Compound 451238 and Radiotherapy in Soft-tissue Sarcoma
Phase: PHASE1
Conditions: Soft-tissue Sarcoma
Sponsor: Royal Marsden NHS Foundation Trust

 
 
 
 
 
 
 
Avelumab and hyPofractionated PaLliative radiotherapy in 
metastatic soft-tissuE sarcoma 
Short title: 
APPLE study   
Sponsor: 
Royal Marsden NHS Foundation Trust 
Sponsor protocol number: 
CCR 4640 
EudraCT: 
2017-001316-11 
ClinicalTrials.gov ID: 
NCT03602833 
Protocol version and date: 
Final Version 3.0, Dated   08 October 2020 
REC / IRAS Reference: 
228888 
 

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PROTOCOL SIGNATURES 
 
Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities 
as an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice 
(GCP) the Declaration of Helsinki (Appendix 2), the applicable regulations of the relevant NHS Trusts 
and the trial protocol.  I agree to conduct the trial according to these regulations and guidelines and to 
appropriately direct and assist the staff under my control who will be involved in the trial, and ensure 
that all staff members are aware of their clinical trial responsibilities. 
 
INVESTIGATOR'S NAME: 
 
 
 
 
 
 
 
SIGNATURE: 
 
 
 
 
 
DATE: 
 
 
 
 
 
Statistician Signature: 
NAME: 
 
 
 
 
 
 
 
SIGNATURE: 
 
 
 
 
 
 
DATE: 
 
 
 
 
 
1The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent 
amendments to it. 
Bernice Asare
Bernice 
Asare
Digitally signed by Bernice Asare 
DN: cn=Bernice Asare, o=Royal 
Marsden NHS Trust Hospital, ou=R 
& D, 
email=Bernice.Asare@rmh.nhs.uk, 
c=GB 
Date: 2021.02.01 14:40:13 Z
01/02/2021
Shane Zaidi
3 February 2021

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Key Trial Contacts and Protocol Contributors 
Chief Investigator 
Name:    Dr Shane Zaidi 
Email:     shane.zaidi@rmh.nhs.uk 
Phone:    0207 808 2591 
Trial Co-ordinator(s) 
Name:     Jeane Guevara  
Email:     Apple.trial@rmh.nhs.uk   
Phone:    020 8915 6666 
Sponsor 
Royal Marsden NHS Foundation Trust  
Fulham Rd, London SW3 6JJ 
Email: GCPcomplianceteam@rmh.nhs.uk or 
research.development@rmh.nhs.uk 
Funder(s) 
Merck KGaA 
Benfont Cross 
Stanwell Road 
Feltham 
Middlesex 
TW14 8NX 
Key Protocol Contributors 
 
 
 
 
 
Name:      Dr Aisha Miah 
Position:   Consultant Clinical Oncologist 
Email:       aisha.miah@rmh.nhs.uk 
Name:      Dr Shane Zaidi 
Position:   Consultant Clinical Oncologist 
Email:       shane.zaidi@rmh.nhs.uk 
Statistician 
Name:     Bernice Asare  
Email:     bernice.asare@rmh.nhs.uk 
Phone:    0208 642 3224 
 
 
 
 
 
 
 
 
Role of Study Sponsor and Funder 
 

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For this trial some of the duties of the Sponsor have been delegated to the Chief Investigator (CI), for 
example the CI has overall responsibility for the design and development of the protocol. The 
sponsorship agreement describes the allocation of such responsibilities, and a summary of this can be 
provided by the Sponsor upon request. The funder of this trial will not be involved in trial design, 
conduct, data analysis and interpretation, manuscript writing, or dissemination of results. 
 
Role of Other Protocol Contributors  
 
All key contributors to the protocol including the PI and Trial Coordinator are involved in study design, 
conduct, data analysis and interpretation, manuscript writing, and dissemination of results. Neither the 
Sponsor not the funder controls the final publication of the trial. An Independent Cancer Patients’ 
Voice representative is involved in the protocol design including methodology, sample collection, 
patient information and consent forms. 
 
 
Roles and Responsibilities of Trial Management Committees/ Groups & 
Individuals 
 
 
Trial Management Group/Trial Steering Committee/ Safety Review Committee 
Please see section 12Trial Summary 
 
Trial Title 
Avelumab  and hyPofractionated PaLliative radiotherapy in metastatic 
soft-tissuE sarcoma (APPLE) 
Clinical Phase  
Phase  I 
Summarised Trial Design 
Interventional single arm study  
 
Summarised Eligibility 
Criteria 
• 
Have measurable (RECIST v1.1) metastatic soft-tissue sarcoma 
disease; requiring palliative radiotherapy for which no curative 
therapy exists will be recruited into the trial.  Patients are 
permitted to have disease that will not be encompassed within 
the radiotherapy field (radiation tumour target volume above 
diaphragm) and will allow assessment for abscopal response. 
• 
At least one site of accessible disease for pre- and post-
treatment core biopsies. 
• 
Patients  ≥18 years of age with ECOG performance status ≤1. 
• 
Tolerate a 2.5 week course of palliative radiotherapy and life 
expectancy of >12 weeks. 
• 
Include but not limited to the following soft-tissue sarcoma 

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histological sub-types: leiomyosarcoma, myxoid liposarcoma, 
liposarcoma, undifferentiated pleomorphic sarcoma, 
fibrosarcoma, epithelioid, clear cell, and synovial sarcoma. 
• 
Patients that have had no previous chemotherapy treatment or 
have received ≥ 1 or more lines chemotherapy therapies  
• 
Male patients and women of childbearing potential (WOCBP) 
and their male partners must agree to use 1 highly effective 
methods of contraception and a condom during the screening 
period (i.e. for a period of 35 days after giving informed consent 
prior to starting avelumab) throughout treatment with avelumab 
and for at least 60 days after Avelumab treatment.  Women of 
childbearing potential include pre-menopausal women and 
women within the first 2 years of the onset of menopause. 
Women of childbearing potential must have a negative 
pregnancy test ≤ 72 hours prior to Day 1 of study as defined in 
section 7.3.7 and following this initial test must agree to monthly 
pregnancy tests whilst receiving avelumab and at the end of 
avelumab treatment. 
• 
If the patient has symptoms, that these, when assessed using 
CTCAE v.4.0, are of grade 0 or 1 severity only. 
Summary of Main 
Exclusion Criteria 
• 
Prior systemic therapy targeting PD-1: PD-L1 axis. 
• 
Patients who are curable by conventional multidisciplinary 
management. 
• 
Patients with known central nervous system metastatic disease 
are ineligible for enrolment. 
• 
Patients with severe and/or uncontrolled concurrent medical 
disease that in the opinion of the investigator could cause 
unacceptable safety risks or compromise compliance with the 
protocol. 
• 
Patients who have received radiotherapy ≤ 4 weeks prior to Day 
1 of study or who have not recovered adequately from side 
effects.  
• 
Previous radiotherapy within the treatment area. 
• 
Patients who have active infections requiring therapy. 

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• 
Patients with a history of Human Immunodeficiency Virus (HIV), 
Hepatitis B or Hepatitis C. Positive test for HBV surface antigen 
and / or confirmatory HCV RNA (if anti-HCV antibody tested 
positive). 
• 
Patients that have a known psychiatric or substance abuse 
disorder that would interfere with cooperation with the 
requirements of the trial. 
• 
Patients who received systemic anti-cancer treatment prior to 
the first dose of study drug within the following time frames: 
• 
Patients who have received biologic therapy (e.g., antibodies) 
within 4 weeks. 
• 
Patients who have undergone major surgery ≤ 2 weeks prior to 
starting study drug 
• 
Patients with active autoimmune disease or a documented 
history of autoimmune disease or syndrome that requires 
systemic steroids or immunosuppressive agents. Patients with 
vitiligo or resolved childhood asthma/atopy would be exception 
to this rule. Patients that require inhaled steroids or local steroid 
injections would not be excluded from the study. Patients with 
hypothyroidism not from autoimmune disease that is stable on 
hormone replacement will not be excluded from the study. 
• 
Women who are pregnant or nursing/breastfeeding. 
• 
Known hypersensitivity to avelumab or another mAb. 
• 
Patients with a history of non-infectious pneumonitis that has 
required a course of oral or intravenous steroids to assist with 
recovery, or interstitial lung disease. 
• 
Immunosupressants: Current use of immunosuppressive 
medication, EXCEPT for the following: a. intranasal, inhaled, 
topical steroids, or local steroid injection (eg, intra-articular 
injection); b. Systemic corticosteroids at physiologic doses ≤ 10 
mg/day of prednisone or equivalent; c. Steroids as 
premedication for hypersensitivity reactions (eg, CT scan 
premedication). 
• 
Patients with the risk factors for bowel obstruction or bowel 

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perforation (examples include but not limited to a history of 
acute diverticulitis, intra-abdominal abscess, abdominal 
carcinomatosis). 
• 
Patients who have received a live vaccine within 30 days prior 
to the first dose of trial treatment. 
• 
Previous malignant disease within the last 5 years with the 
exception of basal or squamous cell carcinoma of the skin or 
cervical carcinoma in situ 
• 
Patients on anticoagulation medication. 
• 
Patients who have symptoms, which when assessed using 
CTCAE v.4.0, are of grade 2 severity or above.   
Planned Sample Size 
n=12 patients, single investigational site. 
Treatment duration 
To be determined by treating doctor. Treatment duration (i.e. Avelumab 
administration) may extend to 6 months (12 cycles). It is estimated that 
the study will take 12 months to accrue 12 patients.   
Follow up duration 
It is anticipated that the survival follow-up period may extend for a 
maximum of 24 months. Thus, the maximum anticipated date of study 
closure would be 3 years and 6 months from the start of the trial. The 
end of the study is defined as completion of the final survival follow up 
assessments in the last patient recruited.    
Planned Trial Period 
3 years and 6 months (maximum duration) 
 
Objectives 
End-points / Outcome Measures 
Primary 
 
• 
Determine the safety and 
tolerability of avelumab 
at a fixed dose of 
10mg/kg in combination 
with RT in patients with 
metastatic soft-tissue 
sarcoma. 
• 
Establish that a fixed dose of 
avelumab (10mg/kg) can be 
safely combined with 
hypofractionated 
radiotherapy to thorax/trunk 
or limb in the absence of 
dose limiting toxicity (DLT). 
Secondary 
 
• 
Evaluate local control 
(LC). 
• 
To determine the 
progression free survival 
• 
To measure the LC at 3 
months. 
• 
To measure the PFS and 

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(PFS) and overall 
survival (OS). 
• 
To determine acute 
toxicity. 
• 
To determine late 
toxicity. 
• 
To evaluate PFS and OS 
in a PD-L1 positive 
population. 
OS at 6 months and 1 year. 
• 
Measure acute ≥ grade 2 
toxicity from initiation of 
radiotherapy and avelumab   
up to 11 weeks following 
initiation of combined 
radiotherapy and avelumab  
• 
Measure late ≥ grade 2 
toxicity from 11 weeks plus 
one day after initiation of 
combined radiotherapy and 
avelumab up to confirmed 
disease progression or 
initiation of new anti-cancer 
treatment therapy.  
• 
To measure PFS and OS in 
PD-L1 positive population at 
6 months and 1 year. 
Exploratory 
• 
To assess for evidence 
of abscopal response 
• 
To evaluate whether RT 
combined with Avelumab 
results in a measureable 
change in anti-tumour 
immunity. 
• 
To evaluate the abscopal 
effect when avelumab and 
RT are combined. 
• 
Identification of biomarkers 
that correlate with 
immunological response to 
therapy. 
Investigational Medicinal 
Product(s) 
Avelumab 
Formulation, Dose, Route 
of Administration 
Intravenous  avelumab and External Beam Radiotherapy 
Treatment/Main study 
Procedures 
All patients will receive avelumab (at a fixed dose of 10mg/kg) 
administered one day before radiotherapy (week 1), and then 
continued every 2 weeks until progression, unacceptable toxicities or 
discontinuation for other reasons or withdrawal from the study. The 
maximum duration of the study is anticipated to be 3 years and 6 
months Figure 1 summarises the recruitment schedule. Figure 2 

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summarises the treatment schedule. Each patient will receive 36 Gy in 
12 daily fractions of hypofractionated radiotherapy as per standard 
protocol.   
Patients will undergo clinical assessment within 72 hours prior to each 
administration of avelumab. After the end of treatment (i.e. 
discontinuation of avelumab) each patient will attend safety follow-up 
visits at 30 days and 90 days (extended safety follow-up) or before 
initiation of a new cancer treatment, whichever comes first. Patients 
who discontinue for reasons other than disease progression will be 
followed up every 12 weeks for disease status until progression, 
initiating new cancer treatment, withdrawing consent or loss to follow-
up.  This will be done by reviewing the medical notes, contacting the 
patient’s GP directly. Patients will remain on follow-up until death, 
withdrawal of consent, or the end of the study which is anticipated to be 
no more than 3 years and 6 months from the first administration of the 
first dose of avelumab in the first patient. 
Patients will undergo tumour assessment by RECIST 1.1 every 12 
weeks from the first dose of avelumab (irrespective of treatment 
delays) whilst they remain on therapy to establish disease response. 
They will also have a CT scan performed at 4 weeks following 
completion of RT (week 7) and 13 weeks. Additional imaging will be 
performed earlier if clinically indicated.   
 
 
 

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Funding 
  
FUNDER(S) 
(Names and contact details of all organisations 
providing funding and/or support in kind for this 
trial) 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
Merck KGaA 
Funding for phase 1 
 
 
 

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LIST OF ABBREVIATIONS 
 
ADCC   
Antibody-Dependent Cellular Cytotoxicity 
ADL 
 
Activities of daily living 
AE  
 
Adverse Event 
AIDS   
Acquired Immune Deficiency Syndrome 
ALT  
 
Alanine Aminotransferase 
ANC   
Absolute Neutrophil Count 
AR 
Adverse Reaction 
AST   
Aspartate Aminotransferase 
AUC   
Area Under the Curve 
BP  
 
Blood Pressure 
BUN   
Blood Urea Nitrogen 
CA 
Competent Authority 
CI 
Chief Investigator 
CL  
 
Clearance 
Cmax   
Maximum Plasma Concentration 
Cmin  
Minimum Plasma Concentration 
CR  
 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CT  
 
Computerized Tomography 
CTA 
Clinical Trial Authorisation 
CTCAE  
Common Terminology Criteria for Adverse Events  
ctDNA  
Circulating tumour DNA 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
 
CTLA-4  
Cytotoxic T-lymphocyte-associated protein 4 
CTV 
 
Clinical Target Volume 
DAI  
 
Dosage and Administration Instructions 
DC 
 
Dendritic Cells 
DILI 
 
Drug induced liver injury  
DLT  
 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA   
Deoxyribonucleic Acid 
DSUR 
Development Safety Update Report 
DW-MRI 
Diffusion weighted magnetic resonance imaging 
EC  
 
Ethics Committee 
ECG   
Electrocardiogram 

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ECI 
 
Evidence of Clinical Interest  
ECOG  
Easter Cooperative Oncology Group 
EDTA  
Ethylenediaminetetraacetic acid 
EMEA 
European Medicines Agency 
EOT   
End of Treatment 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
FDA   
Food and Drug Administration 
FFPE   
Formalin Fixed, Paraffin Embedded 
GCP 
Good Clinical Practice 
GGT   
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice  
GTV 
 
Gross Target Volume 
HBV   
Hepatitis B Virus 
HCV   
Hepatitis C Virus 
HIV  
 
Human Immunodeficiency Virus 
HMGB1 
High-mobility group box 1 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human use. 
ICR 
 
Institute of Cancer Research  
ICRU   
International Commission on Radiation Units and Measurements 
IEC  
 
Independent Ethics Committee 
IFN  
 
Interferon 
IHC 
 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
INR  
 
International Normalized Ratio 
irAE 
 
Immune-related AE 
IRB  
 
Institutional Review Board 
irECI  
Immune-related Events of Clinical interest 
iRECIST 
Guidelines for response criteria for use in trials testing immunotherapeutic 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials Number 
ITT 
Intention to treat 
IV 
 
Intravenous 

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LC 
 
Local Control 
LFT  
 
Liver Function Test 
LLN 
 
Lower limit normal 
MA 
Marketing Authorisation 
mAb   
Monoclonal Antibody 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI  
 
Magnetic Resonance Imaging 
MS 
Member State 
MTD   
Maximum Tolerated Dose 
NCI  
 
National Cancer Institute 
NHS R&D 
National Health Service Research & Development   
NIMP 
Non-Investigational Medicinal Product 
NK 
 
Natural Killer 
NSAIDs  
Nonsteroidal Anti-inflammatory Drugs 
OAR 
 
Organs at risk 
ORR   
Objective Response Rate 
OS  
 
Overall Survival 
OTC 
 
Over-the-counter 
PBMC  
Peripheral Blood Mononuclear Cells 
PD  
 
Progressive Disease 
PD-1   
Programmed Death-1 
PD-L1   
Programmed Death-Ligand 1 
PFS   
Progression-Free Survival 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
PK  
 
Pharmacokinetics 
PP 
Per protocol 
PR  
 
Partial Response 
PS  
 
Performance Status 
PT  
 
Prothrombin Time 
PTV 
 
Planning Target Volume 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RECIST  
Response Evaluation Criteria in Solid Tumours 

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RM  
 
G-SOPs 
RNA   
Ribonucleic Acid 
RT 
 
Radiotherapy 
RTOG  
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SAR 
 
Serious Adverse Reaction 
 
SAR 
Serious Adverse Reaction 
SD  
 
Stable Disease 
SDV 
Source Data Verification 
SMC  
Safety Monitoring Committee 
SmPC 
Summary of Product Characteristics  
SOP 
Standard Operating Procedure  
SPC 
 
Summary of Product characteristics 
SRC 
 
Safety Review Committee 
SSI 
Site Specific Information 
StD 
 
Standard Deviation 
STS 
 
Soft tissue sarcoma 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
T4 
 
free thyroxine 
TEAE   
Treatment Emergent Adverse Event 
TIL  
 
Tumour Infiltrating Lymphocytes 
TMF 
Trial Master File 
TMG  
Trial Management Group 
TO 
 
Target occupancy 
Treg 
 
Regulatory T cells 
TSC 
 
Trial Steering Committee 
TSH   
Thyroid Stimulating Hormone 
ULN   
Upper Limit of Normal 
USM  
Urgent safety measures 
WBC   
White Blood Cell 

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Table of Content 
Signature Page ............................................... Error! Bookmark not defined. 
Role of Study Sponsor and Funder ......................................................... 3 
Role of Other Protocol Contributors ....................................................... 4 
Roles and Responsibilities of Trial Management Committees/ Groups 
& Individuals .................................................................................... 4 
Trial Summary ........................................................................................... 4 
1.1 
Pharmaceutical and Therapeutic Background ........................................... 22 
2 
Rationale ........................................................................................ 23 
2.1 
Rationale for combining anti-PD-L1 with radiation .................................... 23 
2.2 
Preclinical and Clinical Trial Data on Avelumab ........................................ 25 
2.3 
Rationale for the Trial and Selected Subject Population ........................... 25 
2.4 
Rationale for Dose Selection/Regimen/Modification ................................. 26 
2.4.1 
Pharmacokinetics and Target Occupancy ................................................................. 26 
2.4.2 
Clinical Safety Data Related to Dose .......................................................................... 27 
2.4.3 
Conclusion ................................................................................................................... 28 
2.5 
Rationale for Endpoints ................................................................................ 28 
2.5.1 
Safety, Tolerability, Progression free survival and Overall survival Endpoints ...... 28 
2.5.2 
Efficacy Endpoints (Toxicity, PFS and OS, Abscopal effect, and Biomarker 
research) .................................................................................................................................... 29 
3 
Objectives and Endpoints ............................................................. 31 
3.1 
Objectives ....................................................................................................... 33 
3.1.1 
Primary Objective ........................................................................................................ 33 
3.1.2 
Secondary Objectives ................................................................................................. 33 
3.1.3 
Exploratory Objectives ............................................................................................... 34 
3.2 
Endpoints ....................................................................................................... 34 
3.2.1 
Primary Endpoint......................................................................................................... 34 
3.2.2 
Secondary Endpoints .................................................................................................. 34 

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3.2.3 
Exploratory Endpoints ................................................................................................ 35 
4 
Trial Design .................................................................................... 35 
4.1 
Overall Study Design ..................................................................................... 35 
4.2 
Treatment Regimen ....................................................................................... 36 
4.2.1 
Dose Levels ................................................................................................................. 36 
4.2.2  
Study Flow Chart ......................................................................................................... 38 
4.3 
Follow-Up ....................................................................................................... 38 
4.3.1 
30 day Safety Follow-up .............................................................................................. 38 
4.3.2  
Extended Safety Follow-up ......................................................................................... 39 
4.3.3  
Follow-up ..................................................................................................................... 39 
4.3.4  
Survival Follow-up ....................................................................................................... 39 
4.4  Study Termination ......................................................................................... 39 
4.4.1 
Clinical Criteria for Early Termination ........................................................................ 39 
4.5 
Treatment after Study Termination .............................................................. 40 
5 
STUDY SETTING ............................................................................ 40 
6 
Eligibility Criteria ........................................................................... 40 
6.1 
Inclusion criteria ............................................................................................ 41 
6.2 
Exclusion criteria ........................................................................................... 42 
7 
Trial Procedures ............................................................................ 45 
7.2 
Administrative Procedures/Assessments ................................................... 46 
7.2.1 
Informed Consent ........................................................................................................ 46 
7.2.2 
Inclusion/Exclusion Criteria ....................................................................................... 47 
7.2.3 
Demographic Data, Medical History and Treatment History .................................... 47 
7.2.5 
Survival Status ............................................................................................................ 48 
7.2.6 
Prior and Concomitant Medications Review ............................................................. 48 
7.2.6.1 
Prior Medications ................................................................................................. 48 
7.2.6.2 
Concomitant Medications .................................................................................... 48 
7.3 
Clinical Procedures/Assessments ............................................................... 48 
7.3.1 
Adverse Event (AE) Monitoring .................................................................................. 48 
7.3.2 
Radiation Toxicity Assessment .................................................................................. 49 
7.3.3 
Full Physical Exam ...................................................................................................... 49 

