Clinical trial NCT03046953
Conditions: T-Cell Lymphoma Relapsed T-Cell Lymphoma Refractory
Keywords: Lymphoma
Sponsor: University of Birmingham
Start date: 2017-12-08; Completion date: 2021-07-27
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The AVAIL-T trial is a trial to find out how effective avelumab is at treating patients with primary T-cell lymphoma that is refractory to or has relapsed following initial treatment.

Detailed description:
The AVAIL-T trial is designed to find out how effective avelumab is at treating patients with primary T-cell lymphoma that is refractory to or has relapsed following initial treatment. Up to 36 people will be taking part in the AVAIL-T trial at hospitals across the United Kingdom. All patients on the trial will be recruited over 2 years and receive up to 8 cycles of avelumab treatment. Avelumab is an anti-PDL1 (programmed cell death receptor ligand 1) antibody that will be given as an infusion once every 2 weeks in cycles lasting 28 days. The trial will be looking at the response to avelumab, by measuring the change in the tumour size using CT scans, and seeing how long that response is maintained. The trial will also look at toxicity, overall survival, and progression free survival.

In addition we will analyse blood samples and samples of the cancer to understand better how the cancer behaves. This may guide the investigators in developing better treatments in the future.

Arms: arm 1: Avelumab 10mg/kg by IV infusion once every 2 weeks. A maximum of 8 cycles, each cycle is 28 days.
Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: anti-PDL1 antibody

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
A Phase 2a trial of Avelumab, an anti-PD-L1 antibody, in relapsed and refractory peripheral 
T-cell lymphoma (PTCL) 
 
 
 
 
 
 
 
Version 5.0a 
Date: 15-Aug-2018 
 
 
Chief Investigator: 
 
Prof Simon Wagner 
Sponsor:  
 
 
University of Birmingham 
Sponsor number:  
 
RG_16-123 
EudraCT number: 
 
2016-004879-46 
Clinicaltrials.gov 
 
NCT03046953 
UTRN  
 
 
U1111-1192-4931 
CAS number: 
 
 
NH2004 
NIHR CRN portfolio:  
 
33689 
IRAS ID:  
 
 
222665 
 
This application is supported by the facilities funded through Birmingham Science City: Translational 
Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) 
funded project which forms part of the Science City University of Warwick and University of 
Birmingham Research Alliance  
 
 


AVAIL-T 
Protocol  
 
 
 
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AVAIL-T protocol_5.0a_15-Aug-2018 
 
CRCTU-PRT-QCD-001, version 1.0 
TRIAL PERSONNEL  
 
Chief Investigator 
 
 
 
Sponsor 
Prof Simon Wagner 
 
 
 
University of Birmingham 
Consultant Haematologist 
 
 
Correspondence to:  
Room 104, Hodgkin Building,  
 
 
AVAIL-T Trial Office 
University of Leicester,   
 
 
Haematology team 
Lancaster Road,  
 
 
 
Centre for Clinical Haematology 
Leicester LE1 7HB, UK   
 
 
Queen Elizabeth Hospital Birmingham B15 2TH 
Tel: 0116 252 5584 
 
 
 
Tel: 0121 371 7861 
Fax: 0116 252 5616 
 
 
 
Fax: 0121 371 7874 
Email: sw227@le.ac.uk    
 
 
Email: Avail-T@trials.bham.ac.uk 
 
Co-Investigators and Clinical Coordinators 
 
Dr Matthew Ahearne 
 
 
 
Dr Christopher Fox  
NIHR Clinical Lecturer,  
 
 
Consultant Haematologist 
Dept of Cancer Studies,  
 
 
Centre for Clinical Haematology 
Room 105 Hodgkin Building, 
 
 
Nottingham University Hospitals (City Campus) 
Lancaster Road, 
 
 
 
Hucknall Road 
Leicester 
 
 
 
 
Nottingham 
LE1 7HB 
 
 
 
 
NG5 1PB 
Tel: 01162525584 
 
 
 
Tel: 0115 969 1169 ext 56704 
Email: mja40@le.ac.uk  
 
 
Email: christopher.fox@nhs.net 
 
Dr Graham Collins  
 
 
 
Dr Andrew Davies  
Consultant, Clinical Haematology,  
CR UK Senior Lecturer and Honorary Consultant 
Oxford University Hospitals NHS Trust  
Oncologist 
Oxford Cancer and Haematology Centre,  
Somers Cancer Building 
Churchill Hospital, Old Road,  
 
 
Southampton General Hospital 
Oxford,  
 
 
 
 
Southampton 
OX3 7EJ 
 
 
 
 
SO16 6YD 
Tel: 01865 235886 
 
 
 
Tel: 023 8120 6184 
Email: graham.collins@ouh.nhs.uk 
 
Email: a.davies@southampton.ac.uk 
 
 
Aimee Elizabeth Houlton 
CRCTU 
University of Birmingham 
Edgbaston 
Birmingham 
B15 2TT 
Tel: 0121 414 8328 
Email: A.E.Houlton@bham.ac.uk 
 
Haematology Team Leader 
 
 
Trial Statistician 
Sonia Fox 
 
 
 
 
Anesh Panchal 
CRCTU 
 
 
 
 
CRCTU 
Centre for Clinical Haematology  
 
University of Birmingham 
Queen Elizabeth Hospital 
 
 
Edgbaston 
Birmingham 
 
 
 
 
Birmingham 
B15 2TH 
 
 
 
 
B15 2TT 
Tel: 0121 371 7861 
 
 
 
Tel: 0121 414 8328 
Email: Avail-T@trials.bham.ac.uk 
 
Email: A.panchal@bham.ac.uk 
 
 
 
 
 
 


AVAIL-T 
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AVAIL-T protocol_5.0a_15-Aug-2018 
CRCTU-PRT-QCD-001, version 1.0 
SIGNATURE PAGE 
AVAIL-T Trial Protocol 5.0a_15-Aug-2018 
This protocol has been approved by: 
Name: 
Prof Simon Wagner 
Trial Role: 
Chief Investigator 
Signature: 
___________________________ 
Date: 
15 / Aug /2018 
This protocol describes the AVAIL-T trial and provides information about procedures for patients 
taking part in the AVAIL-T trial. The protocol should not be used as a guide for treatment of patients 
not taking part in the AVAIL-T trial. 
AMENDMENTS 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment    Summary of amendment 
1 
25-May-2017
2.0 
Substantial 
Removal of one form of contraception 
from section 5.3 
2 
29-Aug-2017
3.0 
Substantial 
Section 7.5 Dose Modifications updated 
with new information provided in 
Avelumab IV V7.0 
Clarification of patient registration 
processes.  
3 
20-Feb-2018
4.0 
Substantial 
Change to inclusion criteria: 

hepatosplenic T-cell lymphoma
removed as a PTCL histology for
safety reasons

change to hepatic function criteria for
safety reasons

addition of a PTCL histology
Clarification of pregnancy tests (in 
screening and assessments sections (5.1 
and 7.2) 
Clarification of treatment details in section 
7.1 
Clarification of management of IRRs in 
section 7.5 (Table 3) 


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AVAIL-T protocol_5.0a_15-Aug-2018 
 
CRCTU-PRT-QCD-001, version 1.0 
Clarification of management of Hepatic 
AEs (Table 4) 
Clarification of treatment discontinuation 
section (Table 5) 
Clarification of research sample collection 
Contact details updated 
4 
04-May-2018 
5.0 
Substantial  
Update to treatment section – mandate 
dose banding for avelumab 
Clarification of post screening pregnancy 
tests (section 7.2) 
Clarification of steroid use in the 
concomitant medication section 
Update to research sample collection – 
addition of technique used for 
immunophenotyping  
Update to Table 5 to ensure it is 
consistent with guidance in Table 3 
N/A 
15-Aug-2018 
5.0a 
Notification 
Change in Data Protection Regulations 
 
 
 
 
 
 


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AVAIL-T protocol_5.0a_15-Aug-2018 
 
CRCTU-PRT-QCD-001, version 1.0 
TRIAL SYNOPSIS  
 
Title 
AVAIL-T: A Phase 2a trial of Avelumab, an anti-PD-L1 antibody, in relapsed and refractory peripheral 
T-cell lymphoma (PTCL) 
 
Trial Design 
This is a multicentre, single arm, open-label, phase 2a trial to determine responses to avelumab, an 
anti-PD-L1 antibody, in patients with refractory and relapsed PTCL. A single arm study has been 
selected to determine evidence of activity in PTCL to further evaluate in a larger trial. 
 
Objectives 
The primary objective of the trial is to determine overall response during 8 cycles of treatment with 
secondary objectives being toxicity, overall survival (OS), progression free survival (PFS), radiological 
reduction in tumour size and duration of response from time of first documented response until 
relapse, progression or death. 
 
Outcome Measures 
Primary Outcome Measures 
 
Best overall response (Partial Remission (PR) + Complete Response (CR)) during 8 cycles of 
treatment using Revised Response Criteria for Malignant Lymphoma (Appendix 1) 
Secondary Outcome Measures 
 
Toxicity assessed using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4 
 
Best overall response (PR + CR) at any time  of treatment using Revised Response Criteria for 
Malignant Lymphoma27 
 
OS 
 
PFS 
 
Reduction in tumour size measured as maximum percentage change in the radiological sum of 
the product of the diameters from baseline of up to 6 target lesions 
 
Duration of response from time of first documented response until relapse, progression or death 
Exploratory Outcome Measures  
 
PD-L1 expression levels  
 
Cell free DNA analysis 
 
Immunophenotyping 
 
Biomarkers of response  
 
Patient Population and Sample Size 
This trial will recruit 30-35 patients with relapsed or refractory PTCL. 
 
Main Inclusion Criteria 
 
Male or female patients aged ≥ 16 years 
 
Life expectancy > 12 weeks 
 
ECOG performance status ≤ 2 
 
Relapsed or refractory* peripheral T-cell lymphoma including the following histologies: 
peripheral T-cell lymphoma not otherwise specified (PTCL NOS) , angioimmunoblastic T-cell 


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CRCTU-PRT-QCD-001, version 1.0 
lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy associated T-cell 
lymphoma (EATL), extranodal NK/T- cell lymphoma (ENKL), transformed mycosis fungoides 
(LCT MF), and subcutaneous panniculitis and T cell lymphoma * For all relapsed patients, 
relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue 
available). For relapsed and refractory patients, a biopsy must have been obtained within the 
last 3 months of registration 
 
Failed at least 1 prior therapy (but no upper limit of prior regimens) 
 
Adequate haematological function defined by the following at registration: 
o 
absolute neutrophil count (ANC) ≥ 1.0 × 109/L (unsupported) 
o 
platelet count ≥ 75 × 109/L (unsupported) 
o 
haemoglobin ≥ 90 g/L (may have been transfused) 
 
Adequate hepatic function and no evidence of hepatic involvement by T-cell lymphoma as 
defined by: 
o 
total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range (patients with 
elevated bilirubin due to Gilbert’s syndrome are eligible) 
o 
AST and ALT levels ≤ 1.5 × ULN for all patients and  
 
no clinical suspicion of hepatic involvement by T-cell lymphoma and 
 
no liver abnormalities on imaging studies that might be due to T-cell 
lymphoma 
 
Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according 
to the Cockcroft-Gault formula (or local institutional standard method) 
 
CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 
14cm in cranio-caudal length attributable to relapsed/non responding lymphoma 
 
Negative serum pregnancy test at screening for women of childbearing potential.  
 
Highly effective contraception for both male and female patients if the risk of conception 
exists. (Note: women of childbearing potential and men able to father a child must agree to 
use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % 
per year.  Highly effective contraception is required from consent, throughout and for at least 
60 days after avelumab treatment.  
 
Ability to give informed consent  
 
Main Exclusion Criteria 
Patients are not eligible for the trial if they fulfill any of the following exclusion criteria: 
 
All patients with active CNS involvement of lymphoma 
 
Prior organ transplantation, including allogeneic stem-cell transplantation 
 
Significant acute or chronic infections including, among others: 
o 
Known history of testing positive test for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS),  
o 
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive) 
 
Current use of immunosuppressive medication, EXCEPT for the following:  
o 
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); Systemic corticosteroids at a maximum dose of ≤ 1 mg/kg of prednisone or 
equivalent during screening (to be stopped by day 1 of trial treatment); Steroids as 
premedication for hypersensitivity reactions (e.g., CT scan premedication). 
 
Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible 
 
Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI 
CTCAE v4.03 Grade ≥ 3)  


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AVAIL-T protocol_5.0a_15-Aug-2018 
 
CRCTU-PRT-QCD-001, version 1.0 
 
Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia 
and sensory neuropathy Grade ≤ 2 or other Grade ≤ 2 not constituting a safety risk based on 
investigator’s judgment are acceptable  
 
Pregnancy or lactation 
 
Known alcohol or drug abuse 
 
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 
6 months prior to registration), myocardial infarction (< 6 months prior to registration), unstable 
angina, congestive heart failure (≥ New York Heart Association Classification Class II), or 
serious cardiac arrhythmia requiring medication 
 
Other severe acute or chronic medical conditions including colitis, inflammatory bowel 
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the 
past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may 
increase the risk associated with study participation or study treatment administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study 
 
Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except 
for administration of inactivated vaccines (e.g. the flu vaccine) 
 
Active infection requiring systemic therapy  
 
Major surgery within 4 weeks of trial entry  
 
Patients and partners of childbearing potential not willing to use two methods of effective 
contraception during and for 60 days after therapy  
 
Trial Duration 
Patients will be recruited over 24 months from 13 Trials Acceleration Programme (TAP) and non-TAP 
centres.  
Following registration, patients will receive 8 cycles (each of 28 days duration) of avelumab (each 
cycle being two, fortnightly infusions of the antibody) with the possibility of continued treatment if the 
patient is benefitting. The patient will have an end of treatment visit within 28 days of the end of the 
last cycle.  
A contrast enhanced CT scan of the neck, chest, abdomen and pelvis will be performed at cycles 3, 6 
and 8 of treatment to assess response during treatment.  If the patient has not progressed after 8 
cycles they will continue to be followed up with CT scans at 12, 16 and 20 months from treatment start 
or sooner if the Investigator is concerned there may be disease progression or if the patient 
discontinues treatment. After 20 months from treatment start, radiological follow-up will be as per local 
standard with data collected every 6 months. 
Patients will continue to be followed up for progression and survival until the end of trial. 
 
