A Phase I/IIa, Open Label Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs Specific for NY-ESO-1 in Patients With Recurrent or Treatment Refractory Ovarian Cancer.
Phase: PHASE1
Conditions: Ovarian Cancer
Sponsor: Adaptimmune

 
 
 
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TITLE:  A Phase I/IIa, Open Label, Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells 
Expressing Enhanced TCRs Specific for NY-ESO-1 in Patients with Recurrent or Treatment Refractory 
Ovarian Cancer 
 
 
 
Final Version: 07 February 2017 
 
 
CONFIDENTIALITY STATEMENT 
This document contains information which is the property of Adaptimmune Ltd, United Kingdom, and 
Adaptimmune LLC, USA, and therefore is provided in confidence for your review.  It is understood that 
this information will not be disclosed to others without written approval from Adaptimmune Ltd. or 
Adaptimmune LLC. 
 
DECLARATION 
This study will be conducted in compliance with Good Clinical Practice, the Declaration of Helsinki (with 
amendments), and in accordance with local legal and regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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A Phase I/IIa, Open Label Clinical Trial Evaluating the Safety and Efficacy of 
Autologous T Cells Expressing Enhanced TCRs Specific For NY-ESO-1 in Patients 
with Recurrent or Treatment Refractory Ovarian Cancer 
 
 
Study Sponsor: 
Adaptimmune Ltd 
57c Milton Park 
Abingdon 
Oxon 
OX14 4RX 
www.adaptimmune.com 
 
Study Drug: 
NY-ESO-1c259T 
Protocol Number: 
 
IND Number: 
ADP-0011-001 
 
14603 (NY-ESO-1c259T)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                         
  
 
 
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Summary of Changes 
 
Refer to Appendix H for a summary of the changes included in this amendment.  
 
Date: 
July 15, 2011 
NIH RAC 
Amended: 
September 29, 2011 
Initial Institutional Board reviews 
Amended: 
November 14, 2011 
Institutional Board reviews 
Amended: 
December 2, 2011 
FDA requests 
Amended: 
March 14, 2012 
FDA clarification 
Amended: 
July 30, 2012 
 
Amended: 
August 16, 2012 
 
Amended: 
October 14, 2012 
 
Amended: 
March 21, 2013 
Version 1 
Amended: 
June 14, 2013 
Administrative changes only 
Amended: 
July 18, 2013 
Version 2 
Amended: 
December 18, 2013 
Version 3 
Amended: 
July 21, 2014 
Version 4 
Amended: 
April 23, 2015 
Version 5 
Amended:  
June 13, 2016 
Version 6 
 
 
 
 

 
                         
  
 
 
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SIGNATURES AND AGREEMENT WITH THE PROTOCOL 
I, the undersigned, have reviewed the protocol, including the appendices, and I will conduct the clinical 
study as described and will adhere to International Conference on Harmonisation (ICH) guideline E6 
(r1):Guideline for Clinical Practice (GCP) and all the ethical and regulatory considerations stated. I have 
read and understood the contents of the Investigators Brochure. 
 
Investigator Name 
 
Investigator Title 
 
Investigator Site and Address 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                         
  
 
 
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TABLE OF CONTENTS 
1 
Introduction ........................................................................................................................... 19 
1.1 
Background .................................................................................................................... 19 
1.1.1 
Recurrent Ovarian Cancer ....................................................................................... 19 
1.1.2 
Redirected T Cell Therapy for Ovarian Cancer ...................................................... 20 
1.1.3 
Rationale for Targeting Cancer Testes Antigens .................................................... 21 
1.1.4 
Previous Clinical Studies with NY-ESO-1 Vaccines ............................................. 22 
1.1.5 
Rationale for NY-ESO-1 Threshold ....................................................................... 23 
1.1.6 
Rationale for Preconditioning with Chemotherapy ................................................ 24 
1.2 
Investigational Agents .................................................................................................... 25 
1.3 
Preclinical Data .............................................................................................................. 25 
1.4 
Clinical Data to Date ...................................................................................................... 25 
1.4.1 
Prior Human Experience with NY-ESO-1c259T ...................................................... 25 
1.4.2 
Study Progress ........................................................................................................ 25 
1.5 
T-cell Dose Rationale ..................................................................................................... 26 
2 
Objectives ............................................................................................................................. 27 
2.1 
Primary Objectives ......................................................................................................... 27 
2.2 
Secondary Objectives ..................................................................................................... 27 
2.3 
Exploratory Objectives ................................................................................................... 27 
2.4 
Study Design .................................................................................................................. 27 
2.4.1 
General Design........................................................................................................ 27 
2.4.2 
Primary Study Endpoints ........................................................................................ 29 
2.4.3 
Secondary Study Endpoints .................................................................................... 30 
2.4.4 
Exploratory Endpoints ............................................................................................ 30 
3 
Subject Selection and Withdrawal ........................................................................................ 31 
3.1 
Inclusion Criteria ............................................................................................................ 31 
3.2 
Exclusion Criteria ........................................................................................................... 32 
3.3 
Subject Recruitment and Screening ............................................................................... 33 
3.3.1 
Number of Subjects and Duration of Study ............................................................ 34 
3.3.2 
Sites ......................................................................................................................... 34 
3.3.3 
Method for Screening Subjects for HLA Alleles .................................................... 34 

 
                         
  
 
 
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3.3.4 
Method for Screening Subjects for Tumor Antigen ............................................... 34 
3.3.5 
Screen Failures ........................................................................................................ 34 
3.4 
Early Withdrawal of Subjects ........................................................................................ 35 
3.4.1 
When and How to Withdraw Subjects .................................................................... 35 
4 
Study Drug ............................................................................................................................ 36 
4.1 
Description ..................................................................................................................... 36 
4.1.1 
Cytoreductive Chemotherapy ................................................................................. 36 
4.1.2 
Dose adjustments for fludarabine ........................................................................... 37 
4.1.3 
Mesna ...................................................................................................................... 37 
4.1.4 
NY-ESO-1c259T T cell Administration ................................................................... 37 
4.1.5 
Second Infusion ...................................................................................................... 38 
4.2 
Management of Toxicities and Complications............................................................... 39 
4.2.1 
Infection .................................................................................................................. 39 
4.2.1.1 
Cytomegalovirus ............................................................................................................. 39 
4.2.1.2 
Hepatitis B Prophylaxis ................................................................................................... 39 
4.2.2 
Hematologic and Blood Product Support ............................................................... 39 
4.2.2.1 
Blood Product Irradiation................................................................................................ 39 
4.2.2.2 
CMV Screened Blood Products ....................................................................................... 40 
4.2.3 
Management of Neutropenia using Filgrastim ....................................................... 40 
4.2.4 
Management of Symptoms during T Cell Infusion ................................................ 40 
4.2.5 
Management of Autoimmunity ............................................................................... 40 
4.2.6 
Management of Cytokine Release Syndrome ......................................................... 41 
4.2.7 
Management of Graft-versus-Host Disease ............................................................ 43 
4.2.7.1 
Diagnosis of GvHD ........................................................................................................... 43 
4.2.7.2 
Grading of GvHD ............................................................................................................. 44 
4.2.7.3 
Management of GvHD .................................................................................................... 45 
4.2.8 
Management of Pancytopenia with Bone Marrow Failure/ Aplastic Anemia ........ 47 
4.3 
Prior and Concomitant Therapy ..................................................................................... 48 
4.3.1 
Active Infection ...................................................................................................... 48 

 
                         
  
 
 
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4.3.2 
Disallowed Agents .................................................................................................. 48 
4.4 
Subject Compliance Monitoring .................................................................................... 48 
4.5 
Receiving, Storage, Dispensing and Return ................................................................... 49 
4.5.1 
Receipt of Drug Supplies ........................................................................................ 49 
4.5.2 
Storage .................................................................................................................... 49 
4.5.3 
Return or Destruction of Study Drug ...................................................................... 49 
5 
Study Procedures .................................................................................................................. 50 
5.1 
Informed Consent and Study Enrollment Procedures .................................................... 50 
5.2 
Screening and Baseline Evaluations .............................................................................. 50 
5.3 
Leukapheresis ................................................................................................................. 51 
5.4 
Baseline Imaging ............................................................................................................ 51 
5.5 
Cytoreductive Chemotherapy ......................................................................................... 51 
5.6 
T Cell Infusion (Day 0) .................................................................................................. 52 
5.7 
Post Infusion Follow-up (Days 1-4 and Day 7) ............................................................. 53 
5.8 
Post Infusion Follow-Up (Weeks 2 - 4) ......................................................................... 53 
5.9 
Post Infusion Follow-Up (Weeks 5, 6, 10, 16, 20) ........................................................ 54 
5.10 
Post Infusion Follow-Up (Week 8 and Week 12) ...................................................... 54 
5.11 
Post Infusion Follow-Up (6 Months and then every 3 months until disease 
progression)............................................................................................................................... 55 
5.12 
Long Term Follow-Up (Years 1 - 15) ........................................................................ 55 
5.13 
Requirements for a Tumor Biopsy ............................................................................. 56 
5.14 
Requirements for Liquid Biopsies .............................................................................. 57 
5.15 
Requirements for Ascites Fluid Collection ................................................................ 57 
6 
Schedule of Procedures and Observations ............................................................................ 58 
7 
Definitions............................................................................................................................. 62 
7.1 
Medical History and Physical Examination ................................................................... 62 
7.2 
Previous Medications ..................................................................................................... 62 
7.3 
Concomitant Medications .............................................................................................. 62 
7.4 
ECOG Performance Status ............................................................................................. 62 
7.5 
Targeted Physical Examination and Vital Signs ............................................................ 63 
7.6 
Complete Metabolic and Hepatic Panel ......................................................................... 63 

 
                         
  
 
 
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7.7 
CBC, Differential ........................................................................................................... 63 
7.8 
HLA-A*0201, A*0205 and/or A*0206 Screening ........................................................ 63 
7.9 
Dose Limiting Toxicity .................................................................................................. 63 
8 
Response Criteria .................................................................................................................. 65 
8.1 
Endpoints and Assessment Methods .............................................................................. 65 
8.2 
RECIST 1.1 Criteria for Evaluating Response in Solid Tumors.................................... 65 
8.2.1 
Measurable lesions measurement ........................................................................... 65 
8.2.2 
Measurable lesions .................................................................................................. 66 
8.2.3 
Non-measurable lesions .......................................................................................... 66 
8.2.4 
Target Lesions ......................................................................................................... 66 
8.2.5 
Non-target Lesions .................................................................................................. 67 
8.2.6 
Evaluation of Target Lesions .................................................................................. 67 
8.2.7 
Evaluation of Non-Target Lesions .......................................................................... 68 
8.2.8 
Special notes on assessing progression of Non-Target lesions ............................... 68 
8.2.9 
New lesions ............................................................................................................. 68 
8.2.10 Confirmation ........................................................................................................... 70 
8.2.11 Missing Assessments and Inevaluable Designation ............................................... 70 
9 
Statistical Assessment ........................................................................................................... 71 
9.1 
Study Populations ........................................................................................................... 71 
9.2 
Statistical methods for demographics and safety parameters ......................................... 71 
9.3 
Statistical analysis and reporting methods for safety endpoints .................................... 71 
9.3.1 
Adverse Events ....................................................................................................... 71 
9.3.2 
Vital Signs ............................................................................................................... 71 
9.3.3 
Electrocardiogram ................................................................................................... 71 
9.3.4 
Anti-NY-ESO-1 Antibodies.................................................................................... 72 
9.3.5 
T cell Phenotype and Cytokines ............................................................................. 72 
9.3.6 
Clinical Laboratory Tests ........................................................................................ 72 
9.4 
Statistical analysis and reporting methods for efficacy endpoints ................................. 72 
10 Correlative Data Analysis ..................................................................................................... 73 
10.1 
General Overview ....................................................................................................... 73 

 
                         
  
 
 
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10.2 
Core Correlative Studies ............................................................................................. 73 
10.2.1 Evaluation of Tumor ............................................................................................... 73 
10.2.2 T Cell Function and Phenotype............................................................................... 73 
10.2.3 Exploratory Dose- and Exposure-Response Analysis ............................................ 74 
10.2.4 Evaluation of Epitope Spreading ............................................................................ 74 
10.2.5 Liquid biopsy collection and analysis ..................................................................... 75 
10.2.6 Ascites fluid collection and analysis ....................................................................... 75 
10.2.7 Request for Autopsy for Death Following Administration of Gene Transfer Agents
 
76 
10.2.8 Additional Exploration of the T Cell Response ...................................................... 76 
11 Safety and Adverse Events ................................................................................................... 77 
11.1 
Definitions .................................................................................................................. 77 
11.1.1 Adverse Event ......................................................................................................... 77 
11.1.2 Serious Adverse Event ............................................................................................ 77 
11.1.3 Intensity................................................................................................................... 77 
11.1.4 Assessment of Causality ......................................................................................... 78 
11.1.5 Suspected Adverse Reaction ................................................................................... 79 
11.1.6 Unexpected Suspected Adverse Reaction (21 CFR 312.32(a)) .............................. 79 
11.1.7 Preexisting Condition.............................................................................................. 79 
11.1.8 General Physical Examination Findings ................................................................. 79 
11.1.9 Post-Study Adverse Event ...................................................................................... 79 
11.1.10 
Abnormal Laboratory Values .............................................................................. 80 
11.1.11 
Progression of underlying malignancy ................................................................ 80 
11.1.12 
Hospitalization, Prolonged Hospitalization or Surgery....................................... 80 
11.2 
Recording of Adverse Events ..................................................................................... 81 
11.2.1 Adverse Event Reporting Period ............................................................................ 81 
11.3 
Reporting of Serious Adverse Events and Unanticipated Problems .......................... 81 
11.3.1 Reporting Criteria during the Study Intervention Period (Apheresis up to 
discontinuation)..................................................................................................................... 81 
11.3.2 Reporting Criteria during Long Term Follow-Up (Years 1 - 15) ........................... 82 

 
                         
  
 
 
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11.4 
Investigator Reporting of SAEs: Notifying the Study Sponsor .................................. 82 
11.5 
Investigator Reporting to the IRB .............................................................................. 82 
11.6 
Sponsor Responsibility for Reporting Adverse Events .............................................. 83 
11.7 
Stopping Rules ............................................................................................................ 83 
11.8 
Medical Monitoring .................................................................................................... 83 
11.9 
Data Monitoring Committee ....................................................................................... 83 
11.10 
Safety Monitoring ....................................................................................................... 83 
11.10.1 
Monitoring and Management of Replication-Competent Lentivirus (RCL) ...... 83 
11.10.2 
Testing for RCL in Clinical Studies .................................................................... 84 
11.10.3 
Safety Monitoring Results ................................................................................... 85 
11.10.4 
Persistence Testing and Monitoring for Insertional Oncogenesis ....................... 85 
11.10.4.1 
Testing for Persistence of Gene Marked Cells in Clinical Studies ............................... 85 
11.10.4.2 
Testing for Insertional Oncogenesis ............................................................................ 86 
12 Administration ...................................................................................................................... 87 
12.1 
Data Handling and Record Keeping ........................................................................... 87 
12.1.1 Source Documents .................................................................................................. 87 
12.1.2 Case Report Forms .................................................................................................. 87 
12.1.3 Records Retention ................................................................................................... 87 
12.2 
Departure from the Protocol ....................................................................................... 88 
12.3 
Study Monitoring Plan................................................................................................ 88 
13 Regulatory and Ethical Considerations ................................................................................. 89 
13.1 
Confidentiality of Data ............................................................................................... 89 
13.2 
Confidentiality of Subject/Patient Records ................................................................ 89 
13.3 
Compliance with law, audit, and debarment .............................................................. 89 
13.4 
Conflict of Interest ...................................................................................................... 90 
13.5 
Subject Stipends or Payments..................................................................................... 90 
13.6 
Ethical Considerations ................................................................................................ 90 
13.7 
Public Posting of Study Information .......................................................................... 91 
13.8 
Clinical Study Report ................................................................................................. 91 
13.9 
Publication Policy ....................................................................................................... 91 

 
                         
  
 
 
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14 Appendices ............................................................................................................................ 92 
Appendix A: Sample Patient Letter for Long Term Follow-Up ........................................ 92 
Appendix B : Draft Physician Letter .................................................................................. 93 
Appendix C: Long Term Follow Up ..................................................................................... 94 
Appendix D:  Tocilizumab Drug Information ...................................................................... 95 
Appendix E:  Cyclophosphamide: Drug Information ........................................................... 99 
Appendix F: Mesna: Drug Information .............................................................................. 101 
Appendix G: Fludarabine: Drug Information ..................................................................... 102 
Appendix H: Summary of Changes from Protocol Version 6 to Version 7 ....................... 103 
15 References ........................................................................................................................... 104 
 
 
 

 
                         
  
 
 
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LIST OF FIGURES 
Figure 1:  Study Schema .............................................................................................................................. 29 
 
 

 
                         
  
 
 
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LIST OF TABLES 
Table 1: 
Regimen Description ............................................................................................................... 36 
Table 2: 
Schedule of Procedures and Observations ............................................................................. 59 
Table 3:        Blood Volume for Research Assessments ............................................................................... 61 
Table 4: 
ECOG Performance Status Scale and Karnofsky Index of Performance Status ...................... 62 
Table 5:        Summary of the overall response status calculation at each time point: .............................. 69 

 
                         
  
 
 
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List of Abbreviations 
AE, Adverse event 
ASC, American Society of Clinical Oncology 
ATC, Autologous T Cell 
BOR, Best overall response 
CFR, code of federal regulations 
CMV, Cytomegalovirus 
CR, Complete Response 
CRF, case report form 
CRM, Continual Reassessment Method  
CRS, Cytokine Release Syndrome 
CT, Cancer testis 
CTC, common toxicity criteria 
CTCAE, Common Terminology Criteria for Adverse Events 
CTX, chemotherapy 
CTL, cytotoxic T lymphocyte 
DFS, Disease free survival 
DSMB, data safety and monitoring board  
DTC, dose-toxicity curve 
ECHO, Echocardiogram 
EFS, Event Free Survival 
EKG, Electrocardiogram (or ECG) 
FDA, food and drug administration 
GCP, good clinical practices 
G-CSF, Granulocyte colony-stimulating factor 
GMP, good manufacturing practices 
HAIC, Humoral anti-infused cell response 
IB, Investigators Brochure 
IBC, Institutional Biosafety Committee 
IRB, Institutional Review Board 
irRC, Immune-related Response Criteria 
IV, intravenously 
LTFU, Long term follow-up 
MUGA, Multigated acquisition scan 

 
                         
  
 
 
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NCCN, National Comprehensive Cancer Network 
NCI, National Cancer Institute 
ORR, Overall response rate 
OS, Overall survival 
PBMC, peripheral blood mononuclear cells 
PD, Progressive disease 
PFS, Progression free survival 
PR, Partial response 
RAC, NIH Office of Biotechnology Recombinant DNA Advisory Committee 
RECIST, Response Evaluation Criteria in Solid Tumors 
RCL, Replication competent lentivirus 
RPCI, Roswell Park Cancer Institute 
SD, Stable disease 
TCR, T cell receptor 
TIL, Tumor infiltrating lymphocyte 
Treg, T regulatory cell; a T cell characterized by CD25/FOXP3 staining which suppresses effector T cell 
function. 

 
                         
  
 
 
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STUDY SUMMARY 
Title 
A Phase I/IIa, open label clinical trial evaluating the safety and efficacy of autologous 
T cells expressing enhanced TCRs specific for NY-ESO-1 in patients with recurrent or 
treatment refractory ovarian cancer. 
Short Title 
CT Antigen TCR-redirected T cells for ovarian cancer. 
Protocol Number 
ADP-0011-001 
Phase 
Phase I/IIa 
Methodology 
This is an open label clinical trial. Patients with the HLA-A*0201, HLA-A*0205, 
and/or HLA-A*0206 allele and whose tumor expresses the NY-ESO-1 tumor antigen 
will be eligible to receive NY-ESO-1c259T.  The trial is conducted entirely with 
outpatient procedures; however, patients may be hospitalized for the cytoreductive 
chemotherapy at the discretion of the investigator. Upon enrollment, patients will 
undergo leukapheresis for T cell collection, and their cells will be genetically 
engineered and expanded ex vivo.  Seven days prior to receiving T-cells patients will 
undergo a fludarabine/cyclophosphamide conditioning regimen to potentiate the 
immunotherapy. The cell product will be infused as a single infusion. Patients will be 
followed daily for the first week, weekly until 4 weeks, 8 weeks, and 12 weeks and 
then every 3 months until progression. Patients will undergo disease monitoring by 
MRI/CT scan (as appropriate for disease) at baseline, day 28, 8 weeks and 12 weeks, 
and then every 3 months thereafter until progression. Tumor biopsies will be taken 
at baseline, at week 8, and upon progression, as indicated.   
 
In patients who have progressive disease following initial infusion but whose tumors 
continue to express NY-ESO-1, these patients may be eligible for a second infusion 
with redirected T cells.   
 