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7.3.4 
Directed Physical Examination ................................................................................... 49 
7.3.5 
Vital Signs .................................................................................................................... 49 
7.3.6 
Eastern Cooperative Oncology Group (ECOG) Performance Status ....................... 49 
7.3.7 
Pregnancy Tests .......................................................................................................... 50 
7.3.8 
Haematology, Clinical Biochemistry and Urinalysis (β-hCG, PT, aPTT, T3,T4 and 
TSH) 
50 
. ................................................................................................................................................... 51 
7.3.9 
Tumour Imaging and Assessment of Disease ........................................................... 51 
7.3.9.1 
Baseline Tumour Imaging .................................................................................... 51 
7.3.9.2 
Follow-Up Tumour imaging ................................................................................. 52 
7.3.10 
Tumour Tissue Collection and Correlative Studies Blood Sampling ...................... 52 
7.3.10.1 
Archival Tumour Tissue Samples ....................................................................... 52 
7.3.10.2 Tumour Biopsies and Research Blood Samples ................................................... 52 
7.4 
Subject replacement Strategy ...................................................................... 53 
8.0 
Treatments ..................................................................................... 53 
8.1 
Trial Treatments ............................................................................................. 53 
8.2 
Standard Treatment-Radiotherapy............................................................... 53 
8.2.1 
Selection of sites suitable for radiotherapy ............................................................... 54 
8.2.2 
Patient Preparation and Positioning .......................................................................... 54 
8.2.3 
Scan Limits and Slice Thickness ............................................................................... 54 
8.2.4 
Localisation of the target volume and organs at risk (OAR), Volume Definition. ... 54 
8.2.5 
Radiotherapy Treatment Administration ................................................................... 55 
8.3 
Trial Treatment-Avelumab ............................................................................ 55 
8.3.1 
Investigational Product ............................................................................................... 55 
8.3.2 
Product Preparation .................................................................................................... 55 
8.3.3 
Storage and Handling ................................................................................................. 55 
8.3.3.1 
Storage .................................................................................................................. 56 
8.3.3.2 
Handling ................................................................................................................ 56 
8.3.4 
Supply, Packaging and Labelling information .......................................................... 57 
8.3.5 
Returns and Reconciliation ........................................................................................ 57 
8.3.6 
Dose Selection ............................................................................................................. 57 
8.3.7 
Administration of Avelumab ....................................................................................... 58 
8.3.8 
Dose Modification ........................................................................................................ 59 

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8.3.9 
Timing of Dose Administration ................................................................................... 62 
8.3.10 
Trial Blinding/Masking ................................................................................................ 62 
8.4 
Concomitant Medications/Vaccinations (allowed and prohibited) ........... 62 
8.4.1 
Acceptable Concomitant Medications ....................................................................... 62 
8.4.2 
Prohibited Concomitant Medications ......................................................................... 63 
8.5 
Rescue Medications and Supportive Care .................................................. 63 
8.5.1 
Supportive Care Guidelines ........................................................................................ 63 
8.5.1.1 
Diarrhoea: ............................................................................................................. 63 
8.5.1.2 
Nausea/vomiting: ................................................................................................. 64 
8.5.1.3 
Anti-infectives ....................................................................................................... 64 
8.5.1.4 
Immune-related adverse events: ......................................................................... 65 
8.5.1.5 
Management of Infusion Reactions: ................................................................... 65 
8.5.2 
Supportive Care Guidelines for Immune-related Adverse Event (irAE) and Immune-
related Events of Clinical interest (irECI) ................................................................................. 66 
Immune-Related Adverse Events .......................................................................................... 66 
8.5.3 
Supportive Care Guidelines for Pneumonitis ............................................................ 72 
8.6 
Diet/Activity/Other considerations ............................................................... 72 
8.6.1 
Diet ............................................................................................................................... 72 
8.6.3 
Use in Pregnancy and Nursing Women ..................................................................... 74 
8.7 
Treatment of Overdose of IMP...................................................................... 74 
8.8 
Permanent Discontinuation of Trial Medication and Withdrawal from 
Study ........................................................................................................................ 74 
8.8.1 
Permanent Discontinuation of Trial Medication ........................................................ 75 
8.9 
Withdrawal from the Study ........................................................................... 75 
9 
Pharmacovigilance ........................................................................ 76 
9.1 
Definition of an Adverse Event (AE) ............................................................ 76 
9.1.1 
Disease Progression ................................................................................................... 76 
9.1.2 
New Cancers ................................................................................................................ 77 
9.1.3 
Abnormal Laboratory Test Results ............................................................................ 77 
9.1.4 
Pregnancy and Lactation ............................................................................................ 77 
9.1.5 
Radiotherapy toxicities ............................................................................................... 77 
9.2 
Assessing and Recording Adverse Events ................................................ 77 
9.2.1 
Evaluating Adverse Events ......................................................................................... 78 

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9.2.1.1 
Determining AE Severity and Grade ................................................................... 78 
9.2.1.2 
Determining AE Causality .................................................................................... 79 
9.2.2 
Reporting of Pregnancy and Lactation ...................................................................... 80 
9.3 
Definitions of Serious Adverse Events (SAE) ............................................. 80 
9.4 
Definitions of Events of Clinical Interest (ECI) ........................................... 81 
9.5.1 
Events exempt from being reported as SAEs ........................................................... 83 
9.5.2 
Determining SAE Expectedness ................................................................................ 83 
9.6 
Reporting of ECIs .......................................................................................... 84 
9.7 
Definition of an Overdose for this Protocol and Reporting of Overdose. 84 
9.8 
Definition of Serious Adverse Reaction (SAR) ........................................... 85 
9.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions 
(SUSARS) ................................................................................................................. 85 
9.10 
Reporting of SUSARS ................................................................................ 85 
9.11 
Annual Reporting of Serious Adverse Events ......................................... 85 
9.12 
Urgent Safety Measures ............................................................................. 85 
9.13 Safety reporting to Merck KGaA ................................................................... 86 
10 
Statistics and Data Analysis ......................................................... 86 
10.1 
Sample size calculation ............................................................................. 86 
10.2 
Planned recruitment rate ........................................................................... 87 
10.3 
Subject Analysis Population ..................................................................... 87 
10.4 
Statistical analysis plan summary ............................................................ 87 
10.4.1 
Primary and secondary outcome and exploratory analysis methods ..................... 88 
10.5 
Timing and responsibility for analyses .................................................... 89 
11 
Data Handling ................................................................................ 89 
11.1 
Source Data ................................................................................................. 89 
11.2 
Language ..................................................................................................... 89 
11.3 
Data Collection ............................................................................................ 90 
11.4 
Recording of Data ....................................................................................... 90 
11.5 
Data Management ....................................................................................... 90 
12 
Trial Oversight, Monitoring, Inspection and Audit ........................ 91 
12.1 
Study Management Structure .................................................................... 91 
12.1.1 
Delegations of Responsibilities .................................................................................. 91 

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12.2 
Protocol compliance and amendments .................................................... 92 
12.3 
Trial Management ....................................................................................... 92 
12.3.1 
Trial Management Group (TMG) & Safety Review Committee (SRC) ....................... 92 
12.4 
Monitoring ................................................................................................... 93 
12.5 
Quality Control and Quality Assurance .................................................... 93 
12.6 
Clinical Study Report ................................................................................. 93 
12.7 
Record Retention ........................................................................................ 93 
13  
Ethical and Regulatory Considerations ....................................... 94 
13.1 
Good Clinical Practice................................................................................ 94 
13.2 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 94 
13.2.1 
Initial Approval ............................................................................................................ 94 
13.2.2 
Approval of Amendments ........................................................................................... 95 
13.2.3 
Annual Safety Reports and End of Trial Notification ................................................ 95 
13.3 
Regulatory Authority Approval ................................................................. 95 
13.4 
Notifications of Serious Breaches to GCP and / or the Protocol ........... 95 
13.5 
Insurance and Liability ............................................................................... 96 
13.6 
Contact with General Practitioner (GP) .................................................... 96 
13.7 
Patient Confidentiality ................................................................................ 96 
13.7.1 
Patient Confidentiality and Data Sharing ................................................................... 96 
13.7.2 
Pharmacogenetics Confidentiality ............................................................................. 97 
13.8 
Data collection and documentation .......................................................... 97 
13.9 
End of Trial .................................................................................................. 98 
13.10 Post trial access ......................................................................................... 98 
14  
Dissemination policy and Authorship eligibility guidelines ........ 98 
15 
References ...................................................................................... 99 
16.  Appendices ................................................................................... 103 
16.1 
Appendix 1: Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) ................................................................................................................. 103 
16.2 
Appendix 2: RTOG Toxicity ..................................................................... 103 
16.3 
Appendix 3: Response Evaluation Criteria in Solid Tumours (RECIST) 
1.1 Criteria for Evaluating Response in Solid Tumours .................................... 106 

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16.4 
Appendix 4: Immune-Related Response Criteria .................................. 106 
The immune RECIST(iRECIST)* will also be used in this study for assessment 
of tumour response. ............................................................................................. 106 
16.5 
Appendix 5:  Management of Avelumab-Specific Adverse Events or 
Adverse Drug Reactions ...................................................................................... 106 
Severe Hypersensitivity Reactions  and Flu-Like Symptoms ........................................... 106 
Immune-Related Adverse Events ........................................................................................ 108 
16.6 
Appendix 6: Management of Pneumothorax ......................................... 109 
    16.7     Appendix 7: Amendment History   ………………………….....................109 
 
 
 
 
 
 
 
 

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1 
Background 
 
1.1 
Pharmaceutical and Therapeutic Background 
 
Avelumab (also referred to as MSB0010718C) is a fully human IgG1 antibody directed against PD-L1. 
Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. 
This removes the suppressive effects of PD-L1 on anti-tumour CD8+ T cells, resulting in the 
restoration of cytotoxic T ligands, PD-L1 and PD-L2, PD-1 delivers a series of strong inhibitory signals 
through its cytoplasmic tail to inhibit T cell functions (Chemnitz et al 2004, Keir et al 2008, Riley 2009).  
PD-L1 (also called B7-H1 and CD274) can be detected on resting and activated T cells, B cells, 
macrophages, dendritic cells, and mast cells; PD-L1 expression is greatly up-regulated after activation 
or interferon treatment (Keir et al 2008). Numerous results from in vitro cellular assays have 
demonstrated that blockade of the PD-1/PD-L1 interaction enhances T cell responses, such as 
increases in proliferation and cytokine production (Bennett et al 2003, Blank et al 2004, Blank et al 
2006, Brown et al 2003, Dong et al 1999, Freeman et al 2000, Waeckerle-Men et al 2007). In PD-1–/– 
mice both T and/or B cells responses are unregulated resulting in an array of autoimmune pathologies 
(Okazaki and Honjo 2006, Okazaki and Honjo 2007). Breaking tolerance through blocking PD-1 
interaction with its ligands, and thus PD-1 signaling, can be applied to enhance T cell activity towards 
chronic pathologies such as cancer (Blank et al 2005).  
External (Okazaki and Honjo 2007) and internal immunohistochemistry studies have demonstrated 
that PD-L1 is also expressed by a variety of human tumours, both by the tumour cells, as well as by 
the immune cells that are present in the tumour microenvironment. In contrast to very strong 
expression on syncytiotrophoblasts in the placenta and in cancer cells, low levels of PD-L1 expression 
were detected in some normal tissues including fetal cardiac tissue (Brown et al 2003). High levels of 
PD-L1 expression have been found to be associated with disease progression, increased metastasis, 
poor response to treatment, and decreased survival in a number of human cancers (Okazaki and 
Honjo 2007). Importantly anti-PD-L1 blockade has demonstrated therapeutic efficacy in a variety of 
murine tumour models as monotherapy and has shown synergistic effect in combination therapy 
setting (Blank et al 2004, Hirano et al 2005, Iwai et al 2002, Iwai et al 2004, Nomi et al 2007, Strome 
et al 2003, Zhang et al 2009). 
The antitumour activity of avelumab has been investigated in various murine tumour models. Inhibition 
of the PD-1/PD-L1 interaction is proposed to exert a therapeutic effect by restoring anti-tumour CD8+ 
T cell responses.  
To circumvent the need for a surrogate antibody, the lead candidate antibody was specifically selected 
for cross-reactivity to murine PD-L1, and, as consequence all of the nonclinical studies were 
conducted in syngeneic murine tumour models in which the immune system of the host is fully intact. It 

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was demonstrated that the inhibition of the PD-1/PD-L1 interaction restores anti-tumour CD8+ T cell 
responses, which results in an anti-tumour activity.  
Avelumab has demonstrated significant nonclinical activity as a monotherapy and in various 
combination therapy settings. In general, the anti-tumour immunotherapy via blockade of the PD-
1/PD-L1 axis seems not to be limited to any specific tumour types, but there is recent evidence that 
PD-L1 tumour expression is a pre-requisite to achieve an objective response upon blockade of the 
PD-1/PD-L1 axis (Topalian et al 2012b). The clinical relevance of PD-1/PD-L1 blockade has been 
demonstrated in Phase I trials performed with antibodies targeting either PD-L1 or PD-1 (Topalian et 
al 2012b, Brahmer et al 2012).  
Given the important role of PD-L1 in the suppression of T-cell responses, and the mode of action of 
avelumab which blocks the interaction between PD-L1 and its receptors, avelumab is being developed 
as a potential therapy for subjects with various tumours. 
 
2 
Rationale  
 
2.1 
Rationale for combining anti-PD-L1 with radiation 
 
There has been a recent shift in thinking that radiotherapy is a localised treatment and it is now 
accepted that it may mediate some of the anti-tumour response through systemic effects. Although 
radiotherapy has been used as an immunosuppressive agent in total body irradiation as conditioning 
prior to bone marrow transplant, it is also able to act as an immune stimulant in solid tumours 
(Sologuren et al 2014).  Radiation damage results in necrotic and apoptotic cell death releasing large 
amounts of tumour antigens.  These tumour associated antigens are available for uptake and 
processing by antigen presenting cells including dendritic cells and can lead to a specific anti-tumour 
immune response (Burnette et al 2013).  
Radiotherapy creates an inflammatory tumour microenvironment by inducing proinflammatory 
cytokines that can cause tumour growth inhibition and cell death.  In addition, there is upregulation of 
MHC class I, costimulatory molecules, adhesion molecules and death receptors on tumour cells and 
surrounding stroma potentiating the CD8+ T cell cytotoxic cell responses.  Radiation induced cell 
damage leads to increased expression of markers of immunogenic cell death including translocation of 
calreticultin to the tumour cell surface and release of high-mobility group box 1 (HMGB1) which can 
activate dendritic cells.   
Although radiotherapy has traditionally been delivered using low dose per fraction (between 1.8 and 
2.0 Gy), there is evidence that giving a higher dose per fraction (greater than 2.0 Gy or 

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hypofractionation) may mediate more favourable immunological effects, generating a CD8+ T cell anti-
tumour response (Burnette et al 2015).  Unfortunately, although radiotherapy has the potential to offer 
both local control and treat metastatic disease, this effect does not translate into a meaningful clinical 
response due to tumour evasion of the immune response by either immune tolerance or suppression.  
If the radiotherapy induced immune response could be improved, this may translate into improved 
clinical outcomes.   
Cancer immune tolerance is driven by several mechanisms including loss of MHC expression, and 
upregulation of inhibitory molecules of immune response including PD-1.  Although the critical role of 
the immune system in mediating the therapeutic response following radiotherapy has been known 
over the last 40 years, we have only recently combined radiation and immunotherapy in increasing 
numbers in the preclinical and clinical setting.   
There have been many pre-clinical in vivo studies conducted combining immunotherapeutic agents 
including anti-CTLA-4, Flt3 ligand, viral therapies and anti-PD-1 agents with radiotherapy in multiple 
tumour types. Most studies demonstrate an enhanced tumour response that was CD8+ cell dependent 
with evidence of increased CD8+ T cell activation.  The pre-clinical mouse models also suggest that 
hypofractionated radiotherapy is more beneficial although the optimum schedule has not been 
defined.  Multiple fractionation schedules have been investigated in studies, including 5 x 3 Gy, 5 x 6 
Gy, 3 x 8 Gy, 1x 15 Gy, and 1 x 20 Gy, either in isolation or with monoclonal antibodies again CTLA-4, 
and more recently PD-1.  A few studies demonstrated control of both the primary tumour and a distant 
secondary tumour.  Most studies demonstrated either an increase in the CD8+ response or reduction 
in the Treg population.  It remains unclear as to the optimum radiotherapy dose, and fractionation 
schedule.  This clinical trial will provide more information on the T cell response in the clinical setting 
and provide information to design future radiotherapy and anti-PD-L1 therapy combination studies.   
Many cancers including soft tissue sarcoma have demonstrated increased expression of PDL1 ( Kim 
et al 2013, Kim et al 2016).   Retrospective analysis of paired soft tissue sarcoma tumour samples pre- 
and post-radiotherapy have demonstrated changes in immune-related signatures suggesting scope for 
combining radiotherapy with immunotherapy (Sharma et al 2013).  A mouse soft tissue sarcoma 
model demonstrated combining radiotherapy with intra-tumoural DC therapy resulted in an enhanced 
anti-tumour effect with an accompanying tumour-specific immune response (Teitz-Tennenbaum et al 
2013).  Clinical studies are now combining immunotherapy with radiation in patients with soft-tissue 
sarcoma.  One study combined pre-operative radiotherapy with intratumoural injections of DC, 
resulting in a peripheral blood immune response with no increase in toxicity (Finkelstein  et al 2012). 
 
 

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2.2 
Preclinical and Clinical Trial Data on Avelumab 
 
Refer to the current version of the Investigator’s Brochure for Preclinical and Clinical data. 
 
2.3 
Rationale for the Trial and Selected Subject Population 
 
Soft-tissue sarcomas (STS) are a rare heterogeneous group of neoplasms arising from mesenchymal 
tissue. The median survival for patients with metastatic STS is between 12 and 18 months (Harris et 
al, 2015).  Extremity soft-tissue sarcomas (eSTS) most frequently metastasise to the lung.  Metastatic 
STS patients are usually incurable and treated with systemic therapies, focusing on palliating 
symptoms, preventing disease progression and potentially prolonging survival (Linch et al, 2014).  
 
Radiotherapy (RT) provides good local palliation in patients with metastatic STS.  The standard of 
care in this cohort of patients is a short course of hypofractionated RT (fraction dose above 2 Gy) to 
control symptoms and offer local disease control concurrent or sequential to chemotherapy.  Although 
the majority of patients respond to RT, they frequently develop progressive disease at other sites.  
When managing patients with several metastases, it can sometimes be difficult to irradiate multiple 
sites concurrently without causing an unacceptable level of radiation-induced toxicity.   
 
The recent success of immune checkpoint inhibitors in melanoma and other solid tumours has bought 
immunotherapy to the forefront of cancer therapy. One cell surface protein, programmed death 
receptor 1 (PD-1) has been recently targeted with the checkpoint inhibitor, Pembrolizmab, in advanced 
melanoma with durable responses translating into a significant survival benefit (Ribas et al, 2015).  
Several monoclonal antibodies to PD-1 or programmed death ligand 1 (PD-L1) are currently being 
developed.  Avelumab is a fully human IgG1 antibody that inhibits PD-L1, and is being tested across 
several tumour types in early phase clinical trials (Kelley et al 2015). Unlike other monoclonal 
antibodies to PD-1/PD-L1, Avelumab has been designed with the unique ability to mediate antibody-
dependent cell-mediated cytotoxicity (ADCC), by inducing natural killer (NK) mediated tumour cell 
lysis.    
 
There is a strong rationale for using immunotherapy in STS based on the underlying disease biology 
(genetic aberrations and complex chromosomal translocations). Chromosomal translocations resulting 
in fusion proteins (seen in some STS subtypes) represent attractive targets for immunotherapy.  High 
expression of cancer testis antigen may also represent potential targets (NY-ESO-1 is expressed in 
synovial sarcoma and myxoid liposarcoma).  Other STS subtypes express mutations that are also 
potential targets for immunotherapy (myxofibrosarcoma).  The role of the PD-1 axis in STS is currently 
being investigated, and PD-1 staining in tumour infiltrating lymphocytes and PD-L1 overexpression in 

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tumour samples may correlate with a poorer prognosis (Kim JR et al, 2013).   The initial checkpoint 
inhibitor trials in soft tissue sarcoma suggested targeting PD-1 alone in all STS subtypes did not result 
in tumour shrinkage (Paoluzzi et al, 2016; Tawbi et al 2016).  Although tumour responses were seen 
in patients with undifferentiated pleomorphic sarcoma, it was suggested that another treatment may be 
needed to make these tumours more immunogenic.   
 
