A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T Cells in Subjects With Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma
Phase: PHASE2
Conditions: Synovial Sarcoma, Myxoid Liposarcoma
Sponsor: USWM CT, LLC

Study Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects 
with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
NCT number: NCT04044768 
Document: Protocol  
Document Date: 05 Feb 2021 

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
CONFIDENTIAL
Date 05FEB2021 
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PROTOCOL NUMBER ADP-0044-002
A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects 
with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
(SPEARHEAD 1 STUDY)
PROTOCOL VERSION: AMENDMENT 3 
DATE:  05FEB2021

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
CONFIDENTIAL
Date 05FEB2021 
Page 2 of 161
INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™T 
Cells in Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma
(MRCLS)
I, the undersigned, have reviewed the protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to International Council for Harmonization (ICH) 
tripartite guideline E6 (R2): Guideline for Good Clinical Practice (GCP) and all the ethical and 
regulatory considerations stated. I have read and understood the contents of the ADP-A2M4
Investigator’s Brochure.
Investigator Name
Investigator Title
Investigator Site and Address
Investigator Signature
Date

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
CONFIDENTIAL
Date 05FEB2021 
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CLINICAL STUDY PROTOCOL
Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™T Cells in 
Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma (MRCLS)
Product Name: ADP-A2M4
Protocol Number: ADP-0044-002
IND Number: 17235
EudraCT Number: 2019-000589-39
DATE OF ORIGINAL PROTOCOL: 25FEB2019
Amendment Number
Date
Reason for Change
Original
25FEB2019
NA –
Amendment 1
04JUN2019
Change in the lymphodepletion 
regimen
Addition of ECG at Day 5
Added upper age limit
Increase entry criteria for ANC, 
platelets, GFR
Additional exclusion criteria under 
uncontrolled intercurrent illness
Emerging data for ADP-A2M4 added
Updated study physician
Administrative changes

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
CONFIDENTIAL
Date 05FEB2021 
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Amendment Number
Date
Reason for Change
Amendment 2
26MAR2020
Update to sponsor contacts
Updates and clarifications to HLA 
criteria 
Removed futility analysis and 
associated protocol aspects
Updated number of subjects
Decreased duration of enrollment
Increased LVEF criteria
Clarification of washout for prior gene 
therapy
Added updated data from current ADP-
A2M4 Investigator’s Brochure
Update to CRS management guidelines 
Updated Grading for Cytokine Release 
Syndrome and Neurologic Toxicity 
Associated with Immune Effector Cells
Administrative changes and 
clarifications

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
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Date 05FEB2021 
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Amendment Number
Date
Reason for Change
Amendment 3
05FEB2021
Update to sponsor contacts 
Addition of Cohort 2 (45 synovial 
sarcoma subjects)
Updates to safety and efficacy 
information to align with current IB
Information added for COVID-19 
requirements
Exclusion for compression/occlusion 
of a vital structure added
Addition of EORTC QLQ-C30 (Cohort 
2 only)
Removal of CDx and PP Population 
definitions
Additional details added throughout for 
addititional clarity of wording
Template language updated
CONFIDENTIALITY STATEMENT
This document contains information which is the property of Adaptimmune LLC, USA, and 
therefore is provided in confidence for your review. It is understood that this information will 
not be disclosed to others without written approval from Adaptimmune LLC.
DECLARATION
This study will be conducted in compliance with ICH GCP, all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of Helsinki 
(with amendments), and in accordance with local legal and regulatory requirements.

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
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RESPONSIBLE SPONSOR STUDY PHYSICIAN/SPONSOR INFORMATION PAGE
Sponsor Signatory
   
                                                 
_
____________
                                             Date
Responsible Study Physician/SAE Contact Information
Role
Name
Day Phone and 
email
After hours 
phone
Fax Number
Primary Sponsor 
Study Physician
 
 
Secondary 
Sponsor Study 
Physician
 
 
Sponsor Details:
Adaptimmune LLC
351 Rouse Blvd
Philadelphia, PA 19112
USA

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: Amendment 3
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Date 05FEB2021 
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TABLE OF CONTENTS
1.
PROTOCOL SUMMARY..........................................................................................17
1.1.
Synopsis......................................................................................................................17
1.2.
Schema........................................................................................................................30
1.3.
Time and Events Table ...............................................................................................31
1.3.1.
Main Time and Events (T&E) Table..........................................................................31
1.3.2.
Long Term Follow Up Phase Time & Events Table..................................................39
2.
INTRODUCTION ......................................................................................................40
2.1.
Study Rationale...........................................................................................................40
2.1.1.
Rationale for using MAGE-A4 TCR in synovial sarcoma and myxoid/round 
cell liposarcoma..........................................................................................................40
2.2.
Background.................................................................................................................40
2.2.1.
MAGE-A4 background ..............................................................................................40
2.2.2.
Discovery of ADP-A2M4...........................................................................................42
2.2.3.
Synovial sarcoma/MRCLS current therapies and Emerging Data from ADP-
A2M4 and other TCRs................................................................................................42
2.2.4.
Benefit : Risk Assessment ..........................................................................................45
2.2.4.1.
Benefit.........................................................................................................................45
2.2.4.2.
Risk.............................................................................................................................45
2.2.5.
Overall benefit: risk conclusion..................................................................................46
3.
OBJECTIVES AND ENDPOINTS............................................................................48
4.
STUDY DESIGN .......................................................................................................50
4.1.
Overall Design............................................................................................................50
4.1.1.
Pre-screening ..............................................................................................................50
4.1.2.
Screening ....................................................................................................................50
4.1.3.
Enrollment ..................................................................................................................51
4.2.
Scientific Rationale for Study Design ........................................................................52
4.2.1.
Pre-Screening for HLA Alleles and MAGE-A4 Expression......................................53
4.2.1.1.
HLA ............................................................................................................................53

            
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4.2.1.2.
MAGE-A4 Expression in Tumor................................................................................53
4.2.2.
T Cell Manufacturing .................................................................................................54
4.2.3.
Lymphodepletion........................................................................................................54
4.2.4.
Long Term Follow-up.................................................................................................55
4.3.
Justification for Dose..................................................................................................55
4.4.
End of Study Definition..............................................................................................55
5.
STUDY POPULATION.............................................................................................56
5.1.
HLA and Antigen Pre-screening ................................................................................56
5.2.
Inclusion Criteria ........................................................................................................56
5.3.
Exclusion Criteria.......................................................................................................59
5.4.
Screen Failures............................................................................................................62
5.5.
Number of Subjects and Study Duration....................................................................62
5.6.
Sites.............................................................................................................................63
6.
STUDY INTERVENTION ........................................................................................64
6.1.
Leukapheresis .............................................................................................................64
6.2.
Lymphodepleting Chemotherapy ...............................................................................64
6.2.1.
Fludarabine dose adjustment for renal impairment ....................................................66
6.2.2.
Mesna..........................................................................................................................66
6.2.3.
G-CSF.........................................................................................................................66
6.3.
Investigational Product ...............................................................................................66
6.3.1.
Premedication .............................................................................................................66
6.3.2.
T Cell Infusion............................................................................................................67
6.4.
Preparation/Handling/Storage/Accountability............................................................68
6.4.1.
Packaging and Labelling.............................................................................................68
6.4.2.
Receipt and Return .....................................................................................................68
6.4.3.
Storage and Handling .................................................................................................69
6.4.4.
Investigational Product Accountability/Traceability..................................................69
6.4.5.
Alert Cards..................................................................................................................69
6.5.
Concomitant Medications...........................................................................................70

            
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6.5.1.
Prohibited Concomitant Medications .........................................................................70
6.5.2.
Permitted Concomitant Medications ..........................................................................70
6.5.2.1.
Vaccinations Including for COVID-19 ......................................................................71
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................72
7.1.
Temporary Study Suspension.....................................................................................72
7.2.
Ending the Interventional Phase.................................................................................72
7.3.
Subject Discontinuation..............................................................................................73
7.4.
Lost to Follow up........................................................................................................73
8.
STUDY ASSESSMENTS AND PROCEDURES......................................................74
8.1.
Background Assessments ...........................................................................................74
8.1.1.
Demographics.............................................................................................................74
8.1.2.
Disease History...........................................................................................................74
8.2.
HLA MAGE-A4 Tumor Antigen Testing, and Cytogenetics.....................................74
8.2.1.
HLA ............................................................................................................................74
8.2.2.
MAGE-A4 Antigen ....................................................................................................74
8.2.3.
Cytogenetics for Diagnosis.........................................................................................75
8.3.
Efficacy Assessments .................................................................................................75
8.3.1.
CT/MRI.......................................................................................................................75
8.3.2.
Survival.......................................................................................................................76
8.4.
Safety Assessments.....................................................................................................77
8.4.1.
Medical History..........................................................................................................77
8.4.2.
Physical Examination .................................................................................................77
8.4.3.
Prior Anti-cancer Therapies........................................................................................77
8.4.4.
Prior and Concomitant Medications ...........................................................................77
8.4.5.
ECOG .........................................................................................................................77
8.4.6.
Vital Signs ..................................................................................................................78
8.4.7.
Weight and Height......................................................................................................78
8.4.8.
Cardiac Assessments ..................................................................................................78

            
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8.4.8.1.
ECG ............................................................................................................................78
8.4.8.2.
Echo/MUGA...............................................................................................................78
8.4.8.3.
Telemetry....................................................................................................................78
8.4.9.
Brain MRI...................................................................................................................78
8.4.10.
Renal Function Assessment........................................................................................79
8.4.11.
Hematology.................................................................................................................79
8.4.12.
Clinical Chemistry......................................................................................................79
8.4.13.
Coagulation.................................................................................................................79
8.4.14.
Thyroid Function Tests...............................................................................................79
8.4.15.
Hepatic Safety Assessments .......................................................................................79
8.4.16.
Pregnancy Test............................................................................................................79
8.4.17.
Infectious Disease Screening......................................................................................80
8.4.18.
CMV PCR...................................................................................................................80
8.4.19.
ICE Assessment Tool .................................................................................................80
8.4.20.
C-reactive Protein.......................................................................................................80
8.4.21.
Ferritin ........................................................................................................................80
8.4.22.
Persistence (Vector Copies)........................................................................................80
8.4.23.
RCL (VSV-G DNA)...................................................................................................81
8.5.
Adverse Events and Serious Adverse Events.............................................................81
8.5.1.
Time period for collecting AE and SAE Information ................................................81
8.5.2.
Method of Detecting Aes and SAEs...........................................................................82
8.5.3.
Follow-up of AEs and SAEs.......................................................................................82
8.5.4.
Regulatory Reporting Requirements for SAEs...........................................................82
8.5.5.
Pregnancy ...................................................................................................................83
8.5.6.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs...............................................................................................................84
8.5.7.
AEs of Special Interest ...............................................................................................84
8.5.7.1.
Cytokine Release Syndrome.......................................................................................84
8.5.7.2.
Neurotoxicity..............................................................................................................84

            
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8.5.8.
Long Term Follow Up Adverse Events......................................................................85
8.5.8.1.
LTFU Letters to Primary Care Physician/Oncologist ................................................85
8.6.
Biomarkers for Exploratory Objectives......................................................................86
8.6.1.
Tumor Biopsy.............................................................................................................87
8.6.2.
Cytokine and Soluble Protein Analysis ......................................................................87
8.6.3.
Liquid Biopsy Collection and Analysis (Blood Plasma)............................................88
8.6.4.
Cell Phenotype and Functional Assays.......................................................................88
8.6.5.
Persistence of ADP-A2M4 TCR+ Cells.....................................................................88
8.7.
Patient-Reported Outcomes........................................................................................89
8.7.1.
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L).............................................89
8.7.2.
EORTC-QLQ-C30......................................................................................................89
9.
STATISTICAL CONSIDERATIONS .......................................................................90
9.1.
Study Populations .......................................................................................................90
9.2.
Statistical Hypotheses and Sample Size Assumptions ...............................................90
9.3.
Statistical Analyses.....................................................................................................93
9.3.1.
Interim Analysis..........................................................................................................93
9.3.2.
Efficacy Analyses .......................................................................................................93
9.3.3.
Safety Analyses ..........................................................................................................94
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS..................................................................................................96
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................96
10.1.1.
Data Handling and Record Keeping...........................................................................96
10.1.1.1.
Data management .......................................................................................................96
10.1.1.2.
Case Report Forms .....................................................................................................96
10.1.1.3.
Site Documentation and Source Data.........................................................................97
10.1.1.4.
Data Retention and Availability .................................................................................97
10.1.2.
Study Monitoring........................................................................................................97
10.1.2.1.
Audits and Inspections................................................................................................98
10.1.3.
Regulatory and Ethical Considerations ......................................................................98

            
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10.1.3.1.
Competent Authority Submissions.............................................................................98
10.1.3.2.
Independent Ethics Committees .................................................................................98
10.1.3.3.
Local regulations/Declaration of Helsinki..................................................................98
10.1.4.
Informed consent ........................................................................................................99
10.1.5.
Confidentiality............................................................................................................99
10.1.6.
Protocol Adherence ....................................................................................................99
10.1.7.
Study Suspension, Study Termination and Study Completion.................................100
10.1.8.
Public Posting of Study Information ........................................................................100
10.1.9.
Clinical Study Report ...............................................................................................100
10.1.10.
Publication Policy.....................................................................................................100
10.1.11.
Financial Disclosure .................................................................................................100
10.2.
Appendix 2: Safety Reviews ....................................................................................101
10.2.1.
Data Safety Monitoring Board..................................................................................101
10.3.
Appendix 3: Clinical Laboratory Tests.....................................................................102
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting......................................................................104
10.4.1.
Definition of AE .......................................................................................................104
10.4.2.
Definition of SAE.....................................................................................................105
10.4.3.
Recording and Follow-Up of AE and/or SAE..........................................................106
10.4.4.
Reporting of SAEs....................................................................................................109
10.4.5.
Hepatic Monitoring and Follow Up Assessments ....................................................109
10.4.6.
Reporting Criteria during Long Term Follow-Up (Years 1-15)...............................110
10.4.7.
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents.......................................................................................................................112
10.5.
Appendix 5: Supportive Care Guidance...................................................................113
10.5.1.
Lymphodepleting Chemotherapy Symptom Management.......................................113
10.5.1.1.
Management of Neutropenia ....................................................................................113
10.5.2.
T-cell Infusion Symptom Management....................................................................113
10.5.3.
Infection....................................................................................................................114

            
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10.5.3.1.
SARS-CoV-2 (COVID-19) ......................................................................................114
10.5.3.2.
Pneumocystis carinii Pneumonia..............................................................................114
10.5.3.3.
Herpes simplex and Varicella zoster ........................................................................114
10.5.3.4.
Cytomegalovirus.......................................................................................................114
10.5.3.5.
Hepatitis B Prophylaxis............................................................................................115
10.5.3.6.
Syphilis .....................................................................................................................115
10.5.3.7.
Other Anti-Microbial Prophylaxis............................................................................115
10.5.4.
Hematologic and Blood Product Support.................................................................115
10.5.4.1.
Irradiated Blood Product...........................................................................................115
10.5.4.2.
CMV screened blood products .................................................................................115
10.5.5.
Management of Autoimmunity.................................................................................116
10.5.6.
Management of Cytokine Release Syndrome...........................................................116
10.5.7.
Management of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)....................................................................................................................119
10.5.7.1.
Management of ICANS ............................................................................................121
10.5.8.
Management of Prolonged Cytopenia ......................................................................123
10.5.8.1.
Definition of prolonged cytopenia, pancytopenia and plastic anemia......................123
10.5.8.2.
Management of Prolonged Cytopenias.....................................................................124
10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information ...............................................................................................................125
10.6.1.
Contraception Guidance: ..........................................................................................125
10.6.2.
Collection of Pregnancy Information .......................................................................126
10.6.2.1.
Female Participants who become pregnant ..............................................................126
10.6.2.2.
Male participants with partners who become pregnant ............................................127
10.7.
Appendix 7: Long Term Follow Up .........................................................................128
10.7.1.
Background to Safety Monitoring in LTFU .............................................................128
10.7.1.1.
Monitoring and Management of Replication-Competent Lentivirus (RCL)............128
10.7.1.2.
Insertional oncogenesis.............................................................................................128
10.7.2.
Testing for RCL and Persistence..............................................................................129

            
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10.7.3.
Integration Site Analysis...........................................................................................131
10.7.4.
Letter to Physician – LTFU notification...................................................................132
10.8.
Appendix 8:  Efficacy Reporting..............................................................................134
10.8.1.
RECIST 1.1 for Evaluating Response in Solid Tumors ...........................................134
10.9.
Appendix 9: ECOG Performance Status ..................................................................140
10.10.
Appendix 10:  EQ-5D-3L Health Questionnaire (SAMPLE)...................................141
10.11.
Appendix 11:  EORTC-QLQ-C30 Questionnaire (SAMPLE).................................144
10.12.
Appendix 12: Abbreviations.....................................................................................146
10.13.
Appendix 13: Protocol Amendment History............................................................151
10.14.
References.................................................................................................................155

            
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LIST OF TABLES
Table 1:
T&E for Pre-Screening and Interventional Phase ......................................................31
Table 2:
T&E for Long Term Follow Up Phase.......................................................................39
Table 3:
Fludarabine and Cyclophosphamide Treatment Schema ...........................................65
Table 4:
Protocol-Required Safety Laboratory Assessments .................................................102
Table 5: 
Hepatic Monitoring Criteria .....................................................................................109
Table 6: 
Management Guidelines for Cytokine Release Syndrome.......................................117
Table 7:
........................................119
Table 8: 
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)....................................................................................................................120
Table 9: 
Management of ICANS ............................................................................................122

            
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LIST OF FIGURES
Figure 1:
Flow chart for testing for Replication Competent Lentivirus (RCL) .......................130
Figure 2:
Flow Chart for Testing for Persistence.....................................................................131

            
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Title
A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects with Advanced Synovial 
Sarcoma or Myxoid/Round Cell Liposarcoma
Short Title
SPEARHEAD 1 Study
Protocol Number
ADP-0044-002
Phase
2
Methodology
Subjects with advanced synovial sarcoma or myxoid/myxoid round cell liposarcoma 
(Cohort 1 only) will be Pre-screened to determine appropriate human leukocyte 
antigen (HLA) and tumor antigen status. Only subjects with advanced synovial 
sarcoma will be eligible for Cohort 2. Only subjects expressing at least 1 HLA-A*02 
inclusion allele and no exclusion allele and whose tumor expresses the MAGE-A4 
antigen above the cut-off are eligible to undergo further screening for this study.
Subjects who sign the Treatment Informed Consent and meet study entry criteria will 
be enrolled into either Cohort 1 or Cohort 2. Enrolled subjects will undergo 
leukapheresis for collection of autologous cells for processing and manufacture into 
the ADP-A2M4 cell Investigational Product (IP). Leukapheresis should be performed 
as soon as possible after the subject is determined to be eligible for study 
participation.  Subjects who have enrolled into a Cohort may not enroll into the 
other Cohort subsequently.
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria 
will be reconfirmed and baseline tumor assessment obtained. 
Anticancer therapy may be administered between screening and leukapheresis and 
between leukapheresis and the start of lymphodepletion (bridging therapy), if a 
subject has progressive disease and cannot be treatment-free, but mandatory 
washout periods must be adhered to.
When the ADP-A2M4 cells are available at site, subjects will undergo 
lymphodepleting chemotherapy with fludarabine 30 mg/m2/day for 4 days (Day -7 to 
Day -4) and cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5) followed by 
infusion of ADP-A2M4 cells on Day 1. Subjects will remain hospitalized for 
observation for at least 24 hours post T cell infusion.

            
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An independent Data Safety Monitoring Board (DSMB) will review the ongoing safety
during the interventional phase of the study for Cohort 1. Cohort 2 will begin once all 
subjects have been dosed in Cohort 1. Subjects in both cohorts will have the 
following study visits for assessment of eligibility, efficacy, safety, health related-
outcome and biomarkers: Pre-Screening, Screening, Leukapheresis, Baseline, 
Lymphodepleting Chemotherapy (Day -7 to Day -4), T cell infusion (Day 1) and 
immediate post infusion monitoring (Day 1 through Day 8), weekly visits until Week 
4 post infusion, then 6, 8, 12, 16 and 24 weeks then every 2 months until disease 
progression. 
Subjects will undergo disease monitoring by magnetic resonance imaging (MRI) or 
computerized tomography (CT) scan at Screening, Baseline, Week 4, Week 8, Week 
12, Week 16 and Week 24, and every 2 months until confirmed disease progression. 
Once disease progression is established, no further scans will be performed for this 
study and subjects will switch to the long term follow-up (LTFU) schedule of visits at 
Months 2, 3 and 6 followed by 6 monthly visits through Year 5 and annually 
thereafter for Years 6-15. The timepoint at which the subject switches will be driven 
by the timepoint at which the subject progresses e.g. if there is disease progression 
at Week 4, the next visit would be due at Month 2; if there is disease progression at 
Week 12, the next visit would be due at Month 6. 
The Primary Efficacy Analysis will be for Cohort 1 only.  Clinical cut-off for the 
primary analysis will occur once the forty-fifth subject dosed in Cohort 1 has up to 6 
months follow-up post T cell infusion. At this time, all safety and secondary efficacy 
endpoints for Cohort 1 only will also be summarized to provide supportive evidence 
to the primary assessment.
Study Duration
Enrollment is expected to continue for approximately 12 months for Cohort 1 and for 
an additional 12 months for Cohort 2.
The study will be considered complete once all enrolled subjects complete 15 years 
of follow-up or discontinue the study for any reason. 
Study Center(s)
The study will be conducted in approximately 24 sites in North America and Europe. 
Additional sites may be added at the discretion of the Sponsor.
Number of subjects
Ninety (90) subjects: Forty-five (45) synovial sarcoma and MRCLS subjects in Cohort 
1; Forty-five (45) synovial sarcoma subjects in Cohort 2.

            
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Objectives
Endpoints
Primary
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) in 
HLA-A*02 positive subjects with MAGE-A4 
expressing advanced synovial sarcoma or 
MRCLS
Overall Response Rate (ORR) per RECIST v1.1 by independent 
review in Cohort 1.
Secondary
To evaluate the safety and tolerability of 
autologous genetically modified T cells (ADP-
A2M4) in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS
For Cohort 1 and across Cohorts (overall): 
Adverse events (AEs) including serious adverse events 
(SAEs)
Incidence, severity and duration of the AEs of special 
interest
Replication Competent Lentivirus (RCL)
T cell Clonality and Insertional oncogenesis (IO)
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) in 
HLA-A*02 positive subjects with MAGE-A4 
expressing advanced synovial sarcoma or 
MRCLS
Overall Response Rate (ORR) per RECIST v1.1 by 
independent review across Cohorts (overall)
For Cohort 1 and across Cohorts (overall): 
Time to Response (TTR)
Duration of Response (DoR)
Best Overall Response (BOR)
Progression Free Survival (PFS)
Overall Survival (OS)
Development and validation of an in vitro 
diagnostic (IVD) assay for the screening of 
tumor antigen expression for regulatory 
approval
Across Cohorts:
Retention of additional tumor tissue during Pre-screening to 
enable development and validation of the MAGE-A4 antigen 
expression companion diagnostic assay
Characterize the in vivo cellular 
pharmacokinetics (PK) profile of ADP-A2M4
cells
For Cohort 1 and across Cohorts (overall): 
Peak persistence and other relevant PK parameters of ADP-
A2M4 cells
Exploratory

            
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Inclusion Criteria
1.
Subject (or legally authorized representative) voluntarily agrees to participate by 
giving written Informed Consent (and Assent as applicable) in accordance with 
ICH GCP guidelines and applicable local regulations.
2.
Subject (or legally authorized representative) agrees to abide by all protocol 
required procedures including study related assessments and management by 
the treating institution for the duration of the study, including long term follow-
up.
3.
and <75 years at the time the Pre-screening informed consent/assent is 
signed.
4.
Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or myxoid 
liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by
cytogenetics. Inoperable refers to a tumor lesion in which clear surgical excision 
margins cannot be obtained without leading to significant functional 
compromise.
a.
For Synovial Sarcoma (Cohort 1 and Cohort 2): confirmation by the 
presence of a translocation between SYT on the X chromosome and 

            
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SSX1, SSX2 or, SSX4 on chromosome 18 (may be presented in the 
pathology report as t (X; 18)).
b.
For MRCLS (Cohort 1 only): confirmation by the presence of the 
reciprocal chromosomal translocation t(12;16)(q13;p11) or t(12; 22) 
(q13;q12).
5.
Must have previously received either an anthracycline or ifosfamide containing 
regimen. 1st-line metastatic treatment with ADP-A2M4 is permissible if 
ifosamide +/- doxorubicin has been administered in either the pre-operative 
(neoadjuvant) or post-operative (adjuvant) primary tumour setting.(Subjects 
who are intolerant of both anthracycline and ifosfamide must have previously 
received at least one other type of systemic therapy).
6.
Measurable disease according to RECIST v1.1.
7.
Positive for HLA-A*02:01, HLA-A*02:03 or HLA-A*02:06 allele via Adaptimmune 
designated central laboratory testing. HLA-A*02 alleles having the same protein 
sequence in the peptide binding domains (P group) will also be included. Other 
HLA-A*02 alleles may be eligible after adjudication with the sponsor.
8.
Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 
samples must have been pathologically reviewed by an Adaptimmune 
designated central laboratory confirming expression.  
9.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
10.
5
11. Fit for leukapheresis and adequate venous access can be established for the cell 
collection.
12. Female subjects of childbearing potential (FCBP) must have a negative urine or 
serum pregnancy test AND must agree to use an effective method of 
contraception starting at the first dose of chemotherapy and continuing for at 
least 12 months, or 4 months after the gene modified cells are no longer 
detected in the blood, whichever is longer. 
OR 
Male subjects must be surgically sterile or agree to use a double barrier 
contraception method or abstain from heterosexual activity with a FCBP starting 
at the first dose of chemotherapy and continuing for 4 months thereafter (or 
longer if indicated in the country specific monograph/label for 
cyclophosphamide).

            
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13. Must have adequate organ function as indicated by the laboratory values in the 
table below:

            
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System
Laboratory Value
Hematological
Absolute 
Neutrophil 
count 
(ANC)
.5 x109/L (without G-CSF support) within 7 days 
prior to lymphodepletion and leukapheresis
Platelets
9/L (without transfusion support
within 7 days prior to lymphodepletion and 
leukapheresis)
Hemoglobin
within 7 days prior to lymphodepletion and 
leukapheresis)
Coagulation
Prothrombin Time (PT) or INR
unless receiving therapeutic 
anticoagulation
Subjects receiving warfarin anti-coagulation at 
baseline should be converted to either a low 
molecular weight heparin injection or a novel oral 
anticoagulant (NOAC). Reintroduction of warfarin 
after lymphodepleting chemotherapy/ADP-A2M4 
dosing to attain the therapeutic INR range which 
was initially clinically indicated should only start 
when the platelet count is < Grade 2 CTCAE.
Partial Thromboplastin Time 
(PTT)
unless receiving therapeutic 
anticoagulation
Renal
Glomerular filtration rate  
(calculated CrCl using only the 
Cockcroft-Gault equation, or 
measured using either a 24-hr 
urine creatnine collection or a 
radionuclide EDTA test)a
60 mL/min

            
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Hepatic
Serum total bilirubin
Gilbert’s Syndrome with direct bilirubin 
Alanine aminotransferase 
(ALT)/Serum                                  
Glutamic Pyruvic Transaminase 
(SGPT)
a)
24-hour urine creatine clearance or radionuclide EDTA tests should be used to 
measure the GFR in all subjects:
65 years old; clinically obese ( 30KG/m2) or 
underweight ( 18.5KG/m2); borderline low calculated CrCl (Cockcroft-Gault) at 
approximately 60mls/min. 
Renal function will be reassessed at Baseline using the same methodology.
Exclusion Criteria
1.
Positive for HLA-A*02:05 in either allele via Adaptimmune designated central 
laboratory testing. HLA-A*02 alleles having the same protein sequence as HLA-
A*02:05 in the peptide binding domains (P groups) will also be excluded. Other 
alleles may be exclusionary after adjudication with the sponsor. 
2.
Received or plans to receive the following therapy/treatment prior to 
leukapheresis or lymphodepleting chemotherapy: 
Treatment/Therapy
Required Wash-out 
Prior to 
Leukapheresis
Required Wash-out 
Prior to 
Lymphodepletion 
Cytotoxic chemotherapy
3 weeks
3 weeks
Tyrosine kinase inhibitor 
(TKI)  (e.g. pazopanib)
1 week 
1 week 
Immune therapy 
(including monoclonal 
antibody therapy, 
checkpoint inhibitors,)
4 weeks
4 weeks
Anti-cancer Vaccine
8 weeks in the 
absence of tumor 
response. The subject 
8 weeks in the absence 
of tumor response.

            
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should be excluded if 
their disease is 
responding to an 
experimental vaccine 
given within 6 months
The subject should be 
excluded if their 
disease is responding 
to an experimental 
vaccine given within 6 
months
Gene therapy using an 
integrating vector
Subjects who have 
received a gene 
therapy using any 
DNA-integrating 
vector other than a 
lentivirus (retrovirus, 
AAV, etc.) are 
excluded from this 
study. Subjects who 
have received a gene 
therapy using a 
lentiviral vector may 
be eligible if they have 
persistence results 
below the lower limit 
of quantification 
(LLOQ) for at least 2 
samples taken at least 
1 month apart. At 
least 1 of these tests 
must be performed by 
Adaptimmune as part 
of Pre-screening or 
Screening.
Not permitted after 
leukapheresis and prior 
to lymphodepletion. 
Corticosteroids or any 
other 
immunosuppressive 
therapy. NOTE:  Use of 
topical steroids is not an 
exclusion. See Section 
6.5.1 for exceptions. 
2 weeks 
2 weeks 

            
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3.
Toxicity from previous anti-
prior to enrollment (except for non-clinically significant toxicities, e.g., alopecia, 
vitiligo).  Subjects with Grade 2 toxicities that are deemed stable or irreversible 
(e.g. peripheral neuropathy) can be enrolled. 
4.
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to fludarabine, cyclophosphamide or other agents used in 
the study.
5.
History of autoimmune or immune mediated disease. Subjects with 
hypothyroidism, diabetes, adrenal insufficiency or pituitary insufficiency that 
are stable on replacement therapy are eligible. Subjects with disorders such as 
Investigational 
treatment or 
interventional clinical 
trial
4 weeks 
4 weeks
Allogeneic 
hematopoietic stem cell 
transplant
Not permitted within
any amount of time
Not permitted within
any amount of time
Radiotherapy to the 
target lesions
N/A
3 months.  A lesion 
with unequivocal 
progression may be 
considered a target 
lesion regardless of 
time from last 
radiotherapy dose.  
(Note: there is no 
washout period for 
palliative radiation to 
non-target organs).
Major surgery
N/A
4 weeks. Subjects must 
have recovered from 
any surgical related 
toxicities.
NOTE: Duration of any other anti-cancer therapies must be discussed with 
the Sponsor Study Physician

            
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asthma, psoriasis or atopic dermatitis that are well controlled without requiring 
systemic immunosuppression are also eligible.
6.
Symptomatic CNS metastases including leptomeningeal disease.  Subjects with 
a prior history of symptomatic CNS metastasis including leptomeningeal
disease must have received treatment (i.e., stereotactic radiosurgery (SRS), 
whole brain radiation (WBRT) and/or surgery) and be neurologically stable for 
at least 1 month, not requiring anti-seizure medications and off of steroids for 
at least 14 days prior to leukapheresis and lymphodepletion. Anti-seizure 
prophylaxis is permitted.  Subjects who have asymptomatic CNS metastases 
without associated edema, shift, requirement for steroids or anti-seizure 
medications for the treatment of seizures are eligible.  
7.
Any other prior malignancy that is not in complete remission.  Resectable 
squamous or basal cell carcinoma of the skin is acceptable. Prior malignancies 
that have been surgically resected and show no evidence of disease are 
acceptable.  
8.
Uncontrolled intercurrent illness including, but not limited to:
Ongoing or active infection; 
Clinically significant cardiac disease defined by congestive heart failure 
New York Heart Association (NYHA) Class 3 or Class 4;
Uncontrolled clinically significant arrhythmia;
Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months;
Interstitial lung disease (subjects with existing pneumonitis as a result of 
radiation are not excluded, however, subjects must not be oxygen 
dependent);
Congenital or family history of long QT syndrome;
Current uncontrolled hypertension despite optimal medical therapy;
History of stroke or central nervous system bleeding; transient ischemic 
attack (TIA) or reversible ischemic neurologic deficit (RIND) in last 6 
months;
Incipient compression/occlusion of a vital structure (e.g. bronchus; 
superior vena cava; renal outflow tract) which cannot undergo 
prophylactic stenting;
COVID-19 infection or a positive COVID-19 RT-PCR test within 28 days of 
leukapheresis or lymphodepleting chemotherapy. If a subject has a 
positive COVID-19 test, then 2 subsequent negative tests are required, 
taken at least 7 days apart.

            
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9.
Active infection with HIV, HBV, HCV or HTLV as defined below:
Positive serology for HIV;
Active hepatitis B infection as demonstrated by test for hepatitis B surface 
antigen. Subjects who are hepatitis B surface antigen negative but are 
hepatitis B core antibody positive must have undetectable hepatitis B DNA 
and receive prophylaxis against viral reactivation.  Prophylaxis should be 
initiated prior to lymphodepleting therapy and continued for 6 months;
Active hepatitis C infection as demonstrated by hepatitis C RNA test.  
Subjects who are HCV antibody positive will be screened for HCV RNA by any 
RT PCR or bDNA assay. If HCV antibody is positive, eligibility will be 
determined based on a negative screening RNA value;
Positive serology for HTLV 1 or 2;
Re-screening for infectious disease markers is not required at baseline (prior 
to lymphodepletion) unless > 6 months has elapsed.
10. Pregnant or breastfeeding.
11. In the opinion of the Investigator, the subject is unlikely to fully comply with 
protocol requirements.
Investigational Product, 
Dose, Route, Regimen
ADP-A2M4 is the SPEARTM TCR product administered at a dose of 1.0 x 109 to 10 x 
109 transduced cells by a single intravenous infusion on Day 1.
Comparator therapy
None
Statistical Methodology
The primary clinical endpoint for efficacy is Overall Response Rate (ORR) defined as 
the proportion of subjects with a complete response (CR) or partial response (PR) via 
independently reviewed RECIST v1.1 relative to the total number of subjects in the 
analysis population in Cohort 1.
The primary analysis population for safety and efficacy will be the modified intent to 
treat population (mITT) defined as all subjects who received the ADP-A2M4 cell 
infusion in Cohort 1.
(Null Hypothesis) H0
0 , vs. (Alternate Hypothesis) H1: p > p0, where p0 (historical 
control rate)= 0.18. 
Statistical assumptions include:
Exact Binomial methods will be used to test the hypothesis

            
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The assumed ORR for ADP-A2M4 is 0.40
Based on the statistical design assumptions above and the hypotheses and clinical 
assumptions detailed in Section 9, the estimated sample size for the trial is 45 
subjects in Cohort 1 for the primary analysis. An additional 45 subjects are to be 
enrolled in Cohort 2, although no formal hypothesis testing is planned for Cohort 2 
or overall (across cohorts).
The primary endpoint, ORR per RECIST v1.1 by independent review for Cohort 1, will 
be evaluated using a one-sided exact-based Clopper-
pre-specified threshold for demonstrating efficacy. 
The key secondary efficacy endpoints ORR per RECIST v1.1 by independent review 
across Cohorts (overall), TTR, DoR, PFS and OS will be summarized. No hypothesis 
testing is planned for these secondary endpoints. Time to event endpoints will be 
summarized and displayed graphically using Kaplan-Meier (K-M) methodology to 
estimate the median, and the 25th and 75th percentiles. Two-
intervals will be produced.  Overall Survival may be assessed at fixed time points 
such as 1 year and 2 years using K-M methods. 
Descriptive statistics will be provided for demography, safety, PK profile, and 
laboratory assessments. Descriptive statistics on continuous data will include means, 
medians, standard deviations, and ranges, while categorical data will be summarized 
using frequency counts and percentages.  Graphical summaries of the data may be 
presented.
Efficacy and safety summaries will be displayed across tumor types (overall) and by 
tumor type. Efficacy and safety summaries will be displayed across cohorts (overall) 
and by cohort as indicated above. Other subgroups may be explored and these will 
be described in the Statistical Analysis Plan.

            
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1.2.
Schema

            
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2.
INTRODUCTION
2.1.
Study Rationale
2.1.1.
Rationale for using MAGE-A4 TCR in synovial sarcoma and myxoid/round cell 
liposarcoma
Adoptive T cell therapy (ACT) is a treatment that uses a cancer subject’s own T lymphocytes 
with anti-tumor activity, expanded in vitro and re-infused into the subject. The ultimate objective 
of the process is the stimulation and expansion of potent and antigen-specific T cell immunity.  
Kalos, 2013; 
Klebanoff, 2016; Maus, 2014; Morgan, 2010; Rosenberg, 2008 .
Antitumor activity in ‘‘native’’ T cells may not be sufficient to induce tumor cell death in most 
patients with advanced malignancy. Gene-transfer-based strategies have therefore been 
developed to overcome the consequences of immune tolerance on the tumor-specific T cell 
repertoire. These approaches provide the potential to redirect T cells to effectively target tumors 
by the transfer of antigen-specific affinity-optimized TCRs. 
The majority of clinical approaches have employed T cells engineered to stably express 
transgenes via virus-based transduction. Virus-mediated gene transfer approaches typically 
employ vectors that are derived from gamma retroviruses or more recently lentiviruses.
ADP-A2M4 specific peptide enhanced affinity receptor (SPEAR™) T cells are genetically 
engineered to target the subject’s MAGE-A4 positive tumor in the context of the appropriate 
HLA expression. ADP-A2M4 are autologous CD4 and CD8 positive T cells that have been 
transduced with a self-inactivating lentiviral vector expressing a high affinity MAGE-A4 specific 
T cell receptor (TCR). MAGE-A4 is a cancer/testis antigen (CTA) that has restricted expression 
in normal tissue, and is expressed across a range of solid tumors at varying frequencies.
ADP-A2M4 recognizes the MAGE-A4230-239; GVYDGREHTV peptide derived from the 
MAGE-A4 family of CTAs. Thus, ADP-A2M4 incorporates an affinity enhanced TCR capable 
of recognizing the human leukocyte antigen (HLA)-A*02-GVYDGREHTV antigen complex.
The safety of ADP-A2M4 has been shown in subjects with different tumor types in an ongoing 
Phase 1 study (NCT03132922). Data of another genetically engineered T cell investigational 
product, NY-ESOc259T, in synovial sarcoma provides evidence that TCR therapies can be 
effective in solid tumors D’Angelo, 2018a .
2.2.
Background
2.2.1.
MAGE-A4 background
The cancer/testis antigens (CTA) comprise a number of genes that have restricted expression to 
Caballero, 2009
These include NY-ESO-1, MAGE-A family, SSX2, BAGE, GAGE, and CT7 among others.  

            
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Most of these testis-specific genes are coded on the X chromosome. Several of these antigens, 
including MAGE-A3, MAGE-A10 and MAGE-
Caballero,
2009
type, have the highest frequency of RNA expression across the CTAs.  Epithelial cancers such as 
breast, bladder and prostate cancer have intermediate expression, with frequency of mRNA 
expression in the range of 30% to 50%.  CTAs often have coordinated expression, with several 
Gure, 2005   In addition to RNA, immunohistochemistry is often 
used to determine the expression levels of CTAs.  While it is generally seen that mRNA 
expression of these antigens correlates well with protein expression it should be noted that there 
is frequently heterogeneous expression of protein across the tumor, with strong expression in a 
small subset of tumor cells.  There is also epigenetic and post-transcriptional modification that 
determines protein expression levels under certain conditions.
The function of the CTA in germline tissues or in tumors is generally not well understood.  Some 
MAGE-A proteins do have functions that may enhance tumor growth.  For example, MAGE-A1 
proteins may have a role in suppressing differentiation during spermatogenesis and a similar role 
in inhibiting cell differentiation may be a mechanism by which it promotes tumorigenesis 
Laduron, 2004; Simpson, 2005
-A family 
modulate key transcription factors such as SKIP, p300, p160 (TIF2)/androgen receptor ER-
Marcar, 2015
-A4 appears to promote cell growth of 
epithelial cells by preventing cell cycle arrest and inhibiting apoptosis.  In one study, 
overexpression of MAGE-A4 was shown to repress p53 targets, such as BAX and CDKN1A 
Bhan, 2012
In a yeast-two hybrid study, MAGE-A4 was identified as a binding partner for the 
Nagao, 2003
Through these pathways, MAGE expression may protect 
Yang,
2007
MAGE-A4 has been described as having high expression in synovial sarcoma and MRCLS.  A 
recent study showed that 82% of synovial sarcoma samples expressed MAGE-A4 when 
evaluated by Immunohistochemistry (IHC) and high expression of NY-ESO-1 and MAGE-A4 
was significantly correlated with the presence of necrosis and advanced clinical stage Iura,
2017a
 
.  A further report suggested that 67.7% of MRCLS samples, express 
MAGE-
Iura, 2017b
 
 
  
 
 
 
 
 

            
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2.2.2.
Discovery of ADP-A2M4
Several peptides derived from MAGE proteins have been identified by mass spectroscopy from 
tumor cell lines, including the human leukocyte antigen (HLA) HLA-A*02-restricted peptide 
MAGE-A4230-239; GVYDGREHTV.  HLA class I molecules are involved in the presentation 
of antigenic peptides on tumors to T lymphocytes.  The prevalence of HLA subtypes varies from 
population to population, the most common in the western world being HLA-A2.  Among the 
HLA-A2 allelic variants, the most prevalent are HLA-A*02:01 (approximately 45% of 
Caucasian and Hispanic population) and HLA-A*02:06 (www.allelefrequencies.net). 
Adaptimmune generated 20 parental TCRs that recognize the HLA-A*02-restricted MAGE-A4 
peptide GVYDGREHTV.  From these, one demonstrated some response toward natively 
MAGE-B2 and MAGE-A4-positive cell lines and was selected for engineering, resulting in 17 
enhanced affinity TCRs that were tested in cellular assays against MAGE-A4 positive and 
negative cell lines and primary cells.  Cellular testing for potency and specificity identified 
ADB1032 as being optimal, demonstrating enhanced potency against MAGE-A4 positive tumor 
cell lines, while retaining a favorable specificity and safety profile. 
The Investigational Product (IP) is comprised of autologous CD4 and CD8 T cells obtained from 
eligible subjects who have MAGE-A4 expressing tumors and who are HLA-A*02 positive.  
Subjects who are HLA-A*02:05 are excluded because alloreactivity has been observed in vitro 
with ADP-A2M4 to this HLA allele.  The T cells undergo self-inactivating (SIN) lentiviral 
transduction with ADP-A2M4 specific nucleic acid under Good Manufacturing Practice (GMP)
conditions.  The resulting polyclonal ADP-A2M4 specific peptide enhanced affinity receptor 
(SPEAR™) T cells are now genetically engineered to target the antigen on the subject’s MAGE-
A4 positive advanced tumor.
2.2.3.
Synovial sarcoma/MRCLS current therapies and Emerging Data from ADP-
A2M4 and other TCRs
Synovial Sarcoma and Myxoid/Round Cell Liposarcoma
Sarcomas are rare malignant tumors originating from mesenchymal cells and their precursors, 
and represent ~1% of all cancers in adults worldwide each year (10% of cancers in children, and 
8% of cancers in adolescents) and ~2% of cancer related mortality Singer, 2000; Amankwah,
2013 .  The estimated international incidence rates of soft tissue sarcoma ranges between 4 and 6 
Stiller, 2013; Ferrari, 2011 . Soft tissue sarcomas consist of 
approximately 50 different histological subtypes.  
Synovial Sarcoma
Synovial sarcoma represents 5% of all soft tissue sarcoma (STS) and is characterized by the 
presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or SSX4 on 
chromosome 18. The disease affects young individuals with a median age in the third decade; 
with 70% of the diagnoses occurring in subjects under 40 years old.
Surgery is the standard therapy for localized disease.  Patients with advanced synovial sarcoma 
receive ifosfamide and/or doxorubicin, as the first-
ESMO, 2014 .   Doxorubicin-
based first-line metastatic doublet therapies, such as doxorubicin in combination with the anti-

            
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PDGFR alpha monoclonal antibody olaratumab Lilly, 2019
have not demonstrated improved 
clinical benefit compared to single-agent doxorubicin.
There is no specific standard of care (SoC) in second line therapies and beyond. Pazopanib is 
approved in the U.S and in Europe for patients with synovial sarcoma previously treated with 
Votrient™ US Prescribing Information, EU SmPC
A randomized double blind 
placebo controlled Phase 3 trial of pazopanib was conducted in patients with advanced STS.  
Overall response rate (ORR) as assessed by Data Safety Monitoring Board (DSMB) for the 
intent to treat (ITT) population was  4%, median duration of response (DoR) of 9 months,  and 
median progression free survival (PFS) of 4.6 months compared with 1.6 months for placebo 
(HR=0.35, p<0.001). Median overall survival (OS) was 12.6 months compared with 10.7 months 
for placebo (HR=0.87; 95% CI: 0.67, 1.12). Only 38 subjects with synovial sarcoma 
(randomized 2:1) were included in the study with a median PFS of 4.1 months in the pazopanib 
arm vs 0.9 months for placebo (HR= 0.43; 95% CI 0.19, 0.98). The response rate is not reported 
Votrient™ US Prescribing Information, EU SmPC
-randomized 
study of pazopanib (EORTC Study 62043), responses as assessed by the Investigator were 
reported in 5/37 (13%) subje
Sleijfer, 2009
The response rate in a retrospective analysis of gemcitabine and docetaxel in patients with 
synovial sarcoma was 10% Abouharb, 2014 .  Several other agents have shown no appreciable 
anti-tumor activity in synovial sarcoma; these include many novel classes of agents such as 
HDAC-inhibitors Cassier, 2013
IGF-1R antibodies Pappo, 2014; Olmos, 2010 , mTOR 
inhibitors Schwartz, 2013 , vascular disrupting agents Blay, 2015
nti-CTLA4 antibodies 
Maki, 2013 . 
Effective treatment options for patients with advanced relapsed synovial sarcoma are limited. 
The median survival upon relapse from first-
Minchom, 
2010 and the ORR from prospective trials for existing therapies 13%. 
Thirty-eight subjects have received treatment with a single dose of ADP-A2M4 up to 9.9756 x 
109 transduced cells within the phase 1 ADP-0044-001 study. Synovial sarcoma subjects 
represent the most frequent tumor type in the study and the majority of the subjects treated in 
Group 3/Expansion. Of the 16 subjects with synovial sarcoma, most subjects were males
(62.5%), most subjects were White (87.5%) and the median age was was 49.0 years (range 31 to 
76 years). The median ADP-A2M4 dose in synovial sarcoma was 9.28 x 109 transduced cells 
(range: 3.4 to 10 x 109). The reported adverse events are consistent with those typically 
experienced by patients with advanced cancer undergoing cytotoxic chemotherapy or cancer 
immunotherapy (e.g, cytopenias, fatigue, CRS). The most common AE 
25% of subjects with synovial sarcoma were, lymphopenia/lymphocyte count decreased (100%), 
leukopenia/WBC count decreased (93.3%), neutropenia/neutrophil count decreased (88%), 
neutropenia/neutrophil count decreased (81%), anemia/RBC decreased (44%), 
thrombocytopenia/platelet count decreased (44%), hypophosphatemia (44%), rash (19%), CRS 
(13%), decreased appetite (6%) and hypotension (6%). Cytokine release syndrome (any Grade) 
was reported in 88% of the subjects with synovial sarcoma.  There was one (1) Grade 5 SAE of 
prolonged pancytopenia with hypoplastic bone marrow considered possibly related to ADP-
A2M4. In subjects with synovial sarcoma, the ORR (confirmed responses) was 44% (95%CI: 

            
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16.34, 67.71). The Best Overall Response was PR (7), SD (8), and PD (1).Disease control rate 
was 94% with 11 patients still alive at time of 1-September-2020 data cut-off. Subject responses 
were durable with a median duration of response of 28 weeks (range: 12-72 weeks). CTOS
2020 . This data supports the continued evaluation of ADP-A2M4 in advanced/metastatic 
synovial sarcoma.
Myxoid/Round Cell Liposarcoma (MRCLS)
MRCLS is a subtype of liposarcoma which is associated with specific translocation, t (12; 16)
(q13; p11) or t (12; 22) (q13; q12) and represents about 30-35% of liposarcomas and 5-10% of 
all adult STS (WHO, 2002).  MRCLS commonly presents at an age ranging from 35-55 years. 
Myxoid round cell tumors tumors with a round-cell component >5% have a poor prognosis with 
a 5-year survival rate of ~50-75% because they recur locally and tend to metastasize quickly and 
Smith, 1996
Treatment involves the wide surgical excision of the tumor and surrounding tissue. Myxoid 
round cell liposarcoma may be treated with pre-operative chemotherapy and/or pre-operative or 
post-
NCCN, 2012
Doxorubicin and ifosfamide are the first line 
systemic treatment options for patients with metastatic disease. Retrospective analyses in 
previously untreated patients demonstrated response rates of ~38 -
Jones, 2005; Katz,
2012
pace of progression.  A variety of therapies are used in the second-line setting and beyond 
although only trabectedin and eribulin are approved. A randomized open label phase 2 study of 
trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma enrolled 270 
patients. Patients were randomized to receive either a 24 hour infusion of 1.5 mg/m2 of 
trabectedin once every 3 weeks, or a 3 hour infusion of 0.58 mg/m2 of trabectedin once every 
week for three weeks of a 4 week cycle. The treatment regimen that was determined to be most 
beneficial was the 24 hour infusion of 1.5mg/m2 of trabectedin once every 3 weeks.  One 
hundred and thirty six patients were randomized to this arm of the study and the ORR was 5.6% 
Demetri, 2016
A subsequent randomized, phase 3, open-label, active-controlled trial comparing trabectedin 
(n=345) treatment with dacarbazine (n=173) in patients with unresectable, locally advanced or 
metastatic leiomyosarcoma (73%) or liposarcoma (27%) (dedifferentiated, myxoid round cell, or 
pleomorphic) and previous treatment with an anthracycline-containing regimen and one 
additional cytotoxic chemotherapy regimen demonstrated an overall response rate (ORR of 9.9% 
(CI 0.72, 3.2) with trabectedin, an improvement of median progression-free survival (PFS) of 5.6  
vs 1.5 months on dacarbazine but no 
Demetri, 2016 . Eribulin 
demonstrated an improvement in survival (median OS 13.5 vs 11.5 months; HR= 0.768; 95% CI, 
0.618; 0.954) compared with darcarbazine in subjects with liposarcoma and leiomyosarcoma 
who received 2 or more prior lines of therapy.  There was no difference in PFS and ORR was 
3.9% with Eribulin and 4.9% with darcarbazine in all patients enrolled.  In patients with 
liposarcoma the response rate was 1.4% Schöffski, 2016 .  Despite the approval of these two 
agents, overall survival in patients with relapsed disease remains 12-13 months Demetri, 2016;
Schöffski, 2016 and the ORR from prospective trials for existing therapies is < 10%.

            
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A TCR T-cell product targeted against the NY-ESO-1 cancer testsis antigen has shown 
potentially promising clinical activity in eight MRCLS
D’Angelo, 2018b . For MAGE-
A4, in Study ADP-0044-001, two MRCLS subjects were dosed with ADP-A2M4 cells.  At the 
time of Data cut-off, 1 Sept 2020, no MRCLS subjects had responded to ADP-A2M4.  ADP-
A2M4 was however safe and well tolerated in MRCLS subjects in this phase 1 trial.
2.2.4.
Benefit : Risk Assessment
The results of clinical and non-Clinical studies conducted with ADP-A2M4 cells are summarized 
in the ADP-A2M4 Investigator’s Brochure.  This section outlines the potential benefits, risks and 
the overall benefit: risk for this study.
2.2.4.1.
Benefit
Although the basis for including both synovial sarcoma and MRCLS subjects in Cohort 1 of this 
study was the reported high frequency of MAGE-A4 expression in both synovial sarcoma and 
Iura, 2017a; Iura, 2017b , as well as the historical clinical activity of the 
NY-ESO-1 TCR in both synovial sarcoma and MRCLS, preliminary evaluation of MRCLS 
response and MAGE-A4 antigen status in both the ADP-0044-001 and Cohort 1 ADP-0044-002 
studies would suggest that ADP-A2M4 is not as clinically active in MRCLS as it is in synovial 
sarcoma possibly because of a comparatively lower MAGE-A4 antigen score distribution. 
For these reasons, Cohort 2 will only enroll subjects with synovial sarcoma as such patients are 
likely to derive the greatest therapeutic benefit from the ADP-A2M4 cell product especially 
since study ADP-0044-001 has shown an ORR of 44% in sixteen heavily pre-treated metastatic 
synovial sarcoma subjects who had a
CTOS 2020 . This 
data from study ADP-0044-001 in combination with emerging efficacy findings for synovial 
sarcoma subjects in Cohort 1 of study ADP-0044-002 would indicate that ADP-A2M4 is a 
promising cell product in metastatic synovial sarcoma especially since there is no specific 
standard of care beyond first-line ifosfamide and/or doxorubicin for patients with advanced 
(inoperable)/metastatic synovial sarcoma.
2.2.4.2.
Risk
The safety and tolerability of ADP-A2M4 is being assessed in phase 1 trial (study ADP-0044-
001) across multiple tumor types and in the ongoing Cohort 1 of study ADP-0044-002 including 
synovial sarcoma and MRCLS. Toxicities observed with ADP-A2M4 are common to other TCR 
or CAR-T therapies or standard of care chemotherapies.  
Toxicities such as CRS, ICANS and pancytopenia/aplastic anemia are specific to TCR and CAR-
T therapies and therefore guidelines for management of these events are included in 
Section 10.5.  An advantage of TCR therapy is that they are generally administered once, and the 
vast majority of toxicities resolve within 4 to 6 weeks after T cell infusion.
Alloreactivity, whereby TCRs reactive towards a given peptide-MHC complex display cross-
reactivity towards different HLA allelic variants, is a theoretical risk. Pre-clinical data indicate 
strong anti-HLA-A*02:05 alloreactivity, making A*02:05 an exclusion allele. Data also indicate 

            
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decreased potency against MAGE-A4230-239 peptide when presented by HLA-A*02:07, 
therefore subjects with A*02:07P alleles are ineligible unless they also express an inclusion 
allele.  Preclinical studies support the specificity, safety, and anti-tumor activity of ADP-A2M4
and therefore an unacceptable risk of off-target reactivity is not expected. No evidence of 
alloreactivity has been detected in the ongoing Phase 1 study to date.
The study incorporates several measures to address the risks including: 1) extensive preclinical 
evaluation of the ADP-A2M4 which has incorporated learnings from other adoptive T cell 
ADP-A2M4 Investigator Brochure
based on the preclinical alloreactivity 
data, exclusion of subjects with HLA-A*02:05 in either allele or with HLA-A*02 alleles having 
the same protein sequence as HLA-A*02:05 in the antigen binding domains (P groups); 3) use 
of a validated Clinical Trial Assay for the selection of subjects with MAGE-A4 expression in 
their tumors; 4) treatment in specialized academic centers experienced with the management of 
toxicities associated with autologous T cell therapies; 5) protocol guidelines for management of 
toxicities including cytokine release syndrome (CRS), Immune Effector Cell-Associated 
Neurotoxicity Syndrome (ICANS), and pancytopenia/aplastic anemia as well as preventive 
measures for infectious complications, and 6) a Data Safety Monitoring Board (DSMB) to 
evaluate safety during the course of Cohort 1.
The potential risks for Cohort 2 (synovial sarcoma only) are expected to be similar to the 
emerging safety profile in Cohort 1 of study ADP-0044-002, as well as similar to the safety 
profile reported in the sixteen synovial sarcoma subjects previously dosed in the phase 1 trial, 
study ADP-0044-
CTOS 2020
in Cohort 1, the additional 45 synovial sarcoma subjects in Cohort 2 will permit a more deeper 
understanding and a better estimate of the frequency of adverse events of special interest (AESI) 
i.e. incidence of CRS, ICANS and pancytopenia in synovial sarcoma subjects treated with ADP-
A2M4 cells compared to safety data from Cohort 1 alone.
2.2.5.
Overall benefit: risk conclusion
In Cohort 1, based on the initially promising emerging efficacy and safety findings from the 
Phase 1 ADP-A2M4 SPEAR™ T-cell trial (study ADP-0044-001), it was jusfifable from a 
benefit-risk perspective to treat subjects with both advanced synovial sarcoma and MRCLS as 
they each constituted patient populations with a high unmet medical need, albeit with distinctly 
different metastatic disease natural histories.  However, as more mature data has accrued from 
study ADP-0044-001 in combination with emerging findings from Cohort 1 of this ongoing 
Phase 2 trial (see Section 4.2., below), it has become apparent that ADP-A2M4 cells may 
potentially be less clinically active in MRCLS compared to synovial sarcoma. Therefore, at this 
time, continued evaluation of ADP-A2M4 treatment in Cohort 2 is only justifiable for synovial 
sarcoma subjects from a therapeutic benefit perspective. In regard to mitigation of risks, 
measures to ensure safe administration of ADP-A2M4 have been included in this study protocol, 
with close monitoring for toxicities and guidelines for their management.
The potential risks identified in association with ADP-A2M4 are justified by the anticipated 
benefits which may be afforded to patients with advanced (inoperable)/metastatic synovial 
sarcoma in Cohort 2. Indeed, real-world evidence in metastatic synovial sarcoma suggests that 

            
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pazopanib - which is approved for 2nd-line metastatic soft tissue sarcoma treatment in the United 
States and Europe - is not the most frequently administered 2nd-line therapy at several major 
Pollack, 2020
Therefore, this provides a unique therapeutic opportunity for ADP-A2M4 to potentially become 
the first licensed cell therapy product in post-1st-line advanced (inoperable)/metastatic synovial 
sarcoma if the overall benefit-risk findings from this phase 2 trial (study ADP-0044-002) are 
favorable.

            
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3.
OBJECTIVES AND ENDPOINTS
Objectives
End Points
Primary:
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS
Overall Response Rate (ORR) per 
RECIST v1.1 by independent review in 
Cohort 1
Secondary:
To evaluate the safety and tolerability of 
autologous genetically modified T cells 
(ADP-A2M4) in HLA-A*02 positive 
subjects with MAGE-A4 expressing 
advanced synovial sarcoma or MRCLS
For Cohort 1 and across Cohorts (overall): 
Adverse events (AEs) including serious 
adverse events (SAEs)
Incidence, severity and duration of the 
AEs of special interest
Replication Competent Lentivirus 
(RCL)
T cell Clonality and Insertional 
oncogenesis (IO)
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS
Overall Response Rate (ORR) per 
RECIST v1.1 by independent review
across Cohorts (overall)
For Cohort 1 and across Cohorts (overall): 
Time to Response (TTR)
Duration of Response (DoR)
Best Overall Response (BOR)
Progression Free Survival (PFS)
Overall Survival (OS)

            
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Development and validation of an in vitro 
diagnostic (IVD) assay for the screening of 
tumor antigen expression for regulatory 
approval
Across Cohorts: 
Retention of additional tumor tissue 
during Pre-screening to enable 
development and validation of the 
MAGE-A4 antigen expression 
companion diagnostic assay
Characterize the in vivo cellular 
pharmacokinetics (PK) profile of ADP-
A2M4 cells
For Cohort 1 and across Cohorts (overall): 
Peak persistence and other relevant PK 
parameters of ADP-A2M4 cells
Exploratory
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

            
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4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase 2 single arm, open label study of genetically engineered ADP-A2M4 in HLA-
A*02 subjects with MAGE-A4 expressing metastatic or inoperable (advanced) synovial sarcoma
or myxoid/round cell liposarcoma (Cohort 1 only). Only subjects with advanced synovial 
sarcoma will be eligible for Cohort 2. The study consists of two separate, independent, serially 
enrolled subject cohorts: Cohort 1 and Cohort 2.
Enrollment into Cohort 1 is expected to continue for approximately 12 months and is close to 
completion at the time of this amendment. Forty-five subjects have been enrolled and 26 subjects 
have been treated with ADP-A2M4 to date. Enrollment will continue to ensure that at least 45 
subjects are dosed in Cohort 1. Dosing is expected to be complete in Cohort 1 in March 2021. 
Data from subjects in Cohort 1 only will be used for the primary study endpoint and primary 
statistical analysis. 
The clinical and scientific rational for including Cohort 2 is to provide an expanded safety and 
efficacy data set overall in inoperable (advanced)/metastatic synovial sarcoma to supplement the 
primary assessment for Cohort 1 subjects who were previously enrolled in Cohort 1 may not 
enroll into Cohort 2.
4.1.1.
Pre-screening
Subjects will sign a Pre-screening Informed Consent Form (ICF) and undergo initial screening 
for the relevant HLA alleles and MAGE-A4 tumor antigen as part of this study. 
At sites that employ remote consent at pre-screening, it is the responsibility of the Investigator to 
obtain written consent in accordance with IRB/IEC approved processes and any local 
requirements in advance of providing subjects with a HLA buccal/ cheek swab test and/ or 
sending tissue for MAGE-A4 testing.
4.1.2.
Screening
Subjects who have pre-screened positive for the relevant HLA alleles and MAGE-A4 tumor 
antigen will be asked to sign the Treatment ICF and enter Screening to determine full eligibility 
for the study. Screening assessments should be completed within 28 days of leukapheresis; CT/ 
MRI scans and ECHO/MUGA scans, performed as standard of care within 28 days prior to 
Screening Visit 2 (i.e. prior to treatment consent) are acceptable. Cytogenetic confirmation of 
diagnosis can be historic, done as standard of care, or be done any time after signing Treatment 
Consent and does not need to be within 28 day screening window.

            
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4.1.3.
Enrollment
Subjects who sign the Treatment ICF and meet the protocol defined eligibility criteria (Section
5.2 and Section 5.3) will be enrolled. Subjects who do not meet the protocol defined eligibility 
criteria are screen failures. 
Enrolled subjects will undergo leukapheresis for collection of autologous cells for processing and 
manufacture into the ADP-A2M4 cell Investigational Product (IP). Leukapheresis should be 
performed as soon as possible after the subject is determined to be eligible for study 
participation.
Anticancer therapy may be administered between screening and leukapheresis, and between 
leukapheresis and the start of lymphodepletion (bridging therapy), if a subject has progressive 
disease and cannot be treatment-free, but mandatory washout periods must be adhered to (see 
Section 5.3).  Subjects must be ready to receive IP as the next treatment once manufacturing and 
any mandatory washout periods are complete even if they remain stable on bridging therapy, 
provided they have measurable disease per RECIST v1.1.
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria will be 
reconfirmed and Baseline tumor assessment obtained.  
Once the ADP-A2M4 cells are available at site, subjects will undergo lymphodepleting 
chemotherapy with fludarabine 30 mg/m2/day for 4 days (Day -7 to Day -4) and 
cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5) (Section 6.2) followed by infusion 
of ADP-A2M4 cells on Day 1 (Section 6.3).  The lymphodepleting chemotherapy may be given 
as an outpatient treatment or subjects may be hospitalized at the discretion of the Investigator. 
The T cell infusion will be given as an inpatient procedure. Subjects will remain hospitalized for 
observation for at least 24 hours post T cell infusion. Discharge following T cell infusion will be 
at the discretion of the Investigator. All subjects must be reviewed by the investigator (or a 
designated study physician) prior to discharge.
Efficacy, safety, health related-outcome and biomarker assessments to be conducted at each visit 
are outlined in the Time and Events (T&E) Tables (Table 1 and Table 2).  Efficacy will be 
assessed by both local and independent review using RECIST v1.1. To allow time for the 
immune response to become apparent and for potential transient inflammatory reaction of the 
disease to the treatment (‘tumor flare’), disease progression will not be determined before 4 
weeks (28 days) post infusion of ADP-A2M4 unless there is unequivocal clinical evidence of 
deterioration. Therefore, imaging scans should not be performed earlier than 4 weeks (on or after 
28 days) post infusion. 
Subjects will continue to have scans for efficacy during the interventional phase of the study,
until disease progression is established. Once progression is established, no further scans will be 
performed for this study, however, subjects will continue to be followed for observation of 
delayed adverse events in accordance Food and Drug Administration (FDA) and European 
Medicines Agency (EMA)
FDA, 2006a; FDA, 
2010; EMA, 2009

            
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Subjects will be seen in the clinic for evaluation according to Main T&E Table 1 (Section 1.3.1)
until disease progression. Thereafter, subjects will undergo assessments/procedures according to 
the LTFU T&E Table 2 (Section 1.3.2 ). The timepoint at which the subject switches to the 
LTFU assessments/procedures will be driven by the timepoint at which the subject progresses 
e.g. if there is disease progression at Week 12, the next visit would be due at Week 24 (Month 
6).
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason.
4.2.
Scientific Rationale for Study Design
This is a Phase 2 single arm, open-label study with ADP-A2M4 cells for the treatment of 
subjects with advanced synovial sarcoma or MRCLS who are HLA-A*02 positive and have 
tumors that express MAGE-A4.
MAGE-A4 is a cancer testis antigen that is highly expressed in synovial sarcoma and MRCLS 
tumors making it an attractive target. Preliminary clinical evidence in Study ADP-0044-001 has 
shown an ORR (confirmed responses) of 44% (95% CI: 16.34, 67.71) in advanced 
(inoperable)/metatstatic synovial sarcoma with a disease control rate of 94% including 11 out of 
16 patients who were still alive at time of 1-September-2020 data cut-off. Synovial sarcoma 
responses were durable with a median duration of response of 28 weeks (range: 12-72 weeks).
CTOS 2020
This ORR is considerably superior than response rates reported with agents 
currently being used as 2nd line therapies for soft tissue sarcoma (Section 2.2.3).
On this basis, this Phase 2 study (ADP-0044-002) will be a single arm, non-comparative study
with a primary efficacy endpoint of Overall Response Rate (ORR) per RECIST v1.1 by 
independent review in 2 Cohorts where the primary study endpoint will be evaluated in Cohort 1.
The historical ORR for post first-line metastatic soft-tissue sarcoma patient populations ranges 
from 4%-13% (Section 2.2.3). To account for the potential variability in historical control 
response rate, a more conservative historical ORR of 18% has been estimated for therapies 
administered in the post 1st-line metastatic synovial sarcoma setting, and will be used to evaluate 
the efficacy of ADP-A2M4 by hypothesis testing (Section 9).
At the time of this Protocol Amendment (05FEB2021) the ADP-0044-002 study has been 
enrolling subjects for approximately 12 months. Fifty-three subjects have been enrolled, and 31
subjects have received treatment with a single dose of ADP-A2M4 in Cohort 1 including 27
subjects with advanced (inoperable)/metatstatic synovial sarcoma and 4 subjects with MRCLS. 
 
 
 
 
 
The clinical and scientific rationale for including Cohort 2 is to provide an expanded safety and 
efficacy dataset overall for metastatic or inoperable (advanced) synovial sarcoma to supplement 
the primary assessment for Cohort 1.

            
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4.2.1.
Pre-Screening for HLA Alleles and MAGE-A4 Expression
4.2.1.1.
HLA
Subjects must express at least 1 inclusion HLA-A allele of HLA-A*02:01, HLA-A*02:03 or 
HLA-A*02:06. HLA-A*02 alleles having the same protein sequence as these alleles in the 
antigen binding domains (P group) will also be included. There may be other HLA-A*02 alleles 
that may be eligible for inclusion after adjudication with the sponsor. The adjudication process 
will be documented. 
Due to the risk of alloreactivity subjects positive for HLA-A*02:05 in either allele are ineligible. 
Subjects with HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 in the 
antigen binding domains (P groups) will also be excluded. Other alleles may be exclusionary 
after consultation with the sponsor. HLA eligibility testing will be done via Adaptimmune 
designated central laboratory. 
Despite HLA-A*02 being the most common HLA allele group in the western world its 
expression varies greatly among populations of different races and ethnicities.  With a high 
proportion of subjects expected to be excluded based on HLA status, an optional buccal swab kit 
may be offered to subjects during pre-screening at participating sites. This allows subjects to be 
screened for HLA without requiring travel to a clinical study site.  The kit, containing a self-
administered buccal/cheek swab and associated instructions would be sent to potential subjects 
who have provided written consent in accordance with IRB/IEC approved processes and any 
local requirements. Any subject determined to be eligible based on results from the buccal swab 
would still undergo confirmatory HLA genotyping on a blood sample during screening.
4.2.1.2.
MAGE-A4 Expression in Tumor
MAGE-A4 expression was reported in synovial sarcoma (82%) and myxoid liposarcoma (68%)
Iura, 2017a; Iura, 2017b
ADP-A2M4 cells have been shown to 
responses against tumor cell lines (derived from non-small cell lung cancer, prostate carcinoma, 
melanoma and ovarian carcinoma) expressing high MAGE-A4 mRNA levels (>10,000 MAGE-
A4 transcripts). In addition, ADP-A2M4
a primary 
melanoma tissue material expressing high MAGE-A4 mRNA and protein expression levels. Since 
no adequate models to define the threshold of ADP-A2M4 cell activation are currently available, 
this protocol will select for subjects with high MAGE-A4 expression. As such, Adaptimmune will 
be using a 
30% of tumor cells) to ensure sufficient expression of the 
antigen.
To ensure that the subject’s tumor has the potential to be targeted by the ADP-A2M4 cells, the 
tumor specimen will be screened at a central reference laboratory for the expression of MAGE-A4 
by IHC using a Clinical Laboratory Improvement Amendments (CLIA)-validated Clinical Trial 
Assay.

            
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4.2.2.
T Cell Manufacturing
ADP-A2M4 is autologous CD4 and CD8 T cells engineered with an affinity-enhanced TCR to 
target the tumor antigen MAGE-A4.  Autologous T cells are obtained from eligible subjects who 
have MAGE-A4 positive tumors and who have appropriate HLA-A.  The CD4 and CD8 T cells 
are transduced with a SIN lentivirus vector expressing the MAGE-A4 (affinity enhanced clone 
1032) under GMP conditions.  The product of this transduction is polyclonal T cells which are 
designed to target MAGE-A4 in tissue.  The transfer SIN lentiviral vector has been meticulously 
Dull,
1998
nce supporting the relative biosafety of SIN lentiviral vectors 
in terms of genotoxicity, resulting primarily from the lack of enhancer activity in the lentivirus 
long terminal r
Montini, 2006; Maruggi, 
2009; Modlich, 2009; Montini, 2009
Cell product is typically ready to be returned to the site approximately one month after the start 
of manufacturing. Receipt of T cell product at the clinical site is required before the start of 
lymphodepleting chemotherapy.  
4.2.3.
Lymphodepletion
Lymphodepletion prior to adoptive cell therapy may enhance immune reconstitution by the 
transferred cells and increase tumor specific responses.  Immune reconstitution is enhanced 
Baccala, 2005
facilitate t
Pinthus, 2004
the activity of the adoptively transferred cells via the removal of inhibitory factors such as 
Wolf, 2003
inflammatory cytokines and induction of tumor apoptosis with resulting cross presentation of 
tumor antigens to T cells.
Evidence suggests that preparation for successful engraftment and expansion of gene modified 
adoptive cellular therapy depends not just on the depth of cytoreduction but additionally on the 
specific action of some cytotoxic drugs.  Recent studies in lymphoma, chronic leukemia and 
acute leukemia using adoptive cellular therapy including a CAR showed increased T cell 
expansion, persistence and disease-free survival when fludarabine was added in a previously 
cyclophosphamide-
Turtle, 2015
Cyclophosphamide was 
administered at 30 – 60 mg/kg x 1 day and fludarabine at 25 mg/m2/day x 3 – 5 days.  Effective 
lymphodepletion has also been demonstrated in other CAR-T cell studies using reduced 
cyclophosphamide dosing, together with fludarabine Batlevi, 2016 .  
Data from an open label non-randomized multi-cohort pilot study of genetically engineered 
NY-ESO-1 SPEAR™ T cells in HLA-A2+ patients with synovial sarcoma (NCT01343043)
suggests that fludarabine is an important component of T-cell lymphodepleting regimens and 
fludarabine 30 mg/m2 given daily for 4 days in combination with cyclophosphamide may be 
associated with more objective responses D’Angelo, 2018
(see Section 2.2.3). The CD19 
CAR-T product tisagenlecleucel also utilizes fludarabine 30 mg/m2 for 4 days in combination 
with cyclophosphamide.

            
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The lymphodepleting regimen in this study consists of intravenous fludarabine 30 mg/m2/day for 
4 days (Day -7 to Day -4) and cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5). 
4.2.4.
Long Term Follow-up
Subjects exposed to gene therapies may be at risk for delayed adverse events when there is 
persistent biological activity. Contributing factors for delayed adverse events include persistence 
of viral vector, integration of genetic material into host genome, prolonged expression of 
transgene and alterations in the expression of host genes. The long term follow up (LTFU) 
evaluation in the study is designed to adhere to the FDA and EMA guidance for long term 
FDA, 2006a; FDA, 2006b; FDA, 2010;
EMA, 2009
-mediated 
gene transfer in this clinical study for 15 years.  Further information on safety monitoring for 
theoretical risks associated with the use of lentiviral vectors and potential for insertional 
oncogenesis, as well as safety monitoring are available in Section 10.7, Appendix 7.  
4.3.
Justification for Dose
The cell dose of ADP-A2M4 is within the range of 1 × 109 to 10 × 109 transduced cells, 
administered by a single intravenous infusion. If the transduced cell dose is less than the 
minimum dose, manufacturing of additional transduced T cells from excess banked 
leukapheresis product or an additional leukapheresis collection may be undertaken to achieve a 
total dose in the target range.  Doses below the minimum transduced cell dose of 1 x 109 will not 
be administered.
The safety and tolerability of ADP-A2M4 is being assessed in a Phase 1 trial of multiple tumor 
types including synovial sarcoma and MRCLS (NCT03132922). Doses up to 9.96 x 109 have 
been well tolerated in this Phase 1 dose escalation study and was associated with a high ORR in 
16 advanced (inoperable)/metastatic synovial sarcoma subjects CTOS 2020 .
4.4.
End of Study Definition
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason.

            
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5.
STUDY POPULATION
5.1.
HLA and Antigen Pre-screening 
To be eligible for Pre-screening (Visit 1) subjects must be aged 16 and <75 years with a 
diagnosis of advanced (metastatic or inoperable) synovial sarcoma (Cohort 1 or Cohort 2) or 
myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by either 
histology or cytogenetics. Confirmation of diagnosis by cytogenetics is required prior to 
leukapheresis. 
Subjects identified by the Investigator as possible candidates for the study must complete
preliminary screening to determine HLA and tumor antigen status. Only subjects with an 
appropriate HLA-A genotype and whose tumor expresses the MAGE-A4 antigen above the cut-
off according to the applied IHC are eligible to undergo Screening (Visit 2) for this study. 
5.2.
Inclusion Criteria
A subject must meet all of the following criteria prior to leukapheresis (i.e. at Screening (Visit 
2)) AND prior to lymphodepleting chemotherapy (i.e. at Baseline) to be eligible to participate in 
this study.
1. Subject (or legally authorized representative) voluntarily agrees to participate by giving 
written informed consent (and Assent as applicable) in accordance with ICH GCP 
guidelines and applicable local regulations.
2. Subject (or legally authorized representative) agrees to abide by all protocol required 
procedures including study related assessments, and management by the treating 
institution for the duration of the study including long term follow-up.
3. Age 16 and <75 years at the time the Pre-screening Informed Consent/Assent is signed.
4. Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or myxoid 
liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by cytogenetics.
Inoperable refers to a tumor lesion in which clear surgical excision margins cannot be 
obtained without leading to significant functional compromise.
a.
For Synovial Sarcoma (Cohort 1 and Cohort 2): confirmation by the presence of a 
translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on 
chromosome 18 (may be presented in the pathology report as t (X; 18)).
b. For MRCLS (Cohort 1 only): confirmation by the presence of the reciprocal 
chromosomal translocation t(12;16)(q13;p11) or t(12; 22) (q13;q12).
5. Must have previously received either an anthracycline or ifosfamide containing regimen. 
1st-line metastatic treatment with ADP-A2M4 is permissible if ifosamide +/- doxorubicin 
has been administered in either the pre-operative (neoadjuvant) or post-operative 
(adjuvant) primary tumour setting.(Subjects who are intolerant of both anthracycline and 
ifosfamide must have previously received at least one other type of systemic therapy).
6. Measurable disease according to RECIST v1.1.

            
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7. Positive for HLA-A*02:01, HLA-A*02:03 or HLA-A*02:06 allele via Adaptimmune 
designated central laboratory testing. HLA-A*02 alleles having the same protein 
sequence as these alleles in the peptide binding domains (P group) will also be included. 
Other HLA-A*02 alleles may be eligible after adjudication with the sponsor. 
8. Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 expression of 
  All samples must have 
been pathologically reviewed by an Adaptimmune designated central laboratory 
confirming expression.  
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
10. Left ventricular ejection fraction (LVEF)
50%. 
11. Fit for leukapheresis and adequate venous access can be established for the cell 
collection.
12. Female subjects of childbearing potential (FCBP) must have a negative urine or serum 
pregnancy test AND must agree to use an effective method of contraception starting at 
the first dose of chemotherapy and continuing for at least 12 months, or 4 months after 
the gene modified cells are no longer detected in the blood, whichever is longer. 
OR
Male subjects must be surgically sterile or agree to use a double barrier contraception 
method or abstain from heterosexual activity with a FCBP starting at the first dose of 
chemotherapy and continuing for 4 months thereafter (or longer if indicated in the 
country specific monograph/label for cyclophosphamide).
13. Must have adequate organ function as indicated by the laboratory values in the table 
below:
System
Laboratory Value
Hematological
Absolute Neutrophil count (ANC)
.5 x109/L (without G-CSF 
support) within 7 days prior to 
lymphodepletion and leukapheresis
    Platelets
100 x109/L (without transfusion 
support within 7 days prior to 
leukapheresis and lymphodepletion)
    Hemoglobin
within 7 days prior to leukapheresis
and lymphodepletion)

            
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Coagulation
    Prothrombin Time or INR
unless receiving therapeutic 
anticoagulation.
Subjects receiving warfarin anti-
coagulation at baseline should be 
converted to either a low molecular 
weight heparin injection or a novel 
oral anticoagulant (NOAC). 
Reintroduction of warfarin after 
lymphodepleting 
chemotherapy/ADP-A2M4 dosing to 
attain the therapeutic INR range 
which was initially clinically 
indicated should only start when the 
platelet count is < Grade 2 CTCAE.
    Partial Thromboplastin Time (PTT)
unless receiving therapeutic 
anticoagulation.
Renal
    Glomerular filtration rate 
(calculated CrCl using only the Cockcroft-
Gault equation, or measured using either a 24-
hr urine creatnine collection or a radionuclide 
EDTA test) 1
60 mL/min
Hepatic
    Serum total bilirubin
documented Gilbert’s Syndrome with 
direct bilirubin <35% of total 
bilirubin)
Alanine aminotransferase (ALT)/Serum          
Glutamic Pyruvic Transaminase (SGPT)
1  24-hour urine creatine clearance or radionuclide EDTA tests should be used to 
measure the GFR in all subjects: 
65 years old; clinically obese ( 30KG/m2) or 

            
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underweight ( 18.5KG/m2); borderline low calculated CrCl (Cockcroft-Gault) at 
approximately 60mls/min. (see Section 8.4.10 for further details).
Renal function will be reassessed at baseline using the same methodology.
5.3.
Exclusion Criteria
A subject meeting any of the following criteria is not eligible for participation in the study:
1. Positive for HLA-A*02:05 in either allele via Adaptimmune designated central 
laboratory testing. HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 
in the peptide binding domains (P groups) will also be excluded. Other alleles may be 
exclusionary after adjudication with the sponsor.
2. Received or plans to receive the following therapy/treatment prior to leukapheresis or 
lymphodepleting chemotherapy: 
Treatment/Therapy
Required Wash-out Prior to 
Leukapheresis
Required Wash-out Prior to 
Lymphodepletion 
Cytotoxic chemotherapy
3 weeks
3 weeks
Tyrosine kinase inhibitor (TKI)  
(e.g. pazopanib)
1 week 
1 week 
Immune therapy (including 
monoclonal antibody 
therapy, checkpoint 
inhibitors,)
4 weeks
4 weeks
Anti-cancer Vaccine
8 weeks in the absence of 
tumor response. The subject 
should be excluded if their 
disease is responding to an 
experimental vaccine given 
within 6 months
8 week in the absence of 
tumor response.
The subject should be 
excluded if their disease is 
responding to an 
experimental vaccine given 
within 6 months
Gene therapy using an 
integrating vector
Subjects who have received a 
gene therapy using any DNA-
integrating vector other than 
a lentivirus (retrovirus, AAV, 
etc.) are excluded from this 
study. Subjects who have 
received a gene therapy 
using a lentiviral vector may 
Not permitted after 
leukapheresis and prior to 
lymphodepletion.