Trials Office Contact Details 
AVAIL- T trial team  
Centre for Clinical Haematology 
Queen Elizabeth Hospital 
Birmingham B15 2TH 
 
 
 
 
 
Tel: 0121 371 7861 
 
 
 
 
 
Fax: 0121 371 7874 
 
 
 
 
 
Email: Avail-t@trials.bham.ac.uk  
 


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AVAIL-T protocol_5.0a_15-Aug-2018 
 
CRCTU-PRT-QCD-001, version 1.0 
ABBREVIATIONS 
ABPI 
 
ASSOCIATION OF THE BRITISH PHARMACEUTICAL INDUSTRY 
ACTH  
ADRENOCORTICOTROPIC HORMONE 
ADCC  
ANITBODY DEPENDENT CELLULAR CYOTOXICITY 
ADL 
 
ACTIVITES OF DAILY LIVING 
AE 
 
ADVERSE EVENT 
AHA 
 
AMERICAN HEART ASSOCIATION 
AIDS 
 
ACQUIRED IMMUNODEFICIENCY SYNDROME 
AITL 
 
ANGIOIMMUNOBLASTIC LYMPHOMA 
ALCL 
 
ANAPLASTIC LARGE CELL LYMPHOMA  
ALP 
 
ALKALINE PHOSPHATASE 
ALT 
 
ALANINE TRANSAMINASE 
AML 
 
ACUTE MYELOID LEUKEMIA 
ANC 
 
ABSOLUTE NEUTROPHIL COUNT 
AR 
 
ADVERSE REACTION 
AST 
 
ASPARTATE TRANSAMINASE 
CR  
 
COMPLETE REMISSION/RESPONSE 
CrCL 
 
CREATININE CLEARANCE 
CRCTU 
CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) 
CRF  
 
CASE REPORT FORM 
CRP 
 
C-REACTIVE PROTEIN 
CR UK  
CANCER RESEARCH UK 
CT  
 
COMPUTER TOMOGRAPHY  
CTC 
 
COMMON TERMINOLOGY CRITERIA  
CTCAE  
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
CTCL  
CUTANEOUS T-CELL LYMPHOMA 
CV 
 
CURRICULUM VITAE 
DCF 
 
DATA CLARIFATION FORM 
DNA 
 
DEOXYRIBOSE NUCLEIC ACID 
EATL 
 
ENTEROPATHY ASSOCIATED T-CELL LYMPHOMA 
ECG 
 
ELECTROCARDIOGRAM 
ECMC  
EXPERIMENTAL CANCER MEDICINE CENTRE 
ECOG  
EASTERN COOPERATIVE ONCOLOGY GROUP 
EDC 
 
ELECTRONIC DATA CAPTURE 
EMEA  
EUROPEAN MEDICINES AGENCY 
ENKL   
EXTRANODAL NK/T- CELL LYMPHOMA 
EORTC 
EUROPEAN ORGANISATION FOR RESEARCH AND TREATMENT OF CANCER 
ESC 
 
EUROPEAN SOCIETY OF CARDIOLOGY 
FBC 
 
FULL BLOOD COUNT 
FDA 
 
(USA) FOOD AND DRUG ADMINISTRATION  
FSH 
 
FOLLICLE-STIMULATING HORMONE 
GCP 
 
GOOD CLINICAL PRACTICE 


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CRCTU-PRT-QCD-001, version 1.0 
GGT 
 
GAMMA-GLUTAMYL TRANSPEPTIDASE 
GMP 
 
GOOD MANUFACTURING PRACTICE 
GP 
 
GENERAL PRACTITIONER 
HBV 
 
HEPATITIS B VIRUS  
HCG 
 
HUMAN CHORIONIC GONADOTROPHIN 
HCV 
 
HEPATITIS C VIRUS 
HGB 
 
HAEMAGLOBIN 
HIV 
 
HUMAN IMMUNODEFICIENCY VIRUS  
IB 
 
INVESTIGATOR BROCHURE 
ICF 
 
INFORMED CONSENT FORM 
ICOS 
 
INDUCIBLE CO-STIMULATOR 
IMP 
 
INVESTIGATIONAL MEDICINAL PRODUCT 
IRR 
 
INFUSION RELATED REACTIONS 
ISF 
 
INVESTIGATOR SITE FILE 
ISRCTN 
INTERNATIONAL STANDARD RANDOMISED CLINICAL TRIAL NUMBER 
IUD 
 
INTRAUTERINE DEVICE 
IV 
 
INTRAVENOUS 
IWG 
 
INTERNATIONAL WORKING GROUP 
LCT MF 
LARGE CELL TRANSFORMED MYCOSIS FUNGOIDES 
LFT 
 
LIVER FUNCTION TEST 
LLN 
 
LOWER LIMIT OF NORMAL 
MDS 
 
MYELODYSPLASTIC SYNDROME 
ML 
 
MILILITRE 
MHRA  
MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY 
MRI 
 
MAGNETIC RESONANCE IMAGING 
NCI  
 
NATIONAL CANCER INSTITUTE  
NCRI 
 
NATIONAL CANCER RESEARCH INSTITUTE  
NIHR CRN 
NATIONAL INSTITUTE FOR HEALTH RESEARCH CLINICAL RESEARCH 
NETWORK 
NHL 
 
NON HODGKIN’S LYMPHOMA 
NOS 
 
NOT OTHERWISE SPECIFIED 
NSAIDS 
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. 
ORR 
 
OVERALL RESPONSE RATE  
OS 
 
OVERALL SURIVIAL 
PCR 
 
POLYMERASE CHAIN REACTION 
PD-L1  
PD-1 LIGAND 
PFS 
 
PROGRESSION FREE SURVIAL 
PI 
 
PRINCIPAL INVESTIGATOR 
PIS 
 
PATIENT INFORMATION SHEET 
PR 
 
PARTIAL REMISSION/RESPONSE 
PS 
 
PERFORMANCE STATUS  
PTCL  
PERIPHERAL T-CELL LYMPHOMA 
QoL 
 
QUALITY OF LIFE 


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CRCTU-PRT-QCD-001, version 1.0 
R&D 
 
RESEARCH AND DEVELOPMENT 
RBC 
 
RED BLOOD CELL 
REC 
 
RESEARCH ETHICS COMMITTEE 
RNA 
 
RIBOSE NUCLEIC ACID 
SAE 
 
SERIOUS ADVERSE EVENT 
SAR 
 
SERIOUS ADVERSE REACTION 
SPC  
 
SUMMARY OF PRODUCT CHARACTERISTICS 
SPD 
 
SUM OF THE PRODUCT OF DIAMETERS 
SUSAR  
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION 
T4 
 
FREE THYROXINE 
TAP 
 
TRIALS ACCELERATION PROGRAMME 
Thf 
 
FOLLICULAR HELPER T-CELLS 
Tfr 
 
REPRESSIVE FOLLICULAR T-CELL SUBSET 
TLS 
 
TUMOUR LYSIS SYNDROME 
TMA 
 
TISSUE MICROARRAY 
TMG 
 
TRIAL MANAGEMENT GROUP 
TSC 
 
TRIAL SAFETY COMMITTEE  
TSH 
 
THYROID STIMULATING HORMONE 
ULN 
 
UPPER LIMIT OF NORMAL  
WBC 
 
WHITE BLOOD COUNT 
WHO 
 
WORLD HEALTH ORGANIZATION 
WIMM  
WEATHERALL INSITUTE OF MOLECULAR MEDICINE 
WMA 
 
WORLD MEDICAL ASSEMBLY 
 
 


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CRCTU-PRT-QCD-001, version 1.0 
 
Table of contents 
 
Trial Personnel .................................................................................................................... 2 
Signature Page .................................................................................................................... 3 
Amendments ....................................................................................................................... 3 
Trial Synopsis ...................................................................................................................... 5 
Abbreviations ...................................................................................................................... 8 
1.1 
Background............................................................................................................................ 14 
1.2 
Trial Rationale........................................................................................................................ 14 
1.2.1 
Justification for patient population ..................................................................................... 14 
1.2.2 
Justification for design ....................................................................................................... 15 
1.2.3 
Choice of treatment ........................................................................................................... 15 
2. Aims, Objectives and Outcome Measures ...................................................................16 
2.1 
Aims and Objectives .............................................................................................................. 16 
2.2 
Outcome Measures ............................................................................................................... 16 
3. Trial Design ....................................................................................................................16 
4. Eligibility .........................................................................................................................17 
4.1 
Inclusion Criteria .................................................................................................................... 17 
4.2 
Exclusion Criteria ................................................................................................................... 17 
5. Screening and Consent .................................................................................................18 
5.1 
Screening ............................................................................................................................... 18 
5.2 
Informed Consent .................................................................................................................. 19 
5.3 
Contraception ........................................................................................................................ 19 
6. Trial Entry .......................................................................................................................20 
7. Treatment Details ...........................................................................................................20 
7.1 
Trial Treatment ...................................................................................................................... 20 
7.2 
Treatment Schedule .............................................................................................................. 21 
7.3 
Assessments ......................................................................................................................... 22 
7.3.1 
Blood chemistry and Haematology .................................................................................... 24 
7.3.2 
Urinalysis ........................................................................................................................... 24 
7.3.3 
Electrocardiogram (ECG) .................................................................................................. 24 
7.3.4 
Physical examination/clinical disease assessment ........................................................... 25 
7.3.5 
Radiological Assessment – CT scans ............................................................................... 25 
7.3.6 
Bone Marrow Trephine ...................................................................................................... 25 
7.4 
Research Sample Collection ................................................................................................. 25 
7.4.1 
Tumour paraffin blocks ...................................................................................................... 25 
7.4.2 
Blood samples ................................................................................................................... 26 
7.5 
Dose Modifications ................................................................................................................ 26 
7.5.1 Infusion-Related Reactions ................................................................................................... 26 
7.5.2 Severe Hypersensitivity Reactions and Flu-Like Symptoms ................................................ 26 
7.5.3 Tumour Lysis Syndrome ....................................................................................................... 28 
7.5.4 Management of Immune-Related Adverse Events ............................................................... 29 
7.5.5 Treatment related haematological Adverse Events .............................................................. 35 
7.5.6 Drug Induced Liver Injury (Hy’s law cases) ........................................................................... 35 
7.6 
Treatment Compliance .......................................................................................................... 36 
7.7 
Concomitant Medication ........................................................................................................ 36 
7.8 
Patient Treatment Discontinuation ........................................................................................ 37 


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7.9 
Patient Follow Up .................................................................................................................. 38 
7.10 
Patient Withdrawal of Consent .............................................................................................. 38 
8. Adverse Event Reporting ..............................................................................................38 
8.1 
Reporting Requirements ........................................................................................................ 39 
8.1.1 
Adverse Events.................................................................................................................. 39 
8.1.2 
Serious Adverse Advents .................................................................................................. 39 
8.1.3 
Reporting period ................................................................................................................ 40 
8.1.4 
Post study SUSARs ........................................................................................................... 40 
8.2 
Reporting Procedure ............................................................................................................. 40 
8.2.1 
Site ..................................................................................................................................... 40 
8.2.2 
Trials Office ........................................................................................................................ 41 
8.2.3 
Reporting to the Competent Authority and main Research Ethics Committee ................. 41 
8.2.4 
Investigators ...................................................................................................................... 41 
8.2.5 
Data/Safety Committee ..................................................................................................... 41 
8.2.6 
Manufacturer of Investigational Medicinal Product ............................................................ 41 
9. Data Handling and Record Keeping .............................................................................42 
9.1 
Data Collection ...................................................................................................................... 42 
9.2 
Archiving ................................................................................................................................ 42 
10. 
Quality Management .................................................................................................42 
10.1 
Site Set-up and Initiation ....................................................................................................... 42 
10.2 
On-site Monitoring ................................................................................................................. 42 
10.3 
Central Monitoring ................................................................................................................. 43 
10.4 
Audit and Inspection .............................................................................................................. 43 
10.5 
Notification of Serious Breaches ........................................................................................... 43 
11. 
End of Trial Definition ...............................................................................................43 
12. 
Statistical Considerations ........................................................................................44 
12.1 
Definition of Outcome Measures ........................................................................................... 44 
12.1.1 
Primary outcome measures ........................................................................................... 44 
12.1.2 
Secondary outcome measures ...................................................................................... 44 
12.1.3 
Exploratory outcome measures ..................................................................................... 44 
12.2 
Analysis of Outcome Measures ............................................................................................. 44 
12.3 
Planned Interim Analysis ....................................................................................................... 45 
12.4 
Planned Final Analyses ......................................................................................................... 45 
 
Sample size determination ........................................................................................................ 45 
13. 
Trial Organisational Structure ..................................................................................45 
13.1 
Sponsor ................................................................................................................................. 45 
13.2 
Coordinating Centre .............................................................................................................. 45 
13.3 
Trial Management Group ....................................................................................................... 46 
13.4 
Trial Safety Committee .......................................................................................................... 46 
13.5 
Finance .................................................................................................................................. 46 
14. 
Ethical Considerations..............................................................................................46 
15. 
Confidentiality and Data Protection .........................................................................46 
16. 
Insurance and Indemnity ..........................................................................................47 
17. 
Publication Policy .....................................................................................................47 
18. 
Reference List ...........................................................................................................47 
Appendix 1 - Response Criteria for Malignant lymphoma27 ............................................51 
Appendix 2 – AVAIL-T Bayesian Probability plots ...........................................................52 


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Appendix 3 - Definition of Adverse Events .......................................................................55 
Appendix 4 - WMA Declaration of Helsinki .......................................................................57 
Appendix 5 - Common Toxicity Criteria Gradings ...........................................................60 
 
 