Radiotherapy can cause immunogenic cancer cell death, resulting in cross-priming of tumour-specific 
T-cells, and increased NK cell cytotoxicity, acting as an in situ tumour vaccine.  However, RT alone 
rarely induces a prolonged or effective anti-tumour immunity. There is a strong rationale to combine 
immunotherapy with RT in an attempt to introduce more robust anti-tumour immunity (Formenti SC et 
al 2013).   
 
In this study we will irradiate an involved solitary thoracic, trunk or limb tumour deposit, radiation target 
volume between the neck and the diaphragm) in patients with metastatic STS, in combination with PD-
L1 inhibition (Avelumab).  The inclusion of a limited number of patients with extremity disease should 
not adversely affect conclusions about treatment tolerability.      
 
We aim to generate a cytotoxic CD8 T-cell response resulting in an abscopal effect.  We also wish to 
exploit the ability of Avelumab to activate the innate immune system through ADCC and enhance 
radiation-induced NK cytotoxicity. Using a higher dose per fraction RT schedule may induce more 
immunogenic cell death and cause immune priming. Combining this with PD-L1 blockade (and ADCC) 
should enhance the RT-induced immune response. From our experience, tumour deposits, located in 
the extremities, thorax, and trunk are amenable to treatment with a biologically effective dose of 
hypofractionated radiotherapy.  
 
2.4 
Rationale for Dose Selection/Regimen/Modification 
 
In this clinical trial, the Avelumab  dose will be fixed at 10 mg/kg, administered intravenously (iv) once 
every 2 weeks.  This dose was selected for the expansion cohorts of Phase I trials, the Phase II 
pivotal trial (EMR 100070-003), and the ongoing Phase III trials based on the preliminary 
pharmacokinetic (PK), target occupancy, and preliminary clinical safety data collected in the clinical 
trials (see section below). 
 
2.4.1 Pharmacokinetics and Target Occupancy 
 

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Avelumab plasma levels leading to full programmed death ligand 1 (PD-L1) receptor target occupancy 
(TO) on peripheral blood monoculear cells (PBMC) resulted in tumour growth inhibition in a murine 
disease model. Therefore, full TO on PBMCs can be considered a PD marker for the ability of 
avelumab to act on its target and to show clinical activity.  Preliminary PK data from EMR 100070-001 
show that the concentration at the end of dose interval (Cmin) increased more than proportionally to 
dose between 1 to 10 mg/kg, but proportionally for doses above 10 mg/kg. Consistently the t1/2 also 
increased with the dose. However, the average value was 102 and 120 hours for 10 mg/kg and 20 
mg/kg, respectively, with no significant difference between these two dose groups. This PK 
characteristic suggests that target mediated drug disposition is involved in the clearance of avelumab 
and a high PD-L1 TO is likely achieved at the trough concentration for doses of 10 mg/kg and 20 
mg/kg.  The in vitro target occupancy data further support that a high TO is likely achieved at 10 mg/kg 
and above.  
• 
Target occupancy was measured ex vivo by flow cytometry on peripheral blood CD3+ T cells 
from patients (n=9) treated with avelumab. After the first dose of the initial dose-escalation 
portion of Trial EMR 100070-001, the observed mean target occupancy reached a plateau of 
about 90% on Day 15 pre-dose for dose levels of 3 mg/kg and above.  
• 
In addition, in vitro target occupancy was measured using flow cytometry on peripheral blood 
CD3+ T cells from 8 healthy volunteers after spiking avelumab over a concentration range of  
0.003 to 10 μg/mL. A 50% target occupancy was observed at a drug concentration (standard 
deviation [StD]) of 0.122 (0.042) μg/mL, and a concentration of 1 μg/mL avelumab was 
required for > 95% target occupancy. Based on these data and the trough serum levels 
observed in EMR 100070-001, target occupancy was projected to reach or exceed > 95% 
throughout the entire dosing interval for 10/13 subjects at 3 mg/kg, and for all (15/15) subjects 
at 10 mg/kg group from dose escalation group in EMR 1000700-001. 
Based on the ex vivo peripheral blood CD3+ T cell and in vitro target occupancy results, the dose of 
10 mg/kg every 2 weeks is expected to achieve target saturation during the entire dosing interval in 
the majority of patients. 
 
2.4.2 Clinical Safety Data Related to Dose 
 
As of the safety cut-off date of 05 November 2015, 1353 subjects have received at least 1 dose of 
avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, of which 1315 
have received the proposed dose of 10 mg/kg (15 in the dose escalation part of the study and 1300 
subjects in the pooled expansion cohort).  In the dose escalation portion of the Phase I study, there 
was no evidence of differences in the safety profile across all administered dose levels from 1 mg/kg 
to 20 mg/kg. The MTD was not reached. Ongoing review of the safety data by the Safety Monitoring 

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Committee (SMC) suggests an acceptable safety profile of avelumab administered at the 10 mg/kg 
every 2 weeks dose and schedule. Treatment-related treatment-emergent adverse events (TEAEs) 
were observed in 813 (62.5%) subjects in the pooled expansion cohort. The most frequently observed 
treatment related TEAEs (incidence > 5%) were fatigue (212 subjects, 16.3%), infusion-related 
reaction (209 subjects, 16.1%), nausea (108 subjects, 8.3%), chills (102 subjects, 7.8%), diarrhoea 
(79 subjects, 6.1%), and pyrexia (72 subjects, 5.5%). Grade ≥ 3 treatment-related TEAEs were 
observed in 124 subjects (9.5%) in the pooled expansion cohort. The most frequently reported Grade 
≥ 3 treatment related TEAEs were gamma-glutamyl transferase increased (GGT) and infusion-related 
reaction (each occurred in 9 subjects; 0.7%). Infusion-related reactions including drug hypersensitivity 
reactions and immune-mediated adverse reactions have been identified as expected adverse drug 
reactions of avelumab. The safety profile of avelumab is consistent with findings reported for other 
anti-PD-1 or anti-PD-L1 antibodies with data demonstrating immune-mediated colitis rate of 7.5% 
(Hassan et al, 2016) and immune-mediated pneumonitis rate of 2.9% (Investigator’s Brochure).   In 
conclusion, preliminary data from EMR 100070-001 showed that avelumab at doses up to 20mg/kg IV 
every 2 weeks was well tolerated, and the dose of 10 mg/kg iv every 2 weeks was considered to have 
an acceptable safety profile for further investigation in clinical studies. 
 
2.4.3 Conclusion 
 
Based on the PK results and the receptor occupancy data, sufficient trough concentrations appear to 
be achieved for full TO in the blood in the majority of subjects receiving the 10 mg/kg dose.  Within the 
dose range of 1 mg/kg to 20 mg/kg, avelumab was well tolerated and is deemed to have an 
acceptable safety profile.  Based on the above analyses, a dose of 10 mg/kg iv once every 2 weeks is 
considered to have a favourable risk benefit profile and thus represents an appropriate dose for further 
investigation in registration studies of avelumab. 
 
2.5 
Rationale for Endpoints 
 
2.5.1 Safety, Tolerability, Progression free survival and Overall survival Endpoints 
 
The primary objective of this study is to determine the safety and tolerability of combining avelumab 
with hypofractionated radiotherapy.  This particular radiotherapy regimen is well tolerated, with a less 
than 5% risk of pneumonitis and less than 5% risk of colitis.  Recently reported data demonstrate an 
avelumab colitis rate of 7.5% (Hassan et al, 2016). This study will combine these two treatments and 
will focus on ≥grade 2 pneumonitis (during radiotherapy not resolving to grade 2 within 72 hours of 
medical management) as the principle DLT. In the first three patients recruited, if ≥2 develop a DLT 

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the Safety Review Committee (SRC) will review the data and recommend either study termination or 
dose reduction to 3mg/kg. If 1 of the initial three patients recruited develops oesophagitis of ≥grade 4, 
or 2 patients develop myelitis of ≥grade 2, these events would lead to premature study termination.  
However, if these adverse events occurred in patients 4, 5 or 6, they would lead to dose de-escalation 
to 3mg/kg and the cohort would be expanded to 12 patients.  An overview of study recruitment is 
depicted in Figure 1. 
Tolerability will be assessed by documenting all AEs and serious adverse events (SAEs). Currently, 
the median PFS is 5 months and median OS is 12 months.  The secondary endpoint of this study will 
include Progression free survival (PFS) and overall survival (OS). We expect combining avelumab 
with radiotherapy and continuing into a maintenance phase will improve the PFS and OS. 
 
2.5.2 Efficacy Endpoints (Toxicity, PFS and OS, Abscopal effect, and Biomarker research) 
 
Acute and late toxicity as assessed by CTCAEv4 will be used to judge the tolerability of combining 
avelumab with radiotherapy.  Local control will be assessed by CT or MRI (extremity disease only, 
unless contraindication then CT).  Distant control at 3 months will be assessed by CT imaging.  
Patients receiving maintenance therapy will have imaging (CT) repeated every 3 months until 
progression, discontinuation of avelumab due to toxicity or removal from the study. Patients will also 
have a CT scan performed 4 weeks following completion of RT (week 7). Additional imaging may be 
performed earlier dependent on clinical symptoms.   
The abscopal effect is a rare phenomenon observed in the treatment of metastatic cancer where 
localised radiation of a specific tumour site results in tumour regression in a distant site outside of the 
irradiated volume. Although the exact mechanisms are unknown, the process is thought to be 
mediated by the immune system (Demaria et al 2004).  It is possible that combining radiotherapy with 
immune checkpoint inhibition may result in a robust abscopal effect, leading to clinically meaningful 
anti-tumour responses and disease control. In this single arm study, we will conduct an exploratory 
analysis of this phenomenon by determining individual lesion response outside the irradiated area 
(using RECIST v1.1).        
Newly collected tumour samples from the irradiated STS deposit will be obtained pre- and 7 weeks 
post- treatment for PD-L1 expression and biomarker research. These will be paired with optional 
tumour biopsies outside the irradiated field at identical time points. The tumour biopsies are done if 
patient consents and if this is deemed safely accessible for PD-L1 expression and biomarker 
research. Correlative blood samples will be taken at baseline, during and 4 weeks post radiotherapy 
for characterization of T cell functionality.  Circulating tumour DNA analysis will also be performed. 
Preclinical translational research will be performed at the Institute of Cancer Research, London, and 

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The Leeds Institute for Cancer and Pathology (see below).  Samples will be banked for future 
analysis.  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Recruit Patient 1 
 Recruit Patients  2 - 3 
Wait two weeks 
 Dose Limiting  
Toxicity (DLT) 
 No Dose Limiting 
Toxicity (DLT) 
 Review 
STOP 
 Dose Reduction 
to 3mg/kg 
 Dose Limiting  
Toxicity in 2/3 
 Dose Limiting  
Toxicity in 0 – 1/3 
 Recruit Patients  4 - 6 
 Dose Limiting  
Toxicity (DLT) 
 No Dose Limiting 
Toxicity (DLT) 
 Review 
STOP 
 Dose Reduction 
to 3mg/kg 
 Dose Limiting  
Toxicity in ≥2/6 
 Dose Limiting  
Toxicity in ≤1/6 
 Recruit Patients 7 - 12 
 Safety Review Committee 
n=3 
 Safety Review Committee 
n=6 

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Figure 1 APPLE Recruitment Flow Chart 

 
 
 
3 
Objectives and Endpoints 
 
3.1 
Objectives 
 
3.1.1 Primary Objective 
 
Objective: To assess the safety and tolerability of combining hypofractionated radiotherapy (36 Gy in 
12 fractions delivered daily over 2.5 weeks), with avelumab, an anti-PD-L1 antibody, treating 
advanced STS.  
Hypothesis: Avelumab combined with hypofractionated radiotherapy in advanced STS is safe and well 
tolerated in the acute setting (i.e. from first combined administration of patient’s radiotherapy and 
avelumab to a point 11 weeks from the start of the patient’s radiotherapy), coincident with 
administration of cycle 6 of avelumab.  
 
3.1.2 Secondary Objectives 
 
Objective: To evaluate local control rates at 3 months achieved by combining avelumab with 
hypofractionated radiotherapy (based on CT/diffusion-weighted MRI). 
Hypothesis: Avelumab combined with hypofractionated radiotherapy will improve the local control rate.   
Objective: To evaluate progression free (PFS) and overall survival (OS). 
Hypothesis: Combining avelumab with RT and with maintenance treatment leads to prolonged 
responses following palliative RT.  
Objective: To evaluate acute toxicity, defined as toxicity occurring up to 11 weeks following initiation of 
combined radiotherapy and avelumab. 
Hypothesis: Avelumab combined with hypofractionated radiotherapy in advanced STS does not result 
in unacceptable acute toxicity (defined as up to 11 following initiation of combined radiotherapy and 
avelumab). 
Objective: To evaluate late toxicity, defined as toxicity occurring during the period commencing 11 
weeks and one day after the initiation of radiotherapy and avelumab until confirmed disease 
progression or initiation of new anti-cancer treatment therapy. 

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Hypothesis: Avelumab combined with hypofractionated radiotherapy in advanced STS does not result 
in unacceptable late toxicity (defined as commencing at 11 weeks and one day from the initiation of 
combined radiotherapy and avelumab until confirmed disease progression or initiation of new anti-
cancer treatment therapy. 
Objective: To assess the frequency of PD-1/PD-L1 expression in advanced STS and evaluate PFS 
against PD-L1 expression. 
Hypothesis: Prolonged responses following palliative RT are expected in patients with PD-L1 
expression. 
 
3.1.3 Exploratory Objectives 
 
Objective: To determine individual tumour response rate in non-irradiated STS metastases measured 
by RECIST 1.1 and iRECISTat 3 months and 6 months after treatment with avelumab and 
radiotherapy.  This will be used to determine local control and assess abscopal effect. 
Hypothesis: Combining avelumab with RT leads to abscopal responses. 
Objective: To evaluate whether hypofractionated radiotherapy combined with avelumab treating 
advanced STS results in a measurable change in anti-tumour immunity.   
Objective: Identification of tissue and serum biomarkers that correlate with immunological response to 
therapy. 
 
3.2 
Endpoints  
 
3.2.1 Primary Endpoint 
 
1. To establish that Avelumab at a fixed dose of 10mg/kg can be safely combined with 
hypofractionated radiotherapy to the thorax, trunk or limb in the absence of dose limiting 
toxicity (DLT).  
 
3.2.2 Secondary Endpoints 
 

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1. To assess the proportion of patients treated with a combination of avelumab and radiotherapy 
with local control of soft-tissue sarcoma at 3 months. 
2. To assess the PFS and OS achieved with a combination of avelumab and radiotherapy 
followed by maintenance avelumab in patients with metastatic soft-tissue sarcoma at 6 months 
and 1 year. 
3. To measure the rate of acute ≥ grade 2 toxicity for 11 weeks following initiation of radiotherapy 
and avelumab.  
4. To assess the rate of late ≥ grade 2 toxicity assessed from 11 weeks and one day following the 
initiation of avelumab and radiotherapy until confirmed disease progression or initiation of new 
anti-cancer treatment therapy.  
5. To measure PFS and OS in PD-L1 positive population at 6 months and 1 year. 
 
3.2.3 Exploratory Endpoints 
 
1. To assess the RECIST and iRECISTcriteria response rates to treatment in (non-irradiated) 
soft-tissue sarcoma metastases at 3 and 6 months.  
2. Analysis of research blood samples for ctDNA. 
3. Characterisation of Tumour infiltrating lymphocytes (TILs) and tumour antigens in serum and 
tissue samples (as outlined in the immunotherapy trial manual). 
4. Analysis of expression of immune-related gene panel by tumour and infiltrating immune cells, 
in pre- and post-radiotherapy tumour samples using Nanostring technology.  
 
4 
Trial Design 
 
4.1 
Overall Study Design 
 
This is a single centre open label, non-randomized, non-placebo phase 1 clinical trial to establish the 
safety and tolerability of avelumab in combination with radiotherapy in patients with advanced soft 
tissue sarcomas (STS). Metastatic STS patients receiving radiotherapy to a tumour deposit above the 
diaphragm in the thorax, trunk or extremity, will receive hypofractionated radiotherapy (36 Gy in 12 
fractions, delivered daily).  This study will recruit 12 patients and run as a fixed dose study with starting 
dose of 10mg/kg.  Patients will continue on the treatment regimen described in the study flow chart 

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(Figure 2, 4.2.2) unless they progress, suffer unacceptable toxicities, or withdraw from the trial.  
Recruitment is estimated to take 12 months and it is anticipated that a median 12 cycles of avelumab 
will be delivered over an elapsed time of 6 months. The maximum survival follow-up is estimated to be 
24 months. Therefore the end of the study (i.e. follow-up completed in last patient recruited) is 
anticipated to be no more than 3 years and 6 months from the administration of the first dose of 
avelumab to the first patient. 
 
4.2 
Treatment Regimen 
 
Each patient will receive a dose of 36 Gy in 12 daily fractions of hypofractionated radiotherapy as per 
standard protocol.  All patients will receive a dose of avelumab at a dose of 10mg/kg, within 24 hours 
prior to radiotherapy (week 1), and then every 2 weeks until progression, unacceptable toxicities, 
discontinuation for other reasons or withdrawal from the study.  The timing of radiotherapy relative to 
PD-L1 blockade is an important consideration and the optimal schedule remains unclear.  Pre-clinical 
in vivo studies combining radiation with PD-1 blockade demonstrated the best local tumour control 
when administering antibody during radiotherapy (Dovedi et al, 2014).       
Three patients will be recruited initially. If the incidence of DLTs in these patients is acceptable, a 
further 3 patients will be recruited (see figure 1) up to a maximum of 12 patients in total.  A minimum 
gap of 2 weeks will be left between treatment of the first and second patient (with the combination of 
RT) to mitigate against multiple patients suffering acute toxicity. Acute radiotherapy toxicity monitoring 
will be undertaken from the start of the patient’s radiotherapy and first dose of avelumab treatment for 
a period of 11 weeks.  
 
4.2.1 Dose Levels 
For this study, a Dose Limiting Toxicity (DLT) is defined as:  
• 
≥ grade 2 pneumonitis 
• 
≥ grade 4 Oesophagitis  
• 
≥ grade 2 myelitis in 2 patients Any other grade 4 toxicity 
• 
Any grade 3 non-haematological toxicity, likely to be related to study drug. 
• 
Radiotherapy interruption >5 days 
DLTs will be assessed from the start of the patient’s radiotherapy and first dose of avelumab up to 
administration of Cycle 7 of avelumab (i.e. week 13 as depicted in Table 1, Section 7.1, Study 
Schedule) DLTs will be assessed using the Common Terminology Criteria for Adverse Events 

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(CTCAE) v4.0 and must be reviewed by the SRC (Safety Review Committee) once recruitment 
has reached 3 and 6  patients (see Figure 1). Recruitment will proceed to patients 7 to 12 provided 
DLTs are deemed acceptable by the SRC. 
Presence of toxicity constituting DLT’s will be assessed in each patient of the at start of radiotherapy, 
weekly during radiotherapy and at each clinic visit prior to the administration of avelumab until the 
administration of Cycle 7 at week 13. The recruitment of patients 7 – 12 will proceed as an 
expansion phase. Whilst toxicity will be monitored in these patients, the DLT window will have 
closed and thus adverse events occurring in these patients will not be defined as DLTs. Further, 
there will not be requirement for the SRC to meet unless triggered by the Chief Investigator.  
Recruitment will proceed as shown in Figure 1 and as described below: 
• 
If 0-1/3 patients experiences a DLT a further 3 patients will be recruited. . 
• 
If ≤1/6 patients experience a DLT then recruitment will continue to a total of 12 patients. . 
• 
If ≥ 2/6 patients experience a DLT, discussions will be undertaken with Merck KGaA as to 
whether to terminate recruitment or undertake a dose reduction to 3mg/kg. . 
• If 2/3 patients experience a DLT,  discussions will be undertaken with Merck  
KGaA as to whether to terminate recruitment or undertake a dose reduction to 3mg/kg.  
A minimum of 3 patients will be recruited  initially at the fixed dose of 10mg/kg, with a maximum of 12 
patients to be recruited within the trial. Patients will initially receive avelumab at 10mg/kg. If 1 in 3 
patients experience a dose limiting toxicity (DLT) then the cohort will be expanded to 6 patients and if 
≤1 in 6 patients experience a DLT the cohort will be expanded to a maximum of 12 patients all 
receiving the same fixed dose (10mg/kg). , If ≥2 in 6 patients experience a DLT, discussions will be 
undertaken with Merck KGaA as to whether to terminate recruitment or undertake a dose reduction to 
3mg/kg.   If 2 out of 3 patients experience a DLT at dose level 1 then discussions will be undertaken 
with Merck KGaA as to whether to terminate recruitment or undertake a dose reduction to 3mg/kg.   

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4.2.2  Study Flow Chart 
 
 
 
 
Figure 2: Study Flow chart 
 
4.3 
Follow-Up 
 
4.3.1 30 day Safety Follow-up 
 
All patients will be required to attend a safety follow-up visit at 30 days after the last dose of avelumab 
or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs and SAEs that 
occur prior to the safety follow-up visit should be reported as described in section 9. After the safety 
follow-up any unresolved AEs at the patient’s last visit should be followed up for as long as medically 
indicated, but without further recording in the CRF. 
 

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4.3.2  Extended Safety Follow-up 
 
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.  The extended safety follow-up at 90  days 
after last study drug administration may be performed either via a clinic appointment or a telephone 
call with subsequent appointments  requested in case any concerns are noted during the telephone 
call. 
 
