacement/suppression and monitoring of endocrine function as appropriate. Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 29 of 51 Hypopituitarism/Hypophysitis (secondaryendocrinopathies) If secondarythyroid and/or adrenal insufficiencyis confirmed (i.e. subnormal serum FT4 with inappropriatelylow TSH and/or low serum cortisol with inappropriatelylow ACTH): • Refer to endocrinologist for dynamic testing as indicated and measurement of other hormones (FSH, LH, GH/IGF -1, PRL, testosterone in men, estrogens in women) • Hormone replacement/suppressiv e therapy as appropriate • Perform pituitary MRI and visual field examination as indicated If hypophysitis confirmed: • Continue avelumab if mild symptoms with normal MRI. Repeat the MRI in 1 month • Withhold avelumab if moderate, severe or life- threatening symptoms of hypophysitis and/or abnormal MRI. Consider hospitalization. Initiate corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) followed by corticosteroids taper during at least 1 month. • Add prophylactic antibiotics for opportunistic infections. Cardiac irAEs Myocarditis Management Follow -up New onset of cardiac signs or symptoms and / or new laboratory cardiac biomarker elevations (e.g. BNP, troponin, CK-MB) or cardiac imaging abnormalities suggestive of myocarditis. Withhold avelumab therapy Hospitalize. In the presence of life threatening cardiac decompensation consider transfer to a facility experienced in advanced heart failure and arrhythmia management. Cardiology consult to establish If symptoms improve and immune -mediated etiology is ruled out, re-start avelumab therapy. If symptoms do not improve/worsen, viral myocarditis is excluded, and immune- mediated etiology is suspected or confirmed following Memorial Sloan Kettering Cancer Center IRB Number: 17- 358 A(7) Approval date: 25 -Feb-2022 Page 30 of 51 Version: 2/26/16 etiology and rule-out immune - mediated myocarditis. Guideline based supportive treatment as appropriate per cardiology consult. * Consider myocardial biopsyif recommended per cardiology consult. cardiologyconsult, manage as immune - mediated myocarditis. Immune -mediated myocarditis Permanentlydiscontinue avelumab. Guideline based supportive treatment as appropriate per cardiology consult. * Methylprednisolone 1-2 mg/kg/day. Add prophylactic antibiotics for opportunistic infections. Once improving, taper steroids over at least 1 month If no improvement or worsening, consider additional immunosuppressions (e.g. azathioprine, cyclosporine A).