Conditions: Malignant Mesothelioma (MPM)
Keywords: Stereotactic Body Radiation Therapy Avelumab Immunotherapy 17-358
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out whether the combination of avelumab and SBRT is safe and what effect avelumab has on mesothelioma when given in combination with SBRT. In addition, a goal of this protocol is to study the effect of radiation therapy on the immune system. It is thought that radiation treatment may create a form of 'vaccine' against cancer inside the body and immunotherapy may improve this effect. The combination of radiation treatment and immunotherapy may be more effective against cancer than either radiation or immunotherapy alone.

Detailed description:

Arms:
arm 1: 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.

Interventions: intervention 1: Avelumab intervention 2: Stereotactic Body Radiation Therapy
Intervention descriptions: intervention 1: 10mg/kg delivered by IV infusion intervention 2: short course of SBRT after the first two doses of avelumab

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
 
 
 
 
MSK Protocol Cover Sheet 
 
A Safety Study of Avelumab plus SBRT in Malignant Mesothelioma (MPM) 
 
Principal Investigator: Andreas Rimner, MD in the Department of Radiation Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
Page 1  of 51 
Version:  2/26/16 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 5  of 
51 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................................8 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 10 
3.1 
BACKGROUND AND RATIONALE .................................................................................. 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 ASSESSMENT........................... 39 
13.0 
CRITERIA FOR REMOVAL FROM STUDY .................................................................................. 42 
14.0 
BIOSTATISTICS ............................................................................................................... 42 
15.1 
RESEARCH 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 ................................................................................................................................. 50 
20.0 
APPENDICES .................................................................................................................... 51 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 7  of 
51 
 
 
 
 
 
List of Abbreviations (alphabetical) 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 DCE 
DCE 
Dynamic contrast-enhanced 
DLT 
Dose-limiting toxicity 
DWI 
Diffusion-weighted imaging 
EOT 
End of treatment 
GGT 
Gamma-glutamyl transferase 
IRB 
Institutional Review Board 
irAE 
Immune-related  adverse event 
KPS 
Karnofsky Performance Status 
mAb 
Monoclonal antibody 
MPM 
Malignant pleural/peritoneal mesothelioma 
MRI 
Magnetic resonance imaging 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progression of disease 
PD-1 
Programmed death 1 
PD-L1 
Programmed death ligand 1 
PET 
Positron emission tomography 
PR 
Partial response 
Q2W 
Every other week 
RECIST Response Evaluation Criteria in Solid Tumors 
SBRT 
Stereotactic Body Radiotherapy 
SD 
Stable disease 
SPD 
Sum of the products of diameters 
TB 
Tuberculosis 
TCRs 
T-cell receptors 
TILs 
Tumor infiltrating lymphocytes 
ULN 
Upper limit of normal 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 8  of 
51 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title 
A Safety Study of Avelumab plus SBRT in Malignant 
Mesothelioma (MPM) 
Investigational drug 
Avelumab 
Study Centers 
MSKCC Main Campus and Regional S i tes 
Study Objectives 
To evaluate the efficacy and safety (defined as the incidence of  any grade 
3+ non-hematologic toxicity) of combining SBRT and avelumab for the 
treatment of MPM 
Study Endpoints 
Primary Endpoint 
• Safety of avelumab + SBRT: rate of grade 3 or 
higher non- hematologic toxicity (CTCAE v4.0) 
Secondary Endpoint 
• 
• Overall response rate defined by modified 
RECIST 1.1 for mesothelioma 
• Response of irradiated (in-field) and unirradiated (out- 
of-field) lesions as defined by RECIST 1.1 
• Progression-free and overall survival 
Exploratory Objectives 
• T-cell infiltration both in- and outside the irradiated  field 
• Serum immune phenotype at baseline and after avelumab + 
S B RT 
• Concordance of imaging using diffusion-weighted and DCE- 
MRI, and PET with biopsy sample results 
Patient Population 
Patients with a histologically/cytologically  proven 
malignant pleural or peritoneal mesothelioma who have 
received one or more lines of standard treatment. 
Number of Patients 
27 patients maximum 
13 patients will be recruited for Stage 1. If requirements 
for expansion are met, another 14 patients will be 
recruited for Stage 2. 
Inclusion Criteria 
(summarized) 
1. Patient willing and able to provide written informed 
consent for the trial. 
2. Patient age ≥ 18 at time of consent. 
3. Unresectable or stage IV malignant pleural or 
peritoneal mesothelioma (MPM). 
4. Histological and/or cytological confirmation of MP M. 
5. At least one prior therapy 
6. At least one targetable lesion appropriate for palliative SBRT. 
7. Karnofsky Performance Score (KPS) ≥ 70% 
8. Adequate organ function, defined below in Section 6.1 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 9  of 
51 
 