4.3.3  Follow-up 
 
Patients who discontinue trial treatment for any reason other than disease progression will move into a 
follow-up phase and should be assessed every 12 weeks by radiologic imaging to monitor disease 
status. Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, disease progression, death, withdrawal or end of the study. Information 
regarding post-study anticancer treatment will be collected if new treatment is initiated. 
 
4.3.4  Survival Follow-up 
 
Once a patient experiences confirmed progressive disease or starts a new anti-cancer therapy, the 
patient moves into the survival follow-up phase and will be followed up every 12 weeks to determine 
their disease status until the end of the trial which is anticipated to be no more than 3 years and 6 
months from the date of enrolment of the first patient. The follow-up disease status review will be done 
by reviewing the patient’s medical notes and/or contacting the patient and/or General Practitioner 
directly. Patients will remain on this follow-up until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
 
4.4  
Study Termination 
 
The end of the study is defined as completion of the final survival follow-up assessment of the last 
subject recruited which is anticipated to be ≤ 24 months from end of avelumab treatment.  
 
4.4.1 Clinical Criteria for Early Termination 
 
Early trial termination will be the result of the criteria specified below: 

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1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to patients. 
4. The occurrence of 1 patient with oesophagitis ≥ grade 4, at any dose level. 
5. The occurrence of 2 patients with myelitis ≥ grade 2, at any dose level 
6. Plans to modify or discontinue the development of the study drug In accordance with the conditions 
of supply agreement with Merck KGaA, ample notification will be provided to the sponsor and site 
should alterations to the drug supply change. This is to allow time for appropriate adjustments to be 
made in regards to the patient’s treatment. 
 
4.5 
Treatment after Study Termination 
 
Following participation in the study patient care will be decided by the local doctor according to local 
standard practice. 
 
 
5 
STUDY SETTING 
 
This is a single centre single site study that will be performed at The Royal Marsden NHS Foundation 
Trust Hospital. The identification of potentially eligible patients will be performed by clinicians at 
multidisciplinary Sarcoma cancer meetings and/or from patients attending routine outpatient clinics. 
Pre-screening of multidisciplinary meetings and outpatient clinics attended by clinicians will be 
performed by members of the clinical care team supported by members of the research team. No 
participants will be recruited by publicity using posters, leaflets, adverts or websites, although the trial 
will be registered in the public domain. The listed inclusion and exclusion criteria will be used to judge 
eligibility, but other factors will influence suitability and appropriateness of seeking written informed 
consent. Responsibility for seeking informed consent lies with the oncologist managing the patient, but 
other clinical staff, including Sarcoma Trial Nurse(s), will assist in this process as delegated. 
6 
Eligibility Criteria 
 
The following eligibility criteria were designed to select patients for whom the protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 

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consideration when deciding whether this protocol is suitable for a particular patient. Eligibility criteria 
may not be waived by the investigator. 
 
Patients with metastatic soft-tissue sarcoma will be offered recruitment into the trial providing they 
meet the below criteria. 
 
6.1 
Inclusion criteria 
 
i. 
Patients must have a diagnosis of advanced soft tissue sarcoma with at least 2 metastases not 
suitable for cure using conventional treatments.  At least one lesion must be suitable to receive 
palliative radiotherapy.  The radiation tumour target tumour volume must be between the neck 
and the diaphragm in the thorax, trunk or an extremity.     
ii. 
Histologically confirmed diagnosis of metastatic soft-tissue sarcoma of including but not limited 
to one of the following subtypes: soft tissue sarcomas (leiomyosarcoma, myxoid liposarcoma, 
liposarcoma, undifferentiated pleomorphic sarcoma, fibrosarcoma, epithelioid, clear cell, and 
synovial sarcoma). 
iii. 
Age ≥ 18 years. 
iv. 
Life expectancy of >12 weeks. 
v. 
At least one site of accessible disease for pre- and post-treatment core biopsies. 
vi. 
At least two sites of measurable disease on CT/MRI scans as defined by RECIST 1.1. 
vii. 
ECOG Performance Status of ≤1. 
viii. 
Adequate bone marrow  function, defined as: 
a. Absolute Neutrophil Count (ANC) ≥1.5 x 109/L ( ≥1,500/μl); 
b. Platelets ≥100 x 109/L (≥100,000/ μl); 
c. Hemoglobin ≥9 g/dL (>5.6 mmol/L). 
d. Prothrombin Time (PT) ≤X1.5 X ULN 
e. Activated Partial Thromboplastin Time (aPTT) ≤X1.5 X ULN 
f. Patients must be transfusion independent (ie, no blood product transfusions for a 
period of at least 14 days prior to study entry – to be  assessed as part of the patient’s 
medical history. 
ix. 
Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according 
to the Cockcroft-Gault formula. 
x. 
Adequate liver  function, including: 
a. Total serum bilirubin ≤1.5 x upper limit of normal (ULN); 

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b. Aspartate and Alanine aminotransferase (AST & ALT) ≤2.5 x ULN or ≤5 x ULN for 
patients with liver metastases. 
xi. 
Written, voluntary informed consent. 
xii. 
Patients that have had no previous chemotherapy treatment or have received ≥ 1 or more lines 
chemotherapy.  
xiii. 
Male patients and women of childbearing potential (WOCBP) and their male partners must 
agree to use 1 highly effective methods of contraception and a condom from giving informed 
consent for a period of 35 days prior to administration of first dose of avelumab, throughout 
treatment with avelumab and for at least 60 days after avelumab treatment.  Women of 
childbearing potential include pre-menopausal women and women within the first 2 years of the 
onset of menopause. Women of childbearing potential must have a negative pregnancy test ≤ 
72 hours prior to Day 1 of study as defined in section 7.3.7. 
xiv. 
Women of childbearing potential include pre-menopausal women and women within the first 2 
years of the onset of menopause. Women of childbearing potential must have a negative 
pregnancy test ≤ 72 hours prior to Day 1 of study as defined in section 7.3.7. Further they will 
be asked to receive monthly pregnancy tests whilst on avelumab treatment and at the end of 
treatment. See CTFG Contraception Guidance 15.09.2015.Subjects requiring hormone 
replacement with corticosteroids are eligible if the steroids are administered only for the 
purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per 
day 
xv. 
Administration of steroids through a route known to result in a minimal systemic exposure 
(topical, intranasal, intro-ocular, or inhalation) are acceptable. 
xvi. 
Patients with a contraindication to MRI (standard of care imaging for extremity disease only) 
can be entered into the study and will have CT based RECIST 1.1 assessments. 
xvii. 
In patients who have symptoms, when assessed using CTCAE v.4.0, these are of grade 0 or 1 
severity only. 
xviii. 
Patients who are on anti-coagulants can be considered at the investigator’s discretion 
(includes patients in whom the anti-coagulant can be safely discontinued for the 
purpose of conducting a biopsy)  
 
6.2 
Exclusion criteria 
 
i. 
Systemic chemotherapy within 35 days prior to study entry. 

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ii. 
Prior systemic therapy targeti1/ng PD-1: PD-L1 axis. 
iii. 
Patients who are curable by conventional multidisciplinary management. 
iv. 
Patients with known central nervous system metastatic disease are ineligible for enrolment. 
v. 
Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the 
investigator could cause unacceptable safety risks or compromise compliance with the 
protocol. 
vi. 
Patients who have received radiotherapy ≤ 4 weeks prior to Day 1 of study or who have not 
recovered adequately from side effects.  
vii. 
Previous radiotherapy within the treatment area. 
viii. 
Patients who have active infections requiring therapy. 
ix. 
Patients with a history of Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C. 
Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody 
tested positive. 
x. 
Patients that have a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial. 
xi. 
Patients who received systemic anti-cancer treatment prior to the first dose of study drug within 
the following time frames: 
xii. 
Patients who have received biologic therapy (e.g., antibodies) within 4 weeks. 
xiii. 
Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug 
xiv. 
Patients with active autoimmune disease or a documented history of autoimmune disease or 
syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo 
or resolved childhood asthma/atopy would be exception to this rule. Patients that require 
inhaled steroids or local steroid injections would not be excluded from the study. Patients with 
hypothyroidism not from autoimmune disease that is stable on hormone replacement will not 
be excluded from the study. 
xv. 
Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, 
inhaled, topical steroids, or local steroid injection (eg, intra-articular injection); b. Systemic 
corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as 
premedication for hypersensitivity reactions (eg, CT scan premedication). 
xvi. 
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. 
xvii. 
Prior organ transplantation including allogenic stem-cell transplantation. 
xviii. 
Current severe acute or chronic colitis, inflammatory bowel disease, pneumonitis, pulmonary 
fibrosis. 

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xix. 
Women who are pregnant or nursing/breastfeeding. 
xx. 
Known hypersensitivity to avelumab or another mAb. 
xxi. 
Patients with a history of non-infectious pneumonitis that has required a course of oral or 
intravenous steroids to assist with recovery, or interstitial lung disease. 
xxii. 
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. 
xxiii. 
Patients requiring steroid replacement doses above physiological requirements will be 
considered ineligible for this study: allowed up to 20 mg hydrocortisone (or 5 mg of 
prednisolone) in the morning and 10 mg hydrocortisone (or 2.5 mg prednisolone) in the 
evening. 
xxiv. 
Patients with the risk factors for bowel obstruction or bowel perforation (examples include but 
not limited to a history of acute diverticulitis, intra-abdominal abscess, abdominal 
carcinomatosis). 
xxv. 
Patients who have received a live vaccine within 30 days prior to the first dose of trial 
treatment. 
xxvi. 
Previous malignant disease within the last 5 years with the exception of basal or squamous cell 
carcinoma of the skin or cervical carcinoma in situ. 
xxvii. 
Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, 
sensory neuropathy Grade  ≤ 2, or other Grade  ≤ 2 not constituting a safety risk based on 
investigator’s judgment are acceptable. 
xxviii. 
Patients who have symptoms, which when assessed using CTCAE v.4.0, are of grade 2 
severity or above.

 
 
 
7 
Trial Procedures 
7.1 
Study 
Schedule 
Trial Period   
Screening 
phase 
Avelumab administration 
during  Radiotherapy 
 
 
 
 
Avelumab maintenance every 2 weekly 
(can be repeated beyond 10 cycles to progression) 
End of 
treatment 
(if 
applicable)6 
Post-treatment 
 
 
Safety 
Follow-
up (30 
days) 
Extended 
Safety 
Follow-up 
(90 days) 
Follow 
up 
Visits 
Survival 
Follow up 
up 
to 
a 
maximum 
of 
24 
months 
Treatment Cycle/ 
Title: 
C1 
C2 
C3 
C4 
 
C5 
 
C6 
C7 
C8 
C9 
C10 
Discontinuation 
Of IMP 
 
 
Every 
12 
wks from 
SFU 
Every 12 
wks 
Wk  
1 
Wk 
 2 
Wk 
3 
Wk 
4 
Wk 
 5 
Wk  
6 
Wk 
7 
 
Wk  
9 
 
Wk  
11 
Wk 
12 
Wk  
13 
Wk  
15 
Wk  
17 
Wk  
19 
 
 
 
 
 
Scheduling (Day) 
-35 to -1 
RT♯  
1-5 
RT♯ 
6-10 
RT♯ 
11-12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical & 
Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Status  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
New Anti-cancer therapy 
review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Adverse Events 
X 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Con. Medication 
X 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Radiation Toxicity (RTOG) 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Full Physical Exam 
X 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Exam  
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Vital Signs & Weight1 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy Test 2 
X 
 
 
 
x 
 
 
x wk8 
 
 
 
 
x 
 
x wk16 
 
x wk 20 
 
 
 
 
 
PT and aPTT 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Haematology & 
Biochemistry 
X 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysis3 
X 
 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH4 
X 
x 
x 
x 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Admin.of Avelumab 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
 
 
 
 
 
Admin of Radiotherapy 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour Imaging-CT+/- MRI 
X5 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
X7 
 
 
x8 
 
Archival/New Tissue Sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research biopsy (within 
irradiated site) 
X9 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional research biopsy 
(outside irradiated site) 
X9 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 Sample collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood Sample 
 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1:  Study Schedule 
1. 
Weight can be performed within 72 hrs in advance of dosing.  
2. 
Pregnancy test will be performed within 72 hours prior to day 1 and monthly during treatment  
3. 
Urinalysis will be performed at least every 2 weeks during administration of IMP. 
4. 
Thyroid Function Tests to be conducted every cycle (i.e. every fortnight) for the first 3 months and then monthly 
thereafter  
5. 
Imaging should every 12 weeks (regardless of treatment delays) after CT scans have been performed at weeks 7 
and 13 (+ / - 2 weeks)  Images can be up to 7 days before visit to ensure results at the visit except for images 
acquired at 13 weeks which  may be +/- 2 weeks.  Extremity tumours to be imaged using MRI with staging CT.   
MRI intolerant patients will be imaged using CT only. 
6. 
This visit is only applicable if the patient comes off study for reason other than disease progression and no 
measurement had been taken within the last 4 weeks. 
7. 
Or before the initiation of a new anti-cancer therapy.  
8. 
Scans to follow standard of care, i.e. every 3 months 
9. 
The tumour biopsies are done if patient consents and if this is deemed safely accessible for PD-L1 expression 
and biomarker research.  

 
 
 
7.2 
Administrative Procedures/Assessments 
 
7.2.1 Informed Consent 
 
It is the responsibility of the Investigator / designee to give each patient, prior to inclusion in the trial, 
full and adequate verbal and written information regarding the objective and procedures of the trial and 
the possible risks involved. Sufficient time should be allowed for the patient to decide on trial entry. 
Patients must be informed about their right to withdraw from the trial at any time. Written patient 
information must be given to each patient before enrolment. The written patient information is an 
approved patient information sheet (PIS) according to national guidelines. 
The Investigator must obtain documented written informed consent from each potential patient prior to 
participating in a clinical trial. Consent must be documented by the patient dated signature on a 
consent form along with the dated signature of the person conducting the consent discussion. If the 
patient is illiterate, an impartial witness should be present during the entire informed consent reading 
and discussion. Afterwards, the patient should sign and date the informed consent, if capable. The 
impartial witness should also sign and date the informed consent along with the individual who read 
and discussed the informed consent. Only the Principal Investigator (PI) and those Sub-Investigator(s) 
delegated responsibility by the PI, having signed the delegation of responsibilities log, are permitted to 
gain informed consent from patients and sign the consent form. All signatures must be obtained before 
the occurrence of any medical intervention required by the protocol. 
A copy of the signed and dated consent form should be given to the patient before participation in the 
trial. The original consent form should be stored in the site file and their participation in this trial 
recorded in their medical notes. Results from tests conducted as part of patients’ standard care may 
be used as part of screening to determine eligibility as long as the tests were conducted within the 
acceptable time window. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the patient must receive the REC approval/favourable opinion in 
advance of use. The patient should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent form or 
addendum to the original consent form that captures the patient’s dated signature. The informed 
consent will adhere to REC requirements, applicable laws and regulations. 
 

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7.2.2 Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria (see section 6) will be reviewed by the investigator or qualified 
designee to ensure that the patient qualifies for the trial.  
7.2.3 Demographic Data, Medical History and Treatment History 
 
Demographic data collected will include date of birth and race/ethnicity. A medical history will be 
obtained by the investigator or qualified designee. Medical history will include all active conditions, and 
any condition diagnosed within the prior 10 years that are considered to be clinically significant by the 
Investigator. In addition any abnormal and clinically significant results seen during the screening 
period should be recorded in the medical history form. Details regarding the disease for which the 
subject has enrolled in this study will be recorded separately and not listed as medical history. In 
addition to the medical history the investigator or qualified designee will obtain details the patient’s 
current disease status and treatment history including: 
 
• 
Prior and current details regarding disease status 
• 
Review all prior cancer treatments including systemic treatments, radiation and operations. 
 
We will not routinely screen all patients with central nervous system imaging prior to entering this 
study.  CNS metastases in soft tissue sarcoma are extremely rare (<5%).   If a patient is suspected to 
have central nervous system metastatic disease then a CT/MRI scan will be performed to exclude 
disease involvement prior to consideration for entering the study.  
 
7.2.4 Anti-Cancer Therapy Review 
 
Patients that discontinue from avelumab for any other reason than progression will have a follow-up 
visit every 12 weeks in which the investigator should review all new anti-cancer therapy initiated after 
the last dose of trial treatment. If a patient initiates a new anti-cancer therapy within 30 days after the 
last dose of trial treatment, the 30 day Safety Follow-Up visit must occur before the first dose of the 
new therapy. Once new anti-cancer therapy has been initiated the patient will move into the survival 
follow-up period which is not anticipated to extend beyond 24 months 
 

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7.2.5 Survival Status 
 
The investigator or qualified designee will assess the patient for survival status at specified visits as 
defined in the schedule of study assessment (Table 1, Section 7.1) The assessment will include the 
patient status and if applicable details of patient death or details if patient has been lost to follow up. It 
is not anticipated that the survival phase will extend beyond 24 months for any given patient. Thus the 
end of the trial is anticipated to be no more than 3 years and 6 months from the date of enrolment of 
the first patient. 
 
7.2.6 Prior and Concomitant Medications Review 
 
7.2.6.1 
Prior Medications 
 
The investigator / designee will review prior medication use, including any protocol-specified washout 
requirement, and record prior medication taken by the patient within 35 days before starting the trial. 
Treatment for the disease for which the patient has enrolled in this study will be recorded separately 
and not listed as a prior medication. 
 
7.2.6.2 
Concomitant Medications 
 
In addition the investigator / designee will record all medication, if any, taken by the patient during the 
trial. All medications related to reportable SAEs and overdose and liver toxicity ECIs should be 
recorded as defined in Section 7. 
 
7.3 
Clinical Procedures/Assessments 
 
7.3.1 Adverse Event (AE) Monitoring 
 
The investigator / designee will assess each patient for potential new or worsening AEs as specified in 
the schedule of study assessment (Table 1, Section 7.1) and more frequently if clinically indicated. 
Adverse events will be graded and recorded from the first dose of avelumab until the patients’ 30 day 
safety follow-up visit (following the last administration) according to NCI CTCAE Version 4.0 (see 
Appendix 1). Toxicities will be characterised in terms regarding seriousness, causality, toxicity grading, 

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and action taken with regard to trial treatment. An extended 90 day safety follow-up will be carried out 
during which toxicities will be similarly captured and characterised. 
All AEs of unknown aetiology associated with avelumab exposure should be evaluated to determine if 
it is possibly an event of clinical interest (ECI) or a potentially immunologic aetiology (irAE). See 
Section 9 and Appendix 5 regarding the identification, evaluation and management of AEs of a 
potential immunological aetiology. Please refer to section 9 for detailed information regarding the 
assessment and recording of AEs. 
7.3.2 Radiation Toxicity Assessment 
 
Radiotherapy toxicity will be assessed  using the RTOG radiation toxicity grading system (Appendix 
2). Assessments will take place weekly during administration of Avelumab  and during the 
maintenance phase. 
 
7.3.3 Full Physical Exam 
 
The investigator / designee will perform a complete physical exam at screening period. Clinically 
significant abnormal findings should be recorded as adverse events during the trial. 
7.3.4 Directed Physical Examination 
 
For cycles that do not require a full physical exam as described in the schedule of assessment (Table 
1, Section 7.1), the investigator / designee will perform a directed physical exam as clinically indicated 
prior to trial treatment administration. 
 
7.3.5 Vital Signs 
 
The investigator /designee will take vital signs at screening, prior to the administration of each dose of 
trial treatment and at treatment discontinuation as specified in the schedule of study assessment 
(Table 1, Section 7.1) Vital signs should include pulse, weight and blood pressure.   The weight can be 
measured 72 hours in advance of dosing.   Where an accurate dose has been prescribed with a 
variation in the weight from baseline, a maximum of +/- 10% variance in dosage calculation is 
permitted. 
 
7.3.6 Eastern Cooperative Oncology Group (ECOG) Performance Status 
 

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The investigator / designee will assess ECOG status (Table 2) at screening, prior to the administration 
of each dose of trial treatment and discontinuation of trial treatment as specified in the study schedule 
of assessments (Table 1, Section 7.1). 
 
 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
Housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
Out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead.  
*As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J ClinOncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
Table 2: ECOG Performance Status 
7.3.7 Pregnancy Tests 
 
Female patients (women) of childbearing potential (WOCBC) should have a negative urine or serum 
pregnancy test within 72 hours prior to administration of first dose of avelumab for confirmation of 
study eligibility. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. Female patients will also be required to undergo additional pregnancy tests monthly 
from administration of first avelumab treatment, throughout treatment and at the end of avelumab 
treatment. 
 
7.3.8 Haematology, Clinical Biochemistry and Urinalysis (β-hCG, PT, aPTT, T3,T4 and TSH) 
 

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Laboratory tests (including those carried out as part of routine care before consent and within 35 days 
of Day 1) will be performed during the screening phase and at the 30 days and 90 days post-treatment 
safety follow-ups. After this all pre-dose laboratory procedures should be conducted no more than 72 
hours prior to dosing. Urinalysis will be performed at least every 2 weeks.  Results must be reviewed 
by the investigator / designee and found to be acceptable prior to each dose of trial treatment.  
Samples will be analysed by the local study site laboratory using standard methods for routine tests.  
 