At progression, the interventional portion of the protocol ends and long term 
follow-up (LTFU) continues, in accordance with FDA regulations. LTFU occurs 
semiannually for up to 5 years post infusion and then annually thereafter for up to 
15 years. 
Study Duration 
In this trial, patients are restricted by HLA type and tumor antigen expression. Due 
to the rarity of this population of patients, we expect enrollment to be complete in 
approximately 3 years.  
Study Center(s) 
This is a multicenter trial. 
Objectives 
The primary objective is to evaluate the safety and tolerability of autologous 
genetically modified T cells transduced to express the high affinity NY-ESO-1c259 TCR 
in HLA-A*0201, A*0205, and/or A*0206 subjects.  Secondary study objectives are: 1) 
To evaluate the effect of NY-ESO-1 c 259T on tumor activity a, 2) to evaluate the 
persistence of genetically modified cells in the body and correlate with dose 3) 
evaluate the phenotype and functionality of genetically modified cells isolated from 
peripheral blood or tumor post infusion, 4) evaluate NY-ESO-1 expression in tumor 
tissue, before treatment, and correlate with results from archival tumor tissue, and 

 
                         
  
 
 
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5) evaluate NY-ESO-1 expression in tumor tissue, before and after treatment, and 
correlate with clinical response to treatment. 
Number of Subjects 
The target enrollment for this trial—across sites--is approximately 18  patients with 
at least 10 patients receiving fludarabine/cyclophosphamide conditioning  
Diagnosis and Main 
Inclusion Criteria 
Patients must have a diagnosis of recurrent epithelial ovarian, primary peritoneal or 
fallopian tube carcinoma with refractory or platinum resistant disease and/or have 
received ≥ 2 lines of chemotherapy. Patients must be HLA-A*0201, A*0205, and/or 
A*0206, and have expression of NY-ESO-1 in their tumor as determined by IHC. 
Patients must have a life expectancy of > 4 months, be ECOG ≤ 1, have measurable 
disease as defined by RECIST, be able to undergo apheresis, and have normal organ 
and marrow function.  
Study Product, Dose, 
Route, Regimen 
The study drug in this protocol is NY-ESO-1c259T and will be manufactured at a 
central manufacturing site. Patients will receive NY-ESO-1c259T within the range of 
1x109 - 6x109 transduced cells by gravity flow intravenous (IV) infusion.  
Duration of 
administration 
The infusion will take approximately 15-30 minutes, and patients will be followed in 
the clinic for at least 4 hours post infusion. 
Statistical Methodology 
With respect to the primary objectives and endpoints, no specific statistical 
hypotheses are being evaluated.  All analyses will be descriptive and exploratory. 
 

 
                         
  
 
 
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1 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures. 
1.1 
Background 
1.1.1 Recurrent Ovarian Cancer 
[Excerpted from version 2.2011 of the National Comprehensive Cancer Network (NCCN) Guidelines: 
http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf]. 
Epithelial ovarian cancer comprises the majority of malignant ovarian neoplasms (about 80%) (Chan, 
Cheung et al. 2006). Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the 
United States and the country’s fifth most common cause of cancer mortality in women. In the year 2010, 
there will be an estimated 21,900 new diagnoses and an estimated 13,900 deaths from this neoplasm in 
the United States; less than 40% of women with ovarian cancer are cured (Jemal, Siegel et al. 2009; Jemal, 
Siegel et al. 2010). The incidence of ovarian cancer increases with age and is most prevalent in the eighth 
decade of life, with a rate of 57/100,000 women. The median age at the time of diagnosis is 63 years, and 
70% of patients present with advanced disease (Fleming GF 2009). 
Ovarian cancer is classified primarily as Stages I - IV. Since 1997, no significant changes have been made 
in the staging systems for ovarian cancer (Edge SB 2010). Pathologic grading continues to be an important 
prognostic factor and is used in the selection of therapy, primarily for early-stage disease. Grading is 
labeled as 1, 2, or 3. Except for those women with Stage I, Grade 1 tumors (in whom survival is greater 
than 95% after comprehensive laparotomy), patients in all other stages of ovarian cancer should be 
encouraged to enter clinical trials for both primary and recurrence therapy. 
Due to the cryptic location of the ovary in the body and the asymptomatic nature of early stage ovarian 
cancer, the majority (63%) of patients are diagnosed with ovarian cancer after distant metastases have 
formed (http://www.seer.cancer.gov/statfacts/html/ovary.html). New therapies are greatly needed to 
address the unmet medical need of patients with refractory or resistant metastatic ovarian cancer. 
Patients who have refractory or platinum resistant disease and/or have received ≥ 2 lines of 
chemotherapy are targeted for this clinical trial. Overall, the prognosis is poor (1) for patients who 
progress after 2 chemotherapy regimens without sustaining a clinical benefit (refractory); or (2) for those 
whose disease recurs in less than 6 months (platinum resistant). Note that progression in clinical studies 
of new therapies is typically defined using traditional RECIST (Response Evaluation Criteria in Solid Tumor) 
criteria (i.e., a 20% increase in tumor diameter) (Therasse, Arbuck et al. 2000), and more recently for 
immunotherapies by the Immune-related Response Criteria (irRC) for immunotherapies (Wolchok, Hoos 
et al. 2009). [NCCN] Panel members emphasized the importance of clinical trials to identify agents active 

 
                         
  
 
 
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in this group of patients. Because these patients were resistant to their primary induction regimen, 
retreatment with a platinum compound is not generally recommended. 
1.1.2 Redirected T Cell Therapy for Ovarian Cancer 
Ovarian cancer is an ideal candidate for immunotherapy, and for an overview of immunotherapy in 
general for this disease, the following reviews are recommended (Kandalaft, Singh et al. 2010; Liu, Nash 
et al. 2010). The first data clearly indicating a relationship between tumor immunity and ovarian patient 
outcomes was the landmark paper by Coukos and colleagues which reported that the presence of TILs, 
detected by immunohistochemistry in tissue from 186 patients, in the primary tumor strongly correlated 
with patient survival (Zhang, Conejo-Garcia et al. 2003). The 5 year survival rate was 38% versus 4.5% in 
patients with or without TILs, respectively. These findings were strengthened by a subsequent report by 
Odunsi and colleagues that evaluated infiltrating T cell subsets (CD3/4/8 and CD25/FOXP3) in tissue from 
117 patients. This study demonstrated that a CD8/4 ratio of approximately 2 or higher was correlated with 
improved survival time (Sato, Olson et al. 2005). The role of Tregs in poor prognosis would explain this 
ratio effect, and while staining for CD25/FOXP3 was suggestive in the study, it was not statistically 
significant. However, the inverse correlation between Treg infiltration in tumor and survival has been 
elegantly described by Zou and colleagues (Curiel, Coukos et al. 2004). In this study, Treg content was 
evaluated by flow cytometry (in ascites) or by multicolor confocal microscopy (in solid tumor); in vitro 
culture assays showed the Treg cells isolated from ascites or tumor were shown to be as suppressive as 
Treg from peripheral blood, confirming the suppressive phenotype of the cells. In 70 subjects, the 
quantitative Treg data was evaluated for correlation with clinical and pathological information (including 
survival). There was a significant inverse correlation between Treg content and survival, as well as a 
positive correlation with disease stage. Taken together these three studies strongly support the use of 
T cell immunotherapy for ovarian cancer, and in particular using clinical and manufacturing methods that 
reduce, to the extent possible, any contribution of Treg cells. 
Initial studies demonstrating the potential of T cell immunotherapy to eradicate solid tumors came from 
the National Cancer Institute (NCI) in studies of adoptive transfer of in vitro selected tumor infiltrating 
lymphocytes (Dudley, Wunderlich et al. 2002; Dudley, Wunderlich et al. 2005). In these studies, 
35 patients were treated with autologous TILs after lymphodepleting conditioning, and with concomitant 
IL-2. 18 patients (50%) had an objective response to the treatment, at times with large bulky tumors 
disappearing. The method of isolating and manufacturing TILs is labor intensive and only successful in a 
subset of patients (approximately 30% - 40%) (Dudley, Wunderlich et al. 2003). Therefore, the ability to 
genetically engineer tumor specific lymphocytes is an attractive alternative to reach greater numbers of 
patients, and patients with non-bulky disease. 
One way to redirect a patient’s own T cells to a specific tumor antigen is to genetically alter the cells to 
express a tumor antigen specific tumor cell receptor (TCR).  Several studies have been opened for TCR 
redirected T cells to date, and are at various stages of completion. Two studies (Morgan, Dudley et al. 
2006; Johnson, Morgan et al. 2009) evaluated three different TCRs isolated from tumor infiltrating 
lymphocytes, and chosen based on medium or high affinity binding to HLA-peptide complexes (Johnson, 
Heemskerk et al. 2006). In the first trial evaluating medium affinity MART-1 DMF4 TCRs, 31 patients were 

 
                         
  
 
 
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reported. Subjects received as high as 8.6 x 1010 antigen specific redirected T cells. No toxicity related to 
T cell infusions was reported. Objective response rates in these trials were lower than observed in the TIL 
trials, with only 4/31 (13%) patients responding. In the follow-on trial utilizing the high affinity MART-
1 DMF5 TCR or the gp100 TCR, a modestly higher objective response rate was observed of 30% (6/20) and 
19% (3/16), respectively, with concomitant on target off tumor toxicity against the MART-1 or gp100 
antigens causing reversible erythematous skin rash, uveitis and ototoxicity (Johnson, Morgan et al. 2009). 
The lower response rate compared to the TIL trials may in part be due to the low affinity of naturally 
isolated TCRs against self-antigens. The central problem is tolerance: the repertoire of TCRs is generally 
of too low avidity to efficiently recognize tumor antigens, and this explains the failure of most cancer 
vaccines (Greenberg and Riddell 1999; Pardoll and Allison 2004; Rosenberg, Yang et al. 2004). Higher 
affinity recognition allows T cells to respond to lower levels of antigen; this is critically important for tumor 
immunotherapy where the tumor microenvironment has adapted itself to reduce expression of antigen 
and also decrease expression of MHC class I molecules (Marincola, Jaffee et al. 2000; Barrett and Blazar 
2009). To address this problem, Adaptimmune developed a method for high throughput generation and 
analysis of TCRs mutated for higher affinity (Li, Moysey et al. 2005; Dunn, Rizkallah et al. 2006). One of 
these TCRs was derived from the 1G4, a clone specific for NY-ESO-1. In validation experiments performed 
in collaboration with the NCI, the NY-ESO-1c259 TCR was described (Robbins, Li et al. 2008). Of note, 
NY-ESO-1 is a cancer testes (CT) antigen that is less likely to induce on target off tumor toxicity due to its 
restricted expression (more on CT antigens below). This TCR subsequently was taken into a clinical trial by 
the Rosenberg team using a similar trial and manufacturing design as used for the TCR trials described 
above, in patients with melanoma or synovial sarcoma (Robbins, Morgan et al. 2011). The trial 
demonstrated safety and improved objective response rates using this TCR (5/11 in melanoma and 4/6 in 
synovial sarcoma). Notably, this is the same TCR as will be used in this trial, and there are several 
differences in manufacturing from the NCI trial, which may improve response rates. 
In summary, ovarian cancer is an immunogenic cancer that is a reasonable target for T cell based 
immunotherapy. Previous trials using adoptive T cell therapy suggest promise for this approach in solid 
tumors. 
1.1.3 Rationale for Targeting Cancer Testes Antigens 
For a tumor antigen to be effective it must 1) be expressed on tumor but have limited to no expression 
on normal adult tissue, 2) serve a critical function to the tumor cell so that targeting the antigen is less 
likely to lead to tumor escape, and 3) be immunogenic so that it is capable of triggering an immune 
response. Cancer testes (CT) antigens are defined as proteins which are expressed in tumor cells and 
testes, but not expressed in more than 2 non-germline tissues (Simpson, Caballero et al. 2005). These 
genes are commonly expressed in the germline and during gametogenesis, and their core function during 
this process, e.g., cell immortalization, migration, and implantation, is thought to play a parallel role in the 
tumorigenesis process. CT antigens often have heterogeneous expression in tumors (Jungbluth, Busam et 
al. 2000) (Crystal Mackall, personal communication) which some believe may be a result of differential 
expression on cancer stem cells versus differentiated tumor cells. 

 
                         
  
 
 
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CT antigens were first discovered in the late 1980’s, in a melanoma patient who had an unexpectedly 
positive clinical course. The T cells from this patient recognized autologous tumor (Knuth, Wolfel et al. 
1989), and further characterization of the CTLs resulted in discovery of the MAGE-A1, MAGE-A2, and 
MAGE-A3 genes (Traversari, van der Bruggen et al. 1992) (van der Bruggen, Traversari et al. 1991). There 
are at least 44 CT antigens that have now been described using autologous typing and later SELEX, which 
identified NY-ESO-1 (Chen, Scanlan et al. 1997; Simpson, Caballero et al. 2005). 
CT antigens are mainly categorized into CTX, or those located on the X chromosome, and non-X CT 
antigens, which are distributed around the genome. About half the CT antigens are CT-X antigens and 
NY-ESO-1 antigens is in this group. CT-X antigens are often coexpressed (Sahin, Tureci et al. 1998) (Tajima, 
Obata et al. 2003), and this may be due to the global hypomethylation that accompanies expression 
(Kaneda, Tsukamoto et al. 2004). The frequency of CT antigen expression tends to increase with cancer 
stage. 
The immunogenicity of the NY-ESO-1 antigen has been robustly established. Briefly, CT antigens have 
primarily been identified by using serum from patients to identify tumor specific targets, and thus selected 
by their ability to elicit immunity. NY-ESO-1 vaccine trials have demonstrated the ability of these proteins 
to generate a T cell response (Baumgaertner, Rufer et al. 2006). NY-ESO-1 has been extensively tested as 
an immunogen in cancer vaccine studies (summarized in Section 1.1.4), and NY-ESO-1 specific T cells have 
been administered in adoptive T cell studies and shown anti-tumor effects (Hunder, Wallen et al. 2008; 
Robbins, Morgan et al. 2011). 
1.1.4 Previous Clinical Studies with NY-ESO-1 Vaccines 
In the first human study of NY-ESO-1 vaccination, ESO157–165 peptide in conjunction with 
granulocyte/macrophage colony-stimulating factor was shown to induce HLA-A2-restricted CD8+ T cell 
responses in patients without preexisting NY-ESO-1 immunity, although these peptide-induced CD8+ T cell 
responses were generally of low affinity and did not recognize naturally processed NY-ESO-1 (Dutoit, Taub 
et al. 2002). Subsequently, recombinant NY-ESO-1 protein in a saponin-based adjuvant (ISCOMATRIX) was 
used to immunize Stage III and Stage IV melanoma patients after tumor resection (Maraskovsky, Sjölander 
et al. 2004). More recently, patients with a range of tumor types were immunized with recombinant 
vaccinia NY-ESO-1 and recombinant fowlpox NY-ESO-1 (Jäger, Karbach et al. 2006)(15), and recombinant 
protein with CpG adjuvant (Valmori, Souleimanian et al. 2007). These vaccine strategies were found to be 
safe, and induced high-titered NY-ESO-1 Ab, CD4+, and CD8+ T-cell responses in a high proportion of 
patients. 
A number of studies targeting NY-ESO-1 in ovarian cancer patients have been conducted at Roswell Park 
Cancer Institute. Protocol RP02-28, a Phase I clinical trial of immunization with an NY-ESO-1 derived long 
peptide of dual MHC Class I specificities, mixed with incomplete Freund's adjuvant (Montanide ISA51) in 
18 ovarian cancer patients (Odunsi, Qian et al. 2007). Protocol I 13303, a Phase II clinical trial of 
recombinant vaccinia-NY-ESO-1 (rV-NY-ESO-1) and recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in 
ovarian cancer patients whose tumors express NY-ESO-1 or LAGE-1. One serious adverse event (SAE) was 
reported to be unlikely due to rV-NY-ESO-1 or rF-NY-ESO-1. Toxicity and immunological results are 

 
                         
  
 
 
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currently being evaluated. Protocol I27008 is an on-going Phase I study testing epigenetic modulation of 
NY-ESO-1 with 5-Azacytidine in combination with recombinant NY-ESO-1 protein admixed with GMCSF 
and IFA in ovarian cancer patients receiving liposomal doxorubicin for recurrent disease. Nine out of 
12 planned patients have been enrolled; and no treatment related Grade 3 AEs have been noted. 
Protocol I 125207, a Phase I study testing recombinant canarypox expressing NY-ESO-1 and a triad of co-
stimulatory molecules (TRICOM). Planned accrual of 12 patients has been completed and no Grade 3 
toxicities attributable to the vaccine were noted. Our collective experiences from these studies indicate 
that NY-ESO-1 vaccines are safe. Moreover, NY-ESO-1 specific antibody responses and/or CD8+ and CD4+ 
T-cell responses were induced by vaccinations in a high proportion of patients. Vaccine-induced CD8+ and 
CD4+ T cell clones were shown to recognize NY-ESO-1 -expressing tumor targets. However, the relatively 
low frequencies of vaccine induced T cells might limit the clinical efficacy of all of these vaccine 
approaches. 
The current study will seek to improve the efficacy of T cells targeting NY-ESO-1 by the use of redirected 
T cell therapy in order to promote durable tumor control. 
1.1.5 
Rationale for NY-ESO-1 Threshold 
The threshold for NY-ESO-1 positivity (>50% of cells expressing 2+ or 3+) was initially established to 
mirror the threshold used in the first studies with NY-ESO-1 (Robbins, Li et al. 2008).  When these 
studies were initiated a lower expression threshold was not explored.  Currently, anti-tumor activity is 
being evaluated in patients with lower NY-ESO-1 expression (>1% of tumor cells expressing ≥ 1% and 
<50% of cells expressing 2+ or 3+) in Cohort 2 of the synovial sarcoma pilot study (ongoing study ADP-
04511). Preliminary anti-tumor activity (Partial Response) has been observed in 4 patients with low 
expression in the synovial sarcoma. NY-ESO expression in tumor cells for these patients is as follows: 
 50% 1+, 20% 2+, 10% 3+ 
 10% 1+, 20% 2+, 20% 3+ 
 5% 1+, 5% 2+, 5% 3+ 
 90% 1+ 
 
Review of recent data has led to the lowering of the threshold for NY-ESO-1 positivity to >10% of cells 
expressing 1+ in newly initiated studies at Adaptimmune and supports exploring this lower threshold in 
this ovarian cancer study. In addition, the NY-ESO-1 Clinical Trial Assay has undergone extensive good 
laboratory practice and CLIA validation to establish the sensitivity, specificity and performance (i.e. 
precision and reproducibility) of the assay.  Further, the central laboratory director and lead pathologist 
who scores all NY-ESO-1 stained tumors across all Adaptimmune clinical trials has confirmed that the 
Sigma NY-ESO-1 primary antibody has not shown any non-specific staining of tumor cells. The negative 
controls support this.  >10% tumor staining of 1+ intensity or greater is indicative of the presence of NY-
ESO-1. 
 

 
                         
  
 
 
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1.1.6 Rationale for Preconditioning with Chemotherapy 
Following intensive animal and clinical research over the past decade, it is now generally accepted that 
the incorporation of lymphodepletion prior to adoptive T cell therapy enhances immune reconstitution 
by the transferred cells, and increases tumor specific responses. Immune reconstitution is enhanced 
through homeostatic proliferation of T cells which is different from antigen driven T cell expansion in that 
it occurs in the absence of costimulation (Ernst, Lee et al. 1999; Prlic, Blazar et al. 2001). Homeostatic 
proliferation is promoted by an increase in availability of γ-chain cytokines IL-7, IL-15, and IL-21 
(Wrzesinski and Restifo 2005; Rapoport, Stadtmauer et al. 2009; Wallen, Thompson et al. 2009), and also 
by MHC-peptide interactions against self or tumor antigens (Ernst, Lee et al. 1999; Wrzesinski and Restifo 
2005). 
Lymphodepletion also enhances the activity of the adoptively transferred cells via the removal of 
inhibitory factors and activation of antigen presenting cells. It has been well modeled in mice that 
regulatory T cells have the ability to inhibit anti-tumor T cell responses (Shimizu, Yamazaki et al. 1999; 
Casares, Arribillaga et al. 2003). In humans, regulatory T cells have been clearly shown to be correlated 
with poor outcomes in ovarian cancer patients and to predict poor survival (Curiel, Coukos et al. 2004). 
Furthermore, chemotherapy activates antigen presenting cells through the induction of inflammatory 
cytokines and induction of tumor apoptosis and resulting cross presentation of tumor antigens to T cells, 
although the induction of cytokines by cyclophosphamide alone is minimal compared to regimens 
containing irradiation (Xun, Thompson et al. 1994; Chernysheva, Kirou et al. 2002). 
The most common lymphodepletion regimens used in adoptive T cell therapy trials for solid tumors to 
date have incorporated cyclophosphamide and fludarabine (Dudley, Wunderlich et al. 2002; Dudley, 
Wunderlich et al. 2005; Johnson, Morgan et al. 2009; Robbins, Morgan et al. 2011).  The use of 
cyclophosphamide alone can achieve lymphodepletion without long term immunosuppressive side 
effects, and has previously been used in combination with immunotherapy for ovarian cancer 
(Windbichler, Hausmaninger et al. 2000). Therefore, in this trial, cyclophosphamide alone was initially 
chosen for preconditioning.  
 
Recent studies in lymphoma, chronic leukemia and acute leukemia using a chimeric antigen receptor 
showed increased CD4+ and CD8+ CAR-T cell expansion, persistence and disease-free survival when 
fludarabine was added in to a previously cyclophosphamide-only preparative regimen (Turtle et al, 
2015).   The cyclophosphamide was administered at 30 – 60 mg/kg x 1 day and fludarabine at 25 
mg/m2/day x 3 – 5 days.  A recent review by Batlevi et. al included a summary of  lymphodepletion 
regimens with CD19 CAR-T.   A variety of lymphodepleting regimens including cyclophosphamide alone, 
cyclophosphamide plus fludarabine, cyclophosphamide plus fludarabine plus other agents have been 
used and shown to be effective.  The doses and schedule of cyclophosphamide and fludarabine have 
varied across these studies ranging from lower to higher doses of these agents. (Batlevi 2016). 

