A Phase 2 Open-Label Clinical Trial of ADP-A2M4CD8 in Subjects With Advanced Esophageal or Esophagogastric Junction Cancers
Phase: PHASE2
Conditions: Esophageal Cancer, Esophagogastric Junction Cancer
Sponsor: Adaptimmune

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 1 of 144 
 
 
 
 
 
 
PROTOCOL NUMBER ADP-0055-002 
 
 
A PHASE 2 OPEN-LABEL CLINICAL TRIAL OF ADP-A2M4CD8 IN SUBJECTS 
WITH ADVANCED ESOPHAGEAL OR ESOPHAGOGASTRIC JUNCTION CANCERS  
(SURPASS-2 STUDY) 
 
 
PROTOCOL VERSION: AMENDMENT 2.0 
DATE:  17 NOVEMBER 2021 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 2 of 144 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
Protocol Title: 
A Phase 2 Open-Label Clinical Trial of ADP-A2M4CD8 in Subjects with 
Advanced Esophageal or Esophagogastric Junction Cancers 
 
 
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-A2M4CD8 
Investigator’s Brochure. 
 
 
Investigator Name 
 
Investigator Title 
 
Investigator Site and Address 
 
Investigator Signature 
 
Date 
 
 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 3 of 144 
 
CLINICAL STUDY PROTOCOL 
 
Title: 
A Phase 2 Open-Label Clinical Trial of ADP-A2M4CD8 in Subjects with 
Advanced Esophageal or Esophagogastric Junction Cancers 
Product Name: 
ADP-A2M4CD8 
Protocol Number: 
ADP-0055-002  
IND Number: 
 
18950 
EUDRA Number: 
2020-005802-24 
DATE OF ORIGINAL PROTOCOL: 13-JANUARY-2021 
 
Amendment Number 
Date 
Reason for Change 
Original 
13-Jan-2021 
Original version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 4 of 144 
 
Amendment Number 
Date 
Reason for Change 
1.0 
29-JUN-2021 
Addition of futility analysis using 
Chen 3-stage design 
Inclusion criterion #5 updated to limit 
to a maximum of two prior lines of 
combination or single agent systemic 
treatment for advanced or metastatic 
disease before treatment with ADP-
A2M4CD8 as the next therapy and to 
reflect the recent approval of 
pembrolizumab in combination with 
platinum and fluoropyrimidine-based 
chemotherapy in the first line setting 
for this patient population. 
Added secondary endpoint to evaluate 
efficacy in this population based on 
investigator radiological assessments.  
Additional whole blood samples to 
conduct RNA sequencing to support 
understanding of the TCR/BCR 
repertoire at the gene expression level. 
Correction of errors and omissions 
from Original Protocol. 
Updated supportive care guidance, 
including the treatment of subjects 
receiving vaccination for or infected 
with COVID-19.  
Incorporate protocol administrative 
letters related to Brain MRI, dated 
19Feb2021 and wording of entry 
criteria, dated 28 Apr2021. 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 5 of 144 
 
Amendment Number 
Date 
Reason for Change 
2.0 
17-NOV-2021 
Update to statistical methodology 
Addition of Pulmonary Function 
Testing  
Addition of Inclusion Criteria #14 
Update to Exclusion Criteria #8 
Addition of Pulse Oximetry for safety 
assessments 
Addition of Pulmonary Function Tests 
to safety assessments 
Correction to Table 4 lymphodepletion 
regimen 
Update to the Management of 
Cytokine Release Syndrome (CRS) 
 
CONFIDENTIALITY STATEMENT 
This document contains information which is the property of Adaptimmune Limited, United 
Kingdom, 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-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 6 of 144 
 
 
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 
17-Nov-2021

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 7 of 144 
 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Schema ........................................................................................................................29 
1.3. 
Time and Events Table ...............................................................................................30 
 
Main Time and Events (T&E) Table ..........................................................................30 
 
Long-Term Follow-Up Time and Events Table .........................................................35 
2. 
INTRODUCTION ......................................................................................................36 
2.1. 
Study Rationale ...........................................................................................................36 
 
Rationale for Using ADP-A2M4CD8 in Esophageal or Esophagogastric 
Cancers .......................................................................................................................36 
2.2. 
Background .................................................................................................................37 
 
ADP-A2M4CD8 SPEAR T-cell Background ............................................................37 
 
Discovery of ADP-A2M4CD8 ...................................................................................38 
 
Current Therapies for Esophageal or Esophagogastric Junction Cancers 
Emerging Data from ADP-A2M4CD8 and Other TCRs ............................................40 
2.3. 
Benefit/Risk Assessment ............................................................................................41 
 
Benefit .........................................................................................................................41 
 
Risk .............................................................................................................................42 
 
Overall Benefit: Risk Conclusion ...............................................................................43 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................44 
4. 
STUDY DESIGN .......................................................................................................46 
4.1. 
Overall Design ............................................................................................................46 
 
Pre-screening ..............................................................................................................46 
 
Screening ....................................................................................................................46 
 
Enrollment ..................................................................................................................47 
4.2. 
Scientific Rationale for Study Design ........................................................................48 
 
Pre-screening for HLA Alleles and MAGE-A4 Expression .......................................49 
4.2.1.1. 
HLA ............................................................................................................................49 
4.2.1.2. 
MAGE-A4 Expression in Tumor ................................................................................49 
 
T-cell Manufacturing ..................................................................................................50 
 
Lymphodepletion ........................................................................................................50 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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Long-Term Follow-Up ...............................................................................................51 
4.3. 
Justification for Dose ..................................................................................................51 
4.4. 
End of Study Definition ..............................................................................................52 
5. 
STUDY POPULATION .............................................................................................53 
5.1. 
HLA and Antigen Pre-screening ................................................................................53 
5.2. 
Inclusion Criteria ........................................................................................................53 
5.3. 
Exclusion Criteria .......................................................................................................55 
5.4. 
Screen Failures ............................................................................................................59 
5.5. 
Number of Subjects and Study Duration ....................................................................59 
5.6. 
Sites .............................................................................................................................59 
6. 
STUDY INTERVENTION ........................................................................................59 
6.1. 
Leukapheresis .............................................................................................................59 
6.2. 
Lymphodepleting Chemotherapy ...............................................................................60 
 
Fludarabine Dose Adjustment for Renal Impairment .................................................61 
 
Mesna ..........................................................................................................................61 
 
G-CSF .........................................................................................................................62 
6.3. 
Investigational Product ...............................................................................................62 
 
Premedication .............................................................................................................62 
 
T-cell Infusion ............................................................................................................62 
6.4. 
Preparation/Handling/Storage/Accountability ............................................................64 
 
Packaging and Labelling .............................................................................................64 
 
Receipt and Return .....................................................................................................64 
 
Storage and Handling .................................................................................................64 
 
Investigational Product Accountability/Traceability ..................................................64 
 
Alert Cards ..................................................................................................................65 
6.5. 
Concomitant Medications ...........................................................................................65 
 
Prohibited Concomitant Medications .........................................................................65 
 
Permitted Concomitant Medications ..........................................................................66 
6.5.2.1. 
Vaccinations (Including for COVID-19) ....................................................................66 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................67 
7.1. 
Temporary Study Stoppage ........................................................................................67 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
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Version: Amendment 2.0 
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Date: 17-NOV-2021 
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7.2. 
Ending the Interventional Phase .................................................................................67 
7.3. 
Subject Discontinuation ..............................................................................................67 
7.4. 
Lost to Follow-Up.......................................................................................................68 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................69 
8.1. 
Background Assessments ...........................................................................................69 
 
Demographics .............................................................................................................69 
 
Disease History and Tumor-Specific Mutations .........................................................69 
8.2. 
HLA and MAGE-A4 Tumor Antigen Testing ............................................................69 
 
HLA ............................................................................................................................69 
 
MAGE-A4 Antigen ....................................................................................................69 
8.3. 
Efficacy Assessments .................................................................................................70 
 
CT/MRI.......................................................................................................................70 
 
Survival Data ..............................................................................................................71 
8.4. 
Safety Assessments .....................................................................................................71 
 
Medical History ..........................................................................................................72 
 
Physical Examination .................................................................................................72 
 
Prior Anti-Cancer Therapies .......................................................................................72 
 
Prior and Concomitant Medications ...........................................................................72 
 
ECOG .........................................................................................................................72 
 
Vital Signs ..................................................................................................................72 
 
Weight and Height ......................................................................................................72 
 
Pulse Oximetry ...........................................................................................................72 
 
Cardiac Assessments ..................................................................................................72 
8.4.9.1. 
ECG ............................................................................................................................72 
8.4.9.2. 
ECHO/MUGA ............................................................................................................73 
8.4.9.3. 
Telemetry ....................................................................................................................73 
8.4.9.4. 
Pulmonary Function Tests ..........................................................................................73 
 
Brain MRI ...................................................................................................................73 
 
Renal Function Assessment (Creatinine Clearance) ...................................................73 
 
Hematology .................................................................................................................73 
 
Clinical Chemistry ......................................................................................................74 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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Coagulation .................................................................................................................74 
 
Thyroid Function Tests ...............................................................................................74 
 
Hepatic Safety Assessments .......................................................................................74 
 
Pregnancy Test ............................................................................................................74 
 
Infectious Disease Screening ......................................................................................74 
 
CMV PCR ...................................................................................................................74 
 
ICE Assessment Tool .................................................................................................75 
 
C-Reactive Protein ......................................................................................................75 
 
Ferritin ........................................................................................................................75 
 
Persistence (Vector Copies) ........................................................................................75 
 
Replication Competent Lentivirus (VSV-G DNA) ....................................................75 
8.5. 
Adverse Events and Serious Adverse Events .............................................................76 
 
Time Period for Collecting AE and SAE Information ...............................................76 
 
Method of Detecting AEs and SAEs ..........................................................................77 
 
Follow-Up of AEs and SAEs ......................................................................................77 
 
Regulatory Reporting Requirements for SAEs ...........................................................77 
 
Pregnancy ...................................................................................................................77 
 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................78 
 
AEs of Special Interest ...............................................................................................78 
8.5.7.1. 
Cytokine Release Syndrome .......................................................................................78 
8.5.7.2. 
Immune Effector Cell-Associated Neurotoxicity Syndrome ......................................79 
8.5.7.3. 
Prolonged Cytopenias .................................................................................................79 
 
Long-Term Follow-Up Adverse Events .....................................................................80 
8.5.8.1. 
LTFU Letter to Primary Care Physician/Oncologist ..................................................80 
8.6. 
Biomarkers for Exploratory Objectives ......................................................................80 
 
Tumor Biopsy .............................................................................................................81 
 
Cytokine and Soluble Protein Analysis ......................................................................82 
 
Liquid Biopsy Collection and Analysis (Blood Plasma) ............................................82 
 
Gene expression analysis in whole blood ...................................................................83 
 
Cell Phenotype and Functional Assays .......................................................................83 
 
Persistence of ADP-A2M4CD8 Cells ........................................................................83 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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8.7. 
Subject-Reported Outcomes .......................................................................................84 
 
EuroQOL Group EQ-5D 3 Level Version (EQ-5D-3L) .............................................84 
9. 
STATISTICAL CONSIDERATIONS .......................................................................84 
9.1. 
Study Populations .......................................................................................................84 
9.2. 
Statistical Hypotheses and Sample Size Assumptions ...............................................85 
9.3. 
Statistical Analyses .....................................................................................................86 
 
Interim Analysis ..........................................................................................................86 
 
Efficacy Anti-Tumor Activity Analyses .....................................................................86 
 
Safety Analyses ..........................................................................................................88 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................89 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................89 
 
Data Handling and Record Keeping ...........................................................................89 
10.1.1.1. 
Data Management .......................................................................................................89 
10.1.1.2. 
Case Report Forms .....................................................................................................89 
10.1.1.3. 
Site Documentation and Source Data .........................................................................89 
10.1.1.4. 
Data Retention and Availability .................................................................................90 
 
Study Monitoring ........................................................................................................90 
10.1.2.1. 
Audits and Inspections ................................................................................................91 
 
Regulatory and Ethical Considerations ......................................................................91 
10.1.3.1. 
Competent Authority Submissions .............................................................................91 
10.1.3.2. 
Independent Ethics Committees .................................................................................91 
10.1.3.3. 
Local Regulations/Declaration of Helsinki ................................................................91 
 
Informed Consent .......................................................................................................91 
 
Confidentiality ............................................................................................................92 
 
Protocol Adherence ....................................................................................................92 
 
Study Suspension, Study Termination, and Study Completion ..................................92 
 
Public Posting of Study Information ..........................................................................93 
 
Clinical Study Report .................................................................................................93 
 
Publication Policy .......................................................................................................93 
 
Financial Disclosure ...................................................................................................93 
10.2. 
Appendix 2: Safety Review ........................................................................................94 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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Data Safety Monitoring Board ....................................................................................94 
10.3. 
Appendix 3: Clinical Laboratory Tests .......................................................................95 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .......................................................................97 
 
Definition of AE .........................................................................................................97 
 
Definition of SAE .......................................................................................................98 
 
Recording and Follow-Up of AE and/or SAE ............................................................99 
 
Reporting of SAEs ....................................................................................................101 
 
Hepatic Monitoring and Follow-Up Assessments ....................................................101 
 
Reporting Criteria During Long-Term Follow-Up (Years 1-15) .............................103 
 
Request for Autopsy for Death Following Administration of Gene Transfer 
Agents .......................................................................................................................104 
10.5. 
Appendix 5: Supportive Care Guidance ...................................................................104 
 
Lymphodepleting Chemotherapy Symptom Management .......................................104 
10.5.1.1. 
Management of Neutropenia ....................................................................................104 
 
T-cell Infusion Symptom Management ....................................................................105 
 
Infection ....................................................................................................................105 
10.5.3.1. 
SARS-CoV-2 (COVID-19) ......................................................................................105 
10.5.3.2. 
Pneumocystis jiroveci Pneumonia ............................................................................105 
10.5.3.3. 
Herpes Simplex and Varicella Zoster .......................................................................105 
10.5.3.4. 
Cytomegalovirus (CMV) ..........................................................................................106 
10.5.3.5. 
Hepatitis B Prophylaxis ............................................................................................106 
10.5.3.6. 
Syphilis .....................................................................................................................106 
10.5.3.7. 
Other Anti-Microbial Prophylaxis ............................................................................106 
 
Hematologic and Blood Product Support .................................................................106 
10.5.4.1. 
Irradiated Blood Product ...........................................................................................106 
10.5.4.2. 
CMV screened Blood Products ................................................................................107 
 
Management of Autoimmunity .................................................................................107 
 
Management of Cytokine Release Syndrome ...........................................................107 
 
Grading and Management of Neurotoxicity .............................................................111 
10.5.7.1. 
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) ....................................................................................................................111 

 
 
 
             
 
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10.5.7.2. 
Management of ICANS ............................................................................................112 
 
Prolonged Cytopenias ...............................................................................................114 
10.5.8.1. 
Definition of Prolonged Cytopenias, Pancytopenia and Aplastic Anemia ...............114 
10.5.8.2. 
Management of Prolonged Cytopenias .....................................................................115 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information ...............................................................................................................116 
 
Contraception Guidance ...........................................................................................117 
 
Collection of Pregnancy Information .......................................................................117 
10.6.2.1. 
Female Participants Who Become Pregnant .............................................................117 
10.6.2.2. 
Male Participants with Partners Who Become Pregnant ..........................................118 
10.7. 
Appendix 7: Long-Term Follow-Up ........................................................................119 
 
Background to Safety Monitoring in LTFU .............................................................119 
10.7.1.1. 
Monitoring and Management of Replication-Competent Lentivirus (RCL) ............119 
10.7.1.2. 
Insertional Oncogenesis ............................................................................................119 
 
Testing for RCL and Persistence ..............................................................................120 
 
Integration Site Analysis ...........................................................................................122 
 
Letter to Physician - LTFU Notification ..................................................................123 
10.8. 
Appendix 8: Efficacy Reporting ...............................................................................125 
 
RECIST 1.1 Criteria for Evaluating Response in Solid Tumors ..............................125 
10.9. 
Appendix 9: ECOG Performance Status ..................................................................130 
10.10. 
Appendix 10: EQ-5D-3L Health Questionnaire (SAMPLE) ....................................131 
10.11. 
Appendix 12: Abbreviations .....................................................................................134 
10.12. 
Appendix 13: Protocol Amendment History ............................................................138 
10.13. 
References .................................................................................................................139 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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LIST OF TABLES 
Table 1: 
Main T&E Table .........................................................................................................30 
Table 2: 
T&E for Long-Term Follow-Up .................................................................................35 
Table 3: 
MAGE-A4 Expression in Various Cancer Types .......................................................38 
Table 4: 
Fludarabine and Cyclophosphamide Treatment Schema ...........................................61 
Table 5: 
Protocol-Required Safety Laboratory Assessments ...................................................95 
Table 6: 
Hepatic Monitoring Criteria .....................................................................................102 
Table 7:  
ASTCT CRS Consensus Grading .............................................................................108 
Table 8: 
Management Guidelines for CRS .............................................................................109 
Table 9: 
ICE 10‑Point Neurological Assessment (ICE) [Based on Lee, 2019] .....................111 
Table 10: Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) [Based on Lee, 2019] ................................................................................111 
Table 11: Management of ICANS ............................................................................................113 
Table 12: Summary of the best overall response status calculation at each time point ............129 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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LIST OF FIGURES 
Figure 1: 
Flow Chart for Testing for Replication Competent Lentivirus (RCL) .....................121 
Figure 2: 
Flow Chart for Testing for Persistence .....................................................................122 
 
 
 
 
 
 

 
 
 
             
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Title  
A Phase 2 Open-Label Clinical Trial of ADP-A2M4CD8 in Subjects with Advanced Esophageal or 
Esophagogastric Junction Cancers 
Short Title 
ADP-A2M4CD8 in HLA-A2+ Subjects with MAGE-A4 Positive 
Esophageal or Esophagogastric Junction Cancers (SURPASS-2) 
Protocol Number 
ADP-0055-002 
Phase 
2 
Methodology 
This is a single treatment cohort study and subjects will be enrolled based 
upon their tumor type and histology. Subjects with advanced esophageal or 
esophagogastric junction (EGJ; also called GEJ - gastroesophageal 
junction) cancers will be enrolled in this study. Based on the tumor 
histology, this cohort of subjects will have either adenocarcinoma or 
squamous cell carcinoma type of disease.  
Subjects with advanced esophageal or GEJ cancers will be pre-screened to 
determine appropriate HLA and tumor antigen status. Only subjects 
expressing at least 1 HLA-A*02 inclusion allele and no exclusion allele 
(Section 4.2.1.1) and whose tumor expresses the melanoma-associated 
antigen-A (MAGE-A4) antigen by immunohistochemistry (IHC) above a 
designated 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. Enrolled subjects will undergo leukapheresis for 
collection of autologous cells for processing and manufacture into the 
ADP-A2M4CD8 cell Investigational Product (IP).  
At the discretion of the Investigator and to allow for adequate planning for 
the subjects to be treated in this protocol, leukapheresis can be performed as 
soon as possible after the subject is determined to be eligible for study 
participation. Leukapheresis can be performed prior to initiating second-line 
treatment regimen or at the end of second-line treatment. 
Prior to the administration of lymphodepleting chemotherapy, all eligibility 
criteria will be reconfirmed, baseline tumor assessment will be obtained, 
and any issues or concerns will be addressed in advance of 
lymphodepletion, in particular, any factor that might cause or increase the 
risk of prolonged cytopenia. Where issues are identified, the Investigator is 
encouraged to adopt mitigation measures such as reduced lymphodepleting 
regimen or alternative treatment options, if appropriate (Section 6.2).  
If a subject has progressive disease (PD) and cannot be treatment-free, anti-
cancer therapy may be administered between screening and leukapheresis 
and between leukapheresis and the start of lymphodepletion (bridging 
therapy), but the required mandatory wash-out periods must be adhered to 
prior to receiving ADP-A2M4CD8.  