The following variables (Table 3) will be measured: 
Haematology 
Chemistry 
Urinalysis 
Other 
Haemoglobin 
ALT 
Blood 
Thyroid Function 
Tests: TSH, free T4 
Platelets 
AST 
Glucose 
 
WBC 
Alk Phos 
Protein 
 
Absolute Neutrophils 
Sodium 
Leucocytes 
 
Absolute Lymphocytes 
Potassium 
MC+S if urine dipstick 
positive 
 
Absolute Monocytes 
Magnesium 
 
 
Absolute Eosinophils 
Chloride 
 
 
Absolute Basophils 
Total Calcium 
 
 
Prothrombin Time 
Total Bilirubin 
 
 
Activated Partial 
Thromboplastin Time 
BUN or Urea 
 
 
 
Creatinine 
 
 
 
Uric Acid 
 
 
 
Glucose (non-fasted) 
 
 
 
Albumin 
 
 
 
Phosphorous or 
Phosphate 
 
 
 
Total protein 
 
 
 
Gamma glutamyl 
transferase 
 
 
 
 
 
Table 3: Required Laboratory Assessments 
Adrenal insufficiency will be monitored with a clinical assessment (history and examination) and serum 
cortisol, electrolyte and glucose levels.  Due to the low prevalence (0.6%) we have not mandated 
routine testing for adrenal insufficiency. Monitoring of adrenal function is included under the 
biochemistry testing (prior to administration of each cycle of avelumab, See Table 1). 
7.3.9 Tumour Imaging and Assessment of Disease 
 
7.3.9.1 
Baseline Tumour Imaging 
 

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Imaging should be undertaken to confirm that the patient has disease that is measurable disease 
based on RECIST v1.1 where palliative radiotherapy is considered appropriate.  The scan will also be 
assessed for a second lesion that will be outside the proposed irradiation field to assess for abscopal 
response. All baseline CT scans should be performed within 4 weeks of confirmation of eligibility of the 
trial entry. Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within the correct time window. If these 
scans are done at baseline they can be used to assess local control at 7 weeks (4 weeks post 
radiotherapy). In addition, patients with limb tumours would normally have imaging using an MRI scan. 
A CT scan can be performed if the patient is unable to tolerate an MRI scan. 
 
7.3.9.2 
Follow-Up Tumour imaging 
 
Follow-up CT scans (thorax abdomen and pelvis) should be performed every 12 weeks after starting 
avelumab. Patients will also have a CT scan performed at week 7 (4 weeks after completion of 
radiotherapy) and at week 13 (10 weeks after completion of radiotherapy). Additional scans will be 
taken every 12 weeks (regardless of treatment delays) until documented disease progression, the 
start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever 
occurs first. Images can be taken up to 7 days prior to a scheduled visit to allow availability of results. 
 
7.3.10 Tumour Tissue Collection and Correlative Studies Blood Sampling 
 
7.3.10.1 
Archival Tumour Tissue Samples 
 
Archival tissue samples will be requested from the referring hospital for central pathological review 
(standard of care) to confirm histological diagnosis and will not routinely undergo further analysis. 
Archival tumour blocks will be returned to source at the end of the study or, upon request, earlier if 
required for the patient’s clinical management. Cut sections will be retained by the study team. These 
are archived samples and as such participating patients will not need to attend extra visits or undergo 
extra procedures. All collected archival samples will be classed as pre-treatment samples and may be 
used as such in the immunological evaluation as described below. 
 
7.3.10.2 Tumour Biopsies and Research Blood Samples 
 
Research blood samples will be obtained in EDTA and/or Streck tubes (for ctDNA) at baseline and at 
2 other time points during ongoing treatment. Circulating tumour DNA analysis will be analysed in the 
ICR according to standard operating procedures. Samples will undergo next generation sequencing to 
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future correlative work. Analysis of these samples will not yield genetic information of immediate 
concern to patients and thus results will not be shared with patients.  
 
Tumour biopsies will be obtained during the screening period and if the patient consents optional 
research blood samples will be obtained at week 1, week 3 and week 7. Tumour and blood samples 
from this study may undergo proteomic, genomic and transcriptional analyses. Assays may include, 
but are not limited to: 
• Characterisation of TILs and tumour antigens Immunohistochemistry (IHC) will be used to assess the 
number and composition of immune infiltrates in order to define the immune cell subsets present 
within formalin-fixed, paraffin embedded (FFPE) tumour tissue before and after exposure to therapy. 
These IHC analyses will include, but not necessarily be limited to, the following markers: CD4, CD8, 
FOXp3, PD-1, PD-L1, and PD-L2 (see Immunotherapy Trials Manual).  
 
• ctDNA 
 
7.4 
Subject replacement Strategy 
 
All patients who have received at least one cycle of avelumab and one fraction of radiotherapy will be 
included in the intention to treat population. However, for any patients unable to complete four 
fractions of radiotherapy, at least 2 doses of avelumab and the 11 weeks post initiation of radiotherapy 
and avelumab assessment (i.e. for acute toxicity), additional patients may be recruited.  If a patient 
withdraws from the study before the 11 week post radiotherapy time point for reasons other than 
experiencing a DLT, then they cannot be included in making dose-escalation decisions. Up to a 
maximum of 16 patients can be recruited (due to funding restrictions), providing the reason for non-
completion of therapy was not toxicity. A patient that discontinues the trial for progressive disease 
after the 11 week post radiotherapy acute toxicity assessment or a drug-related AE will not be 
replaced and will be counted in the evaluable population of patients for the respective cohort. 
8.0 
Treatments 
 
8.1 
Trial Treatments 
 
Patients will be given avelumab in addition to palliative RT. 
8.2 
Standard Treatment-Radiotherapy 
 

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Radiotherapy will be delivered as outlined below.  Patients will be treated with external beam RT. 
Planning will be done by conformal radiotherapy.  The use of IV contrast is permitted if felt necessary. 
The gross target volume (GTV) will be defined as visible tumour on a planning CT scan. When 
administered without concurrent systemic therapy, 36 Gy in 12 fractions is within the normal 
radiotherapy tissue tolerance for all the organs at risk (OAR). Avelumab will be combined with 
radiotherapy, hence 3D dose-volume information for the tumour and the normal tissues will be 
obtained for subsequent analysis.  
 The CTV/PTV margin will be defined using standard Royal Marsden Hospital criteria for each 
anatomical site. Dose will be prescribed at 100% as per ICRU guidelines. Treatment verification with 
on-board imaging will be carried out as per departmental protocol. 
 
8.2.1 Selection of sites suitable for radiotherapy 
 
Patients must have at least two sites of measurable metastatic disease on CT/MRI scans defined by 
RECIST 1.1.  Lesions must be at least 1 cm in size as measured by the widest dimension on CT/MRI 
scan.  No upper limit of size is defined and this is left to the discretion of the clinical oncologist, taking 
into account the organs at risk (OAR) normal tissue tolerance constraints associated with irradiating 
each lesion.  The radiation target volume must be between the neck and diaphragm, may include 
limbs, and be amenable to an image guided biopsy pre- and post- radiotherapy for the translational 
study.   
8.2.2 Patient Preparation and Positioning 
 
See Royal Marsden Hospital radiotherapy guidelines 
 
8.2.3 Scan Limits and Slice Thickness 
 
Recommended scanning levels are at least 4cm above and below the target volume to include the 
entire bowel or lungs.  Target volumes will be defined on CT scan reconstructions and the CT slice 
thickness should be 3mm or less. 
 
8.2.4 Localisation of the target volume and organs at risk (OAR), Volume Definition. 
 
(See Royal Marsden Hospital Sarcoma radiotherapy guidelines)  
 

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The clinical target volume (CTV) is the contour encompassing the visible tumour, with a margin (1-2 
cm) dependent upon the at risk area. The CTV will be expanded as to create the PTV.  Organs at risk 
(OAR) will be outlined as solid structures by defining their outer wall.  Normal structures to be outlined 
for post treatment analysis are dependent upon the anatomical site being irradiated: 
Chest; heart, lungs and spinal cord 
Limb; no OAR required unless tumour extends into the chest (then as above)  
 
Volumes will be defined according to the International Commission on Radiation Units and 
Measurements (ICRU) report 50, supplement report ICRU 62: Prescribing, Recording and Reporting 
Photon Beam Therapy and ICRU 83: Prescribing, Recording and Reporting Photon-Beam Intensity 
Modulated radiotherapy (IMRT). Outlining should be carried out with the aid of all diagnostic MRI and 
CT scans.   
8.2.5 Radiotherapy Treatment Administration 
 
Lesion(s) will be irradiated to a dose 36Gy in 12 daily fractions over 2.5 weeks. 
8.3 
Trial Treatment-Avelumab 
 
8.3.1 Investigational Product 
 
Avelumab is a fully human antibody of the IgG1 isotype that specifically targets and blocks the ligand 
(PD-L1) for PD-1.  Merck KGaA will package and distribute the IMP to the site via their distribution 
vendor - Fisher Clinical Services. The IMP will be shipped in transport cool containers (20°C to 80°C) 
that are monitored with temperature control devices.  
8.3.2 Product Preparation 
 
The investigational product avelumab is a sterile, clear, colourless and non-pyrogenic solution for 
intravenous infusion.  It is presented in Type I glass vials filled with 10 mL of liquid (200 mg/vial), 
closed with a rubber septum and sealed with an aluminum flip off seal.  Each single-use vial contains 
200 mg of avelumab, formulated as a 20 mg/mL preservative-free acetate buffered solution at pH 5.2 
in presence of Polysorbate 20 and Mannitol.  This product requires further dilution prior to IV infusion.  
The IMP will be labelled with a medication number however supplies will be manually assigned by the 
pharmacy site personnel to study participants (no use of interactive voice/web response system). 
8.3.3 Storage and Handling 
 

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8.3.3.1 
Storage 
 
Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is based on data 
from ongoing long term stability studies with avelumab.  Avelumab drug product stored at room (23°C 
to 27°C) or higher temperatures for extended periods of time might be subject to degradation. 
Avelumab drug product must not be frozen. Rough shaking of the solution must be avoided. 
 
For administration in clinical trials, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection) supplied in an infusion bag; alternatively a 0.45% saline solution can be 
used if needed. The chemical and physical in-use stability for the infusion solution of avelumab in 
0.45% or 0.9% saline solution has been demonstrated for a total of 24 hours at room temperature. 
However, from a microbiological point of view, the diluted solution should be used immediately and is 
not intended to be stored unless dilution has taken place in controlled and validated aseptic 
conditions. If not used immediately, in-use storage times and conditions prior to administration are the 
responsibility of the user.  
 
No other drugs should be added to the solution for infusion containing Avelumab. 
 
8.3.3.2 
Handling 
 
For administration in clinical trials, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection) supplied in an infusion bag; alternatively a 0.45% saline solution can be 
used if needed. Detailed information on infusion bags and medical devices to be used for the 
preparation of the dilutions and subsequent administration will be provided in the manual of 
preparation (ISS avelumab Pharmacy Manual Template).  Dose rounding to the nearest 0.1 mL is 
permitted. 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequate trained 
personnel under a laminar flow box using aseptic techniques: 
 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature. Use a disposable syringe equipped with a needle of suitable size to remove a volume of 
sodium chloride solution to be replaced by avelumab from the infusion bag and discard the removed 
solution. Use a new disposable syringe equipped with a needle of suitable size to inject a volume of 
avelumab drug product identical to the discarded volume of sodium chloride solution into the infusion 
bag. Gently invert the mixture 10 times. Infusion bags must not be shaken, in order to avoid foaming 

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or excessive shearing of the protein solution. The preparation must be carefully inspected as it should 
result in a homogeneous looking clear solution, free of visible particles. 
 
For detailed information on the assigned dose levels and the concrete volumes to be replaced to 
prepare the target doses, please refer to the Investigator’s Brochure. 
 
8.3.4 Supply, Packaging and Labelling information 
 
Avelumab will be supplied by Merck KGaA as a sterile solution for dilution. Avelumab will be 
packaged, labelled and delivered to the participating site by Merck KGaA. The IMP will be supplied 
specifically for the trial and should not be used for any other purpose than that stated in this protocol. 
The drug will be labelled in accordance to Good Manufacturing Practice. As a minimum 
the labels will include the following information: 
a. name of the Sponsor (The Royal Marsden Hospital) 
b. each single vial contains 10 mL liquid (Avelumab), formulated as a 20 mg/mL solution 
c. batch number to identify the contents and packaging operation; 
d. blank space for recording the patient trial ID; 
e. directions for use; 
f. PI name 
g. Trial EudraCT number, Merck Serono protocol number, Royal Marsden protocol (CCR) number 
h. storage conditions; 
i. expiry date; 
j. “for clinical trial use only”; 
k. “keep out of reach of children”. 
8.3.5 Returns and Reconciliation 
 
The Investigator/designee is responsible for keeping accurate accountability records for avelumab 
including the amount dispensed to and returned for each patient and the amount remaining on site at 
the conclusion of the trial. 
 
Upon completion or termination of the study, it is the Investigators/designee responsibility to ensure 
all unused drug is returned to Merck KGaA and partially used trial medication will be destroyed at the 
site per local guidelines and provide appropriate records of disposal to the sponsor with a copy being 
stored in the pharmacy site file. 
8.3.6 Dose Selection 
 

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The rationale for selection the fixed dose to be used in this trial is provided in Section 2.4 –Rationale 
for Dose Selection/Regimen/Modification. 
 
8.3.7 Administration of Avelumab 
 
 All patients will receive Avelumab administered as per standard procedures following manufacturer’s 
instructions. Avelumab dose interval is 14days +/- 7 days. Tolerability of combining avelumab with 
radiotherapy will be examined at the fixed dose of 10mg/kg. In the event that incidence of DLTs 
indicate trial termination or dose reduction, dose may be reduced to 3mg/kg. In order to mitigate 
infusion-related reactions, a premedication with an antihistamine and with paracetamol 
(acetaminophen) 30 to 60 minutes prior to each dose of avelumab is mandatory (for example, 25-50 
mg diphenhydramine and 500-650 mg paracetamol IV or oral).  This may be modified based on local 
treatment standards and guidelines, as appropriate (see IB section 6.2.3). 
Avelumab should be administered in a setting that allows for immediate access to an 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, and oxygen 
should be available for immediate access.  Following avelumab infusions, patients must be observed 
for 30 mins post-infusion for potential infusion-related reactions. 
 
Drug 
Dose level 
Dose/Potency Dose 
Frequency 
Route 
of 
administration 
Regimen/Treatment 
Period 
Avelumab 
 
 
1 
10 mg/kg 
Week 1/ 
Week 3 
 
Every 
2 
weeks from 
week 5 
IV infusion 
 
 
IV infusion  
During RT phase 
 
 
Maintenance phase 
Until progression 
Avelumab 
 
 
 
 
0 
3 mg/kg 
Week 1/ 
Week 3 
 
Every 
2 
weeks from 
week 5 
IV infusion 
 
 
IV infusion  
During RT phase 
 
 
Maintenance phase 
Until progression 
The Avelumab dosing interval may be increased due to toxicity as described in Section 8.3.8 
 

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Table 4: Avelumab treatment regimens for each dosing level. 
 
Trial treatment should begin within 2 weeks of confirmation of eligibility and as close as possible to the 
date on which treatment is allocated/assigned. Details on the preparation and administration of 
avelumab are provided in the IMP handling guidelines. These guidelines contain specific instructions 
for avelumab reconstitution, preparation of the infusion fluid, and administration. 
8.3.8 Dose Modification 
 
Avelumab will be withheld for drug-related grade 4 haematological adverse events and non-
haematological adverse events of toxicity ≥ Grade 3 including laboratory abnormalities (except for 
toxicities seen commonly with radiotherapy alone, namely grade 3 cystitis, urinary frequency and 
urinary incontinence). Drug will be withheld for grade 4 urinary toxicity and severe or life-threatening 
AEs as per Table 5 below. 
 
Toxicity 
NCI CTCAE 
Severity 
Grade  
Treatment 
Discontinuation 
Timing for Restarting 
Treatment 
Haematological 
abnormalities 
1 
no 
N/A 
Haematological 
abnormalities 
2 
no 
• 
If toxicity resolves to Grade ≤1 by the 
next administration, treatment may 
continue. 
 
 
• 
If toxicity does not resolve to Grade 
≤1 by the next administration despite 
optimal treatment, next cycle 
infusion should be omitted. If, at the 
end of the following cycle, the event 
has not resolved to Grade ≤1, the 
patient should permanently 
discontinue treatment. 
 
• 
Upon the second occurrence of the 
same Grade 2 toxicity that does not 
resolve to Grade ≤1 by the next 
administration, treatment must be 
permanently discontinued. 
Haematological 
abnormalities 
3 
yes 
Permanent discontinuation. 
• 
Exceptions are: 
Single laboratory values that do not 
have any clinical correlate, and 
resolve to Grade ≤1 within 7 days 
with adequate medical management. 
Haematological 
4 
yes 
Permanent discontinuation. 

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abnormalities 
• 
Exceptions are: 
Single laboratory values that do not 
have any clinical correlate, and 
resolve within 7 days with adequate 
medical management. 
Infusion-related 
Reaction 
1-4 
 
See section 16.5.1 and Table 11 
Hypersensitivity 
reactions 
3-4 
 
See section 16.5.1 
Tumour lysis 
syndrome 
1-4 
 
See section 16.5.1 and Figure 2 
Immune-related AE 
(irAE) 
1-4 
 
See section 16.5.1 and Table 12 
Other Non-
hematologic 
Toxicities and 
Laboratory 
Abnormalities 
1 
no 
Continue as per schedule 
Other Non-
hematologic 
Toxicities and 
Laboratory 
Abnormalities 
2 
no 
• If toxicity resolves to Grade ≤1 by the next 
administration, treatment may continue. 
• If toxicity does not resolve to Grade ≤1 by 
the next administration despite optimal 
treatment, next infusion should be omitted. 
If after an additional 4 weeks the event has 
not resolved to Grade ≤1, the patient should 
permanently discontinue treatment (except 
for hormone deficiencies that can be 
managed by replacement therapy and for 
which up to 2 additional subsequent doses 
may be omitted). 
• Upon the second occurrence of the same 
Grade 2 toxicity (except for hormone 
deficiencies that can be managed by 
replacement therapy), the treatment must 
be permanently discontinued. 
Other Non-
hematologic 
Toxicities and 
Laboratory 
Abnormalities 
3 
yes 
• Permanent discontinuation, 
• Exceptions are: 
• Transient (≤6 hours) flu-like symptoms or 
fever, which is controlled with medical 
management. 
• Transient (≤24 hours) fatigue, local 
reactions, headache that resolves to Grade 
≤1. 
• Nausea and vomiting controlled by medical 
therapy 
• Diarrhoea, skin toxicity, or liver function 
test (ALT, AST, or GGT) that resolves to 
≤Grade 1 in less than 7 days after medical 
management (eg, immunosuppressant 
treatment) has been initiated. 
• Amylase or lipase abnormality that is not 
associated with symptoms or clinical 

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manifestations of pancreatitis. 
• Tumour flare phenomenon defined as local 
pain, irritation, or rash localized at sites of 
known or suspected tumour. 
• Non hematologic laboratory abnormality 
that do not require medical intervention or 
hospitalization 
• Single non hematologic laboratory values 
that do not have any clinical correlate, and 
resolve to ≤ Grade 1 within 7 days with 
adequate medical management. 
Other Non-
hematologic 
Toxicities and 
Laboratory 
Abnormalities 
4 
yes 
Permanent discontinuation. 
• 
Exceptions are: 
 
Non hematologic laboratory abnormality 
that does not require medical intervention or 
hospitalization 
 
Single non hematologic laboratory values 
that do not have any clinical correlate, and 
resolve within 7 days with adequate medical 
management. 
 
Table 5: Dose modification guidelines for drug-related AEs. 
If the toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment should 
be discontinued at the discretion of the investigator. Patients with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and controlled. For 
information on the management of AEs, see section 9. 
 
Patients who experience a recurrence of the same severe or life-threatening event at the same grade 
or greater with re-challenge of avelumab should be discontinued from trial treatment. RT-related AEs 
will be managed as per institution clinical guidelines. 
 
Events of Clinical interest (ECI) can be potential immune related AEs and dose modifications for these 
toxicities should they occur can be found in Appendix 5.  
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 5 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 

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8.3.9 Timing of Dose Administration 
 
Avelumab will be administered on an outpatient basis on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the schedule of study assessments 
(Table 1, Section 7.1).  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. 
 
Avelumab will be administered as a 60 minute IV infusion (treatment cycle intervals or infusion length 
may be increased due to toxicity as described in Section 8.5.1.5). Due to the variability of infusion 
pumps from site to site, a window of -10 minutes and +20 minutes is permitted (i.e., infusion time is 60 
minutes: -10 min/+20 min). In addition, infusion length may be increased due to toxicity as described 
in Section 8.5.1.5. 
8.3.10 Trial Blinding/Masking 
 
This is an open-label trial; therefore, the Sponsor, investigator and patient will know the treatment 
being administered. 
 
8.4 
Concomitant Medications/Vaccinations (allowed and prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are also not allowed during 
the trial. If there is a clinical indication for one of these or other prohibited medications or vaccinations 
then discontinuation from trial therapy may be required. The Investigator should discuss any questions 
regarding this with the CI/designee/RM-CTU. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the patient's primary physician. However, the decision to 
continue the patient on trial therapy schedule requires the mutual agreement of the Investigator, CI/ 
designee, and the patient. 
 
8.4.1 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a patient’s welfare may be administered at 
the discretion of the investigator in keeping with the standards of medical care. All concomitant 
medication will be recorded on the e-case report form (eCRF/CRF) including all prescriptions, over-
the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the 
trial period, documentation of drug dosage, frequency, route, and date may also be included on the 

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eCRF/CRF. All concomitant medications received within 35 days before the first dose and until the 
safety follow up visits at 30 and 90 days should be recorded. 
 