 
                         
  
 
 
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The lymphodepleting regimen in which objective tumor responses have been observed in an ongoing 
Adaptimmune clinical study in synovial sarcoma uses a cyclophosphamide dose of 1800 mg/m2/day for 2 
days, in addition to fludarabine 30 mg/m2/day for 4 days (ADP-04511).  
Six subjects treated at the time of this Amendment in this ovarian cancer study (ADP-0011-001) have 
received cyclophosphamide alone for lymphodepletion at a range of doses.  Persistence of gene-marked 
T cells have been suboptimal in these subjects.  Circulating gene modified T cell persistence was short; 4 
of 6 subjects had <1,000 copies/μg gDNA only 4 weeks post T cell infusion.  Objective tumor responses 
have not been observed in the subjects with ovarian cancer.  Based on the emerging data that the 
addition of fludarabine to cyclophosphamide may play a role in homeostatic expansion, potentially 
leading to improved efficacy of NY-ESO-1 T in patients with ovarian cancer.  At least 10 subjects with 
cyclophosphamide and fludarabine to further explore the potential impact of combination 
lymphodepleting chemotherapy. 
1.2 
Investigational Agents 
The investigational agent in this protocol is autologous CD4 and CD8 T cells, expressing a high affinity TCR 
specific for NY-ESO-1. This agent is called NY-ESO-1c259T. This agent is on file with the FDA under IND 
(14603). The generation of each of the NYESO TCR along with some information on the lentiviral vector 
used and the cell manufacturing method are provided below. 
1.3 
Preclinical Data 
The Investigator’s Brochure contains detailed information about existing nonclinical experience with NY-
ESO-1c259T. 
1.4 
Clinical Data to Date 
1.4.1 Prior Human Experience with NY-ESO-1c259T 
The Investigator’s Brochure contains detailed information about clinical experience with NY-ESO-1c259T.  
1.4.2  Study Progress  
As of January 2017, 8 patients have been enrolled on this study. The first patient treated in this study 
with pre-conditioning chemotherapy of cyclophosphamide 60 mg/kg/day for 2 days experienced a 
strong immunological response with a significant proliferation of the engineered T cells and symptoms 
of grade 3 cytokine release syndrome (CRS) which was treated with high dose steroids that abrogated 
the engineered T-cell function. Following a dose de-escalation of the pre-conditioning chemotherapy 
(cyclophosphamide 30 mg/kg/day for 2 days) the next four patients did not experience a response so 
the dose was increased (cyclophosphamide 1800mg/m2/day for 2 days). Two patients were enrolled but 
unable to receive the NY-ESO-1c259T cell infusion. One patient was treated under the cyclophosphamide 
1800mg/m2/day for 2 days pre-conditioning regimen and experienced Grade 2 CRS which resolved with 

 
                         
  
 
 
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supportive therapy without the use of steroids or tocilizumab. This patient’s best response was stable 
disease at Week 8, however was determined to have clinical progression at Week 10. No objective 
responses (CR or PR) have been reported. The current lymphodepletion  regimen consists of fludarabine 
30 mg/m2/day x3 days and Cyclophosphamide 600 mg/m2/day x3 days and to date no subjects have 
been treated under this regimen. 
1.5 
T-cell Dose Rationale  
NY-ESO-1c259T will be administered by a single, gravity flow IV infusion. Patients will receive NY-ESO-
1c259T within the range of 1x109 (1 billion) transduced cells to 6 x 109 (6 billion) transduced cells.  For 
patients whose cells fail to meet the minimum cell dose requirement (1x109 transduced cells) during the 
manufacturing process, manufacturing of additional transduced T-cells from excess banked 
leukapheresis product will be undertaken to achieve a total dose in the target range.  In the event that 
no banked leukapheresis product is available a second leukapheresis may be performed to achieve a 
dose in the target range. Patients that are enrolled but do not receive NY-ESO-1c259T cells will be 
replaced. 
Published studies have evaluated broad ranges of cell doses.  Information to date indicates T cell therapy 
has been used up to doses of ~100 x 109 cells (Robbins, Morgan et al. 2011)) although the actual products 
used may differ depending on manufacturing methods. Activity seems to be indirectly related to dose 
administered (depending also on cell expansion and persistence) although high T cell doses may be 
associated with an increased risk of adverse events (e.g. cytokine release) and, conversely, doses as low 
as 0.015 x 109 (15 million) cells may be effective (Kalos, Levine et al. 2011). The initial dose for this trial 
was chosen based on published data, (Robbins, Morgan et al. 2011; Morgan, Dudley et al. 2006; Johnson, 
Morgan et al. 2009), and data supported by our related ongoing studies in myeloma and synovial sarcoma 
(described above in the IB). In general, adoptive transfer of autologous T cells is safe and well tolerated.  
Current experience with NY-ESO-1c259T (n=53 subjects treated as of January 2016) is with total cell doses 
in the range of 0.4 x 109 – 3.47 x 1010 with a transduction level of ~18 – 78% (transduced cell dose range 
of 0.23 x 109 – 14.36 x 109).  No untoward adverse events have been observed in subjects who received 
higher transduced cell doses (>5 x 109 cells).  Of the 5 subject who received <1 x 109 transduced cells, 3 
subjects had poor expansion and persistence of transduced cells; meaningful clinical responses were not 
observed in 4 of the 5 subjects.  No clear dose response relationship has been observed to-date. 
 
 

 
                         
  
 
 
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2 
OBJECTIVES 
This study is designed to assess the safety and antitumor effects of NY-ESO-1c259T in patients with 
treatment resistant or refractory metastatic ovarian cancer. While this study is not powered to detect 
efficacy, the results from this study will be used to establish the sample size necessary to power a 
follow-on Phase II study designed to determine the antitumor efficacy of NY-ESO-1c259T. 
2.1 
Primary Objectives 
To evaluate the safety and tolerability of autologous, genetically modified T cells transduced to express 
the high affinity NY-ESO-1c259 TCR in HLA-A*0201, A*0205 and/or A*0206 subjects. 
2.2 
Secondary Objectives 
• 
To evaluate the effect of NY-ESO-1c259T on anti-tumor activity. 
• 
To evaluate the persistence of genetically modified cells in the body and correlate with dose. 
• 
To evaluate the phenotype and functionality of genetically modified cells isolated from peripheral 
blood or tumor post infusion. 
• 
To evaluate NY-ESO-1 expression in tumor tissue, before treatment, and correlate with results 
from archival tumor tissue.  
• 
To evaluate NY-ESO-1 expression in tumor tissue, before and after treatment, and correlate with 
clinical response to treatment.  
2.3 
Exploratory Objectives 
• 
Evaluate candidate biomarkers in tumor tissue and in blood samples and correlate with clinical 
response to treatment. 
 
• 
To evaluate candidate biomarkers in liquid biopsies (peripheral blood plasma) as a surrogate to 
those from tumor biopsies. 
 
• 
To evaluate candidate biomarkers in ascites fluid and correlate with clinical response to 
treatment.  
2.4 
Study Design 
2.4.1 General Design 
This is an open label clinical trial. HLA-A*0201, HLA-A*0205, and/or HLA-A*0206-positive patients whose 
tumor has been confirmed for expression of NY-ESO-1 will be enrolled in the study providing they meet 
the remaining eligibility criteria as summarized below. Eligible patients will have recurrent epithelial 

 
                         
  
 
 
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ovarian, primary peritoneal or fallopian tube carcinoma with refractory or platinum resistant disease 
and/or have received ≥ 2 lines of chemotherapy. The trial is conducted entirely with outpatient 
procedures; however, patients may be hospitalized for the cytoreductive chemotherapy per investigator’s 
discretion. Upon enrollment, patients will undergo leukapheresis for T cell collection, and their cells will 
be genetically engineered and expanded ex vivo. Seven days prior to receiving cells (recommend Monday), 
patients will start a fludarabine/cyclophosphamide conditioning regimen to potentiate the 
immunotherapy. Patients will receive the cell product as a single infusion (100% on Day 0; recommend 
Monday). Patients will be followed daily for the first week, weekly for 4 weeks, at 8 and 12 weeks, 6 
months and every 3 months until disease progression.  Additional CBCs will be collected at week 5, 6, 10, 
16 and 20 for monitoring of recurrent pancytopenia. Patients will undergo disease monitoring by MRI/CT 
scan (as appropriate for disease) at baseline,  4 weeks, 8 weeks, 12 weeks, and at months 6, and 9 and 
every 3 months thereafter until progression.  
Tumor biopsies and liquid biopsies will be taken at baseline, at Week 8, and upon progression and ascites 
fluid will be collected should there be a clinical need for removal at any time during the study.  At disease 
progression, the interventional portion of the protocol ends and long term follow-up (LTFU) assessments 
continue, in accordance with FDA regulations. LTFU occurs semiannually beginning at progression until 
year 5 post infusion and then annually thereafter until year 15. The study schema is depicted in Figure 1. 
 
 

 
                         
  
 
 
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Figure 1:  Study Schema 
2.4.2 Primary Study Endpoints 
All adverse events will be recorded from the time of apheresis.  All adverse events whether considered 
related or not will be recorded.  This will include infusional toxicity, and any toxicity probably or definitely 
related to the NY-ESO-1c259T including but not limited to: 
• 
Fevers 
• 
Rash 
• 
Neutropenia, thrombocytopenia, anemia, marrow aplasia 
• 
Hepatic dysfunction 
• 
Pulmonary infiltrates or other pulmonary toxicity 
• 
Development of GVHD 
*
*
*
Every 3 
months 
thereafter 
until 
progression
1-2
WEEKS
1
MONTH
3 MONTHS
6 MONTHS
CONSENT
~D-50
APHERESIS
~D-30
T CELLS
D 0 (100%)
STAGING
(CT, MRI)
T CELL
MANUFACTURE
1 WEEK
Cell product 
release
Chemo-
conditioning 
D-7, -6, -5
week
1
week
4
week
8
week
12
Weekly
Daily
TUMOR 
ASSESSMENT 
(CT/MRI)
TUMOR  AND 
LIQUID 
BIOPSY;
(Wk8 onlly)
Month 6
PATIENT 
CTX
SAFETY 
SCREEN
ANTIGEN 
SCREEN /
9 MONTHS
S A F E T Y
Monday
Month 9
TUMOR 
ASSESSMENT 
(CT/MRI)
TUMOR 
ASSESSMENT 
(CT/MRI)
TUMOR 
ASSESSMENT 
(CT/MRI)
weeks
5, 6, 10
TUMOR  AND 
LIQUID BIOPSY
(BASELINE)
TUMOR  AND 
LIQUID BIOPSY;
(PROGRESSION)
ASCITES FLUID COLLECTION
(ANYTIME CLINICALLY NINDICATED)
Months
4&5
CBC
CBC
 

 
                         
  
 
 
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2.4.3 Secondary Study Endpoints 
Secondary endpoints will evaluate correlates of treatment efficacy by measuring 1) clinical response 
rates to treatment and 2) the appearance of target antigen/MHC loss variants upon disease recurrence, 
as well as 3) immunological parameters associated with T cell persistence, bioactivity and functionality. 
1. Clinical response rates to treatment: Tumor response is defined as CR, PR and SD for at least 
4 weeks and PD.  Clinical efficacy in terms of PFS, OS, BOR and Duration of Response will also be 
assessed. Patients will be followed for EFS until progression and for survival until death from any 
cause or loss to follow-up. 
2. Appearance of target antigen/MHC loss variants upon disease recurrence will be evaluated, where 
available, by quantifying expression of targeted antigens/MHC alleles (NY-ESO-1/ HLA-A*0201/ 
A*0205/ A*0206) in tumor samples obtained on disease recurrence, and comparing those values to 
the pre-treatment (diagnosis) samples, as possible. NY-ESO-1 expression will be evaluated by 
Q-RT-PCR and/or immunohistochemistry. HLA expression on samples will be evaluated by 
immunohistochemistry. 
3. Where available Immunological parameters associated with product bioactivity and functionality will 
measure selective migration and engraftment of gene-modified infused cells to the tumor post 
infusion, the ex-vivo immune functionality and phenotype of infused cells in tumor (where biopsies 
are safely accessible) and peripheral blood, the modulation of cytokine milieu in serum at baseline, 
and post T cell infusion as well as the development of an expanded patient immune response 
against tumor via epitope spreading. 
2.4.4 Exploratory Endpoints 
1. Candidate biomarkers will be analyzed from exosomes and cell-free DNA or plasma from subject’s 
blood before and after T cell infusion and compared to those from tumor biopsies. Expression of 
these biomarkers will be correlated with treatment response 
 
2. Candidate biomarkers will be analyzed from soluble and cellular components of the ascites before 
and after T cell infusion and compared to those from tumor biopsies. Expression of these 
biomarkers will be correlated to clinical treatment response 
 
 
 
 

 
                         
  
 
 
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3 
SUBJECT SELECTION AND WITHDRAWAL 
For participation on this study, patients must meet all Inclusion/Exclusion criteria for enrollment (at 
screening) and at baseline (prior to chemotherapy). 
3.1 
Inclusion Criteria 
To be included in this study, subjects must meet the following criteria: 
1. Must have a diagnosis of recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma 
with refractory or platinum resistant disease and/or have received ≥ 2 lines of chemotherapy. 
2. Age ≥ 18 years of age. 
3. No significant immunodeficiency. 
4. Have been informed of other treatment options. 
5. Must be HLA-A*0201, HLA-A*0205, and/or HLA-A*0206 positive by high resolution testing. 
6. Patient’s tumor must be positive by histological assay for NY-ESO-1c259T, according to the screening 
algorithm as described in Section 3.3.  Positive expression,defined as ≥ 10% of cells that are 1+ by 
immunohistochemistry, is determine by pathological review at an Adaptimmune designated central 
laboratory.    
7. ECOG performance status of 0 or 1. Refer to Table 4. 
8. Life expectancy of > 4 months. 
9. Prior therapies: 
a. Prior immunotherapy, monoclonal antibody therapy or prior investigational agents should 
be washed out 4 weeks before apheresis and must be completed 4 weeks prior to pre-
infusion lymphodepletive chemotherapy. 
b. All previous cytotoxic chemotherapy, should be washed out 3 weeks before apheresis and 
must be completed at least 3 weeks prior to pre-infusion lymphodepletive chemotherapy. 
c. Systemic corticosteroid or other immunosuppressive therapy should be washed out 2 
weeks before apheresis and must be completed at least 2 weeks prior to pre-infusion 
lymphodepletive chemotherapy  
d. Biologic or other approved molecular targeted small molecule inhibitors should be washed 
out 1 week before apheresis and must be completed at least 1 week prior to pre-infusion 
lymphodepletive chemotherapy. 
e. Any grade 3 or 4 -hematologic toxicity of previous therapy must have resolved to grade 2 or 
less prior to apheresis and any grade 3 or 4 toxicity must have resolved to grade 2 or less 
prior to pre-infusion lymphodepletive chemotherapy. 

 
                         
  
 
 
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f. All blood products transfused within 4 weeks prior to apheresis and within 4 weeks prior to 
pre-infusion lymphodepletive chemotherapy must be irradiated  
10. Must have measurable disease as defined by RECIST 1.1. 
11. Must have adequate venous access for apheresis. 
12. Women of childbearing potential are requested to use acceptable methods of birth control for the 
duration of the study and until persistence of the study drug is no longer detected in the patient. This 
may be a period of several years. Methods for acceptable birth control include: condoms, diaphragm 
or cervical cap with spermicide, intrauterine device, and hormonal contraception. It is recommended 
that a combination of two methods be used. 
13. Patients must have normal organ and marrow function as defined below: 
• 
Leukocytes  
 
 
≥ 3,000/mcL 
• 
Absolute Neutrophil Count  
≥ 1,500/mcL 
• 
Platelets 
 
 
 
≥ 100,000/mcL 
• 
Total bilirubin 
 
 
≤ 1.5 ULN 
• 
AST(SGOT)/ALT(SGPT) 
 
≤ 2.5 X institutional upper limit of normal 
• 
Creatinine clearance ≥ 50 ml/min  
o Patients <65 yrs of age can be assessed using estimated creatinine clearance 
calculated using the Cockcroft-Gault formula: 
Creatinine clearance =
(140 −age) ∗weight kg
72 ∗serum creatinine mg/dl (∗0.85 in females)  
o Patients >65 yrs of age must have renal function measured either by 24-hour urine 
creatinine collection or by nuclear medicine EDTA Glomular Filtration Rate (GFR) 
measurement, according to standard practice at the treating institution. 
14. Patient must understand the investigational nature of this study and sign an Independent Ethics 
Committee/Institutional Review Board approved written informed consent form prior to receiving 
any study related procedure. 
3.2 
Exclusion Criteria 
Subjects will be excluded from this study for the following: 
1. Currently receiving any other investigational agents. 
2. Patients with active brain metastases. Patients with prior history of brain metastasis who have 
undergone local therapy (i.e., metastatectomy and/or radiation) and show no evidence of local 
recurrence or progression over the past 6 months are eligible. 
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
fludarabine, cyclophosphamide or other agents used in the study. 
4. Prior malignancy (except non-melanoma skin cancer) within 18 months of study entry.  

 
                         
  
 
 
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NOTE:  Patients must be in complete remission from prior malignancy in order to be eligible to 
enter the study.    
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
6. Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g., interleukin-2, 
interferon-alpha or gamma, granulocyte colony stimulating factors, etc.) within 30 days prior to study 
entry. 
NOTE:  Recent or current use of inhaled steroids is not exclusionary. If subjects are prescribed a 
brief course of oral corticosteroids, the use should be limited to less than 7 days. Use of steroids 
before apheresis and immune assessment blood draws should be discouraged as it will affect 
white blood cell function. 
7. Active infection with HIV, HBV, HCV, or HTLV as defined below, due to the immunosuppressive effects 
of cyclophosphamide used and the unknown risks associated with viral replication. 
• 
Positive serology for HIV. 
• 
Active hepatitis B infection as determined by test for hepatitis B surface antigen. Patients 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. Patients will be screened for HCV antibody. If the HCV antibody is positive, a 
screening HCV RNA by any RT-PCR or bDNA assay must be performed at screening by a local 
laboratory with a CLIA certification or its equivalent. Eligibility will be determined based on a 
negative screening value. The test is not required if documentation of a negative result of a HCV 
RNA test performed within 60 days prior to screening is provided. 
• 
Positive serology for HTLV 1 or 2 
8. Receipt of an experimental vaccine within 2 months or in the opinion of the Investigator is responding 
to an experimental vaccine given within 6 months, or has received any previous gene therapy using 
an integrating vector.  
9. History of severe autoimmune disease requiring steroids or other immunosuppressive treatments. 
10. Lack of availability of a patient for immunological and clinical follow-up assessment. 
11. Evidence or history of significant cardiac disease.   
3.3 
Subject Recruitment and Screening 
This trial is posted on www.clinicaltrials.gov. 

 
                         
  
 
 
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3.3.1 Number of Subjects and Duration of Study 
The target enrollment for this trial is approximately 18 subjects. As of January 2017, 7 subjects have been 
enrolled in the initial cohort with cyclophosphamide alone as the cytoreductive chemotherapy for 
lymphodepletion (Cohort 1). With the approval of Protocol Version 6, sites began enrolling into a second 
cohort 
that 
administers 
fludarabine/cyclophosphamide 
cytoreductive 
chemotherapy 
for 
lymphodepletion. It is planned that at least 10 subjects will enroll in the second cohort to receive the 
fludarabine/ cyclophosphamide condition regimen (Cohort 2).  As of January 2017 1 subject has been 
enrolled into Cohort 2. It is estimated that this study will take approximately 24 additional months to 
complete.  The study will be considered complete once the last enrolled subject has transitioned to the 
long-term follow-up phase. 
3.3.2 Sites 
The protocol will be conducted in approximately 6 sites in North America.  The number of centers is 
necessary to ensure recruitment in this targeted population.  Additional centers may be added at the 
discretion of the Sponsor. 
3.3.3 Method for Screening Subjects for HLA Alleles 
NY-ESO-1c259 T specifically recognizes the HLA-A*0201, HLA-A*0205, and HLA-A*0206-restricted NY-ESO-
1 peptide antigen HLA-A*02-SLLMWITQC; therefore, this protocol will select for subjects with these three 
HLA-A2 allelic variants and whose tumor expresses the NY ESO-1 antigen.  
The prevalence of HLA sub-types varies from population to population. Information on the prevalence of 
HLA-A2 allelic variants in specific populations is available in the Allele Frequency Net Database 
(www.allelefrequencies.net). It is recommended that investigators review the database for HLA-A2 allelic 
variants relevant to the subject population at their site.   
3.3.4 Method for Screening Subjects for Tumor Antigen  
Patients’ tumor will initially be screened for antigen expression by immunohistochemistry (IHC) for the 
NY-ESO-1c259T antigen using archived or newly acquired formalin fixed paraffin embedded tissue.  For 
patients to be determined to be NY-ESO-1c259T positive, results will be reported via a central laboratory.   
3.3.5 Screen Failures 
A screen failure log documenting the investigators assessment of each screened patient with regard to 
the protocols inclusion and exclusion criteria is to be maintained by the investigator. Subjects who sign an 
informed consent form but do not meet eligibility criteria are defined as screen failures. For all screen 
failures, all screening data collected prior to the screen failure must be entered onto the database.  

 
                         
  
 
 
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3.4 
Early Withdrawal of Subjects 
3.4.1 When and How to Withdraw Subjects 
Subjects will be withdrawn from the study prior to the expected completion date for the following 
reasons: 
• 
Unacceptable toxicity and other safety reasons that hinder completion of protocol specific 
procedures. 
• 
Confirmed progression or disease relapses. 
• 
Subject consent withdrawal. 
• 
Decision by the investigators and/or Sponsor that withdrawing is in the patient’s best interest. 
Standard supportive therapy may be maintained for subjects withdrawn from active treatment. Every 
effort will be made to collect toxicity information on withdrawn patients. 
 