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1.1 
Background 
 
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous, often aggressive, group of non-Hodgkin 
lymphomas (NHL) comprising about 5% to 10% of all new NHL diagnoses. The most common 
subtypes are peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-
cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL). Recent advances in understanding 
normal T-cell biology together with gene expression and immunohistochemistry studies have 
suggested that a group of PTCL are derived from the CD4+ T-cell subset, follicular helper T-cells (Tfh), 
which are characterised by surface expression of PD-1 and inducible co-stimulator (ICOS) and nuclear 
expression of BCL61-4. The ligand of PD-1, PD-L1, is expressed on both lymphoma cells and stromal 
cells5. Historically the therapeutic approaches for PTCL have been derived from standard treatments 
for various subtypes of aggressive B-cell lymphoma. However, outcomes remain poor when these 
strategies are used in the management of PTCL, with 5-year overall survival (OS) ranging from 25 to 
35% for the common subtypes and excluding ALK-positive ALCL6. 
Four drugs have been approved by the US Food and Drug Administration (FDA) for treatment of 
relapsed PTCL: pralatrexate, romidepsin, brentuximab vedotin (approved for ALCL only), and 
belinostat. In the relapsed/refractory setting, rates of response to single-agent therapy with these 
drugs (other than use of brentuximab vedotin for ALCL) range from 20% to 35%7-10.  
Several mechanistically based therapies are currently in clinical trials for T-cell lymphoma. In patients 
with ALK-positive ALCL there are efforts to study crizotinib, which has been approved for treatment of 
lung cancer harboring a translocation in the ALK gene. As ALK is constitutively expressed in a subset 
of patients with ALCL, this is an attractive therapeutic target. In small series of relapsed patients, 
response rates of 60% to 100% to crizotinib have been seen, including one study of 11 patients (9 with 
ALCL) showing an overall response rate (ORR) of 91% 11. Several other ALK inhibitors are also in 
development but primarily these agents are being investigated in lung cancer.  
IDH2 is an enzyme that normally catalyses the conversion of isocitrate to alpha-ketoglutarate (α-KG) 
in the Krebs cycle. Mutations in the IDH2 gene are seen in several malignancies, including acute 
myeloid leukemia (AML), gliomas and glioblastoma, chondrosarcoma, and cholangiocarcinoma. 
Recently a phase I study of the oral IDH2 inhibitor AG-221 in patients with AML and myelodysplastic 
syndrome (MDS) showed an ORR of 56% in 45 patients, including complete and durable responses 
12. Gain-of-function mutations in IDH2 are seen in 20% to 45% of cases of AITL and rarely in PTCL-
NOS 13,14. Early-phase studies of AG-221 in malignancies harboring an IDH2 mutation, including 
disease-specific cohorts of AITL, are underway (ClinicalTrials.gov ID: NCT02273739).  
Phosphatidylinositol 3-kinase (PI3K) inhibitors and their downstream targets (eg, AKT or mammalian 
target of rapamycin [mTOR]) are important in cell differentiation, metabolism, survival, and 
proliferation. Idelalisib is a PI3K-delta inhibitor currently approved for chronic lymphocytic 
leukemia/small lymphocytic lymphoma, and follicular lymphoma and many other PI3K inhibitors are 
being developed and investigated 15,16. The PI3K-delta/gamma inhibitor duvelisib (IPI-145) has 
demonstrated an ORR of 53% in PTCL 17.  
Another pathway of therapeutic interest in PTCL is the Janus kinase/signal transducer and activator of 
transcription (JAK/STAT) pathway; this is because mutations in JAK3 have been seen in natural killer 
(NK)-cell/T-cell lymphomas, and activation of the JAK/STAT signaling pathway has also been 
described in PTCL 13,14. Ruxolitinib, approved for treatment of myeloproliferative neoplasms, is being 
investigated in relapsed lymphoma, including PTCL (ClinicalTrials.gov ID: NCT01431209).  
Studies incorporating these novel agents as part of upfront treatment regimens are underway, and 
there is hope for improved responses.  
 
1.2 
Trial Rationale 
1.2.1 
Justification for patient population  
The outcome for patients with relapsed / refractory PTCL is extremely poor, with a median survival of 
just 6-18 months and very few patients cured of their disease18. Therefore although these patients are 
uncommon, there is a significant unmet medical need and a requirement for rational drug 
combinations with validated predictive biomarkers.  
 


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1.2.2 
Justification for design  
Avelumab is currently in clinical development across phases 1-3 with safety data in relation to its use 
in solid tumours (see Investigator’s Brochure (IB) for Avelumab). Avail-T has been designed as a 
single arm phase 2a study on the assumption that the safety profile obtained with avelumab in patients 
with solid cancers will be essentially the same as for patients with hematological malignancy.  
Other considerations were to produce a study to determine the primary outcome measures (as listed 
below) including best overall response rate during 8 cycles (each cycle being 28 days) of treatment as 
rapidly as possible in this rare disease population but also with the flexibility to deliver a larger study. 
In order to fulfill these criteria we propose a Bayesian probability plot approach. 
 
1.2.3 
Choice of treatment  
Cross-linking of PD-1 has been shown to inhibit T-cells19 and this has prompted interest in perturbing 
PD-1/PD-L1 signaling in order to enhance T-cell anti-tumour activity in solid cancers20,21. However, this 
model does not appear to explain PD-1/PD-L1 function in Tfh-cells, a CD4+ T-cell subset required for 
germinal centre formation, in part, by providing IL-4 and IL-21 to cause B-cell proliferation22,23. Data 
from mice lacking PD-1 demonstrates important functions for this surface protein in T-cell 
differentiation 24,25. While the earlier study 24 demonstrated that PD-1 deficient animals had increased 
follicular T-cells there was a paradoxical lack of increased functions attributable to the Tfh subset. 
Subsequent work following identification of a repressive follicular T-cell subset (Tfr)25 has provided a 
resolution for this problem: PD-1-/- mice show increased numbers and functions of Tfr whilst Tfh are 
repressed. Interestingly, mice lacking the PD-1 ligand (PD-L1) demonstrated the same phenotype. 
This suggests that in vivo the PD-1/PD-L1 axis regulates the differentiation of follicular T-cells such 
that stimulation of PD1 drives Tfh differentiation whereas blockade of PD-1/PD-L1 produces a 
repressive and Tfr dominated environment.  
PD-L1 is expressed on both tumour and stromal components of PTCL (Table 1)5 by 
immunohistochemistry, which is likely to underestimate patients for which the PD-1/PD-L1 axis is 
functionally important. Avelumab, in distinction from other therapeutic anti-PDL1 antibodies causes 
antibody dependent cellular cytotoxicity (ADCC)26. Therefore, avelumab may deplete essential stromal 
components of the tumour microenvironment as well as causing apoptosis of lymphoma cells. 
 
Table 1 
Percentage of cases expressing PD-L1 on tumour cells and stroma in PTCL (from Wilcox et al.5). 
Cutaneous PTCL have been excluded from the data. 
 
 
 
 
 
 
 
 
EMR 100070-001 is a study of avelumab in metastatic and locally recurrent solid tumours. None of the 
patients treated with doses up to 10 mg/kg experienced a dose limiting toxicity and this dose is, 
therefore, considered a safe and well-tolerated dose (Avelumab Investigators Brochure v4.0, February 
2015). 
A dose-escalation trial of avelumab (MSB0010718C)27 has been reported and investigators 
demonstrated that this antibody could be safely administered in doses up to 20 mg/kg every 2 weeks.  
480 patients have been enrolled in 11 expansion cohorts and treated with avelumab 10 mg/kg every 2 
weeks up to November 2014. 59/480 (12.3%) had at least one treatment related adverse event of > 
grade 3 – anaemia, fatigue, gammaGT increase, infusion related reactions lipase increase, 
lymphocyte count decreased, autoimmune hepatitis, constipation, dyspnoea, hypertension, 
hypokalaemia, hypoxia, pneumonitis, vomiting. 56/480 (11.7%) had potential autoimmune related 
adverse events. As of November 2014 49/480 patients (10.2%) experienced at least one infusion 
 
Tumour PD-L1 (%) 
Stroma PD-L1 (%) 
PTCL-NOS 
17 
43 
AITL 
5 
57 
ALK+ ALCL 
33 
22 
ALK-ALCL 
15 
35 
Other 
10 
24 


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related reaction most of which were grade 1 or 2. Two suspected unexpected serious adverse 
reactions (SUSARs) (infusion-related reaction (IRR) and anaphylaxis) were reported following which a 
premedication regime of piriton and paracetamol was mandated. 
In a "real-world" study of outcomes in PTCL the median OS after relapse/progression in 211 patients 
initially responding (PR or CR) to primary treatment was 6.0 months and among patients with primary 
refractory disease (n = 143), median OS from response evaluation was only 2.5 months28. One trial in 
refractory/relapsed PTCL administered treatment for 6 months29, while the current UK trial, RomiCar, 
administers 8 cycles of treatment. We, therefore, chose a regimen that allows for 8 months treatment 
with avelumab. 
For complete details of the in vitro and non-clinical studies refer to the avelumab IB. 
 
2. AIMS, OBJECTIVES AND OUTCOME MEASURES  
2.1 
Aims and Objectives 
Identify overall response to avelumab in relapsed/refractory PTCL. 
2.2 
Outcome Measures 
 
Primary Outcome Measures 
 
Best overall response (PR + CR) during 8 cycles of treatment using Revised Response Criteria 
for Malignant Lymphoma27 
 
Secondary Outcome Measures 
 
Toxicity using CTCAE v4 
 
Best overall response (PR + CR) at any time  of treatment using Revised Response Criteria for 
Malignant Lymphoma27 
 
OS 
 
PFS 
 
Reduction in tumour size measured as maximum percentage change in the radiological sum of 
the product of the diameters of up to 6 target lesions from baseline 
 
Duration of response from time of first documented response until relapse, progression or death 
 
Exploratory Outcome Measures  
 
PD-L1 expression levels  
 
Cell free DNA analysis 
 
Immunophenotyping 
 
Biomarkers of response  
 
3. TRIAL DESIGN  
This is a single arm phase 2a trial to determine responses to avelumab in patients with refractory and 
relapsed PTCL. A single arm study has been selected to determine evidence of activity in PTCL to 
further evaluate in a larger trial. Patients will be recruited over a 24-month period and will receive 8 
cycles of treatment with the possibility of continued treatment if the patient is showing clinical benefit. 
Patients will continue to be followed up for progression and survival for one year after the end of the 
trial treatment. 
 
The trial will enrol 30 patients with the flexibility to enrol more, up to 35, if required. Based on 30 
patients in the trial, if 11 responses were obtained this would give a probability of 60% that the 
response rate is greater than 35%. If 13/30 responses were obtained there is a probability of 84% that 
the response rate is greater than 35%. Other possible outcomes, both for 30 and 35 patients, have 
been plotted and are presented (Appendix 2). 
 
 


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4. ELIGIBILITY  
4.1 
Inclusion Criteria 
 
Male or female patients aged ≥ 16 years 
 
Life expectancy > 12 weeks 
 
ECOG performance status ≤ 2  
 
Relapsed or refractory* peripheral T-cell lymphoma including the following histologies: 
peripheral T-cell lymphoma not otherwise specified (PTCL NOS) , angioimmunoblastic T-cell 
lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy associated T-cell 
lymphoma (EATL), extranodal NK/T- cell lymphoma (ENKL), transformed mycosis fungoides 
(LCT MF), and subcutaneous panniculitis and T cell lymphoma * For all relapsed patients, 
relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue 
available). For relapsed and refractory patients, a biopsy must have been obtained within the 
last 3 months of registration 
 
Failed at least 1 prior therapy (but no upper limit of prior regimens) 
 
Adequate haematological function defined by the following at registration: 
o 
absolute neutrophil count (ANC) ≥ 1.0 × 109/L (unsupported) 
o 
platelet count ≥ 75 × 109/L (unsupported) 
o 
haemoglobin ≥ 90 g/L (may have been transfused) 
 
Adequate hepatic function and no evidence of hepatic involvement by T-cell lymphoma as 
defined by: 
o 
total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range (patients with 
elevated bilirubin due to Gilbert’s syndrome are eligible) 
o 
AST and ALT levels ≤ 1.5 × ULN for all patients and  
 
no clinical suspicion of hepatic involvement by T-cell lymphoma and 
 
no liver abnormalities on imaging studies that might be due to T-cell 
lymphoma 
 
Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according 
to the Cockcroft-Gault formula (or local institutional standard method) 
 
CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 
14cm in cranio-caudal length attributable to relapsed/non responding lymphoma 
 
Negative serum pregnancy test at screening for women of childbearing potential.  
 
Highly effective contraception for both male and female patients if the risk of conception 
exists. (Note: women of childbearing potential and men able to father a child must agree to 
use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % 
per year.  Highly effective contraception is required from consent, throughout and for at least 
60 days after avelumab treatment.  
 
Ability to give informed consent  
 
4.2 
Exclusion Criteria 
Patients are not eligible for the trial if they fulfill any of the following exclusion criteria: 
 
All patients with active CNS involvement of lymphoma 
 
Prior organ transplantation, including allogeneic stem-cell transplantation  
 
Significant acute or chronic infections including, among others: 
o 
Known history of testing positive test for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS),  
o 
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive) 
 
Current use of immunosuppressive medication, EXCEPT for the following:  
o 
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); Systemic corticosteroids at a maximum dose of ≤ 1 mg/kg of prednisone or 


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equivalent during screening (to be stopped by day 1 of trial treatment); Steroids as 
premedication for hypersensitivity reactions (e.g., CT scan premedication). 
 
Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible 
 
Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI 
CTCAE v4.03 Grade ≥ 3)  
 
Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia 
and sensory neuropathy Grade ≤ 2 or other Grade  ≤ 2 not constituting a safety risk based on 
investigator’s judgment are acceptable  
 
Pregnancy or lactation 
 
Known alcohol or drug abuse 
 
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 
6 months prior to registration), myocardial infarction (< 6 months prior to registration), unstable 
angina, congestive heart failure (≥ New York Heart Association Classification Class II), or 
serious cardiac arrhythmia requiring medication. 
 
Other severe acute or chronic medical conditions including colitis, inflammatory bowel 
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the 
past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may 
increase the risk associated with study participation or study treatment administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study 
 
Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except 
for administration of inactivated vaccines (e.g. the flu vaccine) 
 
Active infection requiring systemic therapy  
 
Major surgery within 4 weeks of trial entry  
 
Patients and partners of childbearing potential not willing to use two methods of effective 
contraception during and for 60 days after therapy  
 
5. SCREENING AND CONSENT  
5.1 
Screening  
The following assessments must be performed within 28 days prior to registration of a patient unless 
otherwise stated: 
 
Medical history – Including prior and current diagnosis,  
 
Physical Exam – Including vital signs (blood pressure, pulse and oxygen saturation), clinical 
disease assessment, ECOG assessment, height and weight 
 
Haematology – Full blood count (FBC) (Haemoglobin, Platelets, White Blood Count (WBC), 
Neutrophils and Lymphocytes) 
 
Blood Chemistry – Standard blood chemistry (to include bilirubin, AST/ALT, Alkaline, Calcium 
(adjusted), Creatinine, Creatinine Clearance, C-Reactive Protein, Magnesium, Potassium, 
Sodium, and glucose –non fasted) plus GGT, phosphate, triglycerides and, cholesterol 
Virology – HIV, HBV and HCV serology 
 
Pregnancy test - For female patients of childbearing potential, a serum pregnancy test, with 
sensitivity of at least 25 mIU/mL. Following a negative pregnancy result at screening, 
appropriate contraception must be commenced.  
 