8.4.2 Prohibited Concomitant Medications 
 
Patients are prohibited from receiving the following therapies during the screening and treatment 
phase (including retreatment for post-complete response relapse) of this trial: 
 
• Anti-cancer systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Radiotherapy not specified in this protocol 
• Investigational agents other than avelumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines 
(e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
• Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest  
of suspected immunologic aetiology. The use of physiologic doses of corticosteroids may be approved 
after consultation with the CI/designee. 
 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Patients may receive other 
medications that the investigator deems to be medically necessary. The Exclusion Criteria describes 
other medications which are prohibited in this trial. There are no prohibited therapies during the Post-
Treatment Follow-up Phase. 
8.5 
Rescue Medications and Supportive Care 
 
8.5.1 Supportive Care Guidelines 
 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator including but not limited to the items outlined below: 
 
8.5.1.1 
Diarrhoea: 
 

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Patients should be carefully monitored for signs and symptoms of: 
• Enterocolitis (diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) 
• Bowel perforation (peritoneal signs and ileus).  In symptomatic patients, infectious aetiologies should 
be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should be 
considered. 
• In patients with severe enterocolitis (Grade 3 with the exception of grade 3 diarrhoea during delivery 
of radiotherapy for <72 hours which responds to anti-diarrhoeal medication and becomes Grade 2 or 
less): 
o Avelumab will be permanently discontinued and treatment with systemic corticosteroids 
should be initiated at a dose of 1 to 2 mg/kg/day of prednisolone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month. 
• In patients with moderate enterocolitis (Grade 2): 
o Avelumab should be withheld and anti-diarrhoeal treatment should be started. If symptoms 
are persistent for more than one week, systemic corticosteroids should be initiated (e.g., 0.5 
mg/kg/day of prednisolone or equivalent). When symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and continued over at least 1 month. Guidelines for 
continuing treatment with Avelumab can be found in Appendix 5. 
 
o All patients who experience diarrhoea should be advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via 
IV infusion. 
 
8.5.1.2 
Nausea/vomiting: 
 
Nausea and vomiting should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to standard 
institutional practice. Patients should be strongly encouraged to maintain liberal oral fluid intake. 
 
8.5.1.3 
Anti-infectives 
 
Patients with a documented infectious complication should receive oral or IV antibiotics or other anti-
infective agents as considered appropriate by the treating investigator for a given infectious condition, 
according to standard institutional practice. 
 

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8.5.1.4 
Immune-related adverse events: 
 
Please see Section 8.5.2 below and the separate ECI guidance document regarding diagnosis and 
management of adverse experiences of a potential immunologic aetiology. 
 
8.5.1.5 
Management of Infusion Reactions: 
 
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or anaphylaxis) 
are different from allergic/hypersensitive reactions, although some of the manifestations are common 
to both AEs. Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Signs/symptoms may include: Allergic 
reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); Bronchospasm; Cough; 
Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; 
Hypertension; Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumour pain (onset or exacerbation of tumour pain 
due to treatment); Urticaria (hives, welts, wheals); Vomiting. 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic medications 
indicated for d 24 h. 
Temporarily discontinue avelumab 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 closely for 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 avelumab infusion immediately and disconnect 
infusion tubing from the subject. 
Subjects have to be withdrawn immediately from study 
avelumab and must not receive any further avelumab 
treatment. 
- If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it 
must remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based on 
investigator’s medical judgment.- If hypersensitivity reaction occurs, the subject must be treated 
according to the best available medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 

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Table 6: Treatment guidelines for patients who experience an infusion reaction associated with 
administration of Avelumab. 
 
8.5.2 Supportive Care Guidelines for Immune-related Adverse Event (irAE) and Immune-
related Events of Clinical interest (irECI) 
 
Immune-Related Adverse Events 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may occur.  
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2:  treat symptomatically or 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 irAEs should follow guidelines set forth in the table below Table 7. 
 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 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  
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 h; 
interfering with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
Withhold avelumab for Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day prednisone 
IV or equivalent 
Add prophylactic antibiotics for 
If improves:  
Continue steroids until Grade ≤ 1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or 
recurs after improvement: 

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peritoneal signs 
Grade 4: life-threatening, 
perforation 
opportunistic infections  
Consider lower endoscopy  
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, topical 
steroids)  
If Grade 2 persists > 1 to 2 weeks or 
recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once 
improving, taper steroids over at least 
1 month, consider prophylactic 
antibiotics for opportunistic infections, 
and resume avelumab therapy 
following steroids taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day prednisone  
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding avelumab 
therapy  
Monitor for symptoms every 2 to 
3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  

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Grade 2 
Mild to moderate new 
symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious Disease 
consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day prednisone  
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, 
taper steroids over at least 1 month, 
and then resume avelumab  therapy 
following steroids taper  
If not improving after 2 weeks or 
worsening or for recurrent Grade 2:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious Disease 
consults. 
1.0 to 2.0 mg/kg/day  prednisone 
or equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 72 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) 
Initial Management 
Follow-up Management 
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  
Withhold avelumab therapy 
Increase frequency of monitoring 
to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
avelumab therapy. 
If elevation persists > 5 to 7 days or 
worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or 
total bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of monitoring 
to every 1 to 2 days  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consult gastroenterologist/ 
If returns to Grade ≤ 1:  
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 

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hepatologist 
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted  
guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
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 frequency of  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. 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue 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 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) 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 etiology 
and rule-out immune-mediated 
myocarditis.  
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 cardiology consult, 

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Guideline based supportive treatment as 
per cardiology consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology consult. 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis Permanently discontinue avelumab. 
Guideline based supportive treatment as 
appropriate as per cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or 
worsening, consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult 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 
Endocrinology consult 
 
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 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.  
Hypopituitarism/Hypophysitis 
If secondary thyroid and/or adrenal 
Resume avelumab once 

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(secondary endocrinopathies) 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately low 
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/suppressive 
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. 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement). 
 
In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once shrinkage 
of the pituitary gland on 
MRI/CT scan is documented.  
 
Continue hormone 
replacement/suppression 
therapy as appropriate. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
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  
Speciality 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 
Permanently discontinue avelumab 
therapy 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 

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1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Speciality consult as appropriate 
month. 
Grade 4  
 
Permanently discontinue 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  
Speciality consult as appropriate. 
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 
Permanently discontinue avelumab 
therapy 
Speciality consult 
 
 
Table 7: Management of Immune-Related Adverse Events 
ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed 
tomography; irAE = immune-related adverse event; IV=intravenous; LFT = liver function test; LLN = lower limit of normal; 
MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; T4 = free thyroxine; TSH = thyroid-stimulating hormone; ULN = upper limit of normal. 
 
8.5.3 Supportive Care Guidelines for Pneumonitis 
 
Monitor patients for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with 
radiographic imaging. Exclude other causes of pneumonitis, and manage treatment in accordance 
with the guidelines above. Administer corticosteroids, withhold avelumab for moderate (Grade 2) 
pneumonitis, and permanently discontinue avelumab for severe (Grade 3) or life-threatening (Grade 4) 
pneumonitis. 
 
8.6 
Diet/Activity/Other considerations 
 
8.6.1 Diet 
 

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Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhoea, nausea or vomiting. 
 
8.6.2 Contraception 
 
Avelumab may have adverse effects on a foetus in utero. Furthermore, it is not known if avelumab has 
transient adverse effects on the composition of sperm. Non-pregnant, non-breastfeeding women may 
be enrolled if they are willing to use 1 highly effective methods of birth control and a condom or are 
considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, 
or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 
year will be considered postmenopausal), or 3) not heterosexually active for the duration of the study. 
Male patients and women of childbearing potential (WOCBP) and their male partners must agree to 
use 1 highly effective methods of contraception and a condom during the screening period (i.e. for a 
period of 35 days from  giving informed consent prior to starting Avelumab), throughout treatment with 
avelumab and for at least 60 days after avelumab treatment.  Women of childbearing potential include 
pre-menopausal women and women within the first 2 years of the onset of menopause. Women of 
childbearing potential must have a negative pregnancy test ≤ 72 hours prior to Day 1 of study as 
defined in section 7.3.7. They will also be asked to have pregnancy tests monthly whilst receiving 
avelumab treatment and at the end of treatment. 
 
Birth control methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods. Patient will be asked to adopt 1 
of these methods and a condom. They include: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
o 
oral 
o 
intravaginal 
o 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation 
o 
oral 
o 
injectable 
o 
implantable 
• 
 Intrauterine device (IUD) 
• 
 Intrauterine hormone-releasing system (IUS) 
• 
 Bilateral tubal occlusion 
• 
 Vasectomised partner 
• 
 Sexual abstinence 

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Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. 
Patients should be informed that taking the study medication may involve unknown risks to the foetus 
(unborn baby) if pregnancy were to occur during the study. In order to participate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study and 
during the safety follow-up period. If there is any question that a patient will not reliably comply with 
the requirements for contraception, that patient should not be entered into the study. See CTFG 
Contraception Guidance 15.09.2015. 
 
8.6.3 Use in Pregnancy and Nursing Women 
 
If a patient inadvertently becomes pregnant while on treatment with avelumab, the patient will 
immediately be removed from the study. The clinical team will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated. If the outcome of 
the pregnancy is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn) this will be reported to RM-CTU 
without delay including the CI and sponsor within 24 hours. The study investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition of the 
foetus or newborn to the RM-CTU. If a male patient impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to RM-CTU and 
followed as described above and in Section 9. 
 
It is unknown whether avelumab is excreted in human milk. Since many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in the nursing infant, patients who are 
breast-feeding are not eligible for enrolment. 
 
8.7 
Treatment of Overdose of IMP 
 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
avelumab by 5% over the prescribed dose. Please see section 9.7 for definitions and reporting 
procedures. 
 
8.8 
Permanent Discontinuation of Trial Medication and Withdrawal from Study 
 

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8.8.1 Permanent Discontinuation of Trial Medication 
 
A patient may be permanently discontinued from the trial medication for any of the following reasons: 
• The subject withdraws consent. 
• Confirmed radiographic disease progression 
Note: A patient may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved. 
• Unacceptable adverse experiences as described in Section 8.5 
• Intercurrent illness that prevents further administration of treatment 
• The patient has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• Administrative reasons 
Trial patients will not be enrolled more than once. The primary reason for discontinuation should be 
recorded on the eCRF/CRF. Once the trial medication has been discontinued the patient should 
complete the end of treatment (if applicable) and safety follow-up visit procedures as listed in the 
schedule of study assessments (Table 1, Section 7.1). After the end of treatment, patients will 
continue to be assessed for AE and SAE monitoring until completion of the safety follow up visit. 
Patients who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up. After documented disease progression each subject will be 
followed by telephone or in clinic for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
 
8.9 
Withdrawal from the Study 
 
Withdrawal from the study refers to discontinuation of both trial medication and future study visits / 
assessments; this can occur at any time according to the following reasons: 
• Patient decision 
• Lost to follow-up 
• Death 
• PI decision 
Patients may withdraw consent at any time for any reason or have trial treatment stopped at the 
discretion of the investigator should any untoward effect occur. In addition, a patient may be withdrawn 
by the investigator if enrolment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons. When a patient discontinues/withdraws prior to trial 
completion, all applicable activities scheduled for the final trial visit should be performed at the time of 

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discontinuation. Any adverse events which are present at that time should be followed in accordance 
with the safety requirements outlined in Section 9. 
 
9 
Pharmacovigilance 
 
Pharmacovigilence has been delegated by the Sponsor (Royal Marsden) to the Chief Investigator. 
 
9.1 
Definition of an Adverse Event (AE) 
 
An AE is defined as any untoward medical occurrence (including deterioration of a pre-existing 
medical condition) in a patient or clinical trial patient administered a medicinal product and which does 
not necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom (e.g. nausea, 
chest pain), signs (e.g. tachycardia, enlarged liver) or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to the medicinal 
product or protocol specified procedure. 
 
Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-
existing condition that is temporally associated with the use of the avelumab and/or radiotherapy, is 
also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered adverse events. Examples of this may include, 
but are not limited to, onset of menses or menopause occurring at a physiologically appropriate time.   
 
Adverse events may also occur in screened patients during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
 
9.1.1 Disease Progression 
 
Disease progression of the cancer under study is not considered an adverse event unless it results in 
hospitalisation or death. 
 

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9.1.2 New Cancers 
 
The development of a new cancer should be regarded as a SAE and reported accordingly. 
 
9.1.3 Abnormal Laboratory Test Results 
 
All clinically important abnormal laboratory test results occurring during the study will be recorded as 
AEs. Clinically important test results are those that require a medical intervention or change to IMP 
dosage. Any lab abnormalities considered to be related to the IMP will also be classed as AEs. The 
clinically important abnormal laboratory tests will be repeated at appropriate intervals until they return 
either to baseline or to a level deemed acceptable by the investigator, or until a diagnosis that explains 
them is made. 
9.1.4 Pregnancy and Lactation 
 
Pregnancy and lactation are not considered adverse events, however these events should be reported 
to the RM-CTU following guidance in section 9.2.2. 
 
9.1.5 Radiotherapy toxicities 
 
Radiotherapy toxicities are detailed in Table 10, Appendix 2. Except for ‘myelitis’, where all 
occurrences of any grade of severity must be regarded as unexpected, all radiotherapy toxicities of 
severity Grade 3 or above must be regarded as unexpected. No localised toxicities below the 
diaphragm are expected to occur as the radiotherapy treatment fields are not expected to extend 
below this point. 
 
9.2 
Assessing and Recording Adverse Events 
 
All adverse events will be recorded from the time the consent form is signed until completion of the 
Safety Follow-up (30 days) and the Extended Safety Follow-up (90 days) in the eCRF/CRF. AEs will 
be followed up until resolution, stability or it is clinically feasible to do so. The final outcome must not 
only be documented in the eCRF/CRF but also recorded in the participant’s medical records. Serious 
Adverse Events (SAEs) will also be recorded throughout the study until the two Safety follow-up visits 
outlined above (i.e. 30 and 90 days). The reporting timeframe for adverse events meeting any serious 
criteria is described in section 9.5.  
 

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Any unresolved AEs at the patient’s last visit should be followed up for as long as medically indicated, 
but without further recording in the eCRF/CRF. 
 
If an Investigator learns of any SAEs, including death, at any time after a patient has completed the 
study and he/she considers there is a reasonable possibility that the event is related to avelumab, the 
Investigator should notify the RM-CTU. 
 
The following details will be collected in the eCRF/CRF for each AE: 
 
• AE description / diagnosis 
• Date of onset and date of resolution 
• NCI-CTCAE grade maximum intensity 
• Seriousness 
• Investigator causality rating against the study medication (yes or no) 
• Action taken with regard to study medication 
• Outcome 
 
In addition, any adverse events occurring during the screening period that are a result of a protocol-
specified intervention should also be recorded according to guidelines for standard AE reporting. 
 
9.2.1 Evaluating Adverse Events 
 
AEs will be evaluated by an investigator who is a qualified physician. 
 
9.2.1.1 
Determining AE Severity and Grade 
 
AE severity and grade will be evaluated according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 and LENT SOMA radiation toxicity grading system. Any 
adverse event which changes CTCAE grade over the course of a given episode should be closed at 
the date the severity changed and a new AE recorded on the AE e-case report forms from that date at 
the new severity. 
 
Grade 1 Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
 

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Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation or hospitalisation indicated; disabling; limiting self-care ADL. 
 
Grade 4 Life threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE 
 
9.2.1.2 
Determining AE Causality 
 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc.) and must provide his/her opinion of the causal 
relationship between each AE and IMP. This may require instituting supplementary investigations of 
significant AEs based on their clinical judgment of the likely causative factors and/or include seeking a 
further opinion from a specialist in the field of the AE. 
Definite: 
• 
There is clear evidence to suggest a causal relationship. 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable: 
• 
There is evidence to suggest a causal relationship 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the 
patient’s clinical state. 
Possible: 
• 
A causal relationship between the IMP and the AE is at least a 
reasonable possibility. 
• 
Starts within a time related to the IMP administration 
• 
However, the influence of other factors may have contributed to the 
event (e.g. the patient’s clinical condition, other concomitant 
treatments). 
Unlikely: 
• 
There is little evidence to suggest there is a causal relationship. 
• 
There is another reasonable explanation for the event (e.g. the patient’s 
clinical condition, other concomitant treatment). 
• 
The time association is such that the trial drug is not likely to have had 
an association with the observed effect. 
Not related: 
• 
The AE is definitely not associated with the IMP administered. 
 

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Table 8: Causality is the relationship of an AE to the IMP and will be determined as follows. 
 
9.2.2 Reporting of Pregnancy and Lactation 
 
It is the responsibility of investigators or their designees to report any pregnancy or lactation in a 
patient (spontaneously reported to them), including the pregnancy of a male patient's female partner 
that occurs during the trial or within 60 days of completing the trial, or 60 days following cessation of 
treatment if the patient initiates new anticancer therapy, whichever is earlier. All patients and female 
partners of male patients who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, foetal 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 24 hours to RM-CTU by Fax 0208 915 
6762 who will inform CI, Sponsor and Merck KGaA. 
9.3 
Definitions of Serious Adverse Events (SAE) 
 
An SAE is an AE occurring during any part of the study that meets one or more of the following 
criteria: 
• Results in death; 
• Is life threatening; or places the patient, in the view of the investigator, at immediate risk of death 
from the event as it occurred1 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalisation2; 
• Is a congenital anomaly/birth defect (in offspring of patient taking the product regardless of time to 
diagnosis); 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose (whether accidental or intentional). Any adverse event associated 
with an overdose is considered a serious adverse event. 
• Is an important medical event that may not result in death, not be life threatening, or not require 
hospitalisation but may be considered a serious adverse event when, based upon appropriate medical 
judgment, the event may jeopardize the patient and require medical or surgical intervention to 
prevent such an outcome. 
1 This does not include an AE which hypothetically might have caused death if had it occurred in a more severe form. 
2 Hospitalisation is defined as an unexpected inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary 
measure for continued observation. It does not usually apply to scheduled admissions that were planned before study inclusion or visits to 
casualty (without admission). 

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9.4 
Definitions of Events of Clinical Interest (ECI) 
 
Selected non-serious and serious adverse events can also be classified as Events of Clinical Interest 
(ECI) and must be reported as described in section 9.6.  Events of clinical interest for this trial include: 
 
1. An overdose of avelumab, as defined in Section 9.7 that is not associated with clinical symptoms or 
abnormal laboratory results. 
 
2. A Drug induced liver injury (DILI) defined as elevated AST or ALT lab value that is greater than or 
equal to 3X the upper limit of normal AND / OR An elevated total bilirubin lab value that is greater than 
or equal to 2X the upper limit of normal AND / OR An alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. 
 
3. Any AEs identified in the below table can be classified as immune-related events of clinical interest. 
A detailed narrative of the event should be reported as an ECI as described in section 9.6: 
 
Pneumonitis - (reported as ECI if ≥Grade 2) 
Pneumothorax (reported as ECI if ≥ Grade 3) 
Acute interstitial Pneumonitis  
Interstitial Lung Disease 
Pneumonitis 
Colitis - (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic 
steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotising colitis 
Diarrhoea 
 
Endocrine - (reported as ECI if ≥Grade 3 or ≥ Grade 2 and resulting in dose modification or use 
of 
systemic steroids to treat the AE) 
Adrenal Insufficiency  
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or 
metabolic acidosis (DKA)  
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
Hematologic - (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Autoimmune haemolytic 
anaemia 
Aplastic anaemia 
Thrombotic thrombocytopenic 
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Idiopathic thrombocytopenia 
purpura 
Disseminated intravascular 
coagulation 
Haemolytic uraemic syndrome 
Any grade 4 anaemia regardless of underlying mechanism 
Hepatic - (reported as ECI if ≥Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis 
Transaminase elevations 
(ALTand/or AST) 
Infusion reactions - (reported as ECI for any grade) 
Autoimmune neuropathy  
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular - (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic 
steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal - (reported as ECI for ≥Grade 2) 
Nephritis  
 
Nephritis autoimmune 
Renal Failure 
Renal failure acute  
 
Creatinine elevations - (report as ECI if ≥ Grade 3 or any 
grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Skin - (reported as ECI for any grade) 
Dermatitis exfoliate 
Erythema multiforme 
Stevens-Johnson Syndrome 
Toxic epidermal necrolysis 
 
 
Skin - (reported as ECI for ≥ Grade 3) 
Pruritus  
Rash 
Rash generalised 
Rash maculo-papular 
Any rash clinical significant in the physicians judgement. 
Other - (reported as ECI for any grade) 
Myocarditis  
Pancreatitis 
Pericarditis 
Any other grade 3 event which is considered immune-related by the physician. 
 
Table 9:  Immune related AEs considered ECIs. 
 
A separate guidance document has been provided entitled “Event of Clinical Interest Guidance 
Document.”  This document provides guidance regarding identification, evaluation and management of 
ECIs and irAEs.  Any additional ECIs identified in this guidance document should also be reported as 
described in section 9.6.  Patients should be assessed for possible ECIs prior to each dose. Lab 
results should be evaluated and patients should be asked for signs and symptoms suggestive of an 
immune-related event. Patients who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a possible 
immune-related ECI, then additional testing should be performed to rule out other etiologic causes. If 
no other cause is found, then it is assumed to be immune related. 