            
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Treatment/Therapy
Required Wash-out Prior to 
Leukapheresis
Required Wash-out Prior to 
Lymphodepletion 
be eligible if they have 
persistence results below the 
lower limit of quantification 
(LLOQ) for at least 2 samples 
taken at least 1 month apart. 
At least 1 of these tests must 
be performed by 
Adaptimmune as part of Pre-
screening or Screening.
Corticosteroids or any other 
immunosuppressive therapy. 
NOTE:  Use of topical steroids 
is not an exclusion. See 
Section 6.5.1 for exceptions. 
2 weeks 
2 weeks 
Investigational treatment or 
interventional clinical trial
4 weeks 
4 weeks
Allogeneic hematopoietic 
stem cell transplant
Not permitted within any 
amount of time
Not permitted within any 
amount of time
Radiotherapy to the target 
lesions
N/A
3 months.  A lesion with 
unequivocal progression may 
be considered a target lesion 
regardless of time from last 
radiotherapy dose.  (Note: 
there is no washout period 
for palliative radiation to 
non-target organs).
Major surgery
N/A
4 weeks. A subject must be 
fully recovered from any 
surgical related toxicities. 
NOTE: Duration of any other anti-cancer therapies must be discussed with the Sponsor Study 
Physician

            
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3. Toxicity from previous anti-
enrollment (except for non-clinically significant toxicities, e.g., alopecia, vitiligo).  
Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral 
neuropathy) can be enrolled. 
4. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to fludarabine, cyclophosphamide or other agents used in the study.
5. History of autoimmune or immune mediated disease. Subjects with hypothyroidism, 
diabetes, adrenal insufficiency or pituitary insufficiency that are stable on replacement 
therapy are eligible. Subjects with disorders such as asthma, psoriasis or atopic dermatitis 
that are well controlled without requiring systemic immunosuppression are also eligible. 
6. Symptomatic CNS metastases including leptomenigeal disease. Subject with a prior 
history of symptomatic CNS metastasis including leptomenigeal disease must have 
received treatment (i.e., stereotactic radiosurgery (SRS), whole brain radiation (WBRT) 
and/or surgery) and be neurologically stable for at least 1 month, not requiring anti-
seizure medications and off of steroids for at least 14 days prior to leukapheresis and 
lymphodepletion. Anti-seizure prophylaxis is permitted.  Subjects who have 
asymptomatic CNS metastases without associated edema, shift, requirement for steroids 
or anti-seizure medications for the treatment of seizures are eligible.  
7. Any other prior malignancy that is not in complete remission. Resectable squamous or 
basal cell carcinoma of the skin is acceptable. Prior malignancies that have been 
surgically resected and show no evidence of disease are acceptable. 
8. Uncontrolled intercurrent illness including, but not limited to:
Ongoing or active infection; 
Clinically significant cardiac disease defined by congestive heart failure New 
York Heart Association (NYHA) Class 3 or Class 4;
Uncontrolled clinically significant arrhythmia;
Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months;
Interstitial lung disease (subjects with existing pneumonitis as a result of radiation 
are not excluded, however, subjects must not be oxygen dependent);
Congenital or family history of long QT syndrome;
Current uncontrolled hypertension despite optimal medical therapy;
History of stroke or central nervous system bleeding; transient ischemic attack 
(TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months; 
Incipient compression/occlusion of a vital structure (e.g. bronchus; superior vena 
cava; renal outflow tract) which cannot undergo prophylactic stenting;

            
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COVID-19 infection or a positive COVID-19 RT-PCR test within 28 days of 
leukapheresis or lymphodepleting chemotherapy. If a subject has a positive 
COVID-19 test, then 2 subsequent negative tests are required, taken at least 7 
days apart.
9. Active infection with HIV, HBV, HCV or HTLV as defined below:
Positive serology for HIV;
Active hepatitis B infection as demonstrated by test for hepatitis B surface 
antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis B 
core antibody positive must have undetectable hepatitis B DNA and receive 
prophylaxis against viral reactivation.  Prophylaxis should be initiated prior to 
lymphodepleting therapy and continued for 6 months;
Active hepatitis C infection as demonstrated by hepatitis C RNA test.  Subjects 
who are HCV antibody positive will be screened for HCV RNA by any RT PCR 
or bDNA assay. If HCV antibody is positive, eligibility will be determined based 
on a negative screening RNA value;
Positive serology for HTLV 1 or 2;
Re-screening for infectious disease markers is not required at baseline (prior to 
lymphodepletion) unless > 6 months has elapsed.
10. Pregnant or breastfeeding.
11. In the opinion of the Investigator, the subject is unlikely to fully comply with protocol 
requirements.
5.4.
Screen Failures
Data on subjects who fail pre-screening or screening, including demographics and disease 
history, will be collected in the electronic case report form (eCRF) to support Companion 
Diagnostic development and validation.
5.5.
Number of Subjects and Study Duration
Forty-five (45) subjects (90 total subjects) are planned to be dosed separately in both Cohort 1
(synovial sarcoma and MRCLS) and Cohort 2 (synovial sarcoma only). In combination, data 
from Cohort 1 and Cohort 2 will provide a better, more comprehensive, characterization of the 
benefit-risk profile in soft-tissue sarcoma patients (especially in synovial sarcoma) than from 
Cohort 1 alone. 
Enrollment into Cohort 1 is expected to continue for approximately 12 months and is close to 
completion at the time of this amendment. Cohort 2 will begin when dosing in Cohort 1 is 
completed. Cohort 2 will dose 45 advanced (inoperable)/metastatic synovial sarcoma subjects
only and enrollment is expected to continue for approximately 12 months. The Primary Clinical 
Analysis will be for Cohort 1 only (i.e. synovial sarcoma plus MRCLS).  Clinical cut-off for the 

            
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primary analysis will occur once the last subject dosed in Cohort 1 has up to 6 months follow-up 
post T cell infusion, or has ended the interventional phase of the study.  At this time, all safety 
and secondary efficacy endpoints from Cohort 1 only will also be summarized to provide 
supportive evidence to the primary assessment.  
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason.
5.6.
Sites
The study will be conducted in approximately 24 sites in North America and Europe. The 
number of centers is necessary to ensure recruitment in this rare patient population.  Additional 
sites may be added at the discretion of the Sponsor.

            
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6.
STUDY INTERVENTION
6.1.
Leukapheresis
Subjects who complete screening procedures defined in Section 5.1 and who meet all eligibility 
criteria defined in Section 5.2 and Section 5.3 will be eligible to undergo leukapheresis to obtain 
starting material for the manufacture of autologous ADP-A2M4.
Refer to the Apheresis and T Cell Product Manual for scheduling of apheresis.
A non-mobilized peripheral blood mononuclear cell (PBMC) collection should be performed by 
an apheresis unit at the enrolling institution according to the institution’s or hospital’s policies 
and procedures. Leukapheresis may be performed at a qualified third-party institution (as may be 
mutually agreed and approved in advance by both Sponsor and the clinical site), as long as the 
policies and procedures in place meet or exceed the primary institution’s policies and procedures. 
Bilateral peripheral venous access should be used whenever possible but a temporary central 
venous catheter (CVC) may be placed for collection if peripheral venous access is inadequate.  
Standard clinical procedures for apheresis should be followed. 
A large volume leukapheresis should be performed.  For subjects who are >50 kg, 10 to 15 liters 
-3 blood-volumes should be processed 
per procedure with a goal of the procedure being collection of 1.0 x 108 PBMC/kg, and a 
minimum of 1.5x107 PBMC/kg. In cases where the minimum number of PBMC is not collected 
or the T cells cannot be administered (e.g. release criteria not met), a second apheresis may be 
performed. Citrate anticoagulant should be used.  Prophylactic intravenous calcium chloride and 
magnesium sulfate infusions should be administered at the discretion of the apheresis physician.
The collected leukapheresis product should be labelled and transported for manufacture as 
detailed in the Apheresis and T Cell Product Manual.
Any remaining subject apheresis material that is not required for further manufacture, may be 
used by the sponsor for research to modify or improve the manufacturing process and to enhance 
the clinical response.
6.2.
Lymphodepleting Chemotherapy
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria will be 
reconfirmed and a Baseline tumor biopsy obtained. 
Once the manufactured ADP-A2M4 cell product has been received at the clinical site and the 
integrity of the bag(s) has been verified by the site, eligible subjects will proceed to have 
lymphodepleting chemotherapy with fludarabine and cyclophosphamide as described in Table 3.
The lymphodepleting chemotherapy may be given as an outpatient treatment or subjects may be 
hospitalized at the discretion of the Investigator. 
On admission for lymphodepleting chemotherapy, commence anti-microbial prophylaxis (see 
Section 10.5.3.7) in line with institutional guidelines.

            
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Appropriate intravenous (IV) hydration should be administered and Mesna should be given to 
prevent urotoxicity while cyclophosphamide is administered, as described below. Other 
premedication (e.g. anti-emetics) may also be provided in accordance with institutional 
standards. Steroids may be used as anti-emetics for cyclophosphamide but must be discontinued 
no later than Day -3. Based on real-world use of Granulocyte-colony stimulating factor (G-CSF)
prophylaxis in Cohort 1 at the study sites, especially those with extensive CD19 CAR-T cell 
therapy expertise, G-CSF prophylaxis in Cohort 2 synovial sarcoma subjects can be given at the 
clinical discretion of the Investigator (as per local instituitional policy) starting on Day -3 until 
resolution of neutropenia in accordance with American Society of Clinical Oncology (ASCO)
guidelines or institutional practice (see Section 6.2.3).
Table 3:
Fludarabine and Cyclophosphamide Treatment Schema
Lymphodepleting Chemotherapy
Day
Drug
Dose
Route
Administration
-7
Fludarabine1
30 mg/m2
IV
in 50-
2
Cyclophosphamide
600 mg/m2
IV
in 200-
3
-6
Fludarabine1
30 mg/m2
IV
in 50-
2
Cyclophosphamide
600 mg/m2
IV
in 200-
3
-5
Fludarabine1
30 mg/m2
IV
in 50-
2
Cyclophosphamide
600 mg/m2
IV
in 200-
2
-4
Fludarabine1
30 mg/m2
IV
in 50-
2
-3
Start G-CSF4
-2
-1
1
ADP-A2M4 infusion3 
1 Fludarabine dose will be adjusted for renal impairment as described in Section 6.2.1
2 Concentration of 1mg/ml or less
3 Administration of ADP-A2M4 infusion is described in Section 6.3.
4 Administration of G-CSF section 6.2.3

            
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6.2.1.
Fludarabine dose adjustment for renal impairment
Dose of fludarabine will be adjusted for subjects with renal dysfunction as follows:
Glomerular Filtration Rate (GFR)
Fludarabine dose
80 mL/min
30 mg/m2
60 – 79 mL/min
20 mg/m2
Renal function should be estimated using the Cockcroft-Gault Creatnine Clearance (CrCl) 
equation (no other renal function equations are permitted).  
A more sensitive evaluation of renal function using either a 24-hr urine creatinine collection or a 
EDTA radionuclide test should be performed in subjects at Screening and/or Baseline who are:
Underweight (i.e. BMI <  18.5 KG/m2)
Low borderline CockCroft-Gault calculated CrCl of approximately 60 ml/min.
6.2.2.
Mesna
Mesna should be administered according to institutional practice or as recommended below:
120 mg/m2 (20% cyclophosphamide dose) as an IV bolus pre infusion, 4 and 8 hours 
post infusion on each day of cyclophosphamide administration.
6.2.3.
G-CSF
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
is also common. It is recommended that G-CSF is given daily from Day -3 until resolution of 
neutropenia in accordance with ASCO guidelines or institutional standard practice. Long-acting 
(pegylated) G-CSF may be given instead of short acting G-CSF according to institutional 
standard practice.  If pegylated G-CSF is administered, give one dose on Day -3.
6.3.
Investigational Product 
6.3.1.
Premedication
Subjects will be premedicated with antihistamine and acetaminophen/paracetamol 30-60 minutes 
prior to the T-cell infusion according to institutional practice.  Steroids must not be administered
as premedication for T-cell infusion because they are lymphotoxic and inhibitory to the T-cell 
product.

            
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6.3.2.
T Cell Infusion
On Day 1, the subject will receive thawed ADP-A2M4 by intravenous infusion. The T cell 
infusion will be given as an inpatient procedure and subjects will remain hospitalized for 
observation for at least 24 hours post T cell infusion. 
Prior to infusion, two clinical personnel in the presence of the subject, will independently verify 
and confirm that the information on the infusion bag is correctly matched to the subject, as per 
the Apheresis and T-cell Product Manual.
The T-cell product must not be thawed until immediately prior to infusion. The T-cell product 
should be thawed at a set temperature of 37oC using a water bath or equivalent device.  Routinely 
the cells should be thawed for approximately 3-5 minutes.  Smaller volumes may take less time 
to thaw.  The infusion bags should be observed during the thaw process to ensure no frozen 
material or ice remains.
The infusion bag(s) may be placed into a secondary containment bag per institutional standard 
procedures.  The secondary containment bag should not be of a design where it will have to be 
cut open after use, so as to avoid sharp objects near the infusion bag.  A standard specimen bag
with a re-sealable zipper closure is recommended.
The cells can be thawed either at the subject’s bedside or in a centralized facility, according to 
institutional standard procedures. If the cells are transported from a central storage location to 
bedside for thawing, it is recommended to place the bag(s) on dry ice or in a cooler with frozen 
gel packs for transport.  If the cells are thawed at a central facility, the thawed cells should be 
transferred to bedside under 2-8oC conditions and must be transported by appropriately trained
staff, to preserve the chain of custody.
The infusion should begin within 10 minutes of completing thaw (per bag) and is recommended 
to complete infusion of each bag within 45 minutes of thawing each bag to minimize exposure of 
the cell product to cryoprotectant. If the cells are provided in multiple bags and thawed at the 
bedside, the second bag should not be thawed until half the first has been infused without 
reaction, if possible based on fill volume. Bags thawed in a central location may be thawed 
simultaneously with consideration given to transport time and the guidance to begin infusion 
within 10 minutes post-thaw. 
If after thawing the infusion bag is damaged or leaking, the Investigator and Sponsor should be 
notified and the cells should not be infused.
The T-cell product must not be washed or otherwise processed. It is recommended that the T-cell 
product is administered using a dual spike infusion set by gravity over 15-45 minutes in the 
absence of infusion reaction.  Cells should ideally be infused without a filter, however if a filter 
is required by Institutional practice the pore size must not be smaller than 170 µm. Infusion 
pumps must not be used. For administration of the cells, 100 - 250 ml of 0.9% sodium chloride 
should be connected to the second lumen of the infusion set, used to prime the line, and then the 
lumen closed. On completion of the infusion of a bag of T-cell product, the main line should be 
closed and approximately 50ml saline transferred into the cell bag, and then infused to minimize 
the loss of cells. This process should be repeated for each cell bag if multiple bags are provided. 

            
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On completion of the cell infusion the set should be flushed using additional saline from the 
attached bag. If Institutional practice requires a single spike infusion set (e.g. macro drip IV 
tubing) standard institutional guidelines for the infusion of autologous cell infusion should be 
followed. The line must be flushed with 0.9% sodium chloride once the infusion is complete. In 
the event of adverse reaction to the cell infusion the infusion rate should be reduced and the 
reaction managed according to institutional standard procedures. Steroid treatment should be 
avoided unless medically required.  
In the event a subject develops a febrile episode following the infusion, appropriate cultures and 
medical management should be initiated, with attention to the initiation of empirical antibiotic 
treatment in the case of febrile neutropenia (see Section10.5.3).
The day of T-cell infusion may be delayed in subjects with significant complications of 
chemotherapy if according to the Investigator it is in the best interest of the subject.  Cytopenias 
alone should not be a reason to delay T-cell infusion unless complications are present. Subjects 
who have undergone leukapheresis but do not receive the T-cell infusion will not be replaced.    
Subjects who undergo leukapheresis and do not receive T cells will be followed for safety events 
for 30 days post leukapheresis or until SAEs have resolved to Grade 1 or baseline, whichever is 
longer.
The timing of all assessments post-infusion will be calculated with reference to the T-cell 
infusion date.  Vital signs will be recorded prior to the infusion and at 5, 15 and 30 minutes and 
at 1, 1.5, 2 and 4 hours after the infusion has started.
Discharge from hospital post-T cell infusion will be at the discretion of the Investigator. All 
subjects must be reviewed by the investigator (or a designated study physician) prior to 
discharge. 
6.4.
Preparation/Handling/Storage/Accountability
6.4.1.
Packaging and Labelling
Selected, qualified manufacturing sites will manufacture, package and label cell product for each 
individual subject in accordance with applicable regulatory requirements.
Refer to the Apheresis and T cell Product Manual for details of T cell product labelling.
6.4.2.
Receipt and Return
Investigational product must be received by a designated person at the site, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and designated 
site personnel have access.  Investigational product is to be dispensed only in accordance with 
the protocol.  The Investigator is responsible for keeping accurate records of the investigational 
product received from the Sponsor, the amount dispensed and any unused investigational product 
remaining at the conclusion of the study.  Contact the Sponsor or designee regarding any 
questions concerning the investigational product.

            
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Sites should contact the Sponsor or designee for specific instructions for investigational product 
returns or destruction.
6.4.3.
Storage and Handling
Manufactured T-cell product should arrive on-
-130°C in the 
vapor phase of a liquid nitrogen or a mechanical freezer until the date of infusion. Please refer to 
the Apheresis and T cell Product Manual for additional information.
6.4.4.
Investigational Product Accountability/Traceability
The investigational product provided for this study is for use only as directed in the protocol. The 
Investigator/Institution must have an established system for subject and product accountability at 
the site. The system should contain sufficient detail to allow linking of each product delivered to 
the investigator to the subject receiving it and vice versa. The investigator must ensure: 
Deliveries of Investigational Product are correctly received by a responsible person
Such deliveries are recorded
Investigational product is handled and stored safely and properly as instructed in the 
Apheresis and T cell Product Manual
Investigational product is only administered to study subjects in accordance with the 
protocol
Investigational product administration is documented. Records must include the 
identification of the person to whom the investigational product was administered, 
date of infusion, start and stop time of infusion and the amount infused.  This record 
is in addition to any investigational product accountability information recorded on 
the eCRF.
Any unused product is accounted for in the sites records before returning to the 
Sponsor (or designee)
At the end of the study, it must be possible to reconcile investigational product delivered with 
records of usage and return/destruction.  Any discrepancies must be accounted for on the 
appropriate forms.
Refer to the Apheresis and T cell Product Manual for additional information.
6.4.5.
Alert Cards
All subjects who receive investigational product in the trial will be provided with an alert card, 
which has been previously agreed by the sponsor and approved by the institutional review 
board (IRB)/ independent ethics committee (IEC). Alert cards will contain at a minimum the 
name of the subject, the investigator contact number and information regarding the 
investigational product received.

            
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6.5.
Concomitant Medications
6.5.1.
Prohibited Concomitant Medications
The following treatments are prohibited post T cell infusion (i.e. prior to disease progression):  
non-protocol chemotherapy, immune therapy, biological therapy (including targeted therapies 
with tyrosine kinase inhibitors or monoclonal antibodies), or investigational anti-cancer therapy. 
Subjects should also not undergo other anticancer locoregional therapies such as non-palliative 
radiation.  
Subjects who undergo any active anticancer therapy, with the exception of surgical resection 
prior to disease progression, will be considered as having met the progressive disease (PD) 
criterion for efficacy and will follow the LTFU schedule.
It is preferred that subjects do not undergo surgical resection of tumor lesions during the study 
prior to disease progression, as it interferes with the assessment of the efficacy of ADP-A2M4.
However, a subject whose tumor becomes resectable and who undergoes surgical resection prior 
to disease progression, will continue to be followed for safety and efficacy (progression of 
remaining lesions, new lesions) in the interventional phase of the study until disease progression
is determined. Upon progression, the subject will follow the LTFU schedule. Subjects who have 
surgery for new lesions consistent with progressive disease or to control progressive disease in 
previously identified lesions will discontinue the interventional phase and follow the LTFU 
schedule.
See Section 5.3 for details of washout and excluded treatments prior to leukapheresis or 
lymphodepleting therapy.
The use of systemic steroids may abrogate the effects of the T-cell therapy and therefore use is 
discouraged unless required to manage CRS (see Section 10.5.6 for CRS treatment 
recommendations) or other significant immune-mediated adverse events.  According to local 
standard of care or ASCO guidelines, steroids may be used as antiemetics before
cyclophosphamide but must be discontinued no later than 3 days prior to infusion of the IP (Day 
-3).  Steroid use is permitted for prophylaxis or treatment of contrast dye allergies.   
Physiological doses of steroids, including stress doses when clinically appropriate, may be 
administered as replacement therapy in subjects with adrenal insufficiency.  Fludrocortisone is 
permitted.  In general, daily prednisone doses of 0.5 mg/kg or lower, or their equivalent for other 
corticosteroid agents are acceptable, as physiologic replacement.  Topical steroids for cutaneous 
application and inhaled steroidal treatments are permitted.
6.5.2.
Permitted Concomitant Medications
Palliative radiation for pain relief to non-measurable lesions or non-target lesions present at 
baseline is permitted during the study.  However, lesion sites requiring radiotherapy after the T-
cell infusion, should be evaluated as to whether this indicates disease progression and record the 
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Other treatment the Investigator considers necessary for a subject’s welfare may be administered 
during the interventional phase of the study at the discretion of the Investigator in keeping with 
community standards of medical care and in adherence to the protocol.  
All concomitant medications will be recorded with dose and frequency, including all prescription 
or over-the-counter (OTC) medications and herbal remedies.  The following will be recorded on 
the appropriate eCRF pages:
All prescription and nonprescription medication, vitamins, herbal and nutritional 
supplements taken by the subject during the 30 days prior to screening (Visit 2) will 
be recorded at the screening visit.
All prior anti-cancer treatments taken by the subject must be recorded regardless of 
time frame taken
All concomitant medications taken while subjects are in the interventional phase
6.5.2.1.
Vaccinations Including for COVID-19
Before immunizing a subject at high risk for vaccine-preventable disease including for SARS-
CoV-2 (COVID-19), consult an Infectious Disease specialist or a guidance, such as the CDC 
Clinical Practice Guideline for Vaccination of the Immunocompromised Host.
The latest COVID-19 vaccination guidelines from NCCN/EBMT/ASTCT should be consulted 
by the Investigator. Any individual subject queries which cannot be addressed by the latest 
expert society guidelines relating to the timing of COVID-19 vaccination prior to either 
apheresis or lymphodepleting chemotherapy, or post ADP-A2M4 cell infusion, should be 
discussed with the Medical Monitor.

            
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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL
7.1.
Temporary Study Suspension
Throughout the conduct of the study, safety data will be reviewed on an ongoing basis by a Data 
Safety Monitoring Board (DSMB) see Section 10.2.1. If the following events occur, further 
enrollment to the study will be suspended and the regulatory authorities informed:
A subject has a positive RCL:
Confirmed positive peripheral blood mononuclear cell (PBMC) replication 
competent lentivirus (RCL) and no other vector lot is available for use in 
transduction for subsequent subjects (refer to Section 10.7.2 and Figure 1 on 
monitoring and management of RCL)
Confirmed biological RCL - all ADP-A2M4 cell infusions are halted (see 
Section 10.7.2 and Figure 1)
Regulatory authorities will be notified of any decisions to halt the study or subject enrollment. 
The study will not enroll further subjects until the regulatory authorities have reviewed the data 
leading to such a decision and agree with a proposal to resume enrollment.
7.2.
Ending the Interventional Phase
Reasons that a subject could end the interventional phase of the study are:
Disease progression per RECIST v1.1
Clinical progression 
Died
Unable/unwilling to comply with study requirements
Withdrawal of consent 
Investigator decision
Adverse Event
Lost to follow-up
Pregnancy (see Section 10.6.2.1)
Termination of enrollment by the Sponsor 
All subjects ending the interventional phase, with the exception of those who withdraw consent, 
die, are unable/unwilling to comply with study requirements, are lost to follow up or did not 
receive any T cells, will switch to the LTFU schedule Table 2, Section 1.3.2 to continue 
observation for delayed adverse events as described in Section 8.5.8. 

            
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7.3.
Subject Discontinuation
A subject will be considered to have completed the study when he/she has died or been followed 
for 15 years from time of T cell infusion. A subject may withdraw from the study at any time for 
any reason without prejudice to their future medical care by the physician or institution. However, 
the Investigator must make every reasonable effort to keep each subject on study for the whole 
duration of the trial. If a subject withdraws, all procedures and assessments listed in the withdrawal 
visit should be performed, unless performed within the previous 30 days.
Reasons for withdrawal of a subject from the study are:
Unable/Unwilling to comply with study requirements 
Adverse event
Withdrawal of consent
Investigator decision
Lost to follow-up (see Section 7.4)
Study termination by Sponsor
7.4.
Lost to Follow up
In cases where the subject is deemed ‘lost to follow-up’, the Investigator or designee must make 
every effort to regain contact with the subject; e.g., 3 documented attempts, one of which must 
be a certified letter to the subject’s last known mailing address or local equivalent methods.  
These contact attempts should be documented in the subject’s medical records.  Should the 
subject continue to be unreachable, only then will he/she be considered to have withdrawn from 
the study with the primary reason as ‘Lost to Follow-up’.

            
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8.
STUDY ASSESSMENTS AND PROCEDURES
8.1.
Background Assessments
8.1.1.
Demographics
Demographic data including year of birth, age, sex, race and ethnicity will be collected at Pre-
Screening.
8.1.2.
Disease History
The following information will be recorded in the eCRF: date of initial diagnosis, primary tumor 
type, anatomical site and size of primary tumor, histology, last known stage of disease and 
chromosomal translocations.  
8.2.
HLA MAGE-A4 Tumor Antigen Testing, and Cytogenetics
There is no window for obtaining HLA, MAGE-A4 antigen and cytogenetic testing prior to 
leukapheresis. 
8.2.1.
HLA
HLA-genotyping at the allelic level (4-digit) will be conducted on a blood sample by an 
accredited central laboratory contracted by the Sponsor using an FDA approved HLA 
Sequencing System for Sequence Based Typing (SBT) of Human Leukocyte Antigen (HLA). 
8.2.2.
MAGE-A4 Antigen
Once subjects are identified as having the appropriate HLA allele, an archival tumor sample, or 
fresh biopsy obtained as standard of care, may be submitted for determination of MAGE-A4 
expression, in which case, the biopsy from the most current setting is preferred provided that 
there is sufficient tissue. If an archival specimen is unavailable, the subject must undergo a new 
biopsy.  The subjects’ tumor will be tested for MAGE-A4 antigen expression by IHC using an 
analytically validated and CLIA-certified Clinical Trial Assay.  Testing will be completed at a 
central laboratory contracted by the Sponsor.
A secondary objective of the study is to collect tumor tissue samples for the development and 
validation of an IVD assay for the screening of tumor MAGE-A4 expression for regulatory 
approval. Tumor tissue will be collected, processed and submitted in accordance with the study 
Sample Collection Manual. The tumor tissue will be tested using the CLIA-validated MAGE-A4 
Clinical Trial Assay for study eligibility determination.  The tumor tissue will then be used for 
the analytical validation (which includes testing for efficiency, sensitivity, specificity, 
exclusivity, accuracy and precision), as well as the clinical validation of an IVD companion 
diagnostic assay.  Since the Clinical Trial Assay used in this study is not the candidate IVD 
companion diagnostic, a bridging study is required in order to demonstrate that the performance 
characteristics of the two tests are very similar.  The bridging study requires that all of the 
original clinical trial samples tested for eligibility using the Clinical Trial Assay are retested with 

            
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the candidate IVD, including samples from subjects excluded from the trial because they were 
marker-negative by the Clinical Trial Assay.
Details regarding the collection and processing of the screening biopsy, sample requirements, 
instructions for sample shipment to the central laboratory for MAGE-A4 IHC analysis, and 
details of subsequent tumor sample storage for companion diagnostic development are located in 
the Sample Collection Manual.
Details for the development and validation of an IVD assay for the screening of tumor antigen 
expression for regulatory approval is available in a separate protocol.
8.2.3.
Cytogenetics for Diagnosis
For Synovial Sarcoma (Cohort 1 and Cohort 2), a confirmation by the presence of a translocation 
between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be 
presented in the pathology report as t (X; 18)) is required prior to leukapheresis
For MRCLS (Cohort 1 only), a confirmation by the presence of the reciprocal chromosomal 
translocation t(12;16)(q13;p11) or t(12; 22) (q13;q12) is required prior to leukapheresis. 
Cytogenetic confirmation of diagnosis can be historic, done as standard of care, or be done any 
time after signing the Treatment ICF and does not need to be within the 28 day screening 
window.
8.3.
Efficacy Assessments
8.3.1.
CT/MRI 
Imaging scans of the chest, abdomen and pelvis should be performed at Screening, Baseline, 
Week 4, Week 8, Week 12, Week 16, and Week 24, and every 2 months +/- 28 days until 
confirmed disease progression. The Week 4 scan must occur on or after Day 29. Subsequent 
scans are to be completed within the visit window permitted in the Main T&E Table with the 
exception of confirmatory scans which should not be performed earlier than 4 weeks (on or after 
28 days) after the criteria for response was first met. As the primary endpoint of the study uses 
independent review, scheduled study scans from Week 4 through Week 16 should be at least 28 
days apart to ensure compliance with the RECIST v1.1 requirement for confirmation of 
response. 
Imaging scans should be performed at the time a subject withdraws from the study.
Lesion sites that have previously required radiotherapy should be recorded in the eCRF prior to 
lymphodepletion.
See Section 8.4.9 regarding brain MRI for safety assessment. 
Acceptable imaging modalities for this study include:
Diagnostic-quality CT scan with oral and/or IV iodinated contrast of the chest and 
abdomen/pelvis (CT is the preferred modality for tumor assessments)

            
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MRI of the abdomen/pelvis acquired before and after gadolinium contrast agent 
administration and a non-contrast enhanced CT of the chest, if contrast enhanced CT 
is contraindicated for a subject
MRI of the extremities if clinically indicated.
Digital photographs of skin lesions including a ruler for estimating the size of the 
lesion.
The same imaging modality and image-acquisition protocol (including the use of IV contrast) 
should be used consistently across all time points for individual subjects to allow uniform 
comparison of lesions. 
To allow time for the immune response to become apparent and for potential transient 
inflammatory reaction of the disease to the treatment (‘tumor inflammation’), disease 
progression will not be determined before 4 weeks post infusion of ADP-A2M4, unless there is 
unequivocal clinical evidence of deterioration.  Therefore, imaging scans should not be 
performed earlier than 4 weeks post infusion (on or after 28 days).  Responses should be 
confirmed by repeat imaging scan performed not earlier than 4 weeks (on or after 28 days) after 
the criteria for response was first met. The minimum duration for BoR = SD is 4 weeks (or 28 
days) post ADP-A2M4 infusion.
Investigators (in collaboration with a radiologist) will assess tumor response according to 
RECIST v1.1 for clinical decision making. Tumor measurements at site should be performed by 
the same Investigator or radiologist (to the extent that this is feasible). 
For the study primary endpoint, a central vendor will be responsible for independent assessment 
of tumor response according to RECIST v1.1.  Review and interpretation of image data will be 
conducted by an appropriately qualified, trained and experienced reviewer. A written Imaging 
Charter will be provided to sites to describe the imaging acquisition protocol and standardized 
procedure for the transfer of image data to the central vendor.  The Imaging Charter will also 
describe the procedures for CT/MRI data handling after the images have been received by the 
central vendor from the sites.
Investigator assessment of response will guide patient care throughout the study.
8.3.2.
Survival 
If a subject dies during the study date of death will be recorded in the eCRF. If a subject is 
unable to attend the site for visit e.g. due to deteriorating condition or a change of 
location/country, the subject may be followed remotely to obtain survival information. If a 
subject decides to withdraw from any further study assessments/procedures, the Investigator 
should ask if the subject is willing for survival data only to be collected, this discussion should 
be documented in the source notes.
If the subject cannot be contacted by the site, information available in public records e.g. 
obituaries may be used by the site to determine date of death if appropriate prior to withdrawing 
the subject from the study due to lost to follow up.

            
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8.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Main T&E table (Table 1) and 
the LTFU T&E Table (Table 2).
Additional tests may be done at any time if clinically indicated.
The Clinical Laboratory Test in Table 4 describe the assessments and parameters to be collected 
and recorded.
Screening visit (Visit 2) assessments should be completed within 28 days of leukapheresis unless 
otherwise specified.  Information regarding ECHO/MUGA scans, ECG and infectious disease 
assays performed as standard of care assessments within four weeks prior to Screening (prior to 
study consent) will be acceptable.
Baseline assessments must be conducted and results obtained within 2 weeks (14 days) prior to T 
cell infusion.
8.4.1.
Medical History
Relevant medical history will be recorded at Screening (Visit 2) in the subject’s eCRF.
8.4.2.
Physical Examination
Subjects will undergo a physical examination at Screening and Baseline. The frequency of 
physical examination at subsequent visits is specified in Table 1 and Table 2.
8.4.3.
Prior Anti-cancer Therapies
All anti-cancer therapies including, but not limited to, chemotherapy, antibodies, anti-cancer 
vaccines, cell therapies, radiation therapy, and surgical resections are to be recorded.  On-study 
cancer surgeries and bridging therapies are to be recorded.
8.4.4.
Prior and Concomitant Medications
Current medications and those for the previous 30 days are to be recorded on the concomitant 
medication page of the CRF at Screening (Visit 2).
For LTFU assessments, this section is limited to new chemotherapies or other anti-cancer 
therapies (including mutagenic agents and other investigational agents).
8.4.5.
ECOG
Performance status will be measured using the ECOG performance scale. See Section 
Section 10.9, Appendix 8 for guidance. It is recommended, where possible, that a subject’s 
ECOG be assessed by the same person throughout the study. The frequency of the ECOG 
assessment is specified in Table 1.

            
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8.4.6.
Vital Signs
Measurement of vital signs (temperature, pulse, respirations and blood pressure) will be made at
the frequency specified in Table 1. 
On the day of T cell infusion (Day 1) vital signs should be measured pre-infusion, and at 5, 15 
and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started.
8.4.7.
Weight and Height
Height will be assessed only once at Baseline. Weight will be measured according to the 
frequency specified in Table 1.
8.4.8.
Cardiac Assessments
Cardiac assessments will be performed locally at the site. 
8.4.8.1.
ECG
A single ECG is required. Heart rate, rhythm, PR, RR (if measured/recorded), QRS and QTc 
intervals will be recorded. QTcB or QTcF is acceptable as per institutional standards but must be 
consistent from visit to visit.
For Screening (Visit 2) ECGs performed as standard of care within 28 days prior the visit are 
acceptable. The ECG on Day 1 will taken before T cell infusion starts.
8.4.8.2.
Echo/MUGA
An ECHO or MUGA scan will be performed at screening to determine left ventricular ejection 
fraction (LVEF) for eligibility. ECHO/MUGA scans performed as standard of care within four 
weeks prior to Screening (Visit 2) are acceptable. Additional scans will only be performed if 
clinically indicated.  NOTE: the same method of evaluation must be used consistently for any 
follow-up scans.
8.4.8.3.
Telemetry
For subjects with known cardiac or pericardial tumor involvement at baseline, inpatient 
telemetry monitoring should be carried out for seven days post-ADP-A2M4 infusion.
8.4.9.
Brain MRI
A MRI of the brain with contrast will be obtained at Baseline, within 1 month of 
lymphodepletion, for all subjects. CT with IV contrast may be used only for subjects with 
contraindications to MRI of the brain. If brain metastases are documented at Baseline, then 
dedicated CT/MRI scans of brain metastases should be performed at every on-study tumor 
assessment, and included as non-target lesions in the tumor worksheet (see Section 8.3.1). If 
brain metastases are not documented at Baseline, then dedicated brain CT/MRI scans should be 
performed as clinically indicated.

            
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8.4.10.
Renal Function Assessment 
Renal function (estimated or measured glomerular filtration rate (GFR)) will be assessed at 
Screening using the Cockcroft-Gault CrCl equation. 24 hour urine collection to measure 
creatinine clearance or by nuclear medicine EDTA measurement should be performed in subjects 
2
2); iii). 
(Cockcroft-Gault).
Renal function will be reassessed at Baseline using the same methodology.
8.4.11.
Hematology
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
In years 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 8.4.22) then laboratory assessments may be 
discontinued.
8.4.12.
Clinical Chemistry 
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
In years 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 8.4.22) then laboratory assessments are 
discontinued.
8.4.13.
Coagulation
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
Subjects receiving warfarin anti-coagulation at baseline should be converted to either a low 
molecular weight heparin injection or a novel oral anticoagulant (NOAC). Reintroduction of 
warfarin after lymphodepleting chemotherapy/ADP-A2M4 dosing to attain the therapeutic INR 
range which was initially clinically indicated should only start when the platelet count is < Grade 
2 CTCAE.
8.4.14.
Thyroid Function Tests
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
8.4.15.
Hepatic Safety Assessments
For subjects who experience evidence of hepatic toxicity, increased hepatic monitoring criteria 
will apply to ensure subject safety and to enable evaluation of liver event etiology (see Appendix 
4, Section 10.4.5).
8.4.16.
Pregnancy Test
Either serum or urine pregnancy test may be performed. Female subjects of childbearing 
potential (FCBP) must have a negative pregnancy test at Screening and prior to starting 
lymphodepleting chemotherapy.

            
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8.4.17.
Infectious Disease Screening
Testing for infectious disease markers is required only at Screening and does not need to be 
repeated at Baseline to satisfy the inclusion / exclusion criteria, unless more than six months has 
elapsed from screening.
Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive 
must have undetectable hepatitis B DNA. Subjects who are HCV antibody positive will be 
screened for HCV RNA by any RT PCR or bDNA assay. Eligibility will be determined based on 
a negative Screening value.
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
8.4.18.
CMV PCR  
Subjects will be screened for cytomegalovirus (CMV) seropositivity at screening. If seropositive 
at screening, then CMV-PCR will be done at Baseline. If CMV viremia is detected at Baseline, 
treatment should be initiated prior to lymphodepletion chemotherapy. All CMV seropositive 
subjects will continue to be monitored for CMV viremia by CMV PCR at day 1, week 2, 4, 6, 
and 8. See Section 10.5.3.4 for CMV prophylaxis and blood product screening if positive.
8.4.19.
ICE Assessment Tool 
The ICE (Immune Effector Cell-Associated Encephalopathy) neurological assessment should be 
performed from Day 1 (prior to T cell infusion) through Day 8 whilst the subject is hospitalized
according to Table 1. The ICE assessment may be discontinued once a subject is discharged from 
hospital.
If a subject is thought to have ICANS, the ICE should be used at least twice per day until 
resolution or stable.  It can also be used at later visits if indicated. See Section 10.5.7, Table 7.
8.4.20.
C-reactive Protein 
If cytokine release syndrome is suspected, C-reactive protein levels should be measured 
approximately every other day until symptoms are improving or an alternative diagnosis is 
confirmed.  
8.4.21.
Ferritin 
If cytokine release syndrome is suspected, ferritin levels should be measured approximately 
every other day with C-reactive protein.
8.4.22.
Persistence (Vector Copies)
PBMC samples will be collected and used as the “surrogate sample” for monitoring persistence 
of gene modified cells in subjects. Persistence of transduced T cells is also a major biomarker 
related to clinical response. Therefore, additional PBMC samples will be collected over the first 
2 years following infusion (Section 8.6.5).
Samples are required for:

            
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Safety at Baseline and Week 24, Month 12 and then every 6 months through Year 5 and 
annually from Years 6-15.
o
If no gene modified cells are detected for three consecutive assessments and 
-infusion (for example, negative persistence assessments at 
year 4, 4.5 and 5), no further monitoring of PBMCs is required for persistence and 
collection of samples may be discontinued.
o
If at Month 12 or beyond post-infusion, greater than 1% PBMCs test positive for 
vector sequences, the subject’s PBMCs will be evaluated for integration site 
analysis (Appendix 6 Section 10.7.3).
Research at Day 2, Day 4, Day 8, Week, 2, Week 4, Week 8, Week 12 and subsequently 
every 2 months (±1 month) until disease progression. 
See Table 1 and Table 2.
Details on collection and shipment of blood sample for vector copies/persistence is described in 
the Sample Collection Manual.  
8.4.23.
RCL (VSV-G DNA)
RCL will be monitored using a PCR-based assay that detects and measures copies of the gene 
coding for the vector’s envelope protein, namely VSV-G that is necessary for the assembly of 
pseudotyped infectious lentiviral particles but absent from the vector’s backbone.
RCL testing will take place on subject’s peripheral blood mononuclear cells (PBMCs) which are
collected at Baseline and  post infusion at Week 12, Week 24, Month 12, and then annually for 
15 years. See Table 1 and Table 2 for scheduling.
If all samples are negative in year one, PBMC samples will be collected and archived annually 
until 15 years post-infusion.  Samples will be archived at Adaptimmune’s centralized 
biorepository.  
If a positive VSV-G DNA signal is obtained, the study investigator will be informed and the 
subject will be scheduled for a retest as soon as possible and no later than one month after the 
initial positive result was reported to the Sponsor. See Appendix 7 Section 10.7.2 for additional 
information.
Details on collection and shipment of blood sample for RCL is described in the Sample 
Collection Manual.
8.5.
Adverse Events and Serious Adverse Events
8.5.1.
Time period for collecting AE and SAE Information
AEs and SAEs will be collected as follows:

            
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During the Pre-screening period, only SAEs related to protocol-specified procedures 
will be collected from the time of the procedure (e.g., blood sampling, tumor biopsy) 
until 24 hours afterwards for blood sampling, or until 2 weeks post-biopsy.
From date of signing the Treatment ICF until the day before lymphodepletion starts, 
only SAEs related to study design/procedures (protocol mandated procedures, 
invasive tests, or change in existing therapy) or Aes leading to withdrawal from the 
study will be collected.
All AEs and SAEs will be collected from the start of lymphodepletion until the 
subject has discontinues the interventional phase of the study. In addition, emerging 
clinical conditions defined in Appendix 4, Section 10.4.6 will be monitored for 
starting Day 1. If the subject has not progressed after 12 months, only those emerging 
clinical conditions defined in Appendix 4, Section 10.4.6 will be collected thereafter.
During the long-term follow-up phase of the study, subjects will only be monitored 
for the emerging clinical conditions defined in Appendix 4, Section 10.4.6 and these 
will be recorded If a subject enters the LTFU phase prior to Week 12, they will have 
full AE collection at the Month 2 visit. 
All SAEs will be recorded on the SAE worksheet (SAEW) and reported to the sponsor or 
designee immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4.
SAE follow up information should be submitted on an updated SAEW within 24 hours if 
associated with a change in diagnosis and/or increased severity. Otherwise follow up should be 
submitted promptly within 7 days, and no later than 30 days of receiving new information.
8.5.2.
Method of Detecting Aes and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4, Section 10.4.
Care will be taken not to introduce bias when detecting Aes and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.5.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All Aes and SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). 
Further information on follow-up procedures is given in Appendix 4, Section 10.4.3.
8.5.4.
Regulatory Reporting Requirements for SAEs
Prompt (within 24 hours) notification by the investigator to the sponsor of a SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.

            
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The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.  These safety reports are forwarded to 
Investigators in the form of Investigator Safety Letters (ISL).
An investigator who receives an investigator safety letter describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and notify the IRB/IEC, 
if appropriate according to local requirements.
On request of a competent authority in whose territory the clinical trial is being 
conducted, the Sponsor will submit detailed records of all adverse events which are 
reported by the relevant Investigator(s).
8.5.5.
Pregnancy
Pregnancy (or pregnancy of a male subject’s partner) is not considered an AE/SAE 
unless there is reason to believe the pregnancy may be the result of failure of the 
contraceptive being used due to interaction with the investigational product.  Details 
of all pregnancies in female participants and female partners of male participants will 
be collected from the start of lymphodepletion for as long as there is evidence of T-
cell persistence, or until the subject has confirmed disease progression.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
6.  See Section 10.6.2 for guidance.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
The safety of ADP-A2M4 during pregnancy and lactation has not been established in humans.  
The target antigen is known to be expressed on fetal germ line tissues and placenta, therefore 
female subjects who are pregnant, intending to become pregnant, or breast feeding are excluded 
from ADP-A2M4 studies.
There is no preclinical or clinical trial data of ADP-A2M4 in pregnant women; however, there is 
a reasonable but unproven likelihood that this intervention may be significantly embryotoxic or 
even an abortifacient given the underlying biology of the target.  The effects on breast milk are 
unknown, therefore breastfeeding should be discontinued for the duration of the study, starting at 
the first dose of chemotherapy and for at least 12 months after receiving the investigational 
product, or four months after there is no evidence of persistence/gene modified cells in the 
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The contraception guidelines provided in Section 10.6.1 should continue to be adhered to during 
long-term follow up.
A woman who becomes and remains pregnant during the study will be discontinued from the-
interventional phase as exposure to radiation from imaging studies would be contraindicated.  
The subject would follow the LTFU T & E schedule Table 2. 
8.5.6.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Progression of underlying malignancy and related symptoms are not reported as an AE if they 
are clearly consistent with the suspected progression of the underlying cancer.  Clinical 
symptoms of progression may be reported as Aes if the symptoms cannot be determined as 
exclusively due to progression of the underlying malignancy, or do not fit the expected pattern of 
progression for the disease under study.
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE /SAE.
8.5.7.
AEs of Special Interest
8.5.7.1.
Cytokine Release Syndrome
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed 
following administration of antibodies and adoptive T-cell therapies for cancer.  It is defined 
clinically by symptoms which can mimic infection including pyrexia, nausea, diarrhea, 
headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea.  Subjects should be 
assessed clinically for CRS at all visits according to Table 1.  Most cases of CRS present within 
seven days following cell infusion. It is important to evaluate the subject for concurrent 
infections.  Potentially life-threatening complications of CRS include cardiac dysfunction, adult
respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure and disseminated 
intravascular coagulation.  CRS may also be associated with findings of macrophage activation 
syndrome or occur coincident with tumor lysis syndrome.
The diagnosis of CRS is clinical, and is supported by the exclusion of infection as well as the 
presence of increased cytokine levels and other biomarkers.  CRS should be graded and managed 
with supportive measures and anti-IL-6 according to the severity of symptoms, see Section 
10.5.6 for detailed guidance on grading and management of CRS.
8.5.7.2.
Neurotoxicity
Neurotoxicity has been described in association with immune effector cell therapy, and termed 
immune effector cell-associated neurotoxicity syndrome, or ICANS Lee, 2019 .  ICANS 
typically manifests as a toxic encephalopathy which is generally reversible.  Early signs include 
diminished attention, language disturbance and impaired handwriting.  Other signs/symptoms 
include confusion, disorientation, agitation, aphasia, somnolence, and tremors.  In severe cases of 

            
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ICANS (defined as grade >2), seizures, motor weakness, incontinence, mental obtundation, 
increased intracranial pressure, papilledema, and cerebral edema may also occur.
ICANS occurring within the first 5 days after immunotherapy may be concurrent with high fever 
and cytokine release syndrome (CRS) symptoms.  This form of ICANS tends to be of shorter 
duration, lower grade (Grade 1–2, see Table 8), and is generally reversible with anti-IL-6 
therapy.  ICANS presenting as delayed neurotoxicity with seizures or episodes of confusion can 
occur three or four weeks after CART cell therapy, after the initial fever and CRS subside  Lee,
2019 .
ICANS may occur with other cancer immunotherapies, including TCRs.  Cancer patients may 
also be at risk for encephalopathic symptoms due to other causes ranging from mild to moderate 
somnolence and confusion as a result of sedating medications, to seizures in relation to brain 
metastases.  The possible contribution of other medications, underlying disease and/or co-
morbidities should be evaluated when considering a diagnosis of ICANSin relation to T cell 
therapy.
8.5.7.2.1. Monitoring for ICANS
The ICE is a neurological assessment tool which is used to assess cognitive function to monitor 
for ICANS (see Section 10.5.7 for details). ICE should be measured on the day of ADP-A2M4
infusion prior to receiving treatment and through Day 8 whilst the subject is hospitalized. If the 
subject is discharged before Day 8 the ICE may be discontinued according to the T&E Table
(Section 1.3.1).  Subjects with known brain metastases should be monitored at least twice per 
day for the first 5 days following ADP-A2M4 infusion if hospitalized.  If a subject is found to 
have ICANS, the ICE should be used at every visit (at least twice per day if hospitalized) until 
resolution or stable.  It can also be used at later visits if indicated.  ICE also forms part of the 
grading system for ICANS developed by Lee, 2019 .
ICANS is graded and managed according to the severity of symptoms, see Section 10.5.7.1 for 
detailed guidance on management of ICANS.
8.5.8.
Long Term Follow Up Adverse Events
During the long term follow-up (LTFU) phase of the study, adverse event collection is limited to: 
new malignancies, new incidence or exacerbation of a pre-existing neurologic disorder, new 
incidence or exacerbation of a prior rheumatologic or other autoimmune disorder, new incidence 
of a hematologic disorder, opportunistic and or serious infections, or unanticipated illness and/or 
hospitalization deemed related to gene modified cell therapy. If a subject enters the LTFU phase 
prior to week 12, they will have full AE collection at the Month 2 visit. See Section 10.4.6 for 
reporting Aes during LTFU.
8.5.8.1.
LTFU Letters to Primary Care Physician/Oncologist
A letter should be sent by the investigator/study coordinator to the subject’s primary care 
physician, local oncologist, or other physician that will notify him or her of this research study 

            
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and will outline the features to look for and report as delayed adverse events potentially related 
to this study (Appendix 7, Section 10.7.4).
8.6.
Biomarkers for Exploratory Objectives
Sample types collected and rationale: Collection of samples for biomarker research is part of this 
study. The following samples for biomarker research are requested and will be collected from all 
participants in this study as specified in the T&E Table (Table 1):
Tissue
Tumor: Efficacy of immunotherapy of cancer is conditioned by the interplay 
between tumor cells and resident or infiltrating immune cells (effector T cells and 
immunosuppressive cells). Therefore, tumor biopsies will be collected to evaluate 
the evolution of both tumor and immune components pre and post-infusion.
Blood
Serum: Serum is collected to allow for measurement of cytokines in the blood in 
relation to T cell expansion, and CRS. Serum samples may also be used to detect
other soluble biomarkers such as anti-tumor antibodies. 
 
 
 
 
 
 
   
 
 
 
 
 
 

            
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8.6.1.
Tumor Biopsy
Baseline biopsy material should be collected within two months of the T cell infusion, with
preference for a biopsy to be taken closer to the time of infusion. Tumor tissue should either be
taken from non-target lesions or from target lesions where sampling can be done without 
impacting lesion measurement. 
As a guidance and if possible, a responding lesion should be biopsied at the Week 4 time point 
and a progressing lesion, or a new lesion should be biopsied at the progression time point. The 
apparent clinical or scan status of the lesion(s) biopsied should be noted at the time (e.g. 
decreased, stable, increased size).
The Week 4 time point tumor biopsy can be collected anytime between Week 3 and Week 8.
The progression time point tumor biopsy can be collected obtained post-progression (e.g. from 
an excisional surgery). 
Additional details regarding the tumor biopsy collection are provided in the Sample Collection
Manual.
8.6.2.
Cytokine and Soluble Protein Analysis
Serum is collected at Baseline, pre-infusion and 2-4 hours post infusion on Day 1 and on Day 2, 
Day 4, Day 8, Week 2, Week 4, Week 8, Week 12, Week 24 and every 2 months post infusion to 
allow for measurement of cytokines in the blood.  Serum is also collected from subjects with 
suspected CRS, samples being taken approximately every other day until symptoms are 
improving or an alternative diagnosis is confirmed.  
Details regarding serum collection are provided in the Sample Collection Manual.

            
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Serum samples may also be used to detect humoral immune responses to tumor antigens and
antibodies to ADP-A2M4.
8.6.3.
 
8.6.4.
8.6.5.
Persistence of ADP-A2M4 TCR+ Cells
The primary research assays for the trial involve monitoring for the persistence of infused
engineered cells in the subjects and for correlation of this with potential therapeutic effect.
Research samples will be taken as detailed in Section 8.4.22. Persistence is also monitored long 
term as a safety measure (Section 10.7.2). Along with the copies of gene-modified DNA per 
DNA, data
or relative to total lymphocyte number will 
be provided for persistence.
 

            
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8.7.
Patient-Reported Outcomes
8.7.1.
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L)
EQ-5D is a standardized measure of health status developed by the EuroQOL Group in order to 
EuroQOL, 1990
The EQ-5D is applicable to a wide range of health conditions and treatments, and provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care.  The EQ-5D-3L descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities pain/discomfort and anxiety/depression. Each 
dimension has 3 levels: no problems, some problems, extreme problems. The respondent is asked 
to indicate his/her health state by selecting the most appropriate statement in each of the 5 
dimensions. The EQ visual analogue scale (VAS) records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ and 
‘Worst imaginable health state’. This information can be used as a quantitative measure of health 
outcome as judged by the individual respondents.
The EQ-5D-3L will be administered at Baseline and post T cell infusion at Week 8, Week 16 , 
Week 24 and Month 12. Once disease progression is established, the EQ-5D-3L assessment is no 
longer required.
8.7.2.
EORTC-QLQ-C30
The EORTC QLQ-C30 is a questionnaire developed by the Quality of Life Group of the European 
Organisation for Research and Treatment of Cancer to assess the quality of life of cancer patients. 
The EORTC QLQ-C30 will only be used in synovial sarcoma subjects in Cohort 2 at Baseline and 
post T-cell infusion at Week 8, Week 16, Week 24 and Month 12. Once disease progression is 
established, the EORTC QLQ-C30 assessment will no longer be required.
The EORTC QLQ-C30 comprises 30 questions. Each of the first 27 questions has 4 levels: Not at 
All, A Little, Quite a Bit, and Very Much. The respondent is asked to indicate his/her health state 
by selecting the most appropriate statement. Questions 29 and 30 records the respondent’s self-
rated health on a horizontal scale where the endpoints are labelled ‘Very Poor’ and ‘Excellent’. 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents.

            
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9.
STATISTICAL CONSIDERATIONS
The objectives and endpoints for this study are described in Section 3, this section focusses on 
key aspects for the analysis and reporting of the primary and secondary efficacy and safety 
endpoints.  Details for the analysis of all clinical endpoints will be provided in the Statistical 
Analysis Plan (SAP).  The analysis plan for the objective related to the development of the 
validated Companion Diagnostic (CDx) will be described in a separate document.  Similarly, a
separate analysis plan will be developed for the exploratory biomarkers.
9.1.
Study Populations
Intent-to-Treat (ITT) population: This is the population of all subjects who were enrolled in the
trial (i.e. met eligibility criteria).  The ITT population will be used to assess the safety of the end-
to-end autologous T cell therapy procedure.
Modified Intent-to-Treat (mITT) population: This is the population of all ITT subjects who 
received T cell infusion. The mITT population is the primary analysis population for safety and 
efficacy evaluations following T cell infusion.
The primary analysis will be for Cohort 1 only occur at the time of clinical cut-off as described 
in Section 5.5.  
9.2.
Statistical Hypotheses and Sample Size Assumptions
The primary objective for this study is to evaluate the efficacy of autologous genetically 
modified T cells (ADP-A2M4) in Cohort 1.
The primary endpoint for efficacy is Overall Response Rate (ORR) in Cohort 1, defined as the 
proportion of subjects with a confirmed CR or PR relative to the total number of subjects in the 
analysis population.  
The ORR will be based on confirmed (tumor) responses per RECIST v1.1 by independent 
review. 
Subjects with unknown or missing response will be treated as non-responders (i.e. they will be 
included in the denominator when calculating the proportion).  
The clinical and statistical assumptions, the hypothesis test, and sample size for the proposed 
single arm open label clinical trial are based on the following factors:
Section 4.2)
The ORR for historical control that will be used for hypothesis testing in this study will 
be 18%.
The mechanism of action for the TCR is assumed to be the same for synovial sarcoma 
and MRCLS.  
Section 2.2.3 states that in subjects with synovial sarcoma, the observed ORR (confirmed 
responses) for ADP-A2M4 cell therapy was 40.0% at the time of data cut off. Therefore, 

            
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for purposes of sample size computation, we assumed ORR for ADP-A2M4 cell therapy 
would be 40%.
No formal hypothesis testing is planned for Cohort 2 or across cohorts (overall).
The hypothesis of interest for the primary endpoint is;
(Null Hypothesis) H0: 
p0 , vs. (Alternate Hypothesis) H1: p > p0, where p0 (historical control 
rate) = 0.18. 
Based on above assumptions, the TCR ORR (i.e., p1) is set at 0.4.  The type I error
test will be no more than 0.025 and the type II er
. Exact Binomial 
methods will be used to test the hypothesis. 
Statistical Design Assumptions:
The assessment for efficacy will be based on the mITT population using confirmed ORR 
via RECIST v1.1 per independent review in Cohort 1;
Exact Binomial method will be used to test the hypothesis;
Cohorts 1 and 2 are independent.
Based on the statistical design assumptions above and the hypotheses and clinical assumptions in
Section 4.2, the estimated sample size for the trial is 45 subjects in Cohort 1)
The ORR for Synovial Sarcoma ranges between 4% – 13% in clinical trials (Section 2.2.3).  If 
we assume that the ORR of the ADP-A2M4 will be 40% (P1), and historical ORR (P0) is 13%, a 
sample size of N=27 provides 90% power to detect an absolute difference of 27% using exact 
binomial assumptions.  
To account for the potential variability in historical control efficacy, a more conservative 
historical ORR of 18% may also be considered.  Using a one-sided alpha=0.025, if we assume 
that the ORR of ADP-A2M4 will be 40% (P1) and historical ORR may be as high as 18% (P0), a 
sample size of N=45 in Cohort 1 provides at least 90% power to detect a difference of 22% using 
exact binomial assumptions. 

            
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The following table describes samples sizes for a single cohort under a range of assumptions for 
the exact binomial assumption as described above.
Historical ORR (P0) 
TCR ORR (P1)
Difference (P1-P0)
N
0.13
0.40
0.27
27 
0.13
0.45
0.32
21
0.15
0.40
0.25
33
0.15
0.45
0.30
24
0.15
0.50
0.35
19
0.18
0.40
0.22
45
0.18
0.45
0.27
32
0.18
0.50
0.32
21
Based on these evaluations, the sample size is 45 subjects in  Cohort 1 for the primary analysis.  
Additional subjects are enrolled in Cohort 2 to supplement Cohort 1 with additional safety and 
efficacy data based on clinical judgement. No formal hypothesis testing is planned for either 
Cohort 2 or overall. One benefit of these additional subjects is an increase in precision for ORR 
by assessing the endpoint across cohorts, and thus in a larger sample of subjects. The following 
table summarizes the width (point estimate – lower bound) of a 97.5% one-sided confidence 
interval using exact binomial methods for different sizes of Cohort 2. Also provided for context 
is the probability that the lower bound of the confidence interval exceeds p0=18% for different 
sizes for Cohort 2. The assumed TCR ORR is 40%.
Size of Cohort 2
Size of Overall (across 
cohort)
CI Width
Probability CI LB 
> 0.18
0
45
0.143
0.916
15
60
0.124
0.959
30
75
0.111
0.989
45
90
0.102
0.994

            
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Based on these evaluations, enrolling an additional 45 subjects in Cohort 2 reduces the width of 
-
confidence interval width when only using Cohort 1. Further, if the TCR ORR is 40% the 
probability that the lower bound of the confidence interval exceeds 18% increases from about 
92% when only using Cohort 1 subjects to greater than 99% if 45 subjects are enrolled in Cohort 
2. These results support enrolling an additional 45 subjects in Cohort 2, for a total of 90 subjects 
aross cohorts.  
9.3.
Statistical Analyses
The statistical analysis plan (SAP) document will provide full details about data derivations and 
displays and analysis methods for primary, secondary and exploratory endpoints. This section 
captures key aspects of the analysis.
Demography and baseline characteristics will be summarized using appropriate descriptive 
statistics. Subject disposition including number of subjects leukapheresed, lymphodepleted and 
treated with ADP-A2M4 will be summarized. Reasons for subject discontinuation from the study 
will be displayed. 
9.3.1.
Interim Analysis
There is no interim analysis planned. 
9.3.2.
Efficacy Analyses
The primary analysis population for efficacy will be the mITT population.  Secondary analyses 
may be conducted on the ITT populations, if it is different from the mITT population.  
The ORR will be based on confirmed (tumor) responses per RECIST v1.1 by independent 
review.
Sensitivity analyses of ORR will be based on confirmed responses per RECIST v1.1, and on 
investigator assessment of overall response (per RECIST v1.1).  
The primary endpoint, ORR per RECIST v1.1 by independent review in Cohort 1, will be 
evaluated using a one-sided exact-based Clopper-Pearson 97.5% confidence interval (CI).  If the 
lower bound of the 97.5% CI exceeds 18%, the trial has met the pre-specified threshold for 
demonstrating efficacy and the trial has met the criterion for statistical significance.     
As a sensitivity analysis, one-sided 97.5% confidence interval using the Wilson method may also 
be provided.
ORR per RECIST v1.1 by independent review will also be evaluated across cohorts (overall).
The following secondary efficacy endpoints will be summarized:
Time to Confirmed Response, defined as the duration between T-cell infusion and the 
initial date of the confirmed response.

            
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Duration of Response (DoR), defined as the duration from the initial date of the 
confirmed response to the date of progressive disease or death.
Progression Free Survival (PFS), defined as the interval between the date T-cell 
infusion and the earliest date of disease progression based on RECIST v1.1 or death 
due to any cause.
Overall Survival (OS), defined the duration between T-cell infusion and death.  
Independent assessment of progression based on RECIST v1.1 will be used for the primary 
analysis of DoR and PFS. As a sensitivity analysis, determination of progression (via RECIST 
v1.1) using lesion assessments will also be provided. 
All secondary efficacy endpoints will be summarized for Cohort 1 and across cohorts (overall).
No hypothesis testing is planned for these secondary endpoints in Cohort 1 or across cohorts. 
Time to event endpoints (i.e., OS and PFS) will be summarized and displayed graphically using 
Kaplan-Meier (K-M) methodology to estimate the median, and the 25th and 75th percentiles. 
Two-sided 95% confidence intervals will be produced.  Overall Survival may be assessed at 
fixed time points such as 1 year and 2 years using K-M methods. 
The following censoring rules will be applied:
For overall survival, subjects who are lost to follow-up or still alive will be censored at 
the date of last contact.
For PFS, subjects who do not have a documented date of disease progression or death 
will be censored at the date of the last study assessment.
The proportion of censored observations will be summarized.
The pharmacokinetic (PK) profile will be described by summaries of Peak expansion (i.e., 
maximum persistence) and time to peak expansion by responder status and overall. Persistence 
data will also be displayed by subject line plots.
9.3.3.
Safety Analyses
The primary analysis population for safety will be the mITT population.  Safety will also be 
summarized for the ITT population and may also include the per protocol (PP) population. All 
safety analyses will be summarized for Cohort 1 and across cohorts (overall).
The safety profile will be based on adverse events, serious adverse events, replication competent 
lentivirus (RCL) and vector integration/clonality. Other safety assessments will include vital 
signs measurements and clinical laboratory test results.
These data will be summarized using appropriate descriptive statistics, i.e., continuous data will 
include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages.
Adverse events will be summarized using two time periods: 
From the time of signing the treatment ICF; 

            
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From start of lymphodepleting chemotherapy, defined as starting on the first day of 
lymphodepleting chemotherapy.
Adverse events throughout the trial will be coded by MedDRA v21.0 or higher.  The number and 
percent of subjects reporting any adverse events will be tabulated by system organ class and 
preferred term. Adverse events will be further classified by toxicity grade, relationship to 
treatment and seriousness in tabulation.
Summary data on duration, grade, time to onset for adverse events of special interest i.e.,
cytokine release syndrome (CRS), ICANS will be presented. Data from ICE will be listed.
For subjects in the LTFU phase, the LTFU AE will be summarized and listed.  

            
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Data Handling and Record Keeping
10.1.1.1.
Data management
An Electronic Data Capture (EDC) system will be used to collect data pertaining to this trial.  
Trial data will be captured through an electronic Case Report Form (eCRF).  Within the EDC 
system the eCRF data will be entered by the site staff and all source document verification and 
data cleaning will be performed by the Sponsor or designee (e.g. CRO).
The specifications for the EDC system will be documented and approved before the EDC system 
is released for live use.  The validation of the eCRF data will be defined in a Data Management 
Plan.  As data are entered into the eCRF, the validation checks will be performed and where 
necessary, queries will be raised.  All queries raised will be held in the EDC database.
The EDC system is a validated software program that has been designed to comply with CFR21 
Part 11 requirements.  All users will access the system via unique user name and password.  A 
full audit history of all actions performed within the system is maintained.  User accounts ensure 
that each user can only perform the tasks applicable to their role and only have access to the data 
applicable to their role.
Standard coding dictionaries, WHO Drug and MedDRA will be used to code medications and 
adverse events.
When all data have been entered and all data cleaning is complete the data will be locked and 
made available for analysis and reporting.
On completion of the study all eCRF data, including all associated queries and audit history, will 
be made available in PDF format to both the study Sponsor and the sites.
10.1.1.2.
Case Report Forms
For each subject enrolled, the completed eCRF must be reviewed and signed by the Principal 
Investigator or authorized delegate.  If a subject discontinues the study, the reason must be noted 
on the eCRF.
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports.

            
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10.1.1.3.
Site Documentation and Source Data
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents are 
classified into two different categories: (1) Investigator Site File (ISF) and (2) subject specific 
source documents.
The Investigator is responsible for maintaining a complete and accurate ISF containing essential 
documents as required by ICH GCP.
Source documents contain the results of original observations and activities of a clinical 
investigation.  Source documents include but are not limited to subject medical records/progress 
notes, appointment book, original laboratory reports, ECG printouts, CT/MRI scans, pathology 
and special assessment reports, and signed informed consent forms.  In no circumstances is the 
eCRF to be considered as source data.
The Investigator must ensure the availability of source documents from which the information on 
the eCRF was derived.
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local or foreign regulatory authorities, the IRB/IEC and auditors to inspect facilities and to have 
direct access to the ISF and all source documents relevant to this study regardless of the type of 
media.
10.1.1.4.
Data Retention and Availability
The Investigator must keep all essential study documents including source data on file for at least 
25 years after completion or discontinuation of the Study.  After that period of time the 
documents may be destroyed, subject to local regulations.
The Investigator will not dispose of any records relevant to this study without written permission 
from the Sponsor.  If the Investigator cannot guarantee the archiving requirement at the 
investigational site for any or all of the documents, such study records may be transferred upon 
request to the Sponsor or its designee.
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in writing in advance.
Study documentation is subject to inspection by the Sponsor, its representatives and regulatory 
agencies and must be stored in such a way that it can be accessed/retrieved within a reasonable 
timeframe at a later date.
10.1.2.
Study Monitoring
Study Monitoring will be conducted by the Sponsor or designated CRO.
It is understood the responsible monitor will contact and visit the Investigator regularly and will 
be allowed, on request, to inspect all records of the trial (e.g. eCRFs, ISF, and source documents) 
provided that subject confidentiality is maintained in accordance with local requirements.

            
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It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify adherence to the protocol and the completeness, consistency and accuracy of the 
data being entered.  The monitor should have direct access to subject source documents to verify 
the entries on the eCRF.  The Investigator (or designee) agrees to cooperate with the monitor (or 
designee) to ensure any discrepancies detected are resolved.
10.1.2.1.
Audits and Inspections
The Sponsor or its representatives may conduct audits at investigative sites including, but not 
limited to, facilities where the study is being conducted, investigational product handling and 
accountability, presence of required documents, the informed consent process and comparison of 
eCRFs with source documents.
All study documentation including source data must be available for audit.
The Investigator agrees to cooperate fully with audits conducted at a convenient time in a 
reasonable manner.
Regulatory agencies may also inspect investigative sites during or after the study.  The 
Investigator (or designee) should contact the Sponsor immediately if this occurs, and provide 
copies of correspondence relating to requests for an inspection of the site facilities.
10.1.3.
Regulatory and Ethical Considerations
10.1.3.1.
Competent Authority Submissions
Adaptimmune or its authorized representatives will be responsible for ensuring that appropriate 
competent authority approvals are obtained according to local country requirements.  Competent 
authority approval (or notification as applicable) will be obtained before initiation of the study.
10.1.3.2.
Independent Ethics Committees
The final study protocol and subject informed consent documentation will be approved by the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and any other site level 
committee deemed appropriate by the Institution.  Approval from each applicable committee will 
be received in writing before initiation of the study.
Protocol amendments must also be approved by the IRB/IEC (and other committees as 
applicable) before implementation, except in the case of changes made to protect subjects from 
immediate hazard, which may be implemented immediately.
10.1.3.3.
Local regulations/Declaration of Helsinki
The Investigator will ensure this study is conducted in full compliance with the principals of the 
“Declaration of Helsinki” or with the laws and regulations of the country in which the research is 
conducted, whichever, affords the greater protection to the subject. The study must fully adhere 
to the principles outlined in ICH GCP or with local law if it affords greater protection to the 
subject.

            
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10.1.4.
Informed consent
It is the responsibility of the Investigator to obtain written informed consent from all study 
subjects prior to any study related procedures being performed.  All consent documentation must 
be in accordance with applicable regulations and ICH GCP.  Documentation must include the 
dated signature of both the subject (or the subject’s parents or legally authorized representative 
as applicable) and the person conducting the consent discussion.  If the subject is illiterate, an 
impartial witness should be present during the consent discussion, and the consent signed and 
dated by the witness, the subject, and the person conducting the consent discussion.  The consent 
form should be translated and communicated to the subject in a language that is understandable 
to the subject.  Certified translations of the informed consent documentation will be provided as 
applicable.
A copy of the signed and dated informed consent should be provided to the subject before 
participation in the study.
Tests performed as standard of care prior to documentation of consent may be used for screening 
results as appropriate (Section 8.4).
10.1.5.
Confidentiality
The confidentiality of records that may identify subjects will be protected in accordance with 
applicable laws, regulation and guidelines.
The Investigator must ensure that each subject’s anonymity is maintained and protected from 
unauthorized parties.  On eCRFs or other documents submitted to the Sponsor, subjects must not 
be identified by their names, but by a unique identification code allocated to them to ensure 
confidentiality on all study documentation. Subjects will retain this unique number throughout 
the study.
The Investigator will keep a subject enrollment log showing subject unique identification codes, 
names and addresses in the ISF.
The Sponsor and/or its representatives accessing subject records and data at site will take all 
reasonable precautions to maintain subject confidentiality.
10.1.6.
Protocol Adherence
The Investigator must sign the protocol to confirm acceptance and willingness to comply with 
the study protocol.
The Investigator or designee will not deviate from the protocol unless necessary to eliminate an 
apparent immediate hazard to the safety, rights or welfare of any study subject.  In the event of a 
protocol deviation for any reason, the Investigator will promptly report the deviation to the 
Sponsor in writing.

            
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10.1.7.
Study Suspension, Study Termination and Study Completion
The Sponsor may suspend or terminate the study at any time for any reason.  If the study is 
suspended or terminated the Sponsor will ensure applicable sites, regulatory agencies and 
IRBs/IECs are notified as appropriate.
If the Investigator stops/terminates the study at their site the Sponsor must be notified.  The 
Sponsor will ensure Regulatory Agencies and IRBs/IECs are notified as appropriate.
The Sponsor will ensure End of Study declarations are made to the relevant Regulatory 
Agencies/IECs in accordance with local regulations.
10.1.8.
Public Posting of Study Information
The Sponsor is responsible for posting appropriate study information on applicable clinical study 
registry websites.  Information included in clinical study registries may include participating 
Investigator’s names and contact information.
10.1.9.
Clinical Study Report
The results of the study will be presented in an integrated Clinical Study Report (CSR) according 
to ICH guideline E3: Structure and Content of Clinical Study Reports.
10.1.10.
Publication Policy
The Investigator may not submit the results of the study for publication or present the results of 
the study without the prior written agreement of the Sponsor in accordance with the Clinical 
Trial Agreement.  The results of this study will be published as a whole once all subjects have 
completed the study and the study results have been analyzed.  Interim publications of data from 
the study may be made if mutually agreed between the Sponsor and the Investigators.  
Agreement will not be provided by the Sponsor where in the Sponsor’s view interim publications 
would introduce bias or lead to any misrepresentation or inaccuracies in data.
Authorship will be determined in conformance with the International Committee of Medical 
Journal Editors (ICMJE) guidelines and/or publication guidelines if applicable.
10.1.11.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing updated information on financial interests during the course of the 
study and for 1 year after completion of the study.

            
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10.2.
Appendix 2: Safety Reviews
10.2.1.
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB) will be implemented for this study for Cohort 1 only 
and will consist of two experienced oncologists who are independent of the study and an 
independent statistician.  
The DSMB will review ongoing safety (including Aes and SAEs) during the interventional phase 
of the study after approximately 5, 15, and 30 subjects have been dosed. At the time of Protocol 
Amendment 3, the DSMB has held 2 operational meetings to review data from after dosing of 5, 
and 15 subjects. Both meetings resulted in the DSMB recommendation to continue the study 
without protocol modification. The final DSMB meeting will be held after the 30th subject has 
been dosed in Cohort 1.
A DSMB charter, defining roles and accountabilities and the process for review, is available.

            
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10.3.
Appendix 3: Clinical Laboratory Tests
Table 4: 
Protocol-Required Safety Laboratory Assessments
Laboratory reference ranges for all tests conducted locally must be provided to Adaptimmune 
before the study initiates.
Hematology:
Red blood cell count (RBC)
Hemoglobin (Hb)
Hematocrit (HCT)
Mean cell volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC)
Reticulocytes (absolute)
Platelet count
White blood cell count (WBC) with differential 
(absolute or percentage)
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils 
Clinical Chemistry:
Calcium
Phosphorus
Magnesium
Albumin
Bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Sodium
Potassium
Bicarbonate
Creatinine
Chloride
Glucose
BUN or Urea
Other Tests:
Ferritin
C-reactive protein

            
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Coagulation Screen:
Prothrombin time (PT) or International Normalized 
Ratio(INR)
Activated partial tissue thromboplastin time (aPTT)
Pregnancy Test:
Serum beta-HCG or Urine test
Thyroid Function Tests:
Thyroid Stimulating Hormone (TSH)
Infectious Disease:
HIV 1+2 antibody#
Hepatitis B surface antigen
Hepatitis B core antibody – if positive, test for HBV 
DNA
Hepatitis C antibody – if positive, test for HCV RNA
HTLV 1+2 IgG
CMV IgG#
EBV (EBNA)#
Treponema IgG or RPR #
Viral reactivation
CMV DNA PCR – peripheral blood for detection of 
reactivation. In the event of suspected end organ CMV 
disease a biopsy may be required
# Per Institutional Standard Practice is acceptable

            
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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Definition of AE
AE Definition
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention.
Events Meeting the AE Definition
3 and Grade 1 and 2 laboratory abnormalities that the Investigator considers clinically significant 
in their medical and scientific judgment.
Any other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease).
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. A pre-existing condition is one that is present at the 
start of the study during Screening and is documented in the subject’s medical history.
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfil the definition of an AE or SAE.

            
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Events NOT Meeting the AE Definition
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant’s condition.
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.4.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are Aes. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE.

            
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d.
Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.
g.
Additional protocol-defined criteria
Review any Grade 4 CTCAE lab value based solely on numerical criteria (e.g. white blood 
cells decreased) to determine whether it should be reported as a SAE.
Hepatic events (see Section 10.4.5):
10.4.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
SAEs should be reported to the Sponsor or designate within 24 hours using the SAEW. The 
investigator will then record all relevant AE/SAE information in the CRF.

            
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It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Adaptimmune in lieu of completion of the SAEW/AE CRF page.
There may be instances when copies of medical records for certain cases are requested by 
Adaptimmune. Supporting documents such as pathology reports or imaging results can also 
be provided in conjunction with the SAEW. In these cases, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical records 
before submission to Adaptimmune.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of Severity
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v 5.0.  See Section 10.5.6 and Section 10.4.7 for guidance on grading of CRS and ES
respectively.  For Aes not specifically listed in the CTCAE, The investigator will make an assessment of 
intensity for each AE and SAE reported during the study and assign it to 1 of the following categories: 
Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2 - Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL1.
Grade 3 - Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care
ADL2.
Grade 4 - Life-threatening consequences; urgent intervention indicated.
Grade 5 - Death related to AE.
1.
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
2.
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not being bedridden.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

            
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A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial SAEW report to Adaptimmune. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAEW to Adaptimmune.
The investigator will also assess the relationship between the lymphodepletion chemotherapy 
and each SAE.
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of Aes and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Adaptimmune to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, 
the investigator will provide Adaptimmune with a copy of any post-mortem findings including 
histopathology.
New or updated information will be recorded in the originally completed CRF.
SAE follow up information should be submitted on an updated SAEW within 24 hours if 
associated with a change in diagnosis and/or increased severity. Otherwise follow up should 
be submitted promptly within 7 days, and no later than 30 days of receiving new information.

            
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10.4.4.
Reporting of SAEs
SAE Reporting to Adaptimmune 
SAEs must be reported to Adaptimmune by completing the paper SAE worksheet (SAEW) 
within 24 hours of the study personnel’s discovery of the event.
Complete the SAEW as fully as possible and obtain the Investigators signature.  Create a PDF 
of the signed SAEW and submit to:
Do not delay reporting an SAE if the Investigator is unavailable to sign.  Report the SAE as 
above and provide a copy of the signed SAEW as soon as possible afterwards.
10.4.5.
Hepatic Monitoring and Follow Up Assessments
Liver chemistry evaluation criteria are designed to assure participant safety and to enable 
evaluation of liver event etiology.  Liver chemistries will be monitored in accordance with the 
Time and Events Table (Section 1.3), and as clinically indicated.
If a Subject meets one of the criteria defined in Table 5, the specified actions and follow up 
assessments will be carried out.
If a Subject moves to the LTFU phase prior to Week 12, all Aes would be collected at the Month 
2 visit (see Section 1.3).  Hepatic safety assessments will be included in this safety follow up.
Table 5: 
Hepatic Monitoring Criteria
Hepatic Monitoring Criteria
ALT Absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1
ALT 3xULN and bilirubin 
INR1
ALT 3xULN and international normalized ratio (INR) >1.5, if INR measured
Symptomatic2
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Suggested Actions and Follow up Assessments
Actions
Follow Up Assessments
Complete the electronic case report form 
(eCRF), and a serious adverse event worksheet 
Viral hepatitis serology3

            
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(SAEW) if the event meets the criteria for an 
SAE within 24 hours.1
Consider hepatologist consultation
Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and INR 
Perform Follow-Up Assessments (See column 
to the right)
Monitor participants weekly with liver 
chemistry and INR until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. For bilirubin or INR criteria, monitor 
participant twice weekly.
Serum CPK and LDH
CBC with differential to assess eosinophilia
PBMC blood sample for persistence4
Assess for the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) 
and alcohol use
For bilirubin or INR criteria:
Hepatologist consultation required
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography)
Consider liver biopsy
1.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 
may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE. The INR stated 
threshold value will not apply to participants receiving anticoagulants. 
2.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
3.
Includes:Hepatitis A immunoglobulin M (IgM) antibody; HbsAg and HbcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody. 
4.
Record the date/time of the PBMC blood sample draw on the CRF. Instructions for sample handling and 
shipping are in the Laboratory Manual.
10.4.6.
Reporting Criteria during Long Term Follow-Up (Years 1-15)
Due to the nature of the treatment, subjects are required to be followed for 15 years after 
treatment with genetically modified T cell
FDA, 2006;
FDA, 2010; EMA, 2009

            
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Section 1.3.2 , Table 2.  Emergence of any of the following new clinical conditions reported or 
observed and the action taken will be reported to the Sponsor:
New Malignancies
New incidence or exacerbation of a pre-existing neurological disorder
Excluding all Grade 1 neurologic AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder
Excluding all Grade 1 autoimmune AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
All rheumatologic disorders will be reported irrespective of grade
New incidence of a hematologic disorder
Excluding cytopenias following cytotoxic chemotherapy before bone marrow 
recovery
Excluding Grade 1 and 2 laboratory abnormalities, unless the Investigator 
considers clinically significant
Opportunistic and/or serious infections
Excluding infections secondary to chemotherapy induced cytopenias
Unanticipated illness or hospitalization deemed at least possibly related to gene 
modified cell therapy
These are the only adverse events that will be collected during LTFU.
A detailed description of the event should include the date of diagnosis and the nature of the 
diagnosis.  If the diagnosis is cancer, record the type and stage of the cancer.  If the cancer is 
metastatic, list the metastatic sites.  If a new malignancy is recorded in a vector target T-cell
type, tumor cells will be evaluated for vector sequences.  If the tumor is positive for vector 
sequences or the surrogate sample is positive for vector sequences and is confirmed in 
accordance to this protocol, clonality analysis will be performed.  If no evidence of oligo-or 
monoclonality is observed, a summary report of any and all analysis for the pattern of vector 
integration will be assembled, and submitted within the annual report of the INDs listed on this 
protocol under which the subject(s) evaluated originally received their treatment.  If evidence of 
oligo- or monoclonality is observed, an information amendment will be submitted within 30 days 
to the INDs listed on this protocol under which the subject(s) evaluated originally received their 
treatment.  