Urinalysis – Protein, Glucose and Blood.  If protein 2+ by semi-quantitative method (eg, urine 
dipstick), protein will have to be quantified by 24-hour urine collection and microscopic 
urinalyses will have to be done (Reflex Testing). If urine dipstick is positive for urine blood, 
microscopic urinalysis will have to be done (Reflex Testing)  
 
ECG - single 12 lead 
 
A bone marrow trephine biopsy (obtained within the last 3 months, however results are not 
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 
Tissue biopsy (or bone marrow trephine if no other tissue available) to confirm relapse for all 
relapsed patients and to confirm refractory disease histology for refractory patients. These 
biopsies must have been obtained within the last 3 months. Sections will be collected for 
research and PD-L1 testing   
 
CT Scan (Neck, Chest, Abdomen and Pelvis)  
 
For full details of the investigations see section 7.3 
 
5.2 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent for each patient prior to 
performing any trial related procedure. A Patient Information Sheet (PIS) is provided to facilitate this 
process. Investigators must ensure that they adequately explain the aim, trial treatment, anticipated 
benefits and potential hazards of taking part in the trial to the patient. The Investigator should also 
stress that the patient is completely free to refuse to take part or withdraw from the trial at any time. 
The patient should be given ample time (e.g. 24 hours) to read the PIS and to discuss their 
participation with others outside of the site research team. The patient must be given an opportunity to 
ask questions which should be answered to their satisfaction. The right of the patient to refuse to 
participate in the trial without giving a reason must be respected. 
If the patient expresses an interest in participating in the trial they should be asked to sign and date 
the latest version of the Informed Consent Form (ICF). The Investigator must then sign and date the 
form. A copy of the ICF should be given to the patient, a copy should be filed in the hospital notes, and 
the original placed in the Investigator Site File (ISF). Once the patient is entered into the trial the 
patient’s trial number should be entered on the ICF maintained in the ISF. In addition, if the patient has 
given explicit consent a copy of the signed ICF must be sent in the post to the Trials Office for review.  
Details of the informed consent discussions should be recorded in the patient’s medical notes, this 
should include date of, and information regarding, the initial discussion, the date consent was given, 
with the name of the trial and the version number of the PIS and ICF. Throughout the trial the patient 
should have the opportunity to ask questions about the trial and any new information that may be 
relevant to the patient’s continued participation should be shared with them in a timely manner. On 
occasion it may be necessary to re-consent the patient in which case the process above should be 
followed and the patient’s right to withdraw from the trial respected.  Patients are permitted to re-
consent at the same visit that new information is provided if they wish to do so.   
 
Electronic copies of the PIS and ICF are available from the Trials Office and should be printed or 
photocopied onto the headed paper of the local institution. 
Details of all patients approached about the trial should be recorded on the Patient 
Screening/Enrolment Log and with the patient’s prior consent their General Practitioner (GP) should 
also be informed that they are taking part in the trial. A GP Letter is provided electronically for this 
purpose. 
 
5.3 
Contraception 
The effects of the trial drug on the developing human foetus are unknown; thus, women of 
childbearing potential and men able to father a child must agree to use two methods of highly effective 
contraception throughout the study and continued for at least 60 days after the last dose or abstain 
from sex throughout the study period.  
Highly effective methods of contraception are those that, alone or in combination, result in a failure 
rate of less than 1% per year when used consistently and correctly (ie, perfect use) and include the 
following: 
1. Established use of oral, inserted, injected, implanted or transdermal hormonal methods of 
contraception is allowed provided the patient plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of time to ensure 
effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male sterilisation with absence of sperm in the post-vasectomy ejaculate. 


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4. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive procedure (provided that 
occlusion has been confirmed in accordance with the device’s label). 
5. Female partner who meets the criteria for non-childbearing potential, defined as: 
 
Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
 
Have medically confirmed ovarian failure; or 
 
Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause. Status may be 
confirmed by having a serum follicle-stimulating hormone (FSH) level within the laboratory’s 
reference range for postmenopausal women. 
All sexually active male patients must agree to prevent potential transfer of and exposure to drug 
through semen to their partners by using a condom beginning with the first dose of investigational 
product and continuing for at least 60 days after the last dose. 
6. TRIAL ENTRY 
Patients will be registered to the trial via the Cancer Research UK Clinical Trials Unit (CRCTU) by 
phone or using the CRCTU systems portal. An eligibility checklist and registration form (found in the 
ISF) should be completed prior to registration by the Investigator or designee. 
 
Registration via CRCTU systems portal: 
 
https://www.cancertrials.bham.ac.uk/AvailTLive 
 
Login details will be provided by the trials office as part of site initiation. The patient trial number will be 
provided by the online system. A report can be printed as confirmation. 
 
Registration via phone: 
 
:0121 371 7861 
 
9am-5pm Monday to Friday 
 
The patient trial number will be given over the telephone, followed by a fax confirmation.  
 
7. TREATMENT DETAILS 
7.1 
Trial Treatment 
All patients registered to the trial will receive avelumab at the dose of 10 mg/kg by intravenous (IV) 
infusion once every 2 weeks for 8 cycles (28 day cycles). Each infusion of avelumab should be 
delivered over 1h (-10/+20min) unless IRR is experienced (see Table 3). Avelumab dose should be 
prepared in accordance with the NHS England National Dose Banding Table for avelumab (please 
refer to the pharmacy manual)  
 
All patients should be weighed within 3 days prior to day 1 dosing for every cycle to ensure they did 
not experience either a weight loss or gain >10% from the weight used for the last dose calculation.  
For weight change less than 10% the decision to recalculate the avelumab dose can be in accordance 
with institutional practice.  If the patient experienced either a weight loss or gain >10% compared to 
the weight used for the last dose calculation, the amount of study drug must be recalculated. 
 
Premedication 
Premedication with an antihistamine and with paracetamol, to mitigate IRRs and is mandatory 
approximately 30 to 60 minutes prior to the first four  doses of avelumab (Cycles 1-2), but may 
continue to be administered for subsequent cycles based upon clinical judgment and 
presence/severity of prior infusion reactions, at the treating Investigator’s discretion. For example, 
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This regimen may be modified based on local treatment standards and guidelines as appropriate 
provided it does not include systemic corticosteroids. 
 
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 2 hours post-infusion for potential IRRs. 
 
Patients will be assessed during the course of treatment, at progression or after completion of 8 cycles 
of treatment as described in section 7.3. 
 
Avelumab will be supplied free of charge for trial patients by Pfizer. This IMP will be packaged and 
labelled in accordance with local regulations and Good Manufacturing Practice (GMP) by a third party 
contracted by the Sponsor. Site pharmacies will be required to add site specific details on receipt of 
avelumab. 
Avelumab Solution for Infusion, 20 mg/mL is supplied as a clear, colourless non-pyrogenic solution, 
packaged in a Type I glass vial containing 10 mL of solution, with a rubber stopper, and aluminium 
overseal and flip off cap. Each single-use vial of MSB0010718C (avelumab) contains a sufficient 
amount of product to ensure an extractable volume of 10 mL (200 mg) at a concentration of 20 mg/mL 
formulated with a preservative-free acetate buffered solution at pH 5.2 in the presence of Polysorbate 
20 and Mannitol.  
The avelumab supplied will require further dilution prior to IV infusion. The investigational product will 
be administered intravenously according to the instructions provided in the AVAIL-T pharmacy 
manual.  Unopened vials should be stored at 2-8oC. 
 
Avelumab must be allowed to reach room temperature (15-25 °C) for minimum 30 minutes prior to use 
in dose preparation. Use immediately after preparation. Infusion is not intended to be stored, however, 
if dilution has taken place in controlled and validated aseptic conditions it may be stored for no more 
than 24 hours under refrigerated conditions (2-8 oC) with no more than 8 of those hours at room 
temperature (15-25 °C) including infusion time. If stored under refrigerated conditions, allow each bag 
to equilibrate to room temperature (15-25 °C), preferably for one hour before administration. 
 
For further details and ordering, please refer to the pharmacy manual.  
7.2 
Treatment Schedule 
Avelumab 10 mg/kg will be administered once every 14 days for a proposed duration of 8 cycles (28 
day cycles), (16 doses).   
If the patient is showing clinical benefit following 8 cycles of trial treatment patients may continue to 
receive avelumab treatment at the treating Investigator’s discretion, until loss of response, toxicity, or 
death.    
 
Every effort should be made for patients to attend on the scheduled visit days. However, if a patient is 
unable to attend on the specified day, assessments may be scheduled for +/- 3 days. 
The full blood count should be assessed prior to each treatment (within 24 hours of treatment) to 
ensure the following criteria are met:  
 
Platelets > 75 x 109/L  
 
Neutrophils >1.0 x109/L 
 
Bilirubin <1.5 x ULN 
 
Creatinine clearance (CrCL) (Cockcroft-Gault) ≥30ml/min). 
 
ALT/AST ≤ 1.5 × ULN on Cycle 1 day1; thereafter ≤ 3 × ULN  
 
Please also refer to Section 7.5 for dose delays and modifications, and to section 7.7 for concomitant 
medications.  


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7.3 Assessments 
 
Table 2. Schedule of Assessments  
Parameter 
Screening 
(28 days 
unless 
otherwise 
stated) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
Subsequent 
cycles 
End of 
Treatment 
/Progress
ion 
12 
month 
Follow-
up (from 
treatment 
start) 
16 
month 
Follow-
up (from 
treatment 
start) 
20 
month 
Follow-
up (from 
treatment 
start) 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
Pregnancy test (if 
applicable)  
X 
X 
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X 
 
X 
  
  
  
Prior Diagnosis/ 
Prior Treatment / 
baseline 
conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
ECOG 
performance 
status 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
 
X 
  
  
  
Height (pre-study 
only) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
Weight 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
 
  
  
  
  
Diagnostic tissue 
biopsy (within 3 
months of 
registration)  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
X 
(optional) 
  
  
  
Bone Marrow 
Trephine biopsy 
(within 3 months) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
X1 
  
  
  
Laboratory Tests 
(Haematology2 
and 
Biochemistry3) 
X4 
X 
X 
X 
X 
X 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
  
  
  
Virology (HIV, 
HBV, HCV) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
Urinalysis 
(protein, glucose 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
 
X 
  
  
  


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Parameter 
Screening 
(28 days 
unless 
otherwise 
stated) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
Subsequent 
cycles 
End of 
Treatment 
/Progress
ion 
12 
month 
Follow-
up (from 
treatment 
start) 
16 
month 
Follow-
up (from 
treatment 
start) 
20 
month 
Follow-
up (from 
treatment 
start) 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
and blood) 
ACTH, Thyroid 
function (T4 & 
TSH), tests for 
pancreatitis  
 
 X 
  
 
  
 X 
  
 
  
 X 
  
  
  
X  
  
  
  
 
 
X 
  
  
  
ECG (single 12 
lead) 
X 
X5 
  
X5 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
X 
  
  
  
Clinical Disease 
assessment / 
physical exam 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
X 
X 
CT scans with IV 
contrast NCAP  
X 
  
  
  
  
  
X6 
  
  
  
  
  
X6 
  
  
  
X6 
 
X7 
X8 
X 
X 
X 
Avelumab 
10mg/kg every 2 
weeks 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Concomitant 
Diseases and 
Treatment 
 
<< Ongoing assessment until 28 days after treatment discontinuation >> 
  
  
  
Adverse Events 
 
<< Ongoing assessment until 28 days after treatment discontinuation >> 
  
  
  
Blood samples 
collected for 
research 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
 
X7 
 X 
X 
X 
X 
1 If baseline showed involvement, a further biopsy is required at radiological CR to confirm CR. Further bone marrow biopsy should also be performed if progression within the marrow is 
suspected and the CT does not show progression. 
2 Haematology – Full blood count (Haemoglobin, Platelets, WBC, Neutrophils and Lymphocytes) 
3 Blood Chemistry – Standard blood chemistry (to include bilirubin, GGT, AST/ALT, Alkaline phosphate, Calcium (adjusted), Creatinine, CRP, Magnesium, Phosphate, Potassium, Sodium, 
and glucose –non fasted)  
4 Triglycerides and cholesterol at baseline, Cycle 4 days 1 and End of Treatment only 
5 To be performed before and after avelumab infusion 
6 CT scans to be performed within the time period after the day 15 dose and prior to next day 1 dose.   
7 Post 8 cycles CT scans and research bloods will be performed in line with the follow-up schedule  
8 End of Treatment scan only required if treatment stopped early and no scan has been conducted in the previous 28 days. Progression scan upon suspected progression outside of 
scheduled scans.   


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CRCTU-PRT-QCD-001, version 1.0 
 
7.3.1 
Blood chemistry and Haematology 
Full Blood count (Haemoglobin, Platelets, WBC, Neutrophils and Lymphocytes) and serum 
biochemistry (to include AST/ALT, Alkaline phosphate, bilirubin,  Calcium (adjusted), Creatinine, 
Creatinine Clearance, C-Reactive Protein, Magnesium, Potassium, Sodium, GGT, Phosphate, and 
glucose -non fasted) will be taken within the 24h prior to each avelumab dose and at the End of 
Treatment visit .   
Triglycerides and Cholesterol should also be assessed at Cycle 4 day 1 and End of Treatment visit 
only  
 
Hormone function tests (ACTH, Free T4, and TSH) and tests for pancreatitis (such as Amylase and or 
Lipase as per institutional standard) will be performed prior to avelumab infusion where possible on 
Cycle 1 Day 1, Cycle 3 day 1, Cycle 5 day 1, Cycle 7 day 1, and at the End of treatment visit (if not 
performed in the previous 8 weeks). Test should additionally be performed in cases of suspected 
hypoadrenalism, hypopituitarism or pancreatitis.  
 
Pregnancy test - For female patients of childbearing potential, a serum pregnancy test, with sensitivity 
of at least 25 mIU/mL and assayed in a certified laboratory, once at the start of screening. Urine or 
serum pregnancy tests will be routinely repeated at every treatment cycle during the active treatment 
period (immediately before investigational product administration) and at the end of study treatment 
visit.  Additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected this test should be repeated. 
 
7.3.2 
Urinalysis  
Urinalysis will be performed on Day 1 (+/- 24 hours) of all treatment cycles and at the End of 
Treatment visit.  If protein 2+ by semi-quantitative method (eg, urine dipstick), protein will have to be 
quantified by 24-hour urine collection and microscopic urinalyses will have to be done (Reflex 
Testing). May also be performed when clinically indicated. If urine dipstick is positive for urine blood, 
microscopic urinalysis will have to be done (Reflex Testing), and the patient will be treated as per local 
standard of care based on Investigator medical judgment.  
 
7.3.3 
Electrocardiogram (ECG) 
Single 12 lead ECGs will be performed at baseline, on Day 1 of Cycles 1 and 2, before avelumab 
infusion, and at the end of avelumab infusion.  This will also be repeated at the End of Treatment visit.   
If the QTc is prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including verification that 
the machine reading is accurate. If manual reading verifies a QTc of >500 msec, immediate correction 
for reversible causes (including electrolyte abnormalities, hypoxia and concomitant medications for 
drugs with the potential to prolong the QTc interval) should be performed. In addition, repeat ECGs 
should be immediately performed hourly for at least 3 hours until the QTc interval falls below 500 
msec. If QTc interval reverts to less than 500 msec, and in the judgment of the investigator(s) and 
Sponsor is determined to be due to cause(s) other than investigational product, treatment may be 
continued with regular ECG monitoring. If in that timeframe the QTc intervals rise above 500 msec the 
investigational product will be held until the QTc interval decreases to 500 msec. If the QTc interval 
has still not decreased to 500 msec after 2 weeks, or if at any time a patient has a QTc interval >515 
msec or becomes symptomatic, the patient will be removed from the study.  
An electronic reading of prolonged QTc must be confirmed by manual reading. Prior to concluding that 
an episode of prolongation of the QTc interval is due to investigational product, thorough consideration 
should be given to potential precipitating factors (eg, change in patient clinical condition, effect of 
concurrent medication, electrolyte disturbance) and possible evaluation by specialist. 
 