 
Exclusion 
Criteria 
(summarized) 
1. Currently participating and receiving another study therapy or has 
participated in a study of an investigational agent and received 
s t u d y  therapy or used an investigational device within 4 weeks of 
the first dose of treatment. 
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 
 
Malignant 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 inductionof 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 enhancetumor 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 P D 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. If the patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting ther apy. 
6.3 
Subject Exclusion Criteria 
 
1. Currently participating and receiving another study therapy or has participated in a 
study of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 
 
2. Prior radiation therapy precluding SBRT 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 17  of 
51 
 
 
 
 
 
3. Continuous oxygen use 
4. Current use of immunosuppressive medication, EXCEPT for the following:  a.   intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. 
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 
5. Active autoimmune disease that might deteriorate when receiving an immuno- 
stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or 
hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment. 
6. Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v4.03 Grade ≥  3) 
7. Patient who rapidly progressed on prior immunotherapy, as determined by the treating 
physician, are not eligible. 
 
8. Prior Therapies: 
a. Treatment with a monoclonal antibody 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. 
b. 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). 
c. 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. 
 
 
9. Comorbidities or Prior Conditions: 
a. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the  trial. 
b. Prior organ transplantation including allogenic stem-cell transplantation. 
c. Known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or in situ cervical cancer that has undergone potentially curative 
t h e r a p y . 
d. Known history of active TB (Tuberculosis). 
e. Known history of HIV or known acquired immunodeficiency syndrome. 
f. 
Active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection at screening or 
positive serologies indicating prior infection. 
g. Active infection requiring systemic ther apy. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 18  of 
51 
 
 
h. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 19  of 
51 
 
 
 
 
i. 
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months 
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication. 
10. Pregnant women or women who are breastfeeding or of childbearing potential and not 
using a highly effective method of birth control for at least one month prior to  
enrollment. If the risk of contraception exists, male and female subjects must use highly 
effective contraception throughout the study and for at least 60 days after last avelumab 
treatment. 
a. Highly effective contraception includes either 2 barrier methods (diaphragm, 
condom by the partner, copper intrauterine device, sponge, or spermicide), or 1 
barrier method and 1 hormonal method (any oral, subcutaneous, intrauterine, or 
intramuscular registered and marketed contraceptive agent that contains an 
estrogen and/or a progesterone  agent). 
11. Vaccination within 4 weeks prior to the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines. 
12. Concomitant use of the following medications 
a. Any investigational  anticancer therapy. 
b. 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. 
c. Immunosuppressive medications including, but not limited to systemic 
corticosteroids (>10 mg/day prednisone 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. 
13. Known contraindications to radiotherapy 
7.0 
RECRUITMENT PLAN 
 
Eligible patients with malignant pleural or peritoneal mesothelioma will be recruited from the 
Thoracic Medical Oncology and Radiation Oncology departments at MSKCC. An attending 
physician of the Thoracic Medical Oncology and Radiation Oncology department will evaluate 
all patients. Participation is voluntary. The consenting physician will inform patients of their 
diagnosis, current treatment options, including standard treatment, and the risks, benefits 
and experimental nature of this treatment  program. 
 
Memorial Hospital is a major referral center for MPM. In addition, the study information may 
be placed on the institutional hospital website to maximize r e c r u i t m e n t . 
Patients under the age of 18 are excluded because this disease does not occur in patients 
that age, and the safety of these treatments  has  not been  established for them. The 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 20  of 
51 
 
 
 
 
patient population includes all patients under the care of attending surgical, medical and 
radiation oncologists at MSKCC main campus or regional sites. Every attempt will be made to 
recruit women and minorities to participate in this study. There are no genders or racial 
restrictions. 
 
8.1 
PRETREATMENT EVALUATION 
 
To be completed within 45 days prior to starting avelumab unless otherwise s p e c i f i e d : 
 