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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Once the ADP-A2M4CD8 cells are available at the site, subjects will 
undergo lymphodepleting chemotherapy with fludarabine 30 mg/m2/day for 
4 days (Day -7 through Day -4) and cyclophosphamide 600 mg/m2/day for 
3 days (Day -7 through Day -5) followed by infusion of ADP-A2M4CD8 
cells on Day 1. Subjects will remain hospitalized for observation for at least 
24 hours post-T-cell infusion. A longer observation period is allowed as 
required per the standard of care at the site level or per regional 
requirements.   
Subjects will have the following study visits for assessment of eligibility, 
efficacy, safety, and biomarkers: Pre-screening, Screening, Leukapheresis, 
Baseline, Lymphodepleting Chemotherapy (Day -7 to Day -4), T-cell 
infusion (Day 1), immediate post-infusion monitoring (Day 1 through to 
Day 8), weekly visits until Week 4 post-infusion, then 6, 8, 12, 16, and 
24 weeks, then every 2 months until disease progression. 
An independent external Data Safety Monitoring Board (DSMB) will be 
responsible for the ongoing monitoring of the safety of subjects during the 
Interventional phase of the study. The DSMB will review safety data 
(including adverse events (AEs) and serious adverse events (SAEs), 
ongoing efficacy data for futility, and overall benefit:risk profile. 
Subjects will undergo disease monitoring by MRI or CT scan at Screening, 
Baseline, Week 4, Week 8, Week 12, Week 16, and Week 24, then every 2 
months ± 28 days 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 through 15. The time 
point at which the subject switches to the LTFU assessments/procedures 
will be driven by the time point at which the subject progresses, for 
example, 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 clinical cut-off for the primary analysis will occur once the last subject 
dosed 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 will also be summarized to provide supportive evidence 
to the primary assessment.  
Study Duration 
Enrollment is expected to be completed in approximately 15 months. The 
study will be considered complete when all subjects complete 15 years of 
follow-up, die, or withdraw early from the study. 
Study Center(s) 
The study will be conducted in approximately 35 sites in North America 
and Europe. Additional sites may be added at the discretion of the Sponsor. 
Number of Subjects 
45 subjects  
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
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Objectives 
Endpoints 
Primary: 
To evaluate the efficacy of 
autologous genetically modified 
specific peptide enhanced affinity 
receptor (SPEAR) T-cells 
(ADP-A2M4CD8) in HLA-A*02 
positive subjects with MAGE-A4 
expressing advanced esophageal or 
GEJ cancers 
Overall response rate (ORR) per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 by independent 
radiological assessment committee 
Secondary: 
To evaluate the safety and 
tolerability of autologous genetically 
modified T-cells (ADP-A2M4CD8) 
in HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced 
esophageal or GEJ cancers 
• 
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-A2M4CD8) in 
HLA-A*02 positive subjects with 
MAGE-A4 expressing advanced 
esophageal or GEJ cancers 
• 
Time to response (TTR) per RECIST v1.1 by 
independent radiological assessment committee 
(IRAC), and by investigator radiological assessment  
• 
Duration of response (DoR) per RECIST v1.1 by the 
IRAC, and by investigator radiological assessment 
• 
Best overall response (BOR) per RECIST v1.1 by the 
IRAC, and by investigator radiological assessment 
• 
Progression-free survival (PFS) per RECIST v1.1 by 
the IRAC, and by investigator radiological 
assessment 
• 
Overall survival (OS) 
• 
ORR per RECIST v1.1 by investigator radiological 
assessment.  
Development and validation of an 
in vitro diagnostic (IVD) assay for 
the screening of tumor antigen 
expression for regulatory approval 
Retention of additional tumor tissue during Pre-screening to 
enable development and validation of the MAGE-A4 antigen 
expression companion diagnostic assay 
Characterize the surrogates of 
treatment effect 
Peak expansion (i.e., maximum persistence) and time to peak 
expansion by responder status and overall 
Exploratory: 
 
 
 
• 
 
 
 
 
 
To characterize the tumor and tumor 
microenvironment pre- and post-T-
• 
 
  

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 19 of 144 
 
 
 
• 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
Page 20 of 144 
 
Inclusion Criteria 
A Subject must meet the following criteria prior to leukapheresis to be 
eligible to participate in the study: 
1. Subject (or legally authorized representative) has voluntarily agreed to 
participate by giving written Informed Consent/Assent (as applicable) 
in accordance with International Council for Harmonization (ICH) GCP 
guidelines and applicable local regulations. 
2. Subject (or legally authorized representative) has agreed to abide by all 
protocol-required procedures including study-related assessments and 
management by the treating institution for the duration of the study, 
including the LTFU. 
3. Age ≥ 18 years to < 75 years at the time the Pre-screening Informed 
Consent is signed. 
4. Histological or cytogenetically confirmed diagnosis of advanced 
(metastatic or inoperable) esophageal or GEJ cancers. 
5. Subject has received a maximum of two prior lines of combination or 
single agent systemic treatment for advanced or metastatic disease 
before treatment with ADP-A2M4CD8 as the next therapy.  
a. Esophageal or GEJ cancers 
Prior therapy requirements in the unresectable locally advanced or 
metastatic setting: 
- 
Subjects should have received a platinum and/or 
fluoropyrimidine-based regimen (such as FOLFOX).  
- 
Subjects may have received anti-PD-1 agent in 
combination with fluoropyrimidine- and platinum-
containing chemotherapy or been offered if available. 
- 
Subjects may have been offered taxane-containing regimen, 
ramucirumab, and/or irinotecan-containing regimen, if 
available.  
- 
Subjects whose tumors are known to be HER2/neu positive 
should have received or been offered a HER2/neu receptor 
inhibitor, if available. 
b. Esophageal squamous cell carcinoma 
Prior therapy requirements in the unresectable locally advanced or 
metastatic setting: 
- 
Subjects should have received a platinum and/or 
fluoropyrimidine-based regimen (such as FOLFOX) and 
may include a taxane-containing regimen, and/or 
irinotecan-containing regimen. 
- 
Subjects whose tumors express PD-L1 or MSI-H/dMMR 
tumors, should have received or been offered anti-PD-
1/anti-PD-L1 therapy if available; unless discussed and 
agreed upon with the sponsor. 
6. Measurable disease according to RECIST v1.1 criteria. 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
Page 21 of 144 
 
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. The Sponsor will review the results 
of HLA typing for inclusion alleles and will adjudicate subject 
eligibility based on HLA results.   
8. Tumor (either an archival specimen or a fresh biopsy) shows 
MAGE-A4 expression of ≥ 2+ staining in ≥ 30% of the cells by IHC.  
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% or the institutional 
lower limit of normal range. 
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 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 subjects must be surgically sterile or agree to use a double barrier 
contraception method or abstain from heterosexual activity with an 
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: 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 22 of 144 
 
14. Subjects must have ≥ 90% room air oxygen saturation test at rest at 
Screening (within 7 days of leukapheresis) and at Baseline. 
System 
Laboratory Value 
Hematology 
ANC 
≥ 1.5 x109/L (without granulocyte-colony 
stimulating factor [G-CSF] support) 
Platelets 
≥ 100 x109/L (without transfusion support within 
7 days prior to lymphodepletion and leukapheresis) 
Hemoglobin 
≥ 90 g/L (without transfusion support within 
7 days prior to lymphodepletion and leukapheresis) 
Coagulation 
Prothrombin Time or 
International 
Normalized Ratio 
≤ 1.5 x upper limit of normal (ULN) unless 
receiving therapeutic anticoagulation 
Partial 
Thromboplastin Time 
(PTT) 
≤ 1.5 x ULN unless receiving therapeutic 
anticoagulation 
Renal 
Glomerular Filtration 
Rate or Creatinine 
Clearance (CrCl) 
(Estimated or 
Calculated)1 
≥ 50 mL/min 
Hepatic 
Serum Total Bilirubin ≤ 1.5 x ULN (unless subject has documented 
Gilbert’s Syndrome with direct bilirubin < 35% of 
total bilirubin) 
Exception: Subjects with liver metastasis ≤ 2.5 x 
ULN 
ALT/AST 
≤ 2.5 x ULN 
Exception: Subjects with liver metastasis ≤ 5.0 x 
ULN 
1   Renal function (GFR) will be estimated or measured according to 
standard practice at the treating institution. Renal function will be 
reassessed at Baseline using the same methodology. 
Exclusion Criteria 
A subject meeting any of the following criteria is not eligible for 
participation in the study: 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 23 of 144 
 
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 
(e.g., dabrafenib, 
trametinib, and 
vemurafanib)  
1 week  
1 week  
Immune therapy 
(including monoclonal 
antibody therapy and 
checkpoint inhibitors) 
2 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 
Use of previous gene 
therapy using a 
Lentiviral vector is 
permitted only if 
transduced T-cells 
represent less than 1% 
of peripheral blood 
mononuclear cell 
(PBMC) (< 1500 
copies of vectors per 
microgram of PBMC 
DNA) at the time of 
screening. Eligibility 
testing must be done 
by Adaptimmune’s 
designated Contract 
Not permitted after 
leukapheresis and prior 
to lymphodepletion 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 24 of 144 
 
Research Organization 
(CRO).  
Corticosteroids or any 
other 
immunosuppressive 
therapy. Note: Use of 
topical steroids is not an 
exclusion. See 
Section 6.5 for 
exceptions.  
2 weeks  
2 weeks  
Anti-MAGE-A4 therapy 
 
Note: Fresh screening 
biopsy post anti-MAGE-
A4 therapy must be 
obtained to confirm 
MAGE-A4 positivity.  
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 
wash-out period for 
palliative radiation to 
non-target organs). 
Major surgery 
N/A 
4 weeks. Subjects must 
have recovered from 
any surgically related 
toxicities. 
Note: Duration of any other anti-cancer therapies must be discussed with the 
Sponsor Study Physician. 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
Page 25 of 144 
 
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 and 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. Leptomeningeal disease, carcinomatous meningitis, or symptomatic 
central nervous system (CNS) metastases.  Subjects with a prior history 
of symptomatic CNS metastases must have received treatment (i.e., 
stereotactic radiosurgery and whole brain radiation 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.  REGIONAL 
REQUIREMENT IN UK:  Leptomeningeal disease, carcinomatous 
meningitis, or symptomatic 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  
• 
COVID-19 infection or a positive COVID-19 Real-Time 
Polymerase Chain Reaction (RT-PCR) test within 28 days of 
leukapheresis or lymphodepleting chemotherapy. If subject has 
had a positive COVID-19 test, then 2 subsequent negative tests 
are required, taken at least 7 days apart   
• 
Clinically significant pulmonary disease with any one 
pulmonary function parameter < 60% predicted (FEV1 or TLC 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 26 of 144 
 
or DLCO) assessed prior to leukapheresis and within 2 months 
of the start of lymphodepleting chemotherapy 
• 
Requirement for oxygen support (for cardiac or pulmonary 
disease) 
• 
Clinically significant cardiac disease defined by congestive 
heart failure New York Heart Association Class 3 or Class 4 
• 
Uncontrolled clinically significant arrhythmia 
• 
Acute Coronary Syndrome (angina or myocardial infarction) in 
last 6 months 
• 
Congenital or family history of long QT syndrome or a history 
of torsade de pointes 
• 
Current uncontrolled hypertension despite optimal medical 
therapy 
• 
History of stroke or CNS bleeding; transient ischemic attack or 
reversible ischemic neurologic deficit in the last 6 months 
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 branched DNA 
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: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
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Date: 17-NOV-2021 
Page 27 of 144 
 
Investigational 
Product, Dose, Route, 
and Regimen 
ADP-A2M4CD8 is the SPEAR 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 main analysis for the primary efficacy endpoint ORR will be based on 
Chen’s three stage design [Chen, 1997], extending the methods outlined in 
[Jung, 2004] and [Koyama, 2008] to a three-stage design. The primary 
endpoint for efficacy is ORR defined as the proportion of subjects with a 
confirmed complete response (CR) or confirmed partial response (PR) per 
RECIST v1.1 via IRAC review, relative to the total number of subjects in 
the analysis population. The primary analysis population for safety and 
efficacy will be the modified intent-to-treat (mITT) population defined as 
all subjects who received T-cell infusion. 
Null Hypothesis (H0): p ≤ p0 vs. Alternate Hypothesis (H1): p > p0, where p0 
(historical ORR) = 0.14. 
Statistical assumptions include: 
• 
The assessment for efficacy will be based on the mITT 
population using confirmed ORR via RECIST v1.1 per the 
IRAC. 
• 
The type I error (α) will be no more than 0.049. 
• 
The type II error (β) will not exceed 0.1. 
• 
Exact binomial methods will be used to test the hypothesis. 
Based on the statistical design assumptions above, approximately 45 
subjects will be enrolled according to a Chen’s three-stage design.  
• 
First Stage: 15 evaluable subjects will be enrolled in stage 1. The 
predefined ORR is met if there are 2 or more confirmed complete 
response (CR) or confirmed partial response (PR) out of the first 15 
evaluable subjects based on investigator radiological assessment.  
Subject enrollment will continue to the next stage if there is a 
demonstrable clinical benefit from treatment with cell therapy and 
there are no major safety concerns. Otherwise, subject enrollment 
will be stopped. The independent DSMB will make this 
recommendation. 
The DSMB will review safety data (including AEs and SAEs), 
ongoing efficacy data for futility, and overall benefit:risk profile, 
and make a recommendation to Adaptimmune. The process for the 
review will be defined in the DSMB charter 
• 
Second Stage: An additional 13 evaluable subjects will be enrolled 
in stage 2, if the predefined ORR is met (i.e., 7 or more responses, 
confirmed CR or confirmed PR, out of the first 28 (15 + 13) 
evaluable subjects based on investigator radiological assessment), 
then the study will continue to the third and final stage.   

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
Version: Amendment 2.0 
CONFIDENTIAL 
Date: 17-NOV-2021 
Page 28 of 144 
 
Subject enrollment will continue to the next stage if there is a 
demonstrable benefit from treatment with cell therapy and there are 
no major safety concerns. Otherwise, subject enrollment will be 
stopped. The independent DSMB will make this recommendation.  
• 
Third Stage: An additional 17 evaluable subjects will be enrolled 
for a total of 45 (15 + 13 +17) evaluable subjects. 
A DSMB charter, defining roles and accountabilities and the process for 
review, will be available prior to the start of the study. 
The primary endpoint, ORR by RECIST v1.1 by an independent 
radiological assessment committee, will be evaluated using Clopper-
Pearson (exact Binomial) 2-sided 95% confidence intervals (CIs).  
The key secondary efficacy endpoints TTR, DoR, BOR, 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. 2-sided Ninety five (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, surrogates of 
treatment effect, health outcomes using the EQ-5D-3L, 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. 
Other subgroups may be explored, and these will be described in the 
Statistical Analysis Plan. 
 