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CRCTU-PRT-QCD-001, version 1.0 
7.3.4 
Physical examination/clinical disease assessment  
Patients will receive a physical exam, including vital signs (blood pressure, pulse, oxygen saturation, 
weight and height (baseline only)), and assessment of ECOG performance status on day 1 of each 
cycle and at the End of Treatment visit. The physical exam should also include investigation of skin 
lymphoma deposits and rashes, liver and spleen assessment and assessment of lymph node 
measurements. 
 
7.3.5 
Radiological Assessment – CT scans  
A contrast enhanced CT scan of the neck, chest, abdomen and pelvis will be performed at cycles 3, 6 
and 8 of treatment to assess response during treatment. If the patient discontinues treatment early an 
End of treatment scan should be performed, if a scan has not been conducted with the last 28 days.  
Scans should be reported with two dimensional measurements of each lesion in millimetres (mm) if 
measureable.    
 
Immunotherapeutic agents such as avelumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses. The response patterns seen with such an approach 
may extend beyond the typical time course of responses seen with cytotoxic agents, and can manifest 
as a clinical response after an initial increase (pseudo-progression) in disease burden. The 
Investigator’s judgment of radiological response on early CT scans should be based on the overall 
benefit-risk assessment and the patient’s clinical condition, including performance status, clinical 
symptoms, adverse events and laboratory data. 
 
If the patient has not progressed after 8 cycles they will continue to be followed up with CT scans at 
12, 16 and 20 months from treatment start or sooner if the investigator is concerned there may be 
disease progression. After 20 months from treatment start radiological follow-up will be as per local 
standard with data collected every 6 months. 
Response will be assessed according to the Revised Response Criteria for malignant lymphoma27 
(appendix 1).  
 
7.3.6 
Bone Marrow Trephine  
A bone marrow trephine biopsy will be performed at screening (within 3 months of registration). If this 
shows involvement, the patient should undergo a further bone marrow trephine biopsy at radiological 
CR if this is achieved to confirm CR. Further bone marrow biopsy should also be performed if 
progression within the marrow is suspected and the CT does not show progression. 
 
7.4 
Research Sample Collection 
7.4.1 
Tumour paraffin blocks 
Samples of the patient’s tumour will be collected in the form of formalin-fixed paraffin embedded 
blocks of their initial, and relapsed or refractory diagnostic material. These samples must have been 
collected within 3 months of the patient registering for the trial.   
 
In order to assay PD-L1 we will employ the VENTANA PD-L1 (SP263) kit (Roche). Results of this 
assay will be reviewed during the course of the trial. 
 
Blocks will be requested immediately following registration and will be sent to the University of 
Leicester.  
 
Three slides will be cut from the tissue blocks to test for PD-L1 levels.   
A tissue microarray (TMA) will also be produced from diagnostic tissue block material from all patients. 
We will employ immunohistochemistry supported by gene expression analysis to establish a molecular 
classification of PTCL (see Iqbal et al. 31) to correlate with response to treatment or predictors of 
relapse.     


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CRCTU-PRT-QCD-001, version 1.0 
 
Upon relapse or progression during the study a further formalin-fixed paraffin embedded tissue block 
will be requested for research purposes.  The collection of this tissue block is optional.  
 
Further details will be provided in the AVAIL-T Sample collection manual.  
 
Translational Research 
Plasma and peripheral blood mononuclear cells (PBMNCs) will be collected at intervals during the 
study. Cell free DNA will be extracted from plasma and DNA from PBMNCs and used for analysis of 
the known mutations32-33 in PTCL by targeted sequencing using an IonTorrent platform. Importantly 
results will be correlated with PD-L1 expression levels assayed by the VENTANA PD-L1 (SP263) kit 
(Roche). 
 
7.4.2 
Blood samples 
Blood samples will be collected at baseline, day 15 cycle 2, day 15 cycle 4, day 15 cycle 6, day 15 
cycle 8, at 12 months, 16 months and 20 months post treatment start (or equivalent time point if 
patient is off treatment). Plasma for cell free DNA studies will be collected and peripheral blood 
mononuclear cells will be isolated for a CyTOF  immunophenotyping sub-study.  
Samples will be processed as per the AVAIL-T laboratory manual and shipped to the University of 
Leicester in the shipment containers supplied by the trial.   
 
We have established droplet digital (dd) PCR assays for some of the common mutations in PTCL - 
RHOAG17V, IDH2 and PLCG1. We plan to employ these assays on cell free DNA from patient 
plasma in order to explore their utility for diagnosis and as markers for response to treatment or 
predictors of relapse. We estimate that one or more of these genetic markers will be detectable in 25 
to 40% of our patient population 31,34-36. 
 
CyTOF is a cutting-edge technology that allows the measurement of an unprecedented number of T-
cell markers on circulating T-cells. We plan to perform CyTOF analysis pre-treatment and after cycles 
2, 4, and 6. These data will allow the characterisation of a relapsed/refractory PTCL signature, identify 
putative biomarkers of response, and correlate immune cell changes with any toxicity. 
 
For further information please see the AVAIL-T sample collection manual.  
 
7.5 
Dose Modifications  
7.5.1 Infusion-Related Reactions 
IRRs have been observed in patients receiving therapy with avelumab. Monitor patients for 
signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, 
hypotension, dyspnoea, wheezing, back pain, abdominal pain, urticaria, rigors, diaphoresis 
and headache.  
Table 3 outlines management guidance in the event of an IRR.  
 
7.5.2 Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the patient must be treated according to the best available medical 
practice. Patients should be instructed to report any delayed reactions to the Investigator immediately. 
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 patients at the discretion 
of the Investigator. 
 


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CRCTU-PRT-QCD-001, version 1.0 
Table 3. Treatment Modification for Symptoms of Infusion-Related Reactions  
NCI-CTCAE Grade  
Examples of Qualifying 
events (NCI CTCAE) 
Treatment Modification for Study 
Drug 
Grade 1 – mild 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated. 
Transient hypotension; 
palpitations; mild 
hypertension; mild allergic 
reaction (transient rash, 
drug fever <38°C), other 
mild reactions: flushing, 
rigor, chills, pruritus, cough, 
pain, nausea, vomiting. 
Decrease the study drug 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  
24 h. 
 
 
 
 
 
 
 
 
 
 
 
Recurrent Grade 2 – 
moderate 
Hypotension requiring fluid 
replacement; advanced 
hypertension or 
symptomatic arrhythmias 
not requiring treatment; 
moderate allergic reaction 
(urticaria, drug fever >38°C) 
or isolated fever 39.1 to 
40°C; severe &/or 
prolonged rigors/chills; 
frequent or drenching 
diaphoresis; controlled or 
intense or widespread 
pruritis; cough requiring 
narcotic antitussive; other 
moderate reactions: pain, 
GI, skin, etc 
Temporarily discontinue study drug 
infusion. 
Resume infusion at 50% of previous 
rate once infusion-related reaction has 
resolved or decreased to at least 
Grade 1 in severity, and monitor 
closely for any worsening. 
If a Grade 2 infusion-related reaction 
does not improve or worsens following 
implementation of the modifications 
indicated above (including reducing 
the infusion rate by 50%), treatment 
should be commenced based on the 
specific symptoms and the infusion 
should not be resumed for that cycle. 
 
At the next cycle, consider the addition 
of an H2-blocker, meperidine, or 
ibuprofen to the mandatory 
premedication. 
 
 
In the event of further recurrence, in 
spite of implementation of all measures 
indicated above, (including reducing 
the infusion rate by 50%), 
hydrocortisone 100 mg IV may be 
added to the premedication schema 
outlined above following discussion 
with the trials office. 
Grade 3 – severe  
Grade 3: Prolonged (for 
example, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalisation indicated for 
clinical sequelae. 
 
 
 
 
Angina, congestive heart 
failure, hypotension, 
hypertension or 
arrhythmias requiring 
medication, moderate 
allergic reaction) severe 
allergic reaction 
(symptomatic 
bronchospasm requiring 
parenteral medications, 
with or without urticaria, 
allergy-related 
edema/angioedema), fever 
>40°C for <24 hrs, 
rigors/chills unresponsive to 
Stop the study drug infusion 
immediately and disconnect infusion 
tubing from the subject. 
 
If IV fluids to maintain blood pressure, 
or prolonged administration of steroids, 
or inotropic agents, or administration of 
oxygen to maintain peripheral 
saturations are required, or the 
symptoms persist for more than 48 
hours:  
 
Permanently discontinue 
avelumab treatment 
If none of the conditions listed above 
applies,  


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CRCTU-PRT-QCD-001, version 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
Recurrent Grade 3 – 
severe 
narcotics; uncontrolled 
intense or widespread 
pruritus, uncontrolled 
severe cough; dyspnoea at 
normal activity; other 
severe pain, GI or skin 
symptoms, etc. 
Or Acute myocardial 
infarction, tamponade, 
hypertensive crisis, life-
threatening arrhythmia, 
shock, anaphylaxis, renal 
failure, fever >40°C for >24 
hrs, other life-threatening or 
disabling reactions. 
 
consider resuming avelumab 
treatment if the risk/benefit 
assessment for the individual 
patient is positive and agreed 
with the trials office/CI 
 
if the decision is made to 
resume treatment, the infusion 
rate must be reduced by 50% 
AND hydrocortisone 200 mg 
IV must be added to the 
standard premedication. 
 
 
Stop the study drug infusion 
immediately and disconnect infusion 
tubing from the subject. 
Subjects have to be withdrawn 
immediately from study drug treatment 
and must not receive any further study 
drug treatment. 
Grade 4 – life-threatening 
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated. 
Stop the study drug infusion 
immediately and disconnect infusion 
tubing from the subject. 
Subjects have to be withdrawn 
immediately from study drug treatment 
and must not receive any further study 
drug treatment. 
In addition, if premedication with hydrocortisone is necessary it should be added for at least the 
subsequent 2 cycles of avelumab treatment. 
 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
 
7.5.3 Tumour Lysis Syndrome 
There is a potential risk of tumor lysis syndrome (TLS) because avelumab can induce antibody-
dependent cell-mediated cytotoxicity. Patients should be monitored closely via standard blood tests 
and if there is a clinical suspicion of TLS it should be managed according to best medical practice. 
Management of TLS may include aggressive hydration, monitoring of renal function, correction of 
electrolyte abnormalities, anti-hyperuricaemic therapy, and supportive care. 
Should this occur, patients should be treated per the local guidelines or the management algorithm 
below (Figure 1)  
 
Figure 1  
Assessment and initial management of tumour lysis syndrome. 
 


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CRCTU-PRT-QCD-001, version 1.0 
 
 
7.5.4 Management of Immune-Related Adverse Events 
 
Since inhibition of PD-L1 stimulates the immune system, immune-related Adverse Events (AEs) may 
occur. Avelumab can result in severe and fatal immune-related adverse reactions. These immune-
related reactions may involve any organ system. Most immune-related reactions initially manifest 
during avelumab treatment; however, immune-related adverse reactions can occur after 
discontinuation of avelumab.  
Monitor patients for signs and symptoms of pneumonitis, colitis, changes in thyroid function, adrenal 
insufficiency, hyperglycaemia (or other signs and symptoms of diabetes), abnormal liver tests and 
elevated serum creatinine at the start of treatment and periodically during treatment. 
Treatment of AEs 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 gastrointestinal, dermatological, pulmonary, hepatic, renal, endocrine and Cardiac AEs 
should follow guidelines set forth in the table below Table 4. 
 
 
Table 4. Management of Immune-Related Adverse Events 


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CRCTU-PRT-QCD-001, version 1.0 
Gastrointestinal AEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (for 
example, loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report 
worsening immediately 
If worsens: 
Treat as Grade 2 or 3/4  
Grade 2 
Diarrhea:  4 to 6 stools per day 
over Baseline; IV fluids indicated 
< 24 hours; not interfering with 
ADL 
Colitis:  abdominal pain; blood in 
stool  
Withhold avelumab therapy 
Symptomatic treatment 
 
Treat Grade 2 colitis with 1.0 to 
2.0 mg/kg/day prednisolone IV or 
equivalent 
 
If improves to Grade 1:  
Resume avelumab therapy 
For Grade 2 colitis continue 
steroids until Grade 1, then 
taper over at least 1 month; 
resume Avelumab therapy 
following steroids taper. 
If persists > 5 to 7 days or 
recur: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 hrs.; 
interfering with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs 
Grade 4:  life-threatening, 
perforation 
Withhold avelumab for Grade 3. 
1.0 to 2.0 mg/kg/day 
prednisolone IV or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider lower GI endoscopy. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
  
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: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: 
Infliximab should not be used in 
cases of perforation or sepsis  
Dermatological AEs 
Grade of Rash 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Symptomatic therapy (for 
example, antihistamines, topical 
steroids)  
Continue avelumab therapy 
If persists > 1 to 2 weeks or 
recurs:  
Withold Avelumab therapy 
Consider skin biopsy  
Consider 0.5 to 1.0 mg/kg/day 
prednisolone 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  


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CRCTU-PRT-QCD-001, version 1.0 
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: life threatening 
consequences  
Withhold avelumab for Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisolone 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 AEs 
Grade of Pneumonitis 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
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  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalisation  
1.0 to 2.0 mg/kg/day 
prednisolone 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:  
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 
prednisolone 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 48 hours 
or worsening:  
Add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil)  
Hepatic AEs 
Inform the CI and trials office immediately if the treating investigator has concerns over liver function 
or liver involvement by lymphoma  
Grade of Liver Test Elevation 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Continue avelumab therapy 
Continue liver function 


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Grade 1 AST or ALT > ULN to 
3.0 x ULN and / or total bilirubin 
> ULN to 1.5 x ULN  
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  
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent 
If returns to Grade ≤1:  
Taper steroids over at least 1 
month, :  
resume routine monitoring, 
resume avelumab therapy 
following steroids taper 
If elevations persist > 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 
prednisolone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consult gastroenterologist / 
hepatologist 
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted  
 
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 guidelines  
Renal AEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue avelumab therapy 
Continue renal function 
monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 
6 x ULN 
Withhold avelumab therapy 
Increase 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 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month. 


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Consider renal biopsy 
Nephrology consult 
Cardiac AEs 
Myocarditis 
Management 
Follow-up 
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.  
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
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, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate 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 AEs 
Endocrine Disorder 
Management 
Follow-up 
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. 