1. Signed informed consent for study participation 
2. FDG-PET scan 
3. CT of the chest, abdomen, and pelvis, preferably with contrast. The companion CT 
scan from the above FDG-PET scan may fulfill this requirement. 
4. MRI of the lesion to be irradiated according to the following guidelines in the MSKCC 
Department of Radiation Oncology 
a. Contraindication to MRI (i.e. pacemaker) = no participation in MRI 
component. 
b. Contraindication to contrast only = MRI w/o contrast 
c. No contraindication = MRI with contrast 
5. 12-lead Electrocardiogram (EKG) 
6. History and physical examination, including height, weight, vital signs (temperature, 
pulse rate, respiration rate, blood pressure), and performance status ( Karnofsky) 
7. Serum or urine pregnancy test for all women of childbearing potential  (serum 
pregnancy test within 14 days or urine pregnancy test within 24 hours of starting 
avelumab) 
8. 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) 
9. Free T4 and TSH 
10. Serology for HEP BsAg, HBcAb and hepatitis C antibody within 30 days prior to 
starting avelumab 
11. Baseline blood test for research purposes (See Section 1 0 . 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 Discontinuation 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). 
*Local guidelines, or e.g. ESC guidelines (https://www.escardio.org/Guidelines/Clinical - 
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. 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 
• 
Pregnancy
1
 
• 
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 
RESEARCH 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. The proposed study population is as described. 
 
Exclusion of Lactating or Pregnant Women: Lactating and pregnant women are also 
excluded because of unknown effects of immunotherapy on a developing fetus or nursing 
infant. 
Children have been excluded from this study as mesothelioma is an adult cancer. Thus, the 
relevance of this drug to the pediatric population has not been   established. 
Benefits: It is possible that this treatment will result in shrinkage of mesothelioma or in a 
stabilization of an otherwise progressing disease. It is not known, of course, whether these or 
any other favorable events will occur. It is not known whether this treatment will affect the 
overall survival of the patients. 
Costs: The patient will be responsible for the costs of standard medical care, including, CT 
scans, all drug administration fees and all hospitalizations, as well as for complications of 
treatment. Avelumab will be supplied to patients by Pfizer at no cost. Patients will not be 
responsible for the costs of blood procurement obtained for research purposes, the cost of 
special testing of any tissue for research purposes, or the cost for obtaining the tumor biopsy 
for research purposes. 
 
Incentives: No incentives will be offered to patients/subjects for participation in the   study. 
 
Alternatives: Patients may be eligible for other investigational studies or focus on palliative 
care options. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patient’s name or any other personally identifying 
information will not be used in reports or publications resulting from this study. The Food and 
Drug Administration or other authorized agencies (e.g., qualified monitors) may review 
patients‟ records and pathology slides, as required. 
17.2 
Privacy 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 47  of 
51 
 
 
 
 
 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized,  de-identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information, which will not include 
protected health information such as the participant’s name, except for dates. It is also stated 
in the Research Authorization that their research data may be shared with others at the time of 
study publication. 
 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition 
• 
List any additional events that require SAE reporting (pregnancy, AEs of special interest 
(AESI), secondary malignancies, etc.) 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30 days after the participant’s last investigational 
treatment/intervention. Any event that occurs after the 30-day period that is unexpected and at 
least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or procedure (e.g., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP Office per IRB    
SOP RR-408 ‘Reporting of Serious Adverse Events,’ the SAE report must be submitted within 5 
calendar days of the event. All other SAEs must be submitted within 30 calendar days of the 
event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 48  of 
51 
 
 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office. 
 
For multicenter trials where MSK is the data coordinating center, please refer to the MSK 
Multicenter Trial Addendum. All required SAE reporting to the funders and/or drug suppliers will 
be completed by MSK only. 
 
 
17.3.1 SAE Reporting to Study Sponsor / Drug Supplier 
The following reportable events must be submitted to Pfizer within 24 hours (or immediately for 
death or life-threatening events) using the provided Investigator-Initiated Research Serious 
Adverse Event Form (IIR SAE) with the Pfizer Reportable Events Fax Cover Sheet with each 
SAE submission. 
 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy‟s Law cases): These events are considered 
important medical events and should be reported as S AE s . 
Detailed guidance on the safety reporting is provided in the Safety Reporting Reference 
Manual. 
Contact information for submission of reportable events to Pfizer: 
• 
Fax:  Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322. 
or 
• 
E-mail:  USA.AEReporting@pfizer.com, specifying: 
o PROTOCOL: 
o SUBJECT: 
o SITE/PI: 
o SAE/ONSET: 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended s tudy. 
2. The length of study and the likely follow-up r equir ed. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 49  of 
51 
 