            
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10.4.7.
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents
In accordance with FDA and EMA guidance FDA, 2018; EMA, 2009
this trial are asked to consider an autopsy and autopsies will be requested of the families for all 
subjects who die during participation in studies after administration of gene transfer agents.
Guidelines for autopsy tissue/sample collection, preparation and shipping are provided in the
Laboratory Manual.

            
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10.5.
Appendix 5: Supportive Care Guidance
It is recommended that a specialist with experience in the administration of hematopoietic stem 
cell transplant and/ or other cell and gene therapy be involved in the care of study subjects.  Staff 
treating trial subjects should be experienced in acute post-transplant care and the management of 
associated toxicities (e.g. cytopenias, cytokine release syndrome, ICANS).
Subjects are at risk for the development of certain adverse effects for which recommended 
management strategies have been developed.  Adverse effects are most likely to occur within the 
first month following T-cell infusion, but may occur at later time points.
Supportive care treatments recommended herein, including tocilizumab will be supplied by the 
pharmacy of the participating institution.
10.5.1.
Lymphodepleting Chemotherapy Symptom Management
Cyclophosphamide and fludarabine are used as pre-conditioning lymphodepleting chemotherapy 
in this study. Symptoms associated with the use of cyclophosphamide and fludarabine are 
included in the respective product labels. Refer to the most current product labels.
10.5.1.1.
Management of Neutropenia
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
is also common. Prophylactic use of G-CSF is recommended in all subjects. G-CSF (i.e., 
filgrastim) should be used for management of neutropenia according to ASCO guidelines Smith,
2015 . G-CSF should be given on Day -3 until resolution of neutropenia (reaching an ANC of at 
least 2 × 109/L to 3 × 109/L or as per institutional practice).
Long-acting (pegylated) G-CSF may be given in preference to short acting daily G-CSF in 
accordance with institutional standard practice. Pegylated G-CSF will be given as one dose on 
Day -3.
10.5.2.
T-cell Infusion Symptom Management
Mild transient symptoms have been observed following infusion of engineered T cells. The 
management of these symptoms is suggested but should not necessarily be confined to the 
below.
Fever, chills, headache and temperature elevations will be managed with 
acetaminophen. It is recommended all subjects that develop fever or chills have a 
blood culture drawn.
Nausea and vomiting may be treated with a non-steroidal anti-emetic of choice.
Hypotension will initially be managed by intravenous fluid administration and further 
measures as dictated by standard medical practice.
Hypoxemia will initially be managed with supplemental oxygen and further measures 
as dictated by standard medical practice.

            
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10.5.3.
Infection
Additional measures to treat and prevent infection are outlined below.  In particular, fever and 
neutropenia should be aggressively managed as well as preemptive influenza therapy and other 
standard therapies for immunocompromised hosts, in accordance with institutional guidelines.
10.5.3.1.
SARS-CoV-2 (COVID-19)
Subjects with a positive RT-PCR test for COVID-19 (irrespective of vaccination status) post 
lymphodepleting chemotherapy or ADP-A2M4 cell infusion should be immediately referred to 
an infectious disease specialist for consideration of anti-viral therapies. Investigators should also 
consult the latest guidelines/instituitional policies pertaining to the management of COVID-19 in 
cancer/cell therapy patients. The Medical Monitor should be be informed if a subject has a 
positive COVID-19 test (irrespective of symptoms) after receiving either lymphodepleting 
chemotherapy or ADP-A2M4 cell infusion.
10.5.3.2.
Pneumocystis carinii Pneumonia
Subjects should receive prophylaxis against Pneumocystis pneumonia with drug, dose and 
duration according to institutional guidelines.  Single strength trimethoprim sulfamethoxazole 
daily is the recommended first line agent, starting at day 28 for one year.  Other regimens
including atovaquone (1500 mg daily with food) or aerosolized pentamidine (300 mg every four 
weeks) are also acceptable, e.g. sulfonamide allergy, and should follow Institutional standards 
for autologous bone marrow transplants.
10.5.3.3.
Herpes simplex and Varicella zoster
All subjects should receive prophylaxis with acyclovir (800 mg twice daily) or valacyclovir 
(500mg twice daily) for one year, or in accordance with institutional guidelines. In general, 
prophylaxis should start on day of T-cell infusion, or on day of lymphodepletion if the subject 
has a history of shingles or multiple HSV episodes.
10.5.3.4.
Cytomegalovirus
Subjects will be screened for cytomegalovirus (CMV) seropositivity at study entry.  If CMV 
viremia is detected at baseline, treatment should be initiated and evidence of viral clearance 
obtained, prior to lymphodepletion chemotherapy.  All CMV seropositive subjects will continue 
to be monitored for CMV viremia by CMV DNA PCR as shown in Table 1 until 60 days post 
infusion of ADP-A2M4.  In the event CMV viremia is observed an Infectious Diseases specialist 
should be consulted and treatment initiated if necessary according to institutional practice.  
<1000.
If a subject experiences prolonged or secondary pancytopenia or lymphopenia additional 
monitoring for viral reactivation should be considered and treatment for viral infection initiated 
if necessary.  A strategy for management of pancytopenia or bone marrow failure is described in 
Section 10.5.8.

            
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10.5.3.5.
Hepatitis B Prophylaxis
Subjects will be screened for hepatitis B (HBV) at study entry. Subjects who are hepatitis B core 
antibody positive must receive prophylaxis against viral reactivation using institutional 
protocols.  Prophylaxis should be initiated prior to lymphodepleting therapy and continued for 6 
months.  Acceptable regimens include lamivudine (300mg daily), entecavir (0.5mg daily), or 
tenofovir (300mg daily).
10.5.3.6.
Syphilis
Subjects will be screened for syphilis at study entry in accordance with institutional standards.  
Subjects with positive screening results should be evaluated by an infectious diseases consultant.  
If determined to have syphilis infection, the subject should be treated before lymphodepletion 
chemotherapy.
10.5.3.7.
Other Anti-Microbial Prophylaxis
Antibacterial and antifungal prophylaxis should follow institutional standards for autologous 
bone marrow transplants.
10.5.4.
Hematologic and Blood Product Support
Blood product support should be provided to maintain platelets > 10 x109/L, Hb > 8.0 g/dL (or in 
accordance with institutional practice) and as clinically indicated. See AABB Guideline on 
Kaufman, 2015
10.5.4.1.
Irradiated Blood Product
The guidance for autologous stem cells is also recommended for use in T- cell therapy. 
Blood products transfused during the following study periods must be irradiated:
7 days prior to and during leukapheresis, to prevent the collection of viable allogeneic 
T lymphocytes,
Irradiated blood components should continue to be used until 3 months following T 
cell infusion unless conditioning, disease or previous treatment determine indefinite 
duration.
Irradiated blood products may be used longer as clinically indicated, otherwise follow 
institutional guidelines on autologous stem cell transplantation..
10.5.4.2.
CMV screened blood products
Subjects will be screened for CMV seropositivity on study entry.  In order to reduce the risk of 
primary CMV infection all subjects (i.e. both CMV-positive and -negative subjects) should 
receive leukoreduced blood products where possible (excluding the IP infusion).  Where 
leukoreduced blood is not available, CMV negative subjects must only receive blood products 
from CMV-seronegative donors from study entry to study completion.

            
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10.5.5.
Management of Autoimmunity
Subjects should be monitored throughout the trial for potential autoimmune reactions in response 
to the genetically engineered T cells that could include skin toxicity, liver toxicity, colitis, eye 
toxicity etc.  If autoimmunity is suspected, the PI should be contacted and every attempt should 
be made to biopsy the affected organ to clarify whether the symptoms are related to the ADP-
A2M4 therapy.  If the subject sustains persistent Grade 2, or Grade 3 or 4 autoimmunity, 
consideration should be given to administration of corticosteroid therapy, either topically (e.g. 
skin, eyes) or systemically as clinically indicated.
10.5.6.
Management of Cytokine Release Syndrome
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed
following administration of antibodies and adoptive T cell therapies for cancer. It is defined 
clinically by symptoms many of which mimic infection including pyrexia, nausea, diarrhea, 
headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea. It is important to 
evaluate the subject for concurrent infections. Potentially life-threatening complications of CRS 
include cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or 
hepatic failure and disseminated intravascular coagulation. CRS may also be associated with 
findings of macrophage activation syndrome or occur coincident with tumor lysis syndrome.
CRS causes a rapid rise in serum cytokine levels under conditions of immune activation and 
although cytokines will be assayed serially throughout the study, results of the assays will not be 
available in real time; therefore CRS should be graded and managed with supportive and 
immunosuppressive interventions according to the severity of symptoms Lee, 2019 .
Table 6 provides the recommended management of CRS according to grade, which has been 
further adapted from CTCAE for use with immunotherapy and should be implemented in 
accordance with institutional guidelines. Symptoms can mimic those seen with infection. The 
diagnosis of CRS is clinical, and is supported by the exclusion of infection as well as the 
presence of increased cytokine levels and other biomarkers. Assessment and treatment guidelines 
are provided below. If CRS is suspected, in addition to assessment for infection, cytokine levels 
(Section 8.6.2) ferritin (Section 8.4.21), as well C-reactive protein (CRP) (Section 8.4.20) levels 
should be measured approximately every other day until symptoms are improving or an 
alternative diagnosis is confirmed.

            
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Table 6: 
Management Guidelines for Cytokine Release Syndrome
Grade
Clinical Presentation for Grading 
Assessment
Management Guidelines
1
Constitutional symptoms not life-
threatening (e.g., fever, nausea, fatigue,
headache, myalgias, malaise)
Vigilant supportive care1
Assess and treat for possible 
infection2
Consider anti-IL-6 therapy3
(tocilizumab 8 mg/kg* IV) if 
clinically indicated (i.e., subjects 
hours or subjects with co-
morbidities or subjects of older age)
2
Symptoms require and respond to 
moderate intervention (Hypotension 
responds to fluids or one low dose 
pressor, hypoxia responds to 
2, 
and/or Grade 2 organ toxicity)
Monitor cardiac and other organ 
function
Vigilant supportive care1
Assess and treat for possible 
infection2
Treat hypotension with fluid and 
pressors.
Administer O2 forhypoxia.
Administer anti-IL-6 therapy3
(tocilizumab 8 mg/kg* IV) at any 
time if clinically indicated (i.e., 
24 hours, or subjects with co-
morbidities or subjects of older age)

            
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3
Symptoms require and respond to 
aggressive intervention
hypotension requires multiple pressors 
or high dose pressors
2, Grade 3 organ 
toxicity or Grade 4 transaminitis
Monitor subject very closely for 
cardiac and other organ 
dysfunction. Most likely will 
require monitoring in an intensive 
care unit (ICU).
Vigilant supportive care1
Assess and treat for possible
infection2
Treat hypotension with fluid and
pressors. Administer O2 for 
hypoxia.
Administer anti-IL-6 therapy3
4
Life-threatening symptoms
Grade 4 organ toxicity (excluding 
transaminitis)
Manage subject in ICU
Intensive supportive care 
including mechanical 
ventilation, fluids, pressors, 
antibiotics and other measures 
as required
Administer anti-IL-6 therapy3
5
Death
1.
Supportive care includes: monitor fluid balance, maintain adequate hydration and blood
pressure
2.
Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever 
and neutropenia as per institutional practice;and antipyretics, analgesics as needed.
3.
For subjects requiring intervention beyond supportive measures, anti-IL-6 therapy should be the first 
line treatment (tocilizumab 8 mg/kg* IV).
*The maximum dose for tocilizumab is 800 mg per dose. Corticosteroids can be used for subjects 
refractory to anti IL-
IL-1R inhibitors. Please see text below for details.
Source: Lee, 2019; Neelapu, 2018
For subjects requiring immunosuppressive intervention anti-IL-6 therapy should be the first line 
treatment. Tocilizumab is a humanized anti-IL-6 receptor antibody that has been approved for 
the treatment of CRS. Anecdotally, tocilizumab has produced rapid and complete correction of 

            
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CRS with single doses
Maude, 2014
The United States product insert (USPI) for
tocilizumab recommends a dose of 8 mg/kg administered over 1 hour in adult subjects as the 
first-line treatment of severe CRS. Subjects may receive a repeat dose(s) if clinical signs and 
symptoms do not improve at least 8 hours apart. Refer to Section 10.5.7 below for subjects 
experiencing Immune Effector Cell-Associated Neurotoxicity Syndrome concurrent with CRS.
Second-line, tocilizumab refractory, management of CRS is at the discretion of the Investigator 
following local institutional policy. This can potentially include the use of corticosteroids either 
Maus, 2020
corticosteroid administered 
as a single agent after two doses of Tocilizumab have been administered and if CRS symptoms 
are persisting. Use of steroid sparing agents (e.g. siltuximab or anakinra) is at the discretion of 
the Investigator.
Lee 2019 recommend steroids as second-line therapy for CRS as the response to anti-IL-6 
therapy may be more rapid and owing to the potential of steroids to attenuate the anti-tumor 
effects of the adoptive T cell therapy. However, in subjects with Grade 3 or 4 CRS associated 
with neurologic dysfunction without significant hemodynamic instability (See Section 10.5.7) or 
other life-threatening symptomatology, consideration may be given to the use of corticosteroids 
as immunosuppressive therapy. High doses (e.g. 2 mg/kg/day prednisone equivalent) may be 
required.
If cytokine release syndrome is suspected, a physician with expertise in the management of 
subjects following bone marrow transplant should be consulted. If high dose corticosteroids are 
required, treatment should generally be continued until resolution to Grade 1 followed by 
tapering doses over several weeks.
Please refer to the most recent version of the product label for tocilizumab and the latest Society 
for Immunotherapy of Cancer (SITC)
e.g. Maus, 2020 .
10.5.7.
Management of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)
See Section 8.5.7.2 for a description of ICANS. Neelapu, et al Lee, 2019 have developed a 
grading system for ICANS which incorporates the Immune Effector Cell-Associated 
Encephalopathy 10 point neurological assessment (ICE) tool, see Table 7. Points are assigned 
for each of the tasks in Table 7 which are performed correctly.  Normal cognitive function is 
defined by an overall score of 10.
The ICE should be used to monitor all subjects for ICANS.
Table 7:
Task
ICE Points
Orientation: Orientation to year, month, city, and 
hospital, 
Total of 4 points (one point for each)

            
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Task
ICE Points
Naming: Ability to name three objects(e.g. point 
to: clock, pen, button)
Total of 3 points (one point for each)
Following commands: ability to follow simple 
commands (e.g., “Show me 2 fingers” or “Close 
your eyes and stick out your tongue”)
1 point
Writing: Ability to write a standard sentence, e.g. 
‘There are seven days in a week’
1 point
Attention: Ability to count backwards from 100 
by tens
1 point
The ICE score is used in grading of ICANS as presented in Table 8.
Table 8: 
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)
Neurotoxicity 
Domain 
Grade 1
Grade 2
Grade 3
Grade 4
ICE Score1
7–9 
3–6 
0–2 
0 (patient is 
unarousable, and 
unable to perform 
ICE)
Depressed level of 
consciousness2
Awakens 
spontaneously
Awakens to 
voice
Awakens only to 
tactile stimulus
Patient is 
unarousable or 
requires vigorous 
or repetitive 
tactile stimuli to 
arouse. Stupor or 
coma
Seizures
NA
NA
Any clinical
seizure, focal or 
generalized that 
resolves rapidly 
or 
nonconvulsive
seizures on EEG 
that resolve with 
intervention
Life-threatening 
prolonged seizure 
(>5 min); or
Repetitive clinical 
or electrical 
seizures without 
return to baseline 
in between
Motor findings 3
NA
NA
N/A
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis

            
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Neurotoxicity 
Domain 
Grade 1
Grade 2
Grade 3
Grade 4
Elevated ICP/
cerebral edema
NA
NA
Focal/local 
edema on 
neuroimaging4
Diffuse cerebral 
edema on 
neuroimaging; 
decerebrate
or decorticate 
posturing; or 
cranial nerve VI
palsy; or 
papilledema; or
Cushing's triad
Source:  Based on Lee, 2019
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has 
a generalized seizure is classified as grade 3 ICANS.
N/A indicates not applicable.
1 A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient 
with an ICE score of 0 may be classified as grade 4 ICANS if unarousable.
2 Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medication).
3 Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, 
but they do not influence ICANS grading.
4 Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0.
10.5.7.1.
Management of ICANS
The recommended management of ICANS should be based on toxicity grade.  Table 9 provides 
guidance on the management of ICANS, and should be implemented in accordance with 
institutional guidelines.  
Grade 1 ICANS is primarily managed with supportive care as outlined below.  For subjects 
requiring intervention beyond supportive measures, anti-IL-6 therapy should be the first line 
treatment of for ICANS in the setting of CRS (See Section 10.5.6 for CRS diagnosis and 
treatment guidelines).  In the setting of concurrent CRS, for Grades 1-3 ICANS additional doses 
of anti-IL-6 therapy should be considered before instituting corticosteroids since the use of 
systemic steroids may abrogate the effects of the T cell therapy.  For subjects with neurologic 
symptoms refractory to an initial dose of anti-IL-6 therapy, consider siltuximab for the second 
dose based on its mechanism of action directly against IL-6.
A neurology consultation should be obtained for subjects with ICANS for thorough neurological 
evaluation, and recommendations for further testing such as EEG and neuroimaging as indicated.

            
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Table 9: 
Management of ICANS
Grade
Treatment
1
For all patients:
• Vigilant supportive care; aspiration precautions; intravenous (IV) hydration
• Withhold oral intake of food, medicines, and fluids, and assess swallowing
• Convert all oral medications and/or nutrition to IV or enteral tube if swallowing is impaired
• Avoid medications that cause central nervous system depression
• Evaluate for other contributing causes and treat accordingly
Unless symptoms are mild and transient (e.g. 1 point change in ICE for less than 12 hours):
• Neurology consultation including funduscopic exam to assess for papilledema
• MRI of the brain with and without contrast (CT scan of the brain if MRI is not feasible).  
Further testing if indicated such as diagnostic lumbar puncture with measurement of opening 
pressure if increased intracranial pressure is suspected, or MRI spine if the subject has focal 
peripheral neurological deficits
• Institute levetiracetam therapy and consider EEG if seizure activity is suspected
• Consider anti IL 6 therapy with tocilizumab 8 mg/kg1 IV or siltuximab 11 mg/kg IV, if 
Grade 1 persists beyond 24 hours, or worsening and associated with concurrent CRS
2
• Supportive care and neurological work up as described for grade 1 ICANS
• Anti-IL-6 therapy if associated with concurrent CRS
• If refractory to anti-IL6 therapy or no evidence of CRS consider Dexamethasone 10 mg IV 
every 6 h or methylprednisolone 1 mg/kg IV every 12 h; Once initiated continue
corticosteroids until improvement to grade 1 ICANS and then taper
• Consider transferring patient to intensive-care unit (ICU) if ICANS associated with grade 
3
• Supportive care and neurological work up as indicated for grade 1 ICANS
• ICU transfer is recommended
• Anti IL 6 therapy if associated with concurrent CRS if not administered previously
• Corticosteroids as outlined for grade 2 ICANS if symptoms worsen despite anti IL 6 
therapy, or for ICANS without concurrent CRS; continue corticosteroids until improvement 
to grade 1 ICANS and then taper
• Stage 1 or 2 papilledema with cerebrospinal fluid (CSF) opening pressure <20 mmHg 
should be treated with a corticosteroid regimen as per Grade 4 below.
• Consider repeat neuroimaging (CT or MRI) every 2–3 days if patient has persistent grade 
ICANS

            
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Grade
Treatment
4
• Supportive care and neurological work up as indicated for grade 1 ICANS
• Consider neurosurgical consultation for patients with evidence of increased intracranial 
pressure
• ICU monitoring; consider mechanical ventilation for airway protection
• Anti IL 6 therapy and repeat neuroimaging as described for grade 3 ICANS
• High-dose corticosteroids continued until improvement to grade 1 ICANS and then taper; 
for example, methylprednisolone IV 1 g/day for 3 days, followed by rapid taper at 250 mg 
every 12 h for 2 days, 125 mg every 12 h for 2 days, and 60 mg every 12 h for 2 days
1 Maximum amount of tocilizumab per dose is 800mg
10.5.8.
Management of Prolonged Cytopenia 
10.5.8.1.
Definition of prolonged cytopenia, pancytopenia and plastic anemia
Prolonged cytopenias are defined as Grade 3 or higher neutropenia, anemia or thrombocytopenia 
The definition of Grade 3 or higher cytopenia is based on CTCAE criteria (Version 5.0) and is 
summarized in the table below
Hgb (g/dL)
Hgb<8.0 g/dL
<2000 mm3, <2.0 x 10^9/L
<1000/mm3; <1.0 x 10^9/L
Platelet decre
<50,000/mm3; <50.0 x 10^9/L
There have been previous reported cases of prolonged cytopenias with lymphodepletion 
KYMRIAH EU SmPC; KYMRIAH USPI; 
YESCARTA EU SmPC; YESCARTA UPSI . Cases of aplastic anemia have also been observed 
D’Angelo, 2017, Chodon, 2014, Nguyen, 2019 .
Pancytopenia refers to an abnormal reduction in the number of red blood cells, white blood cells, 
and blood platelets. Aplastic anemia a rare hematological disorder and is defined as diagnosis of 
severe aplastic anemia made in the setting of a hypocellular bone marrow when 2 of the 
following 3 blood counts are met: Absolute Neutrophil Count 
Absolute Reticulocyte 
Count 
Platelet 
with the exclusion of myelodysplastic 
syndrome.  
Subjects may be symptomatic on presentation, but some are detected incidentally when 
unexpected cytopenias are found on a routine blood count.  The clinical consequences of aplastic 
anemia are life-threatening bleeding from thrombocytopenia, and infection as a result of 

            
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neutropenia.  Bacterial and fungal infections are common and a significant cause of morbidity 
and mortality.
10.5.8.2.
Management of Prolonged Cytopenias
Management of bone marrow suppression and related prolonged cytopenias is challenging, with 
no clearly established guidelines regarding immunosuppression.  Treatment is largely supportive, 
including transfusions and treatment of infections.  If there is evidence of, or concern for the 
development of prolonged cytopenias (decreasing hemoglobin, platelets and neutrophils, or 
increasing transfusion requirements) 
the following 
measures should be implemented:
1. Consult a physician with expertise in the management of bone marrow suppression
2. Increase the frequency of CBCs as clinically indicated.
3. Exclude other alternative etiologies such as other drugs, viral causes, etc.
4. An early bone marrow biopsy is recommended for clinical diagnosis, with a sample to be 
provided to the Sponsor for study. Details on tissue collections, kit use and shipment 
information can be found in the Laboratory Manual.
5. A matched peripheral blood sample should be collected in parallel with the bone marrow 
sample and provided to the Sponsor.
6. Initiate treatment with G-CSF.
7. Consult an Infectious Diseases expert.
8. Once alternative etiologies have been excluded, strongly consider immunosuppression 
(e.g. methylprednisolone 2 mg/kg initial dose) or more aggressive regimens (e.g. 
antithymocyte globulin (ATG), cyclosporine, eltrombopag) as well as antimicrobial 
prophylaxis/therapy with the advice of your Hematology/Infectious Diseases
consultant(s).  If high dose corticosteroids are initiated, duration of therapy and taper 
should be determined with advice from expert consultants.

            
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10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Females of Childbearing Potential (FCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered FCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
10.6.1.
Contraception Guidance:
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively.  The required duration of contraception is described below:

            
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Female subjects of childbearing potential (FCBP) must agree to use an effective 
method of contraception starting at the first dose of chemotherapy and continuing for 
at least 12 months, or 4 months after the gene modified cells are no longer detected in 
the blood, whichever is longer.
Male subjects must be surgically sterile or agree to use a double barrier contraception 
method or abstain from heterosexual activity with a female of childbearing potential
starting at the first dose of chemotherapy and continuing for 4 months thereafter or 
longer (if indicated in the country specific monograph/label for cyclophosphamide).
Effective methods of contraception include: intra-uterine device, injectable hormonal 
contraception, oral contraception, or two adequate barrier methods (e.g. diaphragm with 
spermicide, cervical cap with spermicide, or female condom with spermicide – spermicides alone 
are not an adequate method of contraception).
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local Regulatory Agencies and IRBs/IECs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.
The contraception guidelines should continue to be followed during long-term follow up.
10.6.2.
Collection of Pregnancy Information
10.6.2.1.
Female Participants who become pregnant
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described 
in Section 10.4.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.

            
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Any female participant who becomes pregnant while participating in the study will be 
discontinued from further efficacy assessments (exposure to radiation from imaging 
studies is contraindicated in pregnancy), and will follow the LTFU schedule.
10.6.2.2.
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive ADP-A2M4.
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 

            
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10.7.
Appendix 7: Long Term Follow Up
10.7.1.
Background to Safety Monitoring in LTFU
10.7.1.1.
Monitoring and Management of Replication-Competent Lentivirus (RCL)
Replication Competent Lentivirus (RCL) is a theoretical risk associated with the use of lentiviral 
vectors; no RCL has ever been detected in vitro or in vivo. The risk is derived from the detection 
of replication competent retrovirus (RCR) during the use of early 
retroviral vector packaging 
systems which were inadequately designed to avoid recombination events between the vector and 
packaging components Miller, 1990 . RCR resulted in death due to the onset of lymphoma in 3
of 10 monkeys after receiving bone marrow cells transduced with an RCR contaminated vector lot 
Donahue, 1992 . 
however as a result of the Donahue study, RCR/RCL must continue to be rigorously evaluated in 
vector and cell lots, and in subjects post infusion with any product involving a retrovirus FDA,
2006; EMA, 2009 .
A RCL may be generated during the production phase or subsequently after introduction of vector 
transduced cells into the subject. RCL may be generated by homologous or non-homologous 
recombination between the transfer vector and packaging elements, or endogenous retroviral 
elements Chong, 1998; Garrett, 2000 . A RCL resulting from the production phase of the 
lentivirus used in this trial is highly unlikely since elements are incorporated in the design of the 
vector system that minimize vector recombination and generation of RCL. Nevertheless, 
generation of an RCL by recombination with an endogenous virus (i.e., HIV) in the subject 
following infusion of the cell product remains a theoretical possibility. The consequences of such 
recombination events could be neutral, could reduce the replication rate or pathogenicity of the 
subject’s endogenous virus, or could increase the replication rate or pathogenicity of the subject’s 
endogenous virus. Since the development of a strain with increased pathogenicity would pose 
greater risk to both the subject and their close contact(s), periodic monitoring for RCL is conducted 
during the course of the trial and during the 15 year follow up.
10.7.1.2.
Insertional oncogenesis
Monitoring for insertional oncogenesis follows the recommendations set forth in the FDA and 
EMA guidance FDA, 2006a; FDA, 2006b; EMA, 2009 .  Insertional oncogenesis is a theoretical 
risk in T cells transduced with a lentiviral vector.  T cells appear resistant to transformation by 
integrating viruses Cattoglio, 2010; Newrzela, 2008 . However, there are cases of oncogenesis 
-retroviral transduced stem cells.  Four  of nine subjects with X-linked severe combined 
immunodeficiency (SCID-X1) treated with retrovirus transduced stem cells were found to have 
insertion near the LMO2 proto-oncogene promoter, leading to aberrant transcription and 
expression of LMO2 which resulted in acute T-
Hacien-Bey-Abina,  
2003; Hacien-Bey-Abina, 2014
ditionally,  two subjects treated for X-linked chronic 
granulomatous disease (X-CGD) with retroviral transduced stem cells demonstrated insertional 
activation of the EVI1 transcription factor which resulted in genetic instability, monosomy 7 and 
clonal pro
Stein, 2010

            
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10.7.2.
Testing for RCL and Persistence
RCL will be monitored using a PCR-based assay that detects and measures copies of the gene 
coding for the vector’s envelope protein, namely VSV-G that is necessary for the assembly of 
pseudotyped infectious lentiviral particles but absent from the vector’s backbone. The scheme for 
RCL testing is presented in Figure 1 below.  RCL testing and monitoring will take place on 
subject’s peripheral blood mononuclear cells (PBMCs) which will be collected at Baseline and 
then at 3, 6, and 12 months post-infusion and annually from year 2-15.   Samples will be tested for 
the presence of VSV-G DNA copies. 
If all samples are negative in year one, PBMC samples will be collected and archived annually
until 15 years post-infusion. Samples will be archived at Adaptimmune’s centralized biorepository.  
If a positive VSV-G DNA signal is obtained, the study investigator will be informed and the 
subject will be scheduled for a retest as soon as possible and no later than one month after the 
initial positive result was reported to the Sponsor.   The DSMB will be notified and a review by 
Adaptimmune’s Safety Review Team and Safety Governance Board will take place. 
Response to potential outcomes of second test:
If the second test is negative, then subject samples will continue to be tested for VSV-G 
DNA copies until VSV-G DNA copies are not detected for 3 consecutive annual 
assessments as described in Figure 1, at which time the subject samples will be collected 
and archived annually until year 15.
If the second test is positive, infusions for all subjects receiving T cells modified with the 
same vector lot will be postponed. The subject with the confirmed positive VSV-G signal 
will be scheduled for leukapheresis and a biological RCL test will be performed on the 
leukapheresis product.  The biological RCL test assesses whether there is active production 
Manilla, 2005
If the biological RCL test is positive, all infusions using the same T cell receptor in the 
interventional protocol(s) will be halted.  An action plan will be discussed with FDA and other 
regulatory authorities and experts as appropriate.  Additional subjects will not be treated with the 
same T cell receptor until such time as a plan is completed, reviewed, and agreed upon.  
If the biological RCL test is negative, infusions for all subjects can resume.
Regulatory agencies and the gene therapy community have previously discussed measures to be 
taken should a biological RCL be conf
FDA, 2006a
probability and characteristics of a RCL are unknown, no concrete plans have been put in place. 
As of the writing of this protocol, it is agreed the subject must be isolated and no additional subjects 
treated with the same T cell receptor therapy until a plan is agreed upon as outlined above.
The following approaches have been discussed for subject management:
1. Intensive follow up of subject in consultation with FDA, and other regulatory authorities, 
NIH, gene therapy experts, study investigators, and HIV physicians.
2. Provide targeted antiretroviral therapies based on genotyping of the RCL.

            
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Figure 1:
Flow chart for testing for Replication Competent Lentivirus (RCL)
PBMC samples will be collected and used as the “surrogate sample” for monitoring persistence of 
gene modified cells in subjects. Subject samples will be tested for persistence at 3, 6 and 12 months 
post-infusion and every 6 months for 5 years and annually from year 6-15 in accordance with the 
FDA and EMA guidance FDA, 2006a; FDA, 2006b; EMA, 2009 .  The scheme for testing for 
persistence is presented in Figure 2.
The samples will be tested using a PCR-based method to detect the presence of the integrated 
vector sequences Psi DNA, both of which are part of the lentiviral vector used to transduce T cells. 
Detection of Psi DNA copies reflects persistence of the genetically modified T cells.  If at 1 year 
or beyond post-infusion, greater than 1% PBMCs test positive for vector sequences, the subject’s 
PBMCs will be evaluated for integration site analysis (see Figure 2).  If no gene modified cells are 
-infusion (for example, 
negative persistence assessments at year 4, 4.5 and 5), no further monitoring of PBMCs is required 
for persistence and collection of samples for persistence may be discontinued.   NOTE: Samples 
for RCL must continue to be collected and archived annually for 15 years post-infusion.  
Hematology and chemistry assessments may also be discontinued.  
Test for RCL
Yr 1: mth 3, 6, 12 
Yr2-15: annually
YES
NO
YES
NO
Continue screening
as described
Postpone all infusions 
from same vector lot
Leukapherese positive subject 
and perform 
Biological RCL on product1
YES
NO
Inform investigator and retest 
subject within 30 days
Continue screening 
as described
RCL Positive?
Positive on re-test?
Isolate subject and 
manage accordingly2
STOP all infusions 
from vector lot
Positive?
1 Biological RCL assesses potential to 
grow replicating virus from subject’s 
leukapheresed cells
2 Protocol describes subsequent
subject management
Continue screening
as described
Resume all infusions 
from vector lot
Samples negative in first year or 
negative for 3 consecutive tests?
YES
NO
Continue screening 
as described
Collect sample 
and archive

            
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Figure 2:
Flow Chart for Testing for Persistence
10.7.3.
Integration Site Analysis
If persistence, as detected by the presence of vector sequences (Psi DNA copies), is present in 
>1% of PBMC at 1 year or beyond post-infusion, DNA from the subject’s PBMCs will be sent 
for Next-Gen Sequencing for integration site analysis.  Integration site analysis assesses clonality 
and the possibility of insertional oncogenesis.  
cells; 2) oligoclonality is defined as 2-
If there is clonal dominance in the genetically modified T cell population (either monoclonality 
or oligoclonality) the persistence assessment will be repeated within 3 months on a new sample.  
If the repeated analyses demonstrates: 1) persistent monoclonality, 2) other evidence of 
insertional oncogenesis (for example, integration of the vector in the promoter region of a known 
oncogene or tumor suppressor gene), or 3) clonal expansion (an increase in percent 
predominance of a clone), the DSMB will be notified and there will be a review by 
Adaptimmune’s Safety Review Team and the Sponsor’s Safety Governance Board to develop a 
Test for Persistence
Yr 1:  mth 3, 6, 12
Yr 2-5:  every 6 mths
Yr 6-15:  annually
YES
Persistence Positive?
a - Insertional site analysis will assess 
insertional oncogenesis, as well
b - Protocol describes subsequent
subject management
YES
NO
YES
NO
YES
NO
YES
NO
Continue 
screening as 
described
NO
Inform investigator and 
test for Integration site 
analysis (and clonality)
(after 1 yr post-infusion)
Continue 
screening as 
described
Mono/oligoclonal?
Continue screening
as described
1. Inform 
regulators 
within 30 d
2. Monitoring 
plan developed 
for subjectb
Continue 
screening as 
described
1. Inform 
regulators 
within 30 d
2. Continue 
screening as 
described
At least one:
-Persistent 
monoclonality
-Evidence of 
insertional 
oncogenesisa
-Clonal expansion
Stable 
oligoclonalitya
Polyclonality
Re-test for persistence 
within 3 mths
Stop sample 
collection
Continue 
screening as 
described
Negative for 3 
consecutive tests?
5 yrs 
post-infusion?

            
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monitoring plan specific to the health care risk and strategies to inform appropriate subjects, 
investigators, FDA and other regulators of the findings.  
If the integration site analysis indicates polyclonality of the genetically modified T cell 
population then screening for persistence continues as scheduled (Table 2, Figure 2).
10.7.4.
Letter to Physician – LTFU notification
Dear 
Your patient 
has participated in a clinical research study, interventional study 
name and number , that requires 15 year monitoring for adverse events. To aid in reporting of 
adverse events that are possible related to the clinical research study, we are asking the patients 
on our research study to designate a primary care or infectious disease physician that may help in 
the monitoring and reporting of adverse events. Your patient has designated you. If upon any of 
your visits with your patient, any of the following events are reported or discovered, please 
contact the study nurse or physician as soon as possible:
New Malignancies
New incidence or exacerbation of a pre-existing neurological disorder
Excluding all Grade 1 neurologic AEs and grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder
Excluding all Grade 1 autoimmune AEs and grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
All rheumatologic disorders will be reported irrespective of grade
New incidence of a hematologic disorder
Excluding cytopenias following cytotoxic chemotherapy before bone marrow 
recovery
Excluding Grade 1 and 2 laboratory abnormalities, unless the Investigator 
considers clinically significant
Opportunistic and/or serious infections
Excluding infections secondary to chemotherapy induced cytopenias
Unanticipated illness or hospitalization deemed at least possibly related to gene 
modified cell therapy

            
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If your patient experiences any of these events, please refer them back to their study physician.  
Please contact the study coordinator below as soon as you can so that they can record the event 
and then monitor your patient’s health if necessary. When you call, remember to mention the 
protocol number of the study which is ADP-0044-002, patient ID 
and the study title 
which is “A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in 
subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma”
Study Physician:
Name:  
physician
Phone:  
physician
Email:  
physician e-
Study Coordinator:
Name:  
Address:  
Phone:  
Email:  
e-
If you have any questions about this letter or the study itself, please do not hesitate to contact the 
above study nurse or physician.
Thank you for your support in helping us to monitor for delayed adverse events.
Best regards,
physician/co

            
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10.8.
Appendix 8:  Efficacy Reporting
10.8.1.
RECIST 1.1 for Evaluating Response in Solid Tumors
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. CT with contrast is the best 
currently available and reproducible method to measure lesions selected for response assessment. 
MRI is also acceptable in certain situations (e.g., for body scans but not for lung). Ultrasound 
(US) should not be used to measure tumor lesions.  The same modality should be used when 
comparing or making assessments.
Clinical lesions will only be considered measurable when they are superficial an
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a subject to be considered in complete response.
Cytology and histology can be used in rare cases (e.g., for evaluation of residual masses to 
differentiate between Partial Response and Complete Response or evaluation of new or enlarging 
effusions to differentiate between Progressive Disease and Response/Stable Disease).
Use of endoscopy and laparoscopy is not advised. However, they can be used to confirm 
complete pathological response.
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment.
Measurable lesions
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans 
have slice thickness >5 mm, the minimum size should be twice the slice thickness).
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes to be considered pathologically enlarged and measurable, a 
by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed.
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered measurable if the soft tissue component meets the 
definition of measurability for non-nodal lesions described above.

            
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‘Cystic lesions’ thought to represent cystic metastases can be considered measurable 
if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target 
lesions.
Non-measurable lesions
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm 
or pathological lymph nodes with 10 to <15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. Blastic bone lesions are non-measurable.
Lesions with prior local treatment, such as those situated in a previously irradiated 
area or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion. Study 
protocols should detail the conditions under which such lesions would be considered 
measurable.
Target Lesions
Measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements.
All measurements should be recorded in metric notation using calipers if clinically 
assessed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters, which will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. If lymph nodes are to be 
included in the sum, only the short axis will contribute.
Non-target Lesions
All lesions (or sites of disease) not identified as target lesions, including pathological lymph 
nodes and all non-measurable lesions, should be identified as non-target lesions and be recorded 
at baseline. Measurements of these lesions are not required and they should be followed as 
‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’.
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm

            
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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note:  the appearance of one or more new lesions is also 
considered progression – see below) 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Special notes on the assessment of target lesions:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  When 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even 
if complete response criteria are met since a normal lymph node is defined as having 
a short axis of <10 mm.
Target lesions that become ‘too small to measure’.  While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small.  However, sometimes lesions or 
lymph nodes become so faint on a CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’, in which case a default value of 5 mm should be assigned.  
Lesions that split or coalesce on treatment.  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis)
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits.

            
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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal
progression of existing non-target lesions.
Special notes on assessing progression of Non-Target lesions
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
When subject has measurable disease.  To achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.
When subject has only non-measurable disease. There is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified, a useful 
test that can be applied is to consider if the increase in overall disease burden based 
on change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease. Examples include an 
increase in a pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic 
disease from localized to widespread.
New lesions
The appearance of new malignant lesions denotes disease progression:
The finding of a new lesion should be unequivocal (i.e., not attributable to differences 
in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor, especially when the subject’s baseline lesions show 
partial or complete response).
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the scan where the new lesion was first identified.
A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and disease progression.
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up – is PD based on a new 
lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up:

            
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If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.
Summary of the overall response status calculation at each time point:
Target Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required1
CR
CR
No
CR
>4 wks. Confirmation2
CR
Non-CR
Non-PD
No
PR
>4 wks. Confirmation3
CR
Not evaluated
No
PR
PR
Non-CR
Non-PD
Not evaluated
No
PR
SD
Non-CR
Non-PD
Not evaluated
No
SD
Documented at least once >4 
wks. from ADP-A2M4 infusion
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
No prior SD, PR or CR
Any
PD3
Yes or No
PD
Any
Any
Yes
PD
1.
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion Eisenhauer, 2009
2. Only for non-randomized trials with response as primary endpoint
3.
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression

            
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Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. Confirmation of 
response is established by no evidence of disease progression at the subsequent time point. This
will also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials.
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol.
Missing Assessments and Non-evaluable Designation
When no imaging/measurement is done at all at a particular time point or the imaging is 
technically unreadable, the subject is not evaluable (NE) at that time point. If only a subset of 
lesion measurements are made at an assessment, usually the case is also considered NE at that 
time point, unless a convincing argument can be made that the contribution of the individual 
missing lesion(s) would not change the assigned time point response. This would most likely 
happen in the case of PD.

            
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10.9.
Appendix 9: ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Oken, 1982

            
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10.10.
Appendix 10:  EQ-5D-3L Health Questionnaire (SAMPLE)

            
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10.11.
Appendix 11:  

            
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10.12.
Appendix 12: Abbreviations
The following abbreviations and specialist terms are used in this study protocol.
AE
Adverse event
ALK
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
BBB
Bundle branch block
BOR
Best overall response
BP
Blood pressure
CAR
Chimeric Antigen Receptor
CBC
Complete blood count
CDC
Centers for Disease Control
cfDNA
Cell free DNA
CFR
Code of Federal Regulations
CHF
CLIA
Congestive heart failure
Clinical Laboratory Improvement Amendments
CMV
Cytomegalovirus
COPD
Chronic Obstructive Pulmonary Disease
CR
Complete response
CRP
C-reactive protein
CRO
Contract Research Organization
CRS
Cytokine release syndrome
CSR
Clinical Study Report
CT
Computerized tomography
CTA
Cancer-testis antigen
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
DoSD
Duration of stable disease

            
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DSMB
Data Safety Monitoring Board
EBV
Epstein Barr virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic Data Capture
EDTA
Ethylene-diaminetera acetic acid
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
FCM
Flow cytometry
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin embedded
FTIH
First Time In Human
5-FU
5-Fluorocuracil
GCP
Good clinical practice
G-CSF
Granulocyte-colony stimulating factor
GFR
Glomerular filtration rate
GGTP
Gamma-glutamyl transpeptidase
GI
Gastrointestinal
GLP
Good laboratory practice
GMP
Good manufacturing practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HPV
Human papilloma virus
IB
Investigator’s Brochure
IBW
Ideal body weight
ICANS
Immune Effector Cell-Associated Neurotoxicity Syndrome
ICE
Immune Effector Cell-Associated Encephalopathy
ICF
Informed Consent Form
ICH
International Council on Harmonization
ICU
Intensive care unit

            
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ID
Identifier
IEC
Independent Ethics Committee
IFN
Interferon
IHC
Immunohistochemistry
IL
Interleukin
IMRT
Intensity modulated radiation therapy
IND
Investigational New Drug application
ISL
Investigator Safety Letters
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent-to-Treat 
IVD
In vitro diagnostic
mITT
Modified Intent-to-Treat 
IV
Intravenous
K-M
Kaplan-Meier
LDH
Lactic acid dehydrogenase
LLOQ
Lower Limit of Quantification
LMO2
LIM domain only 2
LTFU
Long term follow up
LTR
Long terminal repeat
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major histocompatibility complex
MHRA
Medicines and Healthcare Products Regulatory Agency
MRCLS
MRI
Myxoid/Round Cell Liposarcoma
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple-gated acquisition scan
NCI
National Cancer Institute
NIH
National Institutes of Health
NK
Natural killer cell
NS
Normal Saline
NSCLC
Non-small cell lung cancer

            
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Page 149 of 161
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PI
Principal Investigator
PTT
Partial thromboplastin time
PR
Partial response
qPCR
Quantitative polymerase chain reaction
RAC
Recombinant DNA Advisory Committee
RC
Research Committee
RCL
Replication competent lentivirus
RCR
Replication competent retrovirus
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RT
Radiation therapy
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCCHN
Squamous cell carcinoma of the head and neck
SCID-X
Severe combined immunodeficiency disease – X linked 
SD
Stable disease
SGPT
Serum glutamate-pyruvate transaminase
SIN
Self-inactivating
SOP
Standard operating procedure
SPEAR
Specific Peptide Enhanced Affinity Receptor
SPM
Study Procedures Manual
SUSAR
Suspected, unexpected serious adverse reactions
TCR
T cell receptors
TILs
Tumor-infiltrating lymphocytes
TKI
Tyrosine kinase inhibitor

            
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TTR
Time to response
TURBT
Transurethral resection of bladder tumor
ULN
Upper limit of normal
VSV-G
Vesicular Stomatitis Virus G glycoprotein
WBC
White blood cell
WHO
World Health Organization
X-CGD
X-linked chronic granulomatous disease

            
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10.13.
Appendix 13: Protocol Amendment History
Protocol Amendment 2 dated 20March 2020 is replaced by Protocol Amendment 3 dated 
05February 2021.
Sections amended
Change
Rationale for change
1.3.1, 4.1.1, 4.2.1.1,
Inclusion of additional 
requirements for remote 
consenting for buccal swab 
(HLA) and /or MAGE-A4 
antigen testing. 
Testing for HLA with buccal 
swab
Updated to provided 
clarification of requirements 
when remote screening is 
performed 
1.3.1, 6.2.1, 8.4.10 
Inclusion of adjustment of 
fludarabine dose for subjects with 
renal impairment 
Updated to give additional 
clarification 
1.3.1, 3, 8.7.2, 9.3.3,
10.11
Inclusion of EORTC-QLQ-C30
questionnaire for subjects 
participating in Cohort 2
New questionnaire is to be 
used In subjects in cohort 2
1.1, 1.3.1, 8.3.1
Clarification that CT/MRI scans 
conducted between Week 4 to 
Week 16 should be at least 28 
days apart
Conducting scans 28 days 
apart ensures compliance with 
RECIST 1.1 requirements
2.2.3
Updated data pertaining to safety
and efficacy of ADP-A2M4
Make consistent with current
ADP-A2M4 Investigator’s
Brochure
1.1, 2.1, , 2.2.4, 4.1, 
4.2, 5.1, 5.2, 8.2.3
Inclusion of Cohort 2 in synovial 
sarcoma subjects
Incldue Cohort 2 for synovial 
sarcoma patients subjectss 
2.2.4, 2.2.5, 
Amended to align with current 
available data
Aligned with current known 
data surrounding synovial 
sarcoma 
3, 9, 9.1, 9.2, 9.3.2, 
9.3.3
Inclusion of separate Cohorts 1 & 
2
Additional cohort has been 
added to further assess 

            
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patients with synovial 
sarcoma 
1.1, 4.1, 4.2, 5.5, 9.2
Clarification that first 45 subjects 
will be included in Cohort 1 and 
addition of subsequent 
independent Cohort 2 
Language added to clarify 
how many subjects will be 
dosed in each cohort 
1.1, 3, 9.3.2, 9.3.3
Clarification that the primary 
efficacy endpoint is Overall 
Response Rate per RECIST v1.1 
by independent review for Cohort 
1.  Secondary endpoints and 
safety endpoints were updated to 
reflect addition of new cohort.
Language updated to reflect 
addition of new cohort and 
that no new hypotheses testing 
is required.
4.3
Additional evidence for dose 
included
Provide evidance for dose 
range up to 10 × 109
1.1, 5.2
Inclusion criteria expanded for 
subjects who have previously 
received anthracycline or 
ifosfamide
To provide clarification of 
systemic therapy inclusion 
1.1, 5.2
Inclusion laboratory values table 
updated
Clarification of inclusion 
criteria based on ANC,  
Prothrombin Time or INR, 
and GFR
1.1, 5.3
Updated exclusion criteria for 
subjects who have a history of 
Symptomatic CNS metastases  
Updated to clarify and be 
clearer regarding exclusion of
patients with  a history of 
Symptomatic CNS metastases
1.1, 5.3 
Exclusion of  subjects with 
incipient compression/occlusion 
of a vital structure
Included in exclusion criteria 
following safety event and as 
recommended by FDA
1.1, 5.3, 10.5.3.1
Addition  of COVID-19 
requirements  
Information added for 
COVID-19 requirements 
6.1
Updated to allow for  local 
luekapheresis 
Updated to allow local 
leukapheresis 

            
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6.2
Granulocyte colony stimulating 
factor (G-CSF) guidance  updated
Updated to align with current 
safety data 
6.5.2, 6.5.2.1
Addition of Guidance on COVID-
19 vaccinations 
Updated to clarify guidance  
related to COVID-19 
vaccinations 
8.1.2
Updated to reflect additional 
information on disease history to 
be collected in eCRF
Updated to include site and 
size of tumor as well as last 
known tumor stage  
8.4.8.1
Updated to confirm that   QTcB or 
QTcF are acceptable 
Updated to confirm that  
QTcB or QTcF are also 
acceptable for collection
8.4.13
Updated to clarify requirements 
for administration of 
anticoagulants.  
Updated to clarify the need 
for either a low molecular 
weight heparin injection or a 
novel oral anticoagulan
8.6.3
Clarification of timing of Baseline 
liquid biopsy collection 
Updated to include collection 
at baseline 
9.1
Reference to CDx analysis 
population removed 
Removed as information 
regarding CDx analysis is 
held outside of protocol
9.1
Reference to PP Polulation 
removed
Based on subjects enrolled to 
date no major protocol 
violations where subjects will 
be excluded from primary 
analysis
9.3.3
Removed reference to QOL 
exploratory endpoints.  
Analysis of exploratory 
endpoints will be addressed in 
the Statistical Analysis Plan
10.4.1
Events meeting the AE definition 
updated
Updated to give clarity 
10.4.4
SAE reporting updatedto remove 
location of SAEW
Nore required to be referenced 
in protocol 

            
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10.5.4.1
Irradiated Blood Product section 
updated
Updated as per latest guidance
10.5.6
Updated Management of CRS
Updated as per latest guidance 
10.5.8
Updated Management of 
prolonged cytopenia 
Updated as per latest guidance 
5.2, 8.4.9, 9.3.2, 
10.2.1, 10.3, 10.4.6, 
10.4.7
Administrative
Administrative updates, 
corrections and clarifications

            
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10.14.
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Turtle CJ, Berger C, Sommermeyer D, et al. Anti-CD19 Chimeric Antigen Receptor-Modified T 
Cell Therapy for B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: 
Fludarabine and Cyclophosphamide Lymphodepletion Improves In Vivo Expansion and 
Persistence of CAR-T Cells and Clinical Outcomes. Oral presentation, Session: 624 American 
Society of Hematology Annual Meeting  2015.
Van Tine BA et al. Durable Responses in Patients with Synovial Sarcoma in the Phase 1 Trial of 
ADP A2M4 (MAGE A4), CTOS, November 2020. 
Votrient™ (pazopanib) EU Summary of Product Characteristics. October 2015
Votrient™ (pazopanib) US Prescribing Information.  September 2015.  
Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of 
regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res. 2003;9(2): 606-
612.
World Health Organization classification of tumours. Pathology and genetics of tumours of soft 
tissue and bone. 2002. C.D.M.Fletcher, K.K.Unni, and F.Mertens, editors. IARC Press, Lyon. 
360-362.
www.allelefrequencies.net 
www.Clinicaltrials.gov
Yang B, O’Herrin SM, Wu J, et al. MAGE-A, mMage-b, and MAGE-C proteins form complexes 
with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines.  Cancer Res. 
2007; 67:9954-9962. 
YESCARTA EU SmPC https://www.medicines.org.uk/emc/product/9439/smpc
YESCARTA (axicabtagene ciloleucel) USPI, Novartis Pharmaceuticals (Feb 2018). 
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-
axicabtagene-ciloleucel Oken 1983 (ECOG Score Reference)

Study Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects 
with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
NCT number: NCT04044768 
Document: Protocol  
Document Date: 02 Mar 2021 

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: UK-3.0
CONFIDENTIAL
Date: 02MAR2021
Page 1 of 164
PROTOCOL NUMBER ADP-0044-002
A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects 
with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
(SPEARHEAD 1 STUDY)
PROTOCOL VERSION: AMENDMENT 3, UK VERSION 3.0
DATE: 02MAR2021

            
Investigational Product: ADP-A2M4
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Version: UK-3.0
CONFIDENTIAL
Date: 02MAR2021
Page 2 of 164
INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™T 
Cells in Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma
(MRCLS)
I, the undersigned, have reviewed the protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to International Council for Harmonization (ICH) 
tripartite guideline E6 (R2): Guideline for Good Clinical Practice (GCP) and all the ethical and 
regulatory considerations stated. I have read and understood the contents of the ADP-A2M4
Investigator’s Brochure.
Investigator Name
Investigator Title
Investigator Site and Address
Investigator Signature
Date

            
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CLINICAL STUDY PROTOCOL
Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™T Cells in
Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma (MRCLS)
Product Name: ADP-A2M4
Protocol Number: ADP-0044-002
IND Number: 17235
EudraCT Number: 2019-000589-39
DATE OF ORIGINAL PROTOCOL: 25FEB2019
Amendment Number
Date
Reason for Change
Original
25FEB2019
NA -
Amendment 1
04JUN2019
Change in the lymphodepletion 
regimen
Addition of ECG at Day 5
Added upper age limit
Increase entry criteria for ANC, 
platelets, GFR
Additional exclusion criteria under 
uncontrolled intercurrent illness
Emerging data for ADP-A2M4 
added
Updated study physician
Administrative changes

            
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CONFIDENTIAL
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Amendment Number
Date
Reason for Change
Amendment 1, UK Original (UK-1.0)
02DEC2019
MHRA requested changes: 
-
requirement for 10 days 
hospitalization
-
clarification of subject 
access to intensive care unit
-
updated contraceptive 
guidance
-
requirement for serum 
pregnancy test at screening
-
clarification of clinically 
significant Grade 1 or 2 lab 
abnormalities reported as AE
-
added guidance for diagnosis 
and management of GVHD
-
added 2 additional stopping 
criteria
-
added ECG Day 2
-
added exclusion for history 
of brain metastasis 
Administrative changes

            
Investigational Product: ADP-A2M4
Protocol Number: ADP-0044-002
Version: UK-3.0
CONFIDENTIAL
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Page 5 of 164
Amendment Number
Date
Reason for Change
Amendment 2
08JUN2020
Updates and clarifications to HLA 
criteria 
Removed futility analysis and 
associated protocol aspects
Updated number of subjects 
Decreased duration of enrollment
Increased LVEF criteria
Clarification of washout for prior 
gene therapy
Added updated data from current 
ADP-A2M4 Investigator’s Brochure
Update to CRS management 
guidelines 
Updated Grading for Cytokine 
Release Syndrome and Neurologic 
Toxicity Associated with Immune 
Effector Cells
Inclusion of optional remote consent 
for MAGE-A4 tissue testing and/ or 
buccal/ mouth swab test for HLA 
assessment at participating sites
Administrative changes and 
clarifications

            
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Version: UK-3.0
CONFIDENTIAL
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Page 6 of 164
Amendment Number
Date
Reason for Change
Amendment 3, UK Original (UK-3.0)
02MAR2021
Update to sponsor contacts 
Addition of Cohort 2 (45 synovial 
sarcoma subjects)
Updates to safety and efficacy 
information to align with current IB
Information added for COVID-19 
requirements
Exclusion for compression/occlusion 
of a vital structure added
Addition of EORTC QLQ-C30 (Cohort 
2 only)
Removal of CDx and PP Population 
definitions
Additional details added throughout for 
additional clarity of wording
Template language updated
CONFIDENTIALITY STATEMENT
This document contains information which is the property of Adaptimmune LLC, USA, and 
therefore is provided in confidence for your review. It is understood that this information will 
not be disclosed to others without written approval from Adaptimmune LLC.
DECLARATION
This study will be conducted in compliance with ICH GCP, all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of Helsinki 
(with amendments), and in accordance with local legal and regulatory requirements.

            
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TABLE OF CONTENTS
1.
PROTOCOL SUMMARY..........................................................................................18
1.1.
Synopsis......................................................................................................................18
1.2.
Schema........................................................................................................................31
1.3.
Time and Events Table ...............................................................................................32
1.3.1.
Main Time and Events (T&E) Table..........................................................................32
1.3.2.
Long Term Follow Up Phase Time & Events Table..................................................39
2.
INTRODUCTION ......................................................................................................40
2.1.
Study Rationale...........................................................................................................40
2.1.1.
Rationale for using MAGE-A4 TCR in synovial sarcoma and myxoid/round 
cell liposarcoma..........................................................................................................40
2.2.
Background.................................................................................................................40
2.2.1.
MAGE-A4 background ..............................................................................................40
2.2.2.
Discovery of ADP-A2M4...........................................................................................42
2.2.3.
Synovial sarcoma/MRCLS current therapies and Emerging Data from ADP-
A2M4 and other TCRs................................................................................................42
2.3.
Benefit: Risk Assessment ...........................................................................................45
2.3.1.
Benefit.........................................................................................................................45
2.3.2.
Risk.............................................................................................................................45
2.3.3.
Overall benefit: risk conclusion..................................................................................46
3.
OBJECTIVES AND ENDPOINTS............................................................................48
4.
STUDY DESIGN .......................................................................................................50
4.1.
Overall Design............................................................................................................50
4.1.1.
Pre-screening ..............................................................................................................50
4.1.2.
Screening ....................................................................................................................50
4.1.3.
Enrollment ..................................................................................................................51
4.2.
Scientific Rationale for Study Design ........................................................................52
4.2.1.
Pre-Screening for HLA Alleles and MAGE-A4 Expression......................................53

            
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4.2.1.1.
HLA ............................................................................................................................53
4.2.1.2.
MAGE-A4 Expression in Tumor................................................................................53
4.2.2.
T Cell Manufacturing .................................................................................................54
4.2.3.
Lymphodepletion........................................................................................................54
4.2.4.
Long Term Follow-up.................................................................................................55
4.3.
Justification for Dose..................................................................................................55
4.4.
End of Study Definition..............................................................................................55
5.
STUDY POPULATION.............................................................................................56
5.1.
HLA and Antigen Pre-screening ................................................................................56
5.2.
Inclusion Criteria ........................................................................................................56
5.3.
Exclusion Criteria.......................................................................................................59
5.4.
Screen Failures............................................................................................................62
5.5.
Number of Subjects and Study Duration....................................................................62
5.6.
Sites.............................................................................................................................63
6.
STUDY INTERVENTION ........................................................................................64
6.1.
Leukapheresis .............................................................................................................64
6.2.
Lymphodepleting Chemotherapy ...............................................................................64
6.2.1.
Fludarabine dose adjustment for renal impairment ....................................................65
6.2.2.
Mesna..........................................................................................................................66
6.2.3.
G-CSF.........................................................................................................................66
6.3.
Investigational Product ...............................................................................................66
6.3.1.
Premedication .............................................................................................................66
6.3.2.
T Cell Infusion............................................................................................................66
6.4.
Preparation/Handling/Storage/Accountability............................................................68
6.4.1.
Packaging and Labelling.............................................................................................68
6.4.2.
Receipt and Return .....................................................................................................68
6.4.3.
Storage and Handling .................................................................................................68
6.4.4.
Investigational Product Accountability/Traceability..................................................68
6.4.5.
Alert Cards..................................................................................................................69

            
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6.5.
Concomitant Medications...........................................................................................69
6.5.1.
Prohibited Concomitant Medications .........................................................................69
6.5.2.
Permitted Concomitant Medications ..........................................................................70
6.5.2.1.
Vaccinations Including for COVID-19 ......................................................................71
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................72
7.1.
Temporary Study Suspension.....................................................................................72
7.2.
Ending the Interventional Phase.................................................................................72
7.3.
Subject Discontinuation..............................................................................................73
7.4.
Lost to Follow up........................................................................................................73
8.
STUDY ASSESSMENTS AND PROCEDURES......................................................74
8.1.
Background Assessments ...........................................................................................74
8.1.1.
Demographics.............................................................................................................74
8.1.2.
Disease History...........................................................................................................74
8.2.
HLA MAGE-A4 Tumor Antigen Testing, and Cytogenetics.....................................74
8.2.1.
HLA ............................................................................................................................74
8.2.2.
MAGE-A4 Antigen ....................................................................................................74
8.2.3.
Cytogenetics for Diagnosis.........................................................................................75
8.3.
Efficacy Assessments .................................................................................................75
8.3.1.
CT/MRI.......................................................................................................................75
8.3.2.
Survival.......................................................................................................................76
8.4.
Safety Assessments.....................................................................................................76
8.4.1.
Medical History ..........................................................................................................77
8.4.2.
Physical Examination .................................................................................................77
8.4.3.
Prior Anti-cancer Therapies........................................................................................77
8.4.4.
Prior and Concomitant Medications ...........................................................................77
8.4.5.
ECOG .........................................................................................................................77
8.4.6.
Vital Signs ..................................................................................................................77
8.4.7.
Weight and Height......................................................................................................78

            
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8.4.8.
Cardiac Assessments ..................................................................................................78
8.4.8.1.
ECG ............................................................................................................................78
8.4.8.2.
Echo/MUGA...............................................................................................................78
8.4.8.3.
Telemetry....................................................................................................................78
8.4.9.
Brain MRI...................................................................................................................78
8.4.10.
Renal Function Assessment........................................................................................78
8.4.11.
Hematology.................................................................................................................79
8.4.12.
Clinical Chemistry......................................................................................................79
8.4.13.
Coagulation.................................................................................................................79
8.4.14.
Thyroid Function Tests...............................................................................................79
8.4.15.
Hepatic Safety Assessments .......................................................................................79
8.4.16.
Pregnancy Test............................................................................................................79
8.4.17.
Infectious Disease Screening......................................................................................79
8.4.18.
CMV PCR...................................................................................................................80
8.4.19.
ICE Assessment Tool .................................................................................................80
8.4.20.
C-reactive Protein .......................................................................................................80
8.4.21.
Ferritin ........................................................................................................................80
8.4.22.
Persistence (Vector Copies)........................................................................................80
8.4.23.
RCL (VSV-G DNA)...................................................................................................81
8.5.
Adverse Events and Serious Adverse Events.............................................................81
8.5.1.
Time period for collecting AE and SAE Information ................................................81
8.5.2.
Method of Detecting AEs and SAEs ..........................................................................82
8.5.3.
Follow-up of AEs and SAEs.......................................................................................82
8.5.4.
Regulatory Reporting Requirements for SAEs...........................................................82
8.5.5.
Pregnancy ...................................................................................................................83
8.5.6.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs...............................................................................................................84
8.5.7.
AE of Special Interest.................................................................................................84
8.5.7.1.
Cytokine Release Syndrome.......................................................................................84

            
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8.5.7.2.
Neurotoxicity..............................................................................................................84
8.5.8.
Long Term Follow Up Adverse Events......................................................................85
8.5.8.1.
LTFU Letters to Primary Care Physician/Oncologist ................................................85
8.6.
Biomarkers for Exploratory Objectives......................................................................85
8.6.1.
Tumor Biopsy.............................................................................................................87
8.6.2.
Cytokine and Soluble Protein Analysis ......................................................................87
8.6.3.
Liquid Biopsy Collection and Analysis (Blood Plasma)............................................87
8.6.4.
Cell Phenotype and Functional Assays.......................................................................88
8.6.5.
Persistence of ADP-A2M4 TCR+ Cells.....................................................................88
8.7.
Patient-Reported Outcomes........................................................................................88
8.7.1.
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L).............................................88
8.7.2.
EORTC-QLQ-C30......................................................................................................89
9.
STATISTICAL CONSIDERATIONS .......................................................................90
9.1.
Study Populations .......................................................................................................90
9.2.
Statistical Hypotheses and Sample Size Assumptions ...............................................90
9.3.
Statistical Analyses.....................................................................................................93
9.3.1.
Interim Analysis..........................................................................................................93
9.3.2.
Efficacy Analyses .......................................................................................................93
9.3.3.
Safety Analyses ..........................................................................................................94
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS..................................................................................................96
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................96
10.1.1.
Data Handling and Record Keeping...........................................................................96
10.1.1.1.
Data management .......................................................................................................96
10.1.1.2.
Case Report Forms .....................................................................................................96
10.1.1.3.
Site Documentation and Source Data.........................................................................97
10.1.1.4.
Data Retention and Availability .................................................................................97
10.1.2.
Study Monitoring........................................................................................................97
10.1.2.1.
Audits and Inspections................................................................................................98

            
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10.1.3.
Regulatory and Ethical Considerations ......................................................................98
10.1.3.1.
Competent Authority Submissions.............................................................................98
10.1.3.2.
Independent Ethics Committees .................................................................................98
10.1.3.3.
Local regulations/Declaration of Helsinki..................................................................98
10.1.4.
Informed consent ........................................................................................................99
10.1.5.
Confidentiality............................................................................................................99
10.1.6.
Protocol Adherence ....................................................................................................99
10.1.7.
Study Suspension, Study Termination and Study Completion.................................100
10.1.8.
Public Posting of Study Information ........................................................................100
10.1.9.
Clinical Study Report ...............................................................................................100
10.1.10.
Publication Policy.....................................................................................................100
10.1.11.
Financial Disclosure .................................................................................................100
10.2.
Appendix 2: Safety Reviews ....................................................................................101
10.2.1.
Data Safety Monitoring Board..................................................................................101
10.3.
Appendix 3: Clinical Laboratory Tests.....................................................................102
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting......................................................................104
10.4.1.
Definition of AE .......................................................................................................104
10.4.2.
Definition of SAE.....................................................................................................105
10.4.3.
Recording and Follow-Up of AE and/or SAE..........................................................106
10.4.4.
Reporting of SAEs....................................................................................................109
10.4.5.
Hepatic Monitoring and Follow Up Assessments ....................................................109
10.4.6.
Reporting Criteria during Long Term Follow-Up (Years 1-15)...............................111
10.4.7.
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents.......................................................................................................................112
10.5.
Appendix 5: Supportive Care Guidance...................................................................113
10.5.1.
Lymphodepleting Chemotherapy Symptom Management.......................................113
10.5.1.1.
Management of Neutropenia ....................................................................................113
10.5.2.
T-cell Infusion Symptom Management....................................................................113

            
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10.5.3.
Infection....................................................................................................................114
10.5.3.1.
SARS-CoV-2 (COVID-19) ......................................................................................114
10.5.3.2.
Pneumocystis carinii Pneumonia..............................................................................114
10.5.3.3.
Herpes simplex and Varicella zoster ........................................................................114
10.5.3.4.
Cytomegalovirus.......................................................................................................114
10.5.3.5.
Hepatitis B Prophylaxis............................................................................................115
10.5.3.6.
Syphilis .....................................................................................................................115
10.5.3.7.
Other Anti-Microbial Prophylaxis............................................................................115
10.5.4.
Hematologic and Blood Product Support.................................................................115
10.5.4.1.
Irradiated Blood Product...........................................................................................115
10.5.4.2.
CMV screened blood products .................................................................................115
10.5.5.
Management of Autoimmunity.................................................................................116
10.5.6.
Management of Cytokine Release Syndrome...........................................................116
10.5.7.
Management of Encephalopathy Syndrome (ES).....................................................119
10.5.7.1.
Management of ICANS ............................................................................................121
10.5.8.
Management of Prolonged Cytopenia ......................................................................123
10.5.8.1.
Definition of prolonged cytopenia, pancytopenia and plastic anemia......................123
10.5.8.2.
Management of Prolonged Cytopenias.....................................................................124
10.5.9.
Management of Graft-versus-Host Disease (GVHD)...............................................124
10.5.9.1.
Diagnosis of GVHD .................................................................................................125
10.5.9.2.
Grading of GVHD ....................................................................................................126
10.5.9.3.
Management of GVHD.............................................................................................126
10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information ...............................................................................................................128
10.6.1.
Contraception Guidance: ..........................................................................................129
10.6.2.
Collection of Pregnancy Information .......................................................................129
10.6.2.1.
Female Participants who become pregnant ..............................................................129
10.6.2.2.
Male participants with partners who become pregnant ............................................130
10.7.
Appendix 7: Long Term Follow Up .........................................................................131

            
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10.7.1.
Background to Safety Monitoring in LTFU .............................................................131
10.7.1.1.
Monitoring and Management of Replication-Competent Lentivirus (RCL)............131
10.7.1.2.
Insertional oncogenesis.............................................................................................131
10.7.2.
Testing for RCL and Persistence..............................................................................132
10.7.3.
Integration Site Analysis...........................................................................................134
10.7.4.
Letter to Physician - LTFU notification ...................................................................135
10.8.
Appendix 8:  Efficacy Reporting..............................................................................137
10.8.1.
RECIST 1.1 for Evaluating Response in Solid Tumors ...........................................137
10.9.
Appendix 9: ECOG Performance Status ..................................................................143
10.10.
Appendix 10:  EQ-5D-3L Health Questionnaire (SAMPLE)...................................144
10.11.
Appendix 11:  EORTC-QLQ-C30 Questionnaire (SAMPLE).................................147
10.12.
Appendix 12: Abbreviations.....................................................................................149
10.13.
Appendix 13: Protocol Amendment History............................................................154
10.14.
References.................................................................................................................157

            
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LIST OF TABLES
Table 1:
T&E for Pre-Screening and Interventional Phase ......................................................32
Table 2:
T&E for Long Term Follow Up Phase.......................................................................39
Table 3:
Fludarabine and Cyclophosphamide Treatment Schema ...........................................65
Table 4:
Protocol-Required Safety Laboratory Assessments .................................................102
Table 5:
Hepatic Monitoring Criteria .....................................................................................109
Table 6:
Management Guidelines for Cytokine Release Syndrome.......................................117
Table 7:
ICE 10 point neurological assessment [based on Lee, 2019] ..................................119
Table 8:
Grading of Immune Effector Cell-Associated Neurotoxicity (ICANS)...................120
Table 9:
Management of ICANS ............................................................................................122
Table 10:
Overview of Clinical Findings/Symptoms of GVHD ..............................................125
Table 11:
Staging of Dermal, Gastrointestinal and Hepatic Involvement with Acute 
GVHD.......................................................................................................................126
Table 12:
Grading of Acute GVHD..........................................................................................126
Table 13:
Management Guidelines for GVHD.........................................................................127

            
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LIST OF FIGURES
Figure 1:
Flow chart for testing for Replication Competent Lentivirus (RCL) .......................133
Figure 2:
Flow Chart for Testing for Persistence.....................................................................134

            
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Title
A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects with Advanced 
Synovial Sarcoma or Myxoid/Round Cell Liposarcoma
Short Title
SPEARHEAD 1 Study
Protocol Number
ADP-0044-002
Phase
2
Methodology
Subjects with advanced synovial sarcoma or myxoid/myxoid round cell 
liposarcoma (Cohort 1 only) will be Pre-screened to determine appropriate 
human leukocyte antigen (HLA) and tumor antigen status. Only subjects
with advanced synovial sarcoma will be eligible for Cohort 2. Only subjects
expressing at least 1 HLA-A*02 inclusion allele and no exclusion allele and 
whose tumor expresses the MAGE-A4 antigen above the cut-off are 
eligible to undergo further screening for this study.
Subjects who sign the Treatment Informed Consent and meet study entry 
criteria will be enrolled into either Cohort 1 or Cohort 2. Enrolled subjects 
will undergo leukapheresis for collection of autologous cells for processing 
and manufacture into the ADP-A2M4 cell Investigational Product (IP). 
Leukapheresis should be performed as soon as possible after the subject is 
determined to be eligible for study participation. Subjects who have 
enrolled into a Cohort may not enroll into the other Cohort subsequently.
Prior to the administration of lymphodepleting chemotherapy all eligibility 
criteria will be reconfirmed and baseline tumor assessment obtained. 
Anticancer therapy may be administered between screening and 
leukapheresis and between leukapheresis and the start of 
lymphodepletion (bridging therapy), if a subject has progressive disease 
and cannot be treatment-free, but mandatory washout periods must be 
adhered to.
When the ADP-A2M4 cells are available at site, subjects will undergo 
lymphodepleting chemotherapy with fludarabine 30 mg/m2/day for 4 days 
(Day -7 to Day -4) and cyclophosphamide 600 mg/ m2/day for 3 days (Days

            
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-7 to -5) followed by infusion of ADP-A2M4 cells on Day 1. Subjects will 
remain hospitalized for observation for at least 10 days post T cell infusion.
An independent Data Safety Monitoring Board (DSMB) will review the 
ongoing safety during the interventional phase of the study for Cohort 1. 
Cohort 2 will begin once all subjects have been dosed in Cohort 1. Subjects 
in both cohorts will have the following study visits for assessment of 
eligibility, efficacy, safety, health related-outcome and biomarkers: Pre-
Screening, Screening, Leukapheresis, Baseline, Lymphodepleting 
Chemotherapy (Day -7 to Day -4), T cell infusion (Day 1) and immediate 
post infusion monitoring (Day 1 through Day 8), weekly visits until Week 4 
post infusion, then 6, 8, 12, 16 and 24 weeks then every 2 months until 
disease progression. 
Subjects will undergo disease monitoring by magnetic resonance imaging 
(MRI) or computerized tomography (CT) scan at Screening, Baseline, Week 
4, Week 8, Week 12, Week 16 and Week 24, and every 2 months until 
confirmed disease progression. 
Once disease progression is established, no further scans will be 
performed for this study and subjects will switch to the long term follow-
up (LTFU) schedule of visits at Months 2, 3 and 6 followed by 6 monthly 
visits through Year 5 and annually thereafter for Years 6-15. The timepoint 
at which the subject switches will be driven by the timepoint at which the 
subject progresses e.g. if there is disease progression at Week 4, the next 
visit would be due at Month 2; if there is disease progression at Week 12, 
the next visit would be due at Month 6. 
The Primary Efficacy Analysis will be for Cohort 1 only.  Clinical cut-off for 
the primary analysis will occur once the forty-fifth subject dosed in Cohort 
1 has up to 6 months follow-up post T cell infusion. At this time, all safety 
and secondary efficacy endpoints for Cohort 1 only will also be 
summarized to provide supportive evidence to the primary assessment.
Study Duration
Enrollment is expected to continue for approximately 12 months for 
Cohort 1 and for an additional 12 months for Cohort 2.
The study will be considered complete once all enrolled subjects complete 
15 years of follow-up or discontinue the study for any reason. 
Study Center(s)
The study will be conducted in approximately 24 sites in North America 
and Europe. Additional sites may be added at the discretion of the 
Sponsor.

            
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4.
Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or 
myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) 
confirmed by cytogenetics. Inoperable refers to a tumor lesion in 
which clear surgical excision margins cannot be obtained without 
leading to significant functional compromise.
a.
For Synovial Sarcoma (Cohort 1 and Cohort 2): confirmation by 
the presence of a translocation between SYT on the X 
chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may 
be presented in the pathology report as t (X; 18)).
b.
For MRCLS (Cohort 1 only): confirmation by the presence of 
the reciprocal chromosomal translocation t(12;16) (q13;p11) 
or t(12; 22) (q13;q12)
5.
Must have previously received either an anthracycline or ifosfamide 
containing regimen. 1st-line metastatic treatment with ADP-A2M4 is 
permissible if ifosamide +/- doxorubicin has been administered in 
either the pre-operative (neoadjuvant) or post-operative (adjuvant) 
primary tumour setting.  (Subjects who are intolerant of both 
anthracycline and ifosfamide must have previously received at least 
one other type of systemic therapy).  
6.
Measurable disease according to RECIST v1.1.
7.
Positive for HLA-A*02:01, HLA-A*02:03 or HLA-A*02:06 allele via 
Adaptimmune designated central laboratory testing. HLA-A*02 alleles 
having the same protein sequence in the peptide binding domains (P 
group) will also be included. Other HLA-A*02 alleles may be eligible 
after adjudication with the sponsor.
8.
Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 
immunohistochemistry.  All samples must have been pathologically 
reviewed by an Adaptimmune designated central laboratory 
confirming expression.  
9.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 
or 1.
10.
50
11. Fit for leukapheresis and adequate venous access can be established 
for the cell collection.