 
 

 
                         
  
 
 
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4 
STUDY DRUG 
4.1 
Description 
The investigational agent in this protocol is autologous CD4 and CD8 T cells expressing a high affinity TCR 
specific for NY-ESO-1. This agent is called NY-ESO-1c259T. The agents are on file with the FDA under 
individual IND 14603. The generation of the TCR, along with some information on the lentiviral vector 
used and the cell manufacturing methods are provided in the IB. 
4.1.1 Cytoreductive Chemotherapy  
Patients will begin infectious prophylaxis for pneumocystis carinii, herpes zoster and herpes simplex the 
day prior to commencing lymphodepletion, or as clinically indicated.  Chemotherapy will be administered 
as indicated in the Table 1.  Antiemetics and hydration for administration of chemotherapy will be given 
according to standard institutional practice. 
Table 1: 
Regimen Description 
Regimen 
 fludarabine + cyclophosphamide 
Conditioning 
Recommended supportive 
medication 
Day 
Drug 
Dose 
Route 
Administration(4) 
Hydration: Ensure adequate 
hydration and antiemetic 
provision prior to 
commencing 
cyclophosphamide infusions 
 
Mesna: may be given per 
institutional guidelines or as 
recommended in 
Section 4.1.3 
 
G-CSF(3): s/c daily from 24 
hours post final 
cyclophosphamide  
 
Cell therapy premedication: 
premedication should be 
given approximately 30 
minutes prior to the NY-
ESO1c259T infusion as 
described in Section 4.1.4 
-7 
Fludarabine(1) 
30 mg/m2 
IV 
in 50 - 100ml (concentration 
of 1mg/mL or less) 0.9% 
NaCl over 30 mins 
Cyclophosphamide 
600 mg/m2 
IV 
in 100 – 250 ml 0.9% NaCl 
over 1 hour 
-6 
Fludarabine(1) 
30 mg/m2 
IV 
in 50 - 100ml (concentration 
of 1mg/mL or less) 0.9% 
NaCl over 30 mins 
Cyclophosphamide 
600 mg/m2 
IV 
in 100 – 250 ml 0.9% NaCl 
over 1 hour 
-5 
Fludarabine(1) 
30 mg/m2 
IV 
in 50 - 100ml (concentration 
of 1mg/mL or less) 0.9% 
NaCl over 30 mins 
Cyclophosphamide 
600 mg/m2 
IV 
in 100 – 250 ml 0.9% NaCl 
over 1 hour 
-4 
start G-CSF(3) 
-3 
 
-2 
 

 
                         
  
 
 
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-1 
 
0 
NY-ESO1c259T infusion(2) 
Notes: 
1  
Fludarabine dose will be adjusted in renal impairment as described in Section 4.1.2 
2  
Administration of NY-ESO1c259T infusion is described in Section 4.1.4 
3  
Long-acting (pegylated) G-CSF may be given instead of short acting G-CSF according to institutional standard 
practice.  
4  
Or per institutional standards 
4.1.2 Dose adjustments for fludarabine 
Dose of fludarabine will be adjusted for patients with renal dysfunction as follows: 
Creatinine clearance 
Fludarabine dose 
>80 mL/min 
30 mg/m2 
50 – 79 mL/min 
20 mg/m2 
4.1.3 Mesna 
Mesna will be given to cover the duration of cyclophosphamide chemotherapy according to local 
practice.  The London Cancer 2014 guideline for high dose cyclophosphamide is provided as an example 
and recommends: 
(50% cyclophosphamide dose) as an IV bolus pre infusion, 3hr, 6hr and 9 hr post on each day of 
cyclophosphamide administration. 
http://www.londoncancer.org/media/75898/140214-London-Cancer-Mesna-Guideline-v1.pdf 
4.1.4 NY-ESO-1c259T T cell Administration 
In the 5 initial patients enrolled under protocol versions prior to Version 5, NY-ESO-1c259T was 
provided as target doses of 5 – 10  x 109 total cells, which were administered in a split infusion.  
All patients enrolled under protocol Version 5 or later will be administered NY-ESO-1c259T by a single 
intravenous infusion. The infusion bag will be labeled according to applicable regulatory requirements 
including batch number, protocol number, number of transduced cells and the subject’s study 
identification number.  Prior to infusion, two clinical personnel will independently verify all the 
information in the presence of the subject and to confirm that the information is correctly matched to the 
subject, as per institutional procedures. 
 Patients will receive at least 1x109 transduced cells, with a maximum possible dose of 6x109.     

 
                         
  
 
 
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Treatment will be administered on an outpatient or inpatient basis, according to the investigator’s 
discretion. Premedication with antihistamines and acetaminophen is recommended and may be given in 
accordance with institutional standards. Aspirin may be substituted for acetaminophen for patients 
allergic to acetaminophen. At the investigators’ discretion, patients may be hospitalized for the 
cytoreductive chemotherapy and/ or T cell infusion. 
NY-ESO-1c259T must not be thawed until immediately prior to infusion. The cells can be thawed either in 
a water bath at the patient’s bedside or in a centralized facility, according to institutional standard 
procedures. The cells must be infused without delay and, if thawed centrally, must be transported to the 
patient by appropriately trained clinical staff, to preserve the chain of custody. The cell product must 
not be washed or otherwise processed. It is expected that the infusion will commence within 
approximately 10 minutes of thawing and complete within 45 minutes of thawing to minimize exposure 
of the cell product to cryoprotectant. If the cells are provided in multiple bags, the second bag must not 
be thawed until half the first has been infused without reaction. If after thawing the inner infusion bag is 
damaged or leaking, the PI and Sponsor should be notified and the cells should not be infused. 
 
NY-ESO-1c259T will be administered using a dual spike infusion set by gravity over 15-30 minutes in the 
absence of reaction. It is recommended that the cells are infused without a filter, however if a filter is 
required by institutional practice the pore size must not be smaller than 170 µm. Infusion pumps must 
not be used. For administration of the cells, 100 - 250 ml of 0.9% sodium chloride should be connected 
to the second lumen of the infusion set, used to prime the line, and then the lumen closed. On 
completion of the infusion of a bag of NY-ESO-1c259T, the main line should be closed and approximately 
50ml saline transferred into the cell bag, and then infused to minimize the loss of cells. This process 
should be repeated for each cell bag if multiple bags are provided. On completion of the cell infusion the 
set should be flushed using additional saline from the attached bag.  
 
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. 
4.1.5 Second Infusion 
Patients who have a clinical response to the first infusion and experience documented progressive disease 
will be eligible for a second T cell infusion with previously manufactured cell product (or from residual or 
gene modified T cell-negative apheresis product, or product from a second apheresis providing there is 
no persistence of gene modified cells detected prior to apheresis) for up to 6 months after confirmation 
of disease progression if their tumors are shown to continue to express the appropriate antigen target.  
Patients must also continue to meet study inclusion and exclusion criteria.  The second infusion will be 
administered following the current protocol specified cytoreductive chemotherapy regimen.   

 
                         
  
 
 
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4.2 
Management of Toxicities and Complications  
4.2.1 Infection   
Patients should receive prophylaxis against Pneumocystis pneumonia, herpes simplex, and varicella 
zoster and according to institutional guidelines.  In addition, measures to treat and prevent infection 
may be provided in accordance with institutional guidelines.  In particular, fever and neutropenia should 
be aggressively managed as well as preemptive influenza therapy and other standard therapies for 
immunocompromised hosts.  
4.2.1.1 Cytomegalovirus 
Subjects will be screened for cytomegalovirus (CMV) seropositivity at study entry.  All CMV seropositive 
subjects will continue to be monitored for CMV viremia by CMV DNA PCR until 60 days post infusion of 
NY-ESO-1c259T. In the event CMV viremia is observed an Infectious Diseases specialist should be 
consulted and treatment initiated if necessary according to institutional practice. 
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 4.2.8 . 
4.2.1.2 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. 
4.2.2 Hematologic and Blood Product Support  
Blood product support should be provided to maintain platelets > 10 x109/L, Hb > 8.0 g/dL (or in 
accordance with the institutional practice) and as clinically indicated.  See AABB Guideline on platelet 
transfusion [2015]. 
4.2.2.1 Blood Product Irradiation  
Bone marrow suppression can be a consequence of transfusion associated GVHD. To minimize the 
possibility of transfusion associated GVHD, all blood products transfused within 4 weeks prior to 
leukapheresis, within 4 weeks prior to initiation of lymphodepleting chemotherapy and following 
lymphodepleting chemotherapy until at least 6 months following IP infusion or until lymphocyte count 
returns to ≥1.0 x109/L (whichever is longer) must be irradiated.  In addition, if a subject requires 
systemic steroids or immunosuppression for the treatment of toxicity, irradiated blood products must 
be given until recovery of immune function 

 
                         
  
 
 
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4.2.2.2 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 NY-ESO-1c259T 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. 
4.2.3 Management of Neutropenia using Filgrastim  
Per ASCO guidelines for the management of neutropenia, filgrastim (G-CSF) should be given 24 hours after 
the administration of myelotoxic chemotherapy.  G-CSF should be continued until reaching an absolute 
neutrophil count (ANC) of at least 2 to 3 × 109/L. 
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 post the final dose of 
cyclophosphamide. 
4.2.4 Management of Symptoms during T Cell Infusion 
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 and temperature elevations will be managed with acetaminophen. All subjects that 
develop fever or chills will have a blood culture drawn. 
• 
Headaches may be managed with acetaminophen following a neurologic examination. 
• 
Nausea, vomiting will 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. 
4.2.5 Management of Autoimmunity 
Subjects should be monitored throughout the trial for potential autoimmune reactions in response to the 
genetically engineered T cells that could include skin toxicity, liver toxicity, colitis, eye toxicity etc.  If 
autoimmunity is suspected, the PI should be contacted and every attempt should be made to biopsy the 
affected organ to clarify whether the symptoms are related to the T cell 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 

 
                         
  
 
 
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4.2.6 Management of Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following 
administration of antibodies and adoptive T-cell therapies for cancer. It is defined clinically by symptoms 
many of which mimic infection including pyrexia, nausea, diarrhea, headache, fatigue, tachycardia, 
hypotension, transaminitis, rash and dyspnea. It is important to evaluate the subject for concurrent 
infections.  Potentially life-threatening complications of CRS include cardiac dysfunction, adult respiratory 
distress syndrome, neurologic toxicity, renal and/or hepatic failure and disseminated intravascular 
coagulation. CRS may also be associated with findings of macrophage activation syndrome or occur 
coincident with tumor lysis syndrome. 
CRS causes a rapid rise in serum cytokine levels under conditions of immune activation and although 
cytokines will be assayed serially throughout the study, results of the assays will not be available in real 
time therefore CRS  should be graded and managed with supportive and immunosuppressive 
interventions according to the severity of symptoms (Lee, Gardner et al. 2014).   
The recommended management of CRS depends on the grade, which has been further adapted from 
CTCAE for use with immunotherapy and should be implemented in accordance with institutional 
guidelines. Symptoms can mimic those seen with infection. The diagnosis of CRS is clinical, and is 
supported by the exclusion of infection as well as the presence of increased cytokine levels and other 
biomarkers. Assessment and treatment guidelines are provided below. If CRS is suspected, in addition to 
assessment for infection, cytokine levels as well CRP levels should be measured approximately every 
other day until symptoms are improving or an alternative diagnosis is confirmed.  
 
Management Guidelines for Cytokine Release Syndrome 
 
Grade 
Clinical Presentation for Grading 
Assessment 
 
Management Guidelines 
1 
Constitutional symptoms not life-
threatening (e.g., fever, nausea, fatigue, 
headache, myalgias, malaise) 
• 
Vigilant supportive care1  
• 
Assess for infection and treat2  
2 
Symptoms require and respond to 
moderate intervention (Hypotension 
responds to fluids or one low dose 
pressor, hypoxia responds to <40% O2, 
and/or Grade 2 organ toxicity) 
• 
Monitor cardiac and other organ 
function 
• 
Vigilant supportive care1. 
• 
Assess for infection and treat2 
• 
Treat hypotension with fluid and 
pressors.   
• 
Administer O2 for hypoxia. 
• 
Administer tocilizumab ± 
corticosteroids3 in subjects with 
extensive co-morbidities or of 
older age. 

 
                         
  
 
 
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3 
Symptoms require and respond to 
aggressive intervention 
hypotension requires multiple pressors or 
high dose pressors 
hypoxia requires ≥40% O2, , Grade 3 organ 
toxicity or Grade 4 transaminitis 
• 
Monitor subject very closely for 
cardiac and other organ 
dysfunction. Most likely will 
require monitoring in an intensive 
care unit (ICU). 
• 
Vigilant supportive care1  
• 
Assess for infection and treat2  
• 
Treat hypotension with fluid and 
pressors. Administer O2 for 
hypoxia. 
• 
Administer tocilizumab ± 
corticosteroids3  
4 
Life-threatening symptoms 
Grade 4 organ toxicity (excluding 
transaminitis) 
• 
Manage subject in ICU  
• 
Intensive supportive care including 
mechanical ventilation, fluids, 
pressors, antibiotics and other 
measures as required 
• 
Administer tocilizumab ± 
corticosteroids3 
5 
Death 
 
1. 
Supportive care includes:  monitor fluid balance, maintain adequate hydration and blood pressure  
2. 
Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever and 
neutropenia as per institutional practice; and antipyretics, analgesics as needed.  
3. 
Other immunosuppressor agents may be used, including TNFα  and IL-1R inhibitors  
Source:  Lee, 2014 
   
Patients requiring immunosuppressive intervention may receive tocilizumab, steroids, or both (Davila, 
Riviere et al. 2014; Lee, Gardner et al. 2014). Tocilizumab is a humanized anti-IL-6 receptor antibody that 
has been used to manage severe CRS (although it is not approved for this indication).  Anecdotally, 
tocilizumab has produced rapid and complete correction of CRS with single doses (Maude, Barrett et al. 
2014). Lee et al., recommend administration of tocilizumab 4 mg/kg administered over 1 hour in adult 
patients as the first-line treatment of severe CRS.  Patients may receive a repeat dose if clinical signs and 
symptoms do not improve within 24-48 hours.  
Side effects attributed to chronic use of tocilizumab in rheumatologic disease include transaminitis, 
thrombocytopenia, elevated cholesterol and low-density lipoproteins, neutropenia and increased 
infections but acute infusional toxicities have not been reported in CRS use (Lee, Gardner et al. 2014). 
Patients unresponsive to tocilizumab or experiencing severe neurological symptoms (e.g. confusion, 
delirium, seizure, etc.) may require treatment with steroids.  Lee et al., recommend steroids as second-
line therapy for CRS due to the potential to inhibit the anti-tumor effects of the adoptive T-cell therapy. 

 
                         
  
 
 
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However, in patients with grade 3 or 4 CRS associated with neurologic dysfunction without significant 
hemodynamic instability or other life-threatening symptomatology, consideration may be given to the 
use of corticosteroids as a preferred first-line immunosuppressive therapy. High doses (e.g. 2 mg/kg/day 
prednisone equivalent) may be required.   
If cytokine release syndrome is suspected, a physician with expertise in the management of subjects 
following bone marrow transplant should be consulted. If high dose corticosteroids are required, 
treatment should generally be continued for at least 5 days followed by tapering doses over several 
weeks.  
The product label for tocilizumab can be found at:   
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125472s000lbl.pdf 
Please note that labels are subject to change and the most current version of the label should be 
referenced if there are any questions. 
4.2.7 Management of Graft-versus-Host Disease  
Autologous graft-versus-host disease (GVHD) has been described in association with adoptive transfer of 
ex-vivo expanded/co-stimulated autologous T-cells [Error! Reference source not found.Error! Reference 
source not found., 2009], as well as infusion of T-cells with engineered specificity for NY-ESO-1 and 
LAGE-1a [Garfall, 2013], following high-dose chemotherapy and autologous stem cell transplant (ASCT) 
in subjects with multiple myeloma.  There is the potential for subjects who receive lymphodepleting 
therapy followed by engineered autologous T-Cell infusion to experience GVHD and/or autoimmune 
GVHD-like symptomatology.  Autologous GVHD is typically milder than classic (allogeneic) GVHD [Kline, 
2008], and is usually manageable with treatment.  However, severe cases (including fatalities) have been 
reported [Fidler, 2012].  There are no published guidelines for the management of autologous GVHD.  
However, lessons can be drawn from published case reports and guidelines for the diagnosis and 
management of acute GVHD following allogeneic transplant [Dignan, 2012]. 
4.2.7.1 Diagnosis of GvHD 
The diagnosis of GVHD is predominantly based on clinical findings and is often one of exclusion.  Many 
of these symptoms can also occur in the setting of the preparative regimen, high dose 
cyclophosphamide as well as with cytokine release syndrome.  Any of these conditions including GVHD 
can be associated with fever.  The skin is the most commonly involved organ, followed by the 
gastrointestinal (GI) tract and liver.  A constellation of symptoms involving these organ systems may be 
helpful in establishing the diagnosis of GVHD.  Diarrhea, rash, fever, and pancytopenia are common 
toxicities in the NY-ESO-1c259T program where we have the most clinical experience.  Mild (Grade 1 or 2) 
transient transaminitis without cholestasis has been observed. 
Organ 
Findings/Symptoms 
Differential Diagnosis 
Histopathology 

 
                         
  
 
 
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Skin 
Maculopapular rash involving 
the neck and shoulders as 
well as the palms and soles 
that spreads to include the 
rest of the body. 
Drug reactions, viral 
exanthems, cytokine 
release syndrome, and 
effects of chemotherapy or 
radiation 
Apoptosis at base of 
epidermal rete pegs, 
dyskeratosis, exocytosis of 
lymphocytes, satellite 
lymphocytes adjacent to 
dyskeratotic epidermal 
keratinocytes and 
perivascular lymphocytic 
infiltration in the dermis. 
GI 
Secretory diarrhea is most 
common but nausea, 
vomiting, anorexia, weight 
loss and abdominal pain can 
also occur.  Diarrhea can be 
copious.  Bleeding may result 
from mucosal ulceration and 
ileus may ensue. 
Side effects of 
chemotherapy or other 
drugs and infection of the 
GI tract 
Patchy ulcerations, apoptotic 
bodies at crypt bases, crypt 
ulceration and flattening of 
surface epithelium 
Liver 
Cholestatic pattern of liver 
injury including elevated 
conjugated bilirubin, alkaline 
phosphatase and GGTP.  
Subjects may present with 
jaundice, with pruritus in 
more severe cases. 
Veno-occlusive disease of 
the liver, viral infections, 
drug toxicity and sepsis. 
Endothelialitis, lymphocytic 
infiltration of the portal 
areas, pericholangitis and 
bile-duct destruction. 
 
Of Note: Bone marrow suppression and related cytopenias have been described in the setting of acute 
GVHD.  Management of this complication is challenging, with no clearly established guidelines regarding 
immunosuppression.  Treatment may be largely supportive, including transfusions and treatment of 
infections. 
Management should include consultation with a physician with expertise in the management of subjects 
following bone marrow transplant. 
Bone marrow suppression is also a feature of transfusion-related GVHD.  To minimize the possibility of 
transfusion-related GVHD, see Section 4.2.2.1for guidance on irradiated blood products.  
4.2.7.2 Grading of GvHD 
Grading of acute GVHD is based on the stage of dermal, gastrointestinal, and hepatic involvement as 
described in the table below.  Careful measurement of stool volume and assessment of percentage of 
body area covered by rash are important for proper grading and treatment. 
 

 
                         
  
 
 
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Stage 
Skin 
Gut 
Liver 
1 
Maculopapular rash <25% of body area 
Diarrhea >500 ml/day 
Bilirubin 2-3 mg/dl 
2 
Maculopapular rash 25%-50% of body 
area 
Diarrhea >1,000 ml/day 
Bilirubin 3-6 mg/dl 
3 
Generalized erythroderma 
Diarrhea>1,500 ml/day 
Bilirubin 6-15 mg/dl 
4 
Desquamation and bullae 
Diarrhea>2,000 ml/day or 
pain or ileus 
Bilirubin >15 mg/dl 
 
 
With the addition of assessment of functional impairment, grading can be determined using the table 
below (Glucksberg 1974). 
 
   
Grade 
Skina 
Guta 
Livera 
Functional statusb 
I 
1-2 
0 
0 
0 
II 
1-3 
1 
1 
1 
III 
2-3 
2-3 
2-3 
2 
IV 
1-4 
2-4 
2-4 
3 
a Staging is described above 
b Mild, moderate, or severe decrease in performance status 
 
4.2.7.3 Management of GvHD 
Although the diagnosis of GVHD is predominantly based on clinical grounds, biopsy of affected organs 
can be helpful in excluding other causes and supporting the diagnosis of GVHD with consistent 
histopathologic findings.  However, awaiting biopsy results should not delay the institution of 
appropriate therapy. 
If GVHD is suspected: 
• 
A physician with expertise in the management of subjects following bone marrow transplant 
should be consulted. 
• 
Consider biopsy of the affected organ(s) 
 
Corticosteroids have been used as the standard first line treatment for GVHD for several decades.  Their 
effect is likely to be due to lympholytic effects and anti-inflammatory properties.  In general, intestinal 
and liver GVHD require more prolonged steroid therapy than skin disease although response times vary. 

 
                         
  
 
 
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Diarrhea should be managed with volume replacement, dietary restriction, and anti-diarrheal agents 
including the consideration of somatostatin for secretory diarrhea.  Agents that slow motility should be 
used cautiously, ensuring that there is no evidence of ileus or toxic megacolon, and infectious causes of 
diarrhea should be excluded. 
General guidelines for first-line treatment based on grade are provided below, and should be considered 
in conjunction with input from the consulting physician with bone marrow transplant expertise. 
 