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Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalisation 
Endocrinology consult 
Start (as appropriate): 
 
thyroid hormone replacement 
therapy for hypothyroidism 
 
anti-thyroid treatment for 
hyperthyroidism,  
 
corticosteroids for adrenal 
insufficiency 
 
anti-hyperglycemics or insulin 
for type I diabetes mellitus  
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 
(secondary endocrinopathies) 
If secondary thyroid and / or adrenal 
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 hospitalisation. 
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. 
 
Resume avelumab once 
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 AEs (not described above) 
Grade of other AEs 
(NCI-CTCAE v4.03) 
Management 
Follow-up 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive 
of a potential immune-related 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
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AE (irAE) 
starting avelumab therapy 
If irAE is confirmed, treat as 
Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month and resume avelumab 
therapy following steroids 
taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue Avelumab 
therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month 
Grade 4 
Permanently discontinue Avelumab 
therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month 
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 
Specialty consult  
Abbreviations: ACTH=adrenocorticotropic hormone; ADL = activities of daily living; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-
MB=creatine kinase MB; CT = computed tomography; FSH=follicle-stimulating hormone; GH=growth 
hormone; IGF-1=insulin-like growth factor 1; irAE = immune-related adverse event; IV=intravenous; 
LH=luteinizing hormone; MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer Institute-
Common Terminology Criteria for Adverse Event; PRL=prolactin; T4 = thyroxine; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal. 
 
7.5.5 Treatment related haematological Adverse Events  
For any treatment related haematological toxicities (e.g. Neutrophil or platelet count decreases) delay 
avelumab treatment for a week until the event resolves to baseline.  If the toxicity has not resolved 
with 1 week delay please check with trials office if continued treatment is recommended.   
 
7.5.6 Drug Induced Liver Injury (Hy’s law cases)  
The threshold of laboratory abnormalities for a potential Drug Induced Liver Injury case depends on 
the patient’s individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential Hy’s law cases to 
definitively determine the etiology of the abnormal laboratory values: 
-Subjects with AST/ALT and Bilirubin baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a Bilirubin value >2 × ULN with 
no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not available; 


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-For subjects with baseline AST OR ALT OR Bilirubin values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on which 
values are above the ULN at baseline: 
o 
Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller). 
o 
Preexisting values of Bilirubin above the normal range: Bilirubin level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).  
If a Hy’s law case is confirmed this must be reported to the trials office as an SAE.  Patients should be 
treated as in Table 4 above.  
 
7.6 
Treatment Compliance  
Non-compliance is not likely to be an issue as patients must attend hospital to receive infusions of 
avelumab. Pharmacy departments will be required to maintain accurate records of drug accountability. 
For further information please see the pharmacy manual.  
 
7.7 
Concomitant Medication  
Primary prophylactic use of granulocyte-colony stimulating factors is permitted during the study. They 
may also be used to treat treatment emergent neutropenia as indicated by local guidelines. 
Use of erythropoietic growth factors is allowed during the study. 
 
Patients are prohibited from receiving the following therapies during the treatment phase of this trial: 
 
Anti-cancer systemic chemotherapy or biological therapy  
 
Immunotherapy not specified in this protocol 
 
Investigational or experimental agents other than avelumab 
 
Radiation therapy (with the exception of Palliative radiotherapy to specific sites of disease 
considered medically necessary by the treating physician. All attempts should be made to rule 
out disease progression in the event of increased localized pain. If palliative radiotherapy is 
needed to control bone pain, the sites of bone disease should be present at baseline, 
otherwise, bone pain requiring radiotherapy will be considered as a sign of disease 
progression.). 
 
Immunosuppressive drugs, unless otherwise indicated for the treatment of AEs (see Tables 3 
and 4). See below Clarification about Steroid Use. 
 
Any vaccine therapies for the prevention of infectious disease (eg, human papilloma virus 
vaccine) except for inactive vaccines (e.g. the flu vaccine). 
 
Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or known to 
potentially interfere with major organ function (eg, hypericin). 
 
Clarifications about Steroid Use: Data indicate that corticosteroids have an adverse effect on T cell 
function and that they inhibit and damage lymphocytes.  
Therefore, the use of steroids during this trial is restricted as follows: 
 
Therapeutic use: for the treatment of infusion-related reactions and short-term treatment of 
AEs, steroids are permitted according to the modalities indicated in table 3 and 4 
 
Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to ≤10 mg 
prednisone daily is acceptable. 
 
Prophylactic use (eg, for the prevention of acute infusion-related reactions): is prohibited – 
unless otherwise indicated in Table 3 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 


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7.8 
Patient Treatment Discontinuation  
In the event of discontinuation of study treatment, e.g. completing treatment, unacceptable toxicity or 
patient choice, full details of the reason/s for discontinuation should be recorded on the appropriate 
pages on the CRF. All patients, including non-compliant patients, should be followed up according to 
the protocol unless they withdraw specific consent.  Patients who stop treatment due to adverse 
experiences (clinical or laboratory) will be treated and followed according to accepted medical 
practice. All pertinent information concerning the outcome of such treatment must be recorded in the 
CRF. 
 
The following are justifiable reasons for the Investigator to stop study treatment: 
 
unforeseen events: any event which in the judgement of the Investigator makes further treatment 
inadvisable 
 
serious violation of the study protocol (including persistent patient non-attendance and persistent 
non-compliance) 
 
stopping by the Investigator for clinical reasons not related to the study drug treatment 
 
Patients must stop study treatment in the event of: 
 
unacceptable toxicity (detailed below) 
 
SAE requiring permanent discontinuation of treatment 
 
the patient becoming pregnant  
 
Disease Progression 
 
 
Table 5. Adverse Events requiring avelumab discontinuation or modification 
Any Grade 4 AEs  
 except for single laboratory values out of normal range that are unlikely related to study 
treatment as assessed by the Investigator, do not have any clinical correlate, and resolve 
within 7 days with adequate medical management 
Any Grade 3 AEs except for any of the following:  
 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
 
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to Grade ≤ 1  
 
Single laboratory values out of normal range  that are unlikely related to study treatment 
according to the Investigator, do not have any clinical correlate, and resolve to Grade ≤ 1 
within 7 days with adequate medical management 
 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor 
 
Change in ECOG PS to ≥ 3 that does not resolve to  2 within 14 days (infusions should not 
be given on the following cycle, if the ECOG PS is ≥ 3 on the day of study drug administration) 
 
First occurrence of a Grade 3 IRR that meets conditions for continued therapy as outlined in 
Table 3. 
Any Grade 2 AE should be managed as follows: 
 
If a Grade 2 AE resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 
 
If a Grade 2 AE does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has 
not resolved to Grade 1, the patient should permanently discontinue treatment with a 
avelumab AE (except for hormone insufficiencies, that can be managed by replacement 
therapy; for these hormone insufficiencies, up to 2 subsequent doses may be omitted). 
 
Upon the second occurrence of the same Grade 2 AE (except for IRR or hormone 


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insufficiencies that can be managed by replacement therapy) in the same patient, treatment 
with avelumab has to be permanently discontinued. 
 
Recurrent Grade 2 IRRs may not require treatment discontinuation and should be managed 
as outlined in Table 3 
 
 
When a patient stops trial treatment an End of Treatment visit should be performed 28 days (+/- 5 
days) after their last dose of avelumab.  Assessments are to be performed as per section 7.3 and 
include:  
 
Physical Exam 
 
ECOG 
 
Vital signs 
 
Full blood count  
 
Biochemistry  
 
Hormone function 
 
Pregnancy test  
 
Urinalysis 
 
12- lead ECG 
 
Disease assessment 
 
Adverse events 
 
7.9 
Patient Follow Up 
All patients will need to be followed up for safety (AEs) up to 30 days (+/- 5 days) after the last dose of 
avelumab and for disease progression / survival until the end of the trial (minimum of 12 months 
follow-up from the date of commencing treatment for the last patient).  
If the patient stops trial treatment but has not progressed, they will be reviewed with a CT scan of 
neck, chest, abdomen and pelvis at 8, 12, 16 and 20 months or on clinical suspicion of progression 
(whichever is sooner).  
 
If there is no evidence of progression after 20 months, patients will have no specific trial follow up, but 
their referring physician may be contacted every 6 months to determine progression and survival data. 
 
7.10 Patient Withdrawal of Consent 
In the event of a patient’s decision to withdraw from the trial, the Investigator should ascertain from 
which aspects of the trial the patient wishes to withdraw and record the details on the appropriate 
CRF. All information and blood/tissue samples collected up until point of retraction will be retained and 
analysed. If a patient chooses to withdraw from treatment only, the patient should discontinue 
treatment and continue to be assessed in accordance with the protocol. If a patient wishes to withdraw 
from the trial (i.e. including trial specific assessments), but is willing for further data to be supplied to 
the Trials Office, then further routine “follow-up” data (e.g. disease status and survival) will continue to 
be supplied by the Investigator to the Trials Office. 
 
8. ADVERSE EVENT REPORTING 
The collection and reporting of Adverse Events (AEs) will be in accordance with the Medicines for 
Human Use Clinical Trials Regulations 2004 and its subsequent amendments. Definitions of different 
types of AE are listed in Appendix 3. The Investigator should assess the seriousness and causality 
(relatedness) of all AEs experienced by the patient (this should be documented in the source data) 
with reference to the Investigator Brochure.  
 


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8.1 
Reporting Requirements 
8.1.1 
Adverse Events 
All medical occurrences which meet the definition of an AE (see Appendix 3 for definition) should be 
reported.  Please note this does not include abnormal laboratory findings. An abnormal laboratory 
value is only considered to be an AE if the abnormality:  
 
Results in early discontinuation from the study treatment and/or  
 
Requires study drug dose modification or interruption, any other therapeutic intervention or is 
judged to be of significant clinical importance 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded. 
Pre-existing conditions should only be reported if the condition worsens by at least 1 CTCAE grade. 
Details of all AEs experienced by the patient should be recorded in the hospital notes. 
 
8.1.2 
Serious Adverse Advents 
Investigators should report AEs that meet the definition of an SAE (see Appendix 3 for definition) and 
are not excluded from the reporting process as described below.   
 
Potential drug-induced liver injury (Hy’s Law cases) are considered important medical events and 
should be reported as SAEs.  Please see section 7 for more information.  
 
8.1.2.1 Events that do not require reporting on a Serious Adverse Event Form  
The following events should not be reported on an SAE Form and are not classed as SAEs for this 
trial: 
 
Hospitalisations for: 
o 
Pre-planned elective procedures unless the condition worsens 
o 
Treatment for progression of the patient’s cancer 
 
Progression or death as a result of the patient’s cancer, as this information is captured elsewhere 
on the Case Report Form 
The below events may not be SAEs but should still be reported by email to the trials office within 24h 
of becoming aware of the event:  
 
Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event) 
 
Occupational exposure during the performance of job duties, a person (whether a healthcare 
professional or otherwise) gets in unplanned direct contact with the product (even if not 
associated with an adverse event) 
Details of these will be forwarded to Pfizer for review.   
 
8.1.2.2 Monitoring pregnancies for potential Serious Adverse Events 
It is important to monitor the outcome of pregnancies of patients in order to provide SAE data on 
congenital anomalies or birth defects. 
In the event that a patient or their partner becomes pregnant during the SAE reporting period please 
complete a Pregnancy Notification Form (providing the patient’s details) and return to the Trials Office 
as soon as possible. If it is the patient who is pregnant provide outcome data on a follow-up 
Pregnancy Notification Form. Where the patient’s partner is pregnant consent must first be obtained 
and the patient should be given a release of medical information form to give to their partner. If the 
partner is happy to provide information on the outcome of their pregnancy they should sign the release 
of medical information form. Once consent has been obtained provide details of the outcome of the 
pregnancy on a follow-up Pregnancy Notification Form. If appropriate also complete an SAE Form as 
detailed below. 


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8.1.3 
Reporting period 
Details of all AEs (except those listed above) will be documented and reported from the date of 
commencement of protocol defined treatment until 30 days after the administration of the last 
treatment.  
 
8.1.4 
Post study SUSARs  
SAEs that are judged to be at least possibly related to the IMP(s) and are unexpected must still be 
reported in an expedited manner irrespective of how long after IMP administration the reaction 
occurred. 
 
8.2 
Reporting Procedure 
8.2.1 
Site 
8.2.1.1 Adverse Events 
AEs should be reported on an AE Form (and where applicable on an SAE Form). An AE Form should 
be completed at each visit and returned to the Trials Office. 
AEs will be reviewed using the Common Terminology Criteria for Adverse Events (CTCAE), version 
4.0 (see Appendix 4). Any AEs experienced by the patient but not included in the CTCAE should be 
graded by an Investigator and recorded on the AE Form using a scale of (1) mild, (2) moderate or (3) 
severe. For each sign/symptom, the highest grade observed since the last visit should be recorded. 
 
8.2.1.2 Serious Adverse Events 
For more detailed instructions on SAE reporting refer to the SAE Form Completion Guidelines 
contained in the Investigator Site File (ISF).  
 
AEs defined as serious and which require reporting as an SAE (excluding events listed in Section 8.1 
above) should be reported on an SAE Form.  When completing the form, the Investigator will be asked 
to define the causality and the severity of the AE which should be documented using the CTCAE 
version 4.0.  
On becoming aware that a patient has experienced an SAE, the Investigator (or delegate) must 
complete, date and sign an SAE Form.  The form should be faxed together with a SAE Fax Cover 
Sheet to the Trials Office using one of the numbers listed below as soon as possible and no later than 
24 hours after first becoming aware of the event: 
To report an SAE, fax the SAE Form with an SAE Fax Cover Sheet to: 
0121 371 7874 or 0121 371 4398 
 
On receipt the Trials Office will allocate each SAE a unique reference number. This number will be 
transcribed onto the SAE Fax Cover Sheet which will then be faxed back to the site as proof of receipt.  
If confirmation of receipt is not received within 1 working day please contact the Trials Office. The SAE 
reference number should be quoted on all correspondence and follow-up reports regarding the SAE. 
The SAE Fax Cover Sheet completed by the Trials Office should be filed with the SAE Form in the 
ISF. 
For SAE Forms completed by someone other than the Investigator the Investigator will be required to 
countersign the original SAE Form to confirm agreement with the causality and severity assessments.  
The form should then be returned to the Trials Office in the post and a copy kept in the ISF. 
Investigators should also report SAEs to their own Trust in accordance with local practice. 


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8.2.1.3 Provision of follow-up information 
Patients should be followed up until resolution or stabilisation of the event. Follow-up information 
should be provided on a new SAE Form (refer to the SAE Form Completion Guidelines for further 
information). 
 