            
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12. Female subjects of childbearing potential (FCBP) must have a negative 
serum pregnancy test AND must agree to use a highly effective 
method of contraception starting at the first dose of chemotherapy 
and continuing for at least 12 months, or 4 months after the gene 
modified cells are no longer detected in the blood, whichever is longer. 
OR 
Male sexually active subjects are required to use a condom in addition 
to the female partner use of a highly effective form of contraception or 
must agree to abstain from heterosexual activity with a FCBP starting at 
the first dose of chemotherapy and continuing for 4 months thereafter 
(or longer if indicated in the country specific monograph/label for 
cyclophosphamide).
13. Must have adequate organ function as indicated by the laboratory 
values in the table below:

            
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Anti-cancer Vaccine
8 weeks in the 
absence of tumor 
response. The subject 
should be excluded if 
their disease is 
responding to an 
experimental vaccine 
given within 6 months
8 weeks in the absence 
of tumor response.
The subject should be 
excluded if their 
disease is responding 
to an experimental 
vaccine given within 6 
months
Gene therapy using an 
integrating vector
Subjects who have 
received a gene 
therapy using any 
DNA-integrating 
vector other than a 
lentivirus (retrovirus, 
AAV, etc.) are 
excluded from this 
study. Subjects who 
have received a gene 
therapy using a 
lentiviral vector may 
be eligible if they have 
persistence results 
below the lower limit 
of quantification 
(LLOQ) for at least 2 
samples taken at least 
1 month apart. At 
least 1 of these tests 
must be performed by 
Adaptimmune as part 
of Pre-screening or 
Screening.
Not permitted after 
leukapheresis and prior 
to lymphodepletion.
Corticosteroids or any 
other 
immunosuppressive 
therapy. NOTE:  Use of 
topical steroids is not an 
2 weeks 
2 weeks 

            
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4.
History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to fludarabine, cyclophosphamide 
or other agents used in the study.
5.
History of autoimmune or immune mediated disease. Subjects with 
hypothyroidism, diabetes, adrenal insufficiency or pituitary 
insufficiency that are stable on replacement therapy are eligible. 
Subjects with disorders such as asthma, psoriasis or atopic dermatitis 
that are well controlled without requiring systemic 
immunosuppression are also eligible.
6.
Leptomeningeal disease, carcinomatous meningitis or CNS 
metastases.  
7.
Any other prior malignancy that is not in complete remission.  
Resectable squamous or basal cell carcinoma of the skin is 
acceptable. Prior malignancies that have been surgically resected and 
show no evidence of disease are acceptable.  
8.
Uncontrolled intercurrent illness including, but not limited to:
Ongoing or active infection; 
Clinically significant cardiac disease defined by congestive 
heart failure New York Heart Association (NYHA) Class 3 or 
Class 4;
Uncontrolled clinically significant arrhythmia;
Acute Coronary Syndrome (ACS) (angina or MI) in last 6 
months;
Interstitial lung disease (subjects with existing pneumonitis as 
a result of radiation are not excluded, however, subjects must 
not be oxygen dependent);
Congenital or family history of long QT syndrome;
Current uncontrolled hypertension despite optimal medical 
therapy;
History of stroke or central nervous system bleeding; transient 
ischemic attack (TIA) or reversible ischemic neurologic deficit 
(RIND) in last 6 months;
Incipient compression/occlusion of a vital structure (e.g. 
bronchus; superior vena cava; renal outflow tract) which 
cannot undergo prophylactic stenting;

            
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1.2.
Schema

            
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2.
INTRODUCTION
2.1.
Study Rationale
2.1.1.
Rationale for using MAGE-A4 TCR in synovial sarcoma and myxoid/round cell 
liposarcoma
Adoptive T cell therapy (ACT) is a treatment that uses a cancer subject’s own T lymphocytes 
with anti-tumor activity, expanded in vitro and re-infused into the subject. The ultimate objective 
of the process is the stimulation and expansion of potent and antigen-specific T cell immunity.  
There are numerous recent publications and reviews of adoptive T cell therapy [Kalos, 2013; 
Klebanoff, 2016; Maus, 2014; Morgan, 2010; Rosenberg, 2008].
Antitumor activity in ‘‘native’’ T cells may not be sufficient to induce tumor cell death in most 
patients with advanced malignancy. Gene-transfer-based strategies have therefore been 
developed to overcome the consequences of immune tolerance on the tumor-specific T cell 
repertoire. These approaches provide the potential to redirect T cells to effectively target tumors 
by the transfer of antigen-specific affinity-optimized TCRs. 
The majority of clinical approaches have employed T cells engineered to stably express 
transgenes via virus-based transduction. Virus-mediated gene transfer approaches typically 
employ vectors that are derived from gamma retroviruses or more recently lentiviruses.
ADP-A2M4 specific peptide enhanced affinity receptor (SPEAR™) T cells are genetically 
engineered to target the subject’s MAGE-A4 positive tumor in the context of the appropriate 
HLA expression. ADP-A2M4 are autologous CD4 and CD8 positive T cells that have been 
transduced with a self-inactivating lentiviral vector expressing a high affinity MAGE-A4 specific 
T cell receptor (TCR). MAGE-A4 is a cancer/testis antigen (CTA) that has restricted expression 
in normal tissue, and is expressed across a range of solid tumors at varying frequencies.
ADP-A2M4 recognizes the MAGE-A4230-239; GVYDGREHTV peptide derived from the 
MAGE-A4 family of CTAs. Thus, ADP-A2M4 incorporates an affinity enhanced TCR capable 
of recognizing the human leukocyte antigen (HLA)-A*02-GVYDGREHTV antigen complex.
The safety of ADP-A2M4 has been shown in subjects with different tumor types in an ongoing 
Phase 1 study (NCT03132922). Data of another genetically engineered T cell investigational 
product, NY-ESOc259T, in synovial sarcoma provides evidence that TCR therapies can be 
effective in solid tumors [D’Angelo, 2018a].
2.2.
Background
2.2.1.
MAGE-A4 background
The cancer/testis antigens (CTA) comprise a number of genes that have restricted expression to 
the testis, but have been identified by their expression in various tumor types [Caballero, 2009].  
These include NY-ESO-1, MAGE-A family, SSX2, BAGE, GAGE, and CT7 among others.  

            
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Most of these testis-specific genes are coded on the X chromosome. Several of these antigens, 
including MAGE-A3, MAGE-A10 and MAGE-A8, also have expression in placenta [Caballero, 
2009].  In general, melanoma, ovarian cancer and lung cancer, particularly of the squamous cell 
type, have the highest frequency of RNA expression across the CTAs.  Epithelial cancers such as 
breast, bladder and prostate cancer have intermediate expression, with frequency of mRNA 
expression in the range of 30% to 50%.  CTAs often have coordinated expression, with several 
expressed in a single tumor [Gure, 2005].  In addition to RNA, immunohistochemistry is often 
used to determine the expression levels of CTAs.  While it is generally seen that mRNA 
expression of these antigens correlates well with protein expression it should be noted that there 
is frequently heterogeneous expression of protein across the tumor, with strong expression in a 
small subset of tumor cells.  There is also epigenetic and post-transcriptional modification that 
determines protein expression levels under certain conditions.
The function of the CTA in germline tissues or in tumors is generally not well understood.  Some 
MAGE-A proteins do have functions that may enhance tumor growth.  For example, MAGE-A1 
proteins may have a role in suppressing differentiation during spermatogenesis and a similar role 
in inhibiting cell differentiation may be a mechanism by which it promotes tumorigenesis 
[Laduron, 2004; Simpson, 2005].  There is also evidence that members of the MAGE-A family 
modulate key transcription factors such as SKIP, p300, p160 (TIF2)/androgen receptor ER-
and the p53 tumor suppressor [Marcar, 2015].  MAGE-A4 appears to promote cell growth of 
epithelial cells by preventing cell cycle arrest and inhibiting apoptosis.  In one study, 
overexpression of MAGE-A4 was shown to repress p53 targets, such as BAX and CDKN1A 
[Bhan, 2012].  In a yeast-two hybrid study, MAGE-A4 was identified as a binding partner for the 
oncogene, gankyrin [Nagao, 2003].  Through these pathways, MAGE expression may protect 
cells from apoptosis and contribute to the development of tumors by promoting survival [Yang, 
2007].  
MAGE-A4 has been described as having high expression in synovial sarcoma and MRCLS.  A 
recent study showed that 82% of synovial sarcoma samples expressed MAGE-A4 when 
evaluated by Immunohistochemistry (IHC) and high expression of NY-ESO-1 and MAGE-A4 
was significantly correlated with the presence of necrosis and advanced clinical stage [Iura 
2017a].
 
  A further report suggested that 67.7% of MRCLS samples, express 
MAGE-A4 [Iura 2017b].   
 
 
  
 
 
 
 
 

            
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2.2.2.
Discovery of ADP-A2M4
Several peptides derived from MAGE proteins have been identified by mass spectroscopy from 
tumor cell lines, including the human leukocyte antigen (HLA) HLA-A*02-restricted peptide 
MAGE-A4230-239; GVYDGREHTV.  HLA class I molecules are involved in the presentation 
of antigenic peptides on tumors to T lymphocytes.  The prevalence of HLA subtypes varies from 
population to population, the most common in the western world being HLA-A2.  Among the 
HLA-A2 allelic variants, the most prevalent are HLA-A*02:01 (approximately 45% of 
Caucasian and Hispanic population) and HLA-A*02:06 (www.allelefrequencies.net). 
Adaptimmune generated 20 parental TCRs that recognize the HLA-A*02-restricted MAGE-A4 
peptide GVYDGREHTV.  From these, one demonstrated some response toward natively 
MAGE-B2 and MAGE-A4-positive cell lines and was selected for engineering, resulting in 17 
enhanced affinity TCRs that were tested in cellular assays against MAGE-A4 positive and 
negative cell lines and primary cells.  Cellular testing for potency and specificity identified 
ADB1032 as being optimal, demonstrating enhanced potency against MAGE-A4 positive tumor 
cell lines, while retaining a favorable specificity and safety profile. 
The Investigational Product (IP) is comprised of autologous CD4 and CD8 T cells obtained from 
eligible subjects who have MAGE-A4 expressing tumors and who are HLA-A*02 positive.  
Subjects who are HLA-A*02:05 are excluded because alloreactivity has been observed in vitro 
with ADP-A2M4 to this HLA allele.  The T cells undergo self-inactivating (SIN) lentiviral 
transduction with ADP-A2M4 specific nucleic acid under Good Manufacturing Practice (GMP)
conditions.  The resulting polyclonal ADP-A2M4 specific peptide enhanced affinity receptor 
(SPEAR™) T cells are now genetically engineered to target the antigen on the subject’s MAGE-
A4 positive advanced tumor.
2.2.3.
Synovial sarcoma/MRCLS current therapies and Emerging Data from ADP-
A2M4 and other TCRs
Synovial Sarcoma and Myxoid/Round Cell Liposarcoma
Sarcomas are rare malignant tumors originating from mesenchymal cells and their precursors, 
and represent ~1% of all cancers in adults worldwide each year (10% of cancers in children, and 
8% of cancers in adolescents) and ~2% of cancer related mortality [Singer, 2000; Amankwah, 
2013].  The estimated international incidence rates of soft tissue sarcoma ranges between 4 and 6 
cases per 100,000 per year [Stiller, 2013; Ferrari, 2011]. Soft tissue sarcomas consist of 
approximately 50 different histological subtypes.  
Synovial Sarcoma
Synovial sarcoma represents 5% of all soft tissue sarcoma (STS) and is characterized by the 
presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or SSX4 on 
chromosome 18. The disease affects young individuals with a median age in the third decade; 
with 70% of the diagnoses occurring in subjects under 40 years old.
Surgery is the standard therapy for localized disease.  Patients with advanced synovial sarcoma 
receive ifosfamide and/or doxorubicin, as the first-line of therapy [ESMO, 2014]. Doxorubicin-
based first-line metastatic doublet therapies, such as doxorubicin in combination with the anti-

            
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PDGFR alpha monoclonal antibody olaratumab [Lilly, 2019], have not demonstrated improved 
clinical benefit compared to single-agent doxorubicin.
There is no specific standard of care (SoC) in second line therapies and beyond. Pazopanib is 
approved in the U.S and in Europe for patients with synovial sarcoma previously treated with 
chemotherapy [Votrient™ US Prescribing Information, EU SmPC].  A randomized double blind 
placebo controlled Phase 3 trial of pazopanib was conducted in patients with advanced STS.  
Overall response rate (ORR) as assessed by Data Safety Monitoring Board (DSMB) for the 
intent to treat (ITT) population was 4%, median duration of response (DoR) of 9 months, and 
median progression free survival (PFS) of 4.6 months compared with 1.6 months for placebo 
(HR=0.35, p<0.001). Median overall survival (OS) was 12.6 months compared with 10.7 months 
for placebo (HR=0.87; 95% CI: 0.67, 1.12). Only 38 subjects with synovial sarcoma 
(randomized 2:1) were included in the study with a median PFS of 4.1 months in the pazopanib 
arm vs 0.9 months for placebo (HR= 0.43; 95% CI 0.19, 0.98). The response rate is not reported 
by histology [Votrient™ US Prescribing Information, EU SmPC].  In a Phase 2 non-randomized 
study of pazopanib (EORTC Study 62043), responses as assessed by the Investigator were 
reported in 5/37 (13%) subjects with synovial sarcoma [Sleijfer, 2009].   
The response rate in a retrospective analysis of gemcitabine and docetaxel in patients with 
synovial sarcoma was 10% [Abouharb, 2014].  Several other agents have shown no appreciable 
anti-tumor activity in synovial sarcoma; these include many novel classes of agents such as 
HDAC-inhibitors [Cassier, 2013], IGF-1R antibodies [Pappo, 2014; Olmos, 2010], mTOR 
inhibitors [Schwartz, 2013], vascular disrupting agents [Blay, 2015] and anti-CTLA4 antibodies 
[Maki, 2013]. 
Effective treatment options for patients with advanced relapsed synovial sarcoma are limited. 
The median survival upon relapse from first-line therapy is approximately 12 months [Minchom, 
2010] and the ORR from prospective trials for existing therapies 
13%. 
Thirty-eight subjects have received treatment with a single dose of ADP-A2M4 up to 9.9756 x 
109 transduced cells within the phase 1 ADP-0044-001 study.  Synovial sarcoma subjects 
represent the most frequent tumor type in the study and the majority of the subjects treated in 
Group 3/Expansion.  Of the 16 subjects with synovial sarcoma, most subjects were males 
(62.5%), most subjects were White (87.5%) and the median age was 49.0 years (range 31 to 76 
years). The median ADP-A2M4 dose in synovial sarcoma was 9.28 x 109 transduced cells 
(range: 3.44 to 10 x 109). The reported adverse events are consistent with those typically 
experienced by patients with advanced cancer undergoing cytotoxic chemotherapy or cancer 
immunotherapy (e.g, cytopenias, fatigue, CRS). The most common AE 
occurri
25% of subjects with synovial sarcoma were, lymphopenia/lymphocyte count decreased (100%), 
leukopenia/WBC count decreased (93.3%), neutropenia/neutrophil count decreased (88%),
neutropenia/neutrophil count decreased (81. %), anemia/RBC decreased (44%), 
thrombocytopenia/platelet count decreased (44%), hypophosphatemia (44%), rash (19%), CRS 
(13%), decreased appetite (6%) and hypotension (6%). Cytokine release syndrome (any Grade) 
was reported in 88% of the subjects with synovial sarcoma.  There was one (1) Grade 5 SAE of 
prolonged pancytopenia with hypoplastic bone marrow considered possibly related to ADP-
A2M4. In subjects with synovial sarcoma, the ORR (confirmed responses) was 44% (95%CI: 

            
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16.34, 67.71).  The Best Overall Response was PR (7), SD (8), PD (1). Disease control rate was 
94% with 11 patients still alive at time of 1-September-2020 data cut-off. Subject responses were 
durable with a median duration of response of 28 weeks range: 12-72 weeks. [CTOS 2020]. This 
data supports the continued evaluation of ADP-A2M4 in advanced/metastatic synovial sarcoma.
Myxoid/Round Cell Liposarcoma (MRCLS)
MRCLS is a subtype of liposarcoma which is associated with specific translocation, t (12; 16
(q13; p11) or t (12; 22) (q13; q12) and represents about 30-35% of liposarcomas and 5-10% of 
all adult STS (WHO 2002).  MRCLS commonly presents at an age ranging from 35-55 years. 
Myxoid round cell tumors with a round-cell component >5% have a poor prognosis with a 5-year 
survival rate of ~50-75% because they recur locally and tend to metastasize quickly and widely 
[Smith, 1996]. The median time from diagnosis to metastases is 35 months.
Treatment involves the wide surgical excision of the tumor and surrounding tissue. Myxoid 
round cell liposarcoma may be treated with pre-operative chemotherapy and/or pre-operative or 
post-operative radiotherapy [NCCN, 2012]. Doxorubicin and ifosfamide are the first line 
systemic treatment options for patients with metastatic disease. Retrospective analyses in 
previously untreated patients demonstrated response rates of ~38 - 45% [Jones, 2005; Katz, 
2012]. Once patients relapse or develop metastatic disease treatment is aimed at slowing that 
pace of progression.  A variety of therapies are used in the second line setting and beyond 
although only trabectedin and eribulin are approved. A randomized open label phase 2 study of 
trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma enrolled 270 
patients. Patients were randomized to receive either a 24-hour infusion of 1.5 mg/m2 of 
trabectedin once every 3 weeks, or a 3 hour infusion of 0.58 mg/m2 of trabectedin once every 
week for three weeks of a 4 week cycle. The treatment regimen that was determined to be most 
beneficial was the 24-hour infusion of 1.5mg/m2 of trabectedin once every 3 weeks.  One 
hundred and thirty-six patients were randomized to this arm of the study and the ORR was 5.6% 
[Demetri, 2016].
A subsequent randomized, phase 3, open-label, active-controlled trial comparing trabectedin 
(n=345) treatment with dacarbazine (n=173) in patients with unresectable, locally advanced or 
metastatic leiomyosarcoma (73%) or liposarcoma (27%) (dedifferentiated, myxoid round cell, or 
pleomorphic) and previous treatment with an anthracycline-containing regimen and one 
additional cytotoxic chemotherapy regimen demonstrated an overall response rate (ORR of 9.9% 
(CI 0.72, 3.2) with trabectedin, an improvement of median progression-free survival (PFS) of 5.6  
vs 1.5 months on dacarbazine but no difference in overall survival [Demetri, 2016]. Eribulin 
demonstrated an improvement in survival (median OS 13.5 vs 11.5 months; HR= 0.768; 95% CI, 
0.618; 0.954) compared with darcarbazine in subjects with liposarcoma and leiomyosarcoma 
who received 2 or more prior lines of therapy.  There was no difference in PFS and ORR was 
3.9% with Eribulin and 4.9% with darcarbazine in all patients enrolled.  In patients with 
liposarcoma the response rate was 1.4% [Schöffski, 2016].  Despite the approval of these two 
agents, overall survival in patients with relapsed disease remains 12-13 months [Demetri, 2016;
Schöffski, 2016] and the ORR from prospective trials for existing therapies is < 10%.

            
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A TCR T-cell product targeted against the NY-ESO-1 cancer testis antigen has shown potentially 
promising clinical activity in eight MRCLS subjects [D’Angelo, 2018b]. For MAGE-A4, in 
Study ADP-0044-001, two MRCLS subjects were dosed with ADP-A2M4 cells.  At the time of 
Data cut-off, 1 Sept 2020, no MRCLS subjects had responded to ADP-A2M4.  ADP-A2M4 was 
however safe and well tolerated in MRCLS subjects in this phase 1 trial.
2.3.
Benefit: Risk Assessment
The results of clinical and non-Clinical studies conducted with ADP-A2M4 cells are summarized 
in the ADP-A2M4 Investigator’s Brochure.  This section outlines the potential benefits, risks and 
the overall benefit: risk for this study.
2.3.1.
Benefit
Although the basis for including both synovial sarcoma and MRCLS subjects in Cohort 1 of this 
study was the reported high frequency of MAGE-A4 expression in both synovial sarcoma and 
myxoid liposarcoma [Iura, 2017a; Iura, 2017b] as well as the historical clinical activity of the 
NY-ESO-1 TCR in both synovial sarcoma and MRCLS, preliminary evaluation of MRCLS 
response and MAGE-A4 antigen status in both the ADP-0044-001 and Cohort 1 ADP-0044-002 
studies would suggest that ADP-A2M4 is not as clinically active in MRCLS as it is in synovial 
sarcoma possibly because of a comparatively lower MAGE-A4 antigen score distribution. 
For these reasons, Cohort 2 will only enroll subjects with synovial sarcoma as such patients are 
likely to derive the greatest therapeutic benefit from the ADP-A2M4 cell product especially 
since study ADP-0044-001 has shown an ORR of 44% in sixteen heavily pre-treated metastatic 
synovial sarcoma subjects who had a median of three prior lines of treatment [CTOS 2020]. This 
data from study ADP-0044-001 in combination with emerging efficacy findings for synovial 
sarcoma subjects in Cohort 1 of study ADP-0044-002 would indicate that ADP-A2M4 is a 
promising cell product in metastatic synovial sarcoma especially since there is no specific 
standard of care beyond first line ifosfamide and/or doxorubicin for patients with advanced
(inoperable)/metastatic synovial sarcoma.
2.3.2.
Risk
The safety and tolerability of ADP-A2M4 is being assessed in a Phase 1 trial (study ADP-0044-
001) across multiple tumor types and in the ongoing Cohort 1 of study ADP-0044-002 including 
synovial sarcoma and MRCLS. Toxicities observed with ADP-A2M4 are common to other TCR 
or CAR-T therapies or standard of care chemotherapies.  
Toxicities such as CRS, ICANS and pancytopenia/aplastic anemia are specific to TCR and CAR-
T therapies and therefore guidelines for management of these events are included in 
Section 10.5.  An advantage of TCR therapy is that they are generally administered once, and the 
vast majority of toxicities resolve within 4 to 6 weeks after T cell infusion.
Alloreactivity, whereby TCRs reactive towards a given peptide-MHC complex display cross-
reactivity towards different HLA allelic variants, is a theoretical risk. Pre-clinical data indicate 
strong anti-HLA-A*02:05 alloreactivity, making A*02:05 an exclusion allele. Data also indicate 

            
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decreased potency against MAGE-A4230-239 peptide when presented by HLA-A*02:07,
therefore subjects with A*02:07P alleles are ineligible unless they also express an inclusion 
allele. Preclinical studies support the specificity, safety, and anti-tumor activity of ADP-A2M4
and therefore an unacceptable risk of off-target reactivity is not expected. No evidence of 
alloreactivity has been detected in the ongoing Phase 1 study to date.
The study incorporates several measures to address the risks including: 1) extensive preclinical 
evaluation of the ADP-A2M4 which has incorporated learnings from other adoptive T cell 
therapy programs [ADP-A2M4 Investigator Brochure]; 2) based on the preclinical alloreactivity 
data, exclusion of subjects with HLA-A*02:05 in either allele or with HLA-A*02 alleles having 
the same protein sequence as HLA-A*02:05 in the antigen binding domains (P groups); 3) use of 
a validated Clinical Trial Assay for the selection of subjects with MAGE-A4 expression in their 
tumors; 4) treatment in specialized academic centers experienced with the management of 
toxicities associated with autologous T cell therapies; 5) protocol guidelines for management of 
toxicities including cytokine release syndrome (CRS), Immune Effector Cell-Associated 
Neurotoxicity Syndrome (ICANS), and pancytopenia/aplastic anemia as well as preventive 
measures for infectious complications, and 6) a Data Safety Monitoring Board (DSMB) to 
evaluate safety during the course of Cohort 1. 
The potential risks for Cohort 2 (synovial sarcoma only) are expected to be similar to the 
emerging safety profile in Cohort 1 of study ADP-0044-002, as well as similar to the safety 
profile reported in the sixteen synovial sarcoma subjects previously dosed in the phase 1 trial, 
study ADP-0044-001 [CTOS 2020]. Moreover, when combined with the emerging safety profile 
in Cohort 1, the additional 45 synovial sarcoma subjects in Cohort 2 will permit a more deeper 
understanding and a better estimate of the frequency of adverse events of special interest (AESI) 
i.e. incidence of CRS, ICANS and pancytopenia in synovial sarcoma subjects treated with ADP-
A2M4 cells compared to safety data from Cohort 1 alone.
2.3.3.
Overall benefit: risk conclusion
In Cohort 1, based on the initially promising emerging efficacy and safety findings from the 
Phase 1 ADP-A2M4 SPEAR™ T-cell trial (study ADP-0044-001), it was justifiable from a 
benefit-risk perspective to treat subjects with both advanced synovial sarcoma and MRCLS as 
they each constituted patient populations with a high unmet medical need, albeit with distinctly 
different metastatic disease natural histories.  However, as more mature data has accrued from 
study ADP-0044-001 in combination with emerging findings from Cohort 1 of this ongoing 
Phase 2 trial (see Section 4.2., below), it has become apparent that ADP-A2M4 cells may 
potentially be less clinically active in MRCLS compared to synovial sarcoma. Therefore, at this 
time, continued evaluation of ADP-A2M4 treatment in Cohort 2 is only justifiable for synovial 
sarcoma subjects from a therapeutic benefit perspective. In regard to mitigation of risks, 
measures to ensure safe administration of ADP-A2M4 have been included in this study protocol, 
with close monitoring for toxicities and guidelines for their management.  
The potential risks identified in association with ADP-A2M4 are justified by the anticipated 
benefits which may be afforded to patients with advanced (inoperable)/metastatic synovial 
sarcoma in Cohort 2. Indeed, real-world evidence in metastatic synovial sarcoma suggests that 

            
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pazopanib - which is approved for 2nd-line metastatic soft tissue sarcoma treatment in the United 
States and Europe - is not the most frequently administered 2nd-line therapy at several major 
synovial sarcoma centres in the United States possibly because of its low ORR [Pollack, 2020]. 
Therefore, this provides a unique therapeutic opportunity for ADP-A2M4 to potentially become 
the first licensed cell therapy product in post-1st-line advanced (inoperable)/metastatic synovial 
sarcoma if the overall benefit-risk findings from this phase 2 trial (study ADP-0044-002) are 
favorable.

            
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4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase 2 single arm, open label study of genetically engineered ADP-A2M4 in HLA-
A*02 subjects with MAGE-A4 expressing metastatic or inoperable (advanced) synovial sarcoma
or myxoid/round cell liposarcoma (Cohort 1 only). Only subjects with advanced synovial 
sarcoma will be eligible for Cohort 2. The study consists of two separate, independent, serially 
enrolled subject cohorts: Cohort 1 and Cohort 2.
Enrollment into Cohort 1 is expected to continue for approximately 12 months and is close to 
completion at the time of this amendment. Forty-five subjects have been enrolled and 26 subjects 
have been treated with ADP-A2M4 to date. Enrollment will continue to ensure that at least 45 
subjects are dosed in Cohort 1. Dosing is expected to be complete in Cohort 1 in March 2021. 
Data from subjects in Cohort 1 only will be used for the primary study endpoint and primary 
statistical analysis. 
The clinical and scientific rational for including Cohort 2 is to provide an expanded safety and 
efficacy data set overall in inoperable (advanced)/metastatic synovial sarcoma to supplement the 
primary assessment for Cohort 1 subjects who were previously enrolled in Cohort 1 may not 
enroll into Cohort 2.
4.1.1.
Pre-screening
Subjects will sign a Pre-screening Informed Consent Form (ICF) and undergo initial screening 
for the relevant HLA alleles and MAGE-A4 tumor antigen as part of this study. 
At sites that employ remote consent at pre-screening, it is the responsibility of the Investigator to 
obtain written consent in accordance with IRB/IEC approved processes and any local 
requirements in advance of providing subjects with a HLA buccal/ cheek swab test and/ or 
sending tissue for MAGE-A4 testing.
4.1.2.
Screening
Subjects who have pre-screened positive for the relevant HLA alleles and MAGE-A4 tumor 
antigen will be asked to sign the Treatment ICF and enter Screening to determine full eligibility 
for the study. Screening assessments should be completed within 28 days of leukapheresis; CT/ 
MRI scans and ECHO/MUGA scans, performed as standard of care within 28 days prior to 
Screening Visit 2 (i.e. prior to treatment consent) are acceptable. Cytogenetic confirmation of 
diagnosis can be historic, done as standard of care, or be done any time after signing Treatment 
Consent and does not need to be within 28-day screening window.

            
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4.1.3.
Enrollment
Subjects who sign the Treatment ICF and meet the protocol defined eligibility criteria (Section
5.2 and Section 5.3) will be enrolled. Subjects who do not meet the protocol defined eligibility 
criteria are screen failures. 
Enrolled subjects will undergo leukapheresis for collection of autologous cells for processing and 
manufacture into the ADP-A2M4 cell Investigational Product (IP). Leukapheresis should be 
performed as soon as possible after the subject is determined to be eligible for study 
participation.
Anticancer therapy may be administered between screening and leukapheresis, and between 
leukapheresis and the start of lymphodepletion (bridging therapy), if a subject has progressive 
disease and cannot be treatment-free, but mandatory washout periods must be adhered to (see 
Section 5.3).  Subjects must be ready to receive IP as the next treatment once manufacturing and 
any mandatory washout periods are complete even if they remain stable on bridging therapy, 
provided they have measurable disease per RECIST v1.1.
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria will be 
reconfirmed and Baseline tumor assessment obtained.  
Once the ADP-A2M4 cells are available at site, subjects will undergo lymphodepleting 
chemotherapy with fludarabine 30 mg/m2/day for 4 days (Day -7 to Day -4) and 
cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5) (Section 6.2) followed by infusion 
of ADP-A2M4 cells on Day 1 (Section 6.3).  The lymphodepleting chemotherapy may be given 
as an outpatient treatment or subjects may be hospitalized at the discretion of the Investigator. 
The T cell infusion will be given as an inpatient procedure. Subjects will remain hospitalized for 
observation for at least 10 days post T cell infusion. Discharge following T cell infusion will be 
at the discretion of the Investigator. All subjects must be reviewed by the investigator (or a 
designated study physician) prior to discharge.
Efficacy, safety, health related-outcome and biomarker assessments to be conducted at each visit 
are outlined in the Time and Events (T&E) Tables (Table 1 and Table 2).  Efficacy will be 
assessed by both local and independent review using RECIST v1.1. To allow time for the 
immune response to become apparent and for potential transient inflammatory reaction of the 
disease to the treatment (‘tumor flare’), disease progression will not be determined before 4 
weeks (28 days) post infusion of ADP-A2M4 unless there is unequivocal clinical evidence of 
deterioration. Therefore, imaging scans should not be performed earlier than 4 weeks (on or after 
28 days) post infusion. 
Subjects will continue to have scans for efficacy during the interventional phase of the study,
until disease progression is established. Once progression is established, no further scans will be 
performed for this study, however, subjects will continue to be followed for observation of 
delayed adverse events in accordance Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) requirements for gene therapy clinical trials [FDA, 2006a; FDA, 
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Subjects will be seen in the clinic for evaluation according to Main T&E Table 1 (Section 1.3.1)
until disease progression. Thereafter, subjects will undergo assessments/procedures according to 
the LTFU T&E Table 2 (Section 1.3.2 ). The timepoint at which the subject switches to the 
LTFU assessments/procedures will be driven by the timepoint at which the subject progresses 
e.g. if there is disease progression at Week 12, the next visit would be due at Week 24 (Month 
6).
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason.
4.2.
Scientific Rationale for Study Design
This is a Phase 2 single arm, open-label study with ADP-A2M4 cells for the treatment of 
subjects with advanced synovial sarcoma or MRCLS who are HLA-A*02 positive and have 
tumors that express MAGE-A4.
MAGE-A4 is a cancer testis antigen that is highly expressed in synovial sarcoma and MRCLS 
tumors making it an attractive target.  Preliminary clinical evidence in Study ADP-0044-001 has 
shown an ORR (confirmed responses) of 44% (95% CI: 16.34, 67.71) in advanced 
(inoperable)/metastatic synovial sarcoma with a disease control rate of 94% including 11 out of 
16 patients who were still alive at time of 1-September-2020 data cut-off. Synovial sarcoma 
responses were durable with a median duration of response of 28 weeks (range: 12-72 weeks). 
[CTOS 2020]. This ORR is considerably superior than response rates reported with agents 
currently being used as 2nd line therapies for soft tissue sarcoma (Section 2.2.3).
On this basis, this Phase 2 study (ADP-0044-002) will be a single arm, non-comparative study
with a primary efficacy endpoint of Overall Response Rate (ORR) per RECIST v1.1 by 
independent review in 2 Cohorts where the primary study endpoint will be evaluated in Cohort 1.
The historical ORR for post first-line metastatic soft-tissue sarcoma patient populations ranges 
from 4%-13% (Section 2.2.3). To account for the potential variability in historical control 
response rate, a more conservative historical ORR of 18% has been estimated for therapies 
administered in the post 1st-line metastatic synovial sarcoma setting, and will be used to evaluate 
the efficacy of ADP-A2M4 by hypothesis testing (Section 9).
At the time of this Protocol Amendment (05FEB2021) the ADP-0044-002 study has been 
enrolling subjects for approximately 12 months. Fifty-three subjects have been enrolled, and 31 
subjects have received treatment with a single dose of ADP-A2M4 in Cohort 1 including 27 
subjects with advanced (inoperable)/metastatic synovial sarcoma and 4 subjects with MRCLS. 
Follow-up is ongoing in these three MRCLS subjects, but preliminary evaluation of therapeutic 
benefit in MRCLS subjects across both the ADP-0044-001 study (2 subjects) and ADP-0044-002 
study (4 subjects) would suggest no discernable evidence of an early therapeutic response to 
ADP-A2M4 cell treatment in MRCLS. For this reason, Cohort 2 in study ADP-0044-002 will 
only enroll patients with advanced/metastatic synovial sarcoma. 
The clinical and scientific rationale for including Cohort 2 is to provide an expanded safety and 
efficacy dataset overall for metastatic or inoperable (advanced) synovial sarcoma to supplement 
the primary assessment for Cohort 1.

            
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4.2.1.
Pre-Screening for HLA Alleles and MAGE-A4 Expression
4.2.1.1.
HLA
Subjects must express at least 1 inclusion HLA-A allele of HLA-A*02:01, A*02:03 or HLA-
A*02:06. HLA-A*02 alleles having the same protein sequence as these alleles in the antigen-
binding domains (P group) will also be included. There may be other HLA-A*02 alleles that may 
be eligible for inclusion after adjudication with the sponsor.  The adjudication process will be 
documented.
Due to the risk of alloreactivity subjects positive for HLA-A*02:05 in either allele are ineligible. 
Subjects with HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 in the 
antigen binding domains (P groups) will also be excluded. Other alleles may be exclusionary 
after consultation with the sponsor.  HLA eligibility testing will be done via Adaptimmune 
designated central laboratory.
Despite HLA-A*02 being the most common HLA allele group in the western world its 
expression varies greatly among populations of different races and ethnicities. With a high
proportion of subjects expected to be excluded based on HLA status, an optional buccal swab kit 
may be offered to subjects during pre-screening at participating sites. This allows subjects to be 
screened for HLA without requiring travel to a clinical study site. The kit, containing a self-
administered buccal/cheek swab and associated instructions would be sent to potential subjects 
who have provided written consent in accordance with IRB/IEC approved processes and any 
local requirements. Any subject determined to be eligible based on results from the buccal swab 
would still undergo confirmatory HLA genotyping on a blood sample during screening. 
4.2.1.2.
MAGE-A4 Expression in Tumor
MAGE-A4 expression was reported in synovial sarcoma (82%) and myxoid liposarcoma (68%)
cases [Iura, 2017a; Iura, 2017b]. ADP-A2M4 cells have been shown to 
responses against tumor cell lines (derived from non-small cell lung cancer, prostate carcinoma, 
melanoma and ovarian carcinoma) expressing high MAGE-A4 mRNA levels (>10,000 MAGE-
A4 transcripts). In addition, ADP-A2M4
a primary 
melanoma tissue material expressing high MAGE-A4 mRNA and protein expression levels. Since 
no adequate models to define the threshold of ADP-A2M4 cell activation are currently available, 
this protocol will select for subjects with high MAGE-A4 expression. As such, Adaptimmune will 
be using a 
30% of tumor cells) to ensure sufficient expression of the 
antigen.
To ensure that the subject’s tumor has the potential to be targeted by the ADP-A2M4 cells, the 
tumor specimen will be screened at a central reference laboratory for the expression of MAGE-A4 
by IHC using a Clinical Laboratory Improvement Amendments (CLIA)-validated Clinical Trial 
Assay.
Optional remote consent to MAGE-A4 testing is permitted for any clinical site that has the 
necessary written consent processes in place and has obtained the relevant IRB/IEC and local 

            
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approvals.  This allows subjects with archival specimens available to consent for MAGE-A4
testing without requiring travel to a clinical study site.  
4.2.2.
T Cell Manufacturing
ADP-A2M4 is autologous CD4 and CD8 T cells engineered with an affinity-enhanced TCR to 
target the tumor antigen MAGE-A4.  Autologous T cells are obtained from eligible subjects who 
have MAGE-A4 positive tumors and who have appropriate HLA-A.  The CD4 and CD8 T cells 
are transduced with a SIN lentivirus vector expressing the MAGE-A4 (affinity enhanced clone 
1032) under GMP conditions.  The product of this transduction is polyclonal T cells which are 
designed to target MAGE-A4 in tissue.  The transfer SIN lentiviral vector has been meticulously 
designed to contain the genetic elements required for function and for maximum biosafety [Dull,
1998].  Many reports provide evidence supporting the relative biosafety of SIN lentiviral vectors 
in terms of genotoxicity, resulting primarily from the lack of enhancer activity in the lentivirus 
long terminal r
Montini, 2006; Maruggi, 
2009; Modlich, 2009; Montini, 2009].
Cell product is typically ready to be returned to the site approximately one month after the start 
of manufacturing. Receipt of T cell product at the clinical site is required before the start of 
lymphodepleting chemotherapy.  
4.2.3.
Lymphodepletion
Lymphodepletion prior to adoptive cell therapy may enhance immune reconstitution by the 
transferred cells and increase tumor specific responses.  Immune reconstitution is enhanced 
through homeostatic mechanisms that facilitate expansion of T lymphocytes [Baccala, 2005] and 
facilitate trafficking of the engineered T cells [Pinthus, 2004].  Lymphodepletion also enhances 
the activity of the adoptively transferred cells via the removal of inhibitory factors such as 
regulatory T cells [Wolf, 2003] and can activate antigen presenting cells through the induction of 
inflammatory cytokines and induction of tumor apoptosis with resulting cross presentation of 
tumor antigens to T cells.
Evidence suggests that preparation for successful engraftment and expansion of gene modified 
adoptive cellular therapy depends not just on the depth of cytoreduction but additionally on the 
specific action of some cytotoxic drugs.  Recent studies in lymphoma, chronic leukemia and 
acute leukemia using adoptive cellular therapy including a CAR showed increased T cell 
expansion, persistence and disease-free survival when fludarabine was added in a previously 
cyclophosphamide-only preparative regimen [Turtle, 2015]. Cyclophosphamide was 
administered at 30 – 60 mg/kg x 1 day and fludarabine at 25 mg/m2/day x 3 – 5 days.  Effective 
lymphodepletion has also been demonstrated in other CAR-T cell studies using reduced 
cyclophosphamide dosing, together with fludarabine [Batlevi, 2016].  
Data from an open label non-randomized multi-cohort pilot study of genetically engineered 
NY-ESO-1 SPEAR™ T cells in HLA-A2+ patients with synovial sarcoma (NCT01343043)
suggests that fludarabine is an important component of T-cell lymphodepleting regimens and 
fludarabine 30 mg/m2 given daily for 4 days in combination with cyclophosphamide may be 

            
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associated with more objective responses [D’Angelo, 2018] (see Section 2.2.3). The CD19 
CAR-T product tisagenlecleucel also utilizes fludarabine 30 mg/m2 for 4 days in combination 
with cyclophosphamide.
The lymphodepleting regimen in this study consists of intravenous fludarabine 30 mg/m2/day for 
4 days (Day -7 to Day -4) and cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5). 
4.2.4.
Long Term Follow-up
Subjects exposed to gene therapies may be at risk for delayed adverse events when there is 
persistent biological activity. Contributing factors for delayed adverse events include persistence 
of viral vector, integration of genetic material into host genome, prolonged expression of transgene 
and alterations in the expression of host genes. The long term follow up (LTFU) evaluation in the 
study is designed to adhere to the FDA and EMA guidance for long term follow up of subjects in 
gene therapy clinical trials [FDA, 2006a; FDA, 2006b, FDA, 2010; EMA, 2009], and involves 
monitoring subjects who have been exposed to lentivirus-mediated gene transfer in this clinical 
study for 15 years.  Further information on safety monitoring for theoretical risks associated with 
the use of lentiviral vectors and potential for insertional oncogenesis, as well as safety monitoring 
are available in Section 10.7, Appendix 7.  
4.3.
Justification for Dose
The cell dose of ADP-A2M4 is within the range of 1 × 109 to 10 × 109 transduced cells, 
administered by a single intravenous infusion. If the transduced cell dose is less than the 
minimum dose, manufacturing of additional transduced T cells from excess banked 
leukapheresis product or an additional leukapheresis collection may be undertaken to achieve a 
total dose in the target range.  Doses below the minimum transduced cell dose of 1 x 109 will not 
be administered.
The safety and tolerability of ADP-A2M4 is being assessed in a Phase 1 trial of multiple tumor 
types including synovial sarcoma and MRCLS (NCT03132922). Doses up to 9.96 x 109 have 
been well tolerated in this dose escalation study and was associated with a high ORR in 16 
advanced (inoperable)/metastatic synovial sarcoma subjects [CTOS 2020].  
4.4.
End of Study Definition
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason.

            
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5.
STUDY POPULATION
5.1.
HLA and Antigen Pre-screening 
To be eligible for Pre-screening (Visit 1) subjects must be aged 16 and <75 years with a 
diagnosis of advanced (metastatic or inoperable) synovial sarcoma (Cohort 1 or Cohort 2) or 
myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by either 
histology or cytogenetics.  Confirmation of diagnosis by cytogenetics is required prior to 
leukapheresis. 
Subjects identified by the Investigator as possible candidates for the study must complete
preliminary screening to determine HLA and tumor antigen status. Only subjects with an 
appropriate HLA-A genotype and whose tumor expresses the MAGE-A4 antigen above the cut-
off according to the applied IHC are eligible to undergo Screening (Visit 2) for this study. 
5.2.
Inclusion Criteria
A subject must meet all of the following criteria prior to leukapheresis (i.e. at Screening (Visit 
2)) AND prior to lymphodepleting chemotherapy (i.e. at Baseline) to be eligible to participate in 
this study.
1. Subject (or legally authorized representative) voluntarily agrees to participate by giving 
written informed consent (and Assent as applicable) in accordance with ICH GCP 
guidelines and applicable local regulations.
2. Subject (or legally authorized representative) agrees to abide by all protocol required 
procedures including study related assessments, and management by the treating 
institution for the duration of the study including long term follow-up.
3. Age 16 and <75 years at the time the Pre-screening Informed Consent/Assent is signed.
4. Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or myxoid 
liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) confirmed by cytogenetics.
Inoperable refers to a tumor lesion in which clear surgical excision margins cannot be 
obtained without leading to significant functional compromise.
a.
For Synovial Sarcoma (Cohort 1 and Cohort 2): confirmation by the presence of a 
translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on 
chromosome 18 (may be presented in the pathology report as t (X; 18)).
b. For MRCLS (Cohort 1 only): confirmation by the presence of the reciprocal 
chromosomal translocation t(12;16) (q13;p11) or t(12; 22) (q13;q12)
5. Must have previously received either an anthracycline or ifosfamide containing regimen. 
1st-line metastatic treatment with ADP-A2M4 is permissible if ifosfamide +/-
doxorubicin has been administered in either the pre-operative (neoadjuvant) or post-
operative (adjuvant) primary tumor setting.  (Subjects who are intolerant of both 
anthracycline and ifosfamide must have previously received at least one other type of 
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History of stroke or central nervous system bleeding; transient ischemic attack 
(TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months;
Incipient compression/occlusion of a vital structure (e.g. bronchus; superior vena 
cava; renal outflow tract) which cannot undergo prophylactic stenting;
COVID-19 infection or a positive COVID-19 RT-PCR test within 28 days of 
leukapheresis or lymphodepleting chemotherapy. If a subject has a positive 
COVID-19 test, then 2 subsequent negative tests are required, taken at least 7 days 
apart.
9. Active infection with HIV, HBV, HCV or HTLV as defined below:
Positive serology for HIV;
Active hepatitis B infection as demonstrated by test for hepatitis B surface 
antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis B 
core antibody positive must have undetectable hepatitis B DNA and receive 
prophylaxis against viral reactivation.  Prophylaxis should be initiated prior to 
lymphodepleting therapy and continued for 6 months;
Active hepatitis C infection as demonstrated by hepatitis C RNA test.  Subjects 
who are HCV antibody positive will be screened for HCV RNA by any RT PCR 
or bDNA assay. If HCV antibody is positive, eligibility will be determined based 
on a negative screening RNA value;
Positive serology for HTLV 1 or 2;
Re-screening for infectious disease markers is not required at baseline (prior to 
lymphodepletion) unless > 6 months has elapsed.
10. Pregnant or breastfeeding.
11. In the opinion of the Investigator, the subject is unlikely to fully comply with protocol 
requirements.
5.4.
Screen Failures
Data on subjects who fail pre-screening or screening, including demographics and disease 
history, will be collected in the electronic case report form (eCRF) to support Companion 
Diagnostic development and validation.
5.5.
Number of Subjects and Study Duration
Forty-five (45) subjects (90 total subjects) are planned to be dosed separately in this Cohort 1 
(synovial sarcoma and MRCLS) and Cohort 2 (synovial sarcoma only). In combination, data 
from Cohort 1 and Cohort 2 will provide a better, more comprehensive, characterization of the
benefit-risk profile in soft-tissue sarcoma patients (especially in synovial sarcoma) than from 
Cohort 1 alone. 

            
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Enrollment into Cohort 1 is expected to continue for approximately 12 months and is close to 
completion at the time of this amendment. Cohort 2 will begin when dosing in Cohort 1 is 
completed. Cohort 2 will dose 45 advanced (inoperable)/metastatic synovial sarcoma subjects 
only and enrollment is expected to continue for approximately 12 months. 
The Primary Clinical Analysis will be for Cohort 1 only (i.e. synovial sarcoma plus MRCLS).  
Clinical cut-off for the primary analysis will occur once the last subject dosed in Cohort 1 has up 
to 6 months follow-up post T cell infusion or has ended the interventional phase of the study.  At 
this time, all safety and secondary efficacy endpoints from Cohort 1 only will also be 
summarized to provide supportive evidence to the primary assessment.  
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason.
5.6.
Sites
The study will be conducted in approximately 24 sites in North America and Europe. The 
number of centers is necessary to ensure recruitment in this rare patient population.  Additional 
sites may be added at the discretion of the Sponsor.
All sites should have appropriate Medical Emergency / Intensive Care access with provision for 
beds for study subjects in the event of an emergency. See Table 6: Management Guidelines for 
Cytokine Release Syndrome and Table 9: Management of ICANS for further guidelines. 

            
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6.
STUDY INTERVENTION
6.1.
Leukapheresis
Subjects who complete screening procedures defined in Section 5.1 and who meet all eligibility 
criteria defined in Section 5.2 and Section 5.3 will be eligible to undergo leukapheresis to obtain 
starting material for the manufacture of autologous ADP-A2M4.
Refer to the Apheresis and T Cell Product Manual for scheduling of apheresis.
A non-mobilized peripheral blood mononuclear cell (PBMC) collection should be performed by 
an apheresis unit at the enrolling institution according to the institution’s or hospital’s policies 
and procedures.  Leukapheresis may be performed at a qualified third-party institution (as may 
be mutually agreed and approved in advance by both Sponsor and the clinical site), as long as the 
policies and procedures in place meet or exceed the primary institution’s policies and procedures.  
Bilateral peripheral venous access should be used whenever possible but a temporary central 
venous catheter (CVC) may be placed for collection if peripheral venous access is inadequate.  
Standard clinical procedures for apheresis should be followed. 
A large volume leukapheresis should be performed.  For subjects who are >50 kg, 10 to 15 liters 
-3 blood-volumes should be processed 
per procedure with a goal of the procedure being collection of 1.0 x 108 PBMC/kg, and a 
minimum of 1.5x107 PBMC/kg. In cases where the minimum number of PBMC is not collected 
or the T cells cannot be administered (e.g. release criteria not met), a second apheresis may be 
performed. Citrate anticoagulant should be used.  Prophylactic intravenous calcium chloride and 
magnesium sulfate infusions should be administered at the discretion of the apheresis physician.
The collected leukapheresis product should be labelled and transported for manufacture as 
detailed in the Apheresis and T Cell Product Manual.
Any remaining subject apheresis material that is not required for further manufacture, may be 
used by the sponsor for research to modify or improve the manufacturing process and to enhance 
the clinical response.
6.2.
Lymphodepleting Chemotherapy
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria will be 
reconfirmed and a Baseline tumor biopsy obtained. 
Once the manufactured ADP-A2M4 cell product has been received at the clinical site and the 
integrity of the bag(s) has been verified by the site, eligible subjects will proceed to have 
lymphodepleting chemotherapy with fludarabine and cyclophosphamide as described in Table 3.
The lymphodepleting chemotherapy may be given as an outpatient treatment or subjects may be 
hospitalized at the discretion of the Investigator. 
On admission for lymphodepleting chemotherapy, commence anti-microbial prophylaxis (see 
Section 10.5.3.7) in line with institutional guidelines.

            
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Renal function should be estimated using the Cockcroft-Gault Creatinine Clearance (CrCl) 
equation (no other renal function equations are permitted).  
A more sensitive evaluation of renal function using either a 24-hr urine creatinine collection or a 
EDTA radionuclide test should be performed in subjects at Screening and/or Baseline who are:
Underweight (i.e. BMI < 18.5 KG/m2)
Low borderline CockCroft-Gault calculated CrCl of approximately 60 ml/min.
6.2.2.
Mesna
Mesna should be administered according to institutional practice or as recommended below:
120 mg/m2 (20% cyclophosphamide dose) as an IV bolus pre infusion, 4 and 8 hours 
post infusion on each day of cyclophosphamide administration.
6.2.3.
G-CSF
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
is also common. It is recommended that G-CSF is given daily from Day -3 until resolution of 
neutropenia in accordance with ASCO guidelines or institutional standard practice. Long-acting 
(pegylated) G-CSF may be given instead of short acting G-CSF according to institutional 
standard practice.  If pegylated G-CSF is administered, give one dose on Day -3.
6.3.
Investigational Product 
6.3.1.
Premedication
Subjects will be premedicated with antihistamine and acetaminophen/paracetamol 30-60 minutes 
prior to the T-cell infusion according to institutional practice.  Steroids must not be administered
as premedication for T-cell infusion because they are lymphotoxic and inhibitory to the T-cell 
product.
6.3.2.
T Cell Infusion
On Day 1, the subject will receive thawed ADP-A2M4 by intravenous infusion. The T cell 
infusion will be given as an inpatient procedure and subjects will remain hospitalized for 
observation for at least 10 days post T cell infusion. 
Prior to infusion, two clinical personnel in the presence of the subject, will independently verify 
and confirm that the information on the infusion bag is correctly matched to the subject, as per 
the Apheresis and T-cell Product Manual.
The T-cell product must not be thawed until immediately prior to infusion. The T-cell product 
should be thawed at a set temperature of 37oC using a water bath or equivalent device.  Routinely 
the cells should be thawed for approximately 3-5 minutes.  Smaller volumes may take less time 

            
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to thaw.  The infusion bags should be observed during the thaw process to ensure no frozen 
material or ice remains.
The infusion bag(s) may be placed into a secondary containment bag per institutional standard 
procedures.  The secondary containment bag should not be of a design where it will have to be 
cut open after use, so as to avoid sharp objects near the infusion bag.  A standard specimen bag 
with a re-sealable zipper closure is recommended.
The cells can be thawed either at the subject’s bedside or in a centralized facility, according to 
institutional standard procedures. If the cells are transported from a central storage location to 
bedside for thawing, it is recommended to place the bag(s) on dry ice or in a cooler with frozen 
gel packs for transport.  If the cells are thawed at a central facility, the thawed cells should be 
transferred to bedside under 2-8oC conditions and must be transported by appropriately trained
staff, to preserve the chain of custody.
The infusion should begin within 10 minutes of completing thaw (per bag) and is recommended 
to complete infusion of each bag within 45 minutes of thawing each bag to minimize exposure of 
the cell product to cryoprotectant. If the cells are provided in multiple bags and thawed at the 
bedside, the second bag should not be thawed until half the first has been infused without 
reaction, if possible based on fill volume.  Bags thawed in a central location may be thawed 
simultaneously with consideration given to transport time and the guidance to begin infusion 
within 10 minutes post-thaw. 
If after thawing the infusion bag is damaged or leaking, the Investigator and Sponsor should be 
notified and the cells should not be infused.
The T-cell product must not be washed or otherwise processed. It is recommended that the T-cell 
product is administered using a dual spike infusion set by gravity over 15-45 minutes in the 
absence of infusion reaction.  Cells should ideally be infused without a filter, however if a filter 
is required by Institutional practice the pore size must not be smaller than 170 µm. Infusion 
pumps must not be used. For administration of the cells, 100 - 250 ml of 0.9% sodium chloride 
should be connected to the second lumen of the infusion set, used to prime the line, and then the 
lumen closed. On completion of the infusion of a bag of T-cell product, the main line should be 
closed and approximately 50ml saline transferred into the cell bag, and then infused to minimize 
the loss of cells. This process should be repeated for each cell bag if multiple bags are provided. 
On completion of the cell infusion the set should be flushed using additional saline from the 
attached bag. If Institutional practice requires a single spike infusion set (e.g. macro drip IV 
tubing) standard institutional guidelines for the infusion of autologous cell infusion should be 
followed. The line must be flushed with 0.9% sodium chloride once the infusion is complete. In 
the event of adverse reaction to the cell infusion the infusion rate should be reduced and the 
reaction managed according to institutional standard procedures. Steroid treatment should be 
avoided unless medically required.  
In the event a subject develops a febrile episode following the infusion, appropriate cultures and 
medical management should be initiated, with attention to the initiation of empirical antibiotic 
treatment in the case of febrile neutropenia (see Section10.5.3).

            
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The day of T-cell infusion may be delayed in subjects with significant complications of 
chemotherapy if according to the Investigator it is in the best interest of the subject.  Cytopenias 
alone should not be a reason to delay T-cell infusion unless complications are present. Subjects 
who have undergone leukapheresis but do not receive the T-cell infusion will not be replaced.    
Subjects who undergo leukapheresis and do not receive T cells will be followed for safety events 
for 30 days post leukapheresis or until SAEs have resolved to Grade 1 or baseline, whichever is 
longer.
The timing of all assessments post-infusion will be calculated with reference to the T-cell 
infusion date.  Vital signs will be recorded prior to the infusion and at 5, 15 and 30 minutes and 
at 1, 1.5, 2 and 4 hours after the infusion has started.
Discharge from hospital post-T cell infusion will be at the discretion of the Investigator. All 
subjects must be reviewed by the investigator (or a designated study physician) prior to 
discharge. 
6.4.
Preparation/Handling/Storage/Accountability
6.4.1.
Packaging and Labelling
Selected, qualified manufacturing sites will manufacture, package and label cell product for each 
individual subject in accordance with applicable regulatory requirements.
Refer to the Apheresis and T cell Product Manual for details of T cell product labelling.
6.4.2.
Receipt and Return
Investigational product must be received by a designated person at the site, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and designated 
site personnel have access.  Investigational product is to be dispensed only in accordance with 
the protocol.  The Investigator is responsible for keeping accurate records of the investigational 
product received from the Sponsor, the amount dispensed and any unused investigational product 
remaining at the conclusion of the study.  Contact the Sponsor or designee regarding any 
questions concerning the investigational product.
Sites should contact the Sponsor or designee for specific instructions for investigational product 
returns or destruction.
6.4.3.
Storage and Handling
Manufactured T-cell product should arrive on-
-130°C in the 
vapor phase of a liquid nitrogen or a mechanical freezer until the date of infusion. Please refer to 
the Apheresis and T cell Product Manual for additional information.
6.4.4.
Investigational Product Accountability/Traceability
The investigational product provided for this study is for use only as directed in the protocol. The 
Investigator/Institution must have an established system for subject and product accountability at 

            
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the site. The system should contain sufficient detail to allow linking of each product delivered to 
the investigator to the subject receiving it and vice versa. The investigator must ensure: 
Deliveries of Investigational Product are correctly received by a responsible person
Such deliveries are recorded
Investigational product is handled and stored safely and properly as instructed in the 
Apheresis and T cell Product Manual
Investigational product is only administered to study subjects in accordance with the 
protocol
Investigational product administration is documented. Records must include the 
identification of the person to whom the investigational product was administered, 
date of infusion, start and stop time of infusion and the amount infused.  This record 
is in addition to any investigational product accountability information recorded on 
the eCRF
Any unused product is accounted for in the sites records before returning to the 
Sponsor (or designee)
At the end of the study, it must be possible to reconcile investigational product delivered with 
records of usage and return/destruction.  Any discrepancies must be accounted for on the 
appropriate forms.
Refer to the Apheresis and T cell Product Manual for additional information.
6.4.5.
Alert Cards
All subjects who receive investigational product in the trial will be provided with an alert card, 
which has been previously agreed by the sponsor and approved by the institutional review 
board (IRB)/ independent ethics committee (IEC). Alert cards will contain at a minimum the 
name of the subject, the investigator contact number and information regarding the 
investigational product received.
6.5.
Concomitant Medications
6.5.1.
Prohibited Concomitant Medications
The following treatments are prohibited post T cell infusion (i.e. prior to disease progression):  
non-protocol chemotherapy, immune therapy, biological therapy (including targeted therapies 
with tyrosine kinase inhibitors or monoclonal antibodies), or investigational anti-cancer therapy. 
Subjects should also not undergo other anticancer locoregional therapies such as non-palliative 
radiation.  
Subjects who undergo any active anticancer therapy, with the exception of surgical resection 
prior to disease progression, will be considered as having met the progressive disease (PD) 
criterion for efficacy and will follow the LTFU schedule.

            
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It is preferred that subjects do not undergo surgical resection of tumor lesions during the study 
prior to disease progression, as it interferes with the assessment of the efficacy of ADP-A2M4.
However, a subject whose tumor becomes resectable and who undergoes surgical resection prior 
to disease progression, will continue to be followed for safety and efficacy (progression of 
remaining lesions, new lesions) in the interventional phase of the study until disease progression
is determined. Upon progression, the subject will follow the LTFU schedule. Subjects who have 
surgery for new lesions consistent with progressive disease or to control progressive disease in 
previously identified lesions will discontinue the interventional phase and follow the LTFU 
schedule.
See Section 5.3 for details of washout and excluded treatments prior to leukapheresis or 
lymphodepleting therapy.
The use of systemic steroids may abrogate the effects of the T-cell therapy and therefore use is 
discouraged unless required to manage CRS (see Section 10.5.6 for CRS treatment 
recommendations) or other significant immune-mediated adverse events.  According to local 
standard of care or ASCO guidelines, steroids may be used as antiemetics before
cyclophosphamide but must be discontinued no later than 3 days prior to infusion of the IP (Day 
-3).  Steroid use is permitted for prophylaxis or treatment of contrast dye allergies.   
Physiological doses of steroids, including stress doses when clinically appropriate, may be 
administered as replacement therapy in subjects with adrenal insufficiency.  Fludrocortisone is 
permitted.  In general, daily prednisone doses of 0.5 mg/kg or lower, or their equivalent for other 
corticosteroid agents are acceptable, as physiologic replacement.  Topical steroids for cutaneous 
application and inhaled steroidal treatments are permitted.
6.5.2.
Permitted Concomitant Medications
Palliative radiation for pain relief to non-measurable lesions or non-target lesions present at 
baseline is permitted during the study.  However, lesion sites requiring radiotherapy after the T-
cell infusion, should be evaluated as to whether this indicates disease progression and record the 
disease progression in the eCRF.
Other treatment the Investigator considers necessary for a subject’s welfare may be administered 
during the interventional phase of the study at the discretion of the Investigator in keeping with 
community standards of medical care and in adherence to the protocol.  
All concomitant medications will be recorded with dose and frequency, including all prescription 
or over the counter (OTC) medications and herbal remedies.  The following will be recorded on 
the appropriate eCRF pages:
All prescription and nonprescription medication, vitamins, herbal and nutritional 
supplements taken by the subject during the 30 days prior to screening (Visit 2) will be 
recorded at the screening visit.
All prior anti-cancer treatments taken by the subject must be recorded regardless of time
frame taken
All concomitant medications taken while subjects are in the interventional phase

            
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6.5.2.1.
Vaccinations Including for COVID-19
Before immunizing a subject at high risk for vaccine-preventable disease including for SARS-
CoV-2 (COVID-19), consult an Infectious Disease specialist or a guidance, such as the CDC 
Clinical Practice Guideline for Vaccination of the Immunocompromised Host.
The latest COVID-19 vaccination guidelines from NCCN/EBMT/ASTCT should be consulted 
by the Investigator. Any individual subject queries which cannot be addressed by the latest 
expert society guidelines relating to the timing of COVID-19 vaccination prior to either 
apheresis or lymphodepleting chemotherapy, or post ADP-A2M4 cell infusion, should be 
discussed with the Medical Monitor.

            
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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL
7.1.
Temporary Study Suspension
Throughout the conduct of the study, safety data will be reviewed on an ongoing basis by a Data 
Safety Monitoring Board (DSMB) see Section 10.2.1. If the following events occur, further 
enrollment to the study will be suspended and the regulatory authorities informed:
Any death that is deemed to be at least probably related to the IMP by the Investigator 
and the Sponsor
Two or more Grade 4 autoimmune events deemed probably or definitely related to 
the IMP by the Investigator and the Sponsor
A subject has a positive RCL:
Confirmed positive peripheral blood mononuclear cell (PBMC) replication 
competent lentivirus (RCL) and no other vector lot is available for use in 
transduction for subsequent subjects (refer to Section 10.7.2 and Figure 1 on 
monitoring and management of RCL)
Confirmed biological RCL - all ADP-A2M4 cell infusions are halted (see 
Section 10.7.2 and Figure 1)
Regulatory authorities will be notified of any decisions to halt the study or subject enrollment. 
The study will not enroll further subjects until the regulatory authorities have reviewed the data 
leading to such a decision and agree with a proposal to resume enrollment.
7.2.
Ending the Interventional Phase
Reasons that a subject could end the interventional phase of the study are:
Disease progression per RECIST v1.1
Clinical progression 
Died
Unable/unwilling to comply with study requirements
Withdrawal of consent 
Investigator decision
Adverse Event
Lost to follow-up
Pregnancy (see Section 10.6.2.1)
Termination of enrollment by the Sponsor 

            
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All subjects ending the interventional phase, with the exception of those who withdraw consent, 
die, are unable/unwilling to comply with study requirements, are lost to follow up or did not 
receive any T cells, will switch to the LTFU schedule Table 2, Section 1.3.2 to continue 
observation for delayed adverse events as described in Section 8.5.8. 
7.3.
Subject Discontinuation
A subject will be considered to have completed the study when he/she has died or been followed 
for 15 years from time of T cell infusion. A subject may withdraw from the study at any time for 
any reason without prejudice to their future medical care by the physician or institution. However, 
the Investigator must make every reasonable effort to keep each subject on study for the whole 
duration of the trial. If a subject withdraws, all procedures and assessments listed in the withdrawal 
visit should be performed, unless performed within the previous 30 days.
Reasons for withdrawal of a subject from the study are:
Unable/Unwilling to comply with study requirements 
Adverse event
Withdrawal of consent
Investigator decision
Lost to follow-up (see Section 7.4)
Study termination by Sponsor
7.4.
Lost to Follow up
In cases where the subject is deemed ‘lost to follow-up’, the Investigator or designee must make 
every effort to regain contact with the subject; e.g., 3 documented attempts, one of which must 
be a certified letter to the subject’s last known mailing address or local equivalent methods.  
These contact attempts should be documented in the subject’s medical records.  Should the 
subject continue to be unreachable, only then will he/she be considered to have withdrawn from 
the study with the primary reason as ‘Lost to Follow-up’.

            
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8.
STUDY ASSESSMENTS AND PROCEDURES
8.1.
Background Assessments
8.1.1.
Demographics
Demographic data including year of birth, age, sex, race and ethnicity will be collected at Pre-
Screening.
8.1.2.
Disease History
The following information will be recorded in the eCRF: date of initial diagnosis, primary tumor 
type, anatomical site and size of primary tumor, histology last known stage of disease. 
Additionally at screening current stage of disease and chromosomal translocations.  
8.2.
HLA MAGE-A4 Tumor Antigen Testing, and Cytogenetics
There is no window for obtaining HLA, MAGE-A4 antigen and cytogenetic testing prior to leukapheresis. 
8.2.1.
HLA
HLA-genotyping at the allelic level (4-digit) will be conducted on a blood sample by an 
accredited central laboratory contracted by the Sponsor using an FDA approved HLA 
Sequencing System for Sequence Based Typing (SBT) of Human Leukocyte Antigen (HLA). 
8.2.2.
MAGE-A4 Antigen
Once subjects are identified as having the appropriate HLA allele, an archival tumor sample, or 
fresh biopsy obtained as standard of care, may be submitted for determination of MAGE-A4 
expression, in which case, the biopsy from the most current setting is preferred provided that 
there is sufficient tissue. If an archival specimen is unavailable, the subject must undergo a new 
biopsy.  The subjects’ tumor will be tested for MAGE-A4 antigen expression by IHC using an
analytically validated and CLIA-certified Clinical Trial Assay.  Testing will be completed at a 
central laboratory contracted by the Sponsor.
A secondary objective of the study is to collect tumor tissue samples for the development and 
validation of an IVD assay for the screening of tumor MAGE-A4 expression for regulatory 
approval. Tumor tissue will be collected, processed and submitted in accordance with the study 
Sample Collection Manual. The tumor tissue will be tested using the CLIA-validated MAGE-A4 
Clinical Trial Assay for study eligibility determination.  The tumor tissue will then be used for 
the analytical validation (which includes testing for efficiency, sensitivity, specificity, 
exclusivity, accuracy and precision), as well as the clinical validation of an IVD companion 
diagnostic assay.  Since the Clinical Trial Assay used in this study is not the candidate IVD 
companion diagnostic, a bridging study is required in order to demonstrate that the performance 
characteristics of the two tests are very similar.  The bridging study requires that all of the 
original clinical trial samples tested for eligibility using the Clinical Trial Assay are retested with 
the candidate IVD, including samples from subjects excluded from the trial because they were 
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Details regarding the collection and processing of the screening biopsy, sample requirements, 
instructions for sample shipment to the central laboratory for MAGE-A4 IHC analysis, and 
details of subsequent tumor sample storage for companion diagnostic development are located in 
the Sample Collection Manual. 
Details for the development and validation of an IVD assay for the screening of tumor antigen 
expression for regulatory approval is available in a separate protocol.
8.2.3.
Cytogenetics for Diagnosis
For Synovial Sarcoma (Cohort 1 and Cohort 2), a confirmation by the presence of a translocation 
between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be 
presented in the pathology report as t (X; 18)) is required prior to leukapheresis.
For MRCLS (Cohort 1 only), a confirmation by the presence of the reciprocal chromosomal 
translocation t(12;16) (q13;p11) or t(12; 22) (q13;q12) is required prior to leukapheresis. 
Cytogenetic confirmation of diagnosis can be historic, done as standard of care, or be done any 
time after signing the Treatment ICF and does not need to be within the 28-day screening 
window.
8.3.
Efficacy Assessments
8.3.1.
CT/MRI 
Imaging scans of the chest, abdomen and pelvis should be performed at Screening, Baseline, 
Week 4, Week 8, Week 12, Week 16, and Week 24, and every 2 months +/- 28 days until 
confirmed disease progression. The Week 4 scan must occur on or after Day 28. Subsequent 
scans are to be completed within the visit window permitted in the Main T&E Table with the 
exception of confirmatory scans which should not be performed earlier than 4 weeks (on or after 
28 days) after the criteria for response was first met. As the primary endpoint of the study uses 
independent review, scheduled study scans from Week 4 through Week 16 should be at least 28 
days apart to ensure compliance with the RECIST v1.1 requirement for confirmation of 
response.
Imaging scans should be performed at the time a subject withdraws from the study.
Lesion sites that have previously required radiotherapy should be recorded in the eCRF prior to 
lymphodepletion.
See Section 8.4.9 regarding brain MRI for safety assessment. 
Acceptable imaging modalities for this study include:
Diagnostic-quality CT scan with oral and/or IV iodinated contrast of the chest and 
abdomen/pelvis (CT is the preferred modality for tumor assessments)
MRI of the abdomen/pelvis acquired before and after gadolinium contrast agent 
administration and a non-contrast enhanced CT of the chest, if contrast enhanced CT 
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MRI of the extremities if clinically indicated
Digital photographs of skin lesions including a ruler for estimating the size of the 
lesion
The same imaging modality and image-acquisition protocol (including the use of IV contrast) 
should be used consistently across all time points for individual subjects to allow uniform 
comparison of lesions. 
To allow time for the immune response to become apparent and for potential transient 
inflammatory reaction of the disease to the treatment (‘tumor inflammation’), disease 
progression will not be determined before 4 weeks post infusion of ADP-A2M4, unless there is 
unequivocal clinical evidence of deterioration.  Therefore, imaging scans should not be 
performed earlier than 4 weeks post infusion (on or after 28 days).  Responses should be 
confirmed by repeat imaging scan performed not earlier than 4 weeks (on or after 28 days) after 
the criteria for response was first met. The minimum duration for BoR = SD is 4 weeks (or 28 
days) post ADP-A2M4 infusion.
Investigators (in collaboration with a radiologist) will assess tumor response according to 
RECIST v1.1 for clinical decision making. Tumor measurements at site should be performed by 
the same Investigator or radiologist (to the extent that this is feasible). 
For the study primary endpoint, a central vendor will be responsible for independent assessment 
of tumor response according to RECIST v1.1.  Review and interpretation of image data will be 
conducted by an appropriately qualified, trained and experienced reviewer. A written Imaging 
Charter will be provided to sites to describe the imaging acquisition protocol and standardized 
procedure for the transfer of image data to the central vendor.  The Imaging Charter will also 
describe the procedures for CT/MRI data handling after the images have been received by the 
central vendor from the sites.
Investigator assessment of response will guide patient care throughout the study. 
8.3.2.
Survival 
If a subject dies during the study date of death will be recorded in the eCRF. If a subject is 
unable to attend the site for visit e.g. due to deteriorating condition or a change of 
location/country, the subject may be followed remotely to obtain survival information. If a 
subject decides to withdraw from any further study assessments/procedures, the Investigator 
should ask if the subject is willing for survival data only to be collected, this discussion should 
be documented in the source notes.
If the subject cannot be contacted by the site, information available in public records e.g. 
obituaries may be used by the site to determine date of death if appropriate prior to withdrawing 
the subject from the study due to lost to follow up.
8.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Main T&E table (Table 1) and 
the LTFU T&E Table (Table 2).

            
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Additional tests may be done at any time if clinically indicated.
The Clinical Laboratory Test in Table 4 describe the assessments and parameters to be collected 
and recorded.
Screening visit (Visit 2) assessments should be completed within 28 days of leukapheresis unless 
otherwise specified.  Information regarding ECHO/MUGA scans, ECG and infectious disease 
assays performed as standard of care assessments within four weeks prior to Screening (prior to 
study consent) will be acceptable.
Baseline assessments must be conducted and results obtained within 2 weeks (14 days) prior to T 
cell infusion.
8.4.1.
Medical History
Relevant medical history will be recorded at Screening (Visit 2) in the subject’s eCRF.
8.4.2.
Physical Examination
Subjects will undergo a physical examination at Screening and Baseline. The frequency of 
physical examination at subsequent visits is specified in Table 1 and Table 2.
8.4.3.
Prior Anti-cancer Therapies
All anti-cancer therapies including, but not limited to, chemotherapy, antibodies, anti-cancer 
vaccines, cell therapies, radiation therapy, and surgical resections are to be recorded.  On-study 
cancer surgeries and bridging therapies are to be recorded.
8.4.4.
Prior and Concomitant Medications
Current medications and those for the previous 30 days are to be recorded on the concomitant 
medication page of the CRF at Screening (Visit 2).
For LTFU assessments, this section is limited to new chemotherapies or other anti-cancer 
therapies (including mutagenic agents and other investigational agents).
8.4.5.
ECOG
Performance status will be measured using the ECOG performance scale. See Section 10.9, 
Appendix 8 for guidance. It is recommended, where possible, that a subject’s ECOG be assessed 
by the same person throughout the study. The frequency of the ECOG assessment is specified in 
Table 1.
8.4.6.
Vital Signs
Measurement of vital signs (temperature, pulse, respirations and blood pressure) will be made at
the frequency specified in Table 1. 
On the day of T cell infusion (Day 1) vital signs should be measured pre-infusion, and at 5, 15 
and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started.

            
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8.4.7.
Weight and Height
Height will be assessed only once at Baseline. Weight will be measured according to the 
frequency specified in Table 1.
8.4.8.
Cardiac Assessments
Cardiac assessments will be performed locally at the site. 
8.4.8.1.
ECG
A single ECG is required. Heart rate, rhythm, PR, RR (if measured/recorded), QRS and QTc 
intervals will be recorded. QTcB or QTcF is acceptable as per institutional standards but must 
be consistent from visit to visit.
For Screening (Visit 2) ECGs performed as standard of care within 28 days prior the visit are 
acceptable. The ECG on Day 1 will be taken before T cell infusion starts.
8.4.8.2.
Echo/MUGA
An ECHO or MUGA scan will be performed at screening to determine left ventricular ejection 
fraction (LVEF) for eligibility. ECHO/MUGA scans performed as standard of care within four 
weeks prior to Screening (Visit 2) are acceptable. Additional scans will only be performed if 
clinically indicated.  NOTE: the same method of evaluation must be used consistently for any 
follow-up scans.
8.4.8.3.
Telemetry
For subjects with known cardiac or pericardial tumor involvement at baseline, inpatient 
telemetry monitoring should be carried out for seven days post-ADP-A2M4 infusion.
8.4.9.
Brain MRI
A MRI of the brain with contrast will be obtained at Screening, within 1 month (28 days) of 
leukapheresis, and Baseline, within 1 month of lymphodepletion, for all subjects. CT with IV 
contrast may be used only for subjects with contraindications to MRI of the brain. If brain
metastases are documented at Screening or Baseline, then then the subject is not eligible for 
enrolment onto the study. If brain metastases are not documented at Screening or Baseline, then 
dedicated brain CT/MRI scans should be performed as clinically indicated.
8.4.10.
Renal Function Assessment 
Renal function (estimated or measured glomerular filtration rate (GFR)) will be assessed at 
Screening using the Cockcroft Gault CrCl. 24-hour urine collection to measure creatinine 
clearance or by nuclear medicine EDTA measurement should be performed in subjects who are 
years old; iv). Low borderline calculated CrCl ~ 60 ml/min (Cockcroft-Gault).
Renal function will be reassessed at Baseline using the same methodology.

            
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8.4.11.
Hematology
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
In years 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 8.4.22) then laboratory assessments may be 
discontinued.
8.4.12.
Clinical Chemistry 
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
In years 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 8.4.22) then laboratory assessments are 
discontinued.
8.4.13.
Coagulation
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
Subjects receiving warfarin anti-coagulation at baseline should be converted to either a low 
molecular weight heparin injection or a novel oral anticoagulant (NOAC). Reintroduction of 
warfarin after lymphodepleting chemotherapy/ADP-A2M4 dosing to attain the therapeutic INR 
range which was initially clinically indicated should only start when the platelet count is < Grade 
2 CTCAE.
8.4.14.
Thyroid Function Tests
Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
8.4.15.
Hepatic Safety Assessments
For subjects who experience evidence of hepatic toxicity, increased hepatic monitoring criteria 
will apply to ensure subject safety and to enable evaluation of liver event etiology (see Appendix 
4, Section 10.4.5).
8.4.16.
Pregnancy Test
Female subjects of childbearing potential (FCBP) must have a negative serum pregnancy test at 
Screening and prior to starting lymphodepleting chemotherapy.
8.4.17.
Infectious Disease Screening
Testing for infectious disease markers is required only at Screening and does not need to be 
repeated at Baseline to satisfy the inclusion / exclusion criteria, unless more than six months has 
elapsed from screening.
Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive 
must have undetectable hepatitis B DNA. Subjects who are HCV antibody positive will be 
screened for HCV RNA by any RT PCR or bDNA assay. Eligibility will be determined based on 
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Section 10.3 Appendix 3 describes the parameters to be collected and recorded.
8.4.18.
CMV PCR  
Subjects will be screened for cytomegalovirus (CMV) seropositivity at screening. If seropositive 
at screening, then CMV-PCR will be done at Baseline. If CMV viremia is detected at Baseline, 
treatment should be initiated prior to lymphodepletion chemotherapy. All CMV seropositive 
subjects will continue to be monitored for CMV viremia by CMV PCR at day 1, week 2, 4, 6, 
and 8. See Section 10.5.3.4 for CMV prophylaxis and blood product screening if positive.
8.4.19.
ICE Assessment Tool
The ICE (Immune Effector Cell-Associated Neurotoxicity Syndrome) neurological assessment 
should be performed from Day 1 (prior to T cell infusion) through Day 8 whilst the subject is 
hospitalized according to Table 1. The ICE assessment may be discontinued once a subject is 
discharged from hospital.
If a subject is thought to have ICANS, the ICE should be used at least twice per day until 
resolution or stable.  It can also be used at later visits if indicated. See Section 10.5.7, Table 7.
8.4.20.
C-reactive Protein 
If cytokine release syndrome is suspected, C-reactive protein levels should be measured 
approximately every other day until symptoms are improving or an alternative diagnosis is 
confirmed.  
8.4.21.
Ferritin 
If cytokine release syndrome is suspected, ferritin levels should be measured approximately 
every other day with C-reactive protein.
8.4.22.
Persistence (Vector Copies)
PBMC samples will be collected and used as the “surrogate sample” for monitoring persistence 
of gene modified cells in subjects. Persistence of transduced T cells is also a major biomarker 
related to clinical response. Therefore, additional PBMC samples will be collected over the first 
2 years following infusion (Section 8.6.5).
Samples are required for:
Safety at Baseline and Week 24, Month 12 and then every 6 months through Year 5 and 
annually from Years 6-15.
o
If no gene modified cells are detected for three consecutive assessments and 
-infusion (for example, negative persistence assessments at 
year 4, 4.5 and 5), no further monitoring of PBMCs is required for persistence and 
collection of samples may be discontinued.

            
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o
If at Month 12 or beyond post-infusion, greater than 1% PBMCs test positive for 
vector sequences, the subject’s PBMCs will be evaluated for integration site 
analysis (Appendix 7 Section 10.7.3).
Research at Day 2, Day 4, Day 8, Week, 2, Week 4, Week 8, Week 12 and subsequently 
every 2 months (±1 month) until disease progression. 
See Table 1 and Table 2.
Details on collection and shipment of blood sample for vector copies/persistence is described in 
the Sample Collection Manual.  
8.4.23.
RCL (VSV-G DNA)
RCL will be monitored using a PCR-based assay that detects and measures copies of the gene 
coding for the vector’s envelope protein, namely VSV-G that is necessary for the assembly of 
pseudotyped infectious lentiviral particles but absent from the vector’s backbone.
RCL testing will take place on subject’s peripheral blood mononuclear cells (PBMCs) which are
collected at Baseline and post infusion at Week 12, Week 24, Month 12, and then annually for 15 
years. See Table 1 and Table 2 for scheduling.
If all samples are negative in year one, PBMC samples will be collected and archived annually 
until 15 years post-infusion.  Samples will be archived at Adaptimmune’s centralized 
biorepository.  
If a positive VSV-G DNA signal is obtained, the study investigator will be informed and the 
subject will be scheduled for a retest as soon as possible and no later than one month after the 
initial positive result was reported to the Sponsor. See Appendix 7 Section 10.7.2 for additional 
information.
Details on collection and shipment of blood sample for RCL is described in the Sample 
Collection Manual.
8.5.
Adverse Events and Serious Adverse Events
8.5.1.
Time period for collecting AE and SAE Information
AEs and SAEs will be collected as follows:
During the Pre-screening period, only SAEs related to protocol-specified procedures 
will be collected from the time of the procedure (e.g., blood sampling, tumor biopsy) 
until 24 hours afterwards for blood sampling, or until 2 weeks post-biopsy.
From date of signing the Treatment ICF until the day before lymphodepletion starts, 
only SAEs related to study design/procedures (protocol mandated procedures, 
invasive tests, or change in existing therapy) or AEs leading to withdrawal from the 
study will be collected.

            
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All AEs and SAEs will be collected from the start of lymphodepletion until the 
subject has discontinues the interventional phase of the study. In addition, emerging 
clinical conditions defined in Appendix 4, Section 10.4.6 will be monitored for 
starting Day 1. If the subject has not progressed after 12 months, only those emerging 
clinical conditions defined in Appendix 4, Section 10.4.6 will be collected thereafter.
During the long-term follow-up phase of the study, subjects will only be monitored 
for the emerging clinical conditions defined in Appendix 4, Section 10.4.6 and these 
will be recorded. If a subject enters the LTFU phase prior to Week 12, they will have 
full AE collection at the Month 2 visit. 
All SAEs will be recorded on the SAE worksheet (SAEW) and reported to the sponsor or 
designee immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4.
SAE follow up information should be submitted on an updated SAEW within 24 hours if 
associated with a change in diagnosis and/or increased severity. Otherwise follow up should be 
submitted promptly within 7 days, and no later than 30 days of receiving new information.
8.5.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4, Section 10.4.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.5.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). 
Further information on follow-up procedures is given in Appendix 4, Section 10.4.3 .
8.5.4.
Regulatory Reporting Requirements for SAEs
Prompt (within 24 hours) notification by the investigator to the sponsor of a SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 

            
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forwarded to investigators as necessary.  These safety reports are forwarded to 
Investigators in the form of Investigator Safety Letters (ISL).
An investigator who receives an investigator safety letter describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and notify the IRB/IEC, 
if appropriate according to local requirements.
On request of a competent authority in whose territory the clinical trial is being 
conducted, the Sponsor will submit detailed records of all adverse events which are 
reported by the relevant Investigator(s).
8.5.5.
Pregnancy
Pregnancy (or pregnancy of a male subject’s partner) is not considered an AE/SAE 
unless there is reason to believe the pregnancy may be the result of failure of the 
contraceptive being used due to interaction with the investigational product.  Details 
of all pregnancies in female participants and female partners of male participants will 
be collected from the start of lymphodepletion for as long as there is evidence of T-
cell persistence, or until the subject has confirmed disease progression.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
6.  See Section 10.6.2 for guidance.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
The safety of ADP-A2M4 during pregnancy and lactation has not been established in humans.  
The target antigen is known to be expressed on fetal germ line tissues and placenta, therefore 
female subjects who are pregnant, intending to become pregnant, or breast feeding are excluded 
from ADP-A2M4 studies.
There is no preclinical or clinical trial data of ADP-A2M4 in pregnant women; however, there is 
a reasonable but unproven likelihood that this intervention may be significantly embryotoxic or 
even an abortifacient given the underlying biology of the target.  The effects on breast milk are 
unknown, therefore breastfeeding should be discontinued for the duration of the study, starting at 
the first dose of chemotherapy and for at least 12 months after receiving the investigational 
product, or four months after there is no evidence of persistence/gene modified cells in the 
Subjects blood, whichever is longer.
The contraception guidelines provided in Section 10.6.1 should continue to be adhered to during 
long-term follow up.
A woman who becomes and remains pregnant during the study will be discontinued from the-
interventional phase as exposure to radiation from imaging studies would be contraindicated.  
The subject would follow the LTFU T & E schedule Table 2. 