Grade 
Management Strategy 
I 
Subjects with grade I disease are not likely to require systemic treatment.  Cutaneous 
GVHD may respond to topical steroid creams.  Antihistamines may be helpful in 
subjects with pruritis.  Subjects should be reviewed frequently for other organ 
manifestations of GVHD. 
II 
Treat skin symptoms with topical steroids.  For GI symptoms - optimize anti-diarrheal 
regimen, dietary restrictions, volume replacement and consider initiation of non-
absorbable steroids.  For refractory or progressive symptoms consider systemic 
steroids as outlined below. 
III 
For more severe or progressive symptoms consider systemic corticosteroids (e.g., 
methylprednisolone one (1) mg/kg per day*) 
IV 
Methylprednisolone two (2) mg/kg per day* 
* The use of ‘nonabsorbable’ steroids (Budesonide and beclomethasone) can be considered for acute intestinal GVHD in 
order to reduce the dose of systemic steroids 
 
If high dose corticosteroids are required, treatment should generally be continued for at least 5 days 
followed by tapering doses over several weeks.  A physician with expertise in infectious diseases in 
immunocompromised hosts should be consulted, and prophylactic antimicrobials should be considered. 
Second line treatment can be considered for subjects who have failed to respond for 5 days or have 
progressive symptoms after 3 days.  There is no clear second-line agent that is preferred for steroid 
refractory GVHD.  General guidelines for second-line treatment based on grade are provided below, and 
should be considered in conjunction with input from the consulting physician with bone marrow 
transplant expertise. 
For steroid refractory skin rash, topical tacrolimus may also be useful. 
Most of the allogeneic transplant subjects are concurrently receiving calcineurin inhibitors in part as 
prophylaxis against GVHD.  Therefore, for grade II-IV disease refractory to high dose steroids, the 
addition of a calcineurin inhibitor can be considered. 
Otherwise, there are several additional second line treatment options for which there is currently 
limited and/or evolving supporting data.  Treating physicians can refer to the Haemato-oncology Task 
Force of the British Committee for Standards in Haematology and the British Society for Blood and 

 
                         
  
 
 
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Marrow Transplantation guideline for diagnosis and management of acute graft-versus-host disease 
[Dignan, 2012]. 
4.2.8 Management of Pancytopenia with Bone Marrow Failure/ Aplastic Anemia 
Pancytopenia with bone marrow failure / aplastic anemia has been reported after initial bone marrow 
recovery from high-dose chemotherapy followed by infusion of NY-ESO-1c259 T-cells.  Bone marrow 
recovery following lymphodepletion will be defined as: 
• 
Absolute neutrophil count ≥ 1,000/μL for 2 consecutive measurements approximately seven 
days apart, and 
• 
Platelet count ≥ 20,000/μL without transfusion support for one week. 
Aplastic anemia is a rare hematological disorder characterized by pancytopenia and a hypocellular 
marrow.  Subjects are usually symptomatic on presentation but some are detected incidentally when 
unexpected cytopenias are found on a routine blood count.  The diagnosis of severe aplastic anemia is 
made in the setting of a hypocellular bone marrow when 2 of the following 3 blood counts are met: 
absolute neutrophil count < 500/μL, absolute reticulocyte count < 60,000/μL, and platelet count < 
20,000/μL, and myelodysplastic syndrome is ruled out.  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. 
Management of bone marrow suppression and related cytopenias in aplastic anemia 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 pancytopenia (decreasing hemoglobin, platelets or neutrophils, or increasing 
transfusion requirements) following initial bone marrow recovery the following measures should be 
implemented: 
1. Consult a physician with expertise in the management of aplastic anemia 
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.  Refer to Section 10 (Correlative Data Analysis).  Details on 
tissue collections, kit use and shipment information can be found in the manual of procedures. 
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 

 
                         
  
 
 
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8. Once alternative etiologies have been excluded, strongly consider immunosuppression (e.g. 
methylprednisolone 2mg/kg initial dose) or more aggressive regimens (e.g. antithymocyte 
globulin (ATG), cyclosporine, eltrombopag) as well as antimicrobial prophylaxis/therapy with the 
advice of your hematology/Infectious Diseases consultant(s).  If high dose corticosteroids are 
initiated, continue for a minimum of 5 days and taper gradually with advice from expert 
consultants. 
Refer to Section 4.2.7 (Management of Graft-versus-Host Disease) regarding bone marrow suppression 
as a feature of GVHD. 
4.3 
Prior and Concomitant Therapy 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, taken by 
the subject during the 30 days prior to screening will be recorded at the screening visit. All anti-cancer 
treatments taken by the subject must be recorded regardless of time.  At every visit, concomitant 
medications will be recorded in the medical record and on the appropriate CRF. Any additions, deletions, 
or changes of these medications will be documented. 
4.3.1 Active Infection 
Active infections occurring after initiating the study should be treated according to the standard of care. 
4.3.2 Disallowed Agents 
The following treatments are prohibited on the study:  Any other anti-cancer treatment including non-
protocol surgery, non-protocol chemotherapy, immune therapy, biological therapy, or investigational 
anti-cancer therapy. Radiotherapy to target lesions or new lesions is not allowed. 
The following agents are not allowed while on study: systemic corticosteroids (unless before 
cytoreductive therapy and except as outlined for management of CRS), immunotherapy (e.g., interleukins, 
interferons, other vaccines, intravenous immunoglobulin, expanded polyclonal TIL or LAK therapy), 
pentoxifylline, or other investigational agents due to their immunosuppressive or immunomodulatory 
effects on the study drug. 
Patients who have not received the influenza vaccine prior to treatment on the protocol may receive the 
vaccine after they have normalized their blood counts. 
4.4 
Subject Compliance Monitoring 
Informed consent must be obtained from all patients before entry into the study. The study team will 
monitor compliance with the protocol. Any steps in this sequence that are missed must be recorded as 
protocol violations.  

 
                         
  
 
 
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4.5 
Receiving, Storage, Dispensing and Return 
4.5.1 Receipt of Drug Supplies 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt log 
filled out and signed by the person accepting the shipment. It is important that the designated study staff 
counts and verifies that the shipment contains all the items noted in the shipment inventory. Any 
damaged or unusable study drug in a given shipment will be documented in the study files. The 
investigator must notify study sponsor of any damaged or unusable study treatments that were supplied 
to the investigator’s site. 
4.5.2 Storage 
The final cell product is frozen and stored at the central manufacturing facility.  Viability tests will be 
performed before releasing the cells for use.  Cells will be shipped in a cryoshipper prior to infusion to the 
clinical site, where the cells will be removed from the shipper and stored in vapor phase liquid nitrogen 
or a mechanical freezer at < -130 oC until the infusion day.  
4.5.3 Return or Destruction of Study Drug 
The study drug may require return to the manufacturing facility.  Any unused study drug will be returned 
to the manufacturing facility at the discretion of the Sponsor.    
 
 

 
                         
  
 
 
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5 
STUDY PROCEDURES 
5.1 
Informed Consent and Study Enrollment Procedures 
All subjects are required to sign a statement of informed consent prior to the conduct of any study-related 
procedures. This Phase I study involves research that presents risk, but holds the prospect of direct benefit 
to the individual subject (46.405-45 Code of the Federal Regulations part 46). It is the responsibility of the 
investigator to give each subject (or the subject’s acceptable representative) prior to inclusion in the 
study, full and adequate verbal and written information regarding the objective and procedures of the 
study and the possible risks involved. The subjects must be informed about their rights to withdraw from 
the study at any time. Written subject information must be given to each subject before enrollment. 
Furthermore, it is the responsibility of the investigator to obtain signed ICF for all subjects prior to 
inclusion in the trial. 
Upon enrollment, it is the responsibility of each investigator to provide to the Sponsor a completed 
enrollment form, and supporting documents providing proof of each eligibility criterion. 
5.2 
Screening and Baseline Evaluations 
Patients will provide their written informed consent for HLA typing and antigen screening.  
If the patient is eligible based on HLA type and tumor antigen expression, then the patient will undergo 
the remainder of the screening and baseline procedures according to Schedule of Procedures outlined in 
Table 2. Procedures include: 
• 
Medical history and concomitant medications 
• 
HLA and Tumor Antigen analysis (Screening) 
• 
CT or MRI  
• 
Targeted physical exam (height collected at screening only) 
• 
Determination of performance status 
• 
CBC and differential 
• 
Ferritin (Screening) 
• 
Complete metabolic and hepatic panel 
• 
Baseline CA-125 reading (Screening) 
• 
Urinalysis 
o Patients >65 years of age must have renal function measured either by 24-hour urine 
creatinine collection or by nuclear medicine EDTA GFR measurement, according to 
standard practice at the treating institution. 

 
                         
  
 
 
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• 
Uric Acid (Screening) 
• 
Prothrombin time 
• 
Screening for active viral infections (Screening) 
• 
ECHO or MUGA (Screening) 
• 
Troponin, EKG 
• 
Collection of blood for research assessments (Baseline) 
• 
Tumor and liquid biopsy (Baseline) 
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study)  
5.3 
Leukapheresis 
After enrollment, the leukapheresis date will be scheduled based on the T cell manufacture schedule at 
the manufacturing facility. All patients will undergo an approximately 10 L – 12 L mononuclear cell 
apheresis procedure to collect steady-state T-cells. Antecubital veins will be used, or when necessary, a 
central catheter will be placed. A standard collection protocol will be used to obtain the peripheral white 
blood cells with settings modified to obtain the best mononuclear cell yield. In order to obtain sufficient 
cells, leukapheresis time may vary from 90 minutes to 240 minutes. The collection goal will be about 
1 x 108 mononuclear cells/kg body weight. The minimum collection will be set a 1.5 x 107 mononuclear 
cells/kg. However, if the minimum collection is not reached, then a second apheresis procedure can be 
performed if recommended by the Sponsor. Cells will be transferred same day/overnight by courier to the 
manufacturing facility where they will be processed. Autologous leukapheresis product, counts, and 
recoveries will be monitored for each donation. The procedure will be performed according leukapheresis 
protocols at the study sites. Refer to Schedule of Procedures outlined in Table 2. 
Requirements for reporting adverse events begin at the time the patient undergoes the leukapheresis 
procedure. 
5.4 
Baseline Imaging 
Per eligibility criteria, patients must have measurable disease.  A baseline CT scan (or MRI) of the chest, 
abdomen and pelvis, should be obtained within 7 days prior to initiation of cytoreductive chemotherapy.  
Lesions must be selected and size measurements recorded according RECIST v 1.1.  Note: lesion size 
must be determined by anatomical imaging with CT or MRI. Size or activity (e.g. SUVmax) from PET 
alone (or other imaging techniques e.g. radioisotope bone scan) is not sufficient.  Throughout the study, 
lesions must be assessed using the same technique as at baseline (CT or MRI).  Refer to Schedule of 
Procedures outlined in Table 2. 
5.5 
Cytoreductive Chemotherapy  
As described earlier in Section 4.1.1.  Refer to Schedule of Procedures outlined in Table 2. 

 
                         
  
 
 
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• 
Concomitant medications 
• 
Adverse events 
• 
Targeted physical exam 
• 
Determination of performance status 
• 
CBC and differential 
• 
Complete metabolic and hepatic panel  
• 
CA-125 monitoring 
• 
Troponin/ EKG 
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study)  
5.6 
T Cell Infusion (Day 0) 
It is recommended that T cell infusions occur typically on Monday (Day 0) for single infusions.  T cell 
products will be shipped to the clinical sites in accordance with validated shipping procedures and SOPs.  
Refer to Schedule of Procedures outlined in Table 2. 
• 
Concomitant medications 
• 
Adverse events 
• 
Determination of performance status 
• 
CBC and differential 
• 
Complete metabolic and hepatic panel  
• 
Uric Acid 
• 
Troponin, EKG 
• 
CA-125 monitoring 
• 
Collection of blood for research assessments (least 1 hour post-infusion) 
• 
Weight (pre-infusion); vitals will be collected pre-infusion and 15 minutes, 30 minutes, 1 hour, 2 
hours, 3 hours, and 4 hours post infusion.  
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study)  
 

 
                         
  
 
 
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5.7 
Post Infusion Follow-up (Days 1-4 and Day 7) 
Patients will be followed daily for Days 1-4 and also at Day 7 following the infusion. Refer to Schedule of 
Procedures outlined in Table 2.  These visits will include the following procedures: 
• 
Concomitant medications 
• 
Adverse events 
• 
Vital signs 
• 
Determination of performance status 
• 
CBC and differential 
• 
Ferritin 
• 
Complete metabolic and hepatic panel  
• 
CA-125 reading 
• 
Uric Acid 
• 
Troponin/ EKG 
• 
Collection of blood for research assessments 
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study) 
5.8 
Post Infusion Follow-Up (Weeks 2 - 4) 
Starting with the second week, patients will be followed weekly until week 4. There is a ± 2 day window 
for these visits, which will include the following procedures.  Refer to Schedule of Procedures outlined in 
Table 2. 
• 
Concomitant medications 
• 
Adverse events 
• 
Targeted physical exam (Weeks 2 and 4) 
• 
Vital signs (Week 3) 
• 
Determination of performance status 
• 
CBC and differential  
• 
Ferritin (Weeks 2 and 4) 
• 
Complete metabolic and hepatic panel  
• 
CT/MRI  

 
                         
  
 
 
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• 
CA-125 reading 
• 
Uric Acid 
• 
Collection of blood for research assessments 
• 
Troponin/ EKG (Week 2) 
• 
ECHO/MUGA (Week 4) 
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study) 
5.9 
Post Infusion Follow-Up (Weeks 5, 6, 10, 16, 20) 
At Weeks 5, 6, 10, 16 and 20 (± 2 days), CBC (with differential) monitoring for the management of 
pancytopenia/aplastic anemia will be performed.  
5.10 Post Infusion Follow-Up (Week 8 and Week 12) 
Patients will be followed at Week 8 (± 2 days) and Week 12 (± 1 week). The reason for the smaller window 
at Week 8 is that this time point is important for staging and monitoring for adverse events. Refer to 
Schedule of Procedures outlined in Table 2.  These visits will include the following procedures: 
• 
Concomitant medication 
• 
Adverse events 
• 
Targeted physical exam 
• 
Determination of performance status 
• 
CBC and differential 
• 
Complete metabolic and hepatic panel  
• 
CA-125 reading 
• 
Collection of blood for research assessments 
• 
CT/MRI  
• 
Ferritin (Week 8) 
• 
Tumor and liquid biopsy (week 8) 
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study) 

 
                         
  
 
 
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5.11 Post Infusion Follow-Up (6 Months and then every 3 months until disease 
progression) 
Patients will be followed at 6 and 9 months (± 1 week) and then every 3 months until disease progression. 
Refer to Schedule of Procedures outlined in Table 2.  These visits will include the following procedures: 
• 
Concomitant medication 
• 
Adverse events 
• 
Targeted physical exam 
• 
Determination of performance status 
• 
CBC and differential 
• 
Complete metabolic and hepatic panel  
• 
CA-125 reading 
• 
Collection of blood for research assessments 
• 
CT/MRI  
• 
Tumor and liquid biopsy (at progression) 
• 
Ascites fluid collection (if clinical need for removal of ascites fluid at any time on study) 
5.12 Long Term Follow-Up (Years 1 - 15) 
Evaluations will be performed for up to 15 years on all subjects as specified by FDA, in accordance with 
recent guidelines for long term follow-up (LTFU) set forth by the ASGT and the FDA. Subjects may be rolled 
over to a LTFU protocol or subjects will continue to be followed as described in Table 2 and Appendix C. 
Please refer to Table 2 and Appendix C for Long Term Follow-up. 
The most recently released (November 2006) Guidance on Monitoring for Delayed Adverse Events states 
that for the first 5 years, all subjects should undergo monitoring of vector sequences every 6 months, and 
a full physical examination including a medical history, concomitant medications and examination of 
appropriate organ systems and a hemogram annually. For the final 10 years, if vector sequences are no 
longer detected in PBMCs, a one page questionnaire or post card may be sufficient for reporting of any 
adverse events and questions relating to the patient’s status. 
For the LTFU in this study: 
• 
Subjects who have completed the 9 month visit, the first visit will occur at 1 year post T cell 
infusion and then every 6 months until the end of year 5 post T cell infusion.   
• 
For subjects who do not complete the 3 month visit, the first visit will occur at 3 months post T 
cell infusion, the second visit will be 6 month post T cell infusion, the third visit will occur at 9 

 
                         
  
 
 
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months post T cell infusion and the next visit will occur 1 year post T cell infusion, and then every 
6 months until the end of year 5 post T cell infusion.    
Visits will include a medical history, physical exam, and blood tests for disease monitoring, CBC, 
chemistries, monitoring for persistence of vector modified cells and annually for RCL testing/archive. The 
physical exam and medical history (including concomitant medications and adverse events) will be 
conducted with careful attention to features possibly related to oncoretroviral diseases including: (1) New 
malignancies, (2) New incidence or exacerbation of a pre-existing neurologic disorder, (3) New incidence 
of exacerbation of a prior rheumatologic or other autoimmune disorder, and (4) New incidence of a 
hematologic disorder. See Appendix C: Long Term Follow Up. 
For the next 10 years, subjects will be asked to return  for testing only if vector modified cells were 
detected in the previous year, and if so, then blood for persistence of vector modified cells and RCL testing 
(archive) will also be performed/collected. If no vector modified cells were detected in the previous year, 
the follow-up will be conducted by means of a clinical questionnaire completed via phone or through the 
mail by the study coordinator. The questionnaire will include the following questions: 
• 
When did you last visit your personal physician? 
• 
Has there been a change in your condition? Are there any adverse events to report? 
• 
Did you have a blood test? 
• 
Did your physician express any concerns with the test results? 
A draft letter to the patient and the patient’s primary doctor (if different than the study Investigator listed 
on this protocol) is provided in Appendix A: 
Sample Patient Letter for Long Term Follow-Up. 
 
5.13 Requirements for a Tumor Biopsy 
Screening Prior to Apheresis 
Collection of a tumor biopsy at screening is only required if there is no archival tissue available to test 
for NY-ESO-1 positivity.  If archival tissue (i.e. FFPE) is available, this can be used for screening purposes 
and a tumor biopsy would not be required.   
Baseline and Week 8 
Core needle tumor biopsies are required at baseline and Week 8, with the exception of patients for 
whom there is no safely accessible tumor tissue.  If possible, biopsies should consist of multiple cores.  
The baseline biopsy material may be collected anytime between two months and 2 weeks prior to the 
start of chemotherapy, with a preference for the biopsy to be taken closer to the time of infusion.   The 
tumor tissue should be taken from non-target lesions and when possible the same lesion(s) should be 
biopsied at both baseline and Week 8. If it is not possible to biopsy the same non-target lesion(s) at 
Week 8, then (an) other non-target lesion(s) preferably in the same anatomical region should be 

 
                         
  
 
 
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biopsied. The apparent clinical or scan status of the lesion(s) biopsied at week 8 should be noted at the 
time (e.g. decreased, stable, increased size or activity).  
Disease Progression 
Biopsy material should be collected (with exception of patients for whom there is no safely accessible 
tumor) after disease progression has been confirmed and documented.  Ideally the biopsy should occur 
on lesions that have progressed (or the same lesion(s) biopsied at Week 8 or another lesion in the same 
anatomical region) if possible.   
Biopsy collection and sample preparation methods can be found in the Manual of Procedures.   
5.14 Requirements for Liquid Biopsies 
In all patients, at baseline, week 8 and at disease progression, we request a parallel blood collection for 
liquid biopsies. Liquid biopsies should be collected at the same time that tumor biopsies are requested.  
 
It is preferable a tumor biopsy be collected if it is feasible  and that the collection of a liquid biopsy be 
conducted in addition to the tumor biopsy and/or ascites, and should not substitute the collection of the 
tumor biopsy and/or ascites.  
5.15 Requirements for Ascites Fluid Collection 
Should there be a clinical requirement for removal of ascites fluid in a patient at any time on study, we 
request that a sample be collected for correlative research studies. This ascites sample is an additional 
collection and is not in place of any protocol specified biopsies.  
 
 
 

 
                         
  
 
 
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6 
SCHEDULE OF PROCEDURES AND OBSERVATIONS 
The schedule of procedures and observations for this study is summarized in Table 2: 
Schedule of 
Procedures and Observations below.