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9.5 
Reporting of SAEs 
 
Any SAE whether or not related to avelumab, occurring from informed consent up to the Safety 
Follow-up (30 days) and the Extended Safety Follow-up (90 days) following cessation of treatment, or 
the initiation of new anti-cancer therapy, whichever is earlier, must be reported on an SAE report form 
within 24 hours of the PI or designee becoming aware of the event to the RM-CTU by Fax 0208 915 
6762 who will inform the Chief Investigator and Merck KGaA.  
 
All SAEs regardless of causality, pregnancy (as per section 9.2.2) or overdose (as per section 9.7) 
should be documented and each episode of an SAE must be recorded on a separate SAE report form. 
The NCI CTCAE Version 4 must be used to grade each SAE, and the worst grade recorded. 
 
If new or amended information on a previously reported SAE becomes available, the Investigator 
should report this to the RM-CTU on a new SAE report form. If the SAE has not been reported within 
the specified timeframes, a reason for lateness must be included when sending the SAE report form. 
Please refer to the SAE completion guidelines for further information. 
 
Additionally, any SAE, considered by an investigator who is a qualified physician to be related to 
avelumab that is brought to the attention of the investigator at any time outside of the time period 
specified in the previous paragraph also must be reported immediately to the RM-CTU who will inform 
the Chief Investigator, the Sponsor and Merck KGaA. 
 
9.5.1 Events exempt from being reported as SAEs 
 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed. The events must still be recorded 
in the appropriate section of the electronic case report form (eCRF/CRF). 
1. Elective admissions to hospital for procedures which were planned and documented in the medical 
records at the time of consent are not SAEs, and do not require SAE reporting. 
2. Hospitalisation for administration of the IMP, or to facilitate study procedures according to the trial 
protocol, is also exempt from being reported as an SAE. 
3. Hospitalisation for the treatment of symptoms resulting from disease progression. 
9.5.2 Determining SAE Expectedness 
 

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Assessment of expectedness for all SAEs will be made by the PI/designee and Chief Investigator or 
delegate against the current version of the Investigator Brochure. Section 6.2.6 of the IB, Table 52 
‘Expected Adverse Reactions in Patients treated with avelumab in Clinical Studies’ defined 
expectedness of adverse reactions.  It is important to note that, with reference to this table, the 
identification of any adverse reactions of Grade 3 and above where the number of Adverse Reactions 
(ARs) reported is ‘1’ or ‘0’ must be regarded as unexpected. In addition, the identification of any 
serious adverse reactions (SARs) where the number of SARs reported is ‘1’ or ‘0’ must be regarded 
as unexpected. If updated versions of the investigator brochure are released during the course of the 
trial then assessment of expectedness will be made against the current regulatory approved version. 
 
9.6 
Reporting of ECIs 
 
Any ECIs irrespective of aetiology or whether or not related to the avelumab, occurring from the first 
dose until 30 days following the last treatment dose, or the initiation of a new anticancer therapy, 
whichever is earlier, must be recorded on the AE e-case report forms. These events should be 
reported using the SAE/ECI report form within 24 hours of the PI/designee becoming aware of the 
event to the RM-CTU who will inform the Chief Investigator, the Sponsor and Merck KGaA. 
 
9.7 
Definition of an Overdose for this Protocol and Reporting of Overdose 
 
At present no specific information is available on the treatment of overdose of avelumab. For purposes 
of this trial, an overdose will be defined as any dose exceeding the prescribed dose for avelumab by 
5% over the prescribed dose. In the event of overdose, avelumab should be discontinued and the 
patient should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of avelumab, the adverse 
event(s) should be recorded on the AE eCRF/CRF and documented in the patients’ medical records. 
The AE should also be reported as a serious adverse event, even if no other seriousness criteria are 
met. If an overdose is taken without any associated clinical symptoms or abnormal laboratory results, 
the overdose is again recorded as an AE on the eCRF/CRF and reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse 
effect.”  All reports of overdose either SAE or ECI must be reported within 1 working day of the PI or 
designee becoming aware of the event to the RM-CTU by Fax 0208 915 6762 who will inform the 
Chief Investigator and Merck KGaA. 

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9.8 
Definition of Serious Adverse Reaction (SAR) 
 
A SAR is defined as a SAE that is judged to be related to any dose of study drug administered to the 
patient. 
9.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions 
(SUSARS) 
 
A SUSAR is a SAR that is classified as ‘unexpected’ i.e. a SAR, the reaction, the nature and severity 
of which is not consistent with the information about the medicinal product in question set out in the 
Investigator Brochure (IB) for that product. 
9.10 Reporting of SUSARS 
 
The Investigator and local study team will rapidly report all SUSARs to the RM-CTU within 24 hours of 
becoming aware of the event. 
The RM-CTU will ensure that SUSARs are notified to the appropriate regulatory authority, the relevant 
Independent Ethics Committee (IEC) / Institutional review board (IRB), the Chief Investigator, Merck 
KGaA, the Sponsor and the participating Principal Investigators in accordance with regulatory 
requirements and within the timelines as defined below: 
 
• 
For fatal and life-threatening SUSARs the sponsor should report at least the minimum information as 
soon as possible and in any case no later than seven days after being made aware of the case. 
 
• 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days 
 
Follow up of patients who have experienced a SUSAR should continue until recovery is complete or 
the condition has stabilised. 
 
9.11 Annual Reporting of Serious Adverse Events 
 
Annual reports will be submitted to regulatory authorities and Independent Ethics Committees (IEC) by 
the Sponsor in accordance with all applicable global laws and regulations. Copies will be forwarded to 
the RM-CTU Trial Manager and Investigators. 
9.12 Urgent Safety Measures 
 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety. This includes 

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procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health. USMs may be taken without prior authorisation from the competent authority. The Medicines 
and Healthcare products Regulations Agency (MHRA) and the Research Ethics Committee (REC) 
must be notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform RM-CTU APPLE Trial Manager either by: 
email: Apple.trial@rmh.nhs.uk 
Telephone: 020 8915 6767 
Fax: 020 8915 6762 
The notification must include: 
the date of the USM; 
who took the decision; and 
why action was taken. 
RM-CTU will then inform the Chief Investigator and the Sponsor and notify the MHRA and the REC 
immediately and in writing within three days of USM initiation. RM-CTU will distribute the response 
and any subsequent amendments to the site. 
 
9.13 Safety reporting to Merck KGaA 
 
The following reportable event’s sponsor team must be submitted to Merck within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form for the study. APPLE 
Trial Manager in RM-CTU will assume responsibility for submitting the reportable event(s) to Merck as 
well as ensuring that any local reporting requirements are completed in parallel. 
• 
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) 
• 
Events of Clinical Interest (ECI) 
• 
Potential drug-induced liver injury (Hy’s Law cases): These events are considered important 
medical events and should be reported as SAEs. 
10 
Statistics and Data Analysis 
 
 
10.1 Sample size calculation  
 
The sample size for this phase 1 study is not based on a formal sample size calculation as no 
statistical hypothesis is being tested.  The total number of patients has been based on a desire to 

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obtain adequate tolerability, safety data while exposing as few patients as possible to the IMP and 
radiotherapy.  From clinical experience, 36 Gy in 12 fractions delivered daily to the thorax, trunk, or 
extremities, is well tolerated with minimal toxicity.   
Following entering the first 3 patients, recruitment will be deferred until they have been assessed for 
acute toxicity (i.e. 11 weeks from the initiation of combined radiotherapy and avelumab) by the SRC 
before recruitment of patients 4 to 6 can proceed  – see Figure 1.  The SRC will review toxicity 
following recruitment following recruitment of patient 6.  If the incidence of DLTs is within acceptable 
limits (see Figure 1) and in the absence of grade 3/4 toxicity (RTOG ACUTE radiation Morbidity), the 
cohort will be expanded up to 12 patients.   We will also monitor for grade 3/4 avelumab related 
toxicity as per the IMP brochure. We expect minimal overlapping toxicity between avelumab and 
radiotherapy.  
10.2 Planned recruitment rate 
 
The planned recruitment rate is one patient per month. 
 
10.3 Subject Analysis Population 
 
• 
The intention-to-treat (ITT) population 
The ITT population will consist of all patients who receive 1 dose of avelumab and 1 fraction of 
radiotherapy. 
• 
Acute toxicity population 
The acute toxicity population will consist of all patients who received at least 1 dose of avelumab and 
at least 1 fraction of radiotherapy and are assessed up to 11 weeks from the start of radiotherapy and 
avelumab treatment unless they exhibit a DLT during this period).  
• 
Late toxicity/efficacy population 
The late toxicity population will include all patients who received at least one dose of avelumab and at 
least one fraction of radiotherapy and will be reported from 11 weeks+1 day from the start of 
radiotherapy and avelumab treatment until confirmed disease progression or initiation of new anti-
cancer treatment therapy.   
• 
Other secondary and exploratory objectives/endpoints population  
This population will include all patients who received at least one dose of avelumab and at least one 
fraction of radiotherapy.   
 
 
10.4 Statistical analysis plan summary 
 

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This is a phase 1 study designed to exclude a significant rate of G3-4 toxicity after an initial 
abbreviated dose escalation phase.   
 
10.4.1 Primary and secondary outcomes and exploratory analysis methods 
 
 
This study will recruit patients (radiation tumour target volume above diaphragm).  Acute toxicity will 
be reported by week using CTCAEv4 grades, using the acute toxicity population. Worst grade will be 
reported as counts and percentages, by type of toxicity and over all types. Numbers of patients with 
missing and non-missing toxicity assessments will be reported for each week. Worst grades by type of 
toxicity and overall types will also be reported at all time points up to and including week 11 from the 
start of radiotherapy. The number and reasons for withdrawal before treatment completion will be 
stated. Acute toxicity will be reported for all patients grouped together regardless of dose level or 
disease stage. 
 
Late toxicity will be reported by time point. The number and percentage of worst grade at that time 
point by type of toxicity, and overall types will be reported. Number of patients with missing and non-
missing toxicity assessment will also be reported for each week. The late toxicity endpoint of the study 
will be reported as the number and percentage of patients experiencing any grade 2+ and grade 3+ 
late toxicity from week 11+1 day from the start of radiotherapy treatment. This will be reported at 
month 6 and month 12 from completion of radiotherapy. The late toxicity population will be used for all 
endpoints. An additional time to event analysis will be performed using Kaplan-Meier methods to show 
time to any grade 3+ toxicity from 11 weeks+1 day from the start of radiotherapy and avelumab 
treatment.  Late toxicity will be reported for all patients grouped together regardless of dose level or 
disease stage. 
 
Duration of local control will be measured from end of radiotherapy to date of first recorded local 
progression, using Kaplan-Meier methods. Patients without local progression will be censored at date 
of last follow-up or death from any cause. The percentage and 95% confidence intervals for rate of 
local control at 3 months after end of radiotherapy will be given. The late toxicity population will be 
used for this endpoint. 
Local control will be reported for all patients comprising the cohort. Progression free survival and 
overall survival will be reported using Kaplan Meier methods, and will be measured from the start of 
avelumab treatment in the acute toxicity population. Survival rates and 95% confidence intervals will 
be given at 1 and 2 years.  
 
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Statistical Analysis Plan (SAP) will be written and agreed by the Statistician and Chief Investigator 
before any analysis is performed. The total numbers of patients in the ITT population will be stated 
together with reasons for early withdrawal. 
 
10.5 Timing and responsibility for analyses 
 
The primary endpoint may be analysed and reported no earlier than 11 weeks following the start of 
radiotherapy and avelumab treatment for the last trial patient. All other secondary and exploratory 
endpoints may be analysed and reported no earlier than 6 months following the completion of 
radiotherapy treatment for the last trial patient. All endpoints will be reported only once, with the 
exception of late toxicity, progression free and overall survival, which may be reported for a second 
and final time once all patients have recorded any one of withdrawal, disease progression, death, or 
three years follow-up post radiotherapy. 
11 
Data Handling 
 
11.1 Source Data 
 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial are classified as source data. Source data are contained in source documents; these are defined 
as original documents, data, and records e.g., hospital records, clinical and office charts, laboratory 
notes, memoranda, patients' diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate 
copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, patient files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the 
clinical trial. 
 
11.2 Language 
 
All CRFs will be in English. Generic names for concomitant medications should be recorded in the 
CRF wherever possible. All written material to be used by patients must use vocabulary that is clearly 
understood, and be in the language appropriate for the study site. 
 

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11.3 Data Collection 
 
The medical records/medical notes should be clearly marked and to allow for easy identification of a 
patient’s participation in the clinical trial. The Investigator (or delegated member of the site study team) 
must record all data relating to protocol procedures, IMP administration, laboratory data, safety data 
and efficacy data into the CRF. 
 
11.4 Recording of Data 
 
Patients’ data will be recorded on a trial specific CRF designed by RM-CTU. Upon signing the 
informed consent form, the patient is assigned to the next sequential patient trial identification number 
available. To ensure recruitment is not delayed in any way a paper CRF will be available for use in the 
event that the electronic CRF is not ready for use. 
 
The Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of the 
data reported in the CRFs. Only the Investigator, and those personnel who have completed the Study 
Team Responsibilities Signature Log/Delegation Log as authorised by the PI, should enter or change 
data in the CRFs. All protocol required investigations must be reported in the CRF. The Investigators 
must retain all original reports, traces and images from these investigations for future reference. The 
data will be entered in a clinical trials database (Macro V4). If a patient withdraws from the study, the 
reason must be noted on the CRF. 
 
Authorised site personnel must not enter study-specific data directly into CRFs and must ensure all 
results are appropriately documented in the patients’ medical records. The CRF will be signed by the 
Investigator or by an authorised staff member. Study specific information will be entered into a CRF 
visit by visit. Data that are derived should be consistent with the source documents or the 
discrepancies should be explained. All CRF data should be anonymous, i.e. identified by study patient 
number only. 
 
Once the patient is ‘off study’ and the CRF has been fully completed, the Investigator must provide a 
signature to authorise the complete patient data. 
 
11.5 Data Management 
 

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Data management will be carried out by RM-CTU using an electronic database and in accordance 
with the data management plan agreed by the RM-CTU and RDSU. Data entry will be carried out by 
appropriately trained personnel at participating centres. Queries will be raised centrally by the trial 
manager / trial monitor and sent to the participating centre for resolution. 
 
12 
Trial Oversight, Monitoring, Inspection and Audit  
 
12.1 Study Management Structure 
12.1.1 Delegations of Responsibilities 
 
This trial is sponsored by the Royal Marsden NHS Foundation Trust. This trial will be conducted in 
accordance with the professional regulatory standards required for non-commercial research in the 
NHS under the research governance framework for health and social care and good clinical practice. 
The following responsibilities have been delegated to: 
 
RM-CTU 
 
RM-CTU has overall responsibility for facilitating and coordinating the conduct of the trial and is also 
responsible for collating data obtained, and undertaking and reporting all analyses. 
The responsibilities of RM-CTU for the day-to-day management of the trial will include the following. 
• Ensuring an appropriate ethics opinion has been sought, and any amendments have been approved. 
• Giving notice of amendments to protocol, make representations about amendments to the Main REC 
and MHRA as applicable. 
• Notifying site and Sponsor that the trial has ended. 
• Raising and resolving queries with local investigators. 
• Keeping records of all SAEs, overdose incidents, pregnancies and overdose and liver toxicity ECIs 
reported by investigators. 
• Notifying the Main REC, MHRA and Investigators of related SAEs. 
 
Merck KGaA 
 
• Provision of avelumab 
 
Participating Site 
 
• Putting and keeping in place arrangements to adhere to the principles of GCP. 

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• Keeping a copy of all ‘essential documents’ (as defined under the principles of GCP) and ensuring 
appropriate archiving of documentation once the trial has ended. 
• Taking appropriate urgent safety measures. 
•Centres wishing to recruit to this study will be asked to provide evidence that they can deliver protocol 
treatment. 
• Responsibilities are defined in an agreement between an individual participating centre and RM-
CTU, which must be signed and in place before recruitment can commence. 
 
12.2 Protocol compliance and amendments 
 
The participating site will be required to sign an agreement with RM-CTU that includes requirement to 
sign and adhere to the trial protocol. Any protocol amendment should be agreed with the trial 
management group (TMG) and be approved by the sponsor prior to submission and review by the 
relevant Ethics Committee and the MHRA where required. Once favourable opinion from REC and if 
applicable the MHRA has been obtained the amendment can be distributed to the site and 
implemented. It is the responsibility of the Principal Investigator to submit amendment to their R&D 
department for R&D approval. 
 
12.3 Trial Management 
 
The RM-CTU will be responsible for trial management. This includes all duties relating to safety 
reporting. Once all relevant trial approvals are in place an initiation visit will be conducted. In addition, 
training and ongoing advice will be provided by the trial management team. 
 
12.3.1 Trial Management Group (TMG) & Safety Review Committee (SRC) 
 
A Trial Management Group (TMG) will be set up and membership will include Chief Investigator, Co-
Investigators, Trial Statistician and Trial Manager. Principal Investigators and other key study 
personnel will be invited to join the TMG as appropriate. The role of the TMG will be defined in a TMG 
charter. Responsibilities will include, but not be limited to: operational responsibility for the conduct of 
the trial, monitoring of recruitment, safety and governance of the trial as well as collaborating with 
subsequent translational sub-studies. A Safety Review Committee will also be set-up and will have an 
independent Chair. The TMG will work in close co-operation with the SRC and as appropriate, will 
review any safety concerns as identified by the SRC. The membership of the SRC will be defined in 
an SRC Charter which will define the role of the Group and the frequency of meetings  to ensure that 
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basis. The statistician may not be required at every meeting but should be called upon if necessary. 
The format of this meeting will be concordant with that used for Phase I studies at RMH. 
12.4 Monitoring 
 
During the study, data quality will be monitored in accordance with relevant standard operating 
procedures (SOPs). Incoming data will be monitored for protocol compliance and if any inconsistent or 
missing data is identified queries will be sent to the site for resolution. Any systematic inconsistencies 
may trigger an onsite monitoring visit. The study will be monitored according to a risk-based 
monitoring plan. Remote monitoring and remote source data verification due to COVID-19 are to be 
amended on the risk-based monitoring plan.  
 
The trial statistician will periodically examine the data for anomalies and outliers. Queries will be raised 
by the trial coordinators in such situations and communication with the clinical teams will take place. In 
addition statistical monitoring of unusual dates and inconsistent data will take place (for example clinic 
visits on Sundays). Again these will raise queries via the trial coordinators. 
12.5 Quality Control and Quality Assurance 
 
Clinical data will be presented at the end of the trial based on final data listings. The CI/designee 
together with the trial statistician will prepare a brief clinical study report / publication based on the final 
data listings. A summary of the report must be provided to the Research Ethics Committee and the 
MHRA within 1 year from the submission of the end of trial notification. 
 
12.6 Clinical Study Report 
 
Clinical data will be presented at the end of the trial based on final data listings. The CI/designee 
together with the trial statistician will prepare a brief clinical study report / publication based on the final 
data listings. A summary of the report must be provided to the Research Ethics Committee and the 
MHRA within 1 year from the submission of the end of trial notification. 
 
12.7 Record Retention 
 
Essential documents are documents that individually and collectively permit evaluation of the conduct 
of the trial and substantiate the quality of the data collected. During the clinical trial and after trial 
closure the Investigator must maintain adequate and accurate records to enable both the conduct of a 

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clinical trial and the quality of the data produced to be evaluated and verified in accordance with 
current legislation. 
 
RM-CTU will maintain essential documents to facilitate the management of the trial, audit and 
inspection in accordance with relevant SOPs and in compliance with the clinical trial regulatory 
requirements. The medical files of trial subjects shall be retained in accordance with national 
legislation and in accordance with the maximum period of time permitted by the hospital, institution or 
private practice. All medical records and TMF documentation will be retained for a minimum of 5 years 
after the study has concluded. 
 
13  
Ethical and Regulatory Considerations 
 
13.1 Good Clinical Practice 
 
The study will be conducted in accordance with the conditions and principles of GCP as defined in the 
clinical trials regulations. 
13.2 Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
 
Before starting the trial, the protocol, patient information sheet, consent form, any other written 
information that will be provided to the patients and any advertisements that will be used and details of 
any patient compensation must be approved by the RM/ICR joint Committee for Clinical Research. 
Once approved, the study will then be submitted to the relevant Ethics Committee for their review and 
approval. 
 
Prior to the shipment of IMP and the enrolling any patients the Investigator at each site is responsible 
for any site specific assessments and obtaining local R&D approval for the study.  The site will be 
required to sign an agreement with RM-CTU which includes requirement to sign and adhere to the trial 
protocol. 
 
13.2.1 Initial Approval 
 
Before starting the trial, the protocol, patient information sheet, consent form, any other written 
information that will be provided to the patients and any advertisements that will be used and details of 
any patient compensation must be approved by the RM/ICR joint Committee for Clinical Research and 
Merck. Once approved, the study will then be submitted to the relevant Ethics Committee and the 

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Health Research Authority (HRA) for their review and approval.  Prior to the shipment of IMP and the 
enrolling of any patients the Investigator at the  site is responsible for any site specific assessments 
and obtaining local R&D approval for the study.   
13.2.2 Approval of Amendments 
 
Any protocol amendment should be agreed with the trial management group (TMG) and be approved 
by Merck and the sponsor prior to submission and review by the relevant Ethics Committee and the 
MHRA. Once favourable opinion from IEC has been obtained the amendment can be distributed to the 
site and implemented. It is the responsibility of the Principal Investigator to submit amendment to their 
R&D department for R&D approval Amendments requiring IEC approval may be implemented only 
after a copy of the IEC/IRB’s approval letter has been obtained. Amendments that are intended to 
eliminate an apparent immediate hazard to patients may be implemented prior to receiving Sponsor or 
IEC/IRB approval. However, in this case, approval must be obtained as soon as possible after 
implementation. 
 