8.2.2 
Trials Office 
On receipt of an SAE Form seriousness and causality will be determined independently by a Clinical 
Coordinator. An SAE judged by the Investigator or Clinical Coordinator to have a reasonable causal 
relationship with the trial medication will be regarded as a Serious Adverse Reaction (SAR). The 
Clinical Coordinator will also assess all SARs for expectedness.  If the event meets the definition of a 
SAR that is unexpected (i.e. is not defined in the Investigator Brochure) it will be classified as a 
Suspected Unexpected Serious Adverse Reaction (SUSAR). 
 
8.2.3 
Reporting to the Competent Authority and main Research Ethics Committee 
8.2.3.1 Suspected Unexpected Serious Adverse Reactions 
The Trials Office will report a minimal data set of all individual events categorised as a fatal or life 
threatening SUSAR to the Medicines and Healthcare products Regulatory Agency (MHRA) and main 
Research Ethics Committee (REC) within 7 days. Detailed follow-up information will be provided within 
an additional 8 days. 
All other events categorised as SUSARs will be reported within 15 days. 
 
8.2.3.2 Serious Adverse Reactions 
The Trials Office will report details of all SARs (including SUSARs) to the MHRA and main REC 
annually from the date of the Clinical Trial Authorisation, in the form of a Development Safety Update 
Report. 
8.2.3.3 Adverse Events 
Details of all AEs will be reported to the MHRA on request. 
 
8.2.3.4 Other safety issues identified during the course of the trial 
The MHRA, main REC and drug manufacturer will be notified immediately if a significant safety issue 
is identified during the course of the trial.  
 
8.2.4 
Investigators 
Details of all SUSARs and any other safety issue which arises during the course of the trial will be 
reported to Principal Investigators. A copy of any such correspondence should be filed in the ISF.  
 
8.2.5 
Data/Safety Committee 
The independent Trial Safety Committee (TSC) will review all SAEs.  
 
8.2.6 
Manufacturer of Investigational Medicinal Product 
All SAEs and other reportable events will be reported by the trials office to the manufacturer of the 
Investigational Medicinal Product (Pfizer) within 24 hours by fax and or email as per the Pfizer Safety 
Reporting Reference Manual.  
 


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9. DATA HANDLING AND RECORD KEEPING  
9.1 
Data Collection  
The Case Report Form (CRF) will comprise a set of forms capturing details of eligibility, baseline 
characteristics, treatment and outcome details.  
 
This trial will use an electronic data capture (EDC) system which will be used for completion of CRFs. 
Access to the EDC system will be granted to individuals via the Trial Office. SAE reporting and 
Notification of Pregnancy will be paper-based. 
 
The CRF must be completed by the Investigator or an authorised member of the site research team 
(as delegated on the Site Signature and Delegation Log) within the timeframe (found in the eCRF 
completion guidelines). The exceptions to this are the eligibility Form, SAE Form and Withdrawal Form 
which must be co-signed by the Investigator and reported in an expedited manner. 
Data reported on each form should be consistent with the source data or the discrepancies should be 
explained. If information is not known, this must be clearly indicated on the form. Missing and 
ambiguous data will be queried in line with the data validation plan and data management guidelines 
for the trial. All sections are to be completed before submitting. 
  
In all cases it remains the responsibility of the Investigator to ensure that the CRF has been completed 
correctly and that the data are accurate.  
Trial forms may be amended by the Trials Office, as appropriate, throughout the duration of the trial. 
Whilst this will not constitute a protocol amendment, new versions of the form will be implemented by 
participating sites via the EDC system. 
 
9.2 
Archiving 
It is the responsibility of the Principal Investigator to ensure all essential trial documentation and 
source records (e.g. signed Informed Consent Forms, Investigator Site Files, Pharmacy Files, patients’ 
hospital notes, copies of CRFs etc) at their site are securely retained for at least 25 years after the end 
of the trial or following the processing of all biological material collected for research, whichever is the 
later.  Do not destroy any documents without prior approval from the CRCTU Document Storage 
Manager.    
 
10. QUALITY MANAGEMENT 
10.1 Site Set-up and Initiation 
All sites will be required to sign a Clinical Study Site Agreement prior to participation. In addition all 
participating Investigators will be asked to sign the necessary agreements registration forms and 
supply a current CV and conformation of GCP training to the Trials Office.  All members of the site 
research team will also be required to sign the Site Signature and Delegation Log, which should be 
returned to the Trials Office. Prior to commencing recruitment all sites will undergo a process of 
initiation.  Key members of the site research team will be required to attend either a meeting or a 
teleconference covering aspects of the trial design, protocol procedures, Adverse Event reporting, 
collection and reporting of data and record keeping.  Sites will be provided with an Investigator Site 
File and a Pharmacy File containing essential documentation, instructions, and other documentation 
required for the conduct of the trial.  The Trials Office must be informed immediately of any change in 
the site research team. 
 
10.2 On-site Monitoring  
Monitoring will be carried out as required following a risk assessment and as documented in the 
AVAIL-T Quality Management Plan.  Additional on-site monitoring visits may be triggered for example 
by poor CRF return, poor data quality, low SAE reporting rates, excessive number of patient 
withdrawals or deviations.  If a monitoring visit is required the Trials Office will contact the site to 


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arrange a date for the proposed visit and will provide the site with written confirmation. Investigators 
will allow the AVAIL-T trial staff access to source documents as requested.   
 
10.3 Central Monitoring  
Where a patient has given explicit consent sites are requested to send in copies of signed ICF for in-
house review. 
Trials staff will be in regular contact with the site research team to check on progress and address any 
queries that they may have.  Trials staff will check incoming CRFs via the EDC for compliance with the 
protocol, data consistency, missing data and timing. Sites will be sent DCFs requesting missing data 
or clarification of inconsistencies or discrepancies.  
Sites may be suspended from further recruitment in the event of serious and persistent non-
compliance with the protocol and/or GCP, and/or poor recruitment.  Any major problems identified 
during monitoring may be reported to Trial Management Group (TMG), Trial Safety Committee (TSC) 
and the relevant regulatory bodies.  This includes reporting serious breaches of GCP and/or the trial 
protocol to the main REC and the MHRA. 
 
10.4 Audit and Inspection 
The Investigator will permit trial-related monitoring, audits, ethical review, and regulatory inspection(s) 
at their site, providing direct access to source data/documents.  
Sites are also requested to notify the Trials Office of any MHRA inspections.   
 
10.5 Notification of Serious Breaches 
In accordance with Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 
and its amendments the Sponsor of the trial is responsible for notifying the licensing authority in 
writing of any serious breach of: 
 
The conditions and principles of GCP in connection with that trial or; 
 
The protocol relating to that trial, within 7 days of becoming aware of that breach  
For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a 
significant degree: 
 
The safety or physical or mental integrity of the patients of the trial; or 
 
The scientific value of the trial 
Sites are therefore requested to notify the Trials Office of a suspected trial-related serious breach of 
GCP and/or the trial protocol. Where the Trials Office is investigating whether or not a serious breach 
has occurred sites are also requested to cooperate with the Trials Office in providing sufficient 
information to report the breach to the MHRA where required and in undertaking any corrective and/or 
preventive action.   
 
11. END OF TRIAL DEFINITION 
The end of trial will be last patient last visit.  The Trials Office will notify the MHRA and main REC that 
the trial has ended and will provide them with a summary of the clinical trial report within 12 months of 
the end of trial.  
 


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12. STATISTICAL CONSIDERATIONS  
12.1 Definition of Outcome Measures 
12.1.1 Primary outcome measures 
 
Best overall response (CR +  PR) during the first 8 cycles of treatment will be assessed using 
contrast-enhanced CT scans of the neck, chest, abdomen and pelvis, using the Revised 
Response Criteria for Malignant Lymphoma (27) 
 
12.1.2 Secondary outcome measures 
 
Toxicity assessed using CTCAE v4.0 will be defined as the number and proportion of patients 
who experience one or more grade 3 or 4 adverse event or serious adverse event of any 
grade 
 
Best overall response (Partial Remission (PR) + Complete Response (CR)) at any time of 
treatment will be assessed using contrast-enhanced CT scans of the neck, chest, abdomen 
and pelvis, using the Revised Response Criteria for Malignant Lymphoma (27) 
 
Maximum percentage change in the sum of the product of diameters (SPD) of target tumour 
masses assessed by contrast-enhanced CT scans of the neck, chest, abdomen and pelvis, 
using the Revised Response Criteria for Malignant Lymphoma27 
 
Duration of response is defined as the time from first documented response until 
relapse/progression, as determined by the Revised Response Criteria27, or death. Patients 
who are relapse/progression free and alive will be censored at date last seen. 
 
Progression free survival is defined as the time from date of registration to the date of disease 
progression or date of death from any cause. Patients not reaching progression or death at 
the time of analysis will be censored at the last date they were known to be alive and 
progression free. Patients will be followed up for a minimum of 12 months. 
 
Overall survival time is defined as the time from date of registration to the date of death from 
any cause. Patients discontinuing the study, lost to follow-up or still alive at the end of the 
study will be censored at the date of last follow-up. Patients will be followed up for a minimum 
of 12 months. 
 
12.1.3 Exploratory outcome measures 
 
PD-L1 expression  will be defined as the percentage of PD-L1 expression in the patients 
baseline tumour samples  
 
Cell free lymphoma DNA levels will be measured and correlated to the patients clinical 
disease status 
 
CyTOF study; putative biomarkers of response will be identified and immune cell changes will 
be correlated with any toxicity 
 
 
12.2 Analysis of Outcome Measures  
 
Primary Outcome Measures 
Best overall response rate (PR + CR) during 8 cycles of treatment will be presented as the number 
and proportion of patients achieving a response over the total number of patients registered to the 
trial. Patients who die due to disease or toxicity during the first 8 cycles of treatment and patients who 
are not assessable will be classed as non-responders. 
Posterior probability plots will also be produced together with the probability that the true effect is 
greater than 35%. 
 
Secondary Outcome Measures 
Toxicity - The number and proportion of patients who experience one or more grade 3 or 4 adverse 
event or serious adverse event of any grade will be reported over the total number patients in the trial 


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Time to event outcomes will be estimated using Kaplan Meier method. Point estimates will be 
presented at 6 and 12 months with 95% confidence intervals. 
 
Reduction in tumour size measured as maximum percentage change in the radiological sum of the 
product of the diameters from baseline will be presented as a mean and standard deviation or 
medians with an interquartile range depending on the distribution of the data. 
 
 
Exploratory outcome measures 
 Percentage of PD-L1 expression will be analyses at the Leicester Cancer Centre 
 Cell free DNA levels and disease status correlation will be performed by the Leicester Cancer Centre 
 Multicolour peripheral blood immunophenotyping will be performed by the Leicester Cancer Centre 
 CyTOF study: biomarkers of response data will be acquired via mass flow cytometry at the Leicester 
Cancer Centre 
 
All summaries and statistical analyses will be performed on an intention-to-treat (ITT) population 
including patients who are ineligible or non-compliant and a per protocol population of only patients 
who were eligible and received at least 1 dose of treatment.     
 
12.3 Planned Interim Analysis 
Accumulating data and analyses will be monitored regularly by the TSC with an independent chair 
(see section 13.4). 
In addition an interim analysis for futility will take place once 15 patients have been recruited and 
reached the cycle 3 CT scan time point. If the probability of the true response rate being greater than 
35% is less than 20% (i.e. observe less than three responses) the TSC would need to make a 
decision on whether to stop or continue the trial.  Both ITT and per protocol analyses will be 
presented.  This stopping rule is provided as guidance only and any decision to stop or continue will 
be based on a pragmatic assessment of all outcomes. 
 
12.4 Planned Final Analyses  
Final analysis will take place 1 year after the last patient entered the study. 
 
Sample size determinationThe trial will recruit 30 patients with the flexibility to recruit more if required. 
Given the rare nature of the disease bayesian probability plots for a binary outcome with an 
uninformative beta prior are used. Given these 30 patients, if the trial observed 11 responses there 
would be a 60% chance that the true response rate is greater than 35%. Given 13 responses are 
observed there would be an 84% chance that the true response rate is greater than 35%.  See 
appendix 2 for plots for different scenarios. 
 
13. TRIAL ORGANISATIONAL STRUCTURE 
13.1 Sponsor 
The trial is sponsored by the University of Birmingham. 
 
13.2 Coordinating Centre 
The trial is being conducted under the auspices of the Cancer Research UK Clinical Trials Unit 
(CRCTU), University of Birmingham according to their local procedures. 
 


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13.3 Trial Management Group 
A TMG will be established and will include the Chief Investigator, co-investigators, the trial statistician 
and trial coordinators. Key trial personnel will be invited to join the TMG as appropriate to ensure 
representation from a range of professional groups. Notwithstanding the legal obligations of the 
Sponsor and Chief Investigator, the TMG will be responsible for the day-to-day running and 
management of the trial and will meet by teleconference or in-person as required, at least every 6 
months during the trial treatment period.   
 
13.4 Trial Safety Committee  
A TSC, with an independent chair, will provide overall supervision for the trial and provide advice 
through its independent chair. The ultimate decision for the continuation of the trial lies with the TSC. 
The TSC will meet at least 6 months after the first patient has been recruited and every 6 months 
thereafter during the recruitment and treatment period, to monitor all safety, futility and primary activity 
data.  
 
13.5 Finance 
This is an Investigator-initiated and Investigator -led trial funded by the Bloodwise Trials Acceleration 
Programme (TAP) and Pfizer.   
Payments will be made to NHS Trusts for research costs associated with the trial.  No other individual 
per patient payment will be made to NHS Trusts, Investigators or patients. 
 
This trial is also included in the NIHR CRN portfolio.  
This project is supported by the facilities funded through Birmingham Science City: Translational 
Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) 
funded project which forms part of the Science City University of Warwick and University of 
Birmingham Research Alliance. 
 
14. ETHICAL CONSIDERATIONS 
The trial will be performed in accordance with the recommendations guiding physicians in biomedical 
research involving human subjects, adopted by the 18th World Medical Association General Assembly, 
Helsinki, Finland, June 1964, amended at the 48th World Medical Association General Assembly, 
Somerset 
West, 
Republic 
of 
South 
Africa, 
October 
1996 
(website: 
http://www.wma.net/en/30publications/10policies/b3/index.html).  
The trial will be conducted in accordance with the Research Governance Framework for Health and 
Social Care, the applicable UK Statutory Instruments, (which include the Medicines for Human Use 
Clinical Trials 2004 and subsequent amendments and the General Data Protection Regulation and the 
Data Protection Act (2018) and Human Tissue Act 2008) and Good Clinical Practice (GCP). This trial 
will be carried out under a Clinical Trial Authorisation in accordance with the Medicines for Human Use 
Clinical Trials regulations. The protocol will be submitted to and approved by the main Research 
Ethics Committee (REC) prior to circulation.  
Before any patients are enrolled into the trial, the Principal Investigator at each site is required to 
obtain local R&D approval. Sites will not be permitted to enrol patients until written confirmation of 
R&D approval is received by the Trials Office.  
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments gain the 
necessary local approval. This does not affect the individual clinicians’ responsibility to take immediate 
action if thought necessary to protect the health and interest of individual patients. 
 