  
 
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Table 2: 
Schedule of Procedures and Observations 
Schedule 8  
Screening 
1 
Screening  
2 
Leuka-
pheresis 
Baseline 
w/in 7 
days prior 
to chemo 
Chemo 
Infusion 
Day -7 
Day -6 
Day -5 
T cell 
infusion 
Day 0 
(Mon.) 
Days 
1-4 
Day 
7 
Weeks 
2-4 
(weekly) 
Week 8 
(Weeks 5, 
6, 10) 19 
Week 
12 
(Weeks 
16, 20) 19 
Month 6 
and 
every 3 
months  
At 
confirmation 
of PD 
LTFU 14 
Years 
1-5 
Years 
6-15 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide and 
fludarabine9 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Apheresis  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T Cell Infusion 
 
 
 
 
 
X 1 
 
 
 
 
 
 
 
 
 
MRI/CT 
 
X 
 
X 
 
 
 
 
X 17 
X 
X 
X 
X 
 
 
Tumor Biopsy 3 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Exosome and cfDNA 
collection (liquid biopsy)3  
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Ascites Fluid Collection 3 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted Physical Exam 
 
X 
 
X 
X 
X4 
X4 
X4 
X4  
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, differential 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ferritin 
 
X 
 
 
 
 
X 15 
 
X 2 
X 
 
 
 
 
 
Complete Metabolic and 
Hepatic Panel  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
 
X12 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
Uric Acid 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Prothrombin Time  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Troponin/EKG 
 
X 
 
X 
X 
X 10 
X 10 
X10 
X 16 
 
 
 
 
 
 
ECHO or MUGA  
 
X 
 
 
 
 
 
 
X 17 
 
 
 
 
 
 
HLA/ Tumor Antigen  
X 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HTLV 1/2, Hep B, Hep C, 
CMV IgG  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CA-125 Monitoring 
 
X 
 
 
X 5 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

  
 
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Schedule 8  
Screening 
1 
Screening 
2 
Leuka-
pheresis 
Baseline 
w/in 7 
days 
prior to 
chemo 
Chemo 
Infusion 
Day -7 
Day -6 
T cell 
infusion 
Day 0 
(Mon.) 
Days 
1-4 
Day 
7 
Weeks 
2-4 
(weekly) 
Week 
8 
Week 
12 
Month 6 
and every 3 
months 
At 
confirmatio
n of PD 
LTFU 14 
Years 
1-5 
Years 
6-15 
Research Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vector Copies (Persistence) 
 
 
 
X 
 
X 6 
X 
X 
X 
X 
X 
X18 
X 
X 
X 
VSV-G DNA (RCL) 7 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X  
X 
PBMC (Functional Assays, 
Immunophenotyping) 
 
 
 
X 
 
X 6 
X 
X 
X 
X 
X 
X 
X 
 
 
Cytokine Analyses and 
Humoral Anti-Infused Cell 
Responses 13 
 
 
 
X 
 
X 6 
X 
X 
X 
X 
X 
X 
X 
 
 
1. 
100% of total dose given on day 0.  Recommended day for infusion is Monday so that all procedures can be collected during business hours Monday-Friday. 
2. 
Weeks 2 and 4 only. 
3. 
Requirements for a tumor biopsy are described in Section 5.13; Requirements for liquid biopsy collection are described in Section 5.14. Requirement for ascites fluid 
collection are described in Section 5.15, Ascites fluid will be collected in patients who have an accumulation of ascites, should there be a clinical need for removal of the 
ascites fluid at any time on study. 
4. 
On Day 0, vitals will be monitored prior to and at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours and 4 hours post infusion. Pre-infusion weight will be collected. Vitals 
only will be collected on Days 0-7 and Week 3. 
5. 
Taken pre-infusion. 
6. 
Sample collected any time at least 1 hour post infusion. 
7. 
If negative at 1 year then VSV-G sample can be archived in years 2 - 5 for look back analysis as needed. 
8. 
Weekdays are shown because in most cases, due to the weekend, the patient procedures will fall on these days. However, the weekdays may be altered as needed. 
Study procedures performed as part of standard of care prior to signing informed consent can be used for screening if they were performed within a 7-10 days prior to 
leukapheresis for laboratory tests, and within four weeks prior to screening for ECHO/MUGA, or MRI/CT. Additional tests may be done at any time if clinically indicated. 
9. 
At the investigators’ discretion, patients may be hospitalized for the cytoreductive chemotherapy; Mesna administered in accordance with institutional standards; 
Patients will begin infectious prophylaxis for pneumocystis carinii, herpes zoster and herpes simplex the day prior to commencing preparative chemotherapy, or as 
clinically indicated; G-CSF should be given from 24 hours after the last dose of cyclophosphamide until resolution of neutropenia in accordance with ASCO guidelines or 
institutional practice. Long-acting (pegylated) G-CSF may be substituted according to institutional practice   
10. Collected prior to infusion on Day 0, and Days 1- 4, and as clinically indicated after Day 4. 
11. Patients eligible for second infusion must continue to meet eligibility for tumor antigen positivity. 
12. Patients >65 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine EDTA GFR measurement  
13. Humoral Anti-infused Cell Responses are collected as part of the cytokine analysis.  Aliquots will be stored at a central vendor for potential analysis from baseline, Week 
8, Month 6 timepoints and every 3 months thereafter. 
14. Follow-up is required for patients that discontinue, see Appendix C: Long Term Follow Up for detailed list of procedures to be performed during long-term follow-up. 
15. Day 4 only. 
16. Week 2 only. 

  
 
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17. Week 4 only. 
18. Month 6 persistence sample is collected for safety assessment 
19. CBC (with differential) only will be collected at Weeks 5, 6, 10, 16, and 20 for monitoring of pancytopenia. 
 
Table 3: Blood Volume for Research Assessments 
 
Blood Collected 
for Research 
Assessments 
Screening 
prior to 
apheresis 
Leuka-
pheresis 
Baseline 
w/in 7 
days prior 
to chemo 
Chemo 
Infusion 
Day -7 
Day -6 
T cell 
infusion 
Day 0 
(Mon.) 
Day
s 
1-4 
Day 
7 
Weeks 
2-4 
(weekly) 
Week 
8 
Week 
12 
Month 6 
and 
every 3 
months 
At 
confirmatio
n of PD 
LTFU 
(maximum 
every 6 
months) 
Vector Copies (Persistence) 
- 
- 
8 
- 
8 
8 
8 
8 
8 
8 
8 
8 
8 
VSV-G DNA (RCL) 
- 
- 
8 
- 
- 
- 
- 
- 
- 
8 
8 1 
- 
8 
PBMC (Functional Assays, 
Immunophenotyping) 
- 
- 
24 
- 
24 
24 
24 
24 
24 
24 
24 
24 
- 
CK Analysis and  
HAIC Responses 
- 
- 
3 
- 
3 
3 
3 
3 
3 
3 
3 
3 
- 
Exosome and cfDNA 
collection (liquid biopsy) 
 
 
17 
 
 
 
 
 
 
 
 
 
 
Total (mL) 
- 
- 
60 
- 
35 
140 
35 
105 
52 
35 
43 1 
52 
16 
Total (tablespoons) 
- 
- 
4.1 
- 
2.3 
9.4 
2.3 
7.1 
3.5 
2.3 
2.9 
3.5 
- 
1. 
RCL (8 ml) is only collected at 6 month intervals 
 
 

 
 
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7 
DEFINITIONS 
7.1 
Medical History and Physical Examination 
The medical history must include all diagnoses and surgical procedures of major organ systems. Any 
allergies to any medications and their formulations must be documented. 
7.2 
Previous Medications 
All prescription and nonprescription medication, vitamins, herbal and nutritional supplements, taken by 
the subject during the 30 days prior to screening will be recorded at the screening visit.  All anti-cancer 
treatments must be recorded regardless of time. 
7.3 
Concomitant Medications 
Concomitant medications will be recorded in the medical record and on the appropriate eCRF. In addition, 
any additions, deletions, or changes of these medications will be documented. 
7.4 
ECOG Performance Status 
Performance status will be assessed by ECOG. If necessary, for reporting purposes, the scale can be 
converted from Karnofsky using the standard scale shown in Table 4. 
Table 4: 
ECOG Performance Status Scale and Karnofsky Index of Performance Status 
ECOG (Zubrod) Performance Status Scale 
Karnofsky Index of Performance Status 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all pre-
disease performance without 
restriction. 
100% 
Normal, no complaints, no evidence of 
disease. 
90% 
Able to carry on normal activity; minor sighs 
of symptoms of disease. 
1 
Restricted in physically strenuous 
activity but ambulatory, able to 
carry out light or sedentary work, 
e.g., light housework, office work. 
80% 
Able to carry on normal activity with effort; 
some signs or symptoms of disease. 
70% 
Cares for self, unable to carry on normal 
activity or do active 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. 
60% 
Requires occasional assistance but is able to 
care for most of own needs. 
50% 
Requires considerable assistance and 
frequent medical care. 
3 
40% 
Disabled; requires special care and assistance. 

 
 
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ECOG (Zubrod) Performance Status Scale 
Karnofsky Index of Performance Status 
Score 
Description 
Score 
Description 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours. 
30% 
Severely disabled; hospitalization indicated, 
although death not imminent. 
4 
Completely disabled. Cannot carry 
on any self-care. Totally confined to 
a bed or chair. 
20% 
Very ill; hospitalization necessary; active 
supportive treatment required. 
10% 
Moribund, fatal process progressing rapidly. 
5 
Dead 
0% 
Patient expired. 
7.5 
Targeted Physical Examination and Vital Signs 
A targeted physical exam will imply assessments in each of the following categories: General (weight, 
height at screening, blood pressure, pulse, respiration rate, and temperature), head, eyes, ear, nose and 
throat examinations, lymph node examination, chest and cardiovascular system examination, breasts, 
respiratory system, abdominal examination, dermatological examination, and neurological examination 
including mental status assessment. 
7.6 
Complete Metabolic and Hepatic Panel 
Complete metabolic panel will include measurements of sodium, potassium, chloride, bicarbonate, urea 
nitrogen, uric acid, creatinine, total protein, albumin, calcium, phosphorous, cholesterol, triglycerides, 
amylase, lipase, and lactic dehydrogenase. Hepatic panel refers to liver function tests will include 
measurements of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), C-reactive protein (CRP).  Prothrombin time (PT) will be listed separately.  In the 
schedule of study procedures, chemistries and liver function tests are always performed together. 
Additionally, Ferritin will be measured.   
7.7 
CBC, Differential 
Hematology tests will include hemoglobin, hematocrit, platelet count, red cell count, and white cell count 
with differential count. 
7.8 
HLA-A*0201, A*0205 and/or A*0206 Screening 
A high resolution test for the HLA-A*0201, A*0205 and A*0206 allele is required. At the present time, only 
HLA-A*0201, HLA-A*0205, and/or HLA-A*0206 subjects are eligible, as the other subtypes (e.g., 
HLA-A*0202) do not interact with the engineered TCR. 
7.9 
Dose Limiting Toxicity 
A dose limiting toxicity (DLT) is defined as something which is both:  

 
 
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Any untoward or adverse event which seems at least possibly related to the modified TCR therapy  
Plus: 
Any Grade 3 or higher event that is sustained for more than 1 week, excepting autoimmune disorders and 
chemotherapy related adverse events.  For cytokine release syndrome, the event must be a grade 4 
adverse event and sustain at grade 4 for more than 1 week to be considered a DLT. 
Any Grade 3 or higher autoimmune disorder that cannot be resolved to less than or equal to a Grade 2 
autoimmune toxicity within 100 days should also be deemed a DLT. 
Any chemotherapy-related event should not normally be considered a DLT unless the investigator is under 
the reasonable impression that the modified TCR therapy specifically has made the event worse in which 
case it will be considered a DLT 
 
 

 
 
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8 
RESPONSE CRITERIA 
8.1 
Endpoints and Assessment Methods 
Tumor response will be assessed by RECIST 1.1. 
Tumor measurements and scan data may be stored at a central imaging vendor as directed by the 
Sponsor for future central analysis as needed. 
8.2 
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 (US) should not be used to measure tumor 
lesions.  The same modality should be used when comparing or making assessments. 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm in diameter as 
assessed using calipers. For the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal 
limit, they must normalize for a subject to be considered in complete response. 
Cytology and histology can be used in rare cases (e.g., for evaluation of residual masses to differentiate 
between Partial Response and Complete Response or evaluation of new or enlarging effusions to 
differentiate between Progressive Disease and Response/Stable Disease). 
Use of endoscopy and laparoscopy is not advised. However, they can be used to confirm complete 
pathological response. 
All baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
8.2.1 Measurable lesions measurement 
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). 

 
 
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8.2.2 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. 
• 
‘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. 
8.2.3 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. 
8.2.4 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 

 
 
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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. 
8.2.5 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’. 
8.2.6 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.  (Note:  the appearance of one or more new lesions is also considered progressions) Note: 
determination of PD will not be made prior to the Day 60 evaluation. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions: 
• 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  When lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met since a normal lymph node is defined as having a short axis of <10 
mm. 
• 
Target lesions that become ‘too small to measure’.  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small.  However, sometimes lesions or lymph nodes 
become so faint on a CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being ‘too small to measure’, in which case a default 
value of 5 mm should be assigned.  Lesions that split or coalesce on treatment.  When non-
nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of 

 
 
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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’. 
8.2.7 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject to 
be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. Unequivocal progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a single lesion increase. 
8.2.8 Special notes on assessing progression of Non-Target lesions 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
• 
When subject has measurable disease.  To achieve ‘unequivocal progression’ on the basis 
of the non-target disease, there must be an overall level of substantial worsening in non-
target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in 
the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. 
• 
When subject has only non-measurable disease. There is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified, a useful test 
that can be applied is to consider if the increase in overall disease burden based on change 
in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’ or an increase in lymphangitic disease from localized to 
widespread. 
8.2.9 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 

 
 
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other than tumor, especially when the subject’s baseline lesions show partial or complete 
response). 
• 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
• 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and disease progression. 
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT in assessment 
of progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up - is PD based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, 
this is PD. 
• 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
• 
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. 
Table 5: Summary of the overall response status calculation at each time point: 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required
(1) 
CR 
CR 
No 
CR 
>4 wks. Confirmation
(2) 
CR 
Non-CR 
Non-PD 
No 
PR 
 
>4 wks. Confirmation(2) 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR 
Non-PD 
Not evaluated 
No 
PR 

 
 
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Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required
(1) 
SD 
Non-CR 
Non-PD 
Not evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline(2) 
Not 
all 
evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
Any 
PD
(3) 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
(1) 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion 
(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 
8.2.10 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. 
8.2.11 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. 
https://www.eortc.be/Recist/documents/RECISTGuidelines.pdf 
 
 
 

 
 
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9 
STATISTICAL ASSESSMENT 
9.1 
Study Populations 
Intent-to-Treat (ITT) population: all subjects who were enrolled in the trial. The ITT population is the 
primary population for the safety of the end-to-end autologous T cell therapy procedure.   
Modified Intent-to-Treat (mITT) population: all subjects who received at least one NY-ESO-1c259T cell 
infusion.  The mITT population is a subset of the ITT population and is the primary analysis population 
for safety evaluations and anti-tumor response/efficacy following NY-ESO-1c259T cell infusion. 
9.2 
Statistical methods for demographics and safety parameters 
With respect to the primary objectives and endpoints, no specific statistical hypotheses are being 
evaluated.  The primary focus will be on determining the safety profile, and the pharmacodynamics of 
NY-ESO-1c259T cells following infusion.  All analyses will be descriptive and exploratory and may be 
performed by cohorts and / overall cohorts. 
Descriptive statistics will be provided for selected demographic, safety, imaging, and cytokine 
assessments as appropriate.  Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges.  Categorical data will be summarized using frequency counts and 
percentages.  Graphical summaries of the data may be presented.   
9.3 
Statistical analysis and reporting methods for safety endpoints 
The safety profile will be based on adverse events reported, vital signs measurements, clinical laboratory 
measurements, EKG recordings, and physical examination results.   
9.3.1 Adverse Events 
All adverse events will be listed and coded by MedRA.  The number and percent of patients reporting any 
adverse events will be tabulated by system organ class and preferred term.  Adverse events with missing 
date of onset will be considered treatment emergent.  Adverse events will be further classified by severity, 
relationship to treatment and seriousness in tabulation.  Tables and/or narratives of any on study death, 
or serious or significant adverse event, including early withdrawals from the interventional period because 
of adverse events, will be provided should they occur. 
9.3.2 Vital Signs 
Vital signs will be listed and summarized 
9.3.3 Electrocardiogram 
Electrocardiogram data will be listed for each patient. Fridericia’s and/or Bazett’s correction will be used 
to adjust QT for RR.   Further details on reporting of EKG data can be will be provided in the RAP. 

 
 
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9.3.4 Anti-NY-ESO-1 Antibodies 
The patient incidence of Anti- NY-ESO-1 antibody formation will be computed and the anti- NY-ESO-1 
Antibodies results will be listed. 
9.3.5 T cell Phenotype and Cytokines 
The results will be listed. 
9.3.6 Clinical Laboratory Tests 
Clinical chemistry, hematology, and urinalysis data will be listed for each patient.  Values outside the 
normal laboratory reference ranges will be flagged as high or low on the listings.  Laboratory abnormalities 
will be graded using CTCAE version 4.  Each patient’s maximum post-baseline grade will be computed for 
each laboratory parameter and referred to as their worst grade for that laboratory parameter.  For each 
parameter shift tables from baseline to worst grade may be presented. 
9.4 
Statistical analysis and reporting methods for efficacy endpoints 
To determine the effect of the treatment of NY-ESO-1c259T cell infusion on tumor response, summaries of 
efficacy will be based on overall response rate (ORR); best overall response (BOR); time to and duration 
of response; progression free survival (PFS); and the overall survival (OS) by cohort.  
Primary Analyses –Primary analyses will be based on RECIST 1.1 measurement ORR is defined as the 
percentage of subjects with a confirmed CR or PR relative to the total number of subjects in the 
corresponding analysis population.  The ORR will be based on confirmed responses from the investigator 
assessment of overall response.  Subjects with unknown or missing response will be treated as non-
responders (i.e., they will be included in the denominator when calculating the percentage).  
Appropriate methods for calculated CIs will be utilized, these will be identified in the analysis plan.  
Tumor measurements and scan data may be stored at a central imaging vendor as directed by the 
Sponsor for future central analysis as needed. 
Further details about the efficacy analyses will be outlined in the RAP. 
The duration of response will be summarized descriptively for subjects using Kaplan-Meier medians.  
Duration of response is defined, for the subset of subjects with a confirmed CR or PR, as the time from 
first documented evidence of CR or PR until first documented disease progression or death due to any 
cause.  
PFS is defined as the interval between the date of first dose and the earliest date of disease progression 
or death due to any cause.  PFS will be summarized using Kaplan-Meier quartile estimates.  If the subject 
does not have a documented date of progression or death, PFS will be censored at the date of the last 
adequate assessment. 
Further details on rules for censoring and about the efficacy analyses will be provided in the RAP. 
 
 

 
 
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10 CORRELATIVE DATA ANALYSIS 
10.1 General Overview 
In this section, a comprehensive summary of potential correlative studies is provided. This description is 
based on the current data available to the investigators. Some studies may not be performed, or different 
studies may be performed, based on the data emerging from the study, availability of samples, or other 
factors. 
10.2 Core Correlative Studies 
For molecular (Q-PCR and Q-RT-PCR), immune phenotyping and functional assays, peripheral blood will 
be collected. For cytokine analyses peripheral blood samples will be collected in serum separator (SST) 
tubes.  Samples will be collected according to the sample collection schedule (Table 2).  
Samples will be shipped to a Central Lab.  All research analyses will be performed based on principles of 
good laboratory practice, with assay-specific SOP using qualified and if possible validated assays. 
Documentation for sample receipt, processing and storage, and primary data from the research analyses 
will be collected and stored at the Central Lab. 
If a subject has an adverse event, an additional biopsy (for example skin, GI tract, bone marrow, tumor) 
or blood (serum and PBMC) samples may be requested with the objective of gaining an understanding of 
the underlying etiology of the adverse event.  The below described research tests may be performed on 
these samples. 
10.2.1 Evaluation of Tumor 
Analysis of tumor biopsies for the purpose of study enrollment is detailed in Section 3.3.3. In patients 
where follow up tumor biopsies are safely accessible, additional tumor biopsies will be analyzed for tumor 
expression of the tumor antigen target; HLA expression, and infiltration by lymphocytes. These analyses 
will be performed either by the Central Lab or other laboratory as indicated by the Sponsor. 
10.2.2 T Cell Function and Phenotype 
Measurement of the following immunological parameters associated with product bioactivity and 
functionality is planned and will be performed at the Central Lab or by the laboratories at the sites. 
• 
Persistence of Infused Cells in the Periphery: Persistence and homing of infused gene marked 
cells to tumor will be evaluated using a qualified Q-PCR assay and DNA isolated directly from 
peripheral blood samples, by quantifying. If persistence levels are high enough (> 0.1% of total 
DNA), flow cytometric analysis using multimer-reagents for the NY-ESO-1 TcR will be used as an 
independent, secondary measure of persistence 
• 
Selective migration and engraftment of gene-modified infused cells to the tumor. 
• 
The ex-vivo immune functionality and phenotype of infused and persisting cell: will be evaluated 
directly ex-vivo and will be possible if persistence levels are shown to be greater than 0.5% of total 

 
 
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cells. Functionality will be evaluated by measuring antigen-specific degranulation and intracellular 
cytokine production in response to target cells that express the HLA-A02 gene as well as NY-ES0-1 
and. Surface differentiation and memory phenotype will be determined using multi-parameter 
flow cytometry and co-staining for markers such as CD45RO, CCR7, CD27, CD28, and CD57. If 
sufficient material is available, parallel analyses may evaluate expression of exhaustion and 
activation markers: PD1, CD154, CD95, CD25, and CD127. 
• 
The modulation of cytokine milieu in periphery: luminex will be used to evaluate cytokine levels 
such as: IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40⁄p70), IL-13, IL-15, IL-17, 
TNF-α, IFN-α, IFN-γ, GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, Eotaxin, RANTES, MCP-1, VEGF, G-CSF, 
EGF, FGF-basic, and HGF. IL-6, TNF-α, IFN-γ will be evaluated at a minimum.  
• 
Evaluation of the immune milieu in tumor biopsies will be possible if sufficient tumor material is 
obtained during the post-treatment biopsies. These analyses will be performed by Q-RT-PCR and 
will measure the influx of immune cell subsets such as CD3, CD4, CD8, CD14, CD16, CD19, CD206, 
T cell activation such as CD25, CD95, CD154, T cell exhaustion (PD1, CD57), as well as 
inflammatory cytokines such as IFN-γ, TNF-α, IL-8, IL-10, and IL-2. 
• 
The development of an expanded patient immune response against tumor via epitope spreading. 
Each of these analyses will be performed in bulk on samples procured according to the schedule 
in Table 2, processed and frozen as per SOP. 
10.2.3 Exploratory Dose- and Exposure-Response Analysis 
The relationship between number/composition of infused cells (dose) and/or persistence of infused cells 
in the periphery (exposure) and changes in immune cell phenotype, cytokine production and tumor size 
will be assessed as data permit. Relationship between dose/exposure and measures of response (immune 
cell phenotype/cytokines/tumor size) will be initially assessed via graphical methods. If data warrant, 
further analysis of dose- and/or exposure-response via population non-linear mixed effects modeling may 
be performed. 
10.2.4 Evaluation of Epitope Spreading 
In order to determine the development of an expanded patient immune response against tumor via 
epitope spreading, cellular immunity may be analyzed. NY-ESO-1 specific CD4+ and CD8+ T cell reactivity 
may be measured by: 
• 
Cytokine secretion (Gnjatic, Nagata et al. 2000; Gnjatic, Atanackovic et al. 2003; Odunsi, Qian et 
al. 2007). 
• 
Enzyme Linked Immunospot (ELISPOT)  (Gnjatic, Nagata et al. 2000; Gnjatic, Atanackovic et al. 
2003; Odunsi, Qian et al. 2007). 
• 
MHC multimer (Gnjatic, Nagata et al. 2000; Gnjatic, Atanackovic et al. 2003; Odunsi, Qian et al. 
2007) 

 
 
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For ELISPOT assays, a response will be considered positive if the number of spots in the peptide-exposed 
well is two-fold or more higher than the number of spots in the unstimulated well, and if there is a 
minimum of ten (after subtraction of background spots) peptide-specific spots/25,000 T cells. The FACS 
analysis following in-vitro-presensitization will serve as the primary assay for the determination if a 
patient is considered an immune responder. For FACS analysis, immune response is defined as positive if 
the frequency of T cells detected in at least one post-vaccine sample exceeds by ≥ 3-fold that found in the 
baseline sample. 
10.2.5 Liquid biopsy collection and analysis 
Recognizing that tumor biopsies cannot always be obtained safely, we set out to investigate whether 
alternative safer approaches can provide similarly valuable information.  Therefore, in addition to tumor 
biopsies, liquid biopsies (peripheral blood plasma) will be collected in order to investigate both cell-free 
DNA (cfDNA) and exosomes. 
Exosomes (source of stable mRNA, produced by all cells, including tumor cells and immune cells) and 
cfDNA, produced by dying tumor cells) will be used to monitor both the molecular signature of the 
tumor burden (including the expression of the target antigen) and the immune response.  The analysis 
of exosomes and cfDNA will allow: 
• 
Estimation and genetic profiling of the global tumor burden (including expression of 
NY-ESO-1c259T mRNA and mutational profiling) from exosomes and cfDNA. 
• 
Systemic assessment of the immune response (gene expression by cytotoxic and regulatory 
immune cells) from exosomes 
10.2.6 Ascites fluid collection and analysis 
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 response to 
therapy. Ascites fluid collected in this protocol 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.  
 