            
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8.5.6.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Progression of underlying malignancy and related symptoms are not reported as an AE if they 
are clearly consistent with the suspected progression of the underlying cancer.  Clinical 
symptoms of progression may be reported as AEs if the symptoms cannot be determined as 
exclusively due to progression of the underlying malignancy, or do not fit the expected pattern of 
progression for the disease under study.
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE /SAE.
8.5.7.
AE of Special Interest
8.5.7.1.
Cytokine Release Syndrome
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed 
following administration of antibodies and adoptive T-cell therapies for cancer.  It is defined 
clinically by symptoms which can mimic infection including pyrexia, nausea, diarrhea, 
headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea.  Subjects should be 
assessed clinically for CRS at all visits according to Table 1.  Most cases of CRS present within 
seven days following cell infusion. It is important to evaluate the subject for concurrent 
infections.  Potentially life-threatening complications of CRS include cardiac dysfunction, adult
respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure and disseminated 
intravascular coagulation.  CRS may also be associated with findings of macrophage activation 
syndrome or occur coincident with tumor lysis syndrome.
The diagnosis of CRS is clinical, and is supported by the exclusion of infection as well as the 
presence of increased cytokine levels and other biomarkers.  CRS should be graded and managed 
with supportive measures and anti-IL-6 according to the severity of symptoms, see Section 
10.5.6 for detailed guidance on grading and management of CRS.
8.5.7.2.
Neurotoxicity
Neurotoxicity has been described in association with immune effector cell therapy, and termed
immune effector cell-associated neurotoxicity or ICANS [Lee, 2019].  ICANS typically 
manifests as a toxic encephalopathy which is generally reversible.  Early signs include 
diminished attention, language disturbance and impaired handwriting.  Other signs/symptoms 
include confusion, disorientation, agitation, aphasia, somnolence, and tremors.  In severe cases of 
ICANS (defined as grade >2), seizures, motor weakness, incontinence, mental obtundation, 
increased intracranial pressure, papilledema, and cerebral edema may also occur.
ICANS occurring within the first 5 days after immunotherapy may be concurrent with high fever 
and cytokine release syndrome (CRS) symptoms.  This form of ICANS tends to be of shorter 
duration, lower grade (Grade 1–2, see Table 8), and is generally reversible with anti-IL-6 
therapy.  ICANS presenting as delayed neurotoxicity with seizures or episodes of confusion can 

            
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occur three or four weeks after CART cell therapy, after the initial fever and CRS subside [Lee, 
2019].
ICANS may occur with other cancer immunotherapies, including TCRs.  Cancer patients may 
also be at risk for encephalopathic symptoms due to other causes ranging from mild to moderate 
somnolence and confusion as a result of sedating medications, to seizures in relation to brain 
metastases.  The possible contribution of other medications, underlying disease and/or co-
morbidities should be evaluated when considering a diagnosis of ICANS in relation to T cell 
therapy.
8.5.7.2.1. Monitoring for ICANS
The ICE is a neurological assessment tool which is used to assess cognitive function to monitor 
for ICANS (see Section 10.5.7 for details). ICE should be measured on the day of ADP-A2M4
infusion prior to receiving treatment and through Day 8 whilst the subject is hospitalized. If the 
subject is discharged before Day 8 the ICE may be discontinued according to the T&E Table
(Section 1.3.1).    If a subject is found to have ICANS, the ICE should be used at every visit (at 
least twice per day if hospitalized) until resolution or stable.  It can also be used at later visits if 
indicated.  ICE also forms part of the grading system for ICANS developed by [Lee, 2019].
ICANS is graded and managed according to the severity of symptoms, see Section 10.5.7.1 for 
detailed guidance on management of ICANS.
8.5.8.
Long Term Follow Up Adverse Events
During the long-term follow-up (LTFU) phase of the study, adverse event collection is limited 
to: new malignancies, new incidence or exacerbation of a pre-existing neurologic disorder, new 
incidence or exacerbation of a prior rheumatologic or other autoimmune disorder, new incidence 
of a hematologic disorder, opportunistic and or serious infections, or unanticipated illness and/or 
hospitalization deemed related to gene modified cell therapy. If a subject enters the LTFU phase 
prior to week 12, they will have full AE collection at the Month 2 visit. See Section 10.4.6 for 
reporting AEs during LTFU.
8.5.8.1.
LTFU Letters to Primary Care Physician/Oncologist
A letter should be sent by the investigator/study coordinator to the subject’s primary care 
physician, local oncologist, or other physician that will notify him or her of this research study 
and will outline the features to look for and report as delayed adverse events potentially related 
to this study (Appendix 7, Section 10.7.4).
8.6.
Biomarkers for Exploratory Objectives
Sample types collected and rationale: Collection of samples for biomarker research is part of this 
study. The following samples for biomarker research are requested and will be collected from all 
participants in this study as specified in the T&E Table (Table 1):
Tissue

            
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Tumor: Efficacy of immunotherapy of cancer is conditioned by the interplay 
between tumor cells and resident or infiltrating immune cells (effector T cells and 
immunosuppressive cells). Therefore, tumor biopsies will be collected to evaluate 
the evolution of both tumor and immune components pre and post-infusion.
Blood
Serum: Serum is collected to allow for measurement of cytokines in the blood in 
relation to T cell expansion, and CRS. Serum samples may also be used to detect
other soluble biomarkers such as anti-tumor antibodies. 
 
 
 
 
 
 
   
 
 
 
 
 
 

            
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8.6.1.
Tumor Biopsy
Baseline biopsy material should be collected within two months of the T cell infusion, with
preference for a biopsy to be taken closer to the time of infusion. Tumor tissue should either be
taken from non-target lesions or from target lesions where sampling can be done without 
impacting lesion measurement. 
As a guidance and if possible, a responding lesion should be biopsied at the Week 4 time point 
and a progressing lesion, or a new lesion should be biopsied at the progression time point. The 
apparent clinical or scan status of the lesion(s) biopsied should be noted at the time (e.g. 
decreased, stable, increased size).
The Week 4 time point tumor biopsy can be collected anytime between Week 3 and Week 8.
The progression time point tumor biopsy can be collected obtained post-progression (e.g. from 
an excisional surgery). 
Additional details regarding the tumor biopsy collection are provided in the Sample Collection
Manual.
8.6.2.
Cytokine and Soluble Protein Analysis
Serum is collected at Baseline, pre-infusion and 2-4 hours post infusion on Day 1 and on Day 2, 
Day 4, Day 8, Week 2, Week 4, Week 8, Week 12, Week 24 and every 2 months post infusion to 
allow for measurement of cytokines in the blood.  Serum is also collected from subjects with 
suspected CRS, samples being taken approximately every other day until symptoms are 
improving or an alternative diagnosis is confirmed.  
Details regarding serum collection are provided in the Sample Collection Manual.
Serum samples may also be used to detect humoral immune responses to tumor antigens and
antibodies to ADP-A2M4.
8.6.3.

            
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8.6.5.
Persistence of ADP-A2M4 TCR+ Cells
The primary research assays for the trial involve monitoring for the persistence of infused
engineered cells in the subjects and for correlation of this with potential therapeutic effect.
Research samples will be taken as detailed in Section 8.4.22. Persistence is also monitored long 
term as a safety measure (Section 10.7.2). Along with the copies of gene-modified DNA per 
DNA, data
or relative to total lymphocyte number will 
be provided for persistence.
 
 
8.7.
Patient-Reported Outcomes
8.7.1.
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L)
EQ-5D is a standardized measure of health status developed by the EuroQOL Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal [EuroQOL,1990].  
The EQ-5D is applicable to a wide range of health conditions and treatments, and provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care.  The EQ-5D-3L descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities pain/discomfort and anxiety/depression. Each 

            
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dimension has 3 levels: no problems, some problems, extreme problems. The respondent is asked 
to indicate his/her health state by selecting the most appropriate statement in each of the 5 
dimensions. The EQ visual analogue scale (VAS) records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ and 
‘Worst imaginable health state’. This information can be used as a quantitative measure of health 
outcome as judged by the individual respondents.
The EQ-5D-3L will be administered at Baseline and post T cell infusion at Week 8, Week 16, 
Week 24 and Month 12. Once disease progression is established, the EQ-5D-3L assessment is no 
longer required.
8.7.2.
EORTC-QLQ-C30
The EORTC QLQ-C30 is a questionnaire developed by the Quality of Life Group of the European 
Organisation for Research and Treatment of Cancer to assess the quality of life of cancer patients. 
The EORTC QLQ-C30 will only be used in synovial sarcoma subjects in Cohort 2 at Baseline and 
post T-cell infusion at Week 8, Week 16, Week 24 and Month 12. Once disease progression is 
established, the EORTC QLQ-C30 assessment will no longer be required.
The EORTC QLQ-C30 comprises 30 questions. Each of the first 27 questions has 4 levels: Not at 
All, A Little, Quite a Bit, and Very Much.  The respondent is asked to indicate his/her health state 
by selecting the most appropriate statement. Questions 29 and 30 records the respondent’s self-
rated health on a horizontal scale where the endpoints are labelled ‘Very Poor’ and ‘Excellent’. 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents.

            
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9.
STATISTICAL CONSIDERATIONS
The objectives and endpoints for this study are described in Section 3, this section focusses on 
key aspects for the analysis and reporting of the primary and secondary efficacy and safety 
endpoints.  Details for the analysis of all clinical endpoints will be provided in the Statistical 
Analysis Plan (SAP).  The analysis plan for the objective related to the development of the 
validated Companion Diagnostic (CDx) will be described in a separate document.  Similarly, a
separate analysis plan will be developed for the exploratory biomarkers.
9.1.
Study Populations
Intent-to-Treat (ITT) population: This is the population of all subjects who were enrolled in the
trial (i.e. met eligibility criteria).  The ITT population will be used to assess the safety of the end-
to-end autologous T cell therapy procedure.
Modified Intent-to-Treat (mITT) population: This is the population of all ITT subjects who 
received T cell infusion. The mITT population is the primary analysis population for safety and 
efficacy evaluations following T cell infusion.
The primary analysis will be for Cohort 1 only occur at the time of clinical cut-off as described 
in Section 5.5.  
9.2.
Statistical Hypotheses and Sample Size Assumptions
The primary objective for this study is to evaluate the efficacy of autologous genetically
modified T cells (ADP-A2M4) in Cohort 1.
The primary endpoint for efficacy is Overall Response Rate (ORR) in Cohort 1 defined as the 
proportion of subjects with a confirmed CR or PR relative to the total number of subjects in the 
analysis population.  
The ORR will be based on confirmed (tumor) responses per RECIST v1.1 by independent 
review. 
Subjects with unknown or missing response will be treated as non-responders (i.e. they will be 
included in the denominator when calculating the proportion).  
The clinical and statistical assumptions, the hypothesis test, and sample size for the proposed 
single arm open label clinical trial are based on the following factors:
Section 4.2)
The ORR for historical control that will be used for hypothesis testing in the study will be 
18%
The mechanism of action for the TCR is assumed to be the same for synovial sarcoma 
and MRCLS. 
Section 2.2.3 states that in subjects with synovial sarcoma, the observed ORR (confirmed 
responses) for ADP-A2M4 cell therapy was 40.0% at the time of data cut off. Therefore, 

            
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for purposes of sample size computation, we assumed ORR for ADP-A2M4 cell therapy 
would be 40%.
No formal hypothesis testing is planned for Cohort 2 or across cohorts (overall).
The hypothesis of interest for the primary endpoint is;
(Null Hypothesis) H0: 
p0 , vs. (Alternate Hypothesis) H1: p > p0, where p0 (historical control 
rate) = 0.18. 
Based on above assumptions, the TCR ORR (i.e., p1) is set at 0.4.  The type I error
test will be no more than 0.025 and the type II er
eed 0.1. Exact Binomial 
methods will be used to test the hypothesis. 
Statistical Design Assumptions:
The assessment for efficacy will be based on the mITT population using confirmed ORR 
via RECIST v1.1 per independent review in Cohort 1;
The type I error 
;
Exact Binomial method will be used to test the hypothesis;
Cohorts 1 and 2 are independent.
Based on the statistical design assumptions above and the hypotheses and clinical assumptions in
Section 4.2, the estimated sample size for the trial is 45 subjects in Cohort 1).
The ORR for Synovial Sarcoma ranges between 4% – 13% in clinical trials (Section 
2.2.3).  If we assume that the ORR of the ADP-A2M4 will be 40% (P1), and historical 
ORR (P0) is 13% a sample size of N=27 provides power to detect an absolute difference 
of 27% using exact binomial assumptions.
To account for the potential variability in historical control efficacy, a more conservative 
historical ORR of 18% may also be considered.  Using a one-sided alpha=0.025, if we assume 
that the ORR of ADP-A2M4 will be 40% (P1) and historical ORR may be as high as 18% (P0), a 
sample size of N=45 in Cohort 1 provides at least 90% power to detect a difference of 22% using 
exact binomial assumptions. 
The following table describes samples sizes for a single cohort under a range of assumptions for 
the exact binomial assumption as described above.
Historical ORR (P0) 
TCR ORR (P1)
Difference (P1-P0)
N
0.13
0.40
0.27
27 
0.13
0.45
0.32
21

            
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9.3.
Statistical Analyses
The statistical analysis plan (SAP) document will provide full details about data derivations and 
displays and analysis methods for primary, secondary and exploratory endpoints. This section 
captures key aspects of the analysis.
Demography and baseline characteristics will be summarized using appropriate descriptive 
statistics. Subject disposition including number of subjects leukapheresed, lymphodepleted and 
treated with ADP-A2M4 will be summarized. Reasons for subject discontinuation from the study 
will be displayed. 
9.3.1.
Interim Analysis
There is no interim analysis planned.
9.3.2.
Efficacy Analyses
The primary analysis population for efficacy will be the mITT population.  Secondary analyses 
may be conducted on the ITT populations, if it is different from the mITT population.  
The ORR will be based on confirmed (tumor) responses per RECIST v1.1 by independent 
review.
Sensitivity analyses of ORR will be based on confirmed responses per RECIST v1.1, and on 
investigator assessment of overall response (per RECIST v1.1).  
The primary endpoint, ORR per RECIST 1.1. by independent review in Cohort 1, will be
evaluated using a one-sided exact-based Clopper-Pearson 97.5% confidence interval (CI).   If the 
lower bound of the 97.5% CI exceeds 18%, the trial has met the pre-specified threshold for 
demonstrating efficacy and the trial has met the criterion for statistical significance.
As a sensitivity analysis, one-sided 97.5% confidence interval using the Wilson method may also 
be provided.
ORR per RECIST v1.1 by independent review will also be evaluated across cohorts (overall).
The following secondary efficacy endpoints will be summarized:
Time to Confirmed Response, defined as the duration between T-cell infusion and the 
initial date of the confirmed response.
Duration of Response (DoR), defined as the duration from the initial date of the 
confirmed response to the date of progressive disease or death.
Progression Free Survival (PFS), defined as the interval between the date T-cell 
infusion and the earliest date of disease progression based on RECIST v1.1 or death 
due to any cause.
Overall Survival (OS), defined the duration between T-cell infusion and death.  

            
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Independent assessment of progression based on RECIST v1.1 will be used for the primary 
analysis of DoR and PFS. As a sensitivity analysis, determination of progression (via RECIST 
v1.1) using lesion assessments will also be provided. 
All secondary efficacy endpoints will be summarized for Cohort 1 and across cohorts (overall).
No hypothesis testing is planned for these secondary endpoints in Cohort 1 or across cohorts. 
Time to event endpoints (i.e., OS and PFS) will be summarized and displayed graphically using 
Kaplan-Meier (K-M) methodology to estimate the median, and the 25th and 75th percentiles. 
Two-sided 95% confidence intervals will be produced.  Overall Survival may be assessed at 
fixed time points such as 1 year and 2 years using K-M methods. 
The following censoring rules will be applied:
For overall survival, subjects who are lost to follow-up or still alive will be censored at 
the date of last contact.
For PFS, subjects who do not have a documented date of disease progression or death 
will be censored at the date of the last study assessment.
The proportion of censored observations will be summarized.
The pharmacokinetic (PK) profile will be described by summaries of Peak expansion (i.e., 
maximum persistence) and time to peak expansion by responder status and overall. Persistence 
data will also be displayed by subject line plots.
9.3.3.
Safety Analyses
The primary analysis population for safety will be the mITT population.  Safety will also be 
summarized for the ITT population and may also include the per protocol (PP) population. All 
safety analyses will be summarized for Cohort 1 and across cohorts (overall).
The safety profile will be based on adverse events, serious adverse events, replication competent 
lentivirus (RCL) and vector integration/clonality. Other safety assessments will include vital 
signs measurements and clinical laboratory test results.
These data will be summarized using appropriate descriptive statistics, i.e., continuous data will 
include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages.
Adverse events will be summarized using two time periods: 
From the time of signing the treatment ICF; 
From start of lymphodepleting chemotherapy, defined as starting on the first day of 
lymphodepleting chemotherapy.
Adverse events throughout the trial will be coded by MedDRA v21.0 or higher.  The number and 
percent of subjects reporting any adverse events will be tabulated by system organ class and 
preferred term. Adverse events will be further classified by toxicity grade, relationship to 
treatment and seriousness in tabulation.

            
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Summary data on duration, grade, time to onset for adverse events of special interest i.e.,
cytokine release syndrome (CRS), ICANS will be presented.  Data from ICE will be listed.
For subjects in the LTFU phase, the LTFU AE will be summarized and listed.  

            
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Data Handling and Record Keeping
10.1.1.1.
Data management
An Electronic Data Capture (EDC) system will be used to collect data pertaining to this trial.  
Trial data will be captured through an electronic Case Report Form (eCRF).  Within the EDC 
system the eCRF data will be entered by the site staff and all source document verification and 
data cleaning will be performed by the Sponsor or designee (e.g. CRO).
The specifications for the EDC system will be documented and approved before the EDC system 
is released for live use.  The validation of the eCRF data will be defined in a Data Management 
Plan.  As data are entered into the eCRF, the validation checks will be performed and where 
necessary, queries will be raised.  All queries raised will be held in the EDC database.
The EDC system is a validated software program that has been designed to comply with CFR21 
Part 11 requirements.  All users will access the system via unique user name and password.  A 
full audit history of all actions performed within the system is maintained.  User accounts ensure 
that each user can only perform the tasks applicable to their role and only have access to the data 
applicable to their role.
Standard coding dictionaries, WHO Drug and MedDRA will be used to code medications and 
adverse events.
When all data have been entered and all data cleaning is complete the data will be locked and 
made available for analysis and reporting.
On completion of the study all eCRF data, including all associated queries and audit history, will 
be made available in PDF format to both the study Sponsor and the sites.
10.1.1.2.
Case Report Forms
For each subject enrolled, the completed eCRF must be reviewed and signed by the Principal 
Investigator or authorized delegate.  If a subject discontinues the study, the reason must be noted 
on the eCRF.
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports.

            
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10.1.1.3.
Site Documentation and Source Data
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents are 
classified into two different categories: (1) Investigator Site File (ISF) and (2) subject specific 
source documents.
The Investigator is responsible for maintaining a complete and accurate ISF containing essential 
documents as required by ICH GCP.
Source documents contain the results of original observations and activities of a clinical 
investigation.  Source documents include but are not limited to subject medical records/progress 
notes, appointment book, original laboratory reports, ECG printouts, CT/MRI scans, pathology 
and special assessment reports, and signed informed consent forms.  In no circumstances is the 
eCRF to be considered as source data.
The Investigator must ensure the availability of source documents from which the information on 
the eCRF was derived.
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local or foreign regulatory authorities, the IRB/IEC and auditors to inspect facilities and to have 
direct access to the ISF and all source documents relevant to this study regardless of the type of 
media.
10.1.1.4.
Data Retention and Availability
The Investigator must keep all essential study documents including source data on file for at least 
25 years after completion or discontinuation of the Study.  After that period of time the 
documents may be destroyed, subject to local regulations.
The Investigator will not dispose of any records relevant to this study without written permission 
from the Sponsor.  If the Investigator cannot guarantee the archiving requirement at the 
investigational site for any or all of the documents, such study records may be transferred upon 
request to the Sponsor or its designee.
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in writing in advance.
Study documentation is subject to inspection by the Sponsor, its representatives and regulatory 
agencies and must be stored in such a way that it can be accessed/retrieved within a reasonable 
timeframe at a later date.
10.1.2.
Study Monitoring
Study Monitoring will be conducted by the Sponsor or designated CRO.
It is understood the responsible monitor will contact and visit the Investigator regularly and will 
be allowed, on request, to inspect all records of the trial (e.g. eCRFs, ISF, and source documents) 
provided that subject confidentiality is maintained in accordance with local requirements.

            
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It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify adherence to the protocol and the completeness, consistency and accuracy of the 
data being entered.  The monitor should have direct access to subject source documents to verify 
the entries on the eCRF.  The Investigator (or designee) agrees to cooperate with the monitor (or 
designee) to ensure any discrepancies detected are resolved.
10.1.2.1.
Audits and Inspections
The Sponsor or its representatives may conduct audits at investigative sites including, but not 
limited to, facilities where the study is being conducted, investigational product handling and 
accountability, presence of required documents, the informed consent process and comparison of 
eCRFs with source documents.
All study documentation including source data must be available for audit.
The Investigator agrees to cooperate fully with audits conducted at a convenient time in a 
reasonable manner.
Regulatory agencies may also inspect investigative sites during or after the study.  The 
Investigator (or designee) should contact the Sponsor immediately if this occurs, and provide 
copies of correspondence relating to requests for an inspection of the site facilities.
10.1.3.
Regulatory and Ethical Considerations
10.1.3.1.
Competent Authority Submissions
Adaptimmune or its authorized representatives will be responsible for ensuring that appropriate 
competent authority approvals are obtained according to local country requirements.  Competent 
authority approval (or notification as applicable) will be obtained before initiation of the study.
10.1.3.2.
Independent Ethics Committees
The final study protocol and subject informed consent documentation will be approved by the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and any other site level 
committee deemed appropriate by the Institution.  Approval from each applicable committee will 
be received in writing before initiation of the study.
Protocol amendments must also be approved by the IRB/IEC (and other committees as 
applicable) before implementation, except in the case of changes made to protect subjects from 
immediate hazard, which may be implemented immediately.
10.1.3.3.
Local regulations/Declaration of Helsinki
The Investigator will ensure this study is conducted in full compliance with the principals of the 
“Declaration of Helsinki” or with the laws and regulations of the country in which the research is 
conducted, whichever, affords the greater protection to the subject. The study must fully adhere 
to the principles outlined in ICH GCP or with local law if it affords greater protection to the 
subject.

            
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10.1.4.
Informed consent
It is the responsibility of the Investigator to obtain written informed consent from all study 
subjects prior to any study related procedures being performed.  All consent documentation must 
be in accordance with applicable regulations and ICH GCP.  Documentation must include the 
dated signature of both the subject (or the subject’s parents or legally authorized representative 
as applicable) and the person conducting the consent discussion.  If the subject is illiterate, an 
impartial witness should be present during the consent discussion, and the consent signed and 
dated by the witness, the subject, and the person conducting the consent discussion.  The consent 
form should be translated and communicated to the subject in a language that is understandable 
to the subject.  Certified translations of the informed consent documentation will be provided as 
applicable.
A copy of the signed and dated informed consent should be provided to the subject before 
participation in the study.
Tests performed as standard of care prior to documentation of consent may be used for screening 
results as appropriate (Section 8.4).
10.1.5.
Confidentiality
The confidentiality of records that may identify subjects will be protected in accordance with 
applicable laws, regulation and guidelines.
The Investigator must ensure that each subject’s anonymity is maintained and protected from 
unauthorized parties.  On eCRFs or other documents submitted to the Sponsor, subjects must not 
be identified by their names, but by a unique identification code allocated to them to ensure 
confidentiality on all study documentation. Subjects will retain this unique number throughout 
the study.
The Investigator will keep a subject enrollment log showing subject unique identification codes, 
names and addresses in the ISF.
The Sponsor and/or its representatives accessing subject records and data at site will take all 
reasonable precautions to maintain subject confidentiality.
10.1.6.
Protocol Adherence
The Investigator must sign the protocol to confirm acceptance and willingness to comply with 
the study protocol.
The Investigator or designee will not deviate from the protocol unless necessary to eliminate an 
apparent immediate hazard to the safety, rights or welfare of any study subject.  In the event of a 
protocol deviation for any reason, the Investigator will promptly report the deviation to the 
Sponsor in writing.

            
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10.1.7.
Study Suspension, Study Termination and Study Completion
The Sponsor may suspend or terminate the study at any time for any reason.  If the study is 
suspended or terminated the Sponsor will ensure applicable sites, regulatory agencies and 
IRBs/IECs are notified as appropriate.
If the Investigator stops/terminates the study at their site the Sponsor must be notified.  The 
Sponsor will ensure Regulatory Agencies and IRBs/IECs are notified as appropriate.
The Sponsor will ensure End of Study declarations are made to the relevant Regulatory 
Agencies/IECs in accordance with local regulations.
10.1.8.
Public Posting of Study Information
The Sponsor is responsible for posting appropriate study information on applicable clinical study 
registry websites.  Information included in clinical study registries may include participating 
Investigator’s names and contact information.
10.1.9.
Clinical Study Report
The results of the study will be presented in an integrated Clinical Study Report (CSR) according 
to ICH guideline E3: Structure and Content of Clinical Study Reports.
10.1.10.
Publication Policy
The Investigator may not submit the results of the study for publication or present the results of 
the study without the prior written agreement of the Sponsor in accordance with the Clinical 
Trial Agreement.  The results of this study will be published as a whole once all subjects have 
completed the study and the study results have been analyzed.  Interim publications of data from 
the study may be made if mutually agreed between the Sponsor and the Investigators.  
Agreement will not be provided by the Sponsor where in the Sponsor’s view interim publications 
would introduce bias or lead to any misrepresentation or inaccuracies in data.
Authorship will be determined in conformance with the International Committee of Medical 
Journal Editors (ICMJE) guidelines and/or publication guidelines if applicable.
10.1.11.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing updated information on financial interests during the course of the 
study and for 1 year after completion of the study.

            
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10.2.
Appendix 2: Safety Reviews
10.2.1.
Data Safety Monitoring Board
A Data Safety Monitoring Board (DSMB) will be implemented for this study for Cohort 1 only 
and will consist of two experienced oncologists who are independent of the study and an 
independent statistician.  
The DSMB will review ongoing safety (including AEs and SAEs) during the interventional 
phase of the study after approximately 5, 15 and 30 subjects have been dosed.  At the time of 
Protocol Amendment 3, the DSMB has held 2 operational meetings to review data from after 
dosing of 5, and 15 subjects. Both meetings resulted in the DSMB recommendation to continue 
the study without protocol modification. The final DSMB meeting will be held after the 30th 
subject has been dosed in Cohort 1.
A DSMB charter, defining roles and accountabilities and the process for review, is available.

            
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Coagulation Screen:
Prothrombin time (PT) or International Normalized 
Ratio (INR)
Activated partial tissue thromboplastin time (aPTT)
Pregnancy Test:
Serum beta-HCG or Urine test
Thyroid Function Tests:
Thyroid Stimulating Hormone (TSH)
Infectious Disease:
HIV 1+2 antibody#
Hepatitis B surface antigen
Hepatitis B core antibody – if positive, test for HBV 
DNA
Hepatitis C antibody – if positive, test for HCV RNA
HTLV 1+2 IgG
CMV IgG#
EBV (EBNA)#
Treponema IgG or RPR #
Viral reactivation
CMV DNA PCR – peripheral blood for detection of 
reactivation. In the event of suspected end organ CMV 
disease a biopsy may be required
# Per Institutional Standard Practice is acceptable

            
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Actions
Follow Up Assessments
Complete the electronic case report form 
(eCRF), and a serious adverse event worksheet 
(SAEW) if the event meets the criteria for an 
SAE within 24 hours.1
Consider hepatologist consultation
Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and INR 
Perform Follow-Up Assessments (See column 
to the right)
Monitor participants weekly with liver 
chemistry and INR until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. For bilirubin or INR criteria, monitor 
participant twice weekly.
Fractionate bilirubin, if t
Viral hepatitis serology3
Serum CPK and LDH
CBC with differential to assess eosinophilia
PBMC blood sample for persistence4
Assess for the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) 
and alcohol use
For bilirubin or INR criteria:
Hepatologist consultation required
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography)
Consider liver biopsy
1.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 
may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE. The INR stated 
threshold value will not apply to participants receiving anticoagulants. 
2.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
3.
Includes:Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody. 
4.
Record the date/time of the PBMC blood sample draw on the CRF. Instructions for sample handling and 
shipping are in the Laboratory Manual.

            
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10.4.6.
Reporting Criteria during Long Term Follow-Up (Years 1-15)
Due to the nature of the treatment, subjects are required to be followed for 15 years after 
treatment with genetically modified T cells according to FDA and EMA guidance [FDA, 2006; 
FDA, 2010; EMA, 2009].  Subjects will be followed according to the schedule outlined in
Section 1.3.2 , Table 2.  Emergence of any of the following new clinical conditions reported or 
observed and the action taken will be reported to the Sponsor:
New Malignancies
New incidence or exacerbation of a pre-existing neurological disorder
Excluding all Grade 1 neurologic AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder
Excluding all Grade 1 autoimmune AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
All rheumatologic disorders will be reported irrespective of grade
New incidence of a hematologic disorder
Excluding cytopenias following cytotoxic chemotherapy before bone marrow 
recovery
Excluding Grade 1 and 2 laboratory abnormalities, unless the Investigator 
considers clinically significant
Opportunistic and/or serious infections
Excluding infections secondary to chemotherapy induced cytopenias
Unanticipated illness or hospitalization deemed at least possibly related to gene 
modified cell therapy
These are the only adverse events that will be collected during LTFU.
A detailed description of the event should include the date of diagnosis and the nature of the 
diagnosis.  If the diagnosis is cancer, record the type and stage of the cancer.  If the cancer is 
metastatic, list the metastatic sites.  If a new malignancy is recorded in a vector target T-cell
type, tumor cells will be evaluated for vector sequences.  If the tumor is positive for vector 
sequences or the surrogate sample is positive for vector sequences and is confirmed in 
accordance to this protocol, clonality analysis will be performed.  If no evidence of oligo-or 
monoclonality is observed, a summary report of any and all analysis for the pattern of vector 
integration will be assembled, and submitted within the annual report of the INDs listed on this 
protocol under which the subject(s) evaluated originally received their treatment.  If evidence of 
oligo- or monoclonality is observed, an information amendment will be submitted within 30 days 

            
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to the INDs listed on this protocol under which the subject(s) evaluated originally received their 
treatment.  
10.4.7.
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents
In accordance with FDA and EMA guidance [FDA, 2018; EMA, 2009], all subjects enrolled in 
this trial are asked to consider an autopsy and autopsies will be requested of the families for all 
subjects who die during participation in studies after administration of gene transfer agents.
Guidelines for autopsy tissue/sample collection, preparation and shipping are provided in the
Laboratory Manual.

            
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10.5.
Appendix 5: Supportive Care Guidance
It is recommended that a specialist with experience in the administration of hematopoietic stem 
cell transplant and/ or other cell and gene therapy be involved in the care of study subjects.  Staff 
treating trial subjects should be experienced in acute post-transplant care and the management of 
associated toxicities (e.g. cytopenias, cytokine release syndrome, ICANS).
Subjects are at risk for the development of certain adverse effects for which recommended 
management strategies have been developed.  Adverse effects are most likely to occur within the 
first month following T-cell infusion, but may occur at later time points.
Supportive care treatments recommended herein, including tocilizumab will be supplied by the 
pharmacy of the participating institution.
10.5.1.
Lymphodepleting Chemotherapy Symptom Management
Cyclophosphamide and fludarabine are used as pre-conditioning lymphodepleting chemotherapy 
in this study. Symptoms associated with the use of cyclophosphamide and fludarabine are 
included in the respective product labels. Refer to the most current product labels.
10.5.1.1.
Management of Neutropenia
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
is also common. Prophylactic use of G-CSF is recommended in all subjects. G-CSF (i.e., 
filgrastim) should be used for management of neutropenia according to ASCO guidelines [Smith, 
2015]. G-CSF should be given on Day -3 until resolution of neutropenia (reaching an ANC of at 
least 2 × 109/L to 3 × 109/L or as per institutional practice).
Long-acting (pegylated) G-CSF may be given in preference to short acting daily G-CSF in 
accordance with institutional standard practice. Pegylated G-CSF will be given as one dose on 
Day-3.
10.5.2.
T-cell Infusion Symptom Management
Mild transient symptoms have been observed following infusion of engineered T cells. The 
management of these symptoms is suggested but should not necessarily be confined to the 
below.
Fever, chills, headache and temperature elevations will be managed with 
acetaminophen. It is recommended all subjects that develop fever or chills have a 
blood culture drawn.
Nausea and vomiting may be treated with a non-steroidal anti-emetic of choice.
Hypotension will initially be managed by intravenous fluid administration and further 
measures as dictated by standard medical practice.
Hypoxemia will initially be managed with supplemental oxygen and further measures 
as dictated by standard medical practice.

            
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10.5.3.
Infection
Additional measures to treat and prevent infection are outlined below.  In particular, fever and 
neutropenia should be aggressively managed as well as preemptive influenza therapy and other 
standard therapies for immunocompromised hosts, in accordance with institutional guidelines.
10.5.3.1.
SARS-CoV-2 (COVID-19)
Subjects with a positive RT-PCR test for COVID-19 (irrespective of vaccination status) post 
lymphodepleting chemotherapy or ADP-A2M4 cell infusion should be immediately referred to 
an infectious disease specialist for consideration of anti-viral therapies. Investigators should also 
consult the latest guidelines/institutional policies pertaining to the management of COVID-19 in 
cancer/cell therapy patients. The Medical Monitor should be informed if a subject has a positive 
COVID-19 test (irrespective of symptoms) after receiving either lymphodepleting chemotherapy 
or ADP-A2M4 cell infusion.
10.5.3.2.
Pneumocystis carinii Pneumonia
Subjects should receive prophylaxis against Pneumocystis pneumonia with drug, dose and 
duration according to institutional guidelines.  Single strength trimethoprim sulfamethoxazole 
daily is the recommended first line agent, starting at day 28 for one year.  Other regimens 
including atovaquone (1500 mg daily with food) or aerosolized pentamidine (300 mg every four 
weeks) are also acceptable, e.g. sulfonamide allergy, and should follow Institutional standards 
for autologous bone marrow transplants.
10.5.3.3.
Herpes simplex and Varicella zoster
All subjects should receive prophylaxis with acyclovir (800 mg twice daily) or valacyclovir 
(500mg twice daily) for one year, or in accordance with institutional guidelines. In general, 
prophylaxis should start on day of T-cell infusion, or on day of lymphodepletion if the subject 
has a history of shingles or multiple HSV episodes.
10.5.3.4.
Cytomegalovirus
Subjects will be screened for cytomegalovirus (CMV) seropositivity at study entry.  If CMV 
viremia is detected at baseline, treatment should be initiated and evidence of viral clearance 
obtained, prior to lymphodepletion chemotherapy.  All CMV seropositive subjects will continue 
to be monitored for CMV viremia by CMV DNA PCR as shown in Table 1 until 60 days post 
infusion of ADP-A2M4.  In the event CMV viremia is observed an Infectious Diseases specialist 
should be consulted and treatment initiated if necessary according to institutional practice.  
<1000.
If a subject experiences prolonged or secondary pancytopenia or lymphopenia additional 
monitoring for viral reactivation should be considered and treatment for viral infection initiated 
if necessary.  A strategy for management of pancytopenia or bone marrow failure is described in 
Section 10.5.8.

            
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10.5.3.5.
Hepatitis B Prophylaxis
Subjects will be screened for hepatitis B (HBV) at study entry. Subjects who are hepatitis B core 
antibody positive must receive prophylaxis against viral reactivation using institutional 
protocols.  Prophylaxis should be initiated prior to lymphodepleting therapy and continued for 6 
months.  Acceptable regimens include lamivudine (300mg daily), entecavir (0.5mg daily), or 
tenofovir (300mg daily).
10.5.3.6.
Syphilis
Subjects will be screened for syphilis at study entry in accordance with institutional standards.  
Subjects with positive screening results should be evaluated by an infectious diseases consultant.  
If determined to have syphilis infection, the subject should be treated before lymphodepletion 
chemotherapy.
10.5.3.7.
Other Anti-Microbial Prophylaxis
Antibacterial and antifungal prophylaxis should follow institutional standards for autologous 
bone marrow transplants.
10.5.4.
Hematologic and Blood Product Support
Blood product support should be provided to maintain platelets > 10 x109/L, Hb > 8.0 g/dL (or in 
accordance with institutional practice) and as clinically indicated. See AABB Guideline on 
platelet transfusion [Kaufman, 2015].
10.5.4.1.
Irradiated Blood Product
The guidance for autologous stem cells is also recommended for use in T- cell therapy. 
Blood products transfused during the following study periods must be irradiated:
7 days prior to and during leukapheresis to prevent the collection of viable allogeneic 
T lymphocytes, Irradiated blood components should continue to be used until 3
months following T-cell infusion unless conditioning, disease or previous treatment 
determine indefinite duration.
Irradiated blood products may be used longer as clinically indicated, otherwise follow 
institutional guidelines on autologous stem cell transplantation
10.5.4.2.
CMV screened blood products
Subjects will be screened for CMV seropositivity on study entry.  In order to reduce the risk of 
primary CMV infection all subjects (i.e. both CMV-positive and -negative subjects) should 
receive leukoreduced blood products where possible (excluding the IP infusion).  Where 
leukoreduced blood is not available, CMV negative subjects must only receive blood products 
from CMV-seronegative donors from study entry to study completion.

            
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10.5.5.
Management of Autoimmunity
Subjects should be monitored throughout the trial for potential autoimmune reactions in response 
to the genetically engineered T cells that could include skin toxicity, liver toxicity, colitis, eye 
toxicity etc.  If autoimmunity is suspected, the PI should be contacted and every attempt should 
be made to biopsy the affected organ to clarify whether the symptoms are related to the ADP-
A2M4 therapy.  If the subject sustains persistent Grade 2, or Grade 3 or 4 autoimmunity, 
consideration should be given to administration of corticosteroid therapy, either topically (e.g. 
skin, eyes) or systemically as clinically indicated.
10.5.6.
Management of Cytokine Release Syndrome
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed 
following administration of antibodies and adoptive T cell therapies for cancer. It is defined 
clinically by symptoms many of which mimic infection including pyrexia, nausea, diarrhea, 
headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea. It is important to 
evaluate the subject for concurrent infections. Potentially life-threatening complications of CRS 
include cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or 
hepatic failure and disseminated intravascular coagulation. CRS may also be associated with 
findings of macrophage activation syndrome or occur coincident with tumor lysis syndrome.
CRS causes a rapid rise in serum cytokine levels under conditions of immune activation and 
although cytokines will be assayed serially throughout the study, results of the assays will not be 
available in real time; therefore CRS should be graded and managed with supportive and 
immunosuppressive interventions according to the severity of symptoms [Lee, 2019].
Table 6 provides the recommended management of CRS according to grade, which has been 
further adapted from CTCAE for use with immunotherapy and should be implemented in 
accordance with institutional guidelines. Symptoms can mimic those seen with infection. The 
diagnosis of CRS is clinical, and is supported by the exclusion of infection as well as the 
presence of increased cytokine levels and other biomarkers. Assessment and treatment guidelines 
are provided below. If CRS is suspected, in addition to assessment for infection, cytokine levels 
(Section 8.6.2) ferritin (Section 8.4.21), as well C-reactive protein (CRP) (Section 8.4.20) levels 
should be measured approximately every other day until symptoms are improving or an 
alternative diagnosis is confirmed.

            
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CRS with single doses [Maude, 2014]. The United States product insert (USPI) for
tocilizumab recommends a dose of 8 mg/kg administered over 1 hour in adult subjects as the 
first-line treatment of severe CRS. Subjects may receive a repeat dose(s) if clinical signs and 
symptoms do not improve at least 8 hours apart. Refer to Section 10.5.7 below for subjects 
experiencing Immune Effector Cell-Associated Neurotoxicity Syndrome concurrent with CRS.
Second-line, tocilizumab refractory, management of CRS is at the discretion of the Investigator 
following local institutional policy. This can potentially include the use of corticosteroids either 
in combination with a second dose of Tocilizumab [Maus, 2020] or a corticosteroid administered 
as a single agent after two doses of Tocilizumab have been administered and if CRS symptoms 
are persisting. Use of steroid sparing agents (e.g. siltuximab or anakinra) is at the discretion of 
the Investigator.
Lee [2019] recommend steroids as second-line therapy for CRS as the response to anti-IL-6 
therapy may be more rapid and owing to the potential of steroids to attenuate the anti-tumor 
effects of the adoptive T cell therapy. However, in subjects with Grade 3 or 4 CRS associated
with neurologic dysfunction without significant hemodynamic instability (See Section 10.5.7) or 
other life-threatening symptomatology, consideration may be given to the use of corticosteroids 
as immunosuppressive therapy. High doses (e.g. 2 mg/kg/day prednisone equivalent) may be 
required.
If cytokine release syndrome is suspected, a physician with expertise in the management of 
subjects following bone marrow transplant should be consulted. If high dose corticosteroids are 
required, treatment should generally be continued until resolution to Grade 1 followed by 
tapering doses over several weeks.
Please refer to the most recent version of the product label for tocilizumab and the latest Society 
for Immunotherapy of Cancer (SITC) guidelines for CRS [e.g. Maus, 2020].
10.5.7.
Management of Encephalopathy Syndrome (ES)
See Section 8.5.7.2 for a description of ICANS. Neelapu, et al [Lee, 2019] have developed a 
grading system for ICANS which incorporates the Immune Effector Cell-Associated 
Encephalopathy 10 point neurological assessment (ICE) tool, see Table 7. Points are assigned 
for each of the tasks in Table 7 which are performed correctly.  Normal cognitive function is 
defined by an overall score of 10.
The ICE should be used to monitor all subjects for ICANS.
Table 7:
ICE 10 point neurological assessment [based on Lee, 2019] 
Task
ICE Points
Orientation to: year, month, city, hospital, and 
President/Prime Minister of country of residence
Total of 4 points (one point for each)
Naming: Ability to name three objects (e.g. point 
to: clock, pen, button)
Total of 3 points (one point for each)

            
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Task
ICE Points
Following commands: ability to follow simple 
commands (e.g., “Show me 2 fingers” or “Close 
your eyes and stick out your tongue”)
1 point
Writing: Ability to a standard sentence, e.g.
‘There are seven days in a week’
1 point
Attention: Ability to count backwards from 100 
by tens
1 point
The ICE score is used in grading of ICANS as presented in Table 8.
Table 8:
Grading of Immune Effector Cell-Associated Neurotoxicity (ICANS)
Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
ICE Score1
7–9 
3–6 
0–2 
0 (patient is 
unarousable, and
unable perform 
ICE)
Depressed level of 
consciousness2
Awakens 
spontaneously
Awakens to 
voice
Awakens only to 
tactile stimulus
Patient is 
unarousable or 
requires vigorous 
or repetitive 
tactile stimuli to 
arouse. Stupor or 
coma
Seizures 
NA
NA
Any clinical
seizure, focal or 
generalized that 
resolves rapidly 
or 
nonconvulsive 
seizures on EEG 
that resolve with 
response to 
intervention
Life-threatening 
prolonged seizure 
(>5 min); or
Repetitive clinical 
or electrical 
seizures without 
return to baseline 
in between
Motor findings 3
NA
NA
N/A
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis

            
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Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
Elevated ICP/
cerebral edema
NA
NA
Focal/local 
edema on 
neuroimaging4
Diffuse cerebral 
edema on 
neuroimaging; 
decerebrate
or decorticate 
posturing; or 
cranial nerve VI
palsy; or 
papilledema; or
Cushing's triad
Source: Based on Lee, 2019
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who 
has a generalized seizure is classified as grade 3 ICANS.
N/A indicates not applicable.
1 A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient 
with an ICE score of 0 may be classified as grade 4 ICANS if unarousable.
2 Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medication).
3 Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE 
v5.0, but they do not influence ICANS grading.
4 Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is 
excluded from ICANS grading. It may be graded according to CTCAE v5.0.
10.5.7.1.
Management of ICANS
The recommended management of ICANS should be based on toxicity grade.  Table 9 provides 
guidance on the management of ICANS, and should be implemented in accordance with 
institutional guidelines.  
Grade 1 ICANS is primarily managed with supportive care as outlined below.  For subjects 
requiring intervention beyond supportive measures, anti-IL-6 therapy should be the first line 
treatment of for ICANS in the setting of CRS (See Section 10.5.6 for CRS diagnosis and 
treatment guidelines).  In the setting of concurrent CRS, for Grades 1-3 ICANS additional doses 
of anti-IL-6 therapy should be considered before instituting corticosteroids since the use of 
systemic steroids may abrogate the effects of the T cell therapy.  For subjects with neurologic 
symptoms refractory to an initial dose of anti-IL-6 therapy, consider siltuximab for the second 
dose based on its mechanism of action directly against IL-6.

            
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neutropenia.  Bacterial and fungal infections are common and a significant cause of morbidity 
and mortality.
10.5.8.2.
Management of Prolonged Cytopenias
Management of bone marrow suppression and related prolonged cytopenias is challenging, with 
no clearly established guidelines regarding immunosuppression.  Treatment is largely supportive, 
including transfusions and treatment of infections.  If there is evidence of, or concern for the 
development of prolonged cytopenias (decreasing hemoglobin, platelets or neutrophils, or 
increasing transfusion requirements) 
the following 
measures should be implemented:
1. Consult a physician with expertise in the management of bone marrow suppression
2. Increase the frequency of CBCs as clinically indicated.
3. Exclude other alternative etiologies such as other drugs, viral causes, etc.
4. An early bone marrow biopsy is recommended for clinical diagnosis, with a sample to be 
provided to the Sponsor for study. Details on tissue collections, kit use and shipment 
information can be found in the Laboratory Manual.
5. A matched peripheral blood sample should be collected in parallel with the bone marrow 
sample and provided to the Sponsor 
6. Initiate treatment with G-CSF
7. Consult an Infectious Diseases expert
8. Once alternative etiologies have been excluded, strongly consider immunosuppression 
(e.g. methylprednisolone 2mg/kg initial dose) or more aggressive regimens (e.g. 
antithymocyte globulin (ATG), cyclosporine, eltrombopag) as well as antimicrobial 
prophylaxis/therapy with the advice of your Hematology/Infectious Diseases
consultant(s).  If high dose corticosteroids are initiated, duration of therapy and taper 
should be determined with advice from expert consultants.
10.5.9.
Management of Graft-versus-Host Disease (GVHD)
Autologous graft-versus-host disease (GVHD) has been described in association with adoptive 
transfer of ex-vivo expanded/co-stimulated autologous T cells (Rapoport, 2009), as well as 
infusion of T cells with engineered specificity for NY-ESO-1 and LAGE-1a (Garfall, 2013), 
following high-dose chemotherapy and autologous stem cell transplant (ASCT) in patients with 
multiple myeloma. There is the potential for subjects who receive cytoreductive therapy followed 
by engineered autologous T cell infusion to experience GVHD and/or autoimmune GVHD-like 
symptomatology.  Autologous GVHD is typically milder than classic (allogeneic) GVHD (Kline, 
2008), and is usually manageable with treatment. However, severe cases (including fatalities) have 
been reported (Fidler, 2012). There are no published guidelines for the management of autologous 
GVHD. However, lessons can be drawn from published case reports and guidelines for the 
diagnosis and management of acute GVHD following allogeneic transplant (Dignan, 2012).

            
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10.5.9.1.
Diagnosis of GVHD
The diagnosis of GVHD is predominantly based on clinical findings and is often one of exclusion. 
Many of these symptoms can also occur in the setting of the preparative regimen, high dose 
cyclophosphamide as well as with cytokine release syndrome.  Any of these conditions including 
GVHD can be associated with fever. The skin is the most commonly involved organ, followed by 
the gastrointestinal (GI) tract and liver. A constellation of symptoms involving these organ systems 
may be helpful in establishing the diagnosis of GVHD.  Diarrhea, rash, fever, and pancytopenia 
are common toxicities in the NY-ESO-1c259T program where we have the most clinical experience.  
Mild (Grade 1 or 2) transient transaminitis without cholestasis has been observed.
Table 10:
Overview of Clinical Findings/Symptoms of GVHD
Organ
Findings/Symptoms
Differential Diagnosis
Histopathology
Skin
Maculopapular rash involving 
the neck and shoulders as 
well as the palms and soles 
that spreads to include the 
rest of the body.
Drug reactions, viral 
exanthems, cytokine 
release syndrome, and 
effects of chemotherapy or 
radiation
Apoptosis at base of 
epidermal rete pegs, 
dyskeratosis, exocytosis of 
lymphocytes, satellite 
lymphocytes adjacent to 
dyskeratotic epidermal 
keratinocytes and 
perivascular lymphocytic 
infiltration in the dermis.
GI
Secretory diarrhea is most 
common but nausea, 
vomiting, anorexia, weight 
loss and abdominal pain can 
also occur. Diarrhea can be 
copious. Bleeding may result 
from mucosal ulceration and 
ileus may ensue.
Side effects of 
chemotherapy or other 
drugs and infection of the 
GI tract
Patchy ulcerations, apoptotic 
bodies at crypt bases, crypt 
ulceration and flattening of 
surface epithelium
Liver
Cholestatic pattern of liver 
injury including elevated 
conjugated bilirubin, alkaline 
phosphatase and GGTP. 
Subjects may present with 
jaundice, with pruritus in 
more severe cases.
Veno-occlusive disease of 
the liver, viral infections, 
drug toxicity and sepsis.
Endothelialitis, lymphocytic 
infiltration of the portal 
areas, pericholangitis and 
bile-duct destruction.
Of Note: Bone marrow suppression and related cytopenias have been described in the setting of 
acute GVHD. Management of this complication is challenging, with no clearly established 

            
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consistent histopathologic findings. However, awaiting biopsy results should not delay the 
institution of appropriate therapy. 
If GVHD is suspected:
A physician with expertise in the management of subjects following bone marrow 
transplant should be consulted.
Consider biopsy of the affected organ(s)
Corticosteroids have been used as the standard first line treatment for GVHD for several decades. 
Their effect is likely to be due to lympholytic effects and anti-inflammatory properties. In general, 
intestinal and liver GVHD require more prolonged steroid therapy than skin disease although 
response times vary. 
Diarrhea should be managed with volume replacement, dietary restriction, and anti-diarrheal 
agents including the consideration of somatostatin for secretory diarrhea. Agents that slow motility 
should be used cautiously, ensuring that there is no evidence of ileus or toxic megacolon, and 
infectious causes of diarrhea should be excluded.
General guidelines for first-line treatment based on grade are provided below, and should be 
considered in conjunction with input from the consulting physician with bone marrow transplant 
expertise.
Table 13:
Management Guidelines for GVHD
Grade
Management Strategy
I
Subjects with Grade I disease are not likely to require systemic treatment. Cutaneous 
GVHD may respond to topical steroid creams. Antihistamines may be helpful in 
subjects with pruritus. Subjects should be reviewed frequently for other organ 
manifestations of GVHD.
II
Treat skin symptoms with topical steroids. For GI symptoms - optimize anti-diarrheal 
regimen, dietary restrictions, volume replacement and consider initiation of non-
absorbable steroids. For refractory or progressive symptoms consider systemic 
steroids as outlined below.
III
For more severe or progressive symptoms consider systemic corticosteroids (e.g., 
methylprednisolone one (1) mg/kg per day*)
IV
Methylprednisolone two (2) mg/kg per day*
* The use of ‘nonabsorbable’ steroids (Budesonide and beclomethasone) can be considered for acute intestinal 
GVHD in order to reduce the dose of systemic steroids
If high dose corticosteroids are required, treatment should generally be continued for at least 5 
days followed by tapering doses over several weeks. A physician with expertise in infectious 

            
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diseases in immunocompromised hosts should be consulted, and prophylactic antimicrobials 
should be considered.
Second line treatment can be considered for subjects who have failed to respond for 5 days or have 
progressive symptoms after 3 days. There is no clear second-line agent that is preferred for steroid 
refractory GVHD. General guidelines for second-line treatment based on grade are provided 
below, and should be considered in conjunction with input from the consulting physician with 
bone marrow transplant expertise. 
For steroid refractory skin rash, topical tacrolimus may also be useful.
Most of the allogeneic transplant subjects are concurrently receiving calcineurin inhibitors in part 
as prophylaxis against GVHD. Therefore, for Grade II-IV disease refractory to high dose steroids, 
the addition of a calcineurin inhibitor can be considered.
Otherwise, there are several additional second line treatment options for which there is currently 
limited and/or evolving supporting data. Treating physicians can refer to the Haemato-oncology 
Task Force of the British Committee for Standards in Haematology and the British Society for 
Blood and Marrow Transplantation guideline for diagnosis and management of acute graft-
versus-host disease (Dignan, 2012).
10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Females of Childbearing Potential (FCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered FCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the above,
(e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview.

            
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3. Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
10.6.1.
Contraception Guidance:
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively.  The required duration of contraception is described below:
Female subjects of childbearing potential (FCBP) must agree to use a highly effective 
method of contraception starting at the first dose of chemotherapy and continuing for 
at least 12 months, or 4 months after the gene modified cells are no longer detected in 
the blood, whichever is longer.
Male sexually active subjects are required to use a condom in addition to the female 
partner use of a highly effective form of contraception or must agree to abstain from 
heterosexual activity with a female of childbearing potential starting at the first dose 
of chemotherapy and continuing for 4 months thereafter or longer (if indicated in the 
country specific monograph/label for cyclophosphamide).
Effective methods of contraception include: intra-uterine device, injectable hormonal 
contraception, oral contraception.
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local Regulatory Agencies and IRBs/IECs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.
The contraception guidelines should continue to be followed during long-term follow up.
10.6.2.
Collection of Pregnancy Information
10.6.2.1.
Female Participants who become pregnant
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 

            
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the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 10.4.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will be 
discontinued from further efficacy assessments (exposure to radiation from imaging 
studies is contraindicated in pregnancy), and will follow the LTFU schedule.
10.6.2.2.
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive ADP-A2M4.
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 

            
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10.7.
Appendix 7: Long Term Follow Up
10.7.1.
Background to Safety Monitoring in LTFU
10.7.1.1.
Monitoring and Management of Replication-Competent Lentivirus (RCL)
Replication Competent Lentivirus (RCL) is a theoretical risk associated with the use of lentiviral 
vectors; no RCL has ever been detected in vitro or in vivo. The risk is derived from the detection 
of replication competent retrovirus (RCR) during the use of early 
retroviral vector packaging 
systems which were inadequately designed to avoid recombination events between the vector and 
packaging components [Miller, 1990]. RCR resulted in death due to the onset of lymphoma in 3
of 10 monkeys after receiving bone marrow cells transduced with an RCR contaminated vector lot 
[Donahue, 1992]. 
ociated with RCR, 
however as a result of the Donahue study, RCR/RCL must continue to be rigorously evaluated in 
vector and cell lots, and in subjects post infusion with any product involving a retrovirus [FDA, 
2006; EMA, 2009].
A RCL may be generated during the production phase or subsequently after introduction of vector 
transduced cells into the subject. RCL may be generated by homologous or non-homologous 
recombination between the transfer vector and packaging elements, or endogenous retroviral 
elements [Chong, 1998; Garrett, 2000]. A RCL resulting from the production phase of the 
lentivirus used in this trial is highly unlikely since elements are incorporated in the design of the 
vector system that minimize vector recombination and generation of RCL. Nevertheless, 
generation of an RCL by recombination with an endogenous virus (i.e., HIV) in the subject 
following infusion of the cell product remains a theoretical possibility. The consequences of such 
recombination events could be neutral, could reduce the replication rate or pathogenicity of the 
subject's endogenous virus, or could increase the replication rate or pathogenicity of the subject's 
endogenous virus. Since the development of a strain with increased pathogenicity would pose 
greater risk to both the subject and their close contact(s), periodic monitoring for RCL is conducted 
during the course of the trial and during the 15 year follow up.
10.7.1.2.
Insertional oncogenesis
Monitoring for insertional oncogenesis follows the recommendations set forth in the FDA and 
EMA guidance [FDA, 2006a; FDA, 2006b; EMA, 2009].  Insertional oncogenesis is a theoretical 
risk in T cells transduced with a lentiviral vector.  T cells appear resistant to transformation by 
integrating viruses [Cattoglio, 2010; Newrzela, 2008]. However, there are cases of oncogenesis 
-retroviral transduced stem cells.  Four  of nine subjects with X-linked severe combined 
immunodeficiency (SCID-X1) treated with retrovirus transduced stem cells were found to have 
insertion near the LMO2 proto-oncogene promoter, leading to aberrant transcription and 
expression of LMO2 which resulted in acute T-cell lymphoblastic leukemia [Hacien-Bey-Abina,  
2003;  Hacien-Bey-Abina, 2014].  Additionally,  two subjects treated for X-linked chronic 
granulomatous disease (X-CGD) with retroviral transduced stem cells demonstrated insertional 
activation of the EVI1 transcription factor which resulted in genetic instability, monosomy 7 and 
clonal progression toward myelodysplasia [Stein, 2010].  

            
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10.7.2.
Testing for RCL and Persistence
RCL will be monitored using a PCR-based assay that detects and measures copies of the gene 
coding for the vector’s envelope protein, namely VSV-G that is necessary for the assembly of 
pseudotyped infectious lentiviral particles but absent from the vector’s backbone. The scheme for 
RCL testing is presented in Figure 1 below.  RCL testing and monitoring will take place on 
subject’s peripheral blood mononuclear cells (PBMCs) which will be collected at Baseline and 
then at 3, 6, and 12 months post-infusion and annually from year 2-15.   Samples will be tested for 
the presence of VSV-G DNA copies. 
If all samples are negative in year one, PBMC samples will be collected and archived annually
until 15 years post-infusion. Samples will be archived at Adaptimmune’s centralized biorepository.  
If a positive VSV-G DNA signal is obtained, the study investigator will be informed and the 
subject will be scheduled for a retest as soon as possible and no later than one month after the 
initial positive result was reported to the Sponsor.   The DSMB will be notified and a review by 
Adaptimmune’s Safety Review Team and Safety Governance Board will take place. 
Response to potential outcomes of second test:
If the second test is negative, then subject samples will continue to be tested for VSV-G 
DNA copies until VSV-G DNA copies are not detected for 3 consecutive annual 
assessments as described in Figure 1, at which time the subject samples will be collected 
and archived annually until year 15.
If the second test is positive, infusions for all subjects receiving T cells modified with the 
same vector lot will be postponed. The subject with the confirmed positive VSV-G signal 
will be scheduled for leukapheresis and a biological RCL test will be performed on the 
leukapheresis product.  The biological RCL test assesses whether there is active production 
of infectious viral particles from the leukapheresis product [Manilla, 2005]. 
If the biological RCL test is positive, all infusions using the same T cell receptor in the 
interventional protocol(s) will be halted.  An action plan will be discussed with FDA and other 
regulatory authorities and experts as appropriate.  Additional subjects will not be treated with the 
same T cell receptor until such time as a plan is completed, reviewed, and agreed upon.  
If the biological RCL test is negative, infusions for all subjects can resume.
Regulatory agencies and the gene therapy community have previously discussed measures to be 
taken should a biological RCL be confirmed in a subject [FDA, 2006a]. However, because the 
probability and characteristics of a RCL are unknown, no concrete plans have been put in place. 
As of the writing of this protocol, it is agreed the subject must be isolated and no additional subjects 
treated with the same T cell receptor therapy until a plan is agreed upon as outlined above.
The following approaches have been discussed for subject management:
1. Intensive follow up of subject in consultation with FDA, and other regulatory authorities, 
NIH, gene therapy experts, study investigators, and HIV physicians.
2. Provide targeted antiretroviral therapies based on genotyping of the RCL.

            
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monitoring plan specific to the health care risk and strategies to inform appropriate subjects, 
investigators, FDA and other regulators of the findings.  
If the integration site analysis indicates polyclonality of the genetically modified T cell 
population then screening for persistence continues as scheduled (Table 2, Figure 2).
10.7.4.
Letter to Physician - LTFU notification
[date]
[name and address]
Dear [physician name],
Your patient [patient name] has participated in a clinical research study, [interventional study 
name and number], that requires 15 year monitoring for adverse events. To aid in reporting of 
adverse events that are possible related to the clinical research study, we are asking the patients 
on our research study to designate a primary care or infectious disease physician that may help in 
the monitoring and reporting of adverse events. Your patient has designated you. If upon any of 
your visits with your patient, any of the following events are reported or discovered, please 
contact the study nurse or physician as soon as possible:
New Malignancies
New incidence or exacerbation of a pre-existing neurological disorder
Excluding all Grade 1 neurologic AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder
Excluding all Grade 1 autoimmune AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant
All rheumatologic disorders will be reported irrespective of grade
New incidence of a hematologic disorder
Excluding cytopenias following cytotoxic chemotherapy before bone marrow 
recovery
Excluding Grade 1 and 2 laboratory abnormalities, unless the Investigator 
considers clinically significant
Opportunistic and/or serious infections
Excluding infections secondary to chemotherapy induced cytopenias
Unanticipated illness or hospitalization deemed at least possibly related to gene 
modified cell therapy

            
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If your patient experiences any of these events, please refer them back to their study physician.  
Please contact the study coordinator below as soon as you can so that they can record the event 
and then monitor your patient’s health if necessary. When you call, remember to mention the 
protocol number of the study which is ADP-0044-002, patient ID [XXX] and the study title 
which is “A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in 
subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma”.
Study Physician:
Name:  [Study physician name]
Phone:  [Study physician phone]
Email:  [Study physician e-mail]
Study Coordinator:
Name:  [Study coordinator name]
Address:  [Study coordinator address]
Phone:  [Study coordinator phone]
Email:  [Study coordinator e-mail]
If you have any questions about this letter or the study itself, please do not hesitate to contact the 
above study nurse or physician.
Thank you for your support in helping us to monitor for delayed adverse events.
Best regards,
[study physician/coordinator]

            
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10.8.
Appendix 8:  Efficacy Reporting
10.8.1.
RECIST 1.1 for Evaluating Response in Solid Tumors
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. CT with contrast is the best 
currently available and reproducible method to measure lesions selected for response assessment. 
MRI is also acceptable in certain situations (e.g., for body scans but not for lung). Ultrasound 
(US) should not be used to measure tumor lesions.  The same modality should be used when 
comparing or making assessments.
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a subject to be considered in complete response.
Cytology and histology can be used in rare cases (e.g., for evaluation of residual masses to 
differentiate between Partial Response and Complete Response or evaluation of new or enlarging 
effusions to differentiate between Progressive Disease and Response/Stable Disease).
Use of endoscopy and laparoscopy is not advised. However, they can be used to confirm 
complete pathological response.
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment.
Measurable lesions
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have 
slice thickness >5 mm, the minimum size should be twice the slice thickness).
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
Malignant lymph nodes to be considered pathologically enlarged and measurable, a 
by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed.
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT or 
MRI can be considered measurable if the soft tissue component meets the definition of 
measurability for non-nodal lesions described above.

            
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‘Cystic lesions’ thought to represent cystic metastases can be considered measurable if 
they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions.
Non-measurable lesions
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm 
or pathological lymph nodes with 10 to <15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.  Blastic bone lesions are non-measurable.
Lesions with prior local treatment, such as those situated in a previously irradiated 
area or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion. Study 
protocols should detail the conditions under which such lesions would be considered 
measurable.
Target Lesions
Measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements.
All measurements should be recorded in metric notation using calipers if clinically 
assessed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters, which will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. If lymph nodes are to be 
included in the sum, only the short axis will contribute.
Non-target Lesions
All lesions (or sites of disease) not identified as target lesions, including pathological lymph 
nodes and all non-measurable lesions, should be identified as non-target lesions and be recorded 
at baseline. Measurements of these lesions are not required and they should be followed as 
‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’.
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters

            
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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note:  the appearance of one or more new lesions is also 
considered progression – see below) 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Special notes on the assessment of target lesions:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  When 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even 
if complete response criteria are met since a normal lymph node is defined as having 
a short axis of <10 mm.
Target lesions that become ‘too small to measure’.  While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small.  However, sometimes lesions or 
lymph nodes become so faint on a CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’, in which case a default value of 5 mm should be assigned.  
Lesions that split or coalesce on treatment.  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis)
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal
progression of existing non-target lesions.
Special notes on assessing progression of Non-Target lesions
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.

            
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When subject has measurable disease.  To achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status.
When subject has only non-measurable disease. There is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified, a useful 
test that can be applied is to consider if the increase in overall disease burden based on 
change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease. Examples include an increase 
in a pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic disease from 
localized to widespread.
New lesions
The appearance of new malignant lesions denotes disease progression:
The finding of a new lesion should be unequivocal (i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent 
something other than tumor, especially when the subject’s baseline lesions show partial 
or complete response).
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the scan where the new lesion was first identified.
A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and disease progression.
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up - is PD based on a new 
lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).

            
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In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol.
Missing Assessments and Non-evaluable Designation
When no imaging/measurement is done at all at a particular time point or the imaging is 
technically unreadable, the subject is not evaluable (NE) at that time point. If only a subset of 
lesion measurements are made at an assessment, usually the case is also considered NE at that 
time point, unless a convincing argument can be made that the contribution of the individual 
missing lesion(s) would not change the assigned time point response. This would most likely 
happen in the case of PD.

            
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10.9.
Appendix 9: ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
[Oken, 1982]

            
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10.10.
Appendix 10:  EQ-5D-3L Health Questionnaire (SAMPLE)

            
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10.12.
Appendix 12: Abbreviations
The following abbreviations and specialist terms are used in this study protocol.
AE
Adverse event
ALK
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
BBB
Bundle branch block
BOR
Best overall response
BP
Blood pressure
CAR
Chimeric Antigen Receptor
CBC
Complete blood count
CDC
Centers for Disease Control
cfDNA
Cell free DNA
CFR
Code of Federal Regulations
CHF
CLIA
Congestive heart failure
Clinical Laboratory Improvement Amendments
CMV
Cytomegalovirus
COPD
Chronic Obstructive Pulmonary Disease
CR
Complete response
CRP
C-reactive protein
CRO
Contract Research Organization
CRS
Cytokine release syndrome
CSR
Clinical Study Report
CT
Computerized tomography
CTA
Cancer-testis antigen
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
DoSD
Duration of stable disease

            
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DSMB
Data Safety Monitoring Board
EBV
Epstein Barr virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic Data Capture
EDTA
Ethylene-diaminetera acetic acid
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
FCM
Flow cytometry
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin embedded
FTIH
First Time In Human
5-FU
5-Fluorocuracil
GCP
Good clinical practice
G-CSF
Granulocyte-colony stimulating factor
GFR
Glomerular filtration rate
GGTP
Gamma-glutamyl transpeptidase
GI
Gastrointestinal
GLP
Good laboratory practice
GMP
Good manufacturing practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HPV
Human papilloma virus
IB
Investigator’s Brochure
IBW
ICANS
ICE
Ideal body weight
Immune Effector Cell-Associated Neurotoxicity Syndrome
Immune Effector Cell-Associated Encephalopathy
ICF
Informed Consent Form
ICH
International Council on Harmonization
ICU
Intensive care unit

            
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ID
Identifier
IEC
Independent Ethics Committee
IFN
Interferon
IHC
Immunohistochemistry
IL
Interleukin
IMRT
Intensity modulated radiation therapy
IND
Investigational New Drug application
ISL
Investigator Safety Letters
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent-to-Treat 
IVD
In vitro diagnostic
mITT
Modified Intent-to-Treat 
IV
Intravenous
K-M
Kaplan-Meier
LDH
LLOQ
Lactic acid dehydrogenase
Lower Limit of Quantification
LMO2
LIM domain only 2
LTFU
Long term follow up
LTR
Long terminal repeat
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major histocompatibility complex
MHRA
Medicines and Healthcare Products Regulatory Agency
MRCLS
MRI
Myxoid/Round Cell Liposarcoma
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple-gated acquisition scan
NCI
National Cancer Institute
NIH
National Institutes of Health
NK
Natural killer cell
NS
Normal Saline
NSCLC
Non-small cell lung cancer

            
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NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PI
Principal Investigator
PTT
Partial thromboplastin time
PR
Partial response
qPCR
Quantitative polymerase chain reaction
RAC
Recombinant DNA Advisory Committee
RC
Research Committee
RCL
Replication competent lentivirus
RCR
Replication competent retrovirus
RECIST
RIND
Response Evaluation Criteria in Solid Tumors
Reversible ischemic neurologic deficit
RNA
Ribonucleic acid
RT
Radiation therapy
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCCHN
Squamous cell carcinoma of the head and neck
SCID-X
Severe combined immunodeficiency disease – X linked 
SD
Stable disease
SGPT
Serum glutamate-pyruvate transaminase
SIN
Self-inactivating
SOP
Standard operating procedure
SPEAR
Specific Peptide Enhanced Affinity Receptor
SPM
Study Procedures Manual
SUSAR
Suspected, unexpected serious adverse reactions
TCR
TIA
T cell receptors
Transient ischemic attack
TILs
Tumor-infiltrating lymphocytes

            
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TKI
Tyrosine kinase inhibitor
TTR
Time to response
TURBT
Transurethral resection of bladder tumor
ULN
Upper limit of normal
VSV-G
Vesicular Stomatitis Virus G glycoprotein
WBC
White blood cell
WHO
World Health Organization
X-CGD
X-linked chronic granulomatous disease

            
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10.13.
Appendix 13: Protocol Amendment History
Protocol Version Amendment 2, UK Original (UK-2.0) dated 20MAR2020 is replaced in the UK 
only by Protocol Amendment 3, UK Version 3.0 (UK-3.0) dated 02MAR2021.  
Sections amended
Change
Rationale for change
1.3.1, 6.2.1, 8.4.10 
Inclusion of adjustment of 
fludarabine dose for subjects with 
renal impairment 
Updated to give additional 
clarification 
1.3.1, 3, 8.7.2, 9.3.3, 
10.11
Inclusion of EORTC-QLQ-C30 
questionnaire for subjects 
participating in Cohort 2
New questionnaire is to be 
used In subjects in cohort 2
1.1, 1.3.1, 8.3.1
Clarification that CT/MRI scans 
conducted between Week 4 to 
Week 16 should be at least 28 
days apart
Conducting scans 28 days 
apart ensures compliance with
RECIST 1.1 requirements
2.2.3
Updated data pertaining to safety
and efficacy of ADP-A2M4
Make consistent with current
ADP-A2M4 Investigator’s
Brochure
1.1, 2.1, 2.2.4, 4.1, 
4.2, 5.1, 5.2, 8.2.3
Inclusion of Cohort 2 in synovial 
sarcoma subjects
Include Cohort 2 for synovial 
sarcoma patients subjects
2.2.4, 2.2.5, 
Amended to align with current 
available data
Aligned with current known 
data surrounding synovial 
sarcoma 
3, 9, 9.1, 9.2, 9.3.2, 
9.3.3
Inclusion of separate Cohorts 1 & 
2
Additional cohort has been 
added to further assess 
patients with synovial 
sarcoma 
1.1, 4.1, 4.2, 5.5, 9.2
Clarification that first 45 subjects 
will be included in Cohort 1 and 
addition of subsequent 
independent Cohort 2 
Language added to clarify 
how many subjects will be 
dosed in each cohort 
1.1, 3, 9.3.2, 9.3.3
Clarification that the primary 
efficacy endpoint is Overall 
Response Rate per RECIST v1.1 
Language updated to reflect 
addition of new cohort and 

            
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by independent review for Cohort 
1.  Secondary endpoints and 
safety endpoints were updated to 
reflect addition of new cohort.
that no new hypotheses testing 
is required.
4.3
Additional evidence for dose 
included
Provide evidence for dose 
range up to 10 × 109
1.1, 5.2
Inclusion criteria expanded for 
subjects who have previously 
received anthracycline or 
ifosfamide
To provide clarification of 
systemic therapy inclusion 
1.1, 5.2
Inclusion laboratory values table 
updated
Clarification of inclusion 
criteria based on ANC, 
Prothrombin Time or INR, 
and GFR
1.1, 5.3 
Exclusion of subjects with 
incipient compression/occlusion 
of a vital structure
Included in exclusion criteria 
following safety event and as 
recommended by FDA
1.1, 5.3, 10.5.3.1
Addition of COVID-19 
requirements  
Information added for 
COVID-19 requirements 
6.1
Updated to allow for local 
leukapheresis
Updated to allow local 
leukapheresis 
6.2
Granulocyte colony stimulating 
factor (G-CSF) guidance updated
Updated to align with current 
safety data 
6.5.2, 6.5.2.1
Addition of Guidance on COVID-
19 vaccinations 
Updated to clarify guidance 
related to COVID-19 
vaccinations 
8.1.2
Updated to reflect additional 
information on disease history to 
be collected in eCRF
Updated to include site and 
size of tumor as well as last 
known tumor stage  
8.4.8.1
Updated to confirm that QTcB or 
QTcF are acceptable 
Updated to confirm that QTcB 
or QTcF are also acceptable 
for collection

            
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8.4.13
Updated to clarify requirements 
for administration of 
anticoagulants.  
Updated to clarify the need 
for either a low molecular 
weight heparin injection or a 
novel oral anticoagulant
8.6.3
Clarification of timing of Baseline 
liquid biopsy collection 
Updated to include collection 
at baseline 
9.1
Reference to CDx analysis 
population removed 
Removed as information 
regarding CDx analysis is 
held outside of protocol
9.1
Reference to PP Population
removed
Based on subjects enrolled to 
date no major protocol 
violations where subjects will 
be excluded from primary 
analysis
9.3.3
Removed reference to QOL 
exploratory endpoints.  
Analysis of exploratory 
endpoints will be addressed in 
the Statistical Analysis Plan
10.4.4
SAE reporting updated to remove 
location of SAEW
Not required to be referenced 
in protocol 
10.5.4.1
Irradiated Blood Product section 
updated
Updated as per latest guidance
10.5.6
Updated Management of CRS
Updated as per latest guidance 
10.5.8
Updated Management of 
prolonged cytopenia 
Updated as per latest guidance 
5.2, 9.3.2, 10.2.1, 
10.3, 10.4.6, 10.4.7
Administrative
Administrative updates, 
corrections and clarifications

            
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10.14.
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axicabtagene-ciloleucel

Study Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects 
with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
NCT number: NCT04044768 
Document: Statistical Analysis Plan  
Document Date: 28 Oct 2021 

 
 
 
             
 
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Page 1 of 174 
 
 
 
 
 
 
 
PROTOCOL NUMBER ADP-0044-002 
 
A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects 
with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
(SPEARHEAD 1 STUDY) 
 
 
 
PROTOCOL VERSION: AMENDMENT 3, FRANCE 5.0 
DATE: 28OCT2021 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
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CONFIDENTIAL 
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Page 2 of 174 
 
 
 
 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
Protocol Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T 
Cells in Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
(MRCLS) 
 
 
I, the undersigned, have reviewed the protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to International Council for Harmonization (ICH) 
tripartite guideline E6 (R2): Guideline for Good Clinical Practice (GCP) and all the ethical and 
regulatory considerations stated.  I have read and understood the contents of the ADP-A2M4 
Investigator’s Brochure. 
 
 
Investigator Name 
 
Investigator Title 
 
Investigator Site and Address 
 
Investigator Signature 
 
Date 
 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 3 of 174 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Title: A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T Cells in 
Subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma (MRCLS) 
Product Name: ADP-A2M4 
Protocol Number: ADP-0044-002  
IND Number: 17235 
EudraCT Number: 2019-000589-39 
DATE OF ORIGINAL PROTOCOL: 25FEB2019 
Amendment Number 
Date 
Reason for Change 
Original 
25FEB2019 
NA –  
Amendment 1 
04JUN2019 
Change in the lymphodepletion 
regimen 
Addition of ECG at Day 5 
Added upper age limit 
Increase entry criteria for ANC, 
platelets, GFR 
Additional exclusion criteria under 
uncontrolled intercurrent illness 
Emerging data for ADP-A2M4 
added 
Updated study physician 
Administrative changes 
Amendment 1, France (FR) Original 
(FR-1.0) 
22NOV2019 
Agence Nationale de Sécurité du 
Médicament et des Produits de 
Santé (ANSM) requested change to:  
- 
requirement for 7 days 
hospitalization 
Administrative changes 

 
 
 
             
 
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Amendment Number 
Date 
Reason for Change 
Amendment 1, France (FR) 2.0 (FR-
2.0) 
09JAN2020 
Agence Nationale de Sécurité du 
Médicament et des Produits de 
Santé (ANSM) requested change to:  
requirement for 10 days 
hospitalization 
Amendment 2, France (FR) 3.0 (FR-
3.0) 
23JUN2020 
Updates and clarifications to HLA 
criteria  
Removed futility analysis and 
associated protocol aspects 
Updated number of subjects  
Decreased duration of enrollment 
Increased LVEF criteria 
Clarification of washout for prior 
gene therapy 
Added updated data from current 
ADP-A2M4 Investigator’s Brochure 
Update to CRS management 
guidelines  
Updated Grading for Cytokine 
Release Syndrome and Neurologic 
Toxicity Associated with Immune 
Effector Cells 
Inclusion of optional remote consent 
for MAGE-A4 tissue testing and/ or  
buccal/ mouth swab test for HLA 
assessment at participating sites 
Administrative changes and 
clarifications 

 
 
 
             
 
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Amendment Number 
Date 
Reason for Change 
Amendment 3, France (FR) 4.0 (FR-
4.0) 
18MAY2021 
Update to sponsor contacts  
Age range updated to include 
pediatric patients from ≥ 10 years 
Addition of Lansky assessment in 
subjects <16 
Addition of Cornell Assessment 
Pediatric Delirium Score in subjects 
<12 
Addition of Cohort 2 (45 synovial 
sarcoma subjects) 
Updates to safety and efficacy 
information to align with current IB 
Information added for COVID-19 
requirements 
Exclusion for 
compression/occlusion of a vital 
structure added 
Addition of EORTC QLQ-C30 
(Cohort 2 only) 
Addition of PedsQLTM 
Removal of CDx and PP Population 
definitions 
Additional details added throughout 
for additional clarity of wording 
Template language updated 

 
 
 
             
 
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Amendment Number 
Date 
Reason for Change 
Amendment 3, France (FR) 5.0 (FR-
5.0) 
28OCT2021 
Update to inclusion criteria  
Addition of SRC for subjects ˂ 16 
years old 
Update to blood volume collection 
to comply with European 
recommendations for pediatric 
subjects 
 
 
CONFIDENTIALITY STATEMENT 
This document contains information which is the property of Adaptimmune LLC, USA, and 
therefore is provided in confidence for your review.  It is understood that this information will 
not be disclosed to others without written approval from Adaptimmune LLC. 
 