 
 

 
 
 
             
 
Investigational Product: ADP-A2M4CD8 
 
 
 
 
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Date: 17-NOV-2021 
Page 29 of 144 
 
1.2. 
Schema 
 
 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
 
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Date:17-NOV -2021 
Page 30 of 144 
 
1.3. 
Time and Events Table 
 
Main Time and Events (T&E) Table 
Written Informed Consent must be obtained prior to performing any protocol procedures. A Pre-screening Informed Consent form 
(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 (Section 8). 
Table 1: 
Main T&E Table 
 
 
 
Interventional Phase 
 
 
Pre-
screen
ing 
Scree
ning1 
Leuka
pheres
is 
Baseline Lymphodepleting 
Chemotherapy 
T-cell 
Infusion 
Post-infusion Assessments 
Every 2 
Months 
End of 
Interventional 
Phase or Study 
Withdrawal 
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 
 
n/a 
n/a 
n/a 
n/a n/a n/a n/a 
n/a 
± 1 day 
± 3 days 
± 7 days 
± 1 mo 
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 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.1 
Inclusion/Exclusion 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.2 and 
Section 5.3  
Disease history/Tumor 
type 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2 
Document 
tumor-specific 
mutations  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2 
HLA16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1 
MAGE-A4 Antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.2 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
 
Protocol Number: ADP-0055-002 
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Date:17-NOV -2021 
Page 31 of 144 
 
 
 
 
Interventional Phase 
 
 
Pre-
screen
ing 
Scree
ning1 
Leuka
pheres
is 
Baseline Lymphodepleting 
Chemotherapy 
T-cell 
Infusion 
Post-infusion Assessments 
Every 2 
Months 
End of 
Interventional 
Phase or Study 
Withdrawal 
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 
 
n/a 
n/a 
n/a 
n/a n/a n/a n/a 
n/a 
± 1 day 
± 3 days 
± 7 days 
± 1 mo 
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 
 
 
 
Safety and Efficacy Assessments 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.1 
Physical examination 
 
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  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X X X X X 
X 
X 
X 
X 
X 
X 
Section 8.4.5 
Height 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.7 
Weight 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
Section 8.4.7 
Vital signs 
 
X 
 
X 
 
 
 
 
X2 
X X X X X X 
 
 
 
 
 
 
 
X 
X 
Section 8.4.6 
Pulse Oximetry 
 
X18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.8  
ECG 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.9.1 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.9.2 
CT/MRI 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
X3a X3a X3a 
X 
X3 
X 
Section 8.3.1 
Brain MRI 
 
X4 
 
X4a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.10 
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 
Renal function (GFR 
estimated or measured) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.11 

 
 
 
             
 
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Date:17-NOV -2021 
Page 32 of 144 
 
 
 
 
Interventional Phase 
 
 
Pre-
screen
ing 
Scree
ning1 
Leuka
pheres
is 
Baseline Lymphodepleting 
Chemotherapy 
T-cell 
Infusion 
Post-infusion Assessments 
Every 2 
Months 
End of 
Interventional 
Phase or Study 
Withdrawal 
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 
 
n/a 
n/a 
n/a 
n/a n/a n/a n/a 
n/a 
± 1 day 
± 3 days 
± 7 days 
± 1 mo 
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 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
X5 
 
X5 
 
 
 
Section 8.4.18 
Pulmonary function 
tests 
 
X 
 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.9.4  
CMV PCR 
 
 
 
X6 
 
 
 
 
X6 
 
 
 
 
 X6  
X6 X6 X6 
 
 
 
 
 
Section 8.4.19 
Thyroid function tests  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.4.15 
C-reactive protein7 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X X 
 
X 
 
 
 
 
 
 
 
Section 8.4.21 
Ferritin7 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X X 
 
X 
 
 
 
 
 
 
 
Section 8.4.22 
ICE Assessment 
 
 
 
 
 
 
 
 
X 
X X X X X 
 
 
 
 
 
 
 
 
 
 
Section 8.4.20 
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 
Leukapheresis, Lymphodepleting Chemotherapy, and Investigational Product Administration 
Leukapheresis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.1 
Fludarabine15 
 
 
 
 
X 
X 
X 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.2 
Cyclophosphamide 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.2 
ADP-A2M4CD8 
infusion 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.3.2 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
 
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Interventional Phase 
 
 
Pre-
screen
ing 
Scree
ning1 
Leuka
pheres
is 
Baseline Lymphodepleting 
Chemotherapy 
T-cell 
Infusion 
Post-infusion Assessments 
Every 2 
Months 
End of 
Interventional 
Phase or Study 
Withdrawal 
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 
 
n/a 
n/a 
n/a 
n/a n/a n/a n/a 
n/a 
± 1 day 
± 3 days 
± 7 days 
± 1 mo 
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 
 
 
 
Biomarker Assessments 
Tumor biopsy10 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 X10a  
 
 
 
X10b 
 
X 
Section 8.6.1 
Cytokine and soluble 
protein analyses 
 
 
 
X 
 
 
 
 
X11 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
 
Section 8.6.2 
Liquid biopsy (blood 
plasma) 
 
 
 
X 
 
 
 
 
X12 
 
 
 
 
 
 
 X10  
 
X 
 
X10 
 
X 
Section 8.6.3 
Gene expression 
analysis (whole blood) 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 X14  
 
X14 
 
 
 
X14 
Section 8.6.4 
Fluids (ascites/pleural) 
 
 
 
X (if fluid develops) 
Section 8.6.1 
Cell phenotyping and 
functional assays 
 
 
 
X 
 
 
 
 
X12 
 
 
 
 
X X 
 
X 
 
X 
X 
 
X 
X 
X 
Section 8.6.5 
Persistence (vector 
copies)  
 
X8 
 
X 
 
 
 
 
 
X 
 
X 
 
X X 
 
X 
 
X 
X 
 
X 
X 
 
Section 8.4.23 
RCL (VSV-G DNA) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
LTFU 
 
Section 8.4.24 
Subject Reported Outcomes 
EQ-5D-3L 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
See 
footnote13 
 
Section 8.7 
1 Screening Visit 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 (prior to study consent) are acceptable. 
2 Vital signs are measured pre-infusion, at 5, 15, and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started. 

 
 
 
             
 
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Date:17-NOV -2021 
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3 The Week 4 scan may occur within +3 days but not before Week 4 (Day 29). 3a On study scans from Week 4 through Week 16 should be at least 28 days apart 
to ensure compliance with RECIST v1.1 requirement for confirmatory scans in the event that an objective response is noted by the independent radiological 
assessment committee (IRAC).  For scans every 2 months, these can be ± 28 days.  
4 Regional requirement in UK - A Screening Brain MRI is required in regions where subjects with leptomeningeal disease, carcinomatous meningitis or central 
nervous system (CNS) metastases are excluded.  
4aThis is required at Baseline and must be within 1 month prior to lymphodepletion.  
5 Subjects who are HBV core antibody positive at Screening will have HBV DNA assessments at Week 4, 8, and 16. 
6 If subjects are CMV seropositive at Screening, CMV PCR is done at Baseline. All CMV seropositive subjects will continue to be monitored by CMV PCR at 
Day 1 and Weeks 2, 4, 6, and 8. 
7 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.  
8 This is only for a subject who has previously received a gene therapy using a Lentiviral vector. Subjects must have results below the lower limit of 
quantification for at least 2 samples taken at least 1 month apart. At least one of these tests must be performed by Adaptimmune as part of Pre-screening or 
Screening. 
9 Begin G-CSF 24 hours after the last dose of lymphodepleting chemotherapy and continue as per Section 6.2.3.  
10 Tumor biopsy and liquid biopsy should be collected at the same visit within 24 hours of each other. 10a can be taken anytime between Week 3 and Week 8; 10b 
can be taken at Week 24 ± 4 weeks. 
11 Day 1 cytokine samples are to be collected pre-infusion and 2 to 4 hours post-infusion. 
12 This is collected pre-infusion. 
13 EQ-5D-3L will also be done at Month 12 if the subject remains in the Interventional phase of the study. 
14 Whole blood collection to be performed on the same day as the tumor biopsy procedure. 
15 Fludarabine dose must be adjusted for renal impairment in accordance with parameters in Section 6.2.1.  
16 Subjects that provide a buccal swab sample may also need to provide a confirmatory blood sample for HLA testing. 
17 Only required if the PFT is not within 2 months of the start of lymphodepleting chemotherapy. 
18 Screening oxygen saturation must be done within 7 days of leukapheresis.  
 
 
 
 

 
 
 
             
 
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Long-Term Follow-Up Time and Events Table 
Table 2: 
T&E for Long-Term Follow-Up  
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 examination  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.2 
Anti-cancer therapies, 
including mutagenic agents 
and other investigational 
agents 
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 
Section 8.4.24 

 
 
 
             
 
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
 
Rationale for Using ADP-A2M4CD8 in Esophageal or Esophagogastric Cancers 
Adoptive T-cell therapy 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]. 
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, melanoma-associated antigen-A (MAGE-A) family, SSX2, BAGE, 
GAGE, and CT7 among others. Most of these testis-specific genes are coded on the X 
chromosome. It should be noted that 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 messenger RNA 
(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 
(IHC) 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 frequent heterogeneous expression of protein across the tumor, with strong 
expression in a small subset of tumor cells. Epigenetic and post-transcriptional modifications 
determine protein expression levels under certain conditions. 
Some CTAs, such as NY-ESO-1, SSX, MAGE-A1, MAGE-A3, and MAGE-A10, have been 
shown to elicit humoral or cell-mediated immune responses [Daudi, 2014]. The approach used 
here redirects T-cells to target tumors effectively by the transduction of antigen-specific 
enhanced-affinity T-cell receptor (TCR). 
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-A2M4CD8 are autologous cluster of differentiation (CD) 4- or CD8-
positive T-cells that have been transduced with a self-inactivating (SIN) Lentiviral vector 
expressing a high affinity MAGE-A4 specific TCR and a CD8α. MAGE-A4 is a CTA that has 
restricted expression in normal tissue and is expressed across a range of solid tumors at varying 
frequencies. 
ADP-A2M4CD8 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 HLA-A*02-GVYDGREHTV antigen complex.  

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
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The safety and efficacy of the next-generation ADP-A2M4CD8 have been shown in subjects 
with several different tumor types in an ongoing phase 1 study ADP-0055-001 (NCT04044859). 
As of 01 October 2020, 6 subjects (1 with Myxoid/Round Cell Liposarcoma [MRCLS], 2 with 
gastroesophageal junction (GEJ) cancers, 1 with ovarian cancer, 1 with head and neck squamous 
cell carcinoma, and 1 with esophageal cancer) have been treated with ADP-A2M4CD8 (range ~1 
to 5.7 billion transduced cells). To date, 1 subject with GEJ cancer had a partial response (PR per 
Response Evaluation Criteria in Solid Tumor [RECIST]) and has had progression-free survival 
(PFS) > 6 months. One subject with head and neck cancer also had a PR. All other subjects have 
had BOR of stable disease (SD). No dose limiting toxicities (DLTs), or serious adverse events 
(SAEs) have been reported. ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety 
profile, and subjects with GEJ cancer and head and neck cancer have demonstrated evidence of 
anti-tumor activity. Translational data and early clinical results indicate that co-expression of the 
CD8α co-receptor on CD4+ SPEAR T-cells may increase the potency of the product by 
conferring additional killing activity to the helper T-cell subset. Further information is detailed in 
the ADP-A2M4CD8 Investigator’s Brochure. 
2.2. 
Background 
 
ADP-A2M4CD8 SPEAR T-cell Background 
The 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.  Most of these testis-specific 
genes are coded on the X chromosome.  It should be noted that 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].  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
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Table 3: 
MAGE-A4 Expression in Various Cancer Types 
MAGE-A4 Screening by IHC 
(Data From 05 June 2017 Through 24 May 2020)1 
Tumor Types 
# Evaluable Subjects 
Tested 
No ≥ 30% at ≥ 2 + IHC 
(%) 
Esophageal Carcinoma 
55 
10 (18%) 
• 
Adenocarcinoma 
48 
7 (15%) 
• 
Squamous cell carcinoma 
6 
2 (33%) 
• 
Adenosquamous carcinoma 
1 
1 (100%) 
GEJ Adenocarcinoma 
48 
11 (23%) 
1 Data obtained from the ADP-0000-001 Screening protocol in support of ADP-0055-001, ADP-0044-001, and 
ADP-0044-001R and from ADP-0044-002  
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 T-
cells from apoptosis and contribute to the development of tumors by promoting survival [Yang, 
2007].   
Some CTAs, such as NY-ESO-1, SSX, MAGE-A1, MAGE-A3, and MAGE-A10, have been 
shown to elicit humoral or cell-mediated immune responses [Daudi, 2014].  The approach used 
here redirects T-cells to target tumors effectively by the transduction of antigen-specific 
enhanced-affinity TCR. 
ADP-A2M4CD8 are autologous CD4- or CD8-positive T-cells that have been transduced with a 
self-inactivating Lentiviral vector expressing a high affinity MAGE-A4 specific TCR and an 
additional wild-type CD8α co-receptor. The CD8α co-receptor, which differentiates ADP-
A2M4CD8 from ADP-A2M4, is designed to provide additional functionality to CD4 T-cells. 
 
 
 
 
Discovery of ADP-A2M4CD8 
Several peptides derived from MAGE proteins have been identified by mass spectroscopy from 
tumor cell lines, including the HLA HLA-A*02-restricted peptide MAGE-A4230-239 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
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Version: Amendment 2.0 
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Date: 17-NOV-2021 
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(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, with 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 [Allele Frequency Net Database, 2020]. 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. A full description of the clinical program and 
studies conducted can be found in the ADP-A2M4CD8 Investigator’s Brochure.  
In ADP-A2M4CD8, a wild-type CD8α co-receptor was introduced alongside the ADP-A2M4 
TCR to enhance engineered CD4+ T polyfunctional responses against tumor antigens. ADP-
A2M4CD8 is designed to improve upon the Investigational Product (IP), ADP-A2M4. It is 
composed of autologous CD4 and CD8 T-cells, which will be obtained from eligible subjects 
who have MAGE-A4 expressing tumors and are HLA-A*02 positive.  
The addition of a CD8α co-receptor directly impacts TCR binding to the HLA-peptide complex 
in CD4+ T-cells, thereby enhancing CD4+ T-cell effector function. ADP-A2M4CD8 cells do not 
display any new cross-reactivity, and transduced T-cells do not display additional alloreactivity 
in vitro. As expected, alloreactivity from both ADP-A2M4 and ADP-A2M4CD8 was only seen 
towards 2 HLA-A*02:05 positive cell lines. Therefore, subjects who are HLA-A*02:05 positive 
will be excluded from the study. Subjects with either HLA-A*02:07 or any A*02 null allele as 
the sole HLA-A*02 allele will be also excluded due to decreased activity with these alleles. No 
additional alloreactivity was noted, and importantly, no targets induced an enhanced alloreactive 
response from ADP-A2M4CD8 cells. Together, these data demonstrate that addition of the 
CD8α co-receptor does not alter the specificity of the ADP-A2M4 TCR. Details regarding design 
and preclinical testing of ADP-A2M4CD8 are provided in the ADP-A2M4CD8 Investigator’s 
Brochure.  
In preclinical in vitro assays, ADP-A2M4CD8 showed a clear improvement in T-cell activation 
(when cultured with antigen positive cells), as measured by increased CD40L surface expression, 
particularly in the CD4+ fraction. When an additional arm of the immune system, dendritic cells 
(DCs), was introduced in co-cultures, a marked improvement was seen with the next-generation 
ADP-A2M4CD8. Cytokines released from both DCs (IL-12 and MIG) and T-cells (IFNγ, IL-2, 
and other Th1) were improved compared to cultures containing the first-generation ADP-A2M4 
cells. Additionally, a conversion of CD4+ T-cells was seen, from being unable to kill MAGE-
A4-positive 3D microspheres to having an effective cytotoxic function when transduced with 
ADP-A2M4CD8. Therefore, CD4+ T-cells transduced with ADP-A2M4CD8 display not only 
CD4+ helper functions, but also improved T-cell effector functions. 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
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Current Therapies for Esophageal or Esophagogastric Junction Cancers 
Emerging Data from ADP-A2M4CD8 and Other TCRs 
There is an unmet need for subjects with advanced disease who have progressed after first-line 
therapy. Subjects with advanced (metastatic or inoperable) esophageal or GEJ cancers whose 
tumors express MAGE-A4 will be included in this study, which is designed to investigate if 
ADP-A2M4CD8 cell can yield a clinically meaningful response rate in this rare subject 
population. 
In Western countries, the incidence of adenocarcinoma of the esophagus and GEJ is rising 
rapidly, while the incidence of squamous cell carcinoma of the esophagus is declining owing to a 
decrease in tobacco use. The estimated combined incidence and mortality of esophageal and 
gastric cancers in 2018 in the United States (US) are 43,710 and 26,650 cases, respectively 
[Cancer Facts and Figures, 2016]. Many subjects present with advanced disease, which is a stage 
associated with 5-year survival of only 5% to 15% and median survival of 8 to 10 months. The 
2019 NCCN guidelines outline the principles of systemic therapy regimens recommended for 
advanced esophageal or GEJ adenocarcinoma, which may be used interchangeably (with some 
exceptions) [NCCN, 2019]. The mainstay of treatment for advanced disease is fluoropyrimidine 
(combined with oxaliplatin or cisplatin) and/or platinum-based combination chemotherapy. Low 
response rates and high levels of toxicity are observed with second-line chemotherapy.  
The selection of regimens for second-line or subsequent therapy is dependent on prior therapy 
and performance status. Based on the available data and FDA approvals, the guidelines have 
included the targeted therapy of ramucirumab (category 1 for GEJ adenocarcinoma and category 
2A for esophageal adenocarcinoma) as a single agent or in combination with paclitaxel 
(preferred) as treatment options for second-line or subsequent therapy [Fuchs, 2014; 
Wilke, 2014]. 
Second-line or subsequent therapy depends on prior therapies and Performance Status (PS).  
Nivolumab was recently approved for the treatment of subjects with advanced esophageal 
squamous cell carcinoma as combination therapy with fluoropyrimidine and platinum therapy in 
the first line setting. Trastuzumab prolongs survival in subjects with HER2/neu overexpressing 
gastric cancer (10% to 30% of gastric cancer) in first-line chemotherapy, and addition of the anti-
VEGFR-2 antibody ramucirumab in second line improves overall survival (OS) and PFS when 
compared to chemotherapy alone [Orditura, 2014]. There is some evidence that esophagogastric 
cancer can respond to immunotherapy [Kim, 2005; Popiela, 2004; Ralph, 2010], but no other 
treatments beyond palliative chemotherapy are available for subjects with advanced disease. 
Pembrolizumab was recently approved as part of combination therapy in the first line setting for 
subjects with recurrent locally advanced or metastatic, gastric, or gastroesophageal junction 
adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. A 
recently published phase 3 trial (TAGS) has shown activity for the combined regimen of 
trifluridine and tipiracil in metastatic gastric and GEJ adenocarcinoma in the third-line setting 
[Shitara, 2018]. It is noted that this treatment should be considered for a very select population of 
subjects with low-volume GEJ adenocarcinoma who have minimal or no symptoms and the 
ability to swallow pills. Other recommended regimens for third-line or subsequent therapy for 
esophageal and GEJ cancers include regimens recommended for second-line therapy that were 
not previously used and pembrolizumab for adenocarcinomas with PD-L1 expression levels by 
CPS of ≥ 1. 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
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In the pivotal study, KEYNOTE-059, the efficacy of pembrolizumab was studied in subjects 
with gastric or gastroesophageal junction adenocarcinoma who progressed on at least 2 prior 
systemic treatments for advanced disease. Among 143 subjects that expressed PD-L1 with a CPS 
≥ 1, the overall response rate (ORR) for pembrolizumab was 13.3% (95% confidence interval 
[CI]: 8.2, 20.0) [Keytruda package, June 2020].  
The efficacy of pembrolizumab in subjects with locally advanced or metastatic esophageal 
squamous carcinoma who progressed on or after at least 2 prior systemic treatments was 
investigated in KEYNOTE-180. For 63 subjects, the observed ORR was 14.3% (95% CI: 6.7%, 
25.4%) (PMID: 30570649). Additional clinical evidence suggests that the historical ORR for 
therapies administered to subjects who progressed on or after at least 2 prior systemic therapies 
for esophageal and GEJ cancers is 14%. 
Emerging evidence of third-line systemic treatment in advanced/metastatic gastric cancer 
supports the efficacy of systemic treatment in refractory gastric cancer beyond second-line 
treatment. Established third-line therapies include chemotherapies (irinotecan, taxane, and 
TAS-102), tyrosine kinase inhibitors (apatinib and regorafenib), and immune-checkpoint 
inhibitors (nivolumab and pembrolizumab). Given the expanding options for third-line therapies, 
there is an unmet need for clinicians to individualize treatment [Chan, 2019]. Tumor -specific 
biomarker stratification is likely to be relevant to targeted and immunotherapy approaches. 
However, it is not yet used for subject stratification or selection. Future studies are warranted to 
focus more on gene signaling to guide subject selection. 
ADP-A2M4CD8 SPEAR T-cells have shown an acceptable safety profile, and subjects with GEJ 
cancer and head and neck cancer have demonstrated evidence of anti-tumor activity. 
Translational data and early clinical results indicate that co-expression of the CD8α co-receptor 
on CD4+ SPEAR T-cells may increase the potency of the product by conferring additional 
killing activity to the helper T-cell subset. This dose escalation trial is ongoing and updated 
clinical and translational data will be presented [Hong, 2020]. 
2.3. 
Benefit/Risk Assessment 
The results of clinical and non-clinical studies conducted with ADP-A2M4CD8 cells are 
summarized in the ADP-A2M4CD8 Investigator’s Brochure.  This section outlines the potential 
benefits, risks, and the overall benefit/risk assessment for this study. 
 