13.2.3 Annual Safety Reports and End of Trial Notification 
 
It is the responsibility of the sponsor to submit the Development Safety Update Report annually to the 
MHRA/REC on the anniversary of the studies MHRA/REC approval. This will facilitate the authorities 
continuing review of the study. These authorities will also be informed of the end of the study by the 
sponsor within 90 days of the trial completion. Copies of these reports will also be held within the main 
trial master file. 
13.3 Regulatory Authority Approval 
 
The study will be performed in compliance with UK regulatory requirements. Clinical Trial 
Authorisation (CTA) from the Medicines and Healthcare products Regulatory Authority (MHRA) will be 
obtained prior to the start of the study.  In addition, the MHRA must approve amendments (as 
instructed by the Sponsor), receive SUSAR reports and annual safety updates, and be notified of the 
end of the trial. 
 
13.4 Notifications of Serious Breaches to GCP and / or the Protocol 
 
The Sponsor will notify the MHRA and REC in writing of any serious breaches of: 
a. The condition and principles of GCP in connection with the trial. 
b. The protocol. 

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This will be done within 7 days if becoming aware of that breach, in accordance with the applicable UK 
regulations as amended from time to time. 
 
For the Purpose of the regulations a “serious breach” is a breach which is likely to effect to a 
significant degree 
a. The safety or physical integrity of the subjects of the trial; or 
b. The scientific integrity of the trial. 
 
Systematic or persistent non-compliance by the site with GCP and/or the study protocol, including 
failure to report SAEs occurring on trial within the specified timeframes, may be deemed a serious 
breach. 
 
13.5 Insurance and Liability 
 
The Sponsors will secure indemnity from the manufacturer of avelumab for patients in relation to 
adverse side effects for medicine-induced injury. Indemnity for participating hospitals is provided by 
the usual NHS indemnity arrangements for clinical negligence. A copy of the relevant insurance 
policy/indemnity scheme or summary shall be provided on request. 
 
13.6 Contact with General Practitioner (GP) 
 
It is the Investigator’s responsibility to inform the patient’s GP by letter that the patient is taking part in 
the study provided the patient agrees to this, and information to this effect is included in the PIS and 
ICF. A copy of the letter should be filed in the Site File. A template letter approved by the IEC/IRB will 
be provided by the Sponsor to the participating site. 
 
13.7 Patient Confidentiality 
13.7.1 Patient Confidentiality and Data Sharing 
 
The Chief investigator must ensure that the patient’s confidentiality is maintained in compliance with 
the UK Data Protection Act of 1998. On the CRFs or other documents submitted to the RM-CTU, 
patients should be identified by their initials and a patient study number only. 
 

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In compliance with GCP guidelines, it is required that the investigator and institution permit authorized 
representatives of the sponsor and of the regulatory agency(s) direct access to review the patient’s 
original medical records for verification of study-related procedures and data. Direct access includes 
examining, analysing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study. The investigator is obligated to inform and obtain the consent of the patient to 
permit named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
13.7.2 Pharmacogenetics Confidentiality 
 
All pharmacogenetic samples and the information associated with the samples will be coded and 
stored appropriately to ensure confidentiality of the patient’s information and to enable destruction of 
the samples if requested. Since the evaluations are not expected to benefit the patient directly or to 
alter the treatment course, the results will not be placed in the patient’s medical record and will not be 
made available to members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
 
13.8 Data collection and documentation 
 
It is the Investigator’s responsibility to ensure that all relevant data is clearly recorded in the medical 
records. The Investigator must allow the RM-CTU direct access to relevant source documentation for 
verification of data entered into the CRF, taking into account data protection regulations. The clinical 
data should be recorded in the CRF and the following must be verifiable by the source data: patient 
consent, medical history, patient’s eligibility for participation in the trial, study treatment administration 
(avelumab and RT), routine haematology and biochemistry and response to treatment. 
 
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the sponsor appointed to audit the trial, or by REC. Details will remain 
confidential and patients’ names or personal information will not be recorded outside the hospital. 
 
The Chief Investigator should confirm agreement with his/her local NHS Trust to ensure that  
• sufficient data is recorded for all participating patients to enable accurate linkage between hospital 
records and CRFs  
• source data and all trial related documentation are accurate, complete, maintained and accessible 
for monitoring and audit visits  

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• original consent forms are dated and signed by both patient and investigator and are kept together in 
a central log together with a copy of the specific patient information sheet(s) given at the time of 
consent  
• all essential documents must be retained after the trial ends to comply with current legislation  
 
No study document will be destroyed without prior written agreement between the Sponsor and the PI. 
Should the PI wish to assign the study records to another party or move them to another location, 
written agreement must be obtained from the Sponsor. 
 
13.9 End of Trial 
 
The end of the trial is defined as the last patient’s last visit. 
 
13.10 Post trial access 
 
If the study closes early, patients who continue to benefit from treatment will continue to receive 
avelumab and Merck will continue to supply the drug free of charge for these patients. 
 
14  
Dissemination policy and Authorship eligibility guidelines 
 
The Study sponsor is The Royal Marsden Hospital and the trial will be registered on a publically 
accessible clinical trial registry (e.g. clinicaltrials.gov). The trial results will be submitted for publication 
in a relevant medical journal with authorship according to the criteria defined by the ICMJE 
(http://www.icmje.org). These state that: Authorship credit should be based 1) substantial contributions 
to conception and design, acquisition of data, or analysis and interpretation of data; 2) drafting the 
article or revising it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors should meet conditions 1, 2, and 3. A lay summary of the results will also be made 
available on the Royal Marsden’s website. 
  
Draft publications (manuscripts, abstracts, slides and posters) should be submitted to the RM-CTU for 
circulation to the relevant parties to allow sufficient time for review prior to submission. There will be a 
fifteen (15) day period to review abstracts or posters and a thirty (30) day period to review slides and 
manuscripts and respond to the author with any revisions. 
 

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15 
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Keir M, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol. 2008; 26: 677–704. 
 
 
Kelly K, Patel MR,  Infante J, Iannotti N, Nikolinakos P, Leach J, Wang D, Chandler JC, Jerusalem 
GHM,  Gurtler JS, Arkenau H, Speit I,  von Heydebreck A,  Chin K, Heery CR, Gulley JR. Avelumab 
(MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic or locally advanced solid 
tumours: assessment of safety and tolerability in a phase I, open-label expansion study.  J Clin Oncol 
33, 2015 (suppl; abstr 3044) 
 
 

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Kim C, Kim EK, Jung H, Chon HJ, Han JW, Shin KH, Hu H, Kim KS, Choi YD, Kim S, Lee YH, Suh JS, 
Ahn JB, Chung HC, Noh SH, Rha SY, Kim SH, Kim HS. Prognostic implications of PD-L1 expression 
in patients with soft tissue sarcoma. BMC Cancer. 2016 Jul 8;16:434.  
 
 
Kim JR, Moon YJ, Kwon KS, Bae JS, Wagle S, Kim KM, Park HS, Lee H, Moon WS, Chung MJ, Kang 
MJ, Jang KY. Tumour infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor 
prognosis of soft tissue sarcomas. PLoS One. 2013 Dec 11;8(12):e82870.  
 
 
Linch M, Miah AB, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma-gold 
standard and novel therapies. Nat Rev Clin Oncol. 2014 Apr;11(4):187-202.  
 
MacDuff A, Arnold A, Harvey J, on behalf of the BTS Pleural Disease Guideline Group. Management 
of spontaneous pneumothorax : British Thoracic Society pleural disease guideline 2010. Thorax 2010 
65(Suppl 2) : ii18 – ii31 
 
 
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed 
death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007; 13: 
2151-7. 
 
 
Okazaki T and Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 
2007; 19: 813-24. 
 
 
Okazaki T and Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends in Immunol. 
2006; 27: 195-201. 
 
 
Paoluzzi L,  Ghesani M, Cacavio A, Rapkiewicz A, Rosen G.  Anti-PD1 therapy with nivolumab in 
sarcoma.  J Clin Oncol 34, 2016 (suppl; abstr 11047) 
 
 
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick 
AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, 
Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, 
Shapira-Frommer R, Gonzalez R,  Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt 
AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy 
for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet 
Oncol. 2015 Aug;16(8):908-18.  
 
 
Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009; 229: 114-25. 
 
 
Sharma A, Bode B, Studer G, Moch H, Okoniewski M, Knuth A, von Boehmer L, van den Broek M. 
Radiotherapy of human sarcoma promotes an intratumoural immune effector signature. Clin Cancer 
Res. 2013 Sep 1;19(17):4843-53.  
 
 
Sologuren I, Rodríguez-Gallego C, Lara PC. Immune effects of high dose radiation treatment: 
implications of ionizing radiation on the development of bystander and abscopal effects. Transl Cancer 
Res 2014;3:18-31. 
 

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Strome S, Sho M, Akahori T, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for 
squamous cell carcinoma. Cancer Res. 2003; 63:6501-5. 
 
 
Tawbi HA, Burgess  MA, Crowley J, Van Tine BA, Hu J, Schuetze S, D'Angelo SP, Attia S, Priebat 
DA, Okuno SH, Riedel RF, Davis LE, Movva S, Reed DR, Baker LH, Reinke DK, Maki RG, Patel S, for 
SARC028 Investigators.  SARC 028: A phase II study of the anti-PD1 antibody pembrolizumab (P) in 
patients (Pts) with advanced sarcomas.  J Clin Oncol 34, 2016 (suppl; abstr 11006). 
 
 
Teitz-Tennenbaum S, Li Q, Rynkiewicz S, Ito F, Davis MA, McGinn CJ, Chang AE.  Radiotherapy 
potentiates the therapeutic efficacy of intratumoural dendritic cell administration. Cancer Res. 2003 
Dec 1;63(23):8466-75. 
 
 
Topalian SL, Drake CG, and Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-
tumour immunity. Curr Opin Immunol. 2012a; 24: 207-12. 
 
 
Waeckerle-Men Y, Starke1 A, and Wuthrich RP. PD-L1 partially protects renal tubular epithelial cells 
from the attack of CD8+ cytotoxic T cells. Nephrol Dial Transplant. 2007; 22: 1527-36. 
 
 
Zhang L, Gajewski TF, and Kline J. PD-1/PD-L1 interactions inhibit antitumour immune responses in a 
murine acute myeloid leukemia model. Blood. 2009; 114: 1545-52. 
 

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16.  Appendices 
 
16.1 Appendix 1: Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for adverse event reporting. Expected versus unexpected events are detailed for 
each organ system. For Myelitis (see end of Table) all occurrences of any grade of severity must be regarded as 
unexpected. http://ctep.cancer.gov/reporting/ctc.html) 
16.2 Appendix 2: RTOG Toxicity  
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Skin 
Follicular, faint 
or dull 
erythema / 
epilation / dry 
desquamation / 
decreased 
sweating 
Tender or bright 
erythema, 
patchy moist 
desquamation / 
moderate 
edema 
Confluent, 
moist 
desquamation 
other than skin 
folds, pitting 
edema 
Ulceration, 
hemorrhage, 
necrosis 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 
Pharynx & 
esophagus 
Mild dysphagia 
or odynophagia 
/ may require 
topical 
anesthetic or 
non-narcotic 
analgesics / 
may require 
soft diet 
Moderate 
dysphagia or 
odynophagia / 
may require 
narcotic 
analgesics / 
may require 
puree or liquid 
diet 
Severe 
dysphagia or 
odynophagia 
with 
dehydration or 
weight loss > 
15% from 
pretreatment 
baseline 
requiring NG 
feeding tube, 
IV fluids, or 
hyperalimentati
on 
Complete 
obstruction, 
ulceration, 
perforation, 
fistula 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 

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Upper GI 
 
Anorexia with ≤ 
5% weight loss 
from 
pretreatment 
baseline / 
nausea not 
requiring 
antiemetics / 
abdominal 
discomfort not 
requiring 
parasympathol
ytic drugs or 
analgesics 
Anorexia with ≤ 
15% weight loss 
from 
pretreatment 
baseline / 
nausea and/or 
vomiting 
requiring 
antiemetics / 
abdominal pain 
requiring 
analgesics 
 
Anorexia with 
> 15% weight 
loss from 
pretreatment 
baseline or 
requiring NG 
tube or 
parenteral 
support. 
Nausea and/or 
vomiting 
requiring tube 
or parenteral 
support / 
abdominal 
pain, severe 
despite 
medication / 
hematemesis 
or melena / 
abdominal 
distention (flat 
plate 
radiograph 
demonstrates 
distended 
bowel loops) 
Ileus, 
subacute or 
acute 
obstruction, 
perforation, 
GI bleeding 
requiring 
transfusion / 
abdominal 
pain 
requiring 
tube 
decompressi
on or bowel 
diversion 
 
 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 
Lung 
Mild symptoms 
of dry cough or 
dyspnea on 
exertion 
Persistent 
cough requiring 
narcotic, 
antitussive 
agents / 
dyspnea with 
minimal effort 
but not at rest 
Severe cough 
unresponsive 
to narcotic 
antitussive 
agent or 
dyspnea at 
rest / clinical or 
radiological 
Severe 
respiratory 
insufficiency 
/ continuous 
oxygen or 
assisted 
ventilation 
Death 
directly 
related to 
radiation 
effects 

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evidence of 
acute 
pneumonitis / 
intermittent 
oxygen or 
steroids may 
be required 
Expected 
NOT EXPECTED 
Liver 
Bilirubin 
 
 
<1.5 X N 
1.5 - 3.0 X N 
>3.0 X N 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 
Liver 
Transaminase 
(SGOT, SGPT) 
 
<=2.5 X N 
2.6 - 5.0 X N 
5.1 - 20.0 X N 
>20.0 X N 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 
Liver 
Alkaline 
Phosphatase 
or 
S'nucleotidase 
 
<=2.5 X N 
2.6 - 5.0 X N 
5.1 - 20.0 X N 
>20.0 X N 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 
Liver/Clinical 
 
 
Precoma 
Hepatic 
coma 
Death 
directly 
related to 
radiation 
effects 
Expected 
NOT EXPECTED 
 
 
 
 
 
 
 
 

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Nervous 
System 
Disorders  
Myelitis 
 
 
Asymptomatic 
mild signs (e.g. 
Babinski’s 
reflex or 
Lhermitte’s 
sign) 
Moderate 
weakness or 
sensory loss; 
limiting 
instrumental 
ADL 
Severe 
weakness or 
sensory loss; 
limiting self 
care ADL 
Life-
threatening 
consequence
s; urgent 
intervention 
indicated 
Death 
NOT EXPECTED 
 
Table 10: RTOG toxicity 
16.3 Appendix 3: Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumours 
 
RECIST version 1.1* will be used in this study for assessment of tumour response. While either CT or 
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. 
Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. 
Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
16.4 Appendix 4: Immune-Related Response Criteria 
 
The immune-RECIST (iRECIST)* will also be used in this study for assessment of tumour response. 
*As published in HHS Public Access. Author manuscript Lancet Oncol. Author manuscript; 
available in PMC 2017 October 19. iRECIST: guidelines for response criteria for use in trials 
testing immunotherpeutics. L.Seymour, J.Bogaerts, A.Perrone, R.Ford, L.H. Schwartz, S. 
Mandrekar, N.U. Lin, S. Litière.16.5 
Appendix 5:  Management of Avelumab-Specific 
Adverse Events or Adverse Drug Reactions 
 
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an infusion-related  
reaction, it must remain decreased for all subsequent infusions.  If the subject has a second infusion-
related reaction Grade ≥ 2 on the slower infusion rate, the infusion should be stopped and the subject 
should be removed from study treatment.  If a subject experiences a Grade 3 or 4 infusion-related 
reaction at any time, the subject must discontinue study drug. 
Severe Hypersensitivity Reactions  and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the subject must be treated according to the best available medical 
practice. Subjects should be instructed to report any delayed reactions to the Investigator immediately. 

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For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable nonsteroidal  
anti-inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 500 mg) may 
be administered 2 hours before and 8 hours after the start of each dose of avelumab IV infusion.  
Alternative treatments for fever (for example, paracetamol) may be given to subjects at the discretion 
of the Investigator. 
Tumour Lysis Syndrome 
In addition, since avelumab can induce antibody-dependent cell-mediated cytotoxicity, there is a 
potential risk of tumour lysis syndrome.  Should this occur, subjects should be treated per the local 
guidelines and the management algorithm below (Howard et al, 2011). 
Assessment and Initial Management of Tumour Lysis Syndrome 

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Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia
 
TLS = tumour lysis syndrome - Figure 2 
Immune-Related Adverse Events 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may occur.  
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring 

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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 irAEs should follow guidelines set forth in the Table 7. 
16.6 Appendix 6: Management of Spontaneous Pneumothorax 
 
Management of spontaneous pneumothorax should be carried out as described in the BTS Guideline 
document (MacDuff et al 2010).  
16.7 Appendix 7: Amendment History 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
First 
Approved 
Final Version 
for external 
submission 
and 
appended to 
Contract 
1.0 
2 Jan 2018 
CI / Trial 
Manager 
First approved protocol with 
incorporation of CCR and PV 
comments.  
Updated 
version in 
response to 
MHRA 
Grounds for 
Non-
Acceptance 
1.1 
6 Mar 2018 
Trial 
Manager 
Incorporation of MHRA comments to 
address grounds for non-acceptance. 
Updated 
version in 
response to 
REC 
comments 
(received: 
06/03/2018) 
and Sponsor 
comments 
(received: 
13/04/2018) 
2.0 
19 April 2018 Trial 
Manager / 
Chief 
Investigator 
Incorporation of REC comments and 
including Sponsor comments following 
review of REC-included comments. 
 

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Change (v 3.0) 15th Jan 2020 
Rationale  
Relevant protocol sections 
Inclusion of ClinicalTriasl.gov 
registration number. 
Update Protocol version & Date 
NCT Number obtained since 
previous version. 
 
 
Title page / Summary Table 
Updates to signature page 
Sign-off of new version 
Signature page 
Updates to Key Trial Contacts 
Change of personnel 
Key Trial Contacts and protocol 
Contributors 
Clarification of inclusion criteria 
regarding: 
 
1) number of lines of previous 
chemotherapy allowed 
 
2) Patients on anti-coagulants 
Statement clarified to avoid 
possible misinterpretation and 
to make it clear that CT naïve 
patients are eligible 
 
 
Patients on anti-coagulants 
need not be excluded if the 
Investigator agrees that their 
anti-coagulant can be safely 
discontinued for the purposes of 
conducting a biopsy 
Summarised Eligibility Criteria, 
bullet point 6 
Section 6.1, Inclusion Criteria, 
number xii 
 
 
Section 6.1, Inclusion Criteria, 
number xviii and Exclusion 
Criteria, number xxviii 
Clarification regarding the 
conducting of optional biopsies. 
New wording added at request 
of CI to ensure appropriate 
patient protection and that 
patients that may be at risk of 
potential SAE during the 
procedure are not invited to 
receive an optional biopsy 
Section 2.5.2, paragraph 3 
Clarification of definition of DLT 
The term ‘colitis / diarrhoea’ is 
felt to be more appropriate than 
diarrhoea alone. Further, colitis 
which is relevant was not 
previously stated. 
Section 4.2.1, bullet points 2 & 
3 
Updates to the Trial Procedures 
table 
Inclusion of fortnightly thyroid 
function tests as recommended 
by ESMO guidelines 
Clarification that it is PD-L1 
sample collection as opposed to 
collection and analysis – which 
may be performed at a later 
stage. 
Section 7.1 ‘Trial Procedures’ 
table 

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Clarification of the key to the 
table. 
Allowance of flexibility in 
delivery interval of 14 days 
between administrations of IMP. 
A window for administration is 
required to accommodate ad-
hoc and unavoidable changes 
in IMP administration.   
Section 8.3.7 
Clarification of the time-period 
and tool used to assess 
radiotherapy-induced toxicity 
(RTOG). Removal of CTCAE 
grading in this respect. 
 
Update time-period for toxicity 
review during the maintenance 
phase (i.e. post-radiotherapy) to 
allow flexibility in the time-
frames for capturing this 
information. 
Consistency with other studies 
in which RTOG is used for the 
assessment of radiotherapy-
induced toxicity. 
 
 
Increased flexibility in toxicity 
assessments post-radiotherapy.  
Section 7.3.2 
Replacement of all references 
to irRECIST with iRECIST  
iRECIST is now the 
recommended tool to assess 
tumour response in studies 
employing immunotherapy 
agents (e.g. PD-L1).  
References throughout the 
protocol. 
PIS – ICF 
Include GDPR Statement 
 
Include changes to the 
Investigator Broucher v10 
PIS – ICF version 4.0 15 Jan 
2020 
Immune side effects 
observed in less than 1% of 
patients.  
 
A disease that results when 
the immune system blocks 
the normal nerve activity in 
the muscles causing muscle 
weakness (myasthenia 
gravis/myasthemic 
syndrome):may include 
weakness in the arms, 
hands, fingers, legs, and 
neck weakness of the eye 
muscle; double vision; 
drooping eyelid; difficulty 
swallowing; impaired speech; 

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and shortness of breath.  
 
PIS – Biopsy – ICF 
Patient to sign consent the day 
of the biopsy  
PIS – Biopsy PIS + ICF Clean 
v1.0 Jan 2020