DECLARATION 
This study will be conducted in compliance with ICH GCP, all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of Helsinki 
(with amendments), and in accordance with local legal and regulatory requirements. 
 
 
 

 
 
 
             
 
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RESPONSIBLE SPONSOR STUDY PHYSICIAN/SPONSOR INFORMATION PAGE 
 
Sponsor Signatory 
 
  
                                                       
_
_________________         
 
____________ 
  
 
 
 
 
 
 
                Date 
 
                                                   
Responsible Study Physician/SAE Contact Information 
Role 
Name 
Day Phone and 
email 
After hours 
phone 
Fax Number 
Primary Sponsor 
Study Physician 
 
  
 
 
 
 
Secondary 
Sponsor Study 
Physician 
 
 
 
 
 
 
 
 
 
 
Sponsor Details: 
Adaptimmune LLC 
351 Rouse Blvd 
Philadelphia, PA 19112 
USA 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................18 
1.1. 
Synopsis ......................................................................................................................18 
1.2. 
Schema ........................................................................................................................32 
1.3. 
Time and Events Table ...............................................................................................33 
1.3.1. 
Main Time and Events (T&E) Table ..........................................................................33 
1.3.2. 
Long Term Follow Up Phase Time & Events Table ..................................................41 
2. 
INTRODUCTION ......................................................................................................42 
2.1. 
Study Rationale ...........................................................................................................42 
2.1.1. 
Rationale for using MAGE-A4 TCR in synovial sarcoma and myxoid/round 
cell liposarcoma ..........................................................................................................42 
2.2. 
Background .................................................................................................................42 
2.2.1. 
MAGE-A4 background ..............................................................................................42 
2.2.2. 
Discovery of ADP-A2M4 ...........................................................................................44 
2.2.3. 
Current Therapeutic Options for Synovial Sarcoma & MRCLS ................................44 
2.2.4. 
Emerging Data for ADP-A2M4 SPEAR T-cells in Synovial Sarcoma ......................46 
2.3. 
Benefit: Risk Assessment ...........................................................................................47 
2.3.1. 
Benefit .........................................................................................................................47 
2.3.2. 
Risk .............................................................................................................................48 
2.3.3. 
Overall benefit: risk conclusion ..................................................................................49 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................50 
4. 
STUDY DESIGN .......................................................................................................52 
4.1. 
Overall Design ............................................................................................................52 
4.1.1. 
Pre-screening ..............................................................................................................52 
4.1.2. 
Screening ....................................................................................................................52 
4.1.3. 
Enrollment ..................................................................................................................53 
4.2. 
Scientific Rationale for Study Design ........................................................................54 
4.2.1. 
Pre-Screening for HLA Alleles and MAGE-A4 Expression ......................................55 
4.2.1.1. 
HLA ............................................................................................................................55 

 
 
 
             
 
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4.2.1.2. 
MAGE-A4 Expression in Tumor ................................................................................55 
4.2.2. 
T Cell Manufacturing .................................................................................................56 
4.2.3. 
Lymphodepletion ........................................................................................................56 
4.2.4. 
Long Term Follow-up .................................................................................................57 
4.3. 
Justification for Dose ..................................................................................................57 
4.4. 
End of Study Definition ..............................................................................................57 
5. 
STUDY POPULATION .............................................................................................58 
5.1. 
HLA and Antigen Pre-screening ................................................................................58 
5.2. 
Inclusion Criteria ........................................................................................................58 
5.3. 
Exclusion Criteria .......................................................................................................61 
5.4. 
Screen Failures ............................................................................................................64 
5.5. 
Number of Subjects and Study Duration ....................................................................65 
5.6. 
Sites .............................................................................................................................65 
6. 
STUDY INTERVENTION ........................................................................................66 
6.1. 
Leukapheresis .............................................................................................................66 
6.2. 
Lymphodepleting Chemotherapy ...............................................................................66 
6.2.1. 
Fludarabine dose adjustment for renal impairment ....................................................68 
6.2.2. 
Mesna ..........................................................................................................................68 
6.2.3. 
G-CSF .........................................................................................................................68 
6.3. 
Investigational Product ...............................................................................................68 
6.3.1. 
Premedication .............................................................................................................68 
6.3.2. 
T Cell Infusion ............................................................................................................69 
6.4. 
Preparation/Handling/Storage/Accountability ............................................................70 
6.4.1. 
Packaging and Labelling .............................................................................................70 
6.4.2. 
Receipt and Return .....................................................................................................70 
6.4.3. 
Storage and Handling .................................................................................................71 
6.4.4. 
Investigational Product Accountability/Traceability ..................................................71 
6.4.5. 
Alert Cards ..................................................................................................................71 
6.5. 
Concomitant Medications ...........................................................................................72 

 
 
 
             
 
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6.5.1. 
Prohibited Concomitant Medications .........................................................................72 
6.5.2. 
Permitted Concomitant Medications ..........................................................................72 
6.5.2.1. 
Vaccinations Including for COVID-19 ......................................................................73 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................74 
7.1. 
Temporary Study Suspension .....................................................................................74 
7.2. 
Ending the Interventional Phase .................................................................................74 
7.3. 
Subject Discontinuation ..............................................................................................75 
7.4. 
Lost to Follow up ........................................................................................................75 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................76 
8.1. 
Background Assessments ...........................................................................................76 
8.1.1. 
Demographics .............................................................................................................76 
8.1.2. 
Disease History ...........................................................................................................76 
8.2. 
HLA MAGE-A4 Tumor Antigen Testing, and Cytogenetics .....................................76 
8.2.1. 
HLA ............................................................................................................................76 
8.2.2. 
MAGE-A4 Antigen ....................................................................................................76 
8.2.3. 
Cytogenetics for Diagnosis .........................................................................................77 
8.3. 
Efficacy Assessments .................................................................................................77 
8.3.1. 
CT/MRI.......................................................................................................................77 
8.3.2. 
Survival .......................................................................................................................78 
8.4. 
Safety Assessments .....................................................................................................79 
8.4.1. 
Medical History ..........................................................................................................79 
8.4.2. 
Physical Examination .................................................................................................79 
8.4.3. 
Prior Anti-cancer Therapies ........................................................................................79 
8.4.4. 
Prior and Concomitant Medications ...........................................................................79 
8.4.5. 
ECOG .........................................................................................................................79 
8.4.6. 
Lansky .........................................................................................................................80 
8.4.7. 
Vital Signs ..................................................................................................................80 
8.4.8. 
Weight and Height ......................................................................................................80 

 
 
 
             
 
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8.4.9. 
Cardiac Assessments ..................................................................................................80 
8.4.9.1. 
ECG ............................................................................................................................80 
8.4.9.2. 
Echo/MUGA ...............................................................................................................80 
8.4.9.3. 
Telemetry ....................................................................................................................80 
8.4.10. 
Brain MRI ...................................................................................................................80 
8.4.11. 
Renal Function Assessment ........................................................................................81 
8.4.12. 
Hematology .................................................................................................................81 
8.4.13. 
Clinical Chemistry ......................................................................................................81 
8.4.14. 
Coagulation .................................................................................................................81 
8.4.15. 
Thyroid Function Tests ...............................................................................................81 
8.4.16. 
Hepatic Safety Assessments .......................................................................................82 
8.4.17. 
Pregnancy Test ............................................................................................................82 
8.4.18. 
Infectious Disease Screening ......................................................................................82 
8.4.19. 
CMV PCR ...................................................................................................................82 
8.4.20. 
ICE/CAPD Assessment Tool ......................................................................................82 
8.4.21. 
C-reactive Protein .......................................................................................................83 
8.4.22. 
Ferritin ........................................................................................................................84 
8.4.23. 
Persistence (Vector Copies) ........................................................................................84 
8.4.24. 
RCL (VSV-G DNA) ...................................................................................................84 
8.5. 
Adverse Events and Serious Adverse Events .............................................................85 
8.5.1. 
Time period for collecting AE and SAE Information ................................................85 
8.5.2. 
Method of Detecting AEs and SAEs ..........................................................................85 
8.5.3. 
Follow-up of AEs and SAEs .......................................................................................86 
8.5.4. 
Regulatory Reporting Requirements for SAEs ...........................................................86 
8.5.5. 
Pregnancy ...................................................................................................................86 
8.5.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................87 
8.5.7. 
AE of Special Interest .................................................................................................87 
8.5.7.1. 
Cytokine Release Syndrome .......................................................................................87 

 
 
 
             
 
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8.5.7.2. 
Neurotoxicity ..............................................................................................................88 
8.5.8. 
Long Term Follow Up Adverse Events ......................................................................89 
8.5.8.1. 
LTFU Letters to Primary Care Physician/Oncologist ................................................89 
8.6. 
Biomarkers for Exploratory Objectives ......................................................................89 
8.6.1. 
Tumor Biopsy .............................................................................................................90 
8.6.2. 
Cytokine and Soluble Protein Analysis ......................................................................91 
8.6.3. 
Liquid Biopsy Collection and Analysis (Blood Plasma) ............................................91 
8.6.4. 
Cell Phenotype and Functional Assays .......................................................................91 
8.6.5. 
Persistence of ADP-A2M4 TCR+ Cells .....................................................................92 
8.7. 
Blood Sampling Volumes ...........................................................................................92 
8.8. 
Patient-Reported Outcomes ........................................................................................92 
8.8.1. 
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L) .............................................92 
8.8.2. 
EORTC-QLQ-C30 ......................................................................................................93 
8.8.3. 
PedsQLTM ...................................................................................................................93 
9. 
STATISTICAL CONSIDERATIONS .......................................................................94 
9.1. 
Study Populations .......................................................................................................94 
9.2. 
Statistical Hypotheses and Sample Size Assumptions ...............................................94 
9.3. 
Statistical Analyses .....................................................................................................97 
9.3.1. 
Interim Analysis ..........................................................................................................97 
9.3.2. 
Efficacy Analyses .......................................................................................................97 
9.3.3. 
Safety Analyses ..........................................................................................................98 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................100 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..................100 
10.1.1. 
Data Handling and Record Keeping .........................................................................100 
10.1.1.1. 
Data management .....................................................................................................100 
10.1.1.2. 
Case Report Forms ...................................................................................................100 
10.1.1.3. 
Site Documentation and Source Data .......................................................................101 
10.1.1.4. 
Data Retention and Availability ...............................................................................101 

 
 
 
             
 
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10.1.2. 
Study Monitoring ......................................................................................................101 
10.1.2.1. 
Audits and Inspections ..............................................................................................102 
10.1.3. 
Regulatory and Ethical Considerations ....................................................................102 
10.1.3.1. 
Competent Authority Submissions ...........................................................................102 
10.1.3.2. 
Independent Ethics Committees ...............................................................................102 
10.1.3.3. 
Local regulations/Declaration of Helsinki ................................................................102 
10.1.4. 
Informed consent ......................................................................................................103 
10.1.5. 
Confidentiality ..........................................................................................................103 
10.1.6. 
Protocol Adherence ..................................................................................................103 
10.1.7. 
Study Suspension, Study Termination and Study Completion .................................104 
10.1.8. 
Public Posting of Study Information ........................................................................104 
10.1.9. 
Clinical Study Report ...............................................................................................104 
10.1.10. 
Publication Policy .....................................................................................................104 
10.1.11. 
Financial Disclosure .................................................................................................104 
10.2. 
Appendix 2: Safety Reviews ....................................................................................105 
10.2.1. 
Data Safety Monitoring Board ..................................................................................105 
10.2.2. 
Safety Review Committee ........................................................................................105 
10.3. 
Appendix 3: Clinical Laboratory Tests .....................................................................106 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................108 
10.4.1. 
Definition of AE .......................................................................................................108 
10.4.2. 
Definition of SAE .....................................................................................................109 
10.4.3. 
Recording and Follow-Up of AE and/or SAE ..........................................................110 
10.4.4. 
Reporting of SAEs ....................................................................................................113 
10.4.5. 
Hepatic Monitoring and Follow Up Assessments ....................................................113 
10.4.6. 
Reporting Criteria during Long Term Follow-Up (Years 1-15) ...............................114 
10.4.7. 
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents .......................................................................................................................116 
10.5. 
Appendix 5: Supportive Care Guidance ...................................................................117 

 
 
 
             
 
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10.5.1. 
Lymphodepleting Chemotherapy Symptom Management .......................................117 
10.5.1.1. 
Management of Neutropenia ....................................................................................117 
10.5.2. 
T-cell Infusion Symptom Management ....................................................................117 
10.5.3. 
Infection ....................................................................................................................118 
10.5.3.1. 
SARS-CoV-2 (COVID-19) ......................................................................................118 
10.5.3.2. 
Pneumocystis carinii Pneumonia ..............................................................................118 
10.5.3.3. 
Herpes simplex and Varicella zoster ........................................................................118 
10.5.3.4. 
Cytomegalovirus .......................................................................................................118 
10.5.3.5. 
Hepatitis B Prophylaxis ............................................................................................119 
10.5.3.6. 
Syphilis .....................................................................................................................119 
10.5.3.7. 
Other Anti-Microbial Prophylaxis ............................................................................119 
10.5.4. 
Hematologic and Blood Product Support .................................................................119 
10.5.4.1. 
Irradiated Blood Product ...........................................................................................119 
10.5.4.2. 
CMV screened blood products .................................................................................119 
10.5.5. 
Management of Autoimmunity .................................................................................120 
10.5.6. 
Management of Cytokine Release Syndrome ...........................................................120 
10.5.7. 
Management of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) ....................................................................................................................123 
10.5.8. 
Management of ICANS ............................................................................................125 
10.5.9. 
Management of Prolonged Cytopenia ......................................................................127 
10.5.9.1. 
Definition of prolonged cytopenia, pancytopenia and plastic anemia ......................127 
10.5.9.2. 
Management of Prolonged Cytopenias .....................................................................128 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information ...............................................................................................................129 
10.6.1. 
Contraception Guidance: ..........................................................................................129 
10.6.2. 
Collection of Pregnancy Information .......................................................................130 
10.6.2.1. 
Female Participants who become pregnant ..............................................................130 
10.6.2.2. 
Male participants with partners who become pregnant ............................................131 
10.7. 
Appendix 7: Long Term Follow Up .........................................................................132 

 
 
 
             
 
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10.7.1. 
Background to Safety Monitoring in LTFU .............................................................132 
10.7.1.1. 
Monitoring and Management of Replication-Competent Lentivirus (RCL) ............132 
10.7.1.2. 
Insertional oncogenesis .............................................................................................132 
10.7.2. 
Testing for RCL and Persistence ..............................................................................133 
10.7.3. 
Integration Site Analysis ...........................................................................................135 
10.7.4. 
Letter to Physician – LTFU notification ...................................................................136 
10.8. 
Appendix 8:  Efficacy Reporting ..............................................................................138 
10.8.1. 
RECIST 1.1 for Evaluating Response in Solid Tumors ...........................................138 
10.9. 
Appendix 9: ECOG Performance Status ..................................................................144 
10.10. 
Appendix 10: Lansky Performance Status (for use in subjects <16 years old) ........144 
10.11. 
Appendix 11:  EQ-5D-3L Health Questionnaire (SAMPLE) ...................................145 
10.12. 
Appendix 12: EORTC-QLQ-C30 Questionnaire (SAMPLE) ..................................148 
10.13. 
Appendix 13: PedsQLTM Questionnaire (SAMPLE) ................................................150 
10.14. 
Appendix 14: Abbreviations .....................................................................................162 
10.15. 
Appendix 15: Protocol Amendment History ............................................................167 
10.16. 
References .................................................................................................................168 

 
 
 
             
 
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LIST OF TABLES 
Table 1: 
T&E for Pre-Screening and Interventional Phase ......................................................33 
Table 2: 
T&E for Long Term Follow Up Phase .......................................................................41 
Table 3: 
Fludarabine and Cyclophosphamide Treatment Schema ...........................................67 
Table 4:  
CAPD‑point neurological assessment [based on Traube, 2014] ................................82 
Table 5:  
Protocol-Required Safety Laboratory Assessments .................................................106 
Table 6:  
Hepatic Monitoring Criteria .....................................................................................113 
Table 7:  
Management Guidelines for Cytokine Release Syndrome .......................................121 
Table 8: 
ICE‑point neurological assessment [based on Lee, 2019] ........................................124 
Table 9:  
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) ....................................................................................................................124 
Table 10:  Management of ICANS ............................................................................................126 
 

 
 
 
             
 
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LIST OF FIGURES 
Figure 1: 
Flow chart for testing for Replication Competent Lentivirus (RCL) .......................134 
Figure 2: 
Flow Chart for Testing for Persistence .....................................................................135 
 

 
 
 
             
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Title  
A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in subjects with 
Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma 
Short Title 
SPEARHEAD 1 Study 
Protocol Number 
ADP-0044-002 
Phase 
2 
Methodology 
Subjects with advanced synovial sarcoma or myxoid/ myxoid round cell 
liposarcoma (Cohort 1 only) will be Pre-screened to determine appropriate 
human leukocyte antigen (HLA) and tumor antigen status. Only subjects with 
advanced synovial sarcoma will be eligible for Cohort 2. Only subjects 
expressing at least 1 HLA-A*02 inclusion allele and no exclusion allele and 
whose tumor expresses the MAGE-A4 antigen above the cut-off are eligible to 
undergo further screening for this study. 
Subjects who sign the Treatment Informed Consent and meet study entry 
criteria will be enrolled into either Cohort 1 or Cohort 2. Enrolled subjects will 
undergo leukapheresis for collection of autologous cells for processing and 
manufacture into the ADP-A2M4 cell Investigational Product (IP). 
Leukapheresis should be performed as soon as possible after the subject is 
determined to be eligible for study participation. Subjects who have enrolled 
into a Cohort may not enroll into the other Cohort subsequently. 
Prior to the administration of lymphodepleting chemotherapy all eligibility 
criteria will be reconfirmed and baseline tumor assessment obtained.  
Anticancer therapy may be administered between screening and leukapheresis 
and between leukapheresis and the start of lymphodepletion (bridging 
therapy), if a subject has progressive disease and cannot be treatment-free, but 
mandatory washout periods must be adhered to.  
When the ADP-A2M4 cells are available at site, subjects will undergo 
lymphodepleting chemotherapy with fludarabine 30 mg/m2/day for 4 days 
(Day -7 to Day -4) and cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 
to -5) followed by infusion of ADP-A2M4 cells on Day 1. Subjects will 
remain hospitalized for observation for at least 10 days post T cell infusion. 

 
 
 
             
 
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An independent Data Safety Monitoring Board (DSMB) will review the 
ongoing safety during the interventional phase of the study for Cohort 1. 
Cohort 2 will begin once all subjects have been dosed in Cohort 1. Subjects in 
both cohorts will have the following study visits for assessment of eligibility, 
efficacy, safety, health related-outcome and biomarkers: Pre-Screening, 
Screening, Leukapheresis, Baseline, Lymphodepleting Chemotherapy (Day -7 
to Day -4), T cell infusion (Day 1) and immediate post infusion monitoring 
(Day 1 through Day 8), weekly visits until Week 4 post infusion, then 6, 8, 12, 
16 and 24 weeks then every 2 months until disease progression.  
Subjects will undergo disease monitoring by magnetic resonance imaging 
(MRI) or computerized tomography (CT) scan at Screening, Baseline, Week 4, 
Week 8, Week 12, Week 16 and Week 24, and every 2 months until confirmed 
disease progression.  
Once disease progression is established, no further scans will be performed for 
this study and subjects will switch to the long term follow-up (LTFU) schedule 
of visits at Months 2, 3 and 6 followed by 6 monthly visits through Year 5 and 
annually thereafter for Years 6-15. The timepoint at which the subject switches 
will be driven by the timepoint at which the subject progresses e.g. if there is 
disease progression at Week 4, the next visit would be due at Month 2; if there 
is disease progression at Week 12, the next visit would be due at Month 6.  
The Primary Efficacy Analysis will be for Cohort 1 only.  Clinical cut-off for 
the primary analysis will occur once the forty-fifth subject dosed in Cohort 1 
has up to 6 months follow-up post T cell infusion. At this time, all safety and 
secondary efficacy endpoints for Cohort 1 only will also be summarized to 
provide supportive evidence to the primary assessment. 
Study Duration 
Enrollment is expected to continue for approximately 12 months for Cohort 1 
and for an additional 12 months for Cohort 2. 
The study will be considered complete once all enrolled subjects complete 15 
years of follow-up or discontinue the study for any reason.  
Study Center(s) 
The study will be conducted in approximately 24 sites in North America and 
Europe. Additional sites may be added at the discretion of the Sponsor. 
Number of subjects 
Ninety (90) subjects: Forty-five (45) synovial sarcoma and MRCLS subjects in 
Cohort 1; Forty-five (45) synovial sarcoma subjects in Cohort 2. 

 
 
 
             
 
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Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS 
Overall Response Rate (ORR) per RECIST v1.1 by 
independent review in Cohort 1. 
 
Secondary 
To evaluate the safety and tolerability of 
autologous genetically modified T cells 
(ADP-A2M4) in HLA-A*02 positive 
subjects with MAGE-A4 expressing 
advanced synovial sarcoma or MRCLS 
For Cohort 1 and across Cohorts (overall):  
• Adverse events (AEs) including serious adverse events 
(SAEs) 
• Incidence, severity and duration of the AEs of special 
interest 
• Replication Competent Lentivirus (RCL) 
• T cell Clonality and Insertional oncogenesis (IO) 
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS 
• Overall Response Rate (ORR) per RECIST v1.1 by 
independent review across Cohorts (overall) 
For Cohort 1 and across Cohorts (overall):  
• Time to Response (TTR) 
• Duration of Response (DoR) 
• Best Overall Response (BOR) 
• Progression Free Survival (PFS) 
• Overall Survival (OS) 
Development and validation of an in vitro 
diagnostic (IVD) assay for the screening of 
tumor antigen expression for regulatory 
approval 
Across Cohorts: 
• Retention of additional tumor tissue during Pre-
screening to enable development and validation of the 
MAGE-A4 antigen expression companion diagnostic 
assay 

 
 
 
             
 
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Characterize the in vivo cellular 
pharmacokinetics (PK) profile of ADP-
A2M4 cells 
For Cohort 1 and across Cohorts (overall): 
• Peak persistence and other relevant PK parameters of 
ADP-A2M4 cells 
Exploratory 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria 
1. Subject (or legally authorized representative) voluntarily agrees to 
participate by giving written Informed Consent (and Assent as applicable) 
in accordance with ICH GCP guidelines and applicable local regulations.  
2. Subject (or legally authorized representative) agrees to abide by all 
protocol required procedures including study related assessments and 
management by the treating institution for the duration of the study, 
including long term follow-up. 
3. Age ≥16 and <75 years at the time the Pre-screening informed 
consent/assent is signed (Cohort 1).  Age ≥10 and <75 years at the time the 

 
 
 
             
 
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Pre-screening informed consent/assent is signed and actual body weight ≥ 
40 KG (Cohort 2) 
4. Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or 
myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1 only) 
confirmed by cytogenetics. Inoperable refers to a tumor lesion in which 
clear surgical excision margins cannot be obtained without leading to 
significant functional compromise. 
a. For Synovial Sarcoma (Cohort 1 and Cohort 2): confirmation by 
the presence of a translocation between SYT on the X chromosome 
and SSX1, SSX2 or, SSX4 on chromosome 18 (may be presented 
in the pathology report as t (X; 18)). 
b. For MRCLS (Cohort 1 only): confirmation by the presence of the 
reciprocal chromosomal translocation t(12;16)(q13;p11) or t(12; 
22) (q13;q12). 
5. Must have previously received either an anthracycline or ifosfamide 
containing regimen. 1st-line metastatic treatment with ADP-A2M4 is 
permissible if ifosfamide +/- doxorubicin has been administered in either 
the pre-operative (neoadjuvant) or post-operative (adjuvant) primary tumor 
setting and has progressed within 6 months of receiving treatment. 
(Subjects who are intolerant of both anthracycline and ifosfamide must 
have previously received at least one other type of systemic therapy).  
6. Measurable disease according to RECIST v1.1.  
7. Positive for HLA-A*02:01, HLA-A*02:03 or HLA-A*02:06 allele via 
Adaptimmune designated central laboratory testing. HLA-A*02 alleles 
having the same protein sequence in the peptide binding domains (P group) 
will also be included. Other HLA-A*02 alleles may be eligible after 
adjudication with the sponsor.  
8. Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 
expression of ≥2+ staining in ≥30% of the cells by immunohistochemistry.  
All samples must have been pathologically reviewed by an Adaptimmune 
designated central laboratory confirming expression.   
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 
1 or for subjects aged 10 to ˂ 16 years of age, Lansky Score ≥80 %. 
10. Left ventricular ejection fraction (LVEF) ≥50%.  
11. Fit for leukapheresis and adequate venous access can be established for the 
cell collection. 

 
 
 
             
 
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12. Female subjects of childbearing potential (FCBP) must have a negative 
urine or serum pregnancy test AND must agree to use an effective method 
of contraception starting at the first dose of chemotherapy and continuing 
for at least 12 months, or 4 months after the gene modified cells are no 
longer detected in the blood, whichever is longer.  
− OR  
Male subjects must be surgically sterile or agree to use a double barrier 
contraception method or abstain from heterosexual activity with a FCBP 
starting at the first dose of chemotherapy and continuing for 4 months 
thereafter (or longer if indicated in the country specific monograph/label 
for cyclophosphamide). 
13. Must have adequate organ function as indicated by the laboratory values in 
the table below: 

 
 
 
             
 
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System 
Laboratory Value 
Hematological 
Absolute Neutrophil count 
(ANC) 
≥ 1.5 x109/L (without G-CSF support)1 
within 7 days prior to lymphodepletion and 
leukapheresis 
Platelets 
≥ 100 x109/L (without transfusion support 
within 7 days prior to lymphodepletion and 
leukapheresis) 
Hemoglobin 
≥ 80 g/L (without transfusion support 
within 7 days prior to lymphodepletion and 
leukapheresis) 
Coagulation 
Prothrombin Time (PT) or 
INR 
≤ 1.5x upper limit of normal (ULN)  
unless receiving therapeutic  
anticoagulation 
Subjects receiving warfarin anti-coagulation at 
baseline should be converted to either a low 
molecular weight heparin injection or a novel 
oral anticoagulant (NOAC). Reintroduction of 
warfarin after lymphodepleting 
chemotherapy/ADP-A2M4 dosing to attain the 
therapeutic INR range which was initially 
clinically indicated should only start when the 
platelet count is < Grade 2 CTCAE. 
Partial Thromboplastin 
Time (PTT) 
≤ 1.5x upper limit of normal (ULN)  
unless receiving therapeutic  
anticoagulation 
Renal 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 25 of 174 
 
 
 
 
 
Glomerular filtration rate 
(calculated CrCl using only 
the Cockcroft-Gault equation, 
or measured using either a 
24-hour urine creatinine 
collection or a radionuclide 
EDTA test)2 
≥ 60 mL/min 
Hepatic 
Serum total bilirubin 
≤ 1.5 x ULN (unless subject has documented  
Gilbert’s Syndrome with direct bilirubin  
<35% of total bilirubin) 
Alanine aminotransferase 
(ALT)/Serum                           
Glutamic Pyruvic 
Transaminase (SGPT) 
≤ 2.5x ULN 
1. ≥1 x109/L (without G-CSF support) in 10 – 15 year olds 
2. 24-hour urine creatine clearance or radionuclide EDTA tests should be 
used to measure the GFR in all subjects: ≥ 65 years old; clinically 
obese (≥ 30KG/m2) or underweight (≤18.5KG/m2); borderline low 
calculated CrCl (Cockcroft-Gault) at approximately 60mls/min.  
Renal function will be reassessed at Baseline using the same methodology. 
Exclusion Criteria 
1. Positive for HLA-A*02:05 in either allele via Adaptimmune designated 
central laboratory testing. HLA-A*02 alleles having the same protein 
sequence as HLA-A*02:05 in the peptide binding domains (P groups) 
will also be excluded. Other alleles may be exclusionary after 
adjudication with the sponsor.   
2. Received or plans to receive the following therapy/treatment prior to 
leukapheresis or lymphodepleting chemotherapy:  
 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 26 of 174 
 
 
 
 
 
Treatment/Therapy 
Required Wash-out 
Prior to 
Leukapheresis 
Required Wash-out 
Prior to 
Lymphodepletion  
Cytotoxic 
chemotherapy 
3 weeks 
3 weeks 
Tyrosine kinase 
inhibitor (TKI)  (e.g. 
pazopanib) 
1 week  
1 week  
Immune therapy 
(including monoclonal 
antibody therapy, 
checkpoint inhibitors,) 
4 weeks 
4 weeks 
Anti-cancer Vaccine 
8 weeks in the 
absence of tumor 
response. The 
subject should be 
excluded if their 
disease is 
responding to an 
experimental 
vaccine given within 
6 months 
8 weeks in the 
absence of tumor 
response. 
The subject should be 
excluded if their 
disease is responding 
to an experimental 
vaccine given within 
6 months 
Gene therapy using an 
integrating vector 
Subjects who have 
received a gene 
therapy using any 
DNA-integrating 
vector other than a 
lentivirus 
(retrovirus, AAV, 
etc.) are excluded 
from this study. 
Subjects who have 
received a gene 
therapy using a 
Not permitted after 
leukapheresis and 
prior to 
lymphodepletion.  

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 27 of 174 
 
 
 
 
 
lentiviral vector may 
be eligible if they 
have persistence 
results below the 
lower limit of 
quantification 
(LLOQ) for at least 
2 samples taken at 
least 1 month apart. 
At least 1 of these 
tests must be 
performed by 
Adaptimmune as 
part of Pre-screening 
or Screening.  
Corticosteroids or any 
other 
immunosuppressive 
therapy. NOTE:  Use 
of topical steroids is 
not an exclusion. See 
Section 6.5.1 for 
exceptions.  
2 weeks  
2 weeks  
Investigational 
treatment or 
interventional clinical 
trial 
4 weeks  
4 weeks 
Allogeneic 
hematopoietic stem 
cell transplant 
Not permitted within 
any amount of time 
Not permitted within 
any amount of time 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 28 of 174 
 
 
 
 
 
 
3. Toxicity from previous anti-cancer therapy must have recovered to ≤ 
Grade 1 prior to enrollment (except for non-clinically significant 
toxicities, e.g., alopecia, vitiligo).  Subjects with Grade 2 toxicities that 
are deemed stable or irreversible (e.g. peripheral neuropathy) can be 
enrolled.  
4. History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to fludarabine, cyclophosphamide or other agents 
used in the study. 
5. History of autoimmune or immune mediated disease. Subjects with 
hypothyroidism, diabetes, adrenal insufficiency or pituitary insufficiency 
that are stable on replacement therapy are eligible. Subjects with 
disorders such as asthma, psoriasis or atopic dermatitis that are well 
controlled without requiring systemic immunosuppression are also 
eligible. 
6. Symptomatic CNS metastases including leptomeningeal disease.  
Subjects with a prior history of symptomatic CNS metastasis including 
leptomeningeal disease must have received treatment (i.e., stereotactic 
radiosurgery (SRS), whole brain radiation (WBRT) and/or surgery) and 
Radiotherapy to the 
target lesions 
N/A 
3 months.  A lesion 
with unequivocal 
progression may be 
considered a target 
lesion regardless of 
time from last 
radiotherapy dose.  
(Note: there is no 
washout period for 
palliative radiation to 
non-target organs). 
Major surgery 
N/A 
4 weeks. Subjects 
must have recovered 
from any surgical 
related toxicities. 
NOTE: Duration of any other anti-cancer therapies must be discussed 
with the Sponsor Study Physician 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 29 of 174 
 
 
 
 
 
be neurologically stable for at least 1 month, not requiring anti-seizure 
medications and off of steroids for at least 14 days prior to leukapheresis 
and lymphodepletion. Anti-seizure prophylaxis is permitted.  Subjects 
who have asymptomatic CNS metastases without associated edema, shift, 
requirement for steroids or anti-seizure medications for the treatment of 
seizures are eligible.   
7. Any other prior malignancy that is not in complete remission.  Resectable 
squamous or basal cell carcinoma of the skin is acceptable. Prior 
malignancies that have been surgically resected and show no evidence of 
disease are acceptable.   
8. Uncontrolled intercurrent illness including, but not limited to: 
• Ongoing or active infection;  
• Clinically significant cardiac disease defined by congestive heart 
failure New York Heart Association (NYHA) Class 3 or Class 4; 
• Uncontrolled clinically significant arrhythmia; 
• Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months; 
• Interstitial lung disease (subjects with existing pneumonitis as a 
result of radiation are not excluded, however, subjects must not be 
oxygen dependent); 
• Congenital or family history of long QT syndrome; 
• Current uncontrolled hypertension despite optimal medical therapy; 
• History of stroke or central nervous system bleeding; transient 
ischemic attack (TIA) or reversible ischemic neurologic deficit 
(RIND) in last 6 months; 
• Incipient compression/occlusion of a vital structure (e.g. bronchus; 
superior vena cava; renal outflow tract) which cannot undergo 
prophylactic stenting; 
• COVID-19 infection or a positive COVID-19 RT-PCR test within 
28 days of leukapheresis or lymphodepleting chemotherapy. If a 
subject has a positive COVID-19 test, then 2 subsequent negative 
tests are required, taken at least 7 days apart. 
9. Active infection with HIV, HBV, HCV or HTLV as defined below: 
• Positive serology for HIV; 
• Active hepatitis B infection as demonstrated by test for hepatitis B 
surface antigen. Subjects who are hepatitis B surface antigen negative 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 30 of 174 
 
 
 
 
 
but are hepatitis B core antibody positive must have undetectable 
hepatitis B DNA and receive prophylaxis against viral reactivation.  
Prophylaxis should be initiated prior to lymphodepleting therapy and 
continued for 6 months; 
• Active hepatitis C infection as demonstrated by hepatitis C RNA test.  
Subjects who are HCV antibody positive will be screened for HCV 
RNA by any RT PCR or bDNA assay. If HCV antibody is positive, 
eligibility will be determined based on a negative screening RNA 
value; 
• Positive serology for HTLV 1 or 2; 
• Re-screening for infectious disease markers is not required at baseline 
(prior to lymphodepletion) unless > 6 months has elapsed. 
10. Pregnant or breastfeeding. 
11. In the opinion of the Investigator, the subject is unlikely to fully comply 
with protocol requirements. 
Investigational 
Product, Dose, Route, 
Regimen 
ADP-A2M4 is the SPEARTM TCR product administered at a dose of 1.0 x 109  
to 10 x 109 transduced cells by a single intravenous infusion on Day 1. 
Comparator therapy 
None 
Statistical 
Methodology 
The primary clinical endpoint for efficacy is Overall Response Rate (ORR) 
defined as the proportion of subjects with a complete response (CR) or partial 
response (PR) via independently reviewed RECIST v1.1 relative to the total 
number of subjects in the analysis population in Cohort 1. 
The primary analysis population for safety and efficacy will be the modified 
intent to treat population (mITT) defined as all subjects who received the 
ADP-A2M4 cell infusion in Cohort 1. 
(Null Hypothesis) H0: p ≤  p0 , vs. (Alternate Hypothesis) H1: p > p0, where p0 
(historical control rate) = 0.18.  
Statistical assumptions include: 
• The type I error (α) will be no more than 0.025 
• The type II error (β) will not exceed 0.1  
• Exact Binomial methods will be used to test the hypothesis 
• The assumed ORR for ADP-A2M4 is 0.40 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 31 of 174 
 
 
 
 
 
Based on the statistical design assumptions above and the hypotheses and 
clinical assumptions detailed in Section 9, the estimated sample size for the 
trial is 45 subjects in Cohort 1 for the primary analysis. An additional 45 
subjects are to be enrolled in Cohort 2, although no formal hypothesis testing 
is planned for Cohort 2 or overall (across cohorts). 
The primary endpoint, ORR per RECIST v1.1 by independent review for 
Cohort 1, will be evaluated using a one-sided exact-based Clopper-Pearson 
97.5% confidence interval (CI).  If the lower bound of the 97.5% CI exceeds 
18%, the trial has met the pre-specified threshold for demonstrating efficacy.  
The key secondary efficacy endpoints ORR per RECIST v1.1 by independent 
review across Cohorts (overall), TTR, DoR, PFS and OS will be summarized. 
No hypothesis testing is planned for these secondary endpoints. Time to event 
endpoints will be summarized and displayed graphically using Kaplan-Meier 
(K-M) methodology to estimate the median, and the 25th and 75th percentiles. 
Two-sided 95% confidence intervals will be produced.  Overall Survival may 
be assessed at fixed time points such as 1 year and 2 years using K-M 
methods.  
Descriptive statistics will be provided for demography, safety, PK profile, and 
laboratory assessments. Descriptive statistics on continuous data will include 
means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages.  Graphical summaries of 
the data may be presented. 
Efficacy and safety summaries will be displayed across tumor types (overall) 
and by tumor type. Efficacy and safety summaries will be displayed across 
cohorts (overall) and by a cohort as indicated above.  Other subgroups may be 
explored and these will be described in the Statistical Analysis Plan. 
 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021  
Page 32 of 174 
 
 
 
 
 
 
1.2. 
Schema 
 
 
 
 
 
 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
Page 33 of 174 
 
 
 
 
 
 
1.3. 
Time and Events Table 
1.3.1. 
Main Time and Events (T&E) Table 
Table 1: 
T&E for Pre-Screening and Interventional Phase 
Written Informed Consent must be obtained prior to performing any protocol procedures. A Pre-screening ICF will be signed prior to 
obtaining a blood sample for HLA testing and tumor tissue for antigen testing. The Treatment ICF will be signed prior to all other 
study procedures. 
 
 
 
Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.1.4 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.1  
Inclusion/Exclusion 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5  
Disease History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2  
HLA typing 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
Page 34 of 174 
 
 
 
 
 
 
 
 
 
Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
MAGE-A4 Expression 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.2  
Cytogenetics testing 
for translocations 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section  8.2.3 
Safety and Efficacy Assessments 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.1 
Physical Exam 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X X 
 
 
 
 
 
 
 
 
 
Section 8.4.2  
Prior Anti-cancer 
Therapies 
 
X 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.3  
 
Prior and 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.4  
ECOG/Lansky15 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.5  

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
Page 35 of 174 
 
 
 
 
 
 
 
 
 
Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
Height 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.8 
Weight 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
Section 8.4.8  
Vital Signs 
 
X  
 
X 
 
 
 
 
X2 
X X X X X X 
 
 
 
 
 
 
 
 
X 
Section 8.4.7   
ECG 
 
X  
 
X  
 
 
 
 
X3 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.9.1  
Echo/MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.9.2  
CT / MRI  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X14 
 
X14 
X14 X14 
X 
X 
X 
Section 8.3.1  
Brain MRI 
 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.10 
ICE18 
 
 
 
 
 
 
 
 
X 
X X X X X 
 
 
 
 
 
 
 
 
 
 
Section 8.4.19 
CAPD18 
(Cohort 2 only) 
 
 
 
 
 
 
 
 
X 
X X X X X 
 
 
 
 
 
 
 
 
 
 
Section 8.4.20 
GFR (estimated or 
measured) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.11  

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
Page 36 of 174 
 
 
 
 
 
 
 
 
 
Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
Hematology 
 
X  
 
X 
X 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X  
X 
Section 8.4.12  
Clinical Chemistry  
 
X  
 
X 
X 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.13  
Coagulation  
 
X   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.14  
Pregnancy Test 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.17  
Infectious Disease 
Screening  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.18  
CMV PCR 
 
 
 
X5 
 
 
 
 
X5 
 
 
 
 
 X5   
X5  X5  
X5  
 
 
 
 
 
Section 8.4.19  
Thyroid Function 
Tests  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.15  
C-reactive Protein6 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X X 
 
X 
 
 
 
 
 
 
 
Section 8.4.21  
Ferritin6 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X X 
 
X 
 
 
 
 
 
 
 
Section 8.4.22  

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
Page 37 of 174 
 
 
 
 
 
 
 
 
 
Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.5 
Persistence (Vector 
Copies)  
X10 
X10 
  
X  
  
  
  
  
 
 X    X   X  X    
X  
  
X  
 X 
  
X 
X 
 
Section 8.4.23  
LTFU Table 2  
RCL (VSV-G DNA) 
 
 
  
X  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
X  
  
X 
LTFU 
Table 2 
 
Section 8.4.24  
LTFU Table 2 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
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Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
Leukapheresis, Lymphodepleting Chemotherapy and Investigational Product Administration 
Leukapheresis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.1  
Fludarabine11 
 
 
 
 
X11 X11 X11 X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.2 
Cyclophosphamide 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.2 
ADP-A2M4 Infusion 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.3  
Biomarker Assessments16 
Tumor Biopsy 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
 
 
 
 
 
 
X 
Section 8.6.1  
Cytokine and Soluble 
Protein Analyses6  
 
 
 
X 
 
 
 
 
X8  
X 
 
X 
 
X X 
X7 
  
X 
X 
 
X 
X 
  
Section 8.6.2  
Liquid Biopsy (Blood 
Plasma) 
 
 
 
X 
 
 
 
 
X3  
 
 
 
 
 
 
 
X 
 
- 
 
 
 
 
X 
Section 8.6.3 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
CONFIDENTIAL 
Date: 28OCT2021 
Page 39 of 174 
 
 
 
 
 
 
 
 
 
Interventional Phase 
 
 
Pre- 
Scree
ning 
Scree
ning1 
Leuka
phere
sis  
Baselin
e 
Lymphodepletin
g Chemotherapy 
T-cell 
Infusi
on 
Post-infusion Assessments 
Every 2 
Months 
Study 
Discontinu
ation 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
19 
20 
21 
22 
 
 
 
Visit Window (days) n/a 
n/a 
n/a 
n/a 
n/a n/a n/a n/a n/a 
±1  
± 3  
±3  ±3 
±7  
±28 
n/a 
 
Day 
 
 
 
-14 to   
-8 
-7 -6 -5 
-4 
1 
2 3 4 5 8 15 22 29 
 
 
 
 
 
 
 
 
Week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 3 
4 
6 
8 
12 
16 
24 
 
 
 
Cell Phenotyping and 
Functional Assays 
 
 
 
X 
 
 
 
 
X  
  
 
  
  
X X 
  
X 
  
X 
X 
  
 X 
X 
X 
Section 8.6.4  
Patient Reported Outcomes 
EQ-5D-3L 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
See 
footnot
e9  
 
Section 8.8.1  
EORTC-QLQ-C30 
(Cohort 2 only) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
See 
footnote 
13 
 
Section 8.8.2  
PedsQLTM 
(Cohort 2 only) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
See 
footnote 
17 
 
Section 8.8.3  
 

 
 
 
             
 
Investigational Product: ADP-A2M4 
 
 
 
 
Protocol Number: ADP-0044-002 
Version: FR-5.0 
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Date: 28OCT2021 
Page 40 of 174 
 
 
 
 
 
 
1 Screening Visit 2 assessments should be completed within 28 days of leukapheresis; CT/ MRI scans and ECHO/MUGA scans, performed as standard of care 
within 4 weeks prior to Screening Visit 2 (prior to study consent) are acceptable. Cytogentic confirmation of diagnosis can be historic, done as standard of care 
or be done any time after signing Treatment Consent and does not need to be within 28 day screening window.  
2 Measured pre-infusion, and at 5, 15 and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started 
3 Pre-infusion 
4 Within 4 weeks of lymphodepletion 
5 If CMV seropositive at screening, CMV-PCR done at baseline. All CMV seropositive subjects will continue to be monitored by CMV PCR at day 1, week, 2, 4, 
6, 8  
6 If CRS is suspected, CRP, ferritin and cytokine levels should be measured approximately every other day until symptoms are improving or an alternative 
diagnosis is confirmed  
7 Can be taken anytime between Week 3 and Week 8 
8 Day 1 samples taken pre-infusion and 2-4 hr. post-start of infusion 
9 EQ-5D-3L will also be done at Month 12 if the subject remains in the interventional phase of the study                                                                                          
10 Only for a subject who has previously received a gene therapy using a lentiviral vector. Subject’s must have results below the LLOQ for at least 2 samples 
taken at least 1 month apart. At least 1 of these tests must be performed by Adaptimmune as part of Pre-screening or Screening. 
11 Fludarabine dose must be adjusted for renal impairment using the Cockcroft-Gault equation/methods described in Section 6.2.1  
12 Subjects that provide a buccal swab sample may also need to provide a confirmatory blood sample for HLA testing 
13 EORTC-QLQ-C30 is for Cohort 2 subjects only; EORTC-QLQ-C30 will also be done at Month 12 if the subject remains in the interventional phase of the 
study        
14 On study scans from Week 4 through Week 16 should be at least 28 days apart to ensure compliance with RECIST 1.1 requirement for confirmatory scans in 
the event that an objective response is noted by central read    
15 ECOG should be used in subjects ≥16 years old and Lansky in subjects < 16 years old 
16 Biomarker research Blood draws (cytokine, liquid biopsy and cell phenotyping) will not be collected in pediatric subjects to comply with European 
recommendations.  Blood draws will not exceed 3% of the total blood volume over a period of four weeks, and should not exceed 1% at any single time In the 
event that blood draws are limited due to these restrictions, blood samples for research will be performed in order of priority as defined in the laboratory 
Manual 
17  Peds-QL is for Cohort 2 and will be used in subject’s 10 - 17 years old 
18 CAPD is for Cohort 2 and will be used in subjects <12 years old. ICE will be used in all subjects ≥ 12 years old 
 
 

 
 
 
             
 
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1.3.2. 
Long Term Follow Up Phase Time & Events Table 
Table 2: 
T&E for Long Term Follow Up Phase 
Time Post-infusion 
Year 1  
Year 2 
Year 3  
Year 4  
Year 5  
Years 6-15  
Comments: 
Months 
2 
3 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
Annually  
 
Visit window 
 
 
± 1 month 
± 3 months 
 
Physical Exam  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.2  
Mutagenic agents, other 
investigational agents or 
anti-cancer therapies  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.4 
LTFU Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.5.8  
Adverse Events 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.5 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X  
Section 8.4.12 
Clinical chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X  
Section 8.4.13 
Vector Copies (Persistence) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.23 
VSV-G DNA (RCL)  
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Sections 8.4.24 
 

 
 
 
             
 
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
2.1.1. 
Rationale for using MAGE-A4 TCR in synovial sarcoma and myxoid/round cell 
liposarcoma 
Adoptive T cell therapy (ACT) is a treatment that uses a cancer subject’s own T lymphocytes 
with anti-tumor activity, expanded in vitro and re-infused into the subject. The ultimate objective 
of the process is the stimulation and expansion of potent and antigen-specific T cell immunity.  
There are numerous recent publications and reviews of adoptive T cell therapy [Kalos, 2013; 
Klebanoff, 2016; Maus, 2014; Morgan, 2010; Rosenberg, 2008] 
Antitumor activity in ‘‘native’’ T cells may not be sufficient to induce tumor cell death in most 
patients with advanced malignancy. Gene-transfer-based strategies have therefore been 
developed to overcome the consequences of immune tolerance on the tumor-specific T cell 
repertoire. These approaches provide the potential to redirect T cells to effectively target tumors 
by the transfer of antigen-specific affinity-optimized TCRs.  
The majority of clinical approaches have employed T cells engineered to stably express 
transgenes via virus-based transduction. Virus-mediated gene transfer approaches typically 
employ vectors that are derived from gamma retroviruses or more recently lentiviruses. 
ADP-A2M4 specific peptide enhanced affinity receptor (SPEAR™) T cells are genetically 
engineered to target the subject’s MAGE-A4 positive tumor in the context of the appropriate 
HLA expression. ADP-A2M4 are autologous CD4 and CD8 positive T cells that have been 
transduced with a self-inactivating lentiviral vector expressing a high affinity MAGE-A4 specific 
T cell receptor (TCR). MAGE-A4 is a cancer/testis antigen (CTA) that has restricted expression 
in normal tissue, and is expressed across a range of solid tumors at varying frequencies. 
ADP-A2M4 recognizes the MAGE-A4230-239; GVYDGREHTV peptide derived from the 
MAGE-A4 family of CTAs. Thus, ADP-A2M4 incorporates an affinity enhanced TCR capable 
of recognizing the human leukocyte antigen (HLA)-A*02-GVYDGREHTV antigen complex.  
The safety of ADP-A2M4 has been shown in subjects with different tumor types in an ongoing 
Phase 1 study (NCT03132922). Data of another genetically engineered T cell investigational 
product, NY-ESOc259T, in synovial sarcoma provides evidence that TCR therapies can be 
effective in solid tumors [D’Angelo, 2018a].  
2.2. 
Background 
2.2.1. 
MAGE-A4 background 
The cancer/testis antigens (CTA) comprise a number of genes that have restricted expression to 
the testis, but have been identified by their expression in various tumor types [Caballero, 2009].  
These include NY-ESO-1, MAGE-A family, SSX2, BAGE, GAGE, and CT7 among others.  

 
 
 
             
 
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Most of these testis-specific genes are coded on the X chromosome. Several of these antigens, 
including MAGE-A3, MAGE-A10 and MAGE-A8, also have expression in placenta [Caballero, 
2009].  In general, melanoma, ovarian cancer and lung cancer, particularly of the squamous cell 
type, have the highest frequency of RNA expression across the CTAs.  Epithelial cancers such as 
breast, bladder and prostate cancer have intermediate expression, with frequency of mRNA 
expression in the range of 30% to 50%.  CTAs often have coordinated expression, with several 
expressed in a single tumor [Gure, 2005].  In addition to RNA, immunohistochemistry is often 
used to determine the expression levels of CTAs.  While it is generally seen that mRNA 
expression of these antigens correlates well with protein expression it should be noted that there 
is frequently heterogeneous expression of protein across the tumor, with strong expression in a 
small subset of tumor cells.  There is also epigenetic and post-transcriptional modification that 
determines protein expression levels under certain conditions. 
The function of the CTA in germline tissues or in tumors is generally not well understood.  Some 
MAGE-A proteins do have functions that may enhance tumor growth.  For example, MAGE-A1 
proteins may have a role in suppressing differentiation during spermatogenesis and a similar role 
in inhibiting cell differentiation may be a mechanism by which it promotes tumorigenesis 
[Laduron, 2004; Simpson, 2005].  There is also evidence that members of the MAGE-A family 
modulate key transcription factors such as SKIP, p300, p160 (TIF2)/androgen receptor ER-α, 
and the p53 tumor suppressor [Marcar, 2015].  MAGE-A4 appears to promote cell growth of 
epithelial cells by preventing cell cycle arrest and inhibiting apoptosis.  In one study, 
overexpression of MAGE-A4 was shown to repress p53 targets, such as BAX and CDKN1A 
[Bhan, 2012].  In a yeast-two hybrid study, MAGE-A4 was identified as a binding partner for the 
oncogene, gankyrin [Nagao, 2003].  Through these pathways, MAGE expression may protect 
cells from apoptosis and contribute to the development of tumors by promoting survival [Yang, 
2007].   
MAGE-A4 has been described as having high expression in synovial sarcoma and MRCLS.  A 
recent study showed that 82% of synovial sarcoma samples expressed MAGE-A4 when 
evaluated by Immunohistochemistry (IHC) and high expression of NY-ESO-1 and MAGE-A4 
was significantly correlated with the presence of necrosis and advanced clinical stage [Iura, 
2017a]. 
 
.  A further report suggested that 67.7% of MRCLS samples, express 
MAGE-A4 [Iura, 2017b].   
 
 
  
 
 
 
 
 
 
. 
 

 
 
 
             
 
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2.2.2. 
Discovery of ADP-A2M4 
Several peptides derived from MAGE proteins have been identified by mass spectroscopy from 
tumor cell lines, including the human leukocyte antigen (HLA) HLA-A*02-restricted peptide 
MAGE-A4230-239; GVYDGREHTV.  HLA class I molecules are involved in the presentation 
of antigenic peptides on tumors to T lymphocytes.  The prevalence of HLA subtypes varies from 
population to population, the most common in the western world being HLA-A2.  Among the 
HLA-A2 allelic variants, the most prevalent are HLA-A*02:01 (approximately 45% of 
Caucasian and Hispanic population) and HLA-A*02:06 (www.allelefrequencies.net). 
Adaptimmune generated 20 parental TCRs that recognize the HLA-A*02-restricted MAGE-A4 
peptide GVYDGREHTV.  From these, one demonstrated some response toward natively 
MAGE-B2 and MAGE-A4-positive cell lines and was selected for engineering, resulting in 17 
enhanced affinity TCRs that were tested in cellular assays against MAGE-A4 positive and 
negative cell lines and primary cells.  Cellular testing for potency and specificity identified 
ADB1032 as being optimal, demonstrating enhanced potency against MAGE-A4 positive tumor 
cell lines, while retaining a favorable specificity and safety profile.  
The Investigational Product (IP) is comprised of autologous CD4 and CD8 T cells obtained from 
eligible subjects who have MAGE-A4 expressing tumors and who are HLA-A*02 positive.  
Subjects who are HLA-A*02:05 are excluded because alloreactivity has been observed in vitro 
with ADP-A2M4 to this HLA allele.  The T cells undergo self-inactivating (SIN) lentiviral 
transduction with ADP-A2M4 specific nucleic acid under Good Manufacturing Practice (GMP) 
conditions.  The resulting polyclonal ADP-A2M4 specific peptide enhanced affinity receptor 
(SPEAR™) T cells are now genetically engineered to target the antigen on the subject’s MAGE-
A4 positive advanced tumor. 
2.2.3. 
Current Therapeutic Options for Synovial Sarcoma & MRCLS  
Sarcomas are rare malignant tumors originating from mesenchymal cells and their precursors, 
and represent ~1% of all cancers in adults worldwide each year (10% of cancers in children, and 
8% of cancers in adolescents) and ~2% of cancer related mortality [Singer, 2000; Amankwah, 
2013].  The estimated international incidence rates of soft tissue sarcoma ranges between 4 and 6 
cases per 100,000 per year [Stiller, 2013; Ferrari, 2011]. Soft tissue sarcomas consist of 
approximately 50 different histological subtypes.   
Synovial Sarcoma 
Synovial sarcoma represents 5% of all soft tissue sarcoma (STS) and is characterized by the 
presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or SSX4 on 
chromosome 18. The disease affects young individuals with a median age in the third decade; 
with 70% of the diagnoses occurring in subjects under 40 years old.  
Surgery is the standard therapy for localized disease.  Patients with advanced synovial sarcoma 
receive ifosfamide and/or doxorubicin, as the first-line of therapy [ESMO, 2014].    

 
 
 
             
 
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Doxorubicin-based first-line metastatic doublet therapies, such as doxorubicin in combination 
with the anti-PDGFR alpha monoclonal antibody olaratumab [Lilly, 2019], have not 
demonstrated improved clinical benefit compared to single-agent doxorubicin. 
There is no specific standard of care (SoC) in second line therapies and beyond. Pazopanib is 
approved in the U.S and in Europe for patients with synovial sarcoma previously treated with 
chemotherapy [Votrient™ US Prescribing Information, EU SmPC].  A randomized double blind 
placebo controlled Phase 3 trial of pazopanib was conducted in patients with advanced STS.  
Overall response rate (ORR) as assessed by Data Safety Monitoring Board (DSMB) for the 
intent to treat (ITT) population was  4%, median duration of response (DoR) of 9 months,  and 
median progression free survival (PFS) of 4.6 months compared with 1.6 months for placebo 
(HR=0.35, p<0.001). Median overall survival (OS) was 12.6 months compared with 10.7 months 
for placebo (HR=0.87; 95% CI: 0.67, 1.12). Only 38 subjects with synovial sarcoma 
(randomized 2:1) were included in the study with a median PFS of 4.1 months in the pazopanib 
arm vs 0.9 months for placebo (HR= 0.43; 95% CI 0.19, 0.98). The response rate is not reported 
by histology [Votrient™ US Prescribing Information, EU SmPC].  In a Phase 2 non-randomized 
study of pazopanib (EORTC Study 62043), responses as assessed by the Investigator were 
reported in 5/37 (13%) subjects with synovial sarcoma [Sleijfer, 2009].    
The response rate in a retrospective analysis of gemcitabine and docetaxel in patients with 
synovial sarcoma was 10% [Abouharb, 2014].  Several other agents have shown no appreciable 
anti-tumor activity in synovial sarcoma; these include many novel classes of agents such as 
HDAC-inhibitors [Cassier, 2013], IGF-1R antibodies [Pappo, 2014; Olmos, 2010], mTOR 
inhibitors [Schwartz, 2013], vascular disrupting agents [Blay, 2015] and anti-CTLA4 antibodies 
[Maki, 2013].  
Pediatric Synovial Sarcoma is the most common primary Non-rhabdomyosarcoma Soft Tissue 
Sarcoma (NRSTS) in children accounting for up to 50% of NRSTS [Sultan 2009].  Treatment 
paradigms for the management of paediatric SS is similar to adult patients and involves the use 
of multimodality treatment (i.e. surgery, radiotherapy and chemotherapy) for high-risk primary 
tumors, and the use of anthracycline-containing chemotherapy for first-line metastatic disease 
management with off-label use of pazopanib as a second-line therapy. The prognoses of primary 
synovial sarcoma in children is better than in adult patients probably because children, especially 
those less than 10 years old, have better tumor biology and lower genetic instability as manifest 
by smaller, ≤ 5cm, primary tumors in this patient subpopulation [Gootee, 2019]; in this context, 
probability of metastatic disease post first-line primary tumor treatment seems to increase with 
age (i.e. prognosis: children less than 10 years old > older adolescents > adults) [Younger, 2020]. 
To date, there are no published patient series’ annotating the natural history and prognosis of 
children with metastatic synovial sarcoma probably because metastatic disease is very rare given 
the biological differences between pediatric and adult sarcomas, and since the majority of 
children who do relapse after primary sarcoma treatment do so with mainly local/locoregional 
disease which in  most cases continues to be therapeutically sensitive to chemotherapy and/or 
radiotherapy [Soole, 2014]. Overall, the potential therapeutic opportunity for ADP-A2M4 cells is 
in children with locoregional or metastatic synovial sarcoma which has become refractory to 
alkylating agent chemotherapy. 

 
 
 
             
 
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2.2.4. 
Emerging Data for ADP-A2M4 SPEAR T-cells in Synovial Sarcoma 
Therapeutically effective treatment options for patients with advanced/metastatic synovial 
sarcoma are limited. The median survival upon relapse from first-line therapy is approximately 
12 months [Minchom, 2010] and the ORR from prospective trials for existing therapies, such as 
alkylating agent chemotherapy and pazopanib are ≤ 13%.   
Thirty-eight adult subjects with a variety of different solid tumors including 16 subjects with 
metastatic synovial sarcoma have received treatment with a single dose of ADP-A2M4 up to 
9.9756 x 109 transduced cells within the phase 1 ADP-0044-001 study. Synovial sarcoma 
subjects represented the most frequent tumor type in the phase 1 study, and the majority of the 
subjects treated in Group 3/Expansion cohort.  Of the 16 subjects with synovial sarcoma, most 
subjects were males (62.5%), most subjects were White (87.5%) and the median age was was 
49.0 years (range 31 to 76 years). The median ADP-A2M4 dose in synovial sarcoma was 9.28 x 
109 transduced cells (range: 3.4 to 10 x 109). The reported adverse events are consistent with 
those typically experienced by patients with advanced cancer undergoing cytotoxic 
chemotherapy or cancer immunotherapy (e.g, cytopenias, fatigue, CRS). The most common AE 
≥ Grade 3 occurring in ≥ 25% of subjects with synovial sarcoma were, lymphopenia/lymphocyte 
count decreased (93.3%), leukopenia/WBC count decreased (100%), neutropenia/neutrophil 
count decreased (88.0%), neutropenia/neutrophil count decreased(81%), anemia/RBC decreased 
(44%), thrombocytopenia/platelet count decreased (44.0%), hypophosphatemia (44%), rash 
(19%), CRS (13%), decreased appetite (6%) and hypotension (6%). Cytokine release syndrome 
(any Grade) was reported in 88% of the subjects with synovial sarcoma.  There was one (1) 
Grade 5 SAE of prolonged pancytopenia with hypoplastic bone marrow considered possibly 
related to ADP-A2M4. In subjects with synovial sarcoma, the ORR (confirmed responses) was 
44% (95%CI: 16.34, 67.71).  The Best Overall Response was PR (7), SD (8), PD (1). Disease 
control rate was 94% with 11 patients still alive at time of 1-September-2020 data cut-off. 
Subject responses were durable with a median duration of response of 28 weeks range: 12-72 
weeks [CTOS, 2020]. This data supports the continued evaluation of ADP-A2M4 in 
advanced/metastatic synovial sarcoma. 
Myxoid/Round Cell Liposarcoma (MRCLS) 
MRCLS is a subtype of liposarcoma which is associated with specific translocation, t (12; 16) 
(q13; p11) or t (12; 22) (q13; q12) and represents about 30-35% of liposarcomas and 5-10% of 
all adult STS (WHO, 2002).  MRCLS commonly presents at an age ranging from 35-55 years. 
Myxoid round cell tumors tumors with a round-cell component >5% have a poor prognosis with 
a 5-year survival rate of ~50-75% because they recur locally and tend to metastasize quickly and 
widely [Smith, 1996]. The median time from diagnosis to metastases is 35 months. 
Treatment involves the wide surgical excision of the tumor and surrounding tissue. Myxoid 
round cell liposarcoma may be treated with pre-operative chemotherapy and/or pre-operative or 
post-operative radiotherapy [NCCN, 2012]. Doxorubicin and ifosfamide are the first line 
systemic treatment options for patients with metastatic disease. Retrospective analyses in 
previously untreated patients demonstrated response rates of ~38 - 45% [Jones, 2005; Katz, 
2012]. Once patients relapse or develop metastatic disease treatment is aimed at slowing that 

 
 
 
             
 
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pace of progression.  A variety of therapies are used in the second-line setting and beyond 
although only trabectedin and eribulin are approved. A randomized open label phase 2 study of 
trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma enrolled 270 
patients. Patients were randomized to receive either a 24 hour infusion of 1.5 mg/m2 of 
trabectedin once every 3 weeks, or a 3 hour infusion of 0.58 mg/m2 of trabectedin once every 
week for three weeks of a 4 week cycle. The treatment regimen that was determined to be most 
beneficial was the 24 hour infusion of 1.5mg/m2 of trabectedin once every 3 weeks.  One 
hundred and thirty six patients were randomized to this arm of the study and the ORR was 5.6% 
[Demetri, 2016]. 
A subsequent randomized, phase 3, open-label, active-controlled trial comparing trabectedin 
(n=345) treatment with dacarbazine (n=173) in patients with unresectable, locally advanced or 
metastatic leiomyosarcoma (73%) or liposarcoma (27%) (dedifferentiated, myxoid round cell, or 
pleomorphic) and previous treatment with an anthracycline-containing regimen and one 
additional cytotoxic chemotherapy regimen demonstrated an overall response rate (ORR of 9.9% 
(CI 0.72, 3.2) with trabectedin, an improvement of median progression-free survival (PFS) of 5.6  
vs 1.5 months on dacarbazine but no difference in overall survival [Demetri, 2016]. Eribulin 
demonstrated an improvement in survival (median OS 13.5 vs 11.5 months; HR= 0.768; 95% CI, 
0.618; 0.954) compared with darcarbazine in subjects with liposarcoma and leiomyosarcoma 
who received 2 or more prior lines of therapy.  There was no difference in PFS and ORR was 
3.9% with Eribulin and 4.9% with darcarbazine in all patients enrolled.  In patients with 
liposarcoma the response rate was 1.4% [Schöffski, 2016].  Despite the approval of these two 
agents, overall survival in patients with relapsed disease remains 12-13 months [Demetri, 2016; 
Schöffski, 2016] and the ORR from prospective trials for existing therapies is < 10%. 
A TCR T-cell product targeted against the NY-ESO-1 cancer testis antigen has shown potentially 
promising clinical activity in eight MRCLS subjects [D’Angelo, 2018b]. For MAGE-A4, in 
Study ADP-0044-001, two MRCLS subjects were dosed with ADP-A2M4 cells.  At the time of 
Data cut-off, 1 Sept 2020, no MRCLS subjects had responded to ADP-A2M4.  ADP-A2M4 was 
however safe and well tolerated in MRCLS subjects in this phase 1 trial. 
2.3. 
Benefit: Risk Assessment 
The results of clinical and non-Clinical studies conducted with ADP-A2M4 cells are summarized 
in the ADP-A2M4 Investigator’s Brochure.  This section outlines the potential benefits, risks and 
the overall benefit: risk for this study. 
2.3.1. 
Benefit 
Although the basis for including both synovial sarcoma and MRCLS subjects in Cohort 1 of this 
study was the reported a high frequency of MAGE-A4 expression in both synovial sarcoma and 
myxoid liposarcoma [Iura, 2017a; Iura, 2017b], as well as the historical clinical activity of the 
NY-ESO-1 TCR in both synovial sarcoma and MRCLS, Preliminary evaluation of MRCLS 
response and MAGE-A4 antigen status in both the ADP-0044-001 and Cohort 1 ADP-0044-002 
studies would suggest that ADP-A2M4 is not as clinically active in MRCLS as it is in synovial 

 
 
 
             
 
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sarcoma. This is possibly because of a comparatively lower MAGE-A4 antigen score 
distribution.   
For these reasons, Cohort 2 will only enroll adult and pediatric (10-17 years old) subjects with 
synovial sarcoma as such patients are likely to derive the greatest therapeutic benefit from the 
ADP-A2M4 cell product especially since study ADP-0044-001 has shown an ORR of 44% in 
sixteen heavily pre-treated metastatic synovial sarcoma adult subjects who had a median of three 
prior lines of treatment [CTOS, 2020]. The therapeutic benefit from ADP-A2M4 SPEAR T-cells 
in children with advanced/metastatic synovial sarcoma is anticipated to be similar to adult 
patients as long as the MAGE-A4 expression distribution and endogenous qualitative function of 
T-cells in pediatric patients are similar to adults.  
The data from study ADP-0044-001 in combination with emerging efficacy findings for synovial 
sarcoma subject in Cohort 1 of study ADP-0044-002 would indicate that ADP-A2M4 is a 
promising cell product in metastatic synovial sarcoma especially since there is no specific 
standard of care beyond first-line ifosfamide and/or doxorubicin for patients with advanced 
(inoperable)/metastatic synovial sarcoma.  
2.3.2. 
Risk 
The safety and tolerability of ADP-A2M4 is being assessed in Phase 1 trial (study ADP-0044-
001) across multiple tumor types and in the ongoing Cohort 1 of study ADP-0044-002 including 
synovial sarcoma and MRCLS. Toxicities observed with ADP-A2M4 are common to other TCR 
or CAR-T therapies or standard of care chemotherapies.   
Toxicities such as CRS, ICANS and pancytopenia/aplastic anemia are specific to TCR and CAR-
T therapies and therefore guidelines for management of these events are included in 
Section 10.5.  An advantage of TCR therapy is that they are generally administered once, and the 
vast majority of toxicities resolve within 4 to 6 weeks after T cell infusion. 
Alloreactivity, whereby TCRs reactive towards a given peptide-MHC complex display cross-
reactivity towards different HLA allelic variants, is a theoretical risk.  Pre-clinical data indicate 
strong anti-HLA-A*02:05 alloreactivity, making A*02:05 an exclusion allele. Data also indicate 
decreased potency against MAGE-A4230-239 peptide when presented by HLA-A*02:07, 
therefore subjects with A*02:07P alleles are ineligible unless they also express an inclusion 
allele.  Preclinical studies support the specificity, safety, and anti-tumor activity of ADP-A2M4 
and therefore an unacceptable risk of off-target reactivity is not expected. No evidence of 
alloreactivity has been detected in the ongoing Phase 1 study to date.  
The study incorporates several measures to address the risks including: 1) extensive preclinical 
evaluation of the ADP-A2M4 which has incorporated learnings from other adoptive T cell 
therapy programs [ADP-A2M4 Investigator Brochure]; 2) based on the preclinical alloreactivity 
data, exclusion of subjects with HLA-A*02:05 in either allele or with HLA-A*02 alleles having 
the same protein sequence  as HLA-A*02:05 in the antigen binding domains (P groups); 3) use 
of a validated Clinical Trial Assay for the selection of subjects with MAGE-A4 expression in 
their tumors; 4) treatment in specialized academic centers experienced with the management of 
toxicities associated with autologous T cell therapies; 5) protocol guidelines for management of 

 
 
 
             
 
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toxicities including cytokine release syndrome (CRS), Immune Effector Cell-Associated 
Neurotoxicity Syndrome (ICANS), and pancytopenia/aplastic anemia as well as preventive 
measures for infectious complications, and 6) a Data Safety Monitoring Board (DSMB) to 
evaluate safety during the course of Cohort 1.  
The potential risks for Cohort 2 (synovial sarcoma only) in both adult and pediatric subjects (10-
17 years old) are expected to be similar to the emerging safety profile in Cohort 1 of study ADP-
0044-002, as well as similar to the safety profile reported in the sixteen synovial sarcoma 
subjects previously dosed in the phase 1 trial, study ADP-0044-001 [CTOS, 2020]. Moreover, 
when combined with the emerging safety profile in Cohort 1, the additional 45 synovial sarcoma 
subjects in Cohort 2 will permit a deeper understanding and a better estimate of the frequency of 
adverse events of special interest (AESI) across a broad age range of patients i.e. incidence of 
CRS, ICANS and pancytopenia in synovial sarcoma subjects treated with ADP-A2M4 cells 
compared to safety data from Cohort 1 alone. 
2.3.3. 
Overall benefit: risk conclusion 
In Cohort 1, based on the initially promising emerging efficacy and safety findings from the 
Phase 1 ADP-A2M4 SPEAR™ T-cell trial (study ADP-0044-001), it was justifiable from a 
benefit-risk perspective to treat subjects with both advanced synovial sarcoma and MRCLS as 
they each constituted patient populations with a high unmet medical need, albeit with distinctly 
different metastatic disease natural histories.  However, as more mature data has accrued from 
study ADP-0044-001 in combination with emerging findings from Cohort 1 of this ongoing 
Phase 2 trial (see Section 4.2, below), it has become apparent that ADP-A2M4 cells may 
potentially be less clinically active in MRCLS compared to synovial sarcoma. Therefore, at this 
time, continued evaluation of ADP-A2M4 treatment in Cohort 2 is only justifiable for synovial 
sarcoma subjects from a therapeutic benefit perspective. In regard to mitigation of risks, in both 
adults and children (10-17 years old), measures to ensure safe administration of ADP-A2M4 
have been included in this study protocol, with close monitoring for toxicities and guidelines for 
their management.   
The potential risks identified in association with ADP-A2M4 are justified by the anticipated 
benefits which may be afforded to both adult and pediatric/adolescent patients with advanced 
(inoperable)/metastatic synovial sarcoma in Cohort 2. Indeed, real-world evidence in metastatic 
synovial sarcoma suggests that pazopanib - which is approved for 2nd-line metastatic soft tissue 
sarcoma treatment in the United States and Europe - is not the most frequently administered 2nd-
line therapy at several major synovial sarcoma centres in the United States possibly because of 
its low ORR [Pollack, 2020]. Since the outcome of both adults and children with advanced 
(inoperable)/metastatic synovial sarcoma is poor, this study provides a unique therapeutic 
opportunity for ADP-A2M4 to potentially become the first licensed cell therapy product in post-
1st-line advanced (inoperable)/metastatic synovial sarcoma, if the overall benefit-risk findings 
from this phase 2 trial (study ADP-0044-002) are favorable. 

 
 
 
             
 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
End Points 
Primary: 
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS 
• Overall Response Rate (ORR) per 
RECIST v1.1 by independent review in 
Cohort 1 
  
Secondary: 
To evaluate the safety and tolerability of 
autologous genetically modified T cells 
(ADP-A2M4) in HLA-A*02 positive 
subjects with MAGE-A4 expressing 
advanced synovial sarcoma or MRCLS 
For Cohort 1 and across Cohorts (overall):  
• Adverse events (AEs) including serious 
adverse events (SAEs) 
• Incidence, severity and duration of the 
AEs of special interest 
• Replication Competent Lentivirus 
(RCL) 
• T cell Clonality and Insertional 
oncogenesis (IO) 
To evaluate the efficacy of autologous 
genetically modified T cells (ADP-A2M4) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced synovial 
sarcoma or MRCLS 
• Overall Response Rate (ORR) per 
RECIST v1.1 by independent review 
across Cohorts (overall) 
For Cohort 1 and across Cohorts (overall):  
• Time to Response (TTR) 
• Duration of Response (DoR) 
• Best Overall Response (BOR) 
• Progression Free Survival (PFS) 
• Overall Survival (OS) 

 
 
 
             
 
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Development and validation of an in vitro 
diagnostic (IVD) assay for the screening of 
tumor antigen expression for regulatory 
approval 
Across Cohorts:  
• Retention of additional tumor tissue 
during Pre-screening to enable 
development and validation of the 
MAGE-A4 antigen expression 
companion diagnostic assay 
Characterize the in vivo cellular 
pharmacokinetics (PK) profile of ADP-
A2M4 cells 
For Cohort 1 and across Cohorts (overall): 
• Peak persistence and other relevant PK 
parameters of ADP-A2M4 cells 
Exploratory 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
             
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2 single arm, open label study of genetically engineered ADP-A2M4 in HLA-
A*02 subjects with MAGE-A4 expressing metastatic or inoperable (advanced) synovial sarcoma 
or myxoid/ myxoid round cell liposarcoma (Cohort 1 only). Only subjects with advanced 
synovial sarcoma will be eligible for Cohort 2. The study consists of two separate, independent, 
serially enrolled subject cohorts: Cohort 1 and Cohort 2.  
Enrollment into Cohort 1 is expected to continue for approximately 12 months and is close to 
completion at the time of this amendment. Forty-five subjects have been enrolled and 26 subjects 
have been treated with ADP-A2M4 to date. Enrollment will continue to ensure that at least 45 
subjects are dosed in Cohort 1. Dosing is expected to be complete in Cohort 1 in March 2021. 
Data from subjects in Cohort 1 only will be used for the primary study endpoint and primary 
statistical analysis.  
The clinical and scientific rational for including Cohort 2 is to provide an expanded safety and 
efficacy data set overall in both adults and children (10-17 years old) with inoperable 
(advanced)/metastatic synovial sarcoma to supplement the primary assessment for Cohort 1. 
Subjects who were previously enrolled in Cohort 1 may not enroll into Cohort 2.  
4.1.1. 
Pre-screening 
Subjects will sign a Pre-screening Informed Consent Form (ICF) and undergo initial screening 
for the relevant HLA alleles and MAGE-A4 tumor antigen as part of this study.  
At sites that employ remote consent at pre-screening, it is the responsibility of the Investigator to 
obtain written consent in accordance with IRB/IEC approved processes and any local 
requirements in advance of providing subjects with a HLA buccal/ cheek swab test and/ or 
sending tissue for MAGE-A4 testing.   
4.1.2. 
Screening 
Subjects who have pre-screened positive for the relevant HLA alleles and MAGE-A4 tumor 
antigen will be asked to sign the Treatment ICF and enter Screening to determine full eligibility 
for the study.  Screening assessments should be completed within 28 days of leukapheresis; CT/ 
MRI scans and ECHO/MUGA scans, performed as standard of care within 28 days prior to 
Screening Visit 2 (i.e. prior to treatment consent) are acceptable. Cytogenetic confirmation of 
diagnosis can be historic, done as standard of care, or be done any time after signing Treatment 
Consent and does not need to be within 28 day screening window. 

 
 
 
             
 
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4.1.3. 
Enrollment 
Subjects who sign the Treatment ICF and meet the protocol defined eligibility criteria (Section 
5.2 and Section 5.3) will be enrolled. Subjects who do not meet the protocol defined eligibility 
criteria are screen failures.  
Enrolled subjects will undergo leukapheresis for collection of autologous cells for processing and 
manufacture into the ADP-A2M4 cell Investigational Product (IP). Leukapheresis should be 
performed as soon as possible after the subject is determined to be eligible for study 
participation. 
Anticancer therapy may be administered between screening and leukapheresis, and between 
leukapheresis and the start of lymphodepletion (bridging therapy), if a subject has progressive 
disease and cannot be treatment-free, but mandatory washout periods must be adhered to (see 
Section 5.3).  Subjects must be ready to receive IP as the next treatment once manufacturing and 
any mandatory washout periods are complete even if they remain stable on bridging therapy, 
provided they have measurable disease per RECIST v1.1. 
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria will be 
reconfirmed and Baseline tumor assessment obtained.   
Once the ADP-A2M4 cells are available at site, subjects will undergo lymphodepleting 
chemotherapy with fludarabine 30 mg/m2/day for 4 days (Day -7 to Day -4) and 
cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5) (Section 6.2) followed by infusion 
of ADP-A2M4 cells on Day 1 (Section 6.3).  The lymphodepleting chemotherapy may be given 
as an outpatient treatment or subjects may be hospitalized at the discretion of the Investigator. 
The T cell infusion will be given as an inpatient procedure. Subjects will remain hospitalized for 
observation for at least 10 days post T cell infusion.  Discharge following T cell infusion will be 
at the discretion of the Investigator. All subjects must be reviewed by the investigator (or a 
designated study physician) prior to discharge. 
Efficacy, safety, health related-outcome and biomarker assessments to be conducted at each visit 
are outlined in the Time and Events (T&E) Tables (Table 1 and Table 2).  Efficacy will be 
assessed by both local and independent review using RECIST v1.1. To allow time for the 
immune response to become apparent and for potential transient inflammatory reaction of the 
disease to the treatment (‘tumor flare’), disease progression will not be determined before 4 
weeks (28 days) post infusion of ADP-A2M4 unless there is unequivocal clinical evidence of 
deterioration. Therefore, imaging scans should not be performed earlier than 4 weeks (on or after 
28 days) post infusion.   
Subjects will continue to have scans for efficacy during the interventional phase of the study, 
until disease progression is established. Once progression is established, no further scans will be 
performed for this study, however, subjects will continue to be followed for observation of 
delayed adverse events in accordance Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) requirements for gene therapy clinical trials [FDA, 2006a; FDA, 
2010; EMA, 2009].  

 
 
 
             
 
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Subjects will be seen in the clinic for evaluation according to Main T&E Table 1 (Section 1.3.1) 
until disease progression.  Thereafter, subjects will undergo assessments/procedures according to 
the LTFU T&E Table 2 (Section 1.3.2 ). The timepoint at which the subject switches to the 
LTFU assessments/procedures will be driven by the timepoint at which the subject progresses 
e.g. if there is disease progression at Week 12, the next visit would be due at Week 24 (Month 
6). 
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason. 
4.2. 
Scientific Rationale for Study Design 
This is a Phase 2 single arm, open-label study with ADP-A2M4 cells for the treatment of 
subjects with advanced synovial sarcoma or MRCLS who are HLA-A*02 positive and have 
tumors that express MAGE-A4.  
MAGE-A4 is a cancer testis antigen that is highly expressed in synovial sarcoma and MRCLS 
tumors making it an attractive target. Preliminary clinical evidence in Study ADP-0044-001 has 
shown an ORR (confirmed responses) of 44% (95% CI: 16.34, 67.71) in advanced 
(inoperable)/metastatic synovial sarcoma with a disease control rate of 94% including 11 out of 
16 patients who were still alive at time of 1-September-2020 data cut-off. Synovial sarcoma 
responses were durable with a median duration of response of 28 weeks (range: 12-72 weeks). 
[CTOS, 2020]. This ORR is considerably superior than response rates reported with agents 
currently being used as 2nd line therapies for soft tissue sarcoma (Section 2.2.3). 
On this basis, this Phase 2 study (ADP-0044-002) will be a single arm, non-comparative study 
with a primary efficacy endpoint of Overall Response Rate (ORR) per RECIST v1.1 by 
independent review in 2 Cohorts where the primary study endpoint will be evaluated in Cohort 1. 
The historical ORR for first-line metastatic soft-tissue sarcoma patient populations ranges from 
4%-13% (Section 2.2.3). To account for the potential variability in historical control response 
rate, a more conservative historical ORR of 18% has been estimated for therapies administered 
in the post 1st-line metastatic synovial sarcoma setting, and will be used to evaluate the efficacy 
of ADP-A2M4 by hypothesis testing (Section 9). 
At the time of this Protocol Amendment (05FEB2021) the ADP-0044-002 study has been 
enrolling subjects for approximately 12 months. Fifty-three adult subjects have been enrolled, 
and 31 subjects have received treatment with a single dose of ADP-A2M4 in Cohort 1 including 
27 adult subjects with advanced (inoperable)/metastatic synovial sarcoma and 4 subjects with 
MRCLS. 
 