Benefit 
The estimated combined incidence and mortality of esophageal and gastric cancers in 2018 in the 
US are 43,710 and 26,650 cases, respectively [Cancer Facts and Figures, 2016]. Many subjects 
present with advanced disease, which is a stage associated with 5-year survival of only 5% to 
15% and median survival of 8 to 10 months. Given the very low survival rates in esophageal and 
gastric cancer, there is a high degree of unmet need across the board.   
Clinical evidence suggests that the historical ORR for therapies administered to subjects who 
progressed on or after at least 2 prior systemic therapies for esophageal and GEJ cancers is 14%. 
This historical ORR will be used to evaluate the efficacy of ADP-A2M4CD8. Preliminary 
evidence from the ADP-0055-001 study suggests that ADP-A2M4CD8 treatment in this subject 
population may result in an ORR of 35% (Section 9). 

 
 
 
             
 
Investigational Product:ADP-A2M4CD8 
 
 
 
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Furthermore, preliminary safety data from the phase 1 Protocol ADP-0055-001 suggests that the 
ADP-A2M4CD8 SPEAR T-cells have an acceptable safety profile, and subjects with 
gastroesophageal cancers and head and neck cancer have demonstrated clinical responses. Five 
of 6 subjects demonstrated initial tumor shrinkage. This trial is ongoing in an expansion cohort 
of subjects [Hong, 2020].   
The benefit of ADP-A2M4CD8 is not known at present, however, the MAGE-A4 antigen is 
highly expressed in the proposed tumor types. An objective response has been observed in 
protocol ADP-0055-001 following treatment with ADP-A2M4CD8; therefore, the potential 
therapeutic benefit of ADP-A2M4CD8 is being investigated in this phase 2 trial.  
Several clinical trials investigating the efficacy and safety of adoptive T-cell therapy with 
Adaptimmune’s TCRs are ongoing. Efficacy has been demonstrated with other adoptive T-cell 
therapies, including NY-ESO-1c259T and ADP-A2M4 [Rapoport, 2015; Merchant, 2015; Araujo, 
2019; D’Angelo, 2018a; Mackall, 2017]. 
MAGE-A4 positivity (≥ 30% at ≥ 2 + IHC) is expressed in esophageal squamous cell carcinoma 
(33%), esophageal adenocarcinoma (15%), GEJ adenocarcinoma (23%), and esophageal 
adenosquamous carcinoma (100%) (Table 3). 
This data suggests that affinity-optimized TCRs can be safe and effective and supports the 
potential therapeutic benefit of TCR therapy in subjects with malignancies expressing the 
relevant antigen. 
 
Risk 
The safety and tolerability of ADP-A2M4CD8 is being assessed in the phase 1 study 
ADP-0055-001 (NCT04044859) across multiple tumor types including esophageal and GEJ 
cancers as described in Section 2.1.  Toxicities observed with ADP-A2M4CD8 are common to 
other TCR or chimeric antigen receptor (CAR)-T therapies, checkpoint inhibitors, or standard of 
care chemotherapies. 
Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated 
neurotoxicity syndrome (ICANS), and prolonged or recurrent pancytopenia are specific to TCR 
and CAR-T therapies; therefore, guidelines for management of these events are included in this 
protocol (Section 10.4). TCR therapy is generally administered once; most toxicities resolve 
within 4 to 6 weeks after T-cell infusion. 
Alloreactivity, whereby TCRs reactive towards a given peptide-major histocompatibility 
complex display cross-reactivity towards different HLA allelic variants, is a theoretical risk.  
Preclinical 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-A2M4CD8; 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 the following:  
1. Extensive preclinical evaluation of the ADP-A2M4CD8, which has incorporated learnings 
from other adoptive T-cell therapy programs ADP-A2M4CD8 Investigator’s Brochure.]  

 
 
 
             
 
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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 CRS, ICANS, and 
pancytopenia/aplastic anemia as well as preventive measures for infectious complications  
6. A Data Safety Monitoring Board (DSMB) to evaluate safety during the study 
 
Overall Benefit: Risk Conclusion 
Subjects with advanced esophageal or GEJ cancers who have received 2 prior lines of therapy 
constitute a population with a high unmet medical need given the aggressive nature and poor 
survival rates. In the clinical setting, the response rates generally decrease with increasing lines 
of therapy. Responses are rare in the third-line setting. Given the lack of standard of care in the 
third line, there is not a single benchmark in this setting. The limited effective third-line 
treatment options create the opportunity for innovative new therapies for expedited approvals. 
The potential risks identified in association with ADP-A2M4CD8 are justified by the anticipated 
benefits that may be afforded to subjects; therefore, the benefit/risk for ADP-A2M4CD8 
supports initial testing in the clinic in the defined study population. A phase 1 clinical study with 
ADP-A2M4CD8 and preclinical studies support the specificity, safety, and anti-tumor activity of 
ADP-A2M4CD8 T-cells. Measures to ensure safe administration of ADP-A2M4CD8 have been 
included in this study protocol, with close monitoring for toxicities and guidelines for their 
management by an external, independent DSMB.  
 

 
 
 
             
 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary: 
To evaluate the efficacy of autologous 
genetically modified SPEAR T-cells (ADP-
A2M4CD8) in HLA-A*02 positive subjects 
with MAGE-A4 expressing advanced 
esophageal or GEJ cancers 
ORR per RECIST v1.1 by independent radiological 
assessment committee 
Secondary: 
To evaluate the safety and tolerability of 
autologous genetically modified T-cells (ADP-
A2M4CD8) in HLA-A*02 positive subjects 
with MAGE-A4 expressing advanced 
esophageal or GEJ cancers 
• 
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-A2M4CD8) 
in HLA-A*02 positive subjects with MAGE-A4 
expressing advanced esophageal or GEJ cancers 
• 
Time to response (TTR) per RECIST v1.1 
by independent radiological assessment 
committee (IRAC), and by investigator 
radiological assessment  
• 
Duration of response (DoR) per RECIST 
v1.1 by the IRAC, and by investigator 
radiological assessment 
• 
Best overall response (BOR) per RECIST 
v1.1 by the IRAC , and by investigator 
radiological assessment 
• 
PFS per RECIST v1.1 by the IRAC, and by 
investigator radiological assessment 
• 
OS 
• 
ORR per RECIST v1.1 by investigator 
radiological assessment 
Development and validation of an in vitro 
diagnostic (IVD) assay for the screening of 
tumor antigen expression for regulatory 
approval 
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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Objectives 
Endpoints 
Characterize the surrogates of treatment effect 
Peak expansion (i.e., maximum persistence) and 
time to peak expansion by responder status and 
overall 
Exploratory 
 
 
• 
 
 
 
 
  
 
 
 
• 
 
  
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 

 
 
 
             
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a phase 2, open-label study of genetically engineered ADP-A2M4C8 in HLA-A*02 
subjects with MAGE-A4 expressing metastatic or inoperable (advanced) esophageal or GEJ 
cancer.  
All subjects will be enrolled into one treatment cohort based upon their tumor type and histology. 
Subjects with advanced esophageal or GEJ cancers will be enrolled in this study. Based on the 
tumor histology, this cohort of subjects will have either adenocarcinoma or squamous cell 
carcinoma type of disease. 
 
 [Chen, 1997]. 
 
 
 
 
Pre-screening  
Subjects must be aged ≥ 18 years and ≤ 75 years and must have a diagnosis of advanced 
(metastatic or inoperable) esophageal or GEJ cancers to be eligible for Pre-screening. 
Subjects will sign a pre-screening ICF and undergo initial screening for the relevant HLA-A 
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 or remote consent in accordance with Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)-approved processes and any local requirements in 
advance of providing subjects with an HLA buccal/cheek swab test and/or sending tissue for 
MAGE-A4 test. This allows subjects to be pre-screened for HLA and MAGE-A4 antigen without 
requiring travel to a clinical study site.  The HLA buccal swab kit contains a self-administered 
buccal/cheek swab, and relevant instructions would be sent to subjects who have provided 
written or remote 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 pre-screening. 
 
Screening 
Subjects who have been identified as 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 this study. Screening assessments should be completed within 28 days of leukapheresis; 
CT/MRI scans and echocardiogram (ECHO)/multiple-gated acquisition (MUGA) scans, 
performed as standard of care within 4 weeks prior to Screening Visit 2 (i.e., prior to treatment 
consent), are acceptable.  

 
 
 
             
 
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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-A2M4CD8 cell IP. At the discretion of the Investigator and to allow 
for adequate planning for the subjects to be treated in this protocol, leukapheresis can be 
performed as soon as possible after the subject is determined to be eligible for study 
participation. Leukapheresis can be performed prior to initiating second-line treatment regimen 
or at the end of second-line treatment. Anti-cancer therapy may be administered to subjects 
between Screening and leukapheresis and between leukapheresis and the start of 
lymphodepletion. However, following the manufacture of a subject’s cells, a subject must 
receive IP as the next therapy. In the event an exception has been granted for early leukapheresis, 
a subject must receive the IP as the third line of therapy; otherwise, subject may receive IP as 
second line of therapy after discussion with the sponsor. If, in the opinion of the Investigator, the 
subject requires immediate therapy after leukapheresis, the subject may receive bridging therapy 
for the period during which the subject is awaiting the manufacture of IP. Following this 
bridging therapy, the subject must adhere to the mandatory wash-out periods (Section 5.3) prior 
to receiving ADP-A2M4CD8. In addition, subjects must continue to have measurable disease 
following the bridging therapy in order to receive ADP-A2M4CD8. 
Prior to the administration of lymphodepleting chemotherapy, all eligibility criteria will be 
reconfirmed, baseline tumor assessment will be obtained, and any issues or concerns are 
addressed in advance of lymphodepletion, in particular, any factor that might cause or increase 
the risk of prolonged cytopenia. Where issues are identified, the Investigator is encouraged to 
adopt mitigation measures such as reduced lymphodepleting regimen or alternative treatment 
options, if appropriate.  Once the ADP-A2M4CD8 cells are available at site, subjects will 
undergo lymphodepleting chemotherapy with fludarabine 30 mg/m2/day for 4 days (Day -7 
through Day -4) and cyclophosphamide 600 mg/m2/day for 3 days (Day -7 through Day -5) 
(Section 6.2), followed by infusion of ADP-A2M4CD8 cells on Day 1 (Section 6.2.3). The 
lymphodepleting chemotherapy may be given as an outpatient treatment, or subjects may be 
hospitalized at the discretion of the Investigator.  Guidelines for this decision are provided in 
Section 6.2. 
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. A longer observation period is allowed as 
required per the standard of care at the site level. 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.   
REGIONAL REQUIREMENTS (UK and France):  Subjects will remain hospitalized for 
observation for at least 10 days post-T-cell infusion, based on regional requirements. 
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 Investigators and independent physicians using RECIST v1.1.  To allow time 
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the disease to the treatment (“tumor flare”), response will not be assessed before 1 month 
post-infusion of ADP-A2M4CD8. Therefore, imaging scans should not be performed earlier than 
4 weeks post-infusion unless there is unequivocal clinical evidence of deterioration.  
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 AEs (Table 2) in accordance to FDA and EMA requirements for gene therapy clinical 
trials [FDA, 2020a; FDA, 2010; EMA, 2009].  
Subjects will be seen in the clinic for evaluation according to the Main T&E table (Table 1) until 
disease progression, death, or withdrawal. 
Subjects who end the Interventional phase of the study will undergo assessments/procedures 
according to the long-term follow-up (LTFU) T&E Table (Table 2).  The time point at which the 
subject switches to the LTFU assessments/procedures will be driven by the time point at which 
the subject progresses, for example, 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 Week 24 (Month 6). 
A subject will be considered to have ended the study when he/she has been followed for 15 years 
of follow-up, died, or withdraw early from the study. 
4.2. 
Scientific Rationale for Study Design 
This is a phase 2, open-label clinical trial with ADP-A2M4CD8 SPEAR T-cells in subjects with 
advanced esophageal or GEJ cancers who are HLA-A*02 positive and tumors that express 
MAGE-A4.    
The ongoing ADP-A2M4CD8 phase 1 study, ADP-0055-001 SURPASS, revealed an 
encouraging safety profile and treatment response in different cancer types. As of 
01 October 2020, 6 subjects (1 with MRCLS, 2 with GEJ cancers, 1 with ovarian cancer, 1 with 
head and neck squamous cell carcinoma, and 1 with esophageal cancer) have been treated with 
ADP-A2M4CD8 (range ~1 to 5.7 billion transduced cells). To date, 1 subject with GEJ cancer 
had a PR per RECIST and has had PFS > 6 months. One subject with head and neck cancer also 
had a PR. All other subjects have had BOR of SD. No DLTs were noted. Two subjects reported 
SAEs and were deemed related to the IP.  ADP-A2M4CD8 SPEAR T-cells have shown an 
acceptable safety profile, and subjects with GEJ cancer and head and neck cancer have 
demonstrated evidence of anti-tumor activity. Translational data and early clinical results 
indicate that co-expression of the CD8α co-receptor on CD4+ SPEAR T-cells may increase the 
potency of the product by conferring additional killing activity to the helper T-cell subset.   
This phase 2 study, ADP-0055-002, is to further evaluate the efficacy, safety, and tolerability of 
autologous genetically modified SPEAR T-cells (ADP-A2M4CD8) specifically in subjects with 
advanced esophageal or GEJ cancers. 
This study will be a non-comparative study with a primary efficacy endpoint of ORR per 
RECIST v1.1 by the IRAC. ORR will be based on confirmed (tumor) responses per RECIST 
v1.1 by the IRAC.  

 
 
 
             
 
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Clinical evidence suggests that the historical ORR for therapies administered to subjects who 
progressed on or after at least 2 prior systemic therapies for esophageal and GEJ cancers is 14%. 
This historical ORR will be used to evaluate the efficacy of ADP-A2M4CD8 by hypothesis 
testing.  Preliminary evidence from the ADP-0055-001 study suggests that ADP-A2M4CD8 
treatment in this subject population may result in an ORR of 35% (Section 9). 
 