15. CONFIDENTIALITY AND DATA PROTECTION 
Personal data recorded on all documents will be regarded as strictly confidential and will be handled 
and stored in accordance with the General Data Protection Regulation and the Data Protection Act 
(2018). With the patient’s consent, their initials and date of birth will be collected at trial entry. Patients 


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will be identified using only their unique trial number, initials and date of birth on the Case Report Form 
and correspondence between the Trials Office and the participating site. However patients are asked 
to give permission for the Trials Office to be sent a copy of their signed Informed Consent Form which 
will not be anonymised. This will be used to perform in-house monitoring of the consent process. 
The Investigator must maintain documents not for submission to the Trials Office (e.g. Patient 
Identification Logs) in strict confidence. In the case of specific issues and/or queries from the 
regulatory authorities, it will be necessary to have access to the complete trial records, provided that 
patient confidentiality is protected.  
The Trials Office will maintain the confidentiality of all patient’s data and will not disclose information 
by which patients may be identified to any third party other than those directly involved in the 
treatment of the patient.  Representatives of the AVAIL-T trial team may be required to have access to 
patient’s notes for quality assurance purposes but patients should be reassured that their 
confidentiality will be respected at all times. 
 
16. INSURANCE AND INDEMNITY  
University of Birmingham employees are indemnified by the University insurers for negligent and non-
negligent harm caused by the design or co-ordination of the clinical trials they undertake whilst in the 
University’s employment. 
In terms of liability at a site, NHS Trust and non-Trust hospitals have a duty to care for patients 
treated, whether or not the patient is taking part in a clinical trial. Compensation is therefore available 
via NHS indemnity in the event of clinical negligence having been proven. 
The University of Birmingham is independent of any pharmaceutical company, and as such it is not 
covered by the Association of the British Pharmaceutical Industry (ABPI) guidelines for patient 
compensation.  
 
17. PUBLICATION POLICY  
Results of this trial will be submitted for publication in a peer reviewed journal in accordance with the 
TAP publication policy. The manuscript will be prepared by the Trial Management Group (TMG) and 
authorship will be determined in line with the TAP publication policy.  
Any secondary publications and presentations prepared by Investigators must be reviewed by the 
TMG. Manuscripts must be submitted to the TMG in a timely fashion and in advance of being 
submitted for publication, to allow time for review and resolution of any outstanding issues.  Authors 
must acknowledge that the trial was performed with the support of The University of Birmingham and 
Bloodwise.  Intellectual property rights will be addressed in the Clinical Study Site Agreement between 
Sponsor and site. 
 
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Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and 
prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):2915-2923. 
doi:10.1182/blood-2013-11-536359. 
41. 
Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844-
1854. doi:10.1056/NEJMra0904569. 
 
 


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APPENDIX 1 - RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA27 
 
Response Category 
Lymph Node Masses 
Spleen and Liver 
Bone Marrow 
CR 
Normal* 
Not palpable, nodules 
disappeared 
Normal or if 
indeterminate** by 
morphology, negative on 
immunohistochemistry 
PR 
Normal* 
 
Persistent morphological 
bone marrow involvement 
≥ 50% decrease in SPD 
of up to 6 largest 
dominant masses***, no 
increase in other lesions 
No increase in size of liver 
or spleen; ≥ 50% 
decrease in SPD of 
nodules 
Irrelevant 
SD 
No change in size of 
previous lesions on CT 
No increase in liver / 
spleen 
 
Relapse/progression 
New or increased**** 
> 50% increase from 
nadir in SPD of any 
previous lesions 
New or recurrent 
involvement 
* ≤ 1.5 cm in their greatest transverse diameter for nodes >1.5 cm before therapy. Previously involved nodes that 
were 1.1 to 1.5 cm in their greatest transverse diameter and > 1.0 cm in the short axis before treatment must have 
decreased to ≤1 cm in their short axis after treatment. 
 
**Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia). 
 
***Select diameters of up to six of the largest dominant nodes or nodal masses. 
These nodes or masses should be selected according to all of the following: they should be clearly measurable in 
at least 2 perpendicular dimensions; if possible they should be from disparate regions of the body; and they 
should include mediastinal and retroperitoneal areas of disease whenever these sites are involved. 
 
****Appearance of a new lesion(s) > 1.5cm in any axis; ≥ 50% increase in SPD of more than one node, or ≥ 50% 
increase in longest diameter of a previously identified node > 1cm in short axis. 
 


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APPENDIX 2 – AVAIL-T BAYESIAN PROBABILITY PLOTS 
 
Design 
Bayesian probability plot approach using a binary outcome. Uninformative beta prior is used.  
 
For 30 evaluable patients in the trial 
 
1) 11 responses observed 
We would be greater than 60% sure that the response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% marks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2) 12 responses observed 
We would be greater than 74% sure that the response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% marks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P (true response rate > 45%) = 
19% 
P (true response rate > 35%) = 
60% 
P (true response rate > 25%) =  94% 
P (true response rate > 45%) = 
30% 
P (true response rate > 35%) = 
74% 
P (true response rate > 25%) =  97% 


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3) 13 responses observed 
We would be greater than 84% sure that the response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% marks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
4) 16 responses observed: 
We would be greater than 98% sure that the true response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% marks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
For 35 evaluable patients in the trial 
 
1) 13 responses observed: 
We would be greater than 63% sure that the response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% response rate 
marks. 
 
 
 
 
 
 
 
 
 
 
P (true response rate > 45%) = 
44% 
P (true response rate > 35%) = 
84% 
P (true response rate > 25%) =  98% 
P (true response rate > 45%) = 
82% 
P (true response rate > 35%) = 
98% 
P (true response rate > 25%) =  >99% 
P (true response rate > 45%) = 
18% 
P (true response rate > 35%) = 
63% 
P (true response rate > 25%) =  95% 


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2) 14 responses observed: 
We would be greater than 75% sure that the response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% response rate 
marks. 
 
 
 
 
 
 
 
 
 
 
 
 
3) 15 responses observed: 
We would be greater than 84% sure that the response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% response rate 
marks. 
 
 
 
 
 
 
 
 
 
 
 
 
4) Anticipated 19 responses observed: 
We would be greater than 98% sure that the true response rate was greater than 35%. The plot below 
shows the distribution of the responses and the red lines show the 25%, 35% and 45% response rate 
marks. 
 
 
 
 
 
 
 
 
 
 
 
 
P (true response rate > 45%) = 
29% 
P (true response rate > 35%) = 
75% 
P (true response rate > 25%) =  97% 
P (true response rate > 45%) = 
41% 
P (true response rate > 35%) = 
84% 
P (true response rate > 25%) =  99% 
P (true response rate > 45%) = 
87% 
P (true response rate > 35%) = 
99% 
P (true response rate > 25%) =  >99% 


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APPENDIX 3 - DEFINITION OF ADVERSE EVENTS  
Adverse Event 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product 
and which does not necessarily have a causal relationship with this treatment. 
Comment:  
An AE can therefore be any unfavourable and unintended sign (including abnormal laboratory findings 
that result in early trial treatment discontinuation from the study treatment, and/or requires study drug 
dose modification or interruption, any other therapeutic intervention or is judged to be of significant 
clinical importance), symptom or disease temporally associated with the use of an investigational 
medicinal product, whether or not related to the investigational medicinal product. 
 
Adverse Reaction 
All untoward and unintended responses to an IMP related to any dose administered.  
Comment:  
An AE judged by either the reporting Investigator or Sponsor as having causal relationship to the IMP 
qualifies as an AR. The expression reasonable causal relationship means to convey in general that 
there is evidence or argument to suggest a causal relationship. 
 
Serious Adverse Event  
Any untoward medical occurrence or effect that at any dose:  
 
Results in death  
 
Is life-threatening* 
 
Requires hospitalisation** or prolongation of existing inpatients’ hospitalisation 
 
Results in persistent or significant disability or incapacity  
 
Is a congenital anomaly/birth defect 
 
Or is otherwise considered medically significant by the Investigator*** 
Comments:  
The term severe is often used to describe the intensity (severity) of a specific event. This is not the 
same as serious, which is based on patients/event outcome or action criteria. 
* Life threatening in the definition of an SAE refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe. 
**Hospitalisation is defined as an unplanned, formal inpatient admission, even if the hospitalisation is a 
precautionary measure for continued observation. Thus hospitalisation for protocol treatment (e.g. line 
insertion), elective procedures (unless brought forward because of worsening symptoms) or for social 
reasons (e.g. respite care) are not regarded as an SAE. 
*** Medical judgment should be exercised in deciding whether an AE is serious in other situations. 
Important AEs that are not immediately life threatening or do not result in death or hospitalisation but 
may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above, should be considered serious. 
 
Serious Adverse Reaction  
An Adverse Reaction which also meets the definition of a Serious Adverse Event. 
 
Suspected Unexpected Serious Adverse Reaction 
A SAR that is unexpected i.e. the nature, or severity of the event is not consistent with the applicable 
product information. 
A SUSAR should meet the definition of an AR, UAR and SAR. 


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Unexpected Adverse Reaction 
An AR, the nature or severity of which is not consistent with the applicable product information (e.g. 
Investigator Brochure for an unapproved IMP or (compendium of) Summary of Product Characteristics 
(SPC) for a licensed product).  
When the outcome of an AR is not consistent with the applicable product information the AR should be 
considered unexpected. 


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APPENDIX 4 - WMA DECLARATION OF HELSINKI  
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Recommendations guiding physicians 
in biomedical research involving human subjects 
Adopted by the 18th World Medical Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
41st World Medical Assembly, Hong Kong, September 1989 
and the 
48th General Assembly, Somerset West, Republic of South Africa, October 1996 
 
INTRODUCTION 
It is the mission of the physician to safeguard the health of the people. His or her knowledge and 
conscience are dedicated to the fulfillment of this mission. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, "The 
Health of my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act only in the patient's interest when providing medical care which 
might have the effect of weakening the physical and mental condition of the patient." 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of 
disease. 
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. 
This applies especially to biomedical research. 
Medical progress is based on research which ultimately must rest in part on experimentation involving 
human subjects. 
In the field of biomedical research a fundamental distinction must be recognized between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, 
the essential object of which is purely scientific and without implying direct diagnostic or therapeutic 
value to the person subjected to the research. 
Special caution must be exercised in the conduct of research which may affect the environment, and 
the welfare of animals used for research must be respected.  
Because it is essential that the results of laboratory experiments be applied to human beings to further 
scientific knowledge and to help suffering humanity, the World Medical Association has prepared the 
following recommendations as a guide to every physician in biomedical research involving human 
subjects. They should be kept under review in the future. It must be stressed that the standards as 
drafted are only a guide to physicians all over the world. Physicians are not relieved from criminal, civil 
and ethical responsibilities under the laws of their own countries. 
 
I. BASIC PRINCIPLES 
Biomedical research involving human subjects must conform to generally accepted scientific principles 
and should be based on adequately performed laboratory and animal experimentation and on a 
thorough knowledge of the scientific literature. 
1. The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol which should be transmitted for consideration, 
comment and guidance to a specially appointed committee independent of the investigator and the 


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sponsor provided that this independent committee is in conformity with the laws and regulations of 
the country in which the research experiment is performed. 
1. Biomedical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the 
subject of the research, even though the subject has given his or her consent. 
2. 4. Biomedical research involving human subjects cannot legitimately be carried out unless the 
importance of the objective is in proportion to the inherent risk to the subject. 
3. Every biomedical research project involving human subjects should be preceded by careful 
assessment of predictable risks in comparison with foreseable benefits to the subject or to others. 
Concern for the interests of the subject must always prevail over the interests of science and 
society. 
4. The right of the research subject to safeguard his or her integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject and to minimize the impact of the 
study on the subject's physical and mental integrity and on the personality of the subject. 
5. Physicians should abstain from engaging in research projects involving human subjects unless 
they are satisfied that the hazards involved are believed to be predictable. Physicians should 
cease any investigation if the hazards are found to outweigh the potential benefits. 
6. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication. 
7. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may 
entail. He or she should be informed that he or she is at liberty to abstain from participation in the 
study and that he or she is free to withdraw his or her consent to participation at any time. The 
physician should then obtain the subject's freely-given informed consent, preferably in writing. 
8. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship to him or her or may consent under duress. In 
that case the informed consent should be obtained by a physician who is not engaged in the 
investigation and who is completely independent of this official relationship. 
9. In case of legal incompetence, informed consent should be obtained from the legal guardian in 
accordance with national legislation. Where physical or mental incapacity makes it impossible to 
obtain informed consent, or when the subject is a minor, permission from the responsible relative 
replaces that of the subject in accordance with national legislation. Whenever the minor child is in 
fact able to give a consent, the minor's consent must be obtained in addition to the consent of the 
minor's legal guardian. 
10. The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that the principles enunciated in the present Declaration are complied with. 
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
 (Clinical Research) 
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgement it offers hope of saving life, reestablishing health or 
alleviating suffering. 


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2. The potential benefits, hazards and discomfort of a new method should be weighed against the 
advantages of the best current diagnostic and therapeutic methods. 
3. In any medical study, every patient - including those of a control group, if any - should be assured 
of the best proven diagnostic and therapeutic method. This does not exclude the use of inert 
placebo in studies where no proven diagnostic or therapeutic method exists. 
4. The refusal of the patient to participate in a study must never interfere with the physician-patient 
relationship. 
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this 
proposal should be stated in the experimental protocol for transmission to the independent 
committee (I, 2). 
6. The physician can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is justified by its 
potential diagnostic or therapeutic value for the patient. 
III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS (Non-Clinical Biomedical Research) 
7. In the purely scientific application of medical research carried out on a human being, it is the duty 
of the physician to remain the protector of the life and health of that person on whom biomedical 
research is being carried out. 
8. The subject should be volunteers - either healthy persons or patients for whom the experimental 
design is not related to the patient's illness. 
9. The investigator or the investigating team should discontinue the research if in his/her or their 
judgement it may, if continued, be harmful to the individual. 
10. In research on man, the interest of science and society should never take precedence over 
considerations 
related 
to 
the 
wellbeing 
of 
the 
subject.


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APPENDIX 5 - COMMON TOXICITY CRITERIA GRADINGS 
Toxicities will be recorded according to the Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0.  The full CTCAE document is available on the National Cancer Institute (NCI) 
website, the following address was correct when this version of the protocol was approved: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
 
 
 
Contact information:  
 
 
 
 
 
AVAIL- T trial team  
Centre for Clinical Haematology  
Queen Elizabeth Hospital  
Birmingham B15 2TH 
 
 
 
 
 
Tel: 0121 371 7861 
 
 
 
 
 
Fax: 0121 371 7874 
 
 
 
 
 
Email: Avail-t@trials.bham.ac.uk