 
 
.  
The clinical and scientific rationale for including Cohort 2 is to provide an expanded safety and 
efficacy dataset overall for metastatic or inoperable (advanced) synovial sarcoma, in both adults 
and children (10-17 years old) to supplement the primary assessment for Cohort 1. 

 
 
 
             
 
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4.2.1. 
Pre-Screening for HLA Alleles and MAGE-A4 Expression 
4.2.1.1. 
HLA 
Subjects must express at least 1 inclusion HLA-A allele of HLA-A*02:01, HLA-A*02:03 or 
HLA-A*02:06. HLA-A*02 alleles having the same protein sequence as these alleles in the 
antigen binding domains (P group) will also be included. There may be other HLA-A*02 alleles 
that may be eligible for inclusion after adjudication with the sponsor. The adjudication process 
will be documented.  
Due to the risk of alloreactivity subjects positive for HLA-A*02:05 in either allele are ineligible. 
Subjects with HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 in the 
antigen binding domains (P groups) will also be excluded. Other alleles may be exclusionary 
after consultation with the sponsor.  HLA eligibility testing will be done via Adaptimmune 
designated central laboratory.  
Despite HLA-A*02 being the most common HLA allele group in the western world its 
expression varies greatly among populations of different races and ethnicities.  With a high 
proportion of subjects expected to be excluded based on HLA status, an optional buccal swab kit 
may be offered to subjects during pre-screening at participating sites. This allows subjects to be 
screened for HLA without requiring travel to a clinical study site.  The kit, containing a self-
administered buccal/cheek swab and associated instructions would be sent to potential subjects 
who have provided written consent in accordance with IRB/IEC approved processes and any 
local requirements. Any subject determined to be eligible based on results from the buccal swab 
would still undergo confirmatory HLA genotyping on a blood sample during screening. 
4.2.1.2. 
MAGE-A4 Expression in Tumor 
MAGE-A4 expression was reported in synovial sarcoma (82%) and myxoid liposarcoma (68%) 
cases [Iura, 2017a; Iura, 2017b]. ADP-A2M4 cells have been shown to produce strong IFNγ 
responses against tumor cell lines (derived from non-small cell lung cancer, prostate carcinoma, 
melanoma and ovarian carcinoma) expressing high MAGE-A4 mRNA levels (>10,000 MAGE-
A4 transcripts). In addition, ADP-A2M4 cells elicited a strong IFNγ response against a primary 
melanoma tissue material expressing high MAGE-A4 mRNA and protein expression levels. Since 
no adequate models to define the threshold of ADP-A2M4 cell activation are currently available, 
this protocol will select for subjects with high MAGE-A4 expression. As such, Adaptimmune will 
be using a conservative cutoff (≥2+ in ≥ 30% of tumor cells) to ensure sufficient expression of the 
antigen. 
To ensure that the subject’s tumor has the potential to be targeted by the ADP-A2M4 cells, the 
tumor specimen will be screened at a central reference laboratory for the expression of MAGE-A4 
by IHC using a Clinical Laboratory Improvement Amendments (CLIA)-validated Clinical Trial 
Assay.  
Optional remote consent to MAGE-A4 testing is permitted for any clinical site that has the 
necessary written consent processes in place and has obtained the relevant IRB/IEC and local 

 
 
 
             
 
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approvals.  This allows subjects with archival specimens available to consent for MAGE-A4 
testing without requiring travel to a clinical study site.    
4.2.2. 
T Cell Manufacturing 
ADP-A2M4 is autologous CD4 and CD8 T cells engineered with an affinity-enhanced TCR to 
target the tumor antigen MAGE-A4.  Autologous T cells are obtained from eligible subjects who 
have MAGE-A4 positive tumors and who have appropriate HLA-A.  The CD4 and CD8 T cells 
are transduced with a SIN lentivirus vector expressing the MAGE-A4 (affinity enhanced clone 
1032) under GMP conditions.  The product of this transduction is polyclonal T cells which are 
designed to target MAGE-A4 in tissue.  The transfer SIN lentiviral vector has been meticulously 
designed to contain the genetic elements required for function and for maximum biosafety [Dull, 
1998].  Many reports provide evidence supporting the relative biosafety of SIN lentiviral vectors 
in terms of genotoxicity, resulting primarily from the lack of enhancer activity in the lentivirus 
long terminal repeat (LTR) in comparison to the γ retroviral vectors [Montini, 2006; Maruggi, 
2009; Modlich, 2009; Montini, 2009]. 
Cell product is typically ready to be returned to the site approximately one month after the start 
of manufacturing. Receipt of T cell product at the clinical site is required before the start of 
lymphodepleting chemotherapy.    
4.2.3. 
Lymphodepletion 
Lymphodepletion prior to adoptive cell therapy may enhance immune reconstitution by the 
transferred cells and increase tumor specific responses.  Immune reconstitution is enhanced 
through homeostatic mechanisms that facilitate expansion of T lymphocytes [Baccala, 2005] and 
facilitate trafficking of the engineered T cells [Pinthus, 2004].  Lymphodepletion also enhances 
the activity of the adoptively transferred cells via the removal of inhibitory factors such as 
regulatory T cells [Wolf, 2003] and can activate antigen presenting cells through the induction of 
inflammatory cytokines and induction of tumor apoptosis with resulting cross presentation of 
tumor antigens to T cells. 
Evidence suggests that preparation for successful engraftment and expansion of gene modified 
adoptive cellular therapy depends not just on the depth of cytoreduction but additionally on the 
specific action of some cytotoxic drugs.  Recent studies in lymphoma, chronic leukemia and 
acute leukemia using adoptive cellular therapy including a CAR showed increased T cell 
expansion, persistence and disease-free survival when fludarabine was added in a previously 
cyclophosphamide-only preparative regimen [Turtle, 2015]. Cyclophosphamide was 
administered at 30 – 60 mg/kg x 1 day and fludarabine at 25 mg/m2/day x 3 – 5 days.  Effective 
lymphodepletion has also been demonstrated in other CAR-T cell studies using reduced 
cyclophosphamide dosing, together with fludarabine [Batlevi, 2016].   
Data from an open label non-randomized multi-cohort pilot study of genetically engineered 
NY-ESO-1 SPEAR™ T cells in HLA-A2+ patients with synovial sarcoma (NCT01343043) 
suggests that fludarabine is an important component of T-cell lymphodepleting regimens and 
fludarabine 30 mg/m2 given daily for 4 days in combination with cyclophosphamide may be 

 
 
 
             
 
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associated with more objective responses [D’Angelo, 2018]  (see Section 2.2.3). The CD19 
CAR-T product tisagenlecleucel, also utilizes fludarabine 30 mg/m2 for 4 days in combination 
with cyclophosphamide. 
The lymphodepleting regimen in this study consists of intravenous fludarabine 30 mg/m2/day for 
4 days (Day -7 to Day -4) and cyclophosphamide 600 mg/ m2/day for 3 days (Days -7 to -5).  
4.2.4. 
Long Term Follow-up  
Subjects exposed to gene therapies may be at risk for delayed adverse events when there is 
persistent biological activity. Contributing factors for delayed adverse events include persistence 
of viral vector, integration of genetic material into host genome, prolonged expression of 
transgene and alterations in the expression of host genes. The long term follow up (LTFU) 
evaluation in  the study is designed to adhere to the FDA and EMA guidance for long term 
follow up of subjects in gene therapy clinical trials [FDA, 2006a; FDA, 2006b; FDA, 2010; 
EMA, 2009], and involves monitoring subjects who have been exposed to lentivirus-mediated 
gene transfer in this clinical study for 15 years.  Further information on safety monitoring for 
theoretical risks associated with the use of lentiviral vectors and potential for insertional 
oncogenesis, as well as safety monitoring are available in Section 10.7, Appendix 7.    
4.3. 
Justification for Dose 
The cell dose of ADP-A2M4 is within the range of 1 × 109 to 10 × 109 transduced cells, 
administered by a single intravenous infusion.  If the transduced cell dose is less than the 
minimum dose, manufacturing of additional transduced T cells from excess banked 
leukapheresis product or an additional leukapheresis collection may be undertaken to achieve a 
total dose in the target range.  Doses below the minimum transduced cell dose of 1 x 109 will not 
be administered. 
The safety and tolerability of ADP-A2M4 is being assessed in a Phase 1 trial of multiple tumor 
types including synovial sarcoma and MRCLS (NCT03132922). Doses up to 9.96 x 109 have 
been well tolerated in this Phase 1 dose escalation study and was associated with a high ORR in 
16 advanced (inoperable)/metastatic synovial sarcoma subjects [CTOS, 2020].  
Since the pharmacological effect of actual body weight on the biodistribution and 
pharmacometric profile of ADP-A2M4 SPEAR T-cells has not been established to date in adult 
patients from Cohort 1, children aged 10-17 years old will only be eligible for dosing in Cohort 2 
if their body weight is ≥ 40KG. It is anticipated that the dosing of children < 40KG in the future 
will only be possibly based on the pediatric dose, exposure and response relationships derived 
from Cohort 2 either through extrapolation, or utilizing modelling/simulation pharmacometric 
techniques if very few or no children with advanced/metastatic synovial sarcoma have been 
dosed in Cohort 2 by the end of study ADP-0044-002. 
4.4. 
End of Study Definition 
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason. 

 
 
 
             
 
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5. 
STUDY POPULATION 
5.1. 
HLA and Antigen Pre-screening  
To be eligible for Pre-screening (Visit 1) subjects must be aged ≥10 and <75 years with a 
diagnosis of advanced (metastatic or inoperable) synovial sarcoma (Cohort1 or Cohort 2) or 
myxoid liposarcoma / myxoid round cell liposarcoma (Cohort 1) confirmed by either histology 
or cytogenetics. Confirmation of diagnosis by cytogenetics is required prior to leukapheresis.  
Subjects identified by the Investigator as possible candidates for the study must complete 
preliminary screening to determine HLA and tumor antigen status. Only subjects with an 
appropriate HLA-A genotype and whose tumor expresses the MAGE-A4 antigen above the cut-
off according to the applied IHC are eligible to undergo Screening (Visit 2) for this study.  
5.2. 
Inclusion Criteria 
A subject must meet all of the following criteria prior to leukapheresis (i.e. at Screening (Visit 
2)) AND prior to lymphodepleting chemotherapy (i.e. at Baseline) to be eligible to participate in 
this study. 
1. Subject (or legally authorized representative) voluntarily agrees to participate by giving 
written informed consent (and Assent as applicable) in accordance with ICH GCP 
guidelines and applicable local regulations.  
2. Subject (or legally authorized representative) agrees to abide by all protocol required 
procedures including study related assessments, and management by the treating 
institution for the duration of the study including long term follow-up. 
3. Age ≥16 and <75 years at the time the Pre-screening informed consent/assent is signed 
(Cohort 1).  Age ≥10 and <75 years at the time the Pre-screening Informed 
Consent/Assent is signed and actual body weight ≥ 40 KG (Cohort 2) 
4. Diagnosis of advanced (metastatic or inoperable) synovial sarcoma or myxoid 
liposarcoma / myxoid round cell liposarcoma (Cohort 1) confirmed cytogenetics. 
Inoperable refers to a tumor lesion in which clear surgical excision margins cannot be 
obtained without leading to significant functional compromise. 
a. For Synovial Sarcoma (Cohort 1 and Cohort 2): confirmation by the presence of a 
translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on 
chromosome 18 (may be presented in the pathology report as t (X; 18)). 
b. For MRCLS (Cohort 1): confirmation by the presence of the reciprocal chromosomal 
translocation t(12;16)(q13;p11) or t(12; 22) (q13;q12). 
5. Must have previously received either an anthracycline or ifosfamide containing regimen. 
1st-line metastatic treatment with ADP-A2M4 is permissible if ifosfamide +/- 
doxorubicin has been administered in either the pre-operative (neoadjuvant) or post-
operative (adjuvant) primary tumor setting and has progressed within 6 months of 

 
 
 
             
 
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receiving treatment.  (Subjects who are intolerant of both anthracycline and ifosfamide 
must have previously received at least one other type of systemic therapy).  
6. Measurable disease according to RECIST v1.1. 
7. Positive for HLA-A*02:01, HLA-A*02:03 or HLA-A*02:06 allele via Adaptimmune 
designated central laboratory testing. HLA-A*02 alleles having the same protein 
sequence as these alleles in the peptide binding domains (P group) will also be included. 
Other HLA-A*02 alleles may be eligible after adjudication with the sponsor.  
8. Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 expression of 
≥2+ staining in ≥30% of the cells by immunohistochemistry.  All samples must have 
been pathologically reviewed by an Adaptimmune designated central laboratory 
confirming expression.   
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 or for 
subjects aged 10 to < 16 years old, Lansky Score ≥ 80 %. 
10. Left ventricular ejection fraction (LVEF) ≥50%.  
11. Fit for leukapheresis and adequate venous access can be established for the cell 
collection. 
12. Female subjects of childbearing potential (FCBP) must have a negative urine or serum 
pregnancy test AND must agree to use an effective method of contraception starting at 
the first dose of chemotherapy and continuing for at least 12 months, or 4 months after 
the gene modified cells are no longer detected in the blood, whichever is longer.  
− OR 
Male subjects must be surgically sterile or agree to use a double barrier contraception 
method or abstain from heterosexual activity with a FCBP starting at the first dose of 
chemotherapy and continuing for 4 months thereafter (or longer if indicated in the 
country specific monograph/label for cyclophosphamide). 
13. Must have adequate organ function as indicated by the laboratory values in the table 
below: 
System 
Laboratory Value 
Hematological 
    Absolute Neutrophil count (ANC) 
≥ 1.5 x109/L (without G-CSF 
support)1 within 7 days prior to 
lymphodepletion and leukapheresis 
    Platelets 
≥ 100 x109/L (without transfusion 
support within 7 days prior to 
leukapheresis and lymphodepletion) 

 
 
 
             
 
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    Hemoglobin 
≥ 80 g/L (without transfusion support 
within 7 days prior to leukapheresis 
and lymphodepletion) 
Coagulation 
    Prothrombin Time or INR 
≤ 1.5x upper limit of normal (ULN) 
unless receiving therapeutic 
anticoagulation. 
Subjects receiving warfarin anti-
coagulation at baseline should be 
converted to either a low molecular 
weight heparin injection or a novel 
oral anticoagulant (NOAC). 
Reintroduction of warfarin after 
lymphodepleting 
chemotherapy/ADP-A2M4 dosing to 
attain the therapeutic INR range 
which was initially clinically 
indicated should only start when the 
platelet count is < Grade 2 CTCAE. 
    Partial Thromboplastin Time (PTT) 
≤ 1.5x upper limit of normal (ULN) 
unless receiving therapeutic 
anticoagulation. 
Renal 
    Glomerular filtration rate  
(calculated CrCl using only the Cockcroft-
Gault equation, or measured using either a 24-
hour urine creatinine collection or a 
radionuclide EDTA test) 2 
≥ 60 mL/min 
Hepatic 
    Serum total bilirubin 
≤ 1.5 x ULN (unless subject has 
documented Gilbert’s Syndrome with 
direct bilirubin <35% of total 
bilirubin) 

 
 
 
             
 
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Alanine aminotransferase (ALT)/Serum          
Glutamic Pyruvic Transaminase (SGPT) 
≤ 2.5x ULN  
1. 
≥1 x109/L (without G-CSF support) in 10 – 15 year olds 
2. 
24-hour urine creatine clearance or radionuclide EDTA tests should be used to measure 
the GFR in all subjects: ≥ 65 years old; clinically obese (≥ 30KG/m2) or underweight 
(≤18.5KG/m2); borderline low calculated CrCl (Cockcroft-Gault) at approximately 
60mls/min. (see Section 8.4.11 for further details). 
Renal function will be reassessed at baseline using the same methodology. 
5.3. 
Exclusion Criteria 
A subject meeting any of the following criteria is not eligible for participation in the study: 
14. Positive for HLA-A*02:05 in either allele via Adaptimmune designated central 
laboratory testing. HLA-A*02 alleles having the same protein sequence as HLA-A*02:05 
in the peptide binding domains (P groups) will also be excluded.  Other alleles may be 
exclusionary after adjudication with the sponsor. 
15. Received or plans to receive the following therapy/treatment prior to leukapheresis or 
lymphodepleting chemotherapy:  
Treatment/Therapy 
Required Wash-out Prior to 
Leukapheresis 
Required Wash-out Prior to 
Lymphodepletion  
Cytotoxic chemotherapy 
3 weeks 
3 weeks 
Tyrosine kinase inhibitor (TKI)  
(e.g. pazopanib) 
1 week  
1 week  
Immune therapy (including 
monoclonal antibody 
therapy, checkpoint 
inhibitors,) 
4 weeks 
4 weeks 
Anti-cancer Vaccine 
8 weeks in the absence of 
tumor response. The subject 
should be excluded if their 
disease is responding to an 
experimental vaccine given 
within 6 months 
8 week in the absence of 
tumor response. 
The subject should be 
excluded if their disease is 
responding to an 
experimental vaccine given 
within 6 months 

 
 
 
             
 
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Treatment/Therapy 
Required Wash-out Prior to 
Leukapheresis 
Required Wash-out Prior to 
Lymphodepletion  
Gene therapy using an 
integrating vector 
Subjects who have received a 
gene therapy using any DNA-
integrating vector other than 
a lentivirus (retrovirus, AAV, 
etc.) are excluded from this 
study. Subjects who have 
received a gene therapy 
using a lentiviral vector may 
be eligible if they have 
persistence results below the 
lower limit of quantification 
(LLOQ) for at least 2 samples 
taken at least 1 month apart. 
At least 1 of these tests must 
be performed by 
Adaptimmune as part of Pre-
screening or Screening. 
Not permitted after 
leukapheresis and prior to 
lymphodepletion. 
Corticosteroids or any other 
immunosuppressive therapy. 
NOTE:  Use of topical steroids 
is not an exclusion. See 
Section 6.5.1 for exceptions.  
2 weeks  
2 weeks  
Investigational treatment or 
interventional clinical trial 
4 weeks  
4 weeks 
Allogeneic hematopoietic 
stem cell transplant 
Not permitted within any 
amount of time 
Not permitted within any 
amount of time 
Radiotherapy to the target 
lesions 
N/A 
3 months.  A lesion with 
unequivocal progression may 
be considered a target lesion 
regardless of time from last 
radiotherapy dose.  (Note: 
there is no washout period 
for palliative radiation to 
non-target organs). 

 
 
 
             
 
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Treatment/Therapy 
Required Wash-out Prior to 
Leukapheresis 
Required Wash-out Prior to 
Lymphodepletion  
Major surgery 
N/A 
4 weeks. A subject must be 
fully recovered from any 
surgical related toxicities.  
NOTE: Duration of any other anti-cancer therapies must be discussed with the Sponsor Study 
Physician 
16. Toxicity from previous anti-cancer therapy must have recovered to ≤ Grade 1 prior to 
enrollment (except for non-clinically significant toxicities, e.g., alopecia, vitiligo).  
Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral 
neuropathy) can be enrolled.  
17. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to fludarabine, cyclophosphamide or other agents used in the study. 
18. History of autoimmune or immune mediated disease. Subjects with hypothyroidism, 
diabetes, adrenal insufficiency or pituitary insufficiency that are stable on replacement 
therapy are eligible. Subjects with disorders such as asthma, psoriasis or atopic dermatitis 
that are well controlled without requiring systemic immunosuppression are also eligible.   
19. Symptomatic CNS metastases including leptomeningeal disease.  Subjects with a prior 
history of symptomatic CNS metastasis including leptomeningeal disease must have 
received treatment (i.e., stereotactic radiosurgery (SRS), whole brain radiation (WBRT) 
and/or surgery) and be neurologically stable for at least 1 month, not requiring anti-
seizure medications and off of steroids for at least 14 days prior to leukapheresis and 
lymphodepletion. Anti-seizure prophylaxis is permitted.  Subjects who have 
asymptomatic CNS metastases without associated edema, shift, requirement for steroids 
or anti-seizure medications for the treatment of seizures are eligible.   
20. Any other prior malignancy that is not in complete remission.  Resectable squamous or 
basal cell carcinoma of the skin is acceptable. Prior malignancies that have been 
surgically resected and show no evidence of disease are acceptable.   
21. Uncontrolled intercurrent illness including, but not limited to: 
• Ongoing or active infection;  
• Clinically significant cardiac disease defined by congestive heart failure New 
York Heart Association (NYHA) Class 3 or Class 4; 
• Uncontrolled clinically significant arrhythmia; 
• Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months; 

 
 
 
             
 
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• Interstitial lung disease (subjects with existing pneumonitis as a result of radiation 
are not excluded, however, subjects must not be oxygen dependent); 
• Congenital or family history of long QT syndrome; 
• Current uncontrolled hypertension despite optimal medical therapy; 
• History of stroke or central nervous system bleeding; transient ischemic attack 
(TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months. 
• Incipient compression/occlusion of a vital structure (e.g. bronchus; superior vena 
cava; renal outflow tract) which cannot undergo prophylactic stenting; 
• COVID-19 infection or a positive COVID-19 RT-PCR test within 28 days of 
leukapheresis or lymphodepleting chemotherapy. If a subject has a positive 
COVID-19 test, then 2 subsequent negative tests are required, taken at least 7 
days apart. 
22. Active infection with HIV, HBV, HCV or HTLV as defined below: 
• Positive serology for HIV; 
• Active hepatitis B infection as demonstrated by test for hepatitis B surface 
antigen. Subjects who are hepatitis B surface antigen negative but are hepatitis B 
core antibody positive must have undetectable hepatitis B DNA and receive 
prophylaxis against viral reactivation.  Prophylaxis should be initiated prior to 
lymphodepleting therapy and continued for 6 months; 
• Active hepatitis C infection as demonstrated by hepatitis C RNA test.  Subjects 
who are HCV antibody positive will be screened for HCV RNA by any RT PCR 
or bDNA assay. If HCV antibody is positive, eligibility will be determined based 
on a negative screening RNA value; 
• Positive serology for HTLV 1 or 2; 
• Re-screening for infectious disease markers is not required at baseline (prior to 
lymphodepletion) unless > 6 months has elapsed. 
23. Pregnant or breastfeeding. 
24. In the opinion of the Investigator, the subject is unlikely to fully comply with protocol 
requirements. 
5.4. 
Screen Failures 
Data on subjects who fail pre-screening or screening, including demographics and disease 
history, will be collected in the electronic case report form (eCRF) to support Companion 
Diagnostic development and validation. 

 
 
 
             
 
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5.5. 
Number of Subjects and Study Duration 
Forty-five (45) subjects (90 total subjects) are planned to be dosed separately in both Cohort 1 
(synovial sarcoma and MRCLS) and Cohort 2 (synovial sarcoma only). In combination, data 
from Cohort 1 and Cohort 2 will provide a better, more comprehensive, characterization of the 
benefit risk profile in soft-tissue sarcoma patients (especially in synovial sarcoma) than from 
Cohort 1 alone.  
Enrollment into Cohort 1 is expected to continue for approximately 12 months and is close to 
completion at the time of this amendment. Cohort 2 will begin when dosing in Cohort 1 is 
completed. Cohort 2 will dose 45 advanced (inoperable)/metastatic synovial sarcoma subjects 
only and enrollment is expected to continue for approximately 12 months. The Primary Clinical 
Analysis will be for Cohort 1 only (i.e. synovial sarcoma plus MRCLS). Clinical cut-off for the 
primary analysis will occur once the last subject dosed in Cohort 1 has up to 6 months follow-up 
post T cell infusion or has ended the interventional phase of the study.  At this time, all safety 
and secondary efficacy endpoints from Cohort 1 only will also be summarized to provide 
supportive evidence to the primary assessment.   
The study will be considered complete once all subjects complete 15 years of follow-up or 
discontinue the study for any reason. 
5.6. 
Sites 
The study will be conducted in approximately 24 sites in North America and Europe. The 
number of centers is necessary to ensure recruitment in this rare patient population.  Additional 
sites, especially specialist pediatric oncology centers for the conduct of Cohort 2, may be added 
at the discretion of the Sponsor. 
 
 

 
 
 
             
 
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6. 
STUDY INTERVENTION 
6.1. 
Leukapheresis 
Subjects who complete screening procedures defined in Section 5.1 and who meet all eligibility 
criteria defined in Section 5.2 and Section 5.3 will be eligible to undergo leukapheresis to obtain 
starting material for the manufacture of autologous ADP-A2M4. 
Refer to the Apheresis and T Cell Product Manual for scheduling of apheresis. 
A non-mobilized peripheral blood mononuclear cell (PBMC) collection should be performed by 
an apheresis unit at the enrolling institution according to the institution’s or hospital’s policies 
and procedures.  Leukapheresis may be performed at a qualified third-party institution (as may 
be mutually agreed and approved in advance by both Sponsor and the clinical site), as long as the 
policies and procedures in place meet or exceed the primary institution’s policies and procedures.  
Bilateral peripheral venous access should be used whenever possible but a temporary central 
venous catheter (CVC) may be placed for collection if peripheral venous access is inadequate.  
Standard clinical procedures for apheresis should be followed.  
A large volume leukapheresis should be performed.  For subjects who are >50 kg, 10 to 15 liters 
should be processed per procedure; in subjects ≤ 50kg, 2-3 blood-volumes should be processed 
per procedure with a goal of the procedure being collection of 1.0 x 108 PBMC/kg, and a 
minimum of 1.5x107 PBMC/kg. In cases where the minimum number of PBMC is not collected 
or the T cells cannot be administered (e.g. release criteria not met), a second apheresis may be 
performed. Citrate anticoagulant should be used.  Prophylactic intravenous calcium chloride and 
magnesium sulfate infusions should be administered at the discretion of the apheresis physician. 
The collected leukapheresis product should be labelled and transported for manufacture as 
detailed in the Apheresis and T Cell Product Manual. 
Any remaining subject apheresis material that is not required for further manufacture, may be 
used by the sponsor for research to modify or improve the manufacturing process and to enhance 
the clinical response. 
Children aged 10-17 years old will undergo leukapheresis under the care of a pediatric apheresis 
unit, or as per local site policy for older adolescents. Blood volume will be processed as per local 
site age-stratified policies. 
6.2. 
Lymphodepleting Chemotherapy 
Prior to the administration of lymphodepleting chemotherapy all eligibility criteria will be 
reconfirmed and a Baseline tumor biopsy obtained.  
Once the manufactured ADP-A2M4 cell product has been received at the clinical site and the 
integrity of the bag(s) has been verified by the site, eligible subjects will proceed to have 
lymphodepleting chemotherapy with fludarabine and cyclophosphamide as described in Table 3. 
The lymphodepleting chemotherapy may be given as an outpatient treatment or subjects may be 
hospitalized at the discretion of the Investigator.   

 
 
 
             
 
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On admission for lymphodepleting chemotherapy, commence anti-microbial prophylaxis (see 
Section 10.5.3.7) in line with institutional guidelines. 
Appropriate intravenous (IV) hydration should be administered and Mesna should be given to 
prevent urotoxicity while cyclophosphamide is administered, as described below. Other 
premedication (e.g. anti-emetics) may also be provided in accordance with institutional 
standards. Steroids may be used as anti-emetics for cyclophosphamide but must be discontinued 
no later than Day -3. Based on real-world use of Granulocyte-colony stimulating factor (G-CSF) 
prophylaxis in Cohort 1 at the study sites, especially those with extensive CD19 CAR-T cell 
therapy expertise, G-CSF prophylaxis in Cohort 2 synovial sarcoma subjects can be given at the 
clinical discretion of the Investigator (as per local institutional policy) starting on Day -3 until 
resolution of neutropenia in accordance with American Society of Clinical Oncology (ASCO) 
guidelines or institutional practice (see Section 6.2.3). 
Children aged 10-17 years old will undergo lymphodepleting chemotherapy under the care of a 
pediatric unit, or as per local site policy for older adolescents.  
 
Table 3: 
Fludarabine and Cyclophosphamide Treatment Schema 
Lymphodepleting Chemotherapy 
Day 
Drug 
Dose 
Route 
Administration 
-7 
Fludarabine1 
30 mg/m2 
IV 
in 50-100mL 0.9% NaCl over 30 mins2 
Cyclophosphamide 
600 mg/m2 
IV 
in 200-500mL 0.9% NaCl over 1 hour3 
-6 
Fludarabine1 
30 mg/m2 
IV 
in 50-100mL 0.9% NaCl over 30 mins2  
Cyclophosphamide 
600 mg/m2 
IV 
in 200-500mL 0.9% NaCl over 1 hour3 
-5 
Fludarabine1 
30 mg/m2 
IV 
in 50-100mL 0.9% NaCl over 30 mins2 
Cyclophosphamide 
600 mg/m2 
IV 
in 200-500mL 0.9% NaCl over 1 hour2 
-4 
Fludarabine1 
30 mg/m2 
IV 
in 50-100mL 0.9% NaCl over 30 mins2 
-3 
Start G-CSF4 
-2 
 
-1 
 
1 
ADP-A2M4 infusion3  
 
1 Fludarabine dose will be adjusted for renal impairment as described in Section 6.2.1 
2  Concentration of 1mg/ml or less 
3  Administration of ADP-A2M4 infusion is described in Section  6.3. 
4 Administration of G-CSF section 6.2.3 

 
 
 
             
 
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6.2.1. 
Fludarabine dose adjustment for renal impairment 
Dose of fludarabine will be adjusted for subjects with renal dysfunction as follows: 
Glomerular Filtration Rate (GFR) 
Fludarabine dose 
≥80 mL/min 
30 mg/m2 
60 – 79 mL/min 
20 mg/m2 
Renal function should be estimated using the Cockcroft-Gault Creatinine Clearance (CrCl) 
equation (no other renal function equations are permitted).   
A more sensitive evaluation of renal function using either a 24-hour urine creatinine collection or 
a EDTA radionuclide test should be performed in subjects at Screening and/or Baseline who are: 
• Obese (i.e. BMI ≥ 30 KG/m2) 
• Underweight (i.e. BMI < 18.5 KG/m2) 
• Low borderline CockCroft-Gault calculated CrCl of approximately 60 ml/min. 
6.2.2. 
Mesna 
Mesna should be administered according to institutional practice or as recommended below: 
• 120 mg/m2 (20% cyclophosphamide dose) as an IV bolus pre infusion, 4 and 8 hours 
post infusion on each day of cyclophosphamide administration. 
6.2.3. 
G-CSF 
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
in adults is also common. It is recommended in adults that G-CSF is given daily from Day -3 
until resolution of neutropenia in accordance with ASCO guidelines or institutional standard 
practice.  Long-acting (pegylated) G-CSF may be given instead of short acting G-CSF according 
to institutional standard practice.  If pegylated G-CSF is administered, give one dose on Day -3. 
Administration of G-CSF in children in Cohort 2 will be as per local site policy for cell therapies. 
6.3. 
Investigational Product  
6.3.1. 
Premedication 
Subjects will be premedicated with antihistamine and acetaminophen/paracetamol 30-60 minutes 
prior to the T-cell infusion according to institutional practice.  Steroids must not be administered 
as premedication for T-cell infusion because they are lymphotoxic and inhibitory to the T-cell 
product. 

 
 
 
             
 
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6.3.2. 
T Cell Infusion 
On Day 1, the subject will receive thawed ADP-A2M4 by intravenous infusion. The T cell 
infusion will be given as an inpatient procedure and subjects will remain hospitalized for 
observation for at least 10 days post T cell infusion.  
Prior to infusion, two clinical personnel in the presence of the subject, will independently verify 
and confirm that the information on the infusion bag is correctly matched to the subject, as per 
the Apheresis and T-cell Product Manual. 
The T-cell product must not be thawed until immediately prior to infusion. The T-cell product 
should be thawed at a set temperature of 37oC using a water bath or equivalent device.  Routinely 
the cells should be thawed for approximately 3-5 minutes.  Smaller volumes may take less time 
to thaw.  The infusion bags should be observed during the thaw process to ensure no frozen 
material or ice remains. 
The infusion bag(s) may be placed into a secondary containment bag per institutional standard 
procedures.  The secondary containment bag should not be of a design where it will have to be 
cut open after use, so as to avoid sharp objects near the infusion bag.  A standard specimen bag 
with a re-sealable zipper closure is recommended. 
The cells can be thawed either at the subject’s bedside or in a centralized facility, according to 
institutional standard procedures. If the cells are transported from a central storage location to 
bedside for thawing, it is recommended to place the bag(s) on dry ice or in a cooler with frozen 
gel packs for transport.  If the cells are thawed at a central facility, the thawed cells should be 
transferred to bedside under 2-8oC conditions and must be transported by appropriately trained 
staff, to preserve the chain of custody.  
 The infusion should begin within 10 minutes of completing thaw (per bag) and is recommended 
to complete infusion of each bag within 45 minutes of thawing each bag to minimize exposure of 
the cell product to cryoprotectant. If the cells are provided in multiple bags and thawed at the 
bedside, the second bag should not be thawed until half the first has been infused without 
reaction, if possible based on fill volume. Bags thawed in a central location may be thawed 
simultaneously with consideration given to transport time and the guidance to begin infusion 
within 10 minutes post-thaw.  
If after thawing the infusion bag is damaged or leaking, the Investigator and Sponsor should be 
notified and the cells should not be infused. 
The T-cell product must not be washed or otherwise processed. It is recommended that the T-cell 
product is administered using a dual spike infusion set by gravity over 15-45 minutes in the 
absence of infusion reaction.  Cells should ideally be infused without a filter, however if a filter 
is required by Institutional practice the pore size must not be smaller than 170 µm. Infusion 
pumps must not be used. For administration of the cells, 100 - 250 ml of 0.9% sodium chloride 
should be connected to the second lumen of the infusion set, used to prime the line, and then the 
lumen closed. On completion of the infusion of a bag of T-cell product, the main line should be 
closed and approximately 50ml saline transferred into the cell bag, and then infused to minimize 
the loss of cells. This process should be repeated for each cell bag if multiple bags are provided.  

 
 
 
             
 
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On completion of the cell infusion the set should be flushed using additional saline from the 
attached bag. If Institutional practice requires a single spike infusion set (e.g. macro drip IV 
tubing) standard institutional guidelines for the infusion of autologous cell infusion should be 
followed. The line must be flushed with 0.9% sodium chloride once the infusion is complete. In 
the event of adverse reaction to the cell infusion the infusion rate should be reduced and the 
reaction managed according to institutional standard procedures.  Steroid treatment should be 
avoided unless medically required.   
In the event a subject develops a febrile episode following the infusion, appropriate cultures and 
medical management should be initiated, with attention to the initiation of empirical antibiotic 
treatment in the case of febrile neutropenia (see Section 10.5.3). 
The day of T-cell infusion may be delayed in subjects with significant complications of 
chemotherapy if according to the Investigator it is in the best interest of the subject.  Cytopenias 
alone should not be a reason to delay T-cell infusion unless complications are present.  Subjects 
who have undergone leukapheresis but do not receive the T-cell infusion will not be replaced.    
Subjects who undergo leukapheresis and do not receive T cells will be followed for safety events 
for 30 days post leukapheresis or until SAEs have resolved to Grade 1 or baseline, whichever is 
longer. 
The timing of all assessments post-infusion will be calculated with reference to the T-cell 
infusion date.  Vital signs will be recorded prior to the infusion and at 5, 15 and 30 minutes and 
at 1, 1.5, 2 and 4 hours after the infusion has started. 
Discharge from hospital post-T cell infusion will be at the discretion of the Investigator. All 
subjects must be reviewed by the investigator (or a designated study physician) prior to 
discharge.  
6.4. 
Preparation/Handling/Storage/Accountability 
6.4.1. 
Packaging and Labelling 
Selected, qualified manufacturing sites will manufacture, package and label cell product for each 
individual subject in accordance with applicable regulatory requirements. 
Refer to the Apheresis and T cell Product Manual for details of T cell product labelling. 
6.4.2. 
Receipt and Return 
Investigational product must be received by a designated person at the site, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and designated 
site personnel have access.  Investigational product is to be dispensed only in accordance with 
the protocol.  The Investigator is responsible for keeping accurate records of the investigational 
product received from the Sponsor, the amount dispensed and any unused investigational product 
remaining at the conclusion of the study.  Contact the Sponsor or designee regarding any 
questions concerning the investigational product. 

 
 
 
             
 
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Sites should contact the Sponsor or designee for specific instructions for investigational product 
returns or destruction. 
6.4.3. 
Storage and Handling 
Manufactured T-cell product should arrive on-site and immediately be stored at ≤ -130°C in the 
vapor phase of a liquid nitrogen or a mechanical freezer until the date of infusion. Please refer to 
the Apheresis and T cell Product Manual for additional information. 
6.4.4. 
Investigational Product Accountability/Traceability 
The investigational product provided for this study is for use only as directed in the protocol. The 
Investigator/Institution must have an established system for subject and product accountability at 
the site. The system should contain sufficient detail to allow linking of each product delivered to 
the investigator to the subject receiving it and vice versa. The investigator must ensure:   
• Deliveries of Investigational Product are correctly received by a responsible person 
• Such deliveries are recorded 
• Investigational product is handled and stored safely and properly as instructed in the 
Apheresis and T cell Product Manual 
• Investigational product is only administered to study subjects in accordance with the 
protocol 
• Investigational product administration is documented. Records must include the 
identification of the person to whom the investigational product was administered, 
date of infusion, start and stop time of infusion and the amount infused.  This record 
is in addition to any investigational product accountability information recorded on 
the eCRF. 
• Any unused product is accounted for in the sites records before returning to the 
Sponsor (or designee) 
At the end of the study, it must be possible to reconcile investigational product delivered with 
records of usage and return/destruction.  Any discrepancies must be accounted for on the 
appropriate forms.  
Refer to the Apheresis and T cell Product Manual for additional information. 
6.4.5. 
Alert Cards 
All subjects who receive investigational product in the trial will be provided with an alert card, 
which has been previously agreed by the sponsor and approved by the institutional review 
board (IRB)/ independent ethics committee (IEC). Alert cards will contain at a minimum the 
name of the subject, the investigator contact number and information regarding the 
investigational product received. 

 
 
 
             
 
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6.5. 
Concomitant Medications 
6.5.1. 
Prohibited Concomitant Medications 
The following treatments are prohibited post T cell infusion (i.e. prior to disease progression):  
non-protocol chemotherapy, immune therapy, biological therapy (including targeted therapies 
with tyrosine kinase inhibitors or monoclonal antibodies), or investigational anti-cancer therapy. 
Subjects should also not undergo other anticancer locoregional therapies such as non-palliative 
radiation.   
Subjects who undergo any active anticancer therapy, with the exception of surgical resection 
prior to disease progression, will be considered as having met the progressive disease (PD) 
criterion for efficacy and will follow the LTFU schedule. 
It is preferred that subjects do not undergo surgical resection of tumor lesions during the study 
prior to disease progression, as it interferes with the assessment of the efficacy of ADP-A2M4. 
However, a subject whose tumor becomes resectable and who undergoes surgical resection prior 
to disease progression, will continue to be followed for safety and efficacy (progression of 
remaining lesions, new lesions) in the interventional phase of the study until disease progression 
is determined. Upon progression, the subject will follow the LTFU schedule. Subjects who have 
surgery for new lesions consistent with progressive disease or to control progressive disease in 
previously identified lesions will discontinue the interventional phase and follow the LTFU 
schedule. 
See Section 5.3 for details of washout and excluded treatments prior to leukapheresis or 
lymphodepleting therapy. 
The use of systemic steroids may abrogate the effects of the T-cell therapy and therefore use is 
discouraged unless required to manage CRS (see Section 10.5.6  for CRS treatment 
recommendations) or other significant immune-mediated adverse events.  According to local 
standard of care or ASCO guidelines, steroids may be used as antiemetics before 
cyclophosphamide but must be discontinued no later than 3 days prior to infusion of the IP (Day 
-3).  Steroid use is permitted for prophylaxis or treatment of contrast dye allergies.   
Physiological doses of steroids, including stress doses when clinically appropriate, may be 
administered as replacement therapy in subjects with adrenal insufficiency.  Fludrocortisone is 
permitted.  In general, daily prednisone doses of 0.5 mg/kg or lower, or their equivalent for other 
corticosteroid agents are acceptable, as physiologic replacement.  Topical steroids for cutaneous 
application and inhaled steroidal treatments are permitted. 
6.5.2. 
Permitted Concomitant Medications 
Palliative radiation for pain relief to non-measurable lesions or non-target lesions present at 
baseline is permitted during the study.  However, lesion sites requiring radiotherapy after the T-
cell infusion, should be evaluated as to whether this indicates disease progression and record the 
disease progression in the eCRF. 

 
 
 
             
 
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Other treatment the Investigator considers necessary for a subject’s welfare may be administered 
during the interventional phase of the study at the discretion of the Investigator in keeping with 
community standards of medical care and in adherence to the protocol.   
All concomitant medications will be recorded with dose and frequency, including all prescription 
or over-the-counter (OTC) medications and herbal remedies.  The following will be recorded on 
the appropriate eCRF pages: 
• All prescription and nonprescription medication, vitamins, herbal and nutritional 
supplements taken by the subject during the 30 days prior to screening (Visit 2) will 
be recorded at the screening visit. 
• All prior anti-cancer treatments taken by the subject must be recorded regardless of 
time frame taken 
• All concomitant medications taken while subjects are in the interventional phase 
6.5.2.1. 
Vaccinations Including for COVID-19 
Before immunizing a subject at high risk for vaccine-preventable disease including for SARS-
CoV-2 (COVID-19), consult an Infectious Disease specialist or a guidance, such as the CDC 
Clinical Practice Guideline for Vaccination of the Immunocompromised Host. 
The latest COVID-19 vaccination guidelines from NCCN/EBMT/ASTCT should be consulted 
by the Investigator. Any individual subject queries which cannot be addressed by the latest 
expert society guidelines relating to the timing of COVID-19 vaccination prior to either 
apheresis or lymphodepleting chemotherapy, or post ADP-A2M4 cell infusion, should be 
discussed with the Medical Monitor. 
 
 

 
 
 
             
 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Temporary Study Suspension 
Throughout the conduct of the study, safety data will be reviewed on an ongoing basis by a Data 
Safety Monitoring Board (DSMB) see Section 10.2.1. If the following events occur, further 
enrollment to the study will be suspended and the regulatory authorities informed: 
• A subject has a positive RCL: 
− Confirmed positive peripheral blood mononuclear cell (PBMC) replication 
competent lentivirus (RCL) and no other vector lot is available for use in 
transduction for subsequent subjects (refer to Section 10.7.2 and Figure 1 on 
monitoring and management of RCL) 
− Confirmed biological RCL - all ADP-A2M4 cell infusions are halted (see 
Section 10.7.2  and Figure 1) 
Regulatory authorities will be notified of any decisions to halt the study or subject enrollment.  
The study will not enroll further subjects until the regulatory authorities have reviewed the data 
leading to such a decision and agree with a proposal to resume enrollment. 
7.2. 
Ending the Interventional Phase 
Reasons that a subject could end the interventional phase of the study are: 
• Disease progression per RECIST v1.1 
• Clinical progression  
• Died 
• Unable/unwilling to comply with study requirements 
• Withdrawal of consent  
• Investigator decision 
• Adverse Event 
• Lost to follow-up 
• Pregnancy (see Section 10.6.2.1) 
• Termination of enrollment by the Sponsor  
All subjects ending the interventional phase, with the exception of those who withdraw consent, 
die, are unable/unwilling to comply with study requirements, are lost to follow up or did not 
receive any T cells, will switch to the LTFU schedule Table 2, Section 1.3.2 to continue 
observation for delayed adverse events as described in Section 8.5.8.  
 

 
 
 
             
 
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7.3. 
Subject Discontinuation 
A subject will be considered to have completed the study when he/she has died or been followed 
for 15 years from time of T cell infusion. A subject may withdraw from the study at any time for 
any reason without prejudice to their future medical care by the physician or institution. However, 
the Investigator must make every reasonable effort to keep each subject on study for the whole 
duration of the trial. If a subject withdraws, all procedures and assessments listed in the withdrawal 
visit should be performed, unless performed within the previous 30 days. 
Reasons for withdrawal of a subject from the study are: 
• Unable/Unwilling to comply with study requirements  
• Adverse event 
• Withdrawal of consent 
• Investigator decision 
• Lost to follow-up (see Section 7.4) 
• Study termination by Sponsor 
7.4. 
Lost to Follow up 
In cases where the subject is deemed ‘lost to follow-up’, the Investigator or designee must make 
every effort to regain contact with the subject; e.g., 3 documented attempts, one of which must 
be a certified letter to the subject’s last known mailing address or local equivalent methods.  
These contact attempts should be documented in the subject’s medical records.  Should the 
subject continue to be unreachable, only then will he/she be considered to have withdrawn from 
the study with the primary reason as ‘Lost to Follow-up’. 
 
 

 
 
 
             
 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Background Assessments 
8.1.1. 
Demographics 
Demographic data including year of birth, age, sex, race and ethnicity will be collected at Pre-
Screening. 
8.1.2. 
Disease History 
The following information will be recorded in the eCRF: date of initial diagnosis, primary tumor 
type, anatomical site and size of primary tumor, histology last known stage of disease and 
chromosomal translocations.   
8.2. 
HLA MAGE-A4 Tumor Antigen Testing, and Cytogenetics 
There is no window for obtaining HLA, MAGE-A4 antigen and cytogenetic testing prior to leukapheresis.  
8.2.1. 
HLA 
HLA-genotyping at the allelic level (4-digit) will be conducted on a blood sample by an 
accredited central laboratory contracted by the Sponsor using an FDA approved HLA 
Sequencing System for Sequence Based Typing (SBT) of Human Leukocyte Antigen (HLA).  
8.2.2. 
MAGE-A4 Antigen 
Once subjects are identified as having the appropriate HLA allele, an archival tumor sample, or 
fresh biopsy obtained as standard of care, may be submitted for determination of MAGE-A4 
expression, in which case, the biopsy from the most current setting is preferred provided that 
there is sufficient tissue. If an archival specimen is unavailable, the subject must undergo a new 
biopsy.  The subjects’ tumor will be tested for MAGE-A4 antigen expression by IHC using an 
analytically validated and CLIA-certified Clinical Trial Assay.  Testing will be completed at a 
central laboratory contracted by the Sponsor.  
A secondary objective of the study is to collect tumor tissue samples for the development and 
validation of an IVD assay for the screening of tumor MAGE-A4 expression for regulatory 
approval. Tumor tissue will be collected, processed and submitted in accordance with the study 
Sample Collection Manual. The tumor tissue will be tested using the CLIA-validated MAGE-A4 
Clinical Trial Assay for study eligibility determination.  The tumor tissue will then be used for 
the analytical validation (which includes testing for efficiency, sensitivity, specificity, 
exclusivity, accuracy and precision), as well as the clinical validation of an IVD companion 
diagnostic assay.  Since the Clinical Trial Assay used in this study is not the candidate IVD 
companion diagnostic, a bridging study is required in order to demonstrate that the performance 
characteristics of the two tests are very similar.  The bridging study requires that all of the 
original clinical trial samples tested for eligibility using the Clinical Trial Assay are retested with 

 
 
 
             
 
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the candidate IVD, including samples from subjects excluded from the trial because they were 
marker-negative by the Clinical Trial Assay.  
Details regarding the collection and processing of the screening biopsy, sample requirements, 
instructions for sample shipment to the central laboratory for MAGE-A4 IHC analysis, and 
details of subsequent tumor sample storage for companion diagnostic development are located in 
the Sample Collection Manual.  
Details for the development and validation of an IVD assay for the screening of tumor antigen 
expression for regulatory approval is available in a separate protocol. 
8.2.3. 
Cytogenetics for Diagnosis 
For Synovial Sarcoma (Cohort 1 and Cohort 2), a confirmation by the presence of a translocation 
between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be 
presented in the pathology report as t (X; 18)) is required prior to leukapheresis 
 
For MRCLS (Cohort 1 only), a confirmation by the presence of the reciprocal chromosomal 
translocation t(12;16)(q13;p11) or t(12; 22) (q13;q12) is required prior to leukapheresis.  
 
Cytogenetic confirmation of diagnosis can be historic, done as standard of care, or be done any 
time after signing the Treatment ICF and does not need to be within the 28-day screening 
window. 
8.3. 
Efficacy Assessments 
8.3.1. 
CT/MRI  
Imaging scans of the chest, abdomen and pelvis should be performed at Screening, Baseline, 
Week 4, Week 8, Week 12, Week 16, and Week 24, and every 2 months +/- 28 days until 
confirmed disease progression. The Week 4 scan must occur on or after Day 29. Subsequent 
scans are to be completed within the visit window permitted in the Main T&E Table with the 
exception of confirmatory scans which should not be performed earlier than 4 weeks (on or after 
28 days) after the criteria for response was first met. As the primary endpoint of the study uses 
independent review, scheduled study scans from Week 4 through Week 16 should be at least 28 
days apart to ensure compliance with the RECIST v1.1 requirement for confirmation of 
response. 
Imaging scans should be performed at the time a subject withdraws from the study. 
Lesion sites that have previously required radiotherapy should be recorded in the eCRF prior to 
lymphodepletion. 
See Section 8.4.10  regarding brain MRI for safety assessment.  
Acceptable imaging modalities for this study include: 
• Diagnostic-quality CT scan with oral and/or IV iodinated contrast of the chest and 
abdomen/pelvis (CT is the preferred modality for tumor assessments) 

 
 
 
             
 
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• MRI of the abdomen/pelvis acquired before and after gadolinium contrast agent 
administration and a non-contrast enhanced CT of the chest, if contrast enhanced CT 
is contraindicated for a subject 
• MRI of the extremities if clinically indicated. 
• Digital photographs of skin lesions including a ruler for estimating the size of the 
lesion. 
The same imaging modality and image-acquisition protocol (including the use of IV contrast) 
should be used consistently across all time points for individual subjects to allow uniform 
comparison of lesions.  
To allow time for the immune response to become apparent and for potential transient 
inflammatory reaction of the disease to the treatment (‘tumor inflammation’), disease 
progression will not be determined before 4 weeks post infusion of ADP-A2M4, unless there is 
unequivocal clinical evidence of deterioration.  Therefore, imaging scans should not be 
performed earlier than 4 weeks post infusion (on or after 28 days).  Responses should be 
confirmed by repeat imaging scan performed not earlier than 4 weeks (on or after 28 days) after 
the criteria for response was first met. The minimum duration for BoR = SD is 4 weeks (or 28 
days) post ADP-A2M4 infusion. 
Investigators (in collaboration with a radiologist) will assess tumor response according to 
RECIST v1.1 for clinical decision making. Tumor measurements at site should be performed by 
the same Investigator or radiologist (to the extent that this is feasible).  
For the study primary endpoint, a central vendor will be responsible for independent assessment 
of tumor response according to RECIST v1.1.  Review and interpretation of image data will be 
conducted by an appropriately qualified, trained and experienced reviewer. A written Imaging 
Charter will be provided to sites to describe the imaging acquisition protocol and standardized 
procedure for the transfer of image data to the central vendor.  The Imaging Charter will also 
describe the procedures for CT/MRI data handling after the images have been received by the 
central vendor from the sites.  
Investigator assessment of response will guide patient care throughout the study.  
8.3.2. 
Survival  
If a subject dies during the study date of death will be recorded in the eCRF. If a subject is 
unable to attend the site for visit e.g. due to deteriorating condition or a change of 
location/country, the subject may be followed remotely to obtain survival information. If a 
subject decides to withdraw from any further study assessments/procedures, the Investigator 
should ask if the subject is willing for survival data only to be collected, this discussion should 
be documented in the source notes. 
If the subject cannot be contacted by the site, information available in public records e.g. 
obituaries may be used by the site to determine date of death if appropriate prior to withdrawing 
the subject from the study due to lost to follow up. 

 
 
 
             
 
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8.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the Main T&E table (Table 1) and 
the LTFU T&E Table (Table 2). 
Additional tests may be done at any time if clinically indicated. 
The Clinical Laboratory Test in Table 5  describe the assessments and parameters to be collected 
and recorded. 
Screening visit (Visit 2) assessments should be completed within 28 days of leukapheresis unless 
otherwise specified.  Information regarding ECHO/MUGA scans, ECG and infectious disease 
assays performed as standard of care assessments within four weeks prior to Screening (prior to 
study consent) will be acceptable.  
Baseline assessments must be conducted and results obtained within 2 weeks (14 days) prior to T 
cell infusion. 
8.4.1. 
Medical History 
Relevant medical history will be recorded at Screening (Visit 2) in the subject’s eCRF. 
8.4.2. 
Physical Examination 
Subjects will undergo a physical examination at Screening and Baseline. The frequency of 
physical examination at subsequent visits is specified in Table 1  and Table 2. 
8.4.3. 
Prior Anti-cancer Therapies 
All anti-cancer therapies including, but not limited to, chemotherapy, antibodies, anti-cancer 
vaccines, cell therapies, radiation therapy, and surgical resections are to be recorded.  On-study 
cancer surgeries and bridging therapies are to be recorded. 
8.4.4. 
Prior and Concomitant Medications 
Current medications and those for the previous 30 days are to be recorded on the concomitant 
medication page of the CRF at Screening (Visit 2). 
For LTFU assessments, this section is limited to new chemotherapies or other anti-cancer 
therapies (including mutagenic agents and other investigational agents). 
8.4.5. 
ECOG 
Performance status will be measured using the ECOG performance scale in subjects who are ≥16 
years old. See Section 10.9, Appendix 9 for guidance. It is recommended, where possible, that a 
subject’s ECOG be assessed by the same person throughout the study. The frequency of the 
ECOG assessment is specified in Table 1. 

 
 
 
             
 
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8.4.6. 
Lansky 
Performance status will be measured using the Lansky performance scale in subjects <16 years 
old. See Section 10.9, Appendix 10 for guidance. It is recommended, where possible, that a 
subject’s Lansky be assessed by the same person throughout the study. The frequency of the 
Lansky assessment is specified in Table 1. 
8.4.7. 
Vital Signs 
Measurement of vital signs (temperature, pulse, respirations and blood pressure) will be made at 
the frequency specified in Table 1.  
On the day of T cell infusion (Day 1) vital signs should be measured pre-infusion, and at 5, 15 
and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started. 
8.4.8. 
Weight and Height 
Height will be assessed only once at Baseline. Weight will be measured according to the 
frequency specified in Table 1. 
8.4.9. 
Cardiac Assessments 
Cardiac assessments will be performed locally at the site.  
8.4.9.1. 
ECG 
A single ECG is required. Heart rate, rhythm, PR, RR (if measured/recorded), QRS and QTc 
intervals will be recorded. QTcB or QTcF is acceptable as per institutional standards but must be 
consistent from visit to visit. 
For Screening (Visit 2) ECGs performed as standard of care within 28 days prior the visit are 
acceptable.  The ECG on Day 1 will taken before T cell infusion starts. 
8.4.9.2. 
Echo/MUGA 
An ECHO or MUGA scan will be performed at screening to determine left ventricular ejection 
fraction (LVEF) for eligibility. ECHO/MUGA scans performed as standard of care within four 
weeks prior to Screening (Visit 2) are acceptable.  Additional scans will only be performed if 
clinically indicated.  NOTE: the same method of evaluation must be used consistently for any 
follow-up scans.   
8.4.9.3. 
Telemetry 
For subjects with known cardiac or pericardial tumor involvement at baseline, inpatient 
telemetry monitoring should be carried out for seven days post-ADP-A2M4 infusion. 
8.4.10. 
Brain MRI 
A MRI of the brain with contrast will be obtained at Baseline, within 1 month of 
lymphodepletion, for all subjects. CT with IV contrast may be used only for subjects with 

 
 
 
             
 
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contraindications to MRI of the brain. If brain metastases are documented at Baseline, then 
dedicated CT/MRI scans of brain metastases should be performed at every on-study tumor 
assessment, and included as non-target lesions in the tumor worksheet (see Section 8.3.1). If 
brain metastases are not documented at Baseline, then dedicated brain CT/MRI scans should be 
performed as clinically indicated. 
8.4.11. 
Renal Function Assessment  
Renal function (estimated or measured glomerular filtration rate (GFR)) will be assessed at 
Screening using Cockcroft CrCl equation, 24 hour urine collection to measure creatinine 
clearance or by nuclear medicine EDTA measurement should be performed in subjects who are 
i). clinically obese adults (i.e. ≥ 30KG/m2); ii). Clinically underweight adults (i.e. ≤ 
18.5KG/m2); iii). ≥ 65 years old; iv). Low borderline calculated CrCl ~ 60 ml/min (Cockcroft-
Gault). 
Renal function will be reassessed at Baseline using the same methodology. 
8.4.12. 
Hematology 
Section 10.3 Appendix 3 describes the parameters to be collected and recorded. 
In years 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 8.4.23) then laboratory assessments may be 
discontinued. 
8.4.13. 
Clinical Chemistry  
Section 10.3 Appendix 3 describes the parameters to be collected and recorded. 
In years 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 8.4.23) then laboratory assessments are 
discontinued. 
8.4.14. 
Coagulation 
Section 10.3 Appendix 3 describes the parameters to be collected and recorded. 
Subjects receiving warfarin anti-coagulation at baseline should be converted to either a low 
molecular weight heparin injection or a novel oral anticoagulant (NOAC). Reintroduction of 
warfarin after lymphodepleting chemotherapy/ADP-A2M4 dosing to attain the therapeutic INR 
range which was initially clinically indicated should only start when the platelet count is < Grade 
2 CTCAE. 
8.4.15. 
Thyroid Function Tests 
Section 10.3 Appendix 3 describes the parameters to be collected and recorded. 

 
 
 
             
 
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8.4.16. 
Hepatic Safety Assessments 
For subjects who experience evidence of hepatic toxicity, increased hepatic monitoring criteria 
will apply to ensure subject safety and to enable evaluation of liver event etiology (see Appendix 
4, Section 10.4.5). 
8.4.17. 
Pregnancy Test 
Either serum or urine pregnancy test may be performed. Female subjects of childbearing 
potential (FCBP) must have a negative pregnancy test at Screening and prior to starting 
lymphodepleting chemotherapy. 
8.4.18. 
Infectious Disease Screening 
Testing for infectious disease markers is required only at Screening and does not need to be 
repeated at Baseline to satisfy the inclusion / exclusion criteria, unless more than six months has 
elapsed from screening. 
Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive 
must have undetectable hepatitis B DNA. Subjects who are HCV antibody positive will be 
screened for HCV RNA by any RT PCR or bDNA assay. Eligibility will be determined based on 
a negative Screening value. 
Section 10.3  Appendix 3 describes the parameters to be collected and recorded. 
8.4.19. 
CMV PCR   
Subjects will be screened for cytomegalovirus (CMV) seropositivity at screening. If seropositive 
at screening, then CMV-PCR will be done at Baseline. If CMV viremia is detected at Baseline, 
treatment should be initiated prior to lymphodepletion chemotherapy.  All CMV seropositive 
subjects will continue to be monitored for CMV viremia by CMV PCR at day 1, week 2, 4, 6, 
and 8. See Section 10.5.3.4 for CMV prophylaxis and blood product screening if positive. 
8.4.20. 
ICE/CAPD Assessment Tool  
Subjects aged ≥ 12 years old: The ICE (Immune Effector Cell-Associated Neurotoxicity 
Syndrome) neurological assessment should be performed from Day 1 (prior to T cell infusion) 
through Day 8 whilst the subject is hospitalized according to Table 1 . The ICE assessment may 
be discontinued once a subject is discharged from hospital.   
If a subject is thought to have ICANS, the ICE should be used at least twice per day until 
resolution or stable.  It can also be used at later visits if indicated. See Section 10.5.7, Table 8. 
Subjects < 12 years old: The Cornell Assessment Pediatric Delirium Score (CAPD) will be 
used to monitor for ICANS. See Section 10.5.7, Table 4. 
Table 4:  
CAPD‑point neurological assessment [based on Traube, 2014] 
RASS Score____ (if -4 or -5 do not proceed) 

 
 
 
             
 
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Please answer the following questions based in your interactions with the patient over the course of your 
shift: 
 
Never 
4 
Rarely 
3 
Sometimes 
2 
Often 
1 
Always 
0 
Score 
1. Does the child make eye 
contact with the caregiver? 
 
 
 
 
 
 
2. Are the child’s actions 
purposeful? 
 
 
 
 
 
 
3. Is the child aware of 
his/her surroundings? 
 
 
 
 
 
 
4. Does the child tale a long 
time to respond to 
interactions? 
 
 
 
 
 
 
 
Never 
4 
Rarely 
3 
Sometimes 
2 
Often 
1 
Always 
0 
 
5. Is the child restless? 
 
 
 
 
 
 
6. Is the child inconsolable? 
 
 
 
 
 
 
7. Is the child underactive: 
very little movement and 
interaction? 
 
 
 
 
 
 
8. Are the child’s responses 
sparse and/or delayed? 
 
 
 
 
 
 
Scores between 1-8 may represent no impairment, grade 1 or grade 2 ICANS and must be 
combined with clinical assessment. Score > 8 corresponds to grade 3 ICANS. If unable to 
perform CAPD due to the patient being unrousable, this would correspond to grade 4 ICANS 
[Brown, 2021]. Any increase in CAPD score requires increasingly escalating and more frequent 
neurological monitoring. 
8.4.21. 
C-reactive Protein  
If cytokine release syndrome is suspected, C-reactive protein levels should be measured 
approximately every other day until symptoms are improving or an alternative diagnosis is 
confirmed.   

 
 
 
             
 
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8.4.22. 
Ferritin  
If cytokine release syndrome is suspected, ferritin levels should be measured approximately 
every other day with C-reactive protein. 
8.4.23. 
Persistence (Vector Copies)   
PBMC samples will be collected and used as the “surrogate sample” for monitoring persistence 
of gene modified cells in subjects. Persistence of transduced T cells is also a major biomarker 
related to clinical response. Therefore, additional PBMC samples will be collected over the first 
2 years following infusion (Section 8.6.5).  
Samples are required for: 
• Safety at Baseline and Week 24, Month 12 and then every 6 months through Year 5 and 
annually from Years 6-15.  
o If no gene modified cells are detected for three consecutive assessments and 
subject is ≥5 years post-infusion (for example, negative persistence assessments at 
year 4, 4.5 and 5), no further monitoring of PBMCs is required for persistence and 
collection of samples may be discontinued.  
o If at Month 12 or beyond post-infusion, greater than 1% PBMCs test positive for 
vector sequences, the subject’s PBMCs will be evaluated for integration site 
analysis (Appendix 6 Section 10.7.3). 
• Research at Day 2, Day 4, Day 8, Week, 2, Week 4, Week 8, Week 12 and subsequently 
every 2 months (±1 month) until disease progression.  
See Table 1 and Table 2. 
Details on collection and shipment of blood sample for vector copies/persistence is described in 
the Sample Collection Manual.   
8.4.24. 
RCL (VSV-G DNA) 
RCL will be monitored using a PCR-based assay that detects and measures copies of the gene 
coding for the vector’s envelope protein, namely VSV-G that is necessary for the assembly of 
pseudotyped infectious lentiviral particles but absent from the vector’s backbone. 
RCL testing will take place on subject’s peripheral blood mononuclear cells (PBMCs) which are 
collected at Baseline and  post infusion at Week 12, Week 24, Month 12, and then annually for 
15 years. See Table 1 and Table 2 for scheduling. 
If all samples are negative in year one, PBMC samples will be collected and archived annually 
until 15 years post-infusion.  Samples will be archived at Adaptimmune’s centralized 
biorepository.   
If a positive VSV-G DNA signal is obtained, the study investigator will be informed and the 
subject will be scheduled for a retest as soon as possible and no later than one month after the 

 
 
 
             
 
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initial positive result was reported to the Sponsor. See Appendix 7 Section 10.7.2 for additional 
information. 
Details on collection and shipment of blood sample for RCL is described in the Sample 
Collection Manual. 
8.5. 
Adverse Events and Serious Adverse Events 
8.5.1. 
Time period for collecting AE and SAE Information 
AEs and SAEs will be collected as follows: 
• During the Pre-screening period, only SAEs related to protocol-specified procedures 
will be collected from the time of the procedure (e.g., blood sampling, tumor biopsy) 
until 24 hours afterwards for blood sampling, or until 2 weeks post-biopsy.  
• From date of signing the Treatment ICF until the day before lymphodepletion starts, 
only SAEs related to study design/procedures (protocol mandated procedures, 
invasive tests, or change in existing therapy) or Aes leading to withdrawal from the 
study will be collected. 
• All AEs and SAEs will be collected from the start of lymphodepletion until the 
subject has discontinues the interventional phase of the study. In addition, emerging 
clinical conditions defined in Appendix 4, Section 10.4.6 will be monitored for 
starting Day 1. If the subject has not progressed after 12 months, only those emerging 
clinical conditions defined in Appendix 4, Section 10.4.6 will be collected thereafter.  
• During the long-term follow-up phase of the study, subjects will only be monitored 
for the emerging clinical conditions defined in Appendix 4, Section 10.4.6 and these 
will be recorded If a subject enters the LTFU phase prior to Week 12, they will have 
full AE collection at the Month 2 visit.  
All SAEs will be recorded on the SAE worksheet (SAEW) and reported to the sponsor or 
designee immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4.  
SAE follow up information should be submitted on an updated SAEW within 24 hours if 
associated with a change in diagnosis and/or increased severity. Otherwise follow up should be 
submitted promptly within 7 days, and no later than 30 days of receiving new information. 
8.5.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4, Section 10.4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 

 
 
 
             
 
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8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). 
Further information on follow-up procedures is given in Appendix 4, Section 10.4.3. 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt (within 24 hours) notification by the investigator to the sponsor of a SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.  These safety reports are forwarded to 
Investigators in the form of Investigator Safety Letters (ISL). 
• An investigator who receives an investigator safety letter describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and notify the IRB/IEC, 
if appropriate according to local requirements. 
• On request of a competent authority in whose territory the clinical trial is being 
conducted, the Sponsor will submit detailed records of all adverse events which are 
reported by the relevant Investigator(s). 
8.5.5. 
Pregnancy 
• Pregnancy (or pregnancy of a male subject’s partner) is not considered an AE/SAE 
unless there is reason to believe the pregnancy may be the result of failure of the 
contraceptive being used due to interaction with the investigational product.  Details 
of all pregnancies in female participants and female partners of male participants will 
be collected from the start of lymphodepletion for as long as there is evidence of T-
cell persistence, or until the subject has confirmed disease progression. 
• If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
6.  See Section 10.6.2 for guidance. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.  

 
 
 
             
 
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The safety of ADP-A2M4 during pregnancy and lactation has not been established in humans.  
The target antigen is known to be expressed on fetal germ line tissues and placenta, therefore 
female subjects who are pregnant, intending to become pregnant, or breast feeding are excluded 
from ADP-A2M4 studies. 
There is no preclinical or clinical trial data of ADP-A2M4 in pregnant women; however, there is 
a reasonable but unproven likelihood that this intervention may be significantly embryotoxic or 
even an abortifacient given the underlying biology of the target.  The effects on breast milk are 
unknown, therefore breastfeeding should be discontinued for the duration of the study, starting at 
the first dose of chemotherapy and for at least 12 months after receiving the investigational 
product, or four months after there is no evidence of persistence/gene modified cells in the 
Subjects blood, whichever is longer. 
The contraception guidelines provided in Section 10.6.1 should continue to be adhered to during 
long-term follow up. 
A woman who becomes and remains pregnant during the study will be discontinued from the-
interventional phase as exposure to radiation from imaging studies would be contraindicated.  
The subject would follow the LTFU T & E schedule Table 2.  
8.5.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Progression of underlying malignancy and related symptoms are not reported as an AE if they 
are clearly consistent with the suspected progression of the underlying cancer.  Clinical 
symptoms of progression may be reported as AEs if the symptoms cannot be determined as 
exclusively due to progression of the underlying malignancy, or do not fit the expected pattern of 
progression for the disease under study. 
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE /SAE. 
8.5.7. 
AE of Special Interest 
8.5.7.1. 
Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed 
following administration of antibodies and adoptive T-cell therapies for cancer.  It is defined 
clinically by symptoms which can mimic infection including pyrexia, nausea, diarrhea, 
headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea.  Subjects should be 
assessed clinically for CRS at all visits according to Table 1.  Most cases of CRS present within 
seven days following cell infusion. It is important to evaluate the subject for concurrent 
infections.  Potentially life-threatening complications of CRS include cardiac dysfunction, adult 
respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure and disseminated 
intravascular coagulation.  CRS may also be associated with findings of macrophage activation 
syndrome or occur coincident with tumor lysis syndrome. 

 
 
 
             
 
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The diagnosis of CRS is clinical, and is supported by the exclusion of infection as well as the 
presence of increased cytokine levels and other biomarkers.  CRS should be graded and managed 
with supportive measures and anti-IL-6 according to the severity of symptoms, see Section 
10.5.6 for detailed guidance on grading and management of CRS. 
8.5.7.2. 
Neurotoxicity 
Neurotoxicity has been described in association with immune effector cell therapy, and termed 
immune effector cell-associated neurotoxicity syndrome, or ICANS [Lee, 2019].  ICANS 
typically manifests as a toxic encephalopathy which is generally reversible.  Early signs include 
diminished attention, language disturbance and impaired handwriting.  Other signs/symptoms 
include confusion, disorientation, agitation, aphasia, somnolence, and tremors.  In severe cases of 
ICANS (defined as grade >2), seizures, motor weakness, incontinence, mental obtundation, 
increased intracranial pressure, papilledema, and cerebral edema may also occur. 
ICANS occurring within the first 5 days after immunotherapy may be concurrent with high fever 
and cytokine release syndrome (CRS) symptoms.  This form of ICANS tends to be of shorter 
duration, lower grade (Grade 1–2, see Table 9), and is generally reversible with anti-IL-6 
therapy.  ICANS presenting as delayed neurotoxicity with seizures or episodes of confusion can 
occur three or four weeks after CART‑cell therapy, after the initial fever and CRS subside [Lee, 
2019]. 
ICANS may occur with other cancer immunotherapies, including TCRs.  Cancer patients may 
also be at risk for encephalopathic symptoms due to other causes ranging from mild to moderate 
somnolence and confusion as a result of sedating medications, to seizures in relation to brain 
metastases.  The possible contribution of other medications, underlying disease and/or co-
morbidities should be evaluated when considering a diagnosis of ICANS in relation to T cell 
therapy. 
8.5.7.2.1. Monitoring for ICANS 
The ICE is a neurological assessment tool for subjects aged ≥ 12 years old which is used to 
assess cognitive function to monitor for ICANS (see Section 10.5.7 for details). ICE or Cornell 
Assessment Pediatric Delirium Score (for subjects < 12 years old) should be measured on the 
day of ADP-A2M4 infusion prior to receiving treatment and through Day 8 whilst the subject is 
hospitalized. If the subject is discharged before Day 8 the ICE or Cornell Assessment Pediatric 
Delirium Score may be discontinued according to the T&E Table (Section 1.3.1).  Subjects with 
known brain metastases should be monitored at least twice per day for the first 5 days following 
ADP-A2M4 infusion if hospitalized.  If a subject is found to have ICANS, the ICE or the Cornell 
Assessment Pediatric Delirium Score should be used at every visit (at least twice per day if 
hospitalized) until resolution or stable.  It can also be used at later visits if indicated.  ICE and the 
Cornell Assessment Pediatric Delirium Score also forms part of the grading system for ICANS 
developed by [Lee, 2019]. 
ICANS is graded and managed according to the severity of symptoms, see Section 10.5.8 for 
detailed guidance on management of ICANS. 

 
 
 
             
 
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8.5.8. 
Long Term Follow Up Adverse Events 
During the long term follow-up (LTFU) phase of the study, adverse event collection is limited to: 
new malignancies, new incidence or exacerbation of a pre-existing neurologic disorder, new 
incidence or exacerbation of a prior rheumatologic or other autoimmune disorder, new incidence 
of a hematologic disorder, opportunistic and or serious infections, or unanticipated illness and/or 
hospitalization deemed related to gene modified cell therapy. If a subject enters the LTFU phase 
prior to week 12, they will have full AE collection at the Month 2 visit. See Section 10.4.6 for 
reporting AEs during LTFU. 
8.5.8.1. 
LTFU Letters to Primary Care Physician/Oncologist 
A letter should be sent by the investigator/study coordinator to the subject’s primary care 
physician, local oncologist, or other physician that will notify him or her of this research study 
and will outline the features to look for and report as delayed adverse events potentially related 
to this study (Appendix 7, Section 10.7.4).  
8.6. 
Biomarkers for Exploratory Objectives 
Sample types collected and rationale: Collection of samples for biomarker research is part of this 
study. The following samples for biomarker research are requested and will be collected from all 
participants in this study as specified in the T&E Table (Table 1): 
•  Tissue  
− Tumor: Efficacy of immunotherapy of cancer is conditioned by the interplay 
between tumor cells and resident or infiltrating immune cells (effector T cells and 
immunosuppressive cells). Therefore, tumor biopsies will be collected to evaluate 
the evolution of both tumor and immune components pre and post-infusion. 
• Blood 
− Serum: Serum is collected to allow for measurement of cytokines in the blood in 
relation to T cell expansion, and CRS. Serum samples may also be used to detect 
other soluble biomarkers such as anti-tumor antibodies.  
− 
 
 
 
 
 
 
 
 
 
    

 
 
 
             
 
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8.6.1. 
Tumor Biopsy 
Baseline biopsy material should be collected within two months of the T cell infusion, with 
preference for a biopsy to be taken closer to the time of infusion. Tumor tissue should either be 
taken from non-target lesions or from target lesions where sampling can be done without 
impacting lesion measurement.   
As a guidance and if possible, a responding lesion should be biopsied at the Week 4 time point 
and a progressing lesion, or a new lesion should be biopsied at the progression time point. The 
apparent clinical or scan status of the lesion(s) biopsied should be noted at the time (e.g. 
decreased, stable, increased size). 
The Week 4 time point tumor biopsy can be collected anytime between Week 3 and Week 8. 

 
 
 
             
 
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The progression time point tumor biopsy can be collected obtained post-progression (e.g. from 
an excisional surgery).   
Additional details regarding the tumor biopsy collection are provided in the Sample Collection 
Manual. 
8.6.2. 
Cytokine and Soluble Protein Analysis 
Serum is collected at Baseline, pre-infusion and 2-4 hours post infusion on Day 1 and on Day 2, 
Day 4, Day 8, Week 2, Week 4, Week 8, Week 12, Week 24 and every 2 months post infusion to 
allow for measurement of cytokines in the blood.  Serum is also collected from subjects with 
suspected CRS, samples being taken approximately every other day until symptoms are 
improving or an alternative diagnosis is confirmed.   
Details regarding serum collection are provided in the Sample Collection Manual. 
Serum samples may also be used to detect humoral immune responses to tumor antigens and 
antibodies to ADP-A2M4. 
8.6.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6.4. 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
             
 
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• 
 
8.6.5. 
 Persistence of ADP-A2M4 TCR+ Cells  
The primary research assays for the trial involve monitoring for the persistence of infused 
engineered cells in the subjects and for correlation of this with potential therapeutic effect. 
Research samples will be taken as detailed in Section 8.4.23. Persistence is also monitored long 
term as a safety measure (Section 10.7.2). Along with the copies of gene-modified DNA per μg 
DNA, data on the number of transduced cells per μL, or relative to total lymphocyte number will 
be provided for persistence. 
 
 
 
 
 
 
 
 
 
8.7. 
Blood Sampling Volumes 
The amount of blood drawn for research purposes from pediatric subjects (those under 18 years 
of age or relative country-specific guidelines) will not exceed 3% of the total blood volume over 
a period of four weeks, and should not exceed 1% at any single time as specified in Ethical 
considerations for clinical trials on medicinal products conducted with minors (2017).  To 
comply with European Recommendations in pediatric subjects biomarker Research Blood draws 
(cytokine, liquid biopsy and cell phenotyping samples) will not be collected as part of this 
protocol.   
 
Body Wt 
(Kg) 
 Circulating Blood 
volume (ml) 
Maximum allowable sample 
volume over 4 weeks (ml) - 
3% of total blood volume  
 
Maximum allowable sample 
volume at single time (ml) - 
1% of total blood volume  
 
30-70  
2400- 5600 
48 – 168  
24 – 56  
In the event that blood draws are limited due to these restrictions, blood samples will be 
collected in order of priority as defined in the Laboratory Manual. 
8.8. 
Patient-Reported Outcomes 
8.8.1. 
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L) 
EQ-5D is a standardized measure of health status developed by the EuroQOL Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal [EuroQOL, 1990].  
The EQ-5D is applicable to a wide range of health conditions and treatments, and provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of health care.  The EQ-5D-3L descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities pain/discomfort and anxiety/depression. Each 

 
 
 
             
 
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dimension has 3 levels: no problems, some problems, extreme problems. The respondent is asked 
to indicate his/her health state by selecting the most appropriate statement in each of the 5 
dimensions. The EQ visual analogue scale (VAS) records the respondent’s self-rated health on a 
vertical, visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ and 
‘Worst imaginable health state’. This information can be used as a quantitative measure of health 
outcome as judged by the individual respondents. 
The EQ-5D-3L will be administered at Baseline and post T cell infusion at Week 8, Week 16 , 
Week 24 and Month 12. Once disease progression is established, the EQ-5D-3L assessment is no 
longer required. 
8.8.2. 
EORTC-QLQ-C30 
The EORTC QLQ-C30 is a questionnaire developed by the Quality of Life Group of the 
European Organisation for Research and Treatment of Cancer to assess the quality of life of 
cancer patients. It can be used for patients ≥ 18 years old in Cohort 2. 
The EORTC QLQ-C30 will only be used in synovial sarcoma subjects in Cohort 2 at Baseline 
and post T-cell infusion at Week 8, Week 16, Week 24 and Month 12. Once disease progression 
is established, the EORTC QLQ-C30 assessment will no longer be required. 
The EORTC QLQ-C30 comprises 30 questions. Each of the first 27 questions has 4 levels: Not 
at All, A Little, Quite a Bit, and Very Much.  The respondent is asked to indicate his/her health 
state by selecting the most appropriate statement. Questions 29 and 30 records the respondent’s 
self-rated health on a horizontal scale where the endpoints are labelled ‘Very Poor’ and 
‘Excellent’. This information can be used as a quantitative measure of health outcome as judged 
by the individual respondents. 
8.8.3. 
PedsQLTM 
The PedsQLTM is a questionnaire developed by the Mapi Research Trust to assess the quality of 
life of pediatric cancer patients.  
The PedsQLTM will only be used in synovial sarcoma subjects in Cohort 2 and 10 -17 years of 
age at Baseline and post T-cell infusion at Week 8, Week 16, Week 24 and Month 12. Once 
disease progression is established, the PedsQLTM assessment will no longer be required. 
The PedsQLTM comprises 27 questions. Each of the 27 questions has 5 levels: Never, Almost 
Never, Sometimes, Often, and Almost Always.  The respondent is asked to indicate his/her 
health state by selecting the most appropriate statement. This information can be used as a 
quantitative measure of health outcome as judged by the individual respondents. 
 