Pre-screening for HLA Alleles and MAGE-A4 Expression 
4.2.1.1. 
HLA 
Subjects must express at least 1 inclusion HLA-A allele (such as A*02:01P, A*02:03P, or 
02:06P), which is defined as having proven capacity to bind the target peptide and ability to 
activate the ADP-A2M4 T-cells specifically in the presence of that peptide (i.e., absence of 
alloreactivity). 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. 
HLA-A*02:07 has been shown to have a reduced affinity for the target peptide but has not 
shown any alloreactivity. Therefore, subjects positive for HLA-A*02:07P (as well as subjects 
positive for any null A*02 allele, designated with an “N” suffix (e.g., A*02:32N), are ineligible 
unless they also express one of the inclusion alleles (e.g., a subject expressing both A*02:01 and 
A*02:07 is eligible). 
Due to the risk of alloreactivity, subjects positive for HLA-A*02:05P in either allele are 
ineligible. Other alleles may be exclusionary after consultation with the Sponsor.  
To ensure that the subject possesses the appropriate HLA-A*02 alleles, HLA testing of a blood 
sample is required.  HLA genotyping will be performed at a central reference laboratory using an 
FDA approved sequence-based typing (SBT) HLA genotyping assay. 
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 significant 
proportion of subjects expected to be excluded based on HLA status, an optional buccal swab kit 
may be offered to subjects prior to the Pre-screening Visit 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 relevant instructions, would be sent to 
possible subjects who have provided written or remote 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 pre-screening. 
4.2.1.2. 
MAGE-A4 Expression in Tumor 
MAGE-A4 positivity (≥ 30% at ≥ 2 + IHC) is expressed in esophageal squamous cell carcinoma 
(33%), esophageal adenocarcinoma (15%), GEJ adenocarcinoma (23%), and esophageal 
adenosquamous carcinoma (100%). High expression of MAGE-A4 has been reported across 
several cancer indications, including lung, esophageal, head and neck, bladder, ovarian, breast, 
and colorectal cancers [Tajima, 2003; Forghanifard, 2011; Errington, 2012; Barrow, 2006; 
Alves, 2007; Cuffel, 2011; Kocher, 2002; Daudi, 2014; Otte, 2001; Cabezón, 2013].  

 
 
 
             
 
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MAGE-A4c1032 T-cells have been shown to produce strong IFNγ responses against tumor cell 
lines expressing high MAGE-A4 mRNA levels (> 10,000 MAGE-A4 transcripts). Since no 
adequate models to define the threshold of MAGE-A4c1032 T-cell activation are currently 
available, this protocol will select for subjects with high MAGE-A4 expression. As such, 
Adaptimmune will be using a conservative cut-off (≥ 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-A2M4CD8 cells, 
the tumor specimen will be screened at a central reference laboratory for the expression of 
MAGE A4 antigens by IHC using a CLIA-validated Clinical Trial Assay. 
Optional remote consent to ADP-A2M4CD8 testing is permitted for any clinical site that has the 
necessary written or verbal consent processes in place and has obtained the relevant IRB/IEC and 
local approvals. This allows subjects with archival specimens available to consent for 
ADP-A2M4CD8 testing without requiring travel to a clinical study site. 
 
T-cell Manufacturing 
ADP-A2M4CD8 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 antigen-positive tumors and who have appropriate HLA-A genotype.  The CD4 and 
CD8 T-cells are transduced with an SIN Lentivirus vector expressing the CD8α MAGE-A4 
(affinity-enhanced clone 1032) under Good Manufacturing Practice conditions.  The product of 
this transduction is polyclonal T-cells that are designed to target MAGE-A4 in tissue. The 
transfer SIN Lentiviral vector has been meticulously designed to contain only the minimal 
genetic elements required for function and no vector proteins 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 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 within 1 month after the start of 
manufacturing.  Receipt of T-cell product at the clinical site is required before the start of 
lymphodepleting chemotherapy. 
 
Lymphodepletion 
Prior to the administration of lymphodepleting chemotherapy, all eligibility criteria will be 
reconfirmed, baseline tumor assessment will be obtained, and any issues or concerns are 
addressed in advance of lymphodepletion, in particular, any factor that might cause or increase 
the risk of prolonged cytopenia. Where issues are identified, the Investigator is encouraged to 
adopt mitigation measures such as reduced lymphodepleting regimen or alternative treatment 
options, if appropriate (Section 6.2).  
Lymphodepletion, typically achieved by the administration of cytotoxic chemotherapy consisting 
of fludarabine in combination with cyclophosphamide, prior to autologous cell transfer 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 

 
 
 
             
 
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[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 on the specific action of some cytotoxic drugs. In this regard, 
fludarabine is specifically T-cell depleting and has shown in multiple CAR-T hematological 
cancer studies to improve T-cell expansion, persistence, and disease-free survival when 
compared to cyclophosphamide [Turtle, 2015]. Cyclophosphamide was administered at 30 to 
60 mg/kg x 1 day and fludarabine at 25 mg/m2/day x 3 to 5 days. Effective lymphodepletion has 
also been demonstrated in other CAR-T-cell studies using reduced cyclophosphamide dosing 
together with fludarabine [Batlevi, 2016]. 
Based on Adaptimmune’s experience using combination fludarabine-cyclophosphamide 
lymphodepleting chemotherapy in the ADP-0044-001 MAGE-A4 study (NCT01343043) and the 
ADP-0055-001 (SURPASS) study’s (NCT04044859) increasing evidence that fludarabine is a 
key component of the adoptive T-cell therapy, the lymphodepleting regimen in this study 
consists of intravenous (IV) fludarabine 30 mg/m2/day for 4 days (Day -7 through Day -4) and 
cyclophosphamide 600 mg/m2/day for 3 days (Day -7 to Day -5). This lymphodepleting regimen 
has previously demonstrated acceptable safety and efficacy in a study of ADP-0044-001 
MAGE-A4 in subjects with multiple tumor types.  
 
Long-Term Follow-Up  
Subjects exposed to gene therapies may be at risk for delayed AEs 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 LTFU evaluation in the study is designed to adhere 
to the FDA and EMA guidance for LTFU of subjects in gene therapy clinical trials [FDA, 2020a; 
FDA, 2020b; FDA, 2010; EMA, 2009], and it involves monitoring of subjects who have been 
exposed to Lentivirus -mediated gene transfer in this clinical study for 15 years. Further 
information on the safety monitoring for the theoretical risks associated with the use of Lentiviral 
vectors and potential for IO as well as safety monitoring are available in Section 8.4 and 
Section 10.7. 
4.3. 
Justification for Dose 
The cell dose of ADP-A2M4CD8 is within the range of 1 x 109 to 10 x 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 is 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-A2M4CD8 are being assessed in the ongoing phase 1 trial of 
multiple tumor types including esophageal or GEJ cancers.  Subjects were treated with ADP-
A2M4CD8 (dose range of ~1 to 10 billion transduced cells). ADP-A2M4CD8 SPEAR T-cells 

 
 
 
             
 
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have shown an acceptable safety profile, and subjects with GEJ cancer and head and neck cancer 
have demonstrated evidence of anti-tumor activity.  
Across the development program, doses of up to 10 x 109 have been administered and well 
tolerated. Most of the adverse events noted were consistent with those typically experienced by 
cancer subjects undergoing cytotoxic chemotherapy or cancer immunotherapy. 
4.4. 
End of Study Definition 
The study will be considered complete once all subjects complete 15 years of follow-up, die, or 
withdraw early from the study. 
 
 

 
 
 
             
 
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5. 
STUDY POPULATION 
Subjects will be assessed for and must meet eligibility for study participation prior to 
leukapheresis (i.e., at Screening [Visit 2]), prior to manufacturing where leukapheresis has been 
stored AND prior to lymphodepleting chemotherapy (i.e., at Baseline).  
5.1. 
HLA and Antigen Pre-screening  
To be eligible for pre-screening, subjects must be aged ≥ 18 years to ≤ 75 years with a diagnosis 
of advanced (metastatic or inoperable) esophageal or esophagogastric cancer confirmed by either 
histology or cytogenetics. 
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 the following criteria prior to leukapheresis to be eligible to participate in 
the study: 
1. Subject (or legally authorized representative) has voluntarily agreed to participate by giving 
written Informed Consent/Assent (as applicable) in accordance with International Council for 
Harmonization (ICH) GCP guidelines and applicable local regulations.  
2. Subject (or legally authorized representative) has agreed to abide by all protocol-required 
procedures including study-related assessments and management by the treating institution 
for the duration of the study, including the LTFU. 
3. Age ≥ 18 years to ≤ 75 years at the time the Pre-screening Informed Consent. 
4. Histologically or cytogenetically confirmed diagnosis of advanced (metastatic or inoperable) 
esophageal or GEJ cancers. 
5. Subject has received a maximum of two prior lines of combination or single agent systemic 
treatment for advanced or metastatic disease before treatment with ADP-A2M4CD8 as the 
next therapy.  
a. Esophageal or GEJ cancers 
Prior therapy requirements in the unresectable locally advanced or metastatic setting: 
- 
Subjects should have received a platinum and/or fluoropyrimidine-based regimen 
(such as FOLFOX).  
- 
Subjects may have received anti-PD-1 agent in combination with 
fluoropyrimidine- and platinum-containing chemotherapy or been offered if 
available. 
- 
Subjects may have been offered taxane-containing regimen, ramucirumab, and/or 
irinotecan-containing regimen, if available; unless discussed and agreed upon 
with the sponsor.  
- 
Subjects whose tumors are known to be HER2/neu positive should have received 
or been offered a HER2/neu receptor inhibitor, if available. 

 
 
 
             
 
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b. Esophageal squamous cell carcinoma 
Prior therapy requirements in the unresectable locally advanced or metastatic setting: 
- 
Subjects should have received a platinum and/or fluoropyrimidine-based regimen 
(such as FOLFOX) and may include a taxane-containing regimen, and/or 
irinotecan-containing regimen. 
- 
Subjects whose tumors express PD-L1 or MSI-H/dMMR tumors, should have 
received or been offered anti-PD-1/anti-PD-L1 therapy if available; unless 
discussed and agreed upon with the sponsor 
6. Measurable disease according to RECIST v1.1 criteria. 
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. The Sponsor will review 
the results of HLA typing for inclusion alleles and will adjudicate subject eligibility based on 
HLA results. 
8. Tumor (either an archival specimen or a fresh biopsy) shows MAGE-A4 expression of ≥ 2+ 
staining in ≥ 30% of the cells by IHC. 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% or the institutional lower limit of normal 
range  
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 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 subjects must be surgically sterile or agree to use a double barrier contraception method 
or abstain from heterosexual activity with an 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. Subject must have adequate organ function as indicated by the laboratory values in the table 
below: 
System 
Laboratory Value 
Hematology 
ANC 
≥ 1.5 x 109/L (without granulocyte-colony 
stimulating factor [G-CSF] support) 

 
 
 
             
 
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Platelets 
≥ 100 x 109/L (without transfusion support 
within 7 days prior to lymphodepletion and 
leukapheresis) 
Hemoglobin 
≥ 90 g/L (without transfusion support 
within 7 days prior to lymphodepletion and 
leukapheresis) 
Coagulation 
Prothrombin Time or International Normalized Ratio 
≤ 1.5 x upper limit of normal (ULN) unless 
receiving therapeutic anticoagulation 
Partial Thromboplastin Time (PTT) 
≤ 1.5 x ULN unless receiving therapeutic 
anticoagulation 
Renal 
Glomerular Filtration Rate or Creatinine Clearance 
(CrCl) (Estimated or Calculated)1 
≥ 50 mL/min 
Hepatic 
Serum Total Bilirubin 
≤ 1.5 x ULN (unless subject has 
documented Gilbert’s Syndrome with direct 
bilirubin < 35% of total bilirubin) 
Exception: Subjects with liver metastasis 
≤ 2.5 x ULN 
ALT/AST  
≤ 2.5 x ULN  
Exception: Subjects with liver metastasis 
≤ 5.0 x ULN 
1Renal function (GFR) will be estimated or measured according to standard practice at the treating institution. 
Renal function will be reassessed at Baseline using the same methodology.  
14. Subjects must have ≥ 90% room air oxygen saturation test at rest at Screening (within 7 days 
of leukapheresis) and at Baseline. 
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 

 
 
 
             
 
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Treatment/Therapy 
Required Wash-Out Prior 
to Leukapheresis 
Required Wash-Out Prior to 
Lymphodepletion  
Tyrosine kinase inhibitor 
(e.g., dabrafenib, trametinib, and 
vemurafenib) 
1 week  
1 week  
Immune therapy (including 
monoclonal antibody therapy and 
checkpoint inhibitors) 
2 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 
Use of previous gene 
therapy using a Lentiviral 
vector is permitted only if 
transduced T-cells represent 
less than 1% of peripheral 
blood mononuclear cells 
(PBMCs) (< 1500 copies of 
vectors per microgram of 
PBMC DNA) at the time of 
screening. Eligibility testing 
must be done by 
Adaptimmune’s designated 
Contract Research 
Organization (CRO). 
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 for 
exceptions.  
2 weeks  
2 weeks  

 
 
 
             
 
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Treatment/Therapy 
Required Wash-Out Prior 
to Leukapheresis 
Required Wash-Out Prior to 
Lymphodepletion  
Anti-MAGE-A4 Therapy 
 
Note: Fresh screening biopsy 
post-anti-MAGE-A4 therapy must be 
obtained to confirm MAGE-A4 
positivity.  
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 wash-out period for 
palliative radiation to 
non-target organs). 
Major surgery 
N/A 
4 weeks. Subjects must have 
recovered from any surgically 
related toxicities. 
Note: Duration of any other anti-cancer therapies must be discussed with the Sponsor Study Physician. 
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 and 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. Leptomeningeal disease, carcinomatous meningitis, or symptomatic CNS metastases. 
Subjects with a prior history of symptomatic CNS metastases must have received treatment 
(i.e., stereotactic radiosurgery and whole brain radiation 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 

 
 
 
             
 
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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.  REGIONAL REQUIREMENT IN UK:  Leptomeningeal disease, carcinomatous 
meningitis, or symptomatic 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 
• COVID-19 infection or a positive COVID-19 Real-Time Polymerase Chain Reaction 
RT-PCR test within 28 days of leukapheresis or lymphodepleting chemotherapy. If 
subject has had a positive COVID-19 test, then 2 subsequent negative tests are 
required, taken at least 7 days apart 
• Clinically significant pulmonary disease with any one pulmonary function parameter 
< 60% predicted (FEV1 or TLC or DLCO) assessed prior to leukapheresis and within 
2 months of the start of lymphodepleting chemotherapy 
• Requirement for oxygen support (for cardiac or pulmonary disease) 
• Clinically significant cardiac disease defined by congestive heart failure New York 
Heart Association Class 3 or Class 4 
• Uncontrolled clinically significant arrhythmia 
• Acute Coronary Syndrome (angina or myocardial infarction) in last 6 months 
• Congenital or family history of long QT syndrome or a history of torsade de pointes 
• Current uncontrolled hypertension despite optimal medical therapy 
• History of stroke or CNS bleeding; transient ischemic attack or reversible ischemic 
neurologic deficit in the last 6 months 
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 
branched DNA (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. 

 
 
 
             
 
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• 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 
A screen failure log documenting the Investigator’s assessment of each screened subject with 
regard to the protocol inclusion and exclusion criteria is to be maintained by the Investigator. 
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. 
Subjects may be re-tested for eligibility criteria, during which time subjects will stay within the 
screening period of the treatment protocol until the criteria is either met or not met before 
recruitment closes. 
5.5. 
Number of Subjects and Study Duration 
Forty-five subjects are planned to be dosed in this study to robustly evaluate clinical benefit/risk 
in subjects who received the ADP-A2M4CD8 T-cell therapy.  
Clinical cut-off for the primary analysis will occur once the last subject dosed 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 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 from the study for any reason. 
5.6. 
Sites 
The study will be conducted in approximately 35 sites in North America and Europe. The 
number of centers is necessary to ensure recruitment in this rare subject population.  Additional 
sites may be added at the discretion of the Sponsor. 
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-A2M4CD8. 
At the discretion of the Investigator and to allow for adequate planning for the subjects to be 
treated in this protocol, leukapheresis can be performed as soon as possible after the subject is 
determined to be eligible for study participation. Leukapheresis can be performed prior to 

 
 
 
             
 
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initiating second-line treatment regimen or at the end of second-line treatment. For early 
leukapheresis, subjects should meet all eligibility requirements with the exception of prior 
anti-cancer therapy.  
Refer to the Apheresis and T-cell Product Manual for scheduling of apheresis. 
A non-mobilized PBMC collection should be performed by an apheresis unit at the enrolling 
institution according to the institution’s or hospital’s policies and procedures.  Bilateral 
peripheral venous access should be used whenever possible, but a temporary central venous 
catheter 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 ≤ 50 kg, 2 to 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 1.5 x 107 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 CaCl2 and 
MgSO4 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 of 
ADP-A2M4CD8 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, baseline tumor assessment will be obtained, and any issues or concerns are 
addressed in advance of lymphodepletion, in particular, any factor that might cause or increase 
the risk of prolonged cytopenia. Where issues are identified, the Investigator is encouraged to 
adopt mitigation measures such as a modified lymphodepleting regimen or alternative treatment 
options, if appropriate.  Once the manufactured ADP-A2M4CD8 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 4. Dose justification for the lymphodepletion regimen is described in 
Section 4.3. 
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 and anti-fungal 
prophylaxis (Section 10.5.3.7) in line with institutional guidelines. 
Appropriate 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.  
G-CSF should be given to all subjects from 24 hours after the last dose of lymphodepleting 

 
 
 
             
 
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chemotherapy until resolution of neutropenia in accordance with American Society of Clinical 
Oncology (ASCO) guidelines or institutional practice (Section 6.2.3). 
Table 4: 
Fludarabine and Cyclophosphamide Treatment Schema 
Lymphodepleting Chemotherapy 
Day 
Drug 
Dose 
Route 
Administration b 
-7 
Fludarabinea 
30 mg/m2 
IV 
in 50–100mL 0.9% NaCl over 30 mins 
Cyclophosphamidec 
600 mg/m2 
IV 
in 100–250mL 0.9% NaCl over 1 hour 
-6 
Fludarabinea 
30 mg/m2 
IV 
in 50–100mL 0.9% NaCl over 30 mins 
Cyclophosphamidec 
600 mg/m2 
IV 
in 100–250mL 0.9% NaCl over 1 hour 
-5 
Fludarabinea 
30 mg/m2 
IV 
in 50–100mL 0.9% NaCl over 30 mins 
Cyclophosphamidec 
600 mg/m2 
IV 
in 100–250mL 0.9% NaCl over 1 hour 
-4 
Fludarabinea, d 
30 mg/m2 
IV 
in 50–100mL 0.9% NaCl over 30 mins 
1 
ADP-A2M4CD8 infusione 
a Fludarabine dose will be adjusted for renal impairment as described in Section 6.2.1.  The Day-4 dose of 
fludarabine may be delayed or omitted based on mitigation measures agreed with sponsor. 
b Per institutional standard practice. 
c  Administration of mesna is described in Section 6.2.2. 
d Begin G-CSF 24 hours after the last dose of lymphodepleting chemotherapy and continue as per Section 6.2.3. 
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 1 dose 24 hours after the last dose of chemotherapy. 
e Administration of ADP-A2M4CD8 infusion is described in Section 6.2.3. 
 