Research studies conducted in ascites samples may include cellular and molecular assays (on DNA and 
RNA) aiming at: 
• 
Analyzing antigen expression by tumor cells, 
• 
Analyzing persistence and phenotype of genetically modified T cells by qPCR and flow 
cytometry, 
• 
Assessing T cell-receptor diversity and clonality, 
• 
Evaluating candidate biomarkers of immune response, anti-tumor activity and resistance to 
therapy, through gene expression analysis (by RNA-Seq, Nanostring or RT-PCR). 
 
As new technologies and data emerge, other assays relevant to the study objectives may be performed. 

 
 
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10.2.7 Request for Autopsy for Death Following Administration of Gene Transfer Agents 
In accordance with FDA and EMA guidance [FDA, 2006b; 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.  To ensure compliance, 
guidelines for performing an autopsy are provided in the Study Procedures Manual. 
10.2.8 Additional Exploration of the T Cell Response 
The methods to analyze the T cell response to cancer antigens used in this study are well established. 
However, as T cell biology and immune regulation are very active fields of discovery, the opportunity exists 
to refine and extend the analysis of the T cell response. This work may also involve establishing cell lines 
and clones in culture, and collaborations with investigators. 
 
 

 
 
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11 SAFETY AND ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• 
results in study withdrawal. 
• 
is associated with a serious adverse event. 
• 
is associated with clinical signs or symptoms. 
• 
leads to additional treatment or to further diagnostic tests. 
• 
is considered by the investigator to be of clinical significance. 
11.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious. 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
11.1.3 Intensity 
Intensity of all AEs will be graded according to the NCI Common Toxicity Criteria for Adverse Events 
(CTCAE) v 4.0 on a five point scale (grade 1-5) and reported in detail on the eCRF. 
AEs not specifically listed on the CTCAE should be graded as follows: 

 
 
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NCI CTCAE v4.0 
CTCAE Grade 
Equivalent to 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal 
daily activity 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily 
activity; minimal medical intervention is indicated. 
Grade 3 
Severe 
Incapacitating with inability to work or perform 
normal daily activity; treatment or medical 
intervention is indicated in order to improve the 
overall well-being or symptoms; delaying the onset 
of treatment is not putting the survival of the 
patient at direct risk. 
Grade 4 
Life threatening/ 
disabling 
An immediate threat to life that requires urgent 
medical intervention 
Grade 5 
Death 
AE resulting in death. 
11.1.4 Assessment of Causality 
An investigator who is a qualified physician will assess the causal relationship between the adverse event 
and NY-ESO-1c259T according to his/her best clinical judgement.  The following scale of criteria will be used 
as a guidance. 
Causality Term 
Assessment Criteria   
Not related 
• 
The patient did not receive the test drug.  Or  
• 
Temporal sequence of the AE onset relative to administration of the test drug is 
not reasonable. Or  
• 
There is another obvious cause of the AE.   
Possibly related 
• 
There is evidence of exposure to the test drug.   
• 
The temporal sequence of the AE onset relative to administration of the test drug 
is reasonable 
• 
The AE could have been due to another equally likely cause.   
Probably related  
• 
There is evidence of exposure to the test drug.   
• 
The temporal sequence of the AE onset relative to administration of the test drug 
is reasonable. 
• 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class   
• 
The AE is more likely explained by the test drug than by any other cause.   
Definitely related 
• 
There is evidence of exposure to the test drug.   
• 
The temporal sequence of the AE onset relative to administration of the test drug 
is reasonable.   
• 
The AE shows a pattern consistent with previous knowledge of the test drug or test 
drug class. 
• 
The AE is most likely explained by the test drug, any other cause is improbable.  

 
 
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11.1.5 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, a reasonable possibility is at 
least “possibly related" according to the table above. 
11.1.6 Unexpected Suspected Adverse Reaction (21 CFR 312.32(a))  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information described in 
the general investigational plan or elsewhere in the current application, as amended. For example, under 
this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator 
brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
listed only cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
11.1.7 Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
11.1.8 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event. 
11.1.9 Post-Study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
stabilized, or the adverse event is otherwise explained with the subject under the care of a qualified 
medical practitioner. At the last scheduled visit, the investigator should instruct each subject to report 
any subsequent serious adverse event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study. The investigator should notify the study sponsor 
of any death or adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study. The sponsor should also be notified if the 
investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study. 

 
 
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11.1.10 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met: 
• 
Is associated with clinical signs or symptoms or suggests a disease and/or toxicity 
• 
Requires treatment or any other therapeutic intervention 
• 
Results in study treatment dose modification, interruption or discontinuation from the study. 
• 
Is associated with death or another serious adverse event, including hospitalization. Is judged by 
the Investigator to be of significant clinical impact 
• 
Any CTCAE lab value≥ Grade 3 should be recorded as an AE. Any value < Grade 3 may still be an 
AE if judged clinically significant. 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the patient’s outcome. 
11.1.11 
Progression of underlying malignancy 
Progression of underlying malignancy is not reported as an AE if it is clearly consistent with the suspected 
progression of the underlying cancer.  Clinical symptoms of progression may be reported as AEs if the 
symptom cannot be determined as exclusively due to the progression of disease the underlying 
malignancy, or does not fit the expected pattern of progression for the disease under study. 
11.1.12 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol. Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for 
and adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition. Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless 
it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 

 
 
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11.2 Recording of Adverse Events 
Adverse events will be assessed using CTC V4. At each contact with the subject, the investigator must seek 
information on adverse events by specific questioning and, as appropriate, by examination. Information 
on all adverse events should be recorded immediately in the source document, and also in the appropriate 
adverse event module of the case report form (CRF/eCRF). All signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
All adverse events, whether considered related to the study drug or not, occurring during the study period 
must be recorded. The clinical course of each event should be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the cause. Serious adverse 
events that are still ongoing at the end of the study period must be followed up 30 days after the end of 
the study or, if related to treatment, until resolution or stabilization to determine the final outcome. Any 
serious adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
11.2.1 Adverse Event Reporting Period 
Patients will be monitored for the duration of the intervention protocol, not including long term follow-
up for AE reporting.  The AE reporting period begins at apheresis until completion.  
During long term follow-up (years 1 - 15), patients will only be monitored for delayed adverse events 
related to the gene transfer aspect of the protocol. These are defined in Section 5.12. 
11.3 Reporting of Serious Adverse Events and Unanticipated Problems 
11.3.1 Reporting Criteria during the Study Intervention Period (Apheresis up to 
discontinuation) 
• 
All adverse events should be reported, not just those considered related. 
If an event meets the criteria definition of a serious adverse event, the investigator or designee (initial 
reporter) must complete a Serious Adverse Event Report (provided as an attachment on the study 
Manual of Operating Procedures -MOP) with at least minimum information as available for the event.  
Minimum reporting criteria include:  
Identifiable patient 
Suspect medicinal product 
Identifiable reporting source (with signatures) 
Event that is identified as serious 
Severity and grading of event 
Relationship to suspect medication. 

 
 
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The initial reporter or designee (Site Coordinator / Investigator) must e-mail the completed SAE Report 
Form with all available information as soon as possible and always within 24 hours of learning of the SAE 
to: ADPSafety@SCiAN.com. 
11.3.2 Reporting Criteria during Long Term Follow-Up (Years 1 - 15) 
Due to the nature of the treatment, patients are required to be followed for up to 15 years after treatment 
with genetically modified T cells.  Patients will be followed according the schedule outlined in Section 5.12.  
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 of exacerbation of a pre-existing neurological disorder 
• 
New incidence of exacerbation of a prior rheumatologic or other autoimmune disorder 
• 
New incidence of hematologic disorder 
• 
Gene marking of the surrogate sample 
Only adverse events deemed related to the gene modified cells are captured by Adaptimmune and 
reported to the regulatory   agencies.  The 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 cell type, tumor cells will be evaluated for vector 
sequences. 
11.4 Investigator Reporting of SAEs: Notifying the Study Sponsor 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type of serious 
adverse event, must be reported to the study sponsor within 24 hours of the Investigator/site staff 
learning of the SAE.  
For specific instructions for reporting SAEs to the Sponsor, please see the Manual of Procedures for the 
study, or contact the study manager at Adaptimmune. 
The investigator must provide further information on the serious adverse event or the unanticipated 
problem in the form of a written narrative. This should include a copy of the completed Serious Adverse 
Event form, and any other diagnostic information that will assist the understanding of the event. 
Significant new information on ongoing serious adverse events should be provided promptly to the study 
sponsor.  SAEs should be followed until resolution. 
11.5 Investigator Reporting to the IRB 
Investigators at each site are responsible for safety reporting to their IRB. Investigators are responsible 
for complying with their IRB’s reporting requirements. 

 
 
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11.6 Sponsor Responsibility for Reporting Adverse Events 
All adverse events will be reported to regulatory agencies, IRB/IECs, and investigators in accordance 
with all applicable global law and regulations.    
11.7 Stopping Rules 
If the following events occur, further enrolment to the study may be suspended on the basis of a joint 
review of the information/data by the Sponsor and Investigators, and pending approval of a subsequent 
protocol amendment (if appropriate): 
Any death occurs that is deemed to be probably or definitely related to the investigational 
medication/cell product; 
Or 
Two (2) or more grade 4 autoimmune events deemed probably or definitely related to the 
investigational medication/cell product by the principal investigator and study sponsor; 
Or 
An apheresis confirmed positive biological RCL occurs and no additional lot of vector is available (see 
Section 11.10.1 on Monitoring for and Management of replication competent Lentivirus (RCL)). 
11.8 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above. 
11.9 Data Monitoring Committee 
The data for this study will be closely monitored by the Sponsor. There is no formal Data Monitoring 
Committee for this study.  
11.10  Safety Monitoring 
11.10.1 
Monitoring and Management of Replication-Competent Lentivirus (RCL) 
Replication Competent Lentivirus (RCL) is a theoretical risk associated with the use of lentiviral vectors; 
no RCL has ever been detected in vitro or in vivo.  The risk is derived from the detection of replication 
competent retrovirus (RCR) during the use of early γ retroviral vector packaging systems which were 
inadequately designed to avoid recombination events between the vector and packaging components 
[Miller, 1990].  Updated γ retroviral packaging systems have not been associated with RCR.  However in a 
study with Rhesus monkeys, three out of 10 animal died of lymphomas at around 6 months after 
transplantation of vector transduced bone marrow cells contaminated with replication-competent virus 
[Donahue, 1992]. Therefore, RCR/L must continue to be rigorously evaluated in vector and cell lots, and 

 
 
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in subjects post infusion with any product involving a retrovirus [FDA, 2006a; FDA, 2006b; FDA, 2010; FDA, 
2009]. 
A RCL may be generated during the production phase or subsequently after introduction of vector 
transduced cells into the subject.  RCL may be generated between 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 vector 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. 
Regulatory agencies and the gene therapy community have previously discussed measures to be taken 
should an RCL be confirmed in a subject [FDA, 2006a; FDA, 2006b EMA, 2009].  However, because the 
probability and characteristics of an 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 until an understanding of how to 
manage the concern becomes clear. 
The following approaches have been discussed for subject management: 
Provide targeted antiretroviral therapies based on genotyping of the RCL. 
Intensive follow up of subject in consultation with gene therapy experts, study investigators, HIV 
physicians, FDA and NIH. 
11.10.2 
Testing for RCL in Clinical Studies 
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 Vesicular Stomatitis Virus G protein (VSV-G) that is necessary for 
the assembly of pseudotyped infectious lentiviral particles but absent from the vector’s backbone.  RCL 
testing and monitoring will take place on: 
1. 
The cell product, whereby RCL testing will be performed by or under the direction of the 
manufacturing facility responsible for manufacturing and release of the vector. 
2. 
Patient’s PBMCs will be collected prior to infusion of transduced T cells and then at 3, 6, and 12 
months post treatment.  If these tests are negative at all time points during the first year, PBMC 
samples will be collected annually and archived for up to 15 years post infusion or until 
assessments for persistence have ended (Section 11.10.4.1); however, if VSV-G DNA copies are 
detected at any time point in the first year post-infusion, the safety monitoring protocol 
(Section 11.10.311.10.3) will be triggered.  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, then 

 
 
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subject samples will be collected annually until year 15 and archived at Adaptimmune’s centralized 
biomarker repository or until assessments for persistence have ended (Section 11.10.4.1). 
11.10.3 
Safety Monitoring Results 
If a positive VSV-G DNA signal is obtained, the Investigator will be informed and the subject scheduled for 
a retest as soon as possible and no later than one month after the initial positive result was reported to 
the Sponsor.  A review by Adaptimmune’s Safety Review Team and Safety Governance Board will take 
place. 
If the second test is positive, infusions for all subjects receiving 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 vector lot will be stopped.  If the test is negative, 
infusions for all subjects can resume. 
11.10.4 
Persistence Testing and Monitoring for Insertional Oncogenesis 
Monitoring for insertional oncogenesis follows the recommendations set forth in the FDA and EMA 
guidance [FDA, 2006a; FDA, 2006b; EMA, 2009].  Insertional oncogenesis is a theoretical risk in T cells 
transduced with a lentiviral vector.  T cells appear resistant to transformation by integrating viruses 
[Cattoglio, 2010; Newrzela, 2008].  However, there are cases of oncogenesis with γ-retroviral transduced 
stem cells.  Four  of nine subjects with X-linked severe combined immunodeficiency (SCID-X1) treated with 
retrovirus transduced stem cells were found to have insertion near the LMO2 proto-oncogene promoter, 
leading to aberrant transcription and expression of LMO2 which resulted in acute T-cell lymphoblastic 
leukemia [Hacein-Bey-Abina, 2003; Hacein-Bey-Abina, 2014].  Additionally, two subjects treated for X-
linked chronic granulomatous disease (X-CGD) with retroviral transduced stem cells demonstrated 
insertional activation of the EVI1 transcription factor which resulted in genetic instability, monosomy 7 
and clonal progression toward myelodysplasia [Stein, 2010]. 
11.10.4.1 Testing for Persistence of Gene Marked Cells in Clinical Studies 
Peripheral blood mononuclear cell (PBMCs) samples will be collected and used as the “surrogate sample” 
for monitoring persistence of gene modified cells in subjects prior to infusion of transduced T cells and at 
3, 6 and 12 months post-infusion, then every 6 months until 5 years post-infusion and every year from 
year 6 post infusion in accordance with the FDA and EMA guidance [FDA, 2006a; FDA, 2006b; EMA, 2009].  
The samples will be tested using a PCR-based method to detect the presence of the Psi gene, 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 
the vector sequence, the subject’s PBMCs will be evaluated for integration site analysis (see 
Section 11.10.4.2).  If no gene modified cells are detected for three consecutive assessments post-
infusion, and the subject is more than 5 years post-infusion, no further monitoring of PBMCs is required 

 
 
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and collection of samples for persistence may be stopped.  All other assessments such as RCL, hematology 
and chemistry may also be stopped.  The subject will continue to be followed by the Investigator, local 
oncologist or local physician by phone call or survey for up to 15 years post-infusion. 
11.10.4.2 Testing for Insertional Oncogenesis 
If persistence, as detected by the presence of a vector sequence (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 integration site 
analysis.  Integration site analysis will also assess the possibility of insertional oncogenesis. 
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 analysis demonstrates: 1) persistent monoclonality, 2) evidence of insertional oncogenesis or 3) 
clonal expansion, there will be a review by Adaptimmune’s Safety Review Team and Safety Governance 
Board to develop a monitoring plan specific to the health care risk, and/or strategies to inform appropriate 
subjects, investigators, and regulators of the findings.  If the integration site analysis indicates 
polyclonality of the genetically modified T cell population, then screening will continue as scheduled. 
 
 

 
 
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12 Administration 
12.1 Data Handling and Record Keeping  
12.1.1 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
It is the responsibility of the investigator and the study staff to maintain a comprehensive and centralized 
filing system of all relevant study documentation. Such documentation includes: 
1. eCRFs: must be kept accurate and up-to-date. 
2. Subject Files/Signed Informed Consent: which substantiates the data entered in the EDC system for 
all required test and evaluation procedures and verifies that the subject has signed an informed 
consent to enter the study prior to any study-related procedures being performed. 
3. Subject Exclusion Record: which should reflect the reason any subject was screened and found 
ineligible for the study.  
4. Monitoring Log: listing dates of monitor visits. 
5. Regulatory Documents: including, but not limited to, protocol and signature form, IB, FDA Form 1572, 
Financial DisclosureForm, laboratory certification and accreditations, laboratory normal ranges, CVs, 
IRB/IEC correspondence, IRB/IEC approval/renewals, IRB/IEC approved consent form, etc. 
6. SAE Report Forms: which should document any SAEs. 
12.1.2 Case Report Forms 
The study case report form (CRF/eCRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded within the timeframe established by contract of subjects’ visit.  In 
case of an SAE, the data must be recorded immediately.  All missing data must be explained.  
12.1.3  Records Retention 
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. 

 
 
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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. 
12.2 Departure from the Protocol 
There should be no departure from the protocol if at all possible. If an emergency occurs that requires 
departure from this protocol, the investigator will, if circumstances and time permit, contact the Sponsor. 
Such contacts will be made to permit a decision as to whether or not the subject will continue in the study. 
Such departures need to be clearly documented and reported to the IRB/IEC by the investigator. 
12.3 Study Monitoring Plan 
This study will be monitored according to the monitoring plan. The investigator will allocate adequate 
time for such monitoring activities. The Investigator will also ensure that the monitor or other compliance 
or quality assurance reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g., pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
 
 

 
 
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13 REGULATORY AND ETHICAL CONSIDERATIONS 
13.1 Confidentiality of Data 
Data generated by this study will be considered confidential by the investigator under the terms 
expressed in the clinical trials agreement between the Sponsor and each Investigator. 
13.2 Confidentiality of Subject/Patient Records 
By signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR representative), 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), or Regulatory Agency 
representatives may consult and/or copy study documents in order to verify worksheet/case report 
form data.  By signing the consent form, the subject/patient agrees to this process.  If study documents 
will be photocopied during the process of verifying worksheet/case report form information, the 
subject/patient will be identified by unique code only; full names/initials will be masked prior to 
transmission to SPONSOR. 
 
By signing this protocol, the investigator agrees to treat all patient data used and disclosed in connection 
with this study in accordance will all applicable privacy laws, rules and regulations, including all 
applicable provisions of the Health Insurance Portability and Accountability Act and its implementing 
regulations, as amended from time to time. (“HIPAA”). 
13.3 Compliance with law, audit, and debarment 
By signing this protocol, the investigator agrees to conduct the study in an efficient and diligent manner 
and in conformance with this protocol; generally accepted standards of Good Clinical Practices; and all 
applicable federal, state and local laws, rules and regulations relating the conduct of the clinical study. 
 
The investigator also agrees to allow monitoring, audits, Institutional Review Board/Independent Ethics 
Committee Review, and regulatory agencies inspection of trial related documents and procedures and 
provide for direct access all study-related source data and documents.  
 
The investigator agrees not to intentionally seek reimbursement from subjects/patients, their insurance 
providers, or from government programs for procedures included as part of the study reimbursed to the 
investigator by the SPONSOR.  
 
The investigator shall prepare and maintain complete and accurate study documentation in compliance 
with Good Clinical Practice standards and applicable federal, state, and local laws, rules and regulations. 
Following reasonable notice by Sponsor, study documentation will be promptly and fully disclosed to the 
SPONSOR by the investigator upon request for each subject/patient participating in the study, and upon 
completion or termination of the clinical study and as required by this protocol or as otherwise required 
pursuant to any agreement with the SPONSOR, or requirements from regulatory agencies.  In addition, 
this information shall be made available at the investigator’s site upon request and for inspection, 
copying, review, and audit at reasonable times by representatives of the SPONSOR or any regulatory 

 
 
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agencies.  The investigator agrees to promptly take any reasonable steps that are requested by the 
SPOSNOR as a result of an audit to cure deficiencies in the study documentation and worksheets/case 
report forms. 
 