 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the pr otoc ol . 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Both the participant and the consenting professional will sign the consent form. The 
participant must receive a copy of the signed informed consent f o r m . 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 50 of 51 
Version:  2/26/16 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Golden, E.B., et al., Local radiotherapy and granulocyte-macrophage colony-stimulating 
factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of- 
principle trial.  The Lancet Oncology, 2015. 16(7):  p. 795-803. 
2. 
Chandra, R.A., et al., A systematic evaluation of abscopal responses following radiotherapy  
in patients with metastatic melanoma treated with ipilimumab. OncoImmunology, 2015. 4(11): 
p.  e1046028. 
3. 
Cicala, C., F. Pompetti, and M. Carbone, SV40 induces mesotheliomas in hamsters. Am J 
Pathol, 1993.  142(5): p. 1524-33. 
4. 
Cleaver, A.L., et al., Long-term exposure of mesothelial cells to SV40 and asbestos leads to 
malignant transformation and chemotherapy resistance. Carcinogenesis, 2014. 35(2): p. 407- 
14. 
5. 
Carbone, M., et al., Malignant mesothelioma: facts, myths, and hypotheses. J Cell Physiol, 
2012. 227(1):  p. 44-58. 
6. 
Moolgavkar, S.H., R. Meza, and J.  Turim, Pleural and peritoneal mesotheliomas in SEER: 
age effects and temporal trends, 1973-2005. Cancer Causes Control, 2009. 20(6): p. 
935-44. 
7. 
Damhuis, R.A., et al., Treatment patterns and survival analysis in 9014 patients with malignant 
pleural mesothelioma from Belgium, the Netherlands and England. Lung Cancer, 2015. 
89(2): p.  212-217. 
8. 
Rimner, A., et al., Failure patterns after hemithoracic pleural intensity modulated radiation 
therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys, 2014. 90(2): p. 
394-401. 
9. 
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced 
cancer. N Engl J Med,  2012. 366(26): p. 2455-65. 
10. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in   cancer. 
N Engl J  Med, 2012. 366(26): p. 2443-54. 
11. 
Alley, E.W., et al., Abstract CT103: Clinical safety and efficacy of pembrolizumab (MK-3475) 
in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028. 
Cancer Research, 2015. 75(15 Supplement): p.   CT103. 
12. 
Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with 
melanoma. N Engl J Med, 2012. 366(10):  p. 925-31. 
13. 
Reits, E.A., et al., Radiation modulates the peptide repertoire, enhances MHC class I 
expression, and induces successful antitumor immunotherapy. J Exp Med, 2006. 203(5): p. 
1259-71. 
14. 
Twyman-Saint Victor, C., et al., Radiation and dual checkpoint blockade activate non- 
redundant immune mechanisms in cancer. Nature, 2015. 520(7547): p.   373-7. 
15. 
Barker, H.E., et al., The tumour microenvironment after radiotherapy: mechanisms of 
resistance and recurrence. Nat Rev Cancer, 2015. 15(7): p.   409-25. 
16. 
Seung, S.K., et al., Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2— 
Tumor and Immunological Responses. Science Translational Medicine, 2012. 4(137): p. 
137ra74-137ra74. 
17. 
Zeng, J., et al., Anti-PD-1 blockade and stereotactic radiation produce long-term survival in 
mice with intracranial gliomas. Int  J Radiat Oncol Biol Phys, 2013. 86(2): p.  343-9. 
18. 
Slovin, S.F., et al., Ipilimumab alone or in combination with radiotherapy in metastatic 
castration-resistant prostate cancer: results from an open-label, multicenterphase I/II study. 
Ann Oncol, 2013. 24(7): p. 1813-21. 
19. 
Boyerinas, B., et al., Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 
Antibody  Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunology 
Research, 2015. 3(10): p.  1148-1157. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-358 A(7) 
Approval date: 25-Feb-2022 
Page 51 of 51 
Version:  2/26/16 
 
 
 
 
 
20. 
Vandeveer, A., et al., Systemic immunotherapy of superficial mouse bladder cancer with 
Avelumab (MSB0010718C), an anti-PD-L1 immune checkpoint inhibitor. Journal for 
ImmunoTherapy of Cancer, 2015.  3(2): p. 1-1. 
21. 
Chang, B.K. and R.D. Timmerman, Stereotactic body radiation therapy: a comprehensive 
review. Am J Clin Oncol, 2007. 30(6): p. 637-44. 
22. 
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid tumors: 
immune-related response criteria. Clin Cancer Res, 2009. 15(23): p.   7412-20. 
23. 
Byrne, M.J. and A.K. Nowak, Modified RECIST criteria for assessment of response in 
malignant pleural mesothelioma. Annals  of Oncology, 2004. 15(2): p.  257-260. 
24. 
Nowak, A.K., CT, RECIST, and malignant pleural mesothelioma. Lung Cancer, 2005. 49, 
Supplement 1: p. S37-S40. 
 
 
20.0 
APPENDICES 
 
Appendix 1: SBRT Organs at Risk Dose  Constraints