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 
50–79 mL/min 
20 mg/m2 
 
Mesna 
Mesna may be given to prevent urotoxicity per institutional guidelines or as recommended 
below: 
• 120 mg/m2 (20% cyclophosphamide dose) per day will be administered pre-infusion 
and then repeated as an IV bolus at 4 hours and 8 hours (giving a total mesna dose of 
360 mg/m2 per day. 

 
 
 
             
 
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G-CSF 
The pre-conditioning chemotherapy is intended to cause lymphodepletion. However, neutropenia 
is also common. G-CSF should be given daily from 24 hours after the last dose of 
lymphodepleting chemotherapy until resolution of neutropenia in accordance with ASCO 
guidelines [Smith, 2015] 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 1 dose 24 hours after the last dose of chemotherapy.  
6.3. 
Investigational Product  
 
Premedication 
Subjects will be premedicated with antihistamine and acetaminophen/paracetamol 30 to 
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. 
Steroids may be used as anti-emetics for cyclophosphamide but must be discontinued no later 
than Day -3. 
 
T-cell Infusion 
On Day 1, the subject will receive thawed ADP-A2M4CD8 by intravenous infusion. 
Prior to infusion, 2 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 Manual. 
The T-cell product must not be thawed until immediately prior to infusion.  The cells can be 
thawed at a set temperature of 37°C using a water bath or equivalent device.  Routinely, the cells 
should be thawed for approximately 3 to 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 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°C to 8°C 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 be complete 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 

 
 
 
             
 
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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 the inner infusion bag is damaged or leaking after thawing, 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 to 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 to 250 mL of 0.9% sodium 
chloride should be connected to the second lumen of the infusion set used to prime the line, and 
the lumen is closed.  On completion of the infusion of a bag of T-cell product, the main line 
should be closed, and approximately 50 mL saline is transferred into the cell bag and 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.  In the event that 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 (Section 10.5.1.1). 
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.  REGIONAL REQUIREMENTS (UK and France):  Subjects will remain hospitalized 
for observation for at least 10 days post-T-cell infusion, based on regional requirements. 

 
 
 
             
 
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6.4. 
Preparation/Handling/Storage/Accountability 
 
Packaging and Labelling 
Selected, qualified manufacturing sites will manufacture, package, and label the T-cell product 
for each individual subject in accordance with applicable regulatory requirements. 
Refer to the Apheresis and T-cell Product Manual for T-cell product labelling. 
 
Receipt and Return 
IP 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.  IP is to be dispensed only in accordance with the protocol. 
The Investigator is responsible for keeping accurate records of the IP received from the Sponsor, 
including the amount dispensed and any unused IP remaining at the conclusion of the study.  
Contact the Sponsor or designee regarding any questions concerning the IP. 
Sites should contact the Sponsor or designee for specific instructions for IP returns or 
destruction. 
 
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. 
 
Investigational Product Accountability/Traceability 
The IP 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 IP are correctly received by a responsible person. 
• Such deliveries are recorded. 
• IP is handled and stored safely and properly as instructed in the Apheresis and T-cell 
Product Manual. 
• IP is only administered to study subjects in accordance with the protocol. 
• IP administration is documented. Records must include the identification of the 
person to whom the IP 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). 

 
 
 
             
 
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At the end of the study, it must be possible to reconcile IP 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. 
 
Alert Cards 
All subjects who receive IP in the trial will be provided with an alert card, which has been 
previously agreed by the Sponsor and approved by the IRB/IEC. Alert cards will contain, at a 
minimum, the name of the subject, the Investigator contact number, and information regarding 
the IP received. 
6.5. 
Concomitant Medications 
 
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 anti-cancer locoregional therapies such as non-palliative 
radiation.   
Subjects who undergo any active anti-cancer 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 
MAGE A4c1032T. However, surgery or radiotherapy after trial inclusion and prior to disease 
progression is a protocol deviation, and if a target lesion has been surgically removed or treated 
with radiotherapy, then the patient’s response is not evaluable. Upon progression, the subject will 
follow the LTFU schedule. Subjects who have surgery for new lesions consistent with PD or to 
control PD in previously identified lesions will discontinue from the Interventional phase and 
follow the LTFU schedule. 
See Section 5.3 for details of wash-out and excluded treatments prior to leukapheresis or 
lymphodepleting therapy. 
The use of systemic steroids may abrogate the effects of the T-cell therapy and should be 
avoided unless required to manage CRS, ICANS (see Section 10.5.6 and Section 10.5.7 for 
treatment recommendations), or other significant immune-mediated AEs.  According to local 
standard of care or ASCO guidelines, steroids may be used as anti-emetics 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 provided that the subject 
continues to meet eligibility criteria (Section 5.2 and Section 5.3).  Topical steroids for cutaneous 
application and inhaled steroidal treatments are permitted. 

 
 
 
             
 
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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, which 
should be recorded in the eCRF. 
Other treatment that the Investigator considers necessary for a subject’s welfare may be 
administered during 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, as well as herbal and 
nutritional supplements taken by the subject during the 30 days prior to screening will 
be recorded at the Screening Visit. 
• All prior anti-cancer treatments taken by the subject will be recorded regardless of 
time. 
• All concomitant medications taken while subjects are being followed for efficacy will 
be recorded. 
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 Immuno-compromised 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-A2M4CD8 cell infusion, should be 
discussed with the Medical Monitor. 
 

 
 
 
             
 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Temporary Study Stoppage 
Throughout the conduct of the study, safety data will be reviewed on an ongoing basis by an 
external DSMB (refer to Section 10.2).  If the following events occur, further enrollment to the 
study will be suspended and the regulatory authorities informed: 
• A subject has a positive RCL if the following occurs: 
− Confirmed positive PBMC RCL and no other vector lot is available (refer to 
Section 10.7.2 and Figure 1) 
− Confirmed biological RCL, all ADP-A2M4CD8 cell infusions are halted 
(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  
• Death 
• Unable/unwilling to comply with study requirements  
• Withdrawal of consent  
• Investigator decision  
• AE 
• Lost to follow-up (Section 7.4) 
• Pregnancy (Section 8.5.5)  
• Termination of the study by the Sponsor  
All subjects, with the exception of those who withdraw consent, die, are lost to follow-up or do 
not receive any T-cells, will continue in LTFU for observation of delayed AEs.  AEs in subjects 
who terminate early for any reason (other than withdrawal of consent or lost to follow-up) will 
be followed 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.  

 
 
 
             
 
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However, the Investigator must make every reasonable effort to keep each subject on study for 
the entire 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 completion or withdrawal of a subject from the study are: 
• Unable/unwilling to comply with study requirements  
• AE 
• Withdrawal of consent 
• Investigator decision 
• Lost to follow-up (Section 7.4) 
• Termination of the study by the 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 
The T&Es are provided in Table 1 for the Interventional phase of the study and in Table 2 for 
LTFU.   
8.1. 
Background Assessments 
 
Demographics 
Demographic data including year of birth, age, sex, race and ethnicity (where permitted by 
national regulations) will be collected at Prescreening and Screening. 
 
Disease History and Tumor-Specific Mutations 
The following information will be collected: primary tumor type, date of initial diagnosis, 
histology grade, and current stage of disease.  Additionally, at Screening, current stage of disease 
and histological molecular tests will be recorded in the eCRF.  
8.2. 
HLA and MAGE-A4 Tumor Antigen Testing 
There is no window for obtaining HLA and MAGE-A4 antigen prior to leukapheresis. 
 
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-validated HLA 
Sequencing System for SBT of HLA.  
 
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 subject’s 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 
Laboratory 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 Laboratory 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. 
8.3. 
Efficacy Assessments 
 
CT/MRI  
Imaging scans of the chest, abdomen, and pelvis should be performed at 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 an IRAC, 
scheduled 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 the following: 
• 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, if contrast enhanced CT is contraindicated for a subject, a 
non-contrast enhanced CT of the chest. 
• MRI of the extremities, if clinically indicated. 
• MRI of the brain acquired without and with contrast-enhancement (pre- and 
post-gadolinium chelate IV) (Section 8.4.10). 
• 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 flare’), response will not be 

 
 
 
             
 
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assessed before 4 weeks post-infusion of ADP-A2M4CD8, 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 no 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-A2M4CD8 
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 subject care throughout the study.  
 
Survival Data 
If a subject dies during the study, the date of death will be recorded.  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). 
Additional tests may be done at any time if clinically indicated. 
The Clinical Laboratory Tests in Table 5, Section 10.3, describes 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 4 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 
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Medical History 
Relevant medical history will be recorded at Screening (Visit 2). 
 
Physical Examination 
Subjects will undergo a physical examination at Screening and Baseline.  The frequency of 
physical examinations at subsequent visits is specified in Table 1 and Table 2. 
 
Prior Anti-Cancer Therapies 
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. 
 
Prior and Concomitant Medications 
Current medications and those for the previous 30 days are to be collected 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). 
 
ECOG 
Performance status will be measured using the ECOG performance scale; see Section 10.9 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 is specified in Table 1. 
 
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. 
 
Weight and Height 
Height will be assessed at the Baseline visit.  Weight will be assessed at Screening, Baseline, and 
other visits according to Table 1. 
 
Pulse Oximetry 
Oxygen saturation at rest will be assessed at Screening (within 7 days of leukapheresis) and at 
Baseline according to Table 1. Oxygen saturation should be measured with room air. 
 
Cardiac Assessments 
Cardiac and pulmonary assessments will be performed locally at the site. 
8.4.9.1. 
ECG 
A single ECG is required. Heart rate, rhythm, PR, RR, QRS, and QTc intervals will be recorded. 

 
 
 
             
 
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For Screening (Visit 2), ECGs performed as standard of care within 4 weeks prior the visit are 
acceptable.  The ECG on Day 1 will be taken before T-cell infusion starts. 
8.4.9.2. 
ECHO/MUGA 
An ECHO or MUGA scan will be performed at Screening to determine LVEF for eligibility.  
ECHO/MUGA scans performed as standard of care within 4 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 a minimum of 7 days post-ADP-A2M4CD8 
T-cell infusion.  
8.4.9.4. 
Pulmonary Function Tests 
Pulmonary function tests (PFTs) (FEV1 and TLC and DLCO) will be performed at Screening to 
determine eligibility and within 2 months of the start of lymphodepleting chemotherapy. 
Additional PFTs will be performed only if clinically indicated. 
 
Brain MRI 
An MRI of the brain with contrast will be obtained at Baseline, within 1 month prior to 
lymphodepletion, for all subjects to rule out newly diagnosed, untreated brain metastases or to 
document stability of previously treated brain metastases.  CT with IV contrast may be used only 
for subjects with contraindications to MRI 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.  If CNS metastases are not documented at Baseline, then 
dedicated brain CNS CT/MRI scans should be performed as clinically indicated (refer to 
Section 5.3, exclusion criterion 6). REGIONAL REQUIREMENT (UK):  Screening brain MRI 
is required where subjects with leptomeningeal disease, carcinomatous meningitis or CNS 
metastases are excluded. 
 
Renal Function Assessment (Creatinine Clearance) 
Renal function (estimated or measured glomerular filtration rate [GFR]) will be assessed at 
Screening according to institutional standard practice e.g., by prediction formula such as the 
Cockcroft Gault equation, modification of diet in renal disease equation, Chronic Kidney Disease 
Epidemiology Collaboration equation, or by 24-hour urine collection to measure CrCl or by 
nuclear medicine GFR measurement. 
Renal function will be reassessed at Baseline using the same methodology. 
 
Hematology 
Section 10.3 describes the parameters to be collected and recorded. 

 
 
 
             
 
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In Years 6 to 15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 10.7.2), then laboratory assessments may be 
discontinued. 
 
Clinical Chemistry  
Section 10.3 describes the parameters to be collected and recorded. 
In Years 6 to 15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 10.7.2), then laboratory assessments are 
discontinued. 
 
Coagulation 
Section 10.3 describes the parameters to be collected and recorded. 
 
Thyroid Function Tests 
Section 10.3 describes the parameters to be collected and recorded. 
 
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 (Section 10.3).  
 
Pregnancy Test 
Either serum or urine pregnancy tests may be performed.  FCBPs must have a negative 
pregnancy test at Screening and prior to starting lymphodepleting chemotherapy. 
 
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 6 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 (see Section 5.3, exclusion criteria 9). 
Section 10.3 describes the parameters to be collected and recorded. 
 
CMV PCR 
Subjects will be screened for CMV seropositivity at Screening.  If subjects are CMV seropositive 
at Screening, CMV PCR assessments will continue at Baseline, Day 1, Weeks 2, 4, 6, and 8.  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 and Weeks 2, 4, 6, and 8 (see Section 10.5.3.4 for CMV prophylaxis and 
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ICE Assessment Tool 
The Immune Effector Cell-Associated Encephalopathy (ICE) neurological assessment should be 
performed from Day 1 (prior to T-cell infusion) through Day 8 while the subject is hospitalized, 
according to Table 1.  The ICE assessment may be discontinued once a subject is discharged 
from the hospital. 
If a subject is thought to have ICANS, the ICE assessment should be used at least twice per day 
until resolution or stabilization.  It can also be used at later visits if indicated (Table 10). 
 
C-Reactive Protein  
If CRS is suspected, C-reactive protein (CRP) levels should be measured approximately every 
other day until symptoms are improving or an alternative diagnosis is confirmed. 
 
Ferritin  
If CRS is suspected, ferritin levels should be measured approximately every other day with CRP. 
 
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 8.6.6).  
Samples are required for the following: 
• Safety at Baseline and Week 24, Month 12 and then every 6 months until Year 5 and 
annually from Years 6 to 15.  
− If no gene modified cells are detected for three consecutive assessments and the 
subject is ≥ 5 years post-infusion (e.g., 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 (Section 10.7.2).  
− 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 (Section 10.7.2). 
• Research at Days 2, 4, and 8 and Weeks 2, 4, 8, and 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 Laboratory Manual. 
 
Replication Competent Lentivirus (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. 

 
 
 
             
 
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RCL testing will take place on the subject’s 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 1, 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 Section 10.7.2 for additional information). 
Details on collection and shipment of blood sample for RCL is described in the Laboratory 
Manual. 
8.5. 
Adverse Events and Serious Adverse Events 
 
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 or tumor 
biopsy) until 24 hours afterwards for blood sampling, or until 2 weeks post-biopsy.  
• From date of signing the Treatment Informed Consent 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 discontinued the Interventional phase of the study. In addition, emerging 
clinical conditions defined in Section 10.4.6 will be monitored starting Day 1.  If the 
subject has not progressed after 12 months, only those emerging clinical condition 
defined in Section 10.4.6 will be collected thereafter. 
• During the LTFU phase of the study, subjects will only be monitored for the 
emerging clinical conditions (LTFU AEs) defined in 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 
Section 10.4.6.  
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 after receiving new information. 

 
 
 
             
 
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Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of an AE and an SAE, and the 
procedures for completing and transmitting SAE reports are provided in 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 subject is the preferred method to inquire about 
AE occurrences. 
 
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 provided in Section 10.4.3. 
 
Regulatory Reporting Requirements for SAEs 
• Prompt (within 24 hours) notification by the Investigator to the Sponsor of an 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, IRB/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 along with Investigator Safety Letters (ISL). 
• An Investigator who receives an Investigator safety letter describing an 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 will 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 that are 
reported by the relevant Investigator(s). 
 
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 IP.  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. 

 
 
 
             
 
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• 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 
Section 10.6.2. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs.  
The safety of ADP-A2M4CD8 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, and 
therefore, female subjects who are pregnant, intending to become pregnant, or breast feeding are 
excluded from ADP-A2M4CD8 studies. 
There is no preclinical or clinical trial data of ADP-A2M4CD8 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, and 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 
IP, or 4 months after there is no evidence of persistence/gene modified cells in the subject’s 
blood, whichever is longer. 
The contraception guidelines provided in Section 10.6.1 should continue to be adhered to during 
LTFU. 
A woman who becomes and remains pregnant during the study will be discontinued from the 
Interventional phase, as exposure to radiation from imaging studies is contraindicated.  The 
subject would follow the LTFU T&E table (Table 2). 
 
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. 
 
AEs of Special Interest 
8.5.7.1. 
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 that 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 7 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, 

 
 
 
             
 
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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 is associated with 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]. 
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 management of CRS. 
8.5.7.2. 
Immune Effector Cell-Associated Neurotoxicity Syndrome 
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 CRS symptoms.  This form of ICANS tends to be of shorter duration, lower grade (Grades 1 
or 2; 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 CAR 
T‑cell therapy, after the initial fever and CRS subside [Lee, 2019]. 
ICANS may occur with other cancer immunotherapies, including TCRs.  Cancer subjects 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. 
8.5.7.3. 
Prolonged Cytopenias  
Prolonged cytopenias for ≥ 4 weeks from T-cell therapy, and pancytopenia after initial bone 
marrow recovery from high-dose chemotherapy followed by infusion of adoptive T-cell therapy 
with bone marrow failure/aplastic anemia have been reported with T-cell therapies 
[D’Angelo 2017; KYMRIAH EU SmPC; KYMRIAH USPI; YESCARTA EU SmPC; 
YESCARTA UPSI].  
Subjects may be symptomatic on presentation, but some are detected incidentally when 
unexpected cytopenias are found on a routine blood count.  Blood counts are collected according 
to Table 1.  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. 