 

 
 
 
             
 
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9. 
STATISTICAL CONSIDERATIONS 
The objectives and endpoints for this study are described in Section 3, this section focusses on 
key aspects for the analysis and reporting of the primary and secondary efficacy and safety 
endpoints.  Details for the analysis of all clinical endpoints will be provided in the Statistical 
Analysis Plan (SAP).  The analysis plan for the objective related to the development of the 
validated Companion Diagnostic (CDx) will be described in a separate document.  Similarly, a 
separate analysis plan will be developed for the exploratory biomarkers. 
9.1. 
Study Populations 
Intent-to-Treat (ITT) population: This is the population of all subjects who were enrolled in the 
trial (i.e. met eligibility criteria).  The ITT population will be used to assess the safety of the end-
to-end autologous T cell therapy procedure. 
Modified Intent-to-Treat (mITT) population: This is the population of all ITT subjects who 
received T cell infusion. The mITT population is the primary analysis population for safety and 
efficacy evaluations following T cell infusion. 
The primary analysis will be for Cohort 1 only occur at the time of clinical cut-off as described 
in Section 5.5.   
9.2. 
Statistical Hypotheses and Sample Size Assumptions 
The primary objective for this study is to evaluate the efficacy of autologous genetically 
modified T cells (ADP-A2M4) in Cohort 1. 
The primary endpoint for efficacy is Overall Response Rate (ORR) in Cohort 1, defined as the 
proportion of subjects with a confirmed CR or PR relative to the total number of subjects in the 
analysis population.   
The ORR will be based on confirmed (tumor) responses per RECIST v1.1 by independent 
review.  
Subjects with unknown or missing response will be treated as non-responders (i.e. they will be 
included in the denominator when calculating the proportion).   
The clinical and statistical assumptions, the hypothesis test, and sample size for the proposed 
single arm open label clinical trial are based on the following factors: 
• The historical ORR for Synovial Sarcoma ≤13% and for MRCLS <10% (Section 4.2) 
• The ORR for historical control that will be used for hypothesis testing in this study will 
be 18%.  
• The mechanism of action for the TCR is assumed to be the same for synovial sarcoma 
and MRCLS.   
• Section 2.2.3 states that in subjects with synovial sarcoma, the observed ORR (confirmed 
responses) for ADP-A2M4 cell therapy was 40.0% at the time of data cut off. Therefore, 

 
 
 
             
 
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for purposes of sample size computation, we assumed ORR for ADP-A2M4 cell therapy 
would be 40%.  
• No formal hypothesis testing is planned for Cohort 2 or across cohorts (overall). 
The hypothesis of interest for the primary endpoint is; 
(Null Hypothesis) H0: p ≤  p0 , vs. (Alternate Hypothesis) H1: p > p0, where p0 (historical control 
rate) = 0.18.  
Based on above assumptions, the TCR ORR (i.e., p1) is set at 0.4.  The type I error (α) for this 
test will be no more than 0.025 and the type II error (β) will not exceed 0.1. Exact Binomial 
methods will be used to test the hypothesis.  
Statistical Design Assumptions: 
• The assessment for efficacy will be based on the mITT population using confirmed ORR 
via RECIST v1.1 per independent review in Cohort 1; 
• The type I error (α) for this test will be no more than 0.025; 
• The type II error (β) will not exceed 0.1;  
• Exact Binomial method will be used to test the hypothesis; 
• Cohorts 1 and 2 are independent; 
• Pediatric subjects in Cohort 2 will not be considered separately to adults. Further, it is 
assumed that the ORR for pediatric subjects is the same as adults for design 
considerations. 
Based on the statistical design assumptions above and the hypotheses and clinical assumptions in 
Section 4.2, the estimated sample size for the trial is 45 subjects in Cohort 1. 
The ORR for Synovial Sarcoma ranges between 4% – 13% in clinical trials (Section 2.2.3).  If 
we assume that the ORR of the ADP-A2M4 will be 40% (P1), and historical ORR (P0) is 13%, a 
sample size of N=27 provides 90% power to detect an absolute difference of 27% using exact 
binomial assumptions.   
To account for the potential variability in historical control efficacy, a more conservative 
historical ORR of 18% may also be considered.  Using a one-sided alpha=0.025, if we assume 
that the ORR of ADP-A2M4 will be 40% (P1) and historical ORR may be as high as 18% (P0), a 
sample size of N=45 in Cohort 1 provides at least 90% power to detect a difference of 22% using 
exact binomial assumptions.   
 
 

 
 
 
             
 
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The following table describes samples sizes for a single cohort under a range of assumptions for 
the exact binomial assumption as described above. 
Historical ORR (P0)  
TCR ORR (P1) 
Difference (P1-P0) 
N 
0.13 
0.40 
0.27 
27  
0.13 
0.45 
0.32 
21 
0.15 
0.40 
0.25 
33 
0.15 
0.45 
0.30 
24 
0.15 
0.50 
0.35 
19 
0.18 
0.40 
0.22 
45 
0.18 
0.45 
0.27 
32 
0.18 
0.50 
0.32 
21 
Based on these evaluations, the sample size is 45 subjects in Cohort 1 for the primary analysis. 
Additional subjects are enrolled in Cohort 2 to supplement Cohort 1 with additional safety and 
efficacy data based on clinical judgement. No formal hypothesis testing is planned for either 
Cohort 2 or overall. One benefit of these additional subjects (irrespective of whether adult or 
pediatric subjects) is an increase in precision for ORR by assessing the endpoint across cohorts, 
and thus in a larger sample of subjects. The following table summarizes the width (point estimate 
– lower bound) of a 97.5% one-sided confidence interval using exact binomial methods for 
different sizes of Cohort 2. Also provided for context is the probability that the lower bound of 
the confidence interval exceeds p0=18% for different sizes for Cohort 2. The assumed TCR ORR 
is 40%. 
Size of Cohort 2 
Size of Overall (across 
cohort) 
CI Width 
Probability CI LB 
> 0.18 
0 
45 
0.143 
0.916 
15 
60 
0.124 
0.959 
30 
75 
0.111 
0.989 
45 
90 
0.102 
0.994 
Based on these evaluations, enrolling an additional 45 subjects in Cohort 2 reduces the width of 
the confidence interval by about 28% [(0.143-0.102)/0.143] compared to the expected 
confidence interval width when only using Cohort 1. Further, if the TCR ORR is 40% the 

 
 
 
             
 
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probability that the lower bound of the confidence interval exceeds 18% increases from about 
92% when only using Cohort 1 subjects to greater than 99% if 45 subjects are enrolled in Cohort 
2. These results support enrolling an additional 45 subjects in Cohort 2, for a total of 90 subjects 
across cohorts.   
9.3. 
Statistical Analyses 
The statistical analysis plan (SAP) document will provide full details about data derivations and 
displays and analysis methods for primary, secondary and exploratory endpoints. This section 
captures key aspects of the analysis. 
Demography and baseline characteristics will be summarized using appropriate descriptive 
statistics. Subject disposition including number of subjects leukapheresed, lymphodepleted and 
treated with ADP-A2M4 will be summarized. Reasons for subject discontinuation from the study 
will be displayed.  
9.3.1. 
Interim Analysis 
There is no interim analysis planned.  
9.3.2. 
Efficacy Analyses 
The primary analysis population for efficacy will be the mITT population.  Secondary analyses 
may be conducted on the ITT populations, if it is different from the mITT population.   
The ORR will be based on confirmed (tumor) responses per RECIST v1.1 by independent 
review. 
Sensitivity analyses of ORR will be based on confirmed responses per RECIST v1.1, and on 
investigator assessment of overall response (per RECIST v1.1).   
The primary endpoint, ORR per RECIST v1.1 by independent review in Cohort 1, will be 
evaluated using a one-sided exact-based Clopper-Pearson 97.5% confidence interval (CI).  If the 
lower bound of the 97.5% CI exceeds 18%, the trial has met the pre-specified threshold for 
demonstrating efficacy and the trial has met the criterion for statistical significance.      
As a sensitivity analysis, one-sided 97.5% confidence interval using the Wilson method may also 
be provided. 
ORR per RECIST v1.1 by independent review will also be evaluated across cohorts (overall). 
The following secondary efficacy endpoints will be summarized: 
• Time to Confirmed Response, defined as the duration between T-cell infusion and the 
initial date of the confirmed response. 
• Duration of Response (DoR), defined as the duration from the initial date of the 
confirmed response to the date of progressive disease or death. 

 
 
 
             
 
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• Progression Free Survival (PFS), defined as the interval between the date T-cell 
infusion and the earliest date of disease progression based on RECIST v1.1 or death 
due to any cause. 
• Overall Survival (OS), defined the duration between T-cell infusion and death.   
Independent assessment of progression based on RECIST v1.1 will be used for the primary 
analysis of DoR and PFS. As a sensitivity analysis, determination of progression (via RECIST 
v1.1) using lesion assessments will also be provided.  
All secondary efficacy endpoints will be summarized for Cohort 1 and across cohorts (overall). 
No hypothesis testing is planned for these secondary endpoints in Cohort 1 or across cohorts. 
Time to event endpoints (i.e., OS and PFS) will be summarized and displayed graphically using 
Kaplan-Meier (K-M) methodology to estimate the median, and the 25th and 75th percentiles. 
Two-sided 95% confidence intervals will be produced.  Overall Survival may be assessed at 
fixed time points such as 1 year and 2 years using K-M methods.  
The following censoring rules will be applied: 
• For overall survival, subjects who are lost to follow-up or still alive will be censored at 
the date of last contact. 
• For PFS, subjects who do not have a documented date of disease progression or death 
will be censored at the date of the last study assessment. 
The proportion of censored observations will be summarized. 
The pharmacokinetic (PK) profile will be described by summaries of Peak expansion (i.e., 
maximum persistence) and time to peak expansion by responder status and overall. Persistence 
data will also be displayed by subject line plots. 
9.3.3. 
Safety Analyses 
The primary analysis population for safety will be the mITT population.  Safety will also be 
summarized for the ITT population and may also include the per protocol (PP) population. All 
safety analyses will be summarized for Cohort 1 and across cohorts (overall). 
The safety profile will be based on adverse events, serious adverse events, replication competent 
lentivirus (RCL) and vector integration/clonality. Other safety assessments will include vital 
signs measurements and clinical laboratory test results. 
These data will be summarized using appropriate descriptive statistics, i.e., continuous data will 
include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages. 
Adverse events will be summarized using two time periods:  
• From the time of signing the treatment ICF;  
• From start of lymphodepleting chemotherapy, defined as starting on the first day of 
lymphodepleting chemotherapy. 

 
 
 
             
 
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Adverse events throughout the trial will be coded by MedDRA v21.0 or higher.  The number and 
percent of subjects reporting any adverse events will be tabulated by system organ class and 
preferred term. Adverse events will be further classified by toxicity grade, relationship to 
treatment and seriousness in tabulation. 
Summary data on duration, grade, time to onset for adverse events of special interest i.e., 
cytokine release syndrome (CRS), ICANS will be presented.  Data from ICE will be listed. 
For subjects in the LTFU phase, the LTFU AE will be summarized and listed.   

 
 
 
             
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Data Handling and Record Keeping 
10.1.1.1. Data management 
An Electronic Data Capture (EDC) system will be used to collect data pertaining to this trial.  
Trial data will be captured through an electronic Case Report Form (eCRF).  Within the EDC 
system the eCRF data will be entered by the site staff and all source document verification and 
data cleaning will be performed by the Sponsor or designee (e.g. CRO). 
The specifications for the EDC system will be documented and approved before the EDC system 
is released for live use.  The validation of the eCRF data will be defined in a Data Management 
Plan.  As data are entered into the eCRF, the validation checks will be performed and where 
necessary, queries will be raised.  All queries raised will be held in the EDC database. 
The EDC system is a validated software program that has been designed to comply with CFR21 
Part 11 requirements.  All users will access the system via unique user name and password.  A 
full audit history of all actions performed within the system is maintained.  User accounts ensure 
that each user can only perform the tasks applicable to their role and only have access to the data 
applicable to their role. 
Standard coding dictionaries, WHO Drug and MedDRA will be used to code medications and 
adverse events. 
When all data have been entered and all data cleaning is complete the data will be locked and 
made available for analysis and reporting. 
On completion of the study all eCRF data, including all associated queries and audit history, will 
be made available in PDF format to both the study Sponsor and the sites. 
10.1.1.2. Case Report Forms 
For each subject enrolled, the completed eCRF must be reviewed and signed by the Principal 
Investigator or authorized delegate.  If a subject discontinues the study, the reason must be noted 
on the eCRF. 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports. 

 
 
 
             
 
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10.1.1.3. Site Documentation and Source Data 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents are 
classified into two different categories: (1) Investigator Site File (ISF) and (2) subject specific 
source documents. 
The Investigator is responsible for maintaining a complete and accurate ISF containing essential 
documents as required by ICH GCP. 
Source documents contain the results of original observations and activities of a clinical 
investigation.  Source documents include but are not limited to subject medical records/progress 
notes, appointment book, original laboratory reports, ECG printouts, CT/MRI scans, pathology 
and special assessment reports, and signed informed consent forms.  In no circumstances is the 
eCRF to be considered as source data. 
The Investigator must ensure the availability of source documents from which the information on 
the eCRF was derived. 
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local or foreign regulatory authorities, the IRB/IEC and auditors to inspect facilities and to have 
direct access to the ISF and all source documents relevant to this study regardless of the type of 
media. 
10.1.1.4. Data Retention and Availability 
The Investigator must keep all essential study documents including source data on file for at least 
25 years after completion or discontinuation of the Study.  After that period of time the 
documents may be destroyed, subject to local regulations. 
The Investigator will not dispose of any records relevant to this study without written permission 
from the Sponsor.  If the Investigator cannot guarantee the archiving requirement at the 
investigational site for any or all of the documents, such study records may be transferred upon 
request to the Sponsor or its designee. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in writing in advance. 
Study documentation is subject to inspection by the Sponsor, its representatives and regulatory 
agencies and must be stored in such a way that it can be accessed/retrieved within a reasonable 
timeframe at a later date. 
10.1.2. 
Study Monitoring 
Study Monitoring will be conducted by the Sponsor or designated CRO. 
It is understood the responsible monitor will contact and visit the Investigator regularly and will 
be allowed, on request, to inspect all records of the trial (e.g. eCRFs, ISF, and source documents) 
provided that subject confidentiality is maintained in accordance with local requirements. 

 
 
 
             
 
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It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify adherence to the protocol and the completeness, consistency and accuracy of the 
data being entered.  The monitor should have direct access to subject source documents to verify 
the entries on the eCRF.  The Investigator (or designee) agrees to cooperate with the monitor (or 
designee) to ensure any discrepancies detected are resolved. 
10.1.2.1. Audits and Inspections 
The Sponsor or its representatives may conduct audits at investigative sites including, but not 
limited to, facilities where the study is being conducted, investigational product handling and 
accountability, presence of required documents, the informed consent process and comparison of 
eCRFs with source documents. 
All study documentation including source data must be available for audit. 
The Investigator agrees to cooperate fully with audits conducted at a convenient time in a 
reasonable manner. 
Regulatory agencies may also inspect investigative sites during or after the study.  The 
Investigator (or designee) should contact the Sponsor immediately if this occurs, and provide 
copies of correspondence relating to requests for an inspection of the site facilities. 
10.1.3. 
Regulatory and Ethical Considerations 
10.1.3.1. Competent Authority Submissions 
Adaptimmune or its authorized representatives will be responsible for ensuring that appropriate 
competent authority approvals are obtained according to local country requirements.  Competent 
authority approval (or notification as applicable) will be obtained before initiation of the study. 
10.1.3.2. Independent Ethics Committees 
The final study protocol and subject informed consent documentation will be approved by the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and any other site level 
committee deemed appropriate by the Institution.  Approval from each applicable committee will 
be received in writing before initiation of the study. 
Protocol amendments must also be approved by the IRB/IEC (and other committees as 
applicable) before implementation, except in the case of changes made to protect subjects from 
immediate hazard, which may be implemented immediately. 
10.1.3.3. Local regulations/Declaration of Helsinki 
The Investigator will ensure this study is conducted in full compliance with the principals of the 
“Declaration of Helsinki” or with the laws and regulations of the country in which the research is 
conducted, whichever, affords the greater protection to the subject. The study must fully adhere 
to the principles outlined in ICH GCP or with local law if it affords greater protection to the 
subject. 

 
 
 
             
 
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10.1.4. 
Informed consent 
It is the responsibility of the Investigator to obtain written informed consent from all study 
subjects prior to any study related procedures being performed.  All consent documentation must 
be in accordance with applicable regulations and ICH GCP.  Documentation must include the 
dated signature of both the subject (or the subject’s parents or legally authorized representative 
as applicable) and the person conducting the consent discussion.  If the subject is illiterate, an 
impartial witness should be present during the consent discussion, and the consent signed and 
dated by the witness, the subject, and the person conducting the consent discussion.  The consent 
form should be translated and communicated to the subject in a language that is understandable 
to the subject.  Certified translations of the informed consent documentation will be provided as 
applicable. 
A copy of the signed and dated informed consent should be provided to the subject before 
participation in the study. 
Tests performed as standard of care prior to documentation of consent may be used for screening 
results as appropriate (Section 8.4). 
10.1.5. 
Confidentiality 
The confidentiality of records that may identify subjects will be protected in accordance with 
applicable laws, regulation and guidelines. 
The Investigator must ensure that each subject’s anonymity is maintained and protected from 
unauthorized parties.  On eCRFs or other documents submitted to the Sponsor, subjects must not 
be identified by their names, but by a unique identification code allocated to them to ensure 
confidentiality on all study documentation. Subjects will retain this unique number throughout 
the study. 
The Investigator will keep a subject enrollment log showing subject unique identification codes, 
names and addresses in the ISF. 
The Sponsor and/or its representatives accessing subject records and data at site will take all 
reasonable precautions to maintain subject confidentiality. 
10.1.6. 
Protocol Adherence 
The Investigator must sign the protocol to confirm acceptance and willingness to comply with 
the study protocol. 
The Investigator or designee will not deviate from the protocol unless necessary to eliminate an 
apparent immediate hazard to the safety, rights or welfare of any study subject.  In the event of a 
protocol deviation for any reason, the Investigator will promptly report the deviation to the 
Sponsor in writing. 

 
 
 
             
 
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10.1.7. 
Study Suspension, Study Termination and Study Completion 
The Sponsor may suspend or terminate the study at any time for any reason.  If the study is 
suspended or terminated the Sponsor will ensure applicable sites, regulatory agencies and 
IRBs/IECs are notified as appropriate. 
If the Investigator stops/terminates the study at their site the Sponsor must be notified.  The 
Sponsor will ensure Regulatory Agencies and IRBs/IECs are notified as appropriate. 
The Sponsor will ensure End of Study declarations are made to the relevant Regulatory 
Agencies/IECs in accordance with local regulations. 
10.1.8. 
Public Posting of Study Information 
The Sponsor is responsible for posting appropriate study information on applicable clinical study 
registry websites.  Information included in clinical study registries may include participating 
Investigator’s names and contact information. 
10.1.9. 
Clinical Study Report 
The results of the study will be presented in an integrated Clinical Study Report (CSR) according 
to ICH guideline E3: Structure and Content of Clinical Study Reports. 
10.1.10. 
Publication Policy 
The Investigator may not submit the results of the study for publication or present the results of 
the study without the prior written agreement of the Sponsor in accordance with the Clinical 
Trial Agreement.  The results of this study will be published as a whole once all subjects have 
completed the study and the study results have been analyzed.  Interim publications of data from 
the study may be made if mutually agreed between the Sponsor and the Investigators.  
Agreement will not be provided by the Sponsor where in the Sponsor’s view interim publications 
would introduce bias or lead to any misrepresentation or inaccuracies in data. 
Authorship will be determined in conformance with the International Committee of Medical 
Journal Editors (ICMJE) guidelines and/or publication guidelines if applicable. 
10.1.11. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing updated information on financial interests during the course of the 
study and for 1 year after completion of the study. 
 
 

 
 
 
             
 
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10.2. 
Appendix 2: Safety Reviews 
10.2.1. 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be implemented for this study for Cohort 1 only 
and will consist of two experienced oncologists who are independent of the study and an 
independent statistician.   
The DSMB will review ongoing safety (including AEs and SAEs) during the interventional 
phase of the study after approximately 5, 15, and 30 subjects have been dosed.  At the time of 
Protocol Amendment 3, the DSMB has held 2 operational meetings to review data from after 
dosing of 5, and 15 subjects. Both meetings resulted in the DSMB recommendation to continue 
the study without protocol modification.  
At the time of Protocol Amendment 4, the final/3rd DSMB meeting was held in March 2021 after 
the 30th subject was dosed in Cohort 1. The decision from the DSMB was to continue the study 
with no safety modifications since the emergent benefit-risk profile was favorable. 
 
10.2.2. 
Safety Review Committee 
A Safety Review Committee (SRC) will be implemented in Cohort 2 of this study to review 
pediatric safety data in subjects < 16 years old, and will consist of at least 3 external physicians 
including 1 with expertise in pediatric oncology, at least 1 of whom is unaffiliated to the studies, 
the Sponsor Pharmacovigilance Physician, the Sponsor Head of Clinical Development, and the 
Sponsor Head of Statistics. 
The SRC can be convened by the discretion of the Adaptimmune pharmacovigilance team at any 
time during the conduct of Cohort 2 based on emergent safety findings in subjects < 16 years old. 
The SRC will use clinical judgment to assess the benefit:risk of the study in the pediatric subjects 
< 16 years old, and will recommend actions regarding study modification for safety reasons, 
halting and restarting pediatric enrollment, termination of pediatric recruitment in Cohort 2, or 
any other safety-related issues 
A SRC charter, defining objectives, roles, accountabilities, meeting frequency, and the process 
for safety review, is available.

 
 
 
             
 
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10.3. 
Appendix 3: Clinical Laboratory Tests 
Table 5:  
Protocol-Required Safety Laboratory Assessments 
Laboratory reference ranges for all tests conducted locally must be provided to Adaptimmune 
before the study initiates. 
Hematology: 
Red blood cell count (RBC) 
Hemoglobin (Hb) 
Hematocrit (HCT) 
Mean cell volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Reticulocytes (absolute) 
Platelet count 
White blood cell count (WBC) with differential 
(absolute or percentage) 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils  
Clinical Chemistry: 
Calcium  
Phosphorus  
Magnesium  
Albumin 
Bilirubin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALK) 
Lactate dehydrogenase (LDH) 
Sodium 
Potassium 
Bicarbonate 
Creatinine 
Chloride 
Glucose 
BUN or Urea 
Other Tests: 
Ferritin 
C-reactive protein 

 
 
 
             
 
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Coagulation Screen: 
Prothrombin time (PT) or International Normalized 
Ratio (INR) 
Activated partial tissue thromboplastin time (aPTT) 
Pregnancy Test: 
Serum beta-HCG or Urine test1 
Thyroid Function Tests: 
Thyroid Stimulating Hormone (TSH) 
Infectious Disease: 
HIV 1+2 antibody# 
Hepatitis B surface antigen 
Hepatitis B core antibody – if positive, test for HBV 
DNA 
Hepatitis C antibody – if positive, test for HCV RNA 
HTLV 1+2 IgG 
CMV IgG# 
EBV (EBNA)# 
Treponema IgG or RPR # 
Viral reactivation 
CMV DNA PCR – peripheral blood for detection of 
reactivation. In the event of suspected end organ CMV 
disease a biopsy may be required 
# Per Institutional Standard Practice is acceptable 
1 Not required for pre-pubertal girls  
 

 
 
 
             
 
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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.4.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) ≥ CTCAE 
grade 3 and Grade 1 and 2 laboratory abnormalities that the Investigator considers clinically 
significant in their medical and scientific judgment.  
• 
Any other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (i.e., not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. A pre-existing condition is one that is present at 
the start of the study during Screening and is documented in the subject’s medical history. 
• 
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE 
or SAE if they fulfil the definition of an AE or SAE. 
 
 
 

 
 
 
             
 
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Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.4.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 

 
 
 
             
 
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Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
d. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
g. 
Additional protocol-defined criteria 
• 
Any Grade ≥3 cytokine release syndrome 
• 
Review any Grade 4 CTCAE lab value based solely on numerical criteria (e.g. white blood 
cells decreased) to determine whether it should be reported as a SAE. 
• 
Hepatic events (see Section 10.4.5): 
− 
ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) 
− 
ALT ≥3xULN and international normalized ratio (INR) >1.5, if INR measured  
10.4.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 

 
 
 
             
 
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• 
SAEs should be reported to the Sponsor or designate within 24 hours using the SAEW. The 
investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Adaptimmune in lieu of completion of the SAEW/AE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
Adaptimmune. Supporting documents such as pathology reports or imaging results can also 
be provided in conjunction with the SAEW. In these cases, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical records 
before submission to Adaptimmune. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of Severity 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v 5.0.  See Section 10.5.6 and 10.4.7 for guidance on grading of CRS and ES respectively.  For 
AEs not specifically listed in the CTCAE, The investigator will make an assessment of intensity for each 
AE and SAE reported during the study and assign it to 1 of the following categories:  
• 
Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2 - Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL1. 
• 
Grade 3 - Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL2. 
• 
Grade 4 - Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 - Death related to AE.  
1. Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
2. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not being bedridden. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 

 
 
 
             
 
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• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial SAEW report to Adaptimmune. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAEW to Adaptimmune. 
• 
The investigator will also assess the relationship between the lymphodepletion chemotherapy 
and each SAE. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Adaptimmune to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, 
the investigator will provide Adaptimmune with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
SAE follow up information should be submitted on an updated SAEW within 24 hours if 
associated with a change in diagnosis and/or increased severity. Otherwise follow up should 
be submitted promptly within 7 days, and no later than 30 days of receiving new information. 

 
 
 
             
 
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10.4.4. 
Reporting of SAEs 
SAE Reporting to Adaptimmune  
• 
SAEs must be reported to Adaptimmune by completing the paper SAE worksheet (SAEW) 
within 24 hours of the study personnel’s discovery of the event. 
• 
Complete the SAEW as fully as possible and obtain the Investigators signature.  Create a PDF 
of the signed SAEW and submit to: 
• 
 
• 
 
• 
Do not delay reporting an SAE if the Investigator is unavailable to sign.  Report the SAE as 
above and provide a copy of the signed SAEW as soon as possible afterwards. 
10.4.5. 
Hepatic Monitoring and Follow Up Assessments 
Liver chemistry evaluation criteria are designed to assure participant safety and to enable 
evaluation of liver event etiology.  Liver chemistries will be monitored in accordance with the 
Time and Events Table (Section 1.3), and as clinically indicated. 
If a Subject meets one of the criteria defined in Table 6, the specified actions and follow up 
assessments will be carried out. 
If a Subject moves to the LTFU phase prior to Week 12, all AEs would be collected at the Month 
2 visit (see Section 1.3).  Hepatic safety assessments will be included in this safety follow up. 
Table 6:  
Hepatic Monitoring Criteria 
Hepatic Monitoring Criteria 
ALT Absolute 
ALT 8xULN 
ALT Increase 
ALT 5xULN but <8xULN persists for 2 weeks 
ALT 3xULN but <5xULN persists for 4 weeks 
Bilirubin1 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)  
INR1  
ALT 3xULN and international normalized ratio (INR) >1.5, if INR measured 
Symptomatic2 
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity 
Suggested Actions and Follow up Assessments 
Actions 
Follow Up Assessments 
• 
Complete the electronic case report form 
(eCRF), and a serious adverse event worksheet 
• 
Viral hepatitis serology3 

 
 
 
             
 
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(SAEW) if the event meets the criteria for an 
SAE within 24 hours.1 
• 
Consider hepatologist consultation 
• 
Repeat liver chemistry tests (include ALT, AST, 
ALK, bilirubin) and INR  
• 
Perform Follow-Up Assessments (See column 
to the right) 
• 
Monitor participants weekly with liver 
chemistry and INR until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. For bilirubin or INR criteria, monitor 
participant twice weekly. 
• 
Fractionate bilirubin, if total bilirubin ≥2xULN 
 
• 
Serum CPK and LDH 
• 
CBC with differential to assess eosinophilia 
• 
PBMC blood sample for persistence4  
• 
Assess for the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) 
and alcohol use 
• 
For bilirubin or INR criteria: 
• 
Hepatologist consultation required 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
• 
Consider liver biopsy 
1. All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5 
may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE. The INR stated 
threshold value will not apply to participants receiving anticoagulants.  
2. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 
3. Includes:Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody.  
4. Record the date/time of the PBMC blood sample draw on the CRF. Instructions for sample handling and 
shipping are in the Laboratory Manual.  
10.4.6. 
Reporting Criteria during Long Term Follow-Up (Years 1-15) 
Due to the nature of the treatment, subjects are required to be followed for 15 years after 
treatment with genetically modified T cells according to FDA and EMA guidance [FDA, 2006; 
FDA, 2010; EMA, 2009].  Subjects will be followed according to the schedule outlined in 

 
 
 
             
 
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Section 1.3.2 , Table 2.  Emergence of any of the following new clinical conditions reported or 
observed and the action taken will be reported to the Sponsor: 
• New Malignancies 
• New incidence or exacerbation of a pre-existing neurological disorder 
− Excluding all Grade 1 neurologic AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant 
• New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder 
− Excluding all Grade 1 autoimmune AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant 
− All rheumatologic disorders will be reported irrespective of grade 
• New incidence of a hematologic disorder 
− Excluding cytopenias following cytotoxic chemotherapy before bone marrow 
recovery 
− Excluding Grade 1 and 2 laboratory abnormalities, unless the Investigator 
considers clinically significant 
• Opportunistic and/or serious infections 
− Excluding infections secondary to chemotherapy induced cytopenias 
• Unanticipated illness or hospitalization deemed at least possibly related to gene 
modified cell therapy 
These are the only adverse events that will be collected during LTFU. 
A detailed description of the event should include the date of diagnosis and the nature of the 
diagnosis.  If the diagnosis is cancer, record the type and stage of the cancer.  If the cancer is 
metastatic, list the metastatic sites.  If a new malignancy is recorded in a vector target T-cell 
type, tumor cells will be evaluated for vector sequences.  If the tumor is positive for vector 
sequences or the surrogate sample is positive for vector sequences and is confirmed in 
accordance to this protocol, clonality analysis will be performed.  If no evidence of oligo-or 
monoclonality is observed, a summary report of any and all analysis for the pattern of vector 
integration will be assembled, and submitted within the annual report of the INDs listed on this 
protocol under which the subject(s) evaluated originally received their treatment.  If evidence of 
oligo- or monoclonality is observed, an information amendment will be submitted within 30 days 
to the INDs listed on this protocol under which the subject(s) evaluated originally received their 
treatment.   

 
 
 
             
 
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10.4.7. 
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents 
In accordance with FDA and EMA guidance [FDA, 2018; EMA, 2009], all subjects enrolled in 
this trial are asked to consider an autopsy and autopsies will be requested of the families for all 
subjects who die during participation in studies after administration of gene transfer agents. 
Guidelines for autopsy tissue/sample collection, preparation and shipping are provided in the 
Laboratory Manual.

 
 
 
             
 
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10.5. 
Appendix 5: Supportive Care Guidance 
It is recommended that a specialist with experience in the administration of hematopoietic stem 
cell transplant and/ or other cell and gene therapy be involved in the care of study subjects.  Staff 
treating trial subjects should be experienced in acute post-transplant care and the management of 
associated toxicities (e.g. cytopenias, cytokine release syndrome, ICANS). 
Subjects are at risk for the development of certain adverse effects for which recommended 
management strategies have been developed.  Adverse effects are most likely to occur within the 
first month following T-cell infusion, but may occur at later time points. 
Supportive care treatments recommended herein, including tocilizumab will be supplied by the 
pharmacy of the participating institution. 
10.5.1. 
Lymphodepleting Chemotherapy Symptom Management 
Cyclophosphamide and fludarabine are used as pre-conditioning lymphodepleting chemotherapy 
in this study. Symptoms associated with the use of cyclophosphamide and fludarabine are 
included in the respective product labels. Refer to the most current product labels. 
10.5.1.1. Management of Neutropenia 
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
is also common. Prophylactic use of G-CSF is recommended in all subjects. G-CSF (i.e., 
filgrastim) should be used for management of neutropenia according to ASCO guidelines [Smith, 
2015]. G-CSF should be given on Day -3 until resolution of neutropenia (reaching an ANC of at 
least 2 × 109/L to 3 × 109/L or as per institutional practice). 
Long-acting (pegylated) G-CSF may be given in preference to short acting daily G-CSF in 
accordance with institutional standard practice. Pegylated G-CSF will be given as one dose on 
Day -3. 
10.5.2. 
T-cell Infusion Symptom Management 
Mild transient symptoms have been observed following infusion of engineered T cells. The 
management of these symptoms is suggested but should not necessarily be confined to the 
below. 
• Fever, chills, headache and temperature elevations will be managed with 
acetaminophen. It is recommended all subjects that develop fever or chills have a 
blood culture drawn. 
• Nausea and vomiting may be treated with a non-steroidal anti-emetic of choice. 
• Hypotension will initially be managed by intravenous fluid administration and further 
measures as dictated by standard medical practice. 
• Hypoxemia will initially be managed with supplemental oxygen and further measures 
as dictated by standard medical practice. 

 
 
 
             
 
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10.5.3. 
Infection 
Additional measures to treat and prevent infection are outlined below.  In particular, fever and 
neutropenia should be aggressively managed as well as preemptive influenza therapy and other 
standard therapies for immunocompromised hosts, in accordance with institutional guidelines. 
10.5.3.1. SARS-CoV-2 (COVID-19) 
Subjects with a positive RT-PCR test for COVID-19 (irrespective of vaccination status) post 
lymphodepleting chemotherapy or ADP-A2M4 cell infusion should be immediately referred to 
an infectious disease specialist for consideration of anti-viral therapies. Investigators should also 
consult the latest guidelines/institutional policies pertaining to the management of COVID-19 in 
cancer/cell therapy patients. The Medical Monitor should be informed if a subject has a positive 
COVID-19 test (irrespective of symptoms) after receiving either lymphodepleting chemotherapy 
or ADP-A2M4 cell infusion. 
10.5.3.2. Pneumocystis carinii Pneumonia 
Subjects should receive prophylaxis against Pneumocystis pneumonia with drug, dose and 
duration according to institutional guidelines.  Single strength trimethoprim sulfamethoxazole 
daily is the recommended first line agent, starting at day 28 for one year.  Other regimens 
including atovaquone (1500 mg daily with food) or aerosolized pentamidine (300 mg every four 
weeks) are also acceptable, e.g. sulfonamide allergy, and should follow Institutional standards 
for autologous bone marrow transplants. 
10.5.3.3. Herpes simplex and Varicella zoster 
All subjects should receive prophylaxis with acyclovir (800 mg twice daily) or valacyclovir 
(500mg twice daily) for one year, or in accordance with institutional guidelines. In general, 
prophylaxis should start on day of T-cell infusion, or on day of lymphodepletion if the subject 
has a history of shingles or multiple HSV episodes. 
10.5.3.4. Cytomegalovirus 
Subjects will be screened for cytomegalovirus (CMV) seropositivity at study entry.  If CMV 
viremia is detected at baseline, treatment should be initiated and evidence of viral clearance 
obtained, prior to lymphodepletion chemotherapy.  All CMV seropositive subjects will continue 
to be monitored for CMV viremia by CMV DNA PCR as shown in Table 1 until 60 days post 
infusion of ADP-A2M4.  In the event CMV viremia is observed an Infectious Diseases specialist 
should be consulted and treatment initiated if necessary according to institutional practice.  
Recommended regimens include ganciclovir based therapy if ANC ≥1000, and foscarnet if ANC 
<1000. 
If a subject experiences prolonged or secondary pancytopenia or lymphopenia additional 
monitoring for viral reactivation should be considered and treatment for viral infection initiated 
if necessary.  A strategy for management of pancytopenia or bone marrow failure is described in 
Section 10.5.9. 

 
 
 
             
 
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10.5.3.5. Hepatitis B Prophylaxis 
Subjects will be screened for hepatitis B (HBV) at study entry. Subjects who are hepatitis B core 
antibody positive must receive prophylaxis against viral reactivation using institutional 
protocols.  Prophylaxis should be initiated prior to lymphodepleting therapy and continued for 6 
months.  Acceptable regimens include lamivudine (300mg daily), entecavir (0.5mg daily), or 
tenofovir (300mg daily). 
10.5.3.6. Syphilis 
Subjects will be screened for syphilis at study entry in accordance with institutional standards.  
Subjects with positive screening results should be evaluated by an infectious diseases consultant.  
If determined to have syphilis infection, the subject should be treated before lymphodepletion 
chemotherapy. 
10.5.3.7. Other Anti-Microbial Prophylaxis 
Antibacterial and antifungal prophylaxis should follow institutional standards for autologous 
bone marrow transplants. 
10.5.4. 
Hematologic and Blood Product Support 
Blood product support should be provided to maintain platelets > 10 x109/L, Hb > 8.0 g/dL (or in 
accordance with institutional practice) and as clinically indicated.  See AABB Guideline on 
platelet transfusion [Kaufman, 2015]. 
10.5.4.1. Irradiated Blood Product 
The guidance for autologous stem cells is also recommended for use in T- cell therapy.  
Blood products transfused during the following study periods must be irradiated: 
• 7 days prior to and during leukapheresis to prevent the collection of viable allogeneic 
T lymphocytes; 
• Irradiated blood components should continue to be used until 3 months following T-
cell infusion unless conditioning, disease or previous treatment determine indefinite 
duration. 
Irradiated blood products may be used longer as clinically indicated, otherwise follow 
institutional guidelines on autologous stem cell transplantation 
10.5.4.2. CMV screened blood products 
Subjects will be screened for CMV seropositivity on study entry.  In order to reduce the risk of 
primary CMV infection all subjects (i.e. both CMV-positive and -negative subjects) should 
receive leukoreduced blood products where possible (excluding the IP infusion).  Where 
leukoreduced blood is not available, CMV negative subjects must only receive blood products 
from CMV-seronegative donors from study entry to study completion. 

 
 
 
             
 
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10.5.5. 
Management of Autoimmunity 
Subjects should be monitored throughout the trial for potential autoimmune reactions in response 
to the genetically engineered T cells that could include skin toxicity, liver toxicity, colitis, eye 
toxicity etc.  If autoimmunity is suspected, the PI should be contacted and every attempt should 
be made to biopsy the affected organ to clarify whether the symptoms are related to the ADP-
A2M4 therapy.  If the subject sustains persistent Grade 2, or Grade 3 or 4 autoimmunity, 
consideration should be given to administration of corticosteroid therapy, either topically (e.g. 
skin, eyes) or systemically as clinically indicated. 
10.5.6. 
Management of Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed 
following administration of antibodies and adoptive T cell therapies for cancer. It is defined 
clinically by symptoms many of which mimic infection including pyrexia, nausea, diarrhea, 
headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea. It is important to 
evaluate the subject for concurrent infections. Potentially life-threatening complications of CRS 
include cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or 
hepatic failure and disseminated intravascular coagulation. CRS may also be associated with 
findings of macrophage activation syndrome or occur coincident with tumor lysis syndrome. 
CRS causes a rapid rise in serum cytokine levels under conditions of immune activation and 
although cytokines will be assayed serially throughout the study, results of the assays will not be 
available in real time; therefore CRS should be graded and managed with supportive and 
immunosuppressive interventions according to the severity of symptoms [Lee, 2019]. 
Table 7 provides the recommended management of CRS according to grade, which has been 
further adapted from CTCAE for use with immunotherapy and should be implemented in 
accordance with institutional guidelines. Symptoms can mimic those seen with infection. The 
diagnosis of CRS is clinical, and is supported by the exclusion of infection as well as the 
presence of increased cytokine levels and other biomarkers. Assessment and treatment guidelines 
are provided below. If CRS is suspected, in addition to assessment for infection, cytokine levels 
(Section 8.6.2) ferritin (Section 8.4.22), as well C-reactive protein (CRP) (Section 8.4.21) levels 
should be measured approximately every other day until symptoms are improving or an 
alternative diagnosis is confirmed. 
 

 
 
 
             
 
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Table 7:  
Management Guidelines for Cytokine Release Syndrome 
 
Grade 
Clinical Presentation for Grading 
Assessment 
Management Guidelines 
1 
Constitutional symptoms not life- 
threatening (e.g., fever, nausea, fatigue, 
headache, myalgias, malaise) 
• 
Vigilant supportive care1 
• 
Assess and treat for possible 
infection2 
• 
Consider anti-IL-6 therapy3 
(tocilizumab 8 mg/kg* IV) if 
clinically indicated (i.e., subjects 
with symptoms persisting ≥ 24 
hours or subjects with co-
morbidities or subjects of older age) 
2 
Symptoms require and respond to 
moderate intervention (Hypotension 
responds to fluids or one low dose 
pressor, hypoxia responds to <40% O2, 
and/or Grade 2 organ toxicity) 
• 
Monitor cardiac and other organ 
function 
• 
Vigilant supportive care1 
• 
Assess and treat for possible 
infection2 
• 
Treat hypotension with fluid and 
pressors. 
• 
Administer O2 for hypoxia. 
Administer anti-IL-6 therapy3 
(tocilizumab 8 mg/kg* IV) at any 
time if clinically indicated (i.e., 
subjects with symptoms persisting ≥ 
24 hours, or subjects with co-
morbidities or subjects of older age) 

 
 
 
             
 
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3 
Symptoms require and respond to 
aggressive intervention 
hypotension requires multiple pressors 
or high dose pressors 
hypoxia requires ≥40% O2, Grade 3 organ 
toxicity or Grade 4 transaminitis 
• 
Monitor subject very closely for 
cardiac and other organ 
dysfunction. Most likely will 
require monitoring in an intensive 
care unit (ICU). 
• 
Vigilant supportive care1 
• 
Assess and treat for possible 
infection2 
• 
Treat hypotension with fluid and 
pressors. Administer O2 for 
hypoxia. 
• 
Administer anti-IL-6 therapy3 
4 
Life-threatening symptoms 
Grade 4 organ toxicity (excluding 
transaminitis) 
• 
Manage subject in ICU 
• 
Intensive supportive care 
including mechanical 
ventilation, fluids, pressors, 
antibiotics and other measures 
as required 
• 
Administer anti-IL-6 therapy3 
5 
Death 
1. 
Supportive care includes: monitor fluid balance, maintain adequate hydration and blood pressure 
2. 
Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever 
and neutropenia as per institutional practice; and antipyretics, analgesics as needed. 
3. 
For subjects requiring intervention beyond supportive measures, anti-IL-6 therapy should be the first line 
treatment (tocilizumab 8 mg/kg* IV). 
*The maximum dose for tocilizumab is 800 mg per dose. Corticosteroids can be used for subjects 
refractory to anti IL-6 therapy. Other immunosuppressor agents may also be used, including TNFα and 
IL-1R inhibitors. Please see text below for details. 
Source: Lee, 2019; Neelapu, 2018 
Management of children with CRS should be guided by the pediatric cell therapy team with 
multi-disciplinary involvement where deemed clinically necessary from pediatric Investigators 
and other specialists especially for serious adverse events, or those refractory to tocilizumab. 
Age based management of CRS-related hypotension or hypoxia should follow local pediatric 
guidelines, and/or those outlined by Mahadeo et al [Mahadeo, 2019]. 

 
 
 
             
 
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For subjects requiring immunosuppressive intervention anti-IL-6 therapy should be the first line 
treatment. Tocilizumab is a humanized anti-IL-6 receptor antibody that has been approved for 
the treatment of CRS. Anecdotally, tocilizumab has produced rapid and complete correction of 
CRS with single doses [Maude, 2014].  The United States product insert (USPI) for 
tocilizumab recommends a dose of 8 mg/kg administered over 1 hour in adult subjects as the 
first-line treatment of severe CRS. Subjects may receive a repeat dose(s) if clinical signs and 
symptoms do not improve at least 8 hours apart. Refer to Section 10.5.7 below for subjects 
experiencing Immune Effector Cell-Associated Neurotoxicity Syndrome concurrent with CRS. 
Second-line, tocilizumab refractory, management of CRS is at the discretion of the Investigator 
following local institutional policy. This can potentially include the use of corticosteroids either 
in combination with a second dose of Tocilizumab [Maus, 2020] or a corticosteroid administered 
as a single agent after two doses of Tocilizumab have been administered and if CRS symptoms 
are persisting. Use of steroid sparing agents (e.g. siltuximab or anakinra) is at the discretion of 
the Investigator.  
Lee [2019] recommend steroids as second-line therapy for CRS as the response to anti-IL-6 
therapy may be more rapid and owing to the potential of steroids to attenuate the anti-tumor 
effects of the adoptive T cell therapy. However, in subjects with Grade 3 or 4 CRS associated 
with neurologic dysfunction without significant hemodynamic instability (See Section 10.5.7) or 
other life-threatening symptomatology, consideration may be given to the use of corticosteroids 
as immunosuppressive therapy. High doses (e.g. 2 mg/kg/day prednisone equivalent) may be 
required. 
If cytokine release syndrome is suspected, a physician with expertise in the management of 
subjects following bone marrow transplant should be consulted. If high dose corticosteroids are 
required, treatment should generally be continued until resolution to Grade 1 followed by 
tapering doses over several weeks. 
Please refer to the most recent version of the product label for tocilizumab and the latest Society 
for Immunotherapy of Cancer (SITC) guidelines for CRS [e.g. Maus, 2020]. 
10.5.7. 
Management of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) 
See Section 8.5.7.2 for a description of ICANS. Neelapu, et al [Lee, 2019] have developed a 
grading system for ICANS which incorporates the Immune Effector Cell-Associated 
Encephalopathy 10‑point neurological assessment (ICE) tool, see Table 8.  Points are assigned 
for each of the tasks in Table 8 which are performed correctly.  Normal cognitive function is 
defined by an overall score of 10. 
The ICE should be used to monitor subjects ≥ 12 years old for ICANS. In subjects ˂ 12 years old 
The CAPD should be used to monitor ICANS, see Table 4. 

 
 
 
             
 
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Table 8: 
ICE‑point neurological assessment [based on Lee, 2019] 
Task 
ICE Points 
Orientation: Orientation to year, month, city, and 
hospital,  
Total of 4 points (one point for each) 
Naming: Ability to name three objects(e.g. point 
to: clock, pen, button) 
Total of 3 points (one point for each) 
Following commands: ability to follow simple 
commands (e.g., “Show me 2 fingers” or “Close 
your eyes and stick out your tongue”) 
1 point 
Writing: Ability to write a standard sentence, e.g. 
‘There are seven days in a week’ 
1 point 
Attention: Ability to count backwards from 100 
by tens 
1 point 
The ICE score is used in grading of ICANS as presented in Table 9Error! Reference source not 
found..  
Table 9:  
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Neurotoxicity 
Domain  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 ICE Score1 
7–9  
3–6  
0–2  
0 (patient is 
unarousable, and 
unable to perform 
ICE) 
Depressed level of 
consciousness2 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to 
tactile stimulus 
Patient is 
unarousable or 
requires vigorous 
or repetitive 
tactile stimuli to 
arouse. Stupor or 
coma 
Seizures 
NA 
NA 
Any clinical 
seizure, focal or 
generalized that 
resolves rapidly 
or 
nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(>5 min); or 
Repetitive clinical 
or electrical 
seizures without 
return to baseline 
in between 

 
 
 
             
 
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Neurotoxicity 
Domain  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Motor findings 3 
NA 
NA 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated ICP/ 
cerebral edema 
NA 
NA 
Focal/local 
edema on 
neuroimaging4 
Diffuse cerebral 
edema on 
neuroimaging; 
decerebrate 
or decorticate 
posturing; or 
cranial nerve VI 
palsy; or 
papilledema; or 
Cushing's triad 
Source:  Based on Lee, 2019 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not 
attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
N/A indicates not applicable. 
1 A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be 
classified as grade 4 ICANS if unarousable. 
2 Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medication). 
3 Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do not influence 
ICANS grading. 
4 Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It 
may be graded according to CTCAE v5.0. 
10.5.8. 
Management of ICANS 
The recommended management of ICANS should be based on toxicity grade.  Table 10 provides 
guidance on the management of ICANS and should be implemented in accordance with 
institutional guidelines.   
Grade 1 ICANS is primarily managed with supportive care as outlined below.  For subjects 
requiring intervention beyond supportive measures, anti-IL-6 therapy should be the first line 
treatment of for ICANS in the setting of CRS (See Section 10.5.6 for CRS diagnosis and 
treatment guidelines).  In the setting of concurrent CRS, for Grades 1-3 ICANS additional doses 
of anti-IL-6 therapy should be considered.  For subjects with neurologic symptoms refractory to 
anti-IL-6 therapy, management should follow local cell therapy policies/investigator discretion 
including the use of corticosteroids. 

 
 
 
             
 
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A neurology consultation should be obtained for subjects with ICANS for thorough neurological 
evaluation, and recommendations for further testing such as EEG and neuroimaging as indicated. 
Table 10:  
Management of ICANS 
Grade 
Treatment 
1 
For all patients: 
• Vigilant supportive care; aspiration precautions; intravenous (IV) hydration 
• Withhold oral intake of food, medicines, and fluids, and assess swallowing 
• Convert all oral medications and/or nutrition to IV or enteral tube if swallowing is impaired 
• Avoid medications that cause central nervous system depression 
• Evaluate for other contributing causes and treat accordingly 
Unless symptoms are mild and transient (e.g. 1 point change in ICE for less than 12 hours): 
• Neurology consultation including funduscopic exam to assess for papilledema 
• MRI of the brain with and without contrast (CT scan of the brain if MRI is not feasible).  
Further testing if indicated such as diagnostic lumbar puncture with measurement of opening 
pressure if increased intracranial pressure is suspected, or MRI spine if the subject has focal 
peripheral neurological deficits 
• Institute levetiracetam therapy and consider EEG if seizure activity is suspected 
• Consider anti‑IL‑6 therapy with tocilizumab 8 mg/kg1 IV if Grade 1 persists beyond 24 
hours, or worsening and associated with concurrent CRS 
2 
• Supportive care and neurological work‑up as described for grade 1 ICANS 
• Anti-IL-6 therapy if associated with concurrent CRS 
• If refractory to anti-IL6 therapy or no evidence of CRS consider Dexamethasone 10 mg IV 
every 6 h or methylprednisolone 1 mg/kg IV every 12 h; Once initiated continue 
corticosteroids until improvement to grade 1 ICANS and then taper 
• Consider transferring patient to intensive-care unit (ICU) if ICANS associated with grade 
≥2 CRS 
3 
• Supportive care and neurological work‑up as indicated for grade 1 ICANS 
• ICU transfer is recommended 
• Anti‑IL‑6 therapy if associated with concurrent CRS if not administered previously 
• Corticosteroids as outlined for grade 2 ICANS if symptoms worsen despite anti‑IL‑6 
therapy, or for ICANS without concurrent CRS; continue corticosteroids until improvement 
to grade 1 ICANS and then taper 
• Stage 1 or 2 papilledema with cerebrospinal fluid (CSF) opening pressure <20 mmHg 
should be treated with a corticosteroid regimen as per Grade 4 below. 
• Consider repeat neuroimaging (CT or MRI) every 2–3 days if patient has persistent grade 
≥3 ICANS 

 
 
 
             
 
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Grade 
Treatment 
4 
• Supportive care and neurological work‑up as indicated for grade 1 ICANS 
• Consider neurosurgical consultation for patients with evidence of increased intracranial 
pressure 
• ICU monitoring; consider mechanical ventilation for airway protection 
• Anti‑IL‑6 therapy and repeat neuroimaging as described for grade 3 ICANS 
• High-dose corticosteroids continued until improvement to grade 1 ICANS and then taper; 
for example, methylprednisolone IV 1 g/day for 3 days, followed by rapid taper at 250 mg 
every 12 h for 2 days, 125 mg every 12 h for 2 days, and 60 mg every 12 h for 2 days 
1 Maximum amount of tocilizumab per dose is 800mg 
Management of children with ICANS or other suspected neurotoxicities should be guided by the 
pediatric cell therapy team with multi-disciplinary involvement where deemed clinically 
necessary from pediatric neurologists, intensivists, and other specialists especially for serious 
adverse events, or those refractory to first-line immunosuppression [Mahadeo, 2019].  
 
10.5.9. 
Management of Prolonged Cytopenia  
10.5.9.1. Definition of prolonged cytopenia, pancytopenia and plastic anemia 
Prolonged cytopenias are defined as Grade 3 or higher neutropenia, anemia or thrombocytopenia 
persisting for ≥ 4 weeks from receiving T cell therapy. 
The definition of Grade 3 or higher cytopenia is based on CTCAE criteria (Version 5.0) and is 
summarized in the table below: 
Hgb (g/dL) 
 Hgb<8.0 g/dL 
White blood cell decreased (K/μL) 
<2000 mm3, <2.0 x 10^9/L 
Neutrophil count (K/μL) 
<1000/mm3; <1.0 x 10^9/L 
Platelet decreased (K/μL) 
 <50,000/mm3; <50.0 x 10^9/L 
There have been previous reported cases of prolonged cytopenias with lymphodepletion 
regimens prior to other adoptive T cell therapies [KYMRIAH EU SmPC; KYMRIAH USPI; 
YESCARTA EU SmPC; YESCARTA UPSI; TECARTUS SmPC; TECARTUS USPI; 
BREYANZI USPI]. Cases of aplastic anemia have also been observed after high dose 
lymphodepletion regimens [D’Angelo, 2017, Chodon, 2014, Nguyen, 2019]. 
Pancytopenia refers to an abnormal reduction in the number of red blood cells, white blood cells, 
and blood platelets.  Aplastic anemia is a rare hematological disorder and is defined as diagnosis 
of severe aplastic anemia made in the setting of a hypocellular bone marrow when 2 of the 
following 3 blood counts are met: Absolute Neutrophil Count < 500/μL, Absolute Reticulocyte 

 
 
 
             
 
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Count < 60,000/μL, and Platelet Count < 20,000/μL with the exclusion of myelodysplastic 
syndrome.   
Subjects may be symptomatic on presentation, but some are detected incidentally when 
unexpected cytopenias are found on a routine blood count. The clinical consequences of aplastic 
anemia are life-threatening bleeding from thrombocytopenia, and infection as a result of 
neutropenia.  Bacterial and fungal infections are common and a significant cause of morbidity 
and mortality. 
10.5.9.2. Management of Prolonged Cytopenias 
Management of bone marrow suppression and related prolonged cytopenias is challenging, with 
no clearly established guidelines regarding immunosuppression.  Treatment is largely supportive, 
including transfusions and treatment of infections.  If there is evidence of, or concern for the 
development of prolonged cytopenias (decreasing hemoglobin, platelets or neutrophils, and 
increasing transfusion requirements) persisting for ≥4 weeks from T cell therapy the following 
measures should be implemented: 
1. Consult a physician with expertise in the management of bone marrow suppression 
2. Increase the frequency of CBCs as clinically indicated. 
3. Exclude other alternative etiologies such as other drugs, viral causes, etc. 
4. An early bone marrow biopsy is recommended for clinical diagnosis, with a sample to be 
provided to the Sponsor for study. Details on tissue collections, kit use and shipment 
information can be found in the Laboratory Manual. 
5. A matched peripheral blood sample should be collected in parallel with the bone marrow 
sample and provided to the Sponsor  
6. Initiate treatment with G-CSF 
7. Consult an Infectious Diseases expert 
8. Once alternative etiologies have been excluded, strongly consider immunosuppression 
(e.g. methylprednisolone 2 mg/kg initial dose) or more aggressive regimens (e.g. 
antithymocyte globulin (ATG), cyclosporine, eltrombopag) as well as antimicrobial 
prophylaxis/therapy with the advice of your Hematology/Infectious Diseases 
consultant(s).  If high dose corticosteroids are initiated, duration of therapy and taper 
should be determined with advice from expert consultants. 
 
Management of prolonged cytopenias in children should be guided by a pediatric haematologist 
with expertise in cell therapy/stem cell transplantation following the above guidelines.  

 
 
 
             
 
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10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Females of Childbearing Potential (FCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered FCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.6.1. 
Contraception Guidance: 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively.  The required duration of contraception is described below: 

 
 
 
             
 
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• Female subjects of childbearing potential (FCBP) must agree to use an effective 
method of contraception starting at the first dose of chemotherapy and continuing for 
at least 12 months, or 4 months after the gene modified cells are no longer detected in 
the blood, whichever is longer. 
• Male subjects must be surgically sterile or agree to use a double barrier contraception 
method or abstain from heterosexual activity with a female of childbearing potential 
starting at the first dose of chemotherapy and continuing for 4 months thereafter or 
longer (if indicated in the country specific monograph/label for cyclophosphamide). 
Effective methods of contraception include: intra-uterine device, injectable hormonal 
contraception, oral contraception, or two adequate barrier methods (e.g. diaphragm with 
spermicide, cervical cap with spermicide, or female condom with spermicide – spermicides alone 
are not an adequate method of contraception). 
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local Regulatory Agencies and IRBs/IECs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
The contraception guidelines should continue to be followed during long-term follow up. 
10.6.2. 
Collection of Pregnancy Information 
10.6.2.1. Female Participants who become pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as described in 
Section 10.4.4 . While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

 
 
 
             
 
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• Any female participant who becomes pregnant while participating in the study will be 
discontinued from further efficacy assessments (exposure to radiation from imaging 
studies is contraindicated in pregnancy), and will follow the LTFU schedule. 
10.6.2.2. Male participants with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive ADP-A2M4. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  

 
 
 
             
 
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10.7. 
Appendix 7: Long Term Follow Up 
10.7.1. 
Background to Safety Monitoring in LTFU 
10.7.1.1. Monitoring and Management of Replication-Competent Lentivirus (RCL) 
Replication Competent Lentivirus (RCL) is a theoretical risk associated with the use of lentiviral 
vectors; no RCL has ever been detected in vitro or in vivo.  The risk is derived from the detection 
of replication competent retrovirus (RCR) during the use of early γ retroviral vector packaging 
systems which were inadequately designed to avoid recombination events between the vector and 
packaging components [Miller, 1990].  RCR resulted in death due to the onset of lymphoma in 3 
of 10 monkeys after receiving bone marrow cells transduced with an RCR contaminated vector lot 
[Donahue, 1992].  Updated γ retroviral packaging systems have not been associated with RCR, 
however as a result of the Donahue study, RCR/RCL must continue to be rigorously evaluated in 
vector and cell lots, and in subjects post infusion with any product involving a retrovirus [FDA, 
2006; EMA, 2009]. 
A RCL may be generated during the production phase or subsequently after introduction of vector 
transduced cells into the subject. RCL may be generated by homologous or non-homologous 
recombination between the transfer vector and packaging elements, or endogenous retroviral 
elements [Chong, 1998; Garrett, 2000].  A RCL resulting from the production phase of the 
lentivirus used in this trial is highly unlikely since elements are incorporated in the design of the 
vector system that minimize vector recombination and generation of RCL. Nevertheless, 
generation of an RCL by recombination with an endogenous virus (i.e., HIV) in the subject 
following infusion of the cell product remains a theoretical possibility. The consequences of such 
recombination events could be neutral, could reduce the replication rate or pathogenicity of the 
subject's endogenous virus, or could increase the replication rate or pathogenicity of the subject's 
endogenous virus. Since the development of a strain with increased pathogenicity would pose 
greater risk to both the subject and their close contact(s), periodic monitoring for RCL is conducted 
during the course of the trial and during the 15 year follow up. 
10.7.1.2. Insertional oncogenesis 
Monitoring for insertional oncogenesis follows the recommendations set forth in the FDA and 
EMA guidance [FDA, 2006a; FDA, 2006b; EMA, 2009].  Insertional oncogenesis is a theoretical 
risk in T cells transduced with a lentiviral vector.  T cells appear resistant to transformation by 
integrating viruses [Cattoglio, 2010; Newrzela, 2008]. However, there are cases of oncogenesis 
with γ-retroviral transduced stem cells.  Four  of nine subjects with X-linked severe combined 
immunodeficiency (SCID-X1) treated with retrovirus transduced stem cells were found to have 
insertion near the LMO2 proto-oncogene promoter, leading to aberrant transcription and 
expression of LMO2 which resulted in acute T-cell lymphoblastic leukemia [Hacien-Bey-Abina,  
2003; Hacien-Bey-Abina, 2014].  Additionally,  two subjects treated for X-linked chronic 
granulomatous disease (X-CGD) with retroviral transduced stem cells demonstrated insertional 
activation of the EVI1 transcription factor which resulted in genetic instability, monosomy 7 and 
clonal progression toward myelodysplasia [Stein, 2010].    

 
 
 
             
 
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10.7.2. 
Testing for RCL and Persistence 
RCL will be monitored using a PCR-based assay that detects and measures copies of the gene 
coding for the vector’s envelope protein, namely VSV-G that is necessary for the assembly of 
pseudotyped infectious lentiviral particles but absent from the vector’s backbone. The scheme for 
RCL testing is presented in Figure 1 below.  RCL testing and monitoring will take place on 
subject’s peripheral blood mononuclear cells (PBMCs) which will be collected at Baseline and 
then at 3, 6, and 12 months post-infusion and annually from year 2-15.   Samples will be tested for 
the presence of VSV-G DNA copies.  
If all samples are negative in year one, PBMC samples will be collected and archived annually 
until 15 years post-infusion. Samples will be archived at Adaptimmune’s centralized biorepository.   
If a positive VSV-G DNA signal is obtained, the study investigator will be informed and the 
subject will be scheduled for a retest as soon as possible and no later than one month after the 
initial positive result was reported to the Sponsor.   The DSMB will be notified and a review by 
Adaptimmune’s Safety Review Team and Safety Governance Board will take place.  
Response to potential outcomes of second test: 
• If the second test is negative, then subject samples will continue to be tested for VSV-G 
DNA copies until VSV-G DNA copies are not detected for 3 consecutive annual 
assessments as described in Figure 1, at which time the subject samples will be collected 
and archived annually until year 15. 
• If the second test is positive, infusions for all subjects receiving T cells modified with the 
same vector lot will be postponed. The subject with the confirmed positive VSV-G signal 
will be scheduled for leukapheresis and a biological RCL test will be performed on the 
leukapheresis product.  The biological RCL test assesses whether there is active production 
of infectious viral particles from the leukapheresis product [Manilla, 2005].  
If the biological RCL test is positive, all infusions using the same T cell receptor in the 
interventional protocol(s) will be halted.  An action plan will be discussed with FDA and other 
regulatory authorities and experts as appropriate.  Additional subjects will not be treated with the 
same T cell receptor until such time as a plan is completed, reviewed, and agreed upon.   
If the biological RCL test is negative, infusions for all subjects can resume. 
Regulatory agencies and the gene therapy community have previously discussed measures to be 
taken should a biological RCL be confirmed in a subject [FDA, 2006a]. However, because the 
probability and characteristics of a RCL are unknown, no concrete plans have been put in place. 
As of the writing of this protocol, it is agreed the subject must be isolated and no additional subjects 
treated with the same T cell receptor therapy until a plan is agreed upon as outlined above. 
The following approaches have been discussed for subject management: 
1. Intensive follow up of subject in consultation with FDA, and other regulatory authorities,   
NIH, gene therapy experts, study investigators, and HIV physicians. 
2. Provide targeted antiretroviral therapies based on genotyping of the RCL. 

 
 
 
             
 
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Figure 1: 
Flow chart for testing for Replication Competent Lentivirus (RCL) 
 
 
PBMC samples will be collected and used as the “surrogate sample” for monitoring persistence of 
gene modified cells in subjects. Subject samples will be tested for persistence at 3, 6 and 12 months 
post-infusion and every 6 months for 5 years and annually from year 6-15 in accordance with the 
FDA and EMA guidance [FDA, 2006a; FDA, 2006b; EMA, 2009].  The scheme for testing for 
persistence is presented in Figure 2. 
The samples will be tested using a PCR-based method to detect the presence of the integrated 
vector sequences Psi DNA, both of which are part of the lentiviral vector used to transduce T cells. 
Detection of Psi DNA copies reflects persistence of the genetically modified T cells.  If at 1 year 
or beyond post-infusion, greater than 1% PBMCs test positive for vector sequences, the subject’s 
PBMCs will be evaluated for integration site analysis (see Figure 2).  If no gene modified cells are 
detected for three consecutive assessments and subject is ≥5 years post-infusion (for example, 
negative persistence assessments at year 4, 4.5 and 5), no further monitoring of PBMCs is required 
for persistence and collection of samples for persistence may be discontinued.   NOTE: Samples 
for RCL must continue to be collected and archived annually for 15 years post-infusion.  
Hematology and chemistry assessments may also be discontinued.   
 
Test for RCL 
Yr 1: mth 3, 6, 12 
Yr2-15: annually 
YES 
NO  
YES 
NO 
Continue screening 
as described 
Postpone all infusions 
from same vector lot 
Leukapherese positive subject 
and perform  
Biological RCL on product1  
YES 
NO 
Inform investigator and retest 
subject within 30 days 
Continue screening 
as described 
 
RCL Positive? 
Positive on re-test? 
Isolate subject and 
manage accordingly2 
STOP all infusions 
from vector lot 
Positive? 
1 Biological RCL assesses potential to 
grow replicating virus from subject’s 
leukapheresed cells 
2 Protocol describes subsequent 
subject management 
Continue screening 
as described 
Resume all infusions 
from vector lot 
Samples negative in first year or 
negative for 3 consecutive tests? 
YES 
NO  
Continue screening 
as described 
Collect sample 
and archive 

 
 
 
             
 
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Figure 2: 
Flow Chart for Testing for Persistence 
 
10.7.3. 
Integration Site Analysis 
If persistence, as detected by the presence of vector sequences (Psi DNA copies), is present in 
>1% of PBMC at 1 year or beyond post-infusion, DNA from the subject’s PBMCs will be sent 
for Next-Gen Sequencing for integration site analysis.  Integration site analysis assesses clonality 
and the possibility of insertional oncogenesis.   
Clonality is defined as follows: 1) monoclonality is 1 predominant clone at ≥5% of transduced T 
cells; 2) oligoclonality is defined as 2-5 predominant clones, each at ≥5% of transduced T cells; 
and 3) polyclonality is defined as no single predominant clone of ≥5% of transduced T cells. 
If there is clonal dominance in the genetically modified T cell population (either monoclonality 
or oligoclonality) the persistence assessment will be repeated within 3 months on a new sample.  
If the repeated analyses demonstrates: 1) persistent monoclonality, 2) other evidence of 
insertional oncogenesis (for example, integration of the vector in the promoter region of a known 
oncogene or tumor suppressor gene), or 3) clonal expansion (an increase in percent 
predominance of a clone), the DSMB will be notified and there will be a review by 
Adaptimmune’s Safety Review Team and the Sponsor’s Safety Governance Board to develop a 
 
Test for Persistence 
Yr 1:  mth 3, 6, 12 
Yr 2-5:  every 6 mths 
Yr 6-15:  annually 
YES 
 
Persistence Positive? 
a - Insertional site analysis will assess 
insertional oncogenesis, as well 
b - Protocol describes subsequent 
subject management 
YES 
NO  
YES 
NO  
YES 
NO  
YES 
NO  
Continue 
screening as 
described 
NO 
Inform investigator and 
test for Integration site 
analysis (and clonality) 
>1% of PBMC 
(after 1 yr post-infusion) 
Continue 
screening as 
described 
Mono/oligoclonal? 
Continue screening 
as described 
1. Inform 
regulators 
within 30 d 
2. Monitoring 
plan developed 
for subjectb  
Continue 
screening as 
described 
1. Inform 
regulators 
within 30 d 
2. Continue 
screening as 
described 
At least one: 
-Persistent 
monoclonality 
-Evidence of 
insertional 
oncogenesisa 
-Clonal expansion 
Stable 
oligoclonalitya 
Polyclonality 
Re-test for persistence 
within 3 mths 
Stop sample 
collection 
Continue 
screening as 
described 
Negative for 3 
consecutive tests? 
≥ 5 yrs  
post-infusion? 

 
 
 
             
 
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monitoring plan specific to the health care risk and strategies to inform appropriate subjects, 
investigators, FDA and other regulators of the findings.   
If the integration site analysis indicates polyclonality of the genetically modified T cell 
population then screening for persistence continues as scheduled (Table 2, Figure 2). 
10.7.4. 
Letter to Physician – LTFU notification 
[date] 
[name and address] 
 
Dear [physician name], 
 
Your patient [patient name] has participated in a clinical research study, [interventional study 
name and number], that requires 15 year monitoring for adverse events. To aid in reporting of 
adverse events that are possible related to the clinical research study, we are asking the patients 
on our research study to designate a primary care or infectious disease physician that may help in 
the monitoring and reporting of adverse events. Your patient has designated you. If upon any of 
your visits with your patient, any of the following events are reported or discovered, please 
contact the study nurse or physician as soon as possible: 
• New Malignancies 
• New incidence or exacerbation of a pre-existing neurological disorder 
− Excluding all Grade 1 neurologic AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant 
• New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder 
− Excluding all Grade 1 autoimmune AEs and Grade 2 AEs assessed as unrelated, 
unless the Investigator considers clinically significant 
− All rheumatologic disorders will be reported irrespective of grade 
• New incidence of a hematologic disorder 
− Excluding cytopenias following cytotoxic chemotherapy before bone marrow 
recovery 
− Excluding Grade 1 and 2 laboratory abnormalities, unless the Investigator 
considers clinically significant 
• Opportunistic and/or serious infections 
• Excluding infections secondary to chemotherapy induced cytopenias 
• Unanticipated illness or hospitalization deemed at least possibly related to gene 
modified cell therapy 

 
 
 
             
 
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If your patient experiences any of these events, please refer them back to their study physician.  
Please contact the study coordinator below as soon as you can so that they can record the event 
and then monitor your patient’s health if necessary. When you call, remember to mention the 
protocol number of the study which is ADP-0044-002, patient ID [XXX] and the study title 
which is “A Phase 2 Single Arm Open-Label Clinical Trial of ADP-A2M4 SPEAR™ T cells in 
subjects with Advanced Synovial Sarcoma or Myxoid/Round Cell Liposarcoma” 
Study Physician: 
Name:  [Study physician name] 
Phone:  [Study physician phone] 
Email:  [Study physician e-mail] 
Study Coordinator: 
Name:  [Study coordinator name] 
Address:  [Study coordinator address] 
Phone:  [Study coordinator phone] 
Email:  [Study coordinator e-mail] 
If you have any questions about this letter or the study itself, please do not hesitate to contact the 
above study nurse or physician. 
Thank you for your support in helping us to monitor for delayed adverse events. 
Best regards, 
[study physician/coordinator] 

 
 
 
             
 
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10.8. 
Appendix 8:  Efficacy Reporting 
10.8.1. 
RECIST 1.1 for Evaluating Response in Solid Tumors 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. CT with contrast is the best 
currently available and reproducible method to measure lesions selected for response assessment. 
MRI is also acceptable in certain situations (e.g., for body scans but not for lung). Ultrasound 
(US) should not be used to measure tumor lesions.  The same modality should be used when 
comparing or making assessments. 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm in 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a subject to be considered in complete response. 
Cytology and histology can be used in rare cases (e.g., for evaluation of residual masses to 
differentiate between Partial Response and Complete Response or evaluation of new or enlarging 
effusions to differentiate between Progressive Disease and Response/Stable Disease). 
Use of endoscopy and laparoscopy is not advised. However, they can be used to confirm 
complete pathological response. 
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
Measurable lesions 
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:  
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans 
have slice thickness >5 mm, the minimum size should be twice the slice thickness). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• Malignant lymph nodes to be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered measurable if the soft tissue component meets the 
definition of measurability for non-nodal lesions described above. 

 
 
 
             
 
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• ‘Cystic lesions’ thought to represent cystic metastases can be considered measurable 
if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target 
lesions. 
Non-measurable lesions 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm 
or pathological lymph nodes with 10 to <15 mm short axis), as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. Blastic bone lesions are non-measurable. 
• Lesions with prior local treatment, such as those situated in a previously irradiated 
area or in an area subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion. Study 
protocols should detail the conditions under which such lesions would be considered 
measurable. 
Target Lesions 
• Measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. 
• Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements. 
• All measurements should be recorded in metric notation using calipers if clinically 
assessed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters, which will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. If lymph nodes are to be 
included in the sum, only the short axis will contribute. 
Non-target Lesions 
All lesions (or sites of disease) not identified as target lesions, including pathological lymph 
nodes and all non-measurable lesions, should be identified as non-target lesions and be recorded 
at baseline. Measurements of these lesions are not required and they should be followed as 
‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’. 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm 

 
 
 
             
 
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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note:  the appearance of one or more new lesions is also 
considered progression – see below)  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions: 
• Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  When 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even 
if complete response criteria are met since a normal lymph node is defined as having 
a short axis of <10 mm. 
• Target lesions that become ‘too small to measure’.  While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small.  However, sometimes lesions or 
lymph nodes become so faint on a CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’, in which case a default value of 5 mm should be assigned.   
• Lesions that split or coalesce on treatment.  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits. 
 

 
 
 
             
 
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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
Special notes on assessing progression of Non-Target lesions 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
• When subject has measurable disease.  To achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. 
• When subject has only non-measurable disease. There is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified, a useful 
test that can be applied is to consider if the increase in overall disease burden based 
on change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease. Examples include an 
increase in a pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic 
disease from localized to widespread. 
New lesions 
The appearance of new malignant lesions denotes disease progression: 
• The finding of a new lesion should be unequivocal (i.e., not attributable to differences 
in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor, especially when the subject’s baseline lesions show 
partial or complete response). 
• If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the scan where the new lesion was first identified. 
• A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion and disease progression. 
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up – is PD based on a new 
lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 

 
 
 
             
 
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• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
Summary of the overall response status calculation at each time point: 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required1 
CR 
CR 
No 
CR 
>4 wks. Confirmation2 
CR 
Non-CR 
Non-PD 
No 
PR 
 
>4 wks. Confirmation3 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR 
Non-PD 
Not evaluated 
No 
PR 
SD 
Non-CR 
Non-PD 
Not evaluated 
No 
SD 
Documented at least once >4 
wks. from ADP-A2M4 infusion 
Not all evaluated Non-PD 
No 
NE 
 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
Any 
PD3 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. See RECIST 1.1 manuscript for further details on what is evidence of a new lesion [Eisenhauer, 2009] 
2.  Only for non-randomized trials with response as primary endpoint 
3. In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression 

 
 
 
             
 
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Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. Confirmation of 
response is established by no evidence of disease progression at the subsequent time point. This 
will also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
Missing Assessments and Non-evaluable Designation 
When no imaging/measurement is done at all at a particular time point or the imaging is 
technically unreadable, the subject is not evaluable (NE) at that time point.  If only a subset of 
lesion measurements are made at an assessment, usually the case is also considered NE at that 
time point, unless a convincing argument can be made that the contribution of the individual 
missing lesion(s) would not change the assigned time point response.  This would most likely 
happen in the case of PD. 
 

 
 
 
             
 
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10.9. 
Appendix 9: ECOG Performance Status 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
[Oken, 1982] 
10.10. 
Appendix 10: Lansky Performance Status (for use in subjects <16 
years old) 
 
Mapping 
to ECOG 
Lansky 
Score 
Score 
Description 
0 
100% 
Fully active, normal. 
90% 
Minor restrictions in physically strenuous activity. 
1 
80% 
Active, but tires more quickly. 
70% 
Both greater restriction of, and less time spent in, play activities. 
2 
60% 
Up and around, but minimal active play; keeps busy with quieter activities. 
50% 
Gets dressed, but lies around much of the day; no active play; able to 
participate in quiet play and activities.  
3 
40% 
Mostly in bed; participates in quiet activities. 
30% 
In bed; needs assistance even for quiet play. 
4 
20% 
Often sleeping; play entirely limited to very passive activities. 
10% 
No play; does not get out of bed 
5 
0% 
Unresponsive; Dead 
[Lansky, 1987] 

 
 
 
             
 
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10.11. 
Appendix 11:  EQ-5D-3L Health Questionnaire (SAMPLE) 
 

 
 
 
             
 
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10.12. 
Appendix 12: EORTC-QLQ-C30 Questionnaire (SAMPLE) 

 
 
 
             
 
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10.13. 
Appendix 13: PedsQLTM Questionnaire (SAMPLE) 

 
 
 
             
 
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10.14. 
Appendix 14: Abbreviations 
The following abbreviations and specialist terms are used in this study protocol. 
AE 
Adverse event 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANSM 
Agence Nationale de Sécurité du Médicament et des Produits de Santé 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
CAPD 
Cornell Assessment Pediatric Delirium Score  
CBC 
Complete blood count 
CDC 
Centers for Disease Control 
cfDNA 
Cell free DNA 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMV 
Cytomegalovirus 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
CRO 
Complete response 
Contract Research Organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSR 
Clinical Study Report 
CT 
Computerized tomography 
CTA 
Cancer-testis antigen 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DoSD 
Duration of stable disease 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein Barr virus 

 
 
 
             
 
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EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EDTA 
Ethylene-diaminetera acetic acid 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
FCM 
Flow cytometry 
FCBP  
Female of childbearing potential 
FDA 
Food and Drug Administration  
FFPE 
Formalin-fixed, paraffin embedded 
FR 
France 
FTIH 
First Time In Human 
5-FU 
5-Fluorocuracil 
GCP 
Good clinical practice 
G-CSF 
Granulocyte-colony stimulating factor 
GFR 
Glomerular filtration rate 
GGTP 
Gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GMP 
Good manufacturing practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HPV 
Human papilloma virus 
IB 
Investigator’s Brochure 
IBW 
Ideal body weight 
ICANS 
Immune Effector Cell-Associated Neurotoxicity Syndrome 
ICE 
Immune Effector Cell-Associated Encephalopathy 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
ID 
Identifier 

 
 
 
             
 
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IEC 
Independent Ethics Committee 
IFN 
Interferon 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMRT 
Intensity modulated radiation therapy 
IND 
Investigational New Drug application 
ISL 
Investigator Safety Letters 
INR  
International normalized ratio 
IP 
Investigational Product  
IRB 
Institutional Review Board 
ITT 
IV 
Intent-to-Treat  
Intravenous 
IVD 
In vitro diagnostic 
K-M 
Kaplan-Meier 
LDH 
Lactic acid dehydrogenase 
LLOQ 
Lower Limit of Quantification 
LMO2 
LIM domain only 2 
LTFU 
Long term follow up 
LTR 
Long terminal repeat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MHRA 
mITT 
Medicines and Healthcare Products Regulatory Agency 
Modified Intent-to-Treat 
MRCLS 
MRI 
Myxoid/Round Cell Liposarcoma 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple-gated acquisition scan 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NK 
Natural killer cell 
NRSTS 
Non-rhabdomyosarcoma Soft Tissue Sarcoma  
NS 
Normal Saline 
NSCLC 
Non-small cell lung cancer 

 
 
 
             
 
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NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PI 
Principal Investigator 
PTT 
Partial thromboplastin time 
PR 
Partial response 
qPCR 
Quantitative polymerase chain reaction 
RAC 
Recombinant DNA Advisory Committee 
RC 
Research Committee 
RCL 
Replication competent lentivirus 
RCR 
Replication competent retrovirus 
RECIST 
RIND 
Response Evaluation Criteria in Solid Tumors 
Reversible ischemic neurologic deficit 
RNA 
Ribonucleic acid 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SCID-X 
Severe combined immunodeficiency disease – X linked  
SD 
Stable disease 
SGPT 
Serum glutamate-pyruvate transaminase 
SIN 
Self-inactivating 
SOP 
Standard operating procedure 
SPEAR 
Specific Peptide Enhanced Affinity Receptor 
SPM 
Study Procedures Manual 
SRC 
Safety Review Committee  
SUSAR 
Suspected, unexpected serious adverse reactions 
TCR 
TIA 
T cell receptors 
Transient ischemic attack 

 
 
 
             
 
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TILs 
Tumor-infiltrating lymphocytes 
TKI 
Tyrosine kinase inhibitor 
TTR 
Time to response 
TURBT 
Transurethral resection of bladder tumor 
ULN 
Upper limit of normal 
VSV-G 
Vesicular Stomatitis Virus G glycoprotein 
WBC 
White blood cell 
WHO 
World Health Organization 
X-CGD 
X-linked chronic granulomatous disease 

 
 
 
             
 
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10.15. 
Appendix 15: Protocol Amendment History 
Protocol Version Amendment 3, FR 4.0 (FR-4.0) dated 18MAY2021 is replaced in France only 
by Protocol Amendment 3, FR 5.0 (FR-5.0) dated 28OCT2021. 
 
 
Sections amended 
Change  
Rationale for change 
Time and Events 1.3 
and section 8.7 
Update to blood volume 
collection to comply with 
European recommendations for 
pediatric subjects 
Addition requested by ANSM 
Synopsis, 5.2 
Inclusion criteria 5 updated to 
include progression within 6 
months of the 
neoadjuvant/adjuvant treatment 
Addition requested by ANSM 
Synopsis, 5.2 
Inclusion Criteria 9 updated to 
include Lansky score ≥ 80% 
Addition requested by ANSM 
10.2.2 
Inclusion of SRC 
Addition of SRC to ensure 
safety oversight of pediatric 
subjects as requested by ANSM 

 
 
 
             
 
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10.16. 
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