 
 
 
             
 
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Management of bone marrow suppression and related cytopenias in prolonged or recurrent 
cytopenia with aplastic anemia is challenging. Treatment is largely supportive, including 
transfusions and treatment of infections.  
See Section 10.5.8 for management guidance if there is evidence of, or concern for the 
development of cytopenia (decreasing hemoglobin, platelets or neutrophils, or increasing 
transfusion requirements) that is either prolonged for ≥ 4 weeks from T-cell therapy or following 
initial bone marrow recovery.  
 
Long-Term Follow-Up Adverse Events 
During the 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 Letter 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 (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 Time and Events 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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− 
 
 
  
• 
 
− 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
• 
 
 
 
 
 
Tumor Biopsy 
Baseline biopsy material may be collected anytime within 2 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 

 
 
 
             
 
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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, or activity). 
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 obtained post-progression (e.g., from an 
excisional surgery).  Additional details regarding the tumor biopsy collection are provided in the 
Laboratory Manual. 
In subjects who have a pleural effusion or ascites, if there is a clinical requirement for removal of 
the effusion fluid at any time during the study, collection of samples for Adaptimmune 
translational research studies are requested, and if possible, all cells recovered in the draw. 
Note: If available, pleural effusion or ascites fluid should be collected in addition to, and not 
instead of the requested tumor biopsies. 
Clinically obtained pleural effusion/ascites samples have been shown to be a rich source of 
tumor cells, tumor infiltrating leukocytes, and soluble factors, changes in which have been 
reported to correlate with disease prognosis and therapy response.  Pleural effusions/ascites fluid 
collected in this study will be used to interrogate soluble and cellular components of the tumor 
microenvironment before and after T-cell infusion to address mechanisms of sensitivity or 
resistance to therapy. 
 
Cytokine and Soluble Protein Analysis 
Serum is collected at Baseline, pre-infusion and 2 to 4 hours post-infusion on Day 1, Day 2, Day 
4, Day 8, Week 2, Week 3 (Day 22), 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 Laboratory Manual. 
Serum samples may also be used to detect humoral immune responses to tumor antigens and 
antibodies to ADP-A2M4CD8. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
             
 
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Gene expression analysis in whole blood 
RNA sequencing will be performed on whole blood to investigate changes in global gene 
expression over time. The analysis will include characterization of T-cell and B-cell receptor 
(BCR) repertoires in blood and tumor tissues at Baseline and after infusion. These studies will 
support the understanding of TCR/BCR diversity and clonality and how these relate to the 
trafficking of ADP-A2M4CD8 SPEAR T-cells from peripheral blood to tumor lesions, and their 
expansion within the tumor microenvironment (TME).  
Whole blood collections scheduled at Baseline, Pre-infusion, Week 4, (anytime between Week 3 
and Week 8), Week 12 and withdrawal, are to be collected within 24 hours of the corresponding 
tumor biopsy tissue. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Persistence of ADP-A2M4CD8 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.  
 
 
 
 
 
 

 
 
 
             
 
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8.7. 
Subject-Reported Outcomes 
 
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 dimension has 3 levels: no problems, some problems, and 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 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 at Month 12 if the subject remains in the interventional phase of the study.  Once 
disease progression is established, the EQ-5D-3L assessment is no longer required. 
9. 
STATISTICAL CONSIDERATIONS 
The objectives and endpoints for this study are described in Section 3. This section focusses on 
key aspects of 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).  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. 
Per-protocol (PP) population: A PP population may be included if there are subjects in the 
mITT population who have protocol violations that are expected to affect efficacy assessments 
(e.g., subjects enrolled who do not meet key eligibility criteria) during the trial.  Protocol 
violators resulting in exclusion from the PP population will be identified and documented prior 
to database lock.   
The primary analysis will occur at the time of clinical cut-off as described in Section 5.5.   

 
 
 
             
 
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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-A2M4CD8). 
The primary endpoint for efficacy is ORR defined as the proportion of subjects with a confirmed 
complete response (CR) or confirmed partial response (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 the IRAC. 
Subjects with an 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 the sample size for the proposed 
clinical trial are based on the following factors:  
• As stated in Section 2.2.3, clinical evidence indicates the historical ORR for therapies 
administered to subjects who progressed on or after at least 2 prior systemic therapies 
for esophageal and GEJ cancers is 14%. 
• The ORR for the historical control that will be used for hypothesis testing in this 
study will be 14%.  
• The mechanism of action for the TCR is assumed to be the same for adenocarcinoma 
and squamous cell carcinoma. 
• As stated in Section 2.1.1, 1 of 2 subjects with GEJ cancers treated with 
ADP-A2M4CD8 cells had a PR in the ADP-0055-001 SURPASS phase 1 study. In 
that same study, 4 additional subjects with other tumor types were treated, with 1 
such subject also having a PR. All other subjects had best overall response of stable 
disease. Because of this preliminary evidence, for purposes of sample size 
computation, we assumed ORR for ADP-A2M4CD8 cell therapy would be 35% 
(Section 2.3.1).  
The hypothesis of interest for the primary endpoint is: 
Null Hypothesis (H0): p ≤ p0 vs. Alternative Hypothesis (H1): p > p0, where p0 (historical ORR) = 
0.14. 
Statistical design assumptions: 
• The assessment for efficacy will be based on the mITT population using confirmed 
ORR via RECIST v1.1 by the IRAC. 
• The type I error (α) for this test will be no more than 0.049. 
• The type II error (β) will not exceed 0.1. 
• Exact binomial methods will be used to test the hypothesis. 
According to a Chen’s three-stage design, approximately 45 subjects will be enrolled.  

 
 
 
             
 
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• First Stage: 15 evaluable subjects will be enrolled in stage 1. The predefined ORR is met 
if there are 2 or more confirmed complete response (CR) or confirmed partial response 
(PR) out of the first 15 evaluable subjects based on investigator radiological assessment. 
Subject enrollment will continue to the next stage if there is a demonstrable clinical 
benefit from treatment with cell therapy and there are no major safety concerns. 
Otherwise, subject enrollment will be stopped. The independent DSMB will make this 
recommendation. 
The DSMB will review safety data (including AEs and SAEs), ongoing efficacy data for 
futility, and overall benefit:risk profile, and make a recommendation to Adaptimmune. 
The process for the review will be defined in the DSMB charter. 
• Second Stage: An additional 13 evaluable subjects will be enrolled in stage 2, if the 
predefined ORR is met (i.e., 7 or more responses, confirmed CR or confirmed PR, out of 
the first 28 (15 + 13) evaluable subjects based on investigator radiological assessment), 
then the study will continue to the third and final stage.   
Subject enrollment will continue to the next stage if there is a demonstrable benefit from 
treatment with cell therapy and there are no major safety concerns. Otherwise, subject 
enrollment will be stopped. The independent DSMB will make this recommendation.  
• Third Stage: An additional 17 evaluable subjects will be enrolled for a total of 45 (15 + 
13 +17) evaluable subjects. 
9.3. 
Statistical Analyses 
The SAP document will provide full details about analysis methods, data derivations, and 
displays. This section captures key aspects of the analysis. 
Demography and baseline characteristics will be summarized using appropriate descriptive 
statistics. Subject disposition, including the number of subjects leukapheresed, lymphodepleted, 
and treated with ADP-A2M4CD8, will be summarized. Reasons for subject discontinuation from 
the study will be displayed.  Other subgroups, such as region, may be explored, and these will be 
discussed in the SAP. 
 
Interim Analysis 
Interim analysis will be performed according to Chen’s three stage design based on the mITT 
population as described in Section 9.2. 
 
Efficacy Anti-Tumor Activity Analyses 
The primary analysis population for efficacy will be the mITT population.  Secondary analyses 
may be conducted on the ITT and PP populations if they are different from the mITT population.  
The primary endpoint, ORR will be based on confirmed (tumor) responses per RECIST v1.1 by  
the IRAC. The ORR will be summarized using Clopper-Pearson (exact binomial) 2-sided 95% 
CIs.  
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).   

 
 
 
             
 
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As a sensitivity analysis, 2-sided 95% confidence intervals using the Wilson method may also be 
provided. 
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, by primarily the IRAC and secondarily the 
investigator radiological assessment. 
• DoR, defined as the duration between the initial date of the confirmed response to the 
date of PD or death, where tumor response and disease progression are evaluated by 
primarily the IRAC and secondarily the investigator radiological assessment. 
• BOR, defined as the best response recorded from the date of T-cell infusion until 
disease progression. Response categories from best to worse are: confirmed CR, 
confirmed PR, SD, PD, and NE (per RECIST v1.1 by primarily the IRAC and 
secondarily the investigator radiological assessment). 
• PFS, defined as the duration between the date T-cell infusion and the earliest date of 
disease progression based on RECIST v1.1 (by primarily the IRAC and secondarily 
the investigator radiological assessment) or death due to any cause. 
− Since subjects are expected to progress in the Interventional phase (see 
Section 4.4) before entering LTFU, it is expected that most subjects will have a 
date of disease progression in the Interventional phase. In the event that the 
subject did not progress but entered LTFU (see Section 4.2.4), the death date will 
be captured from LTFU to summarize PFS. 
• OS, defined as 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 TTR, DoR, BOR, and PFS. Investigator assessment of progression based on RECIST 
v1.1 will be used for the secondary analysis of TTR, DoR, BOR, and PFS. As a sensitivity 
analysis, determination of progression (via RECIST v1.1) using lesion assessments will also be 
provided.  
No hypothesis testing is planned for these secondary endpoints. Time-to-event endpoints 
(e.g., 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. 2-sided 95% CIs will be 
produced.  OS may be assessed at fixed time points such as 1 year and 2 years using K-M 
methods.  
Detailed censoring rules for all time-to-event endpoints will be specified in the SAP. The 
proportion of censored observations will be summarized. 
The surrogates of treatment effect 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.  
The exploratory endpoint of EQ-5D-3L will be summarized using appropriate summary 
statistics, by time, responder status, and overall. 

 
 
 
             
 
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Safety Analyses 
The primary analysis population for safety will be the mITT population.  Safety will also be 
summarized for the ITT population and may include the per protocol (PP) population. 
The safety profile will be based on AEs, SAEs, LTFU AEs, RCL, and T-cell persistence. 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. 
AEs will be summarized using three 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 through the end of interventional phase 
• From the end of interventional phase until up to 15 years after the last T-cell infusion 
AEs throughout the trial will be coded by MedDRA v 23.0 or higher.  The number and 
percentage of subjects reporting any AEs will be tabulated by system organ class and preferred 
term. AEs 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. 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 
 
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 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 usernames and passwords. 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, World Health Organization Drug and MedDRA will be used to code 
medications, medical history, and AEs. 
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 portable document format (PDF) 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 withdraws from 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. 
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. 

 
 
 
             
 
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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. 
 
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. 
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. 

 
 
 
             
 
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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, IP 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. 
 
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 
IRB/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 principles 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 individual. The study must fully 
adhere to the principles outlined in ICH GCP or with local law if it affords greater protection to 
the subject. 
 
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 ICF 

 
 
 
             
 
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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). 
 
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. 
 
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. 
 
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. 

 
 
 
             
 
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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. 
 
Clinical Study Report 
The results of the study will be presented in an integrated clinical study report according to ICH 
guideline E3: Structure and Content of Clinical Study Reports. 
 
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 guidelines and/or publication guidelines if applicable. 
 
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 Review 
 
Data Safety Monitoring Board 
An external, independent DSMB will be implemented for this study 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 as outlined in the DSMB charter. The DSMB will review safety data 
(including AEs and SAEs), ongoing efficacy data for futility, and overall benefit:risk profile. 
A DSMB charter, defining roles and accountabilities and the process for review, will be available 
prior to the start of the study. 
 
 

 
 
 
             
 
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10.3. 
Appendix 3: Clinical Laboratory Tests 
Laboratory reference ranges for all tests conducted locally must be provided to the Sponsor 
before the study initiates. 
Table 5: 
Protocol-Required Safety Laboratory Assessments 
Hematology: 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean cell volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Reticulocytes 
Platelet count 
White blood cell count 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/CO2 
Creatinine* 
Chloride 
Glucose 
Blood urea nitrogen or urea 
* 24 hr urine test or GFR per institutional standards 
Other Tests: 
Ferritin 
C-reactive protein (CRP) 

 
 
 
             
 
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Coagulation Screen: 
Prothrombin time (PT) or International Normalized 
Ratio (INR) 
Activated partial tissue thromboplastin time (aPTT) 
Pregnancy Test: 
Serum beta-human chorionic gonadotropin 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# 
Epstein Barr Virus# 
Treponema IgG or RPR # 
Viral reactivation 
CMV DNA PCR1 – peripheral blood for detection of 
reactivation. In the event of suspected end organ CMV 
disease a biopsy may be required1 
# Per Institutional Standard Practice is acceptable 
1Not included in infectious disease screening panel. Tested at timepoints in Schedule of Assessments for patients 
who are CMV seropositive at Screening.  
 

 
 
 
             
 
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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting 
 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a subject 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 fulfill the definition of an AE or SAE. 
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. 

 
 
 
             
 
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• 
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. 
 
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). 
An 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. 
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. 

 
 
 
             
 
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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: 
− 
ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin)  
− ALT ≥ 3 x ULN and international normalized ratio (INR) > 1.5, if INR measured  
 
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 eCRF. 
• 
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 eCRF 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 except for CRS and ICANS will be graded according to the NCI CTCAE v 5.0.  See 
Section 10.5.6 and Section 10.5.7 for guidance on grading of CRS and ICANS, 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 activities of daily living (ADL)1 
• 
Grade 3 - Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL2 

 
 
 
             
 
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• 
Grade 4 - Life-threatening consequences; urgent intervention indicated 
• 
Grade 5 - Death related to AE 
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. 
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. 
Assessment of Causality 
• 
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. 

 
 
 
             
 
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• 
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 eCRF. 
• 
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. 
 
Reporting of SAEs 
SAE Reporting to Adaptimmune  
• 
SAEs must be reported to Adaptimmune by completing the paper SAEW within 24 hours 
of the study personnel’s discovery of the event. 
• 
Complete the SAEW as fully as possible and obtain the Investigator’s 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. 
The SAEW and additional information can be found in the Study Procedures Manual. 
 
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 
T&E table (Table 1) 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 (Section 1.3). Hepatic safety assessments will be included in this safety follow-up. 

 
 
 
             
 
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Table 6: 
Hepatic Monitoring Criteria 
Hepatic Monitoring Criteria 
ALT-absolute 
ALT ≥ 8 x ULN 
ALT Increase 
ALT ≥ 5 x ULN but < 8 x ULN persists for ≥ 2 weeks 
ALT ≥ 3 x ULN but < 5 x ULN persists for ≥ 4 weeks 
Bilirubin1 
ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin)  
International 
Normalized Ratio 
(INR)1  
ALT ≥ 3 x ULN and INR > 1.5, if INR measured 
Symptomatic2 
ALT ≥3 x ULN 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 eCRF, and an 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, 
and 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 
≥ 2 x ULN. 
• 
Viral hepatitis serology3 
• 
Serum creatinine phosphokinase and LDH 
• 
Complete blood count (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 OTC 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 IgG or 
gamma globulins. 
• 
Liver imaging (ultrasound, MRI, or CT) 
• 
Consider liver biopsy 
1 All events of ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin) or ALT ≥ 3 x ULN 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; CMV 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 eCRF. Instructions for sample handling and shipping 
are in the Laboratory Manual. 

 
 
 
             
 
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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, 2020a; 
FDA, 2010; EMA, 2009].  Subjects will be followed according to the schedule outlined in 
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 with 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 investigational new drug applications 
(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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Unexpected serious LTFU adverse reactions deemed at least possibly related to the gene 
modified cells (i.e., SUSARs) will be reported to the Regulatory Agencies and shared with 
Investigators as necessary in the form of ISLs.   
 
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. 
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, CRS, 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. 
 
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 (i.e., filgrastim) should be used in all subjects. 
G-CSF should be used for management of neutropenia according to ASCO guidelines [Smith, 
2015]. G-CSF should be given 24 hours after the last dose of chemotherapy until resolution of 
neutropenia (reaching an ANC of at least 2 × 109/L to 3 × 109/L or as per ASCO guidelines 
[Smith, 2015] or 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 24 
hours after the last dose of chemotherapy. 

 
 
 
             
 
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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. 
 
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-A2M4CD8 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-A2M4CD8 cell infusion. 
10.5.3.2. Pneumocystis jiroveci Pneumonia 
Subjects should receive prophylaxis against Pneumocystis jiroveci 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 in the case of sulfonamide allergy or sulfa intolerance. 
Treatment 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 herpes simplex virus episodes. 

 
 
 
             
 
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10.5.3.4. Cytomegalovirus (CMV) 
Subjects will be screened for 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 in Table 1 until 60 days post-infusion of ADP-
A2M4CD8 cells. 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 10.5.8. 
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 (300 mg daily), entecavir (0.5 mg daily), or 
tenofovir (300 mg 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 anti-fungal prophylaxis should follow Institutional standards for autologous 
bone marrow transplants. 
 
Hematologic and Blood Product Support 
Blood product support should be provided to maintain platelets > 10 x 109/L, hemoglobin 
> 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 allogenic 
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• 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 including during LTFU. 
 
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 Investigator should be contacted, and every 
attempt should be made to biopsy the affected organ to clarify whether the symptoms are related 
to the ADP-A2M4CD8 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. 
 
Management of Cytokine Release Syndrome 
Table 7 provides the recommended grading of CRS according to grade, which has been further 
adapted from CTCAE for use with immune effector cell therapy [Lee, 2019] 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 (as described in Section 8.5.7.1) and CRP levels should be measured 
approximately every other day until symptoms are improving or an alternative diagnosis is 
confirmed.  

 
 
 
             
 
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Table 7:  
ASTCT CRS Consensus Grading  
[Lee, 2019] 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading. 
1 Fever is defined as temperature ≥ 38°C not attributable to any other cause. Inpatients who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
2 CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a subject with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-
flow nasal cannula is classified as grade 3 CRS. 
3 Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute. 
 
 
 
 
 
 
 
 
 
 
 
CRS 
parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever1 
Temperature 
≥ 38°C 
Temperature 
≥ 38°C 
Temperature 
≥ 38°C 
Temperature ≥ 38°C 
with 
Hypotension 
None  
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
And/or2 
Hypoxia 
None 
Requiring low-flow 
nasal cannula3 or 
blow-by 
Requiring high-
flow nasal 
cannula3, facemask, 
nonrebreather 
mask, or Venturi 
mask 
Requiring positive 
pressure (e.g., 
continuous positive 
airway pressure and 
bilevel positive airway 
pressure, intubation, 
and mechanical 
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Management guidelines for CRS are provided in Table 8 below: 
Table 8: 
Management Guidelines for CRS  
Grade 
Management Guidelines 
1 
Fever 
• 
Vigilant supportive care including acetaminophen and hypothermia blanket for the 
treatment of fever. Ibuprofen can be used as second treatment option for fever, if not 
contraindicated  
• 
Assess for infection using blood and urine cultures, and chest radiography1 
• 
Empiric broad-spectrum antibiotics if neutropenic or otherwise indicated 
• 
Maintenance intravenous (IV) fluids for hydration 
• 
Symptomatic management of constitutional symptoms and organ toxicities 
• 
Initiate tocilizumab 8 mg/kg3 IV in patients at high risk2, or if CRS lasts ≥ 24 hours 
• 
If fever persists for ≥ 8 hours after tocilizumab, or chest imaging demonstrates 
evidence of pneumonitis or tumor flare, initiate methylprednisolone 1 mg/kg IV daily 
for 3 days 
 
2 
Hypotension 
• 
IV fluid bolus of 500–1,000 ml of normal saline. Can give a second IV fluid bolus if 
systolic blood pressure (SBP) remains <90 mmHg 
• 
Tocilizumab 8 mg/kg3 IV for the treatment of hypotension that is refractory to fluid 
boluses; tocilizumab can be repeated if clinically indicated 
• 
If hypotension persists after two fluid boluses and tocilizumab, start vasopressors, 
consider transfer to intensive-care unit (ICU), obtain echocardiogram, and initiate 
other methods of hemodynamic monitoring 
• 
In patients at high-risk2 or if hypotension persists requiring a second dose of 
tocilizumab, dexamethasone should be used at 10 mg IV every 6 h or 
methylprednisolone equivalent 
• 
Manage fever and constitutional symptoms as indicated for grade 1 CRS 
Hypoxia 
• 
Supplemental oxygen 
• 
Tocilizumab ± corticosteroids and supportive care, as indicated for the management of 
hypotension 
Organ Toxicity 
• 
Symptomatic management of organ toxicities, as per standard guidelines 
• 
Tocilizumab ± corticosteroids and supportive care, as indicated for hypotension 
 

 
 
 
             
 
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Grade 
Management Guidelines 
3 
Hypotension 
• 
IV fluid boluses as needed, as recommended for the treatment of grade 2 CRS 
• 
Tocilizumab as recommended for grade 2 CRS, if not administered previously 
• 
Vasopressors as needed 
• 
Transfer to ICU, obtain echocardiogram, and perform hemodynamic monitoring as in 
the management of grade 2 CRS 
• 
Dexamethasone 10 mg IV every 6 h; if refractory, increase to 20 mg IV every 6 h, or 
methylprednisolone equivalent 
• 
Manage fever and constitutional symptoms as indicated for grade 1 CRS 
Hypoxia 
• 
Supplemental oxygen including high-flow oxygen delivery and non-invasive positive 
pressure ventilation 
• 
Tocilizumab plus corticosteroids and supportive care, as indicated for the management 
of hypotension 
Organ Toxicity 
• 
Symptomatic management of organ toxicities as per standard guidelines 
• 
Tocilizumab plus corticosteroids and supportive care, as indicated for the management 
of hypotension 
 
4 
Hypotension 
• 
IV fluids, tocilizumab, vasopressors, and haemodynamic monitoring as defined for the 
management of grade 3 CRS 
• 
Methylprednisolone 1 g/day IV 
• 
Manage fever and constitutional symptoms as in grade 1 CRS 
Hypoxia 
• 
Mechanical ventilation 
• 
Tocilizumab plus corticosteroids and supportive care, as recommended for the 
management of hypotension 
Organ Toxicity 
• 
Symptomatic management of organ toxicities as per standard guidelines 
• 
Tocilizumab plus corticosteroids and supportive care, as recommended for the 
management of hypotension 
 
1 Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of anti-microbial agents for concurrent bacterial infections. 
2 High-risk defined as high tumor burden (SD >100 mm), bilateral pulmonary tumor involvement, age ≥ 60 years, or 
other significant comorbidities, such as moderate underlying lung disease, as identified by the Investigator 
3 For subjects requiring intervention beyond supportive measures tocilizumab 8 mg/kg IV should be the first line 
treatment. Siltuximab 11 mg/kg IV may be used instead of tocilizumab, if unavailable. The maximum dose for 
tocilizumab is 800 mg per dose. Repeat doses should be given according to tocilizumab prescribing information. 
 Source: Lee, 2019; Neelapu, 2018 

 
 
 
             
 
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In addition to the above guidelines, consider holding G-CSF during CRS. GM-CSF should be 
avoided during CRS [Maus, 2020]. 
Refer to Section 10.5.7.1 below for subjects experiencing Immune Effector Cell-Associated 
Neurotoxicity Syndrome concurrent with CRS. 
If CRS 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.  
Please review the most recent version of the product label for tocilizumab. 
 
Grading and Management of Neurotoxicity 
10.5.7.1. Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
The American Society for Transplantation and Cellular Therapy (ASTCT) have developed a 
grading system for ICANS that incorporates the ICE 10‑point neurological assessment (Lee, 
2019) tool (Table 9). Points are assigned for each of the tasks in Table 9 that are performed 
correctly. Normal cognitive function is defined by an overall score of 10. The ICE assessment 
should be used to monitor all subjects for ICANS.  
The ICE assessment used for grading ICANS is presented in Table 9. 
Table 9: 
ICE 10‑Point Neurological Assessment (ICE) [Based on Lee, 2019] 
Task 
ICE Assessment Points 
Orientation: Orientation to year, month, city, and 
hospital 
Total of 4 points (1 point for each) 
Naming: ability to name 3 objects (e.g., point to 
clock, pen, button) 
Total of 3 points (1 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 assessment score is used in grading of ICANS as presented in Table 10. 
Table 10: 
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) [Based on Lee, 2019] 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE Assessment 
Score1 
7–9  
3–6  
0–2  
0 (subject is unarousable 
and unable to perform 
ICE assessment) 

 
 
 
             
 
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Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Depressed level of 
consciousness2 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to 
tactile stimulus 
Subject is unarousable 
or requires vigorous or 
repetitive tactile stimuli 
to arouse. Stupor or 
coma 
Seizures  
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves 
rapidly or 
nonconvulsive 
seizures on 
electroencephalogr
aphy (EEG) 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or 
Repetitive clinical or 
electrical seizures 
without return to 
baseline in between 
Motor findings3 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
intercranial 
pressure (ICP)/ 
cerebral edema 
N/A 
N/A 
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 
ICANS grade is determined by the most severe event (ICE assessment score, level of consciousness, seizure, motor 
findings, raised ICP/cerebral edema) not attributable to any other cause; for example, a subject with an ICE 
assessment score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
N/A indicates not applicable. 
1 A subject with an ICE assessment score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but 
a subject with an ICE assessment 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. 
10.5.7.2. Management of ICANS 
Brain MRI (or CT scan if MRI is not feasible) is required at Baseline for all subjects.  Baseline 
brain MRI should be repeated if more than 4 weeks have elapsed prior to lymphodepletion. 
The ICE 10‑point neurological assessment tool is used to assess neurologic function to monitor 
for ICANS (Section 10.5.5).  The ICE assessment can be administered by a study physician or 
other healthcare professional.  The ICE assessment should be measured on the day of ADP-

 
 
 
             
 
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A2M4CD8 infusion prior to receiving treatment and through Day 8 while the subject is 
hospitalized.  If the subject is discharged before Day 8, the ICE assessment may be discontinued 
according to the Main T&E table (Table 1).  Subjects with known brain metastases should be 
monitored at least twice per day for the first 5 days following ADP-A2M4CD8 infusion if 
hospitalized.  If a subject is found to have ICANS, the ICE assessment 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.  The ICE assessments forms part of the grading system for ICANS developed 
by Lee et al [Lee, 2019]. 
The recommended management of ICANS should be based on toxicity grade.  Table 11 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. 
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 11: 
Management of ICANS 
Grade 
Treatment 
1 
For all subjects: 
• 
Vigilant supportive care; aspiration precautions; 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 CNS depression 
• 
Evaluate for other contributing causes and treat accordingly 
Unless symptoms are mild and transient (e.g. 1-point change in ICE assessment 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 ICP 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 

 
 
 
             
 
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Grade 
Treatment 
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 subject 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 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 subject has persistent 
Grade ≥ 3 ICANS 
4 
• 
Supportive care and neurological work‑up as indicated for Grade 1 ICANS 
• 
Consider neurosurgical consultation for subjects 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 800 mg 
 
Prolonged Cytopenias  
10.5.8.1. Definition of Prolonged Cytopenias, Pancytopenia and Aplastic 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 

 
 
 
             
 
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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 USPI; KYMIRAH EU SmPC; 
YESCARTA USPI; YESCARTA EU SmPC]. 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 hypocellular bone marrow when 2 of the 
following 3 blood counts are met: Absolute Neutrophil Count < 500/μL, Absolute Reticulocyte 
Count < 60,000/μL, and Platelet count < 20,000/μL, with the exclusion of myelodysplastic 
syndrome. 
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) 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, cyclosporine, eltrombopag) as well as anti-microbial prophylaxis/therapy with the 
advice of your Hematology/Infectious Diseases consultant(s).  If high dose corticosteroids 
are initiated, duration of therapy and gradual 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. 

 
 
 
             
 
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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: 
• FCBPs must agree to use an effective method of contraception starting at the first 
dose of chemotherapy for at least 12 months thereafter and 4 months after the gene 
modified cells are no longer detected in the blood 
• 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 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 LTFU. 
 
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-A2M4CD8. 
• 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 
 
Background to Safety Monitoring in LTFU 
10.7.1.1. Monitoring and Management of Replication-Competent Lentivirus (RCL) 
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, 
2020a; EMA, 2009]. 
An 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 IO follows the recommendations set forth in the FDA and EMA guidance’s 
[FDA, 2020a; FDA, 2020b; EMA, 2009].  IO 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 treated with 
retrovirus transduced stem cells were found to have insertion near the LIM domain only 2 
(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 
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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Testing for RCL and Persistence 
RCL (VSV-G DNA) 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 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 the Sponsor’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 is reported to the Sponsor.  The DSMB and the Safety Governance Board 
will be notified.  
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 TCR 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 TCR 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, 2020a]. 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 will be treated with the same TCR 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, 
National Institutes of Health, 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, 2020a; FDA, 2020b; 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 packaging 
signal sequence (Psi) which is 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 (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 
 
 
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 IO.   
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 demonstrate: 1) persistent monoclonality, 2) other evidence of IO (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 and the Safety Governance Board will be notified. Adaptimmune will develop a 
monitoring plan specific to the health care risk and strategies to inform appropriate subjects, 
Investigators, FDA, and other regulators of the findings.   
 
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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If the integration site analysis indicates polyclonality of the genetically modified T-cell 
population, then screening for persistence continues as scheduled (Table 2 and Figure 2). 
 
Letter to Physician - LTFU Notification 
[date] 
[name and address] 
Dear [physician name], 
Your subject [subject name] has participated in a clinical research study, A Phase 2 Open-Label 
Clinical Trial of ADP-A2M4CD8 in Subjects with Advanced Esophageal or Esophagogastric 
Junction Cancers, that requires 15-year monitoring for adverse events. To aid in reporting of 
adverse events that are possibly related to the clinical research study, we are asking the subjects 
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 subject has designated you. If upon any of 
your visits with your subject, 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 
If your subject 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 subject’s health if necessary. When you call, remember to mention the 
protocol number of the study which is ADP-005-002, subject ID [XXX] and the study title which 
is A Phase 2 Open-Label Clinical Trial of ADP-A2M4CD8 in Subjects with Advanced 
Esophageal or Esophagogastric Junction Cancers”. 

 
 
 
             
 
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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 
 
RECIST 1.1 Criteria 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 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 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 PR and CR or evaluation of new or enlarging effusions to differentiate 
between PD and Response/SD). 
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). 
Measurable lesions 
• 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 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 
• All 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 (Table 12) 
CR: Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm. 
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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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 progressions).  
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 
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. 
PD: Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. Unequivocal progression should not normally trump target lesion status.  It must 
be representative of overall disease status change, not a single lesion increase. 
Special notes on assessing progression of Non-Target lesions 
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 

 
 
 
             
 
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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 PR 
or CR). 
• 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 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 fluorodeoxyglucose-positron emission 
tomography (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). 
• 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. 

 
 
 
             
 
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Table 12: 
Summary of the best overall response status calculation at each time point 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Best 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. Confirmation2 
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 weeks from ADP-
A2M4CD8 infusion2 
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 (Eisenhauer, 2009) for further details on what is evidence of a new lesion 
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 
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.  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. 

 
 
 
             
 
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Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, 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. 
http://recist.eortc.org/recist-1-1-2/ 
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 housework, 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 12: Abbreviations 
The following abbreviations and specialist terms are used in this study protocol. 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
BOR 
Best overall response 
CAR 
Chimeric antigen receptor 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CT 
Computerized tomography 
CTA 
Cancer-testis antigen 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Dendritic cell 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 

 
 
 
             
 
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ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalography 
EMA 
European Medicines Agency 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose–positron emission tomography 
FEV1 
Forced expiratory volume 
FSH 
Follicle stimulating hormone 
GEJ 
Gastroesophageal junction 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
GFR 
Glomerular filtration rate 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HTLV 
Human T-cell leukemia virus 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICANS 
Immune effector cell-associated neurotoxicity syndrome 
ICE 
Immune effector cell-associated encephalopathy 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ICP 
Intercranial pressure 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
IFNγ 
Interferon gamma 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 

 
 
 
             
 
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IND 
Investigational new drug application 
INR 
International normalized ratio 
IO 
Insertional oncogenesis 
IRAC 
Independent radiological assessment committee 
ISF 
Investigator Site File 
ISL 
Investigator Safety Letter 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  
IVD 
In vitro diagnostic 
IV 
Intravenous 
K-M 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
LMO2 
LIM domain only 2 
LTFU 
Long-term follow-up 
LVEF 
Left ventricular ejection fraction 
MAGE-A 
Melanoma-associated antigen-A 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
mITT 
Modified Intent-to-Treat 
MRCLS 
Myxoid/Round Cell Liposarcoma 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger RNA 
MUGA 
Multiple-gated acquisition 
N/A 
Not applicable 
NE 
Not evaluable 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
OTC 
Over the counter 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 

 
 
 
             
 
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PDF 
Portable document format 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PP 
Per-protocol 
Psi 
Packaging signal sequence 
PR 
Partial response 
PTT 
Partial thromboplastin time 
RCL 
Replication competent lentivirus 
RCR 
Replication competent retrovirus 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAEW 
Serious adverse event worksheet 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SBT 
Sequence based typing 
SD 
Stable disease 
SIN 
Self-inactivating 
SPEAR 
Specific peptide enhanced affinity receptor 
SUSAR 
Suspected unexpected serious adverse reactions 
T&E 
Time and Events 
TCR 
T-cell receptor 
TLC 
Total lung capacity 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States product insert  
VEGFR 
Vascular endothelial growth factor receptor 
VSV-G 
Vesicular Stomatitis Virus G glycoprotein 

 
 
 
             
 
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10.12. 
Appendix 13: Protocol Amendment History 
Protocol Version: Amendment 1.0 dated  29-June-2021 is replaced by Protocol Amendment 
Version 2.0 dated  17-November-2021.  
Section amended in version 
2.0 
Change 
Rationale for change 
Throughout 
Administrative updates to 
section numbering and addition 
of abbreviations. 
Administrative updates for 
clarity. 
Synopsis, T&E table, 5.2, 
8.4.8 
Addition of Inclusion Criteria 
#14 detailing oxygen support 
requirements. 
Revised to reflect updated safety 
measures. 
Synopsis, T&E table, 5.3, 
8.4.9.4 
Update to Exclusion Criteria #8 
to Pulmonary Function Test 
requirements and requirements 
for oxygen support. 
Revised to reflect updated safety 
measures. 
4.1 
Update to statistical 
methodology. 
Correct error in previous 
protocol versions. 
Table 4 
Correction to lymphodepletion 
dosing and addition of footnote 
to allow use of institutional 
guidelines. 
Revised to correct error and to 
allow use of institutional 
guidelines. 
10.5.6 
Update to the Management of 
Cytokine Release Syndrome. 
Revised to reflect updated safety 
measures and to align with 2020 
SITC guidelines. 
 
 
 
 
 

 
 
 
             
 
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