International Conference of Harmonization Good Clinical Practice guidelines recommend that the 
investigator inform the subject’s primary physician about the subject’s participation in the study if the 
subject has a primary physician and if the subject agrees to the primary physician being informed. 
 
The investigator will promptly inform the SPONSOR of any regulatory agency inspection conducted for 
this study.  
 
Persons debarred from conducting or working on clinical studies by any court or regulatory agency will 
not be allowed to conduct work on this SPONSOR’s study.  The investigator will immediately disclose in 
writing to the SPONSOR if any person who is involved in conducting the study is debarred or if any 
proceeding for debarment is pending or, to the best of the investigator’s knowledge, threatened.  
 
In the event the SPONSOR prematurely terminates a particular study site, the SPONSOR will promptly 
notify the site’s IRB/IEC.  
13.4 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. 
13.5 Subject Stipends or Payments 
Stipends or payments to subjects are as dictated by the site level contracts and IRB/EC approved consent 
forms. 
13.6 Ethical Considerations 
 This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct. The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study. The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. The consent 

 
 
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form will be submitted with the protocol for review and approval by the EC/IRB for the study. The formal 
consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure. The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent. 
13.7 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. 
13.8 Clinical Study Report 
The results of the study will be presented in an integrated Clinical Study Report (CSR) according to ICH 
guideline E3: Structure and Content of Clinical Study Reports. 
13.9 Publication Policy 
The Investigator may not submit the results of the study for publication or present the results of the 
study without the prior written agreement of the Sponsor in accordance with the Clinical Trial 
Agreement.  The results of this study will be published as a whole once all subjects have completed the 
study and the study results have been analyzed.  Interim publications of data from the study may be 
made if mutually agreed between the Sponsor and the Investigators.  Agreement will not be provided by 
the Sponsor where in the Sponsor’s view interim publications would introduce bias or lead to any 
misrepresentation or inaccuracies in data. 
Authorship will be determined in conformance with the International Committee of Medical Journal 
Editors (ICMJE) guidelines and/or publication guidelines if applicable. 
 
 

 
 
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14 APPENDICES 
Appendix A: Sample Patient Letter for Long Term Follow-Up 
[date] 
[name and address] 
Dear [patient name], 
You have participated in a clinical research study that requires the study doctors and nurses to monitor 
your health for 15 years. In addition to the semi-annual and annual visits you will be attending, we would 
like for you to report certain events listed below to your study doctor or nurse if they occur: 
1. Your doctor tells you that you have been diagnosed with any new type of cancer, including blood 
disorders such as leukemia or lymphoma (this would be separate from your diagnosis of ovarian 
cancer). 
2. You develop loss of feeling in any part of your body, especially hands and feet; you develop a loss of 
control of any body part (e.g., arms, legs); you have a seizure; you experience memory loss. In 
addition, if you experience a worsening of any of the symptoms listed, please contact your study nurse 
or doctor. These types of symptoms are called neurological disorders. If your primary doctor or 
specialist tells you that you have developed neurological symptoms, contact your study doctor or 
nurse. 
3. You develop arthritis or autoimmune disease, or worsening of any previously experienced arthritis or 
autoimmune disease which you were experiencing prior to participation in the study. If you are 
experiencing symptoms of arthritis or have been told by your doctor that you have an autoimmune 
disease, contact your study doctor or nurse. 
If you experience any of these events, please contact your study physician or the study nurse listed 
below as soon as you can. They may ask you questions about your health and will record your 
symptoms/disease and then monitor your health if they decide that it is necessary. When you call, 
please mention the protocol number of your study which is #(XXXXXX), or the brief study title which is   
“A Phase I/IIa, Open Label, Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells 
Expressing Enhanced TCRs Specific for NY-ESO-1 in Patients with Recurrent or Treatment Refractory 
Ovarian Cancer” 
”. Your patient identification number under this protocol is (XXX). 
Study Coordinator: 
Name: 
Address: 
Phone: 
Email: 
If you have any questions about this letter or the follow up procedures for the study itself, please do not 
hesitate to contact the above study nurse or doctor. 
Thank you for your continued participation in our clinical research study. 
 [study coordinator] 

 
 
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Appendix B : Draft Physician Letter 
 
[date] 
[name and address] 
Dear [physician name], 
 
 
Your patient [patient name] has participated in a clinical research study that requires 15 year monitoring 
for adverse events. To aid in reporting of adverse events that are possible related to the clinical research 
study, we are asking the patients on our research study to designate a primary care or infectious disease 
physician that may help in the monitoring and reporting of adverse events. Your patient has designated 
you. If upon any of your visits with your patient, any of the following events are reported or discovered, 
please contact the study nurse or physician as soon as possible: 
1. New malignancies 
2. New incidence of exacerbation of a pre-existing neurologic disorder 
3. New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
4. New incidence of a hematologic disorder. 
If your patient experiences any of these events, please contact the study coordinator below as soon as 
you can so that they can record the event and then monitor your patient’s health if necessary. When you 
call, remember to mention the protocol number of the study which is #(XXXXXX), patient ID (XXX) and the 
study title which is “A Phase I/IIa, Open Label, Clinical Trial Evaluating the Safety and Efficacy of 
Autologous T Cells Expressing Enhanced TCRs Specific for NY-ESO-1 in Patients with Recurrent or 
Treatment Refractory Ovarian Cancer 
Study Coordinator: 
Name: 
Address: 
Phone: 
Email: 
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 coordinator] 
 
 
 

 
 
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Appendix C: Long Term Follow Up 
Long Term Follow Up – Years 1-5 
Assessment 
Every 6 months 
Annually 
Physical Exam 
X 
  
Medical History 
X 
  
Concomitant Meds 
X 
  
AE Collection (only delayed AEs 
related to gene transfer are 
captured) 
X 
  
Chemistries 
X 
  
CBC 
X 
  
Cell collection for RCL archive 
  
X 
Persistence of Vector Sequences 
X 
  
Long Term Follow Up – Years 6-15 
Assessment 
Annual office visits if vector 
modified cells were detected 
in the previous visit.  If yes, 
RCL testing (archive) is 
collected 
If vector modified cells were 
not detected, follow up can 
be conducted by means of 
clinical questionnaire 
thorough an annual phone 
call or postcard 
Physical Exam 
X 
  
Medical History 
X 
  
Concomitant Meds 
X 
  
AE Collection (only delayed AEs 
related to gene transfer are 
captured) 
X 
X 
Chemistries 
X 
  
CBC 
X 
  
Persistence of Vector Sequences 
X 
  
Interview 
  
X 

 
 
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Appendix D:  Tocilizumab Drug Information 
 
Initial U.S. Approval: 2013 
 
U.S. BRAND NAMES: ACTEMRA® (tocilizumab) 
 
ADMINISTRATION:  Injection, for intravenous infusion 
 
ADVERSE REACTIONS: Most common adverse reactions (incidence ≥ 5%): upper respiratory tract 
infections, nasopharyngitis, headache, hypertension, increased ALT. 
 
WARNINGS AND PRECAUTIONS 
 
Serious Infections 
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, 
or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents 
including ACTEMRA for rheumatoid arthritis. The most common serious infections included pneumonia, 
urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. 
Among 
opportunistic 
infections, 
tuberculosis, 
cryptococcus, 
aspergillosis, 
candidiasis, 
and 
pneumocystosis were reported with ACTEMRA. Other serious infections, not reported in clinical studies, 
may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with 
disseminated rather than localized disease, and were often taking concomitant immunosuppressants such 
as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to 
infections. 
 
ACTEMRA should not be administered in patients with an active infection, including localized infections. 
The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients: 
• with chronic or recurrent infection; 
• who have been exposed to tuberculosis; 
• with a history of serious or an opportunistic infection; 
• who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or 
• with underlying conditions that may predispose them to infection. 
 
Patients should be closely monitored for the development of signs and symptoms of infection during and 
after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to 
suppression of the acute phase reactants.   
 
ACTEMRA should be interrupted if a patient develops a serious infection, an opportunistic infection, or 
sepsis. A patient who develops a new infection during treatment with ACTEMRA should undergo a prompt 
and complete diagnostic workup appropriate for an immunocompromised patient, appropriate 
antimicrobial therapy should be initiated, and the patient should be closely monitored. 

 
 
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Tuberculosis 
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating 
ACTEMRA. Anti-tuberculosis therapy should also be considered prior to initiation of ACTEMRA in patients 
with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be 
confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for 
tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is 
recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an 
individual patient. Patients should be closely monitored for the development of signs and symptoms of 
tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating 
therapy. It is recommended that patients be screened for latent tuberculosis infection prior to starting 
ACTEMRA. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients 
with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating 
ACTEMRA. 
 
Viral Reactivation 
Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes 
zoster exacerbation were observed in clinical studies with ACTEMRA. No cases of Hepatitis B reactivation 
were observed in the trials; however patients who screened positive for hepatitis were excluded. 
 
 
Gastrointestinal Perforations 
Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of 
diverticulitis. ACTEMRA should be used with caution in patients who may be at increased risk for 
gastrointestinal perforation. Patients presenting with new onset abdominal symptoms should be 
evaluated promptly for early identification of gastrointestinal perforation. 
 
Laboratory Parameters 
 
Neutrophils 
Treatment with ACTEMRA was associated with a higher incidence of neutropenia. Infections have been 
uncommonly reported in association with treatment-related neutropenia in long-term extension studies 
and postmarketing clinical experience.  It is not recommended to initiate ACTEMRA treatment in patients 
with a low neutrophil count i.e., absolute neutrophil count (ANC) <2000/mm3. In patients who develop 
an absolute neutrophil count <500/mm3 treatment is not recommended. Neutrophils should be 
monitored every 4 to 8 weeks.   
 
Platelets 
Treatment with ACTEMRA was associated with a reduction in platelet counts. Treatment-related 
reduction in platelets was not associated with serious bleeding events in clinical trials. It is not 
recommended to initiate ACTEMRA treatment in patients with a platelet count below 100,000/mm3. In 
patients who develop a platelet count <50,000/mm3 treatment is not recommended. Platelets should be 
monitored every 4 to 8 weeks.  

 
 
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Liver Function Tests 
Treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. These 
elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials. 
Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs 
(e.g., MTX) were used in combination with ACTEMRA. In one case, a patient who had received ACTEMRA 
8 mg/kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x 
ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with ACTEMRA. 
Transaminases normalized when both treatments were held, but elevations recurred when MTX and 
ACTEMRA were restarted at lower doses. Elevations resolved when MTX and ACTEMRA were 
discontinued. It is not recommended to initiate ACTEMRA treatment in patients with elevated 
transaminases ALT or AST > 1.5x ULN. In patients who develop elevated ALT or AST > 5x ULN treatment is 
not recommended. ALT and AST levels should be monitored every 4 to 8 weeks. When clinically indicated, 
other liver function tests such as bilirubin should be considered.  
 
Lipids 
Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, 
triglycerides, LDL cholesterol, and/or HDL cholesterol.  Assessment of lipid parameters should be 
performed approximately 4 to 8 weeks following initiation of ACTEMRA therapy, then at approximately 6 
month intervals.  Patients should be managed according to clinical guidelines [e.g., National Cholesterol 
Educational Program (NCEP)] for the management of hyperlipidemia. 
 
Immunosuppression 
The impact of treatment with ACTEMRA on the development of malignancies is not known but 
malignancies were observed in clinical studies.  ACTEMRA is an immunosuppressant, and treatment with 
immunosuppressants may result in an increased risk of malignancies. 
 
Hypersensitivity Reactions 
Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with infusion 
of ACTEMRA.  Appropriate medical treatment should be available for immediate use in the event of an 
anaphylactic reaction during administration of ACTEMRA. 
 
Demyelinating Disorders 
The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis 
and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies. Patients 
should be closely monitored for signs and symptoms potentially indicative of demyelinating disorders. 
Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or 
recent onset demyelinating disorders. 
 
Active Hepatic Disease and Hepatic Impairment 
Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic 
impairment.  

 
 
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Vaccinations 
Live vaccines should not be given concurrently with ACTEMRA as clinical safety has not been established. 
No data are available on the secondary transmission of infection from persons receiving live vaccines to 
patients receiving ACTEMRA. No data are available on the effectiveness of vaccination in patients 
receiving ACTEMRA. Because IL-6 inhibition may interfere with the normal immune response to new 
antigens, patients should be brought up to date on all recommended vaccinations, except for live vaccines, 
prior to initiation of therapy with ACTEMRA. 
 
MECHANISM OF ACTION -- Tocilizumab binds specifically to both soluble and membrane-bound IL-6 
receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signalling through these 
receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- 
and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse 
physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of 
hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and 
differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in 
joints affected by inflammatory processes such as rheumatoid arthritis. 
 

 
 
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Appendix E:  Cyclophosphamide: Drug Information 
 
Copyright 1978-2009 Lexi-Comp, Inc. All rights reserved. 
 
U.S. BRAND NAMES — Cytoxan® 
 
PHARMACOLOGIC CATEGORY 
Antineoplastic Agent, Alkylating Agent 
 
ADMINISTRATION:  I.V. infusions may be administered over 1-24 hours. 
Doses >500 mg to approximately 2 g may be administered over 20-30 minutes. 
To minimize bladder toxicity, increase normal fluid intake during and for 1-2 days after 
cyclophosphamide dose. Most adult patients will require a fluid intake of at least 2 L/day. High-dose 
regimens should be accompanied by vigorous hydration with or without mesna therapy. 
 
ADVERSE REACTIONS SIGNIFICANT 
Greater than 10%: 
Dermatologic: Alopecia (40% to 60%) but hair will usually regrow although it may be a different color 
and/or texture. Hair loss usually begins 3-6 weeks after the start of therapy. 
Endocrine & metabolic: Fertility: May cause sterility; interferes with oogenesis and spermatogenesis; 
may be irreversible in some patients; gonadal suppression (amenorrhea) 
Gastrointestinal: Nausea and vomiting occur more frequently with larger doses, usually beginning 6-10 
hours after administration; anorexia, diarrhea, mucositis, and stomatitis are also seen 
Genitourinary: Severe, potentially fatal acute hemorrhagic cystitis, believed to be a result of chemical 
irritation of the bladder by acrolein, a cyclophosphamide metabolite, occurs in 7% to 12% of patients 
and has been reported in up to 40% of patients in some series. Patients should be encouraged to drink 
plenty of fluids during therapy (most adults will require at least 2 L/day), void frequently, and avoid 
taking the drug at night. With large I.V. doses, I.V. hydration is usually recommended. The use of mesna 
and/or continuous bladder irrigation is rarely needed for doses <2 g/m2. 
Hematologic: Thrombocytopenia and anemia are less common than leukopenia. Onset: 7 days, Nadir: 
10-14 days, Recovery: 21 days 
From 1% to 10%: 
Cardiovascular: Facial flushing 
Central nervous system: Headache 
Dermatologic: Skin rash 
Renal: SIADH may occur, usually with doses >50 mg/kg (or 1 g/m2); renal tubular necrosis, which usually 
resolves with discontinuation of the drug, is also reported 
Respiratory: Nasal congestion occurs when I.V. doses are administered too rapidly (large doses via 30-60 
minute infusion); patients experience runny eyes, rhinorrhea, sinus congestion, and sneezing during or 
immediately after the infusion. If needed, a decongestant or decongestant/antihistamine (eg, 
pseudoephedrine or pseudoephedrine/triprolidine) can be used to prevent or relieve these symptoms. 

 
 
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Less than 1% (Limited to important or life-threatening): High-dose therapy may cause cardiac 
dysfunction manifested as CHF; cardiac necrosis or hemorrhagic myocarditis has occurred rarely, but 
may be fatal. Cyclophosphamide may also potentiate the cardiac toxicity of anthracyclines. Other 
adverse reactions include anaphylactic reactions, darkening of skin/fingernails, dizziness, hemorrhagic 
colitis, hemorrhagic ureteritis, hepatotoxicity, hyperuricemia, hypokalemia, jaundice, neutrophilic 
eccrine hidradenitis, radiation recall, renal tubular necrosis, secondary malignancy (eg, bladder 
carcinoma), Stevens-Johnson syndrome, toxic epidermal necrolysis; interstitial pneumonitis and 
pulmonary fibrosis are occasionally seen with high doses 
 
BMT: 
Cardiovascular: Heart failure, cardiac necrosis, pericardial tamponade 
Endocrine & metabolic: Hyponatremia 
Hematologic: Methemoglobinemia 
Gastrointestinal: Severe nausea and vomiting 
Miscellaneous: Hemorrhagic cystitis, secondary malignancy 
 
MECHANISM OF ACTION — Cyclophosphamide is an alkylating agent that prevents cell division by cross-
linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. 
Cyclophosphamide also possesses potent immunosuppressive activity. Cyclophosphamide is a prodrug 
that must be metabolized to active metabolites in the liver. 
 
 
 

 
 
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Appendix F: Mesna: Drug Information 
 
Copyright 1978-2009 Lexi-Comp, Inc. All rights reserved. 
 
U.S. BRAND NAMES — Mesnex® 
 
PHARMACOLOGIC CATEGORY 
Antidote; Uroprotectant 
 
ADMINISTRATION:  For IV administration, the required dose of mesna should be withdrawn from the 
multidose vial labeled as containing 100 mg/mL and diluted with an appropriate volume of a compatible 
IV solution (i.e., 5% dextrose; 5% dextrose and 0.2, 0.33, or 0.45% sodium chloride; 0.9% sodium 
chloride; lactated Ringer’s) to obtain a solution containing 20 mg/mL. The diluted solution may then be 
given by direct IV injection or infused IV over a period of 15–30 minutes.  
 
ADVERSE REACTIONS SIGNIFICANT 
Mesna monotherapy: Headache, injection site reactions, flushing, dizziness, nausea, vomiting, 
somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, coughing, 
constipation, flatulence, rhinitis, rigors, back pain, rash, conjunctivitis, arthralgia.  
 
Mesna alone (frequency not defined): 
Cardiovascular: Flushing 
Central nervous system: Dizziness, fever, headache, hyperesthesia, somnolence 
Dermatologic: Rash 
Gastrointestinal: Anorexia, constipation, diarrhea, flatulence, nausea, taste alteration/bad taste (with 
oral administration), vomiting 
Local: Injection site reactions 
Neuromuscular: Arthralgia, back pain, rigors 
Ocular: Conjunctivitis 
Respiratory: Cough, pharyngitis, rhinitis 
Miscellaneous: Flu-like syndrome 
 
Mesna alone or in combination: Post-marketing and/or case reports: Allergic reaction, anaphylactic 
reaction, hypersensitivity, hyper-/hypotension, injection site erythema, injection site pain, limb pain, 
malaise, myalgia, platelets decreased, ST-segment increased, tachycardia, tachypnea, transaminases 
increased 
 
MECHANISM OF ACTION — In blood, mesna is oxidized to dimesna which in turn is reduced in the 
kidney back to mesna, supplying a free thiol group which binds to and inactivates acrolein, the urotoxic 
metabolite of ifosfamide and cyclophosphamide 
 

 
 
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Appendix G: Fludarabine: Drug Information 
 
U.S. BRAND NAMES — Fludara® 
 
Availability: Fludarabine monophosphate is commercially available and will be supplied by the pharmacy 
of the enrolling institution. FLUDARA IV, is supplied as a white, lyophilized powder. Each vial contains 50 
mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH. Fludara is stored 
at room temperature. 
 
Storage and Stability: Reconstituted FLUDARA IV is chemically and physically stable for 24 hours at room 
temperature, or for 48 hours if refrigerated. Because reconstituted FLUDARA IV contains no 
antimicrobial preservative, care must be taken to assure the sterility of the prepared solution; for this 
reason, reconstituted FLUDARA IV should be used or discarded within 8 hours.  
 
Preparation: FLUDARA IV should be prepared for parenteral use by aseptically adding Sterile Water for 
Injection, USP. When reconstituted with 2 ml of Sterile Water for Injection, each ml of the resulting 
solution will contain 25 mg of Fludarabine Phosphate, 25 mg of mannitol, and sodium hydroxide to 
adjust the pH to 7-8.5. The product may be further diluted for intravenous administration in 50 ml of 5% 
Dextrose for Injection USP, or in 0.9% Sodium Chloride, USP. 
 
Administration: Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Fludarabine will be mixed in 50 ml of 0.9% NaCl, and infused i.v. 
over 30 minutes. 
 
Toxicity: Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, nausea, 
vomiting, stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin rashes, myalgias, 
headache, agitation, hearing loss, transient episodes of somnolence and fatigue, autoimmune hemolytic 
anemia, autoimmune thrombocytopenia, paresthesias, peripheral neuropathy, renal, and pulmonary 
toxicity (interstitial pneumonitis). Severe fatal CNS toxicity presenting with loss of vision and progressive 
deterioration of mental status has occurred after very high doses (approximately 4 times higher than the 
standard doses employed in this protocol). Severe neurologic toxicity has only rarely been demonstrated 
at the 25-30 mg/m2/day dosage of fludarabine. Rarely describe complications include transfusion-
associated graft-versus-host disease, thrombotic thrombocytopenic purpura, and liver failure. Tumor 
lysis syndrome following fludarabine administration has been observed, especially in patients with 
advanced bulky disease. Opportunistic infections (protozoan, viral, fungal, and bacterial) have been 
observed post-fludarabine, especially in heavily pre-treated individuals, and in individuals receiving 
fludarabine combined with other agents.  
 
Note: Investigators should refer to manufacturer prescribing information on each drug for full details on 
safety and administration.  
 

 
 
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Appendix H: Summary of Changes from Protocol Version 6 to Version 7 
 
Section of Protocol 
Version 6 
Section of Protocol 
Version 7 
Change 
Table of Contents 
Table of Contents 
Updated for current version 
NA 
1.1.5 
New section added: Rationale for NY-ESO-1 
Threshold 
1.2; 4.1; 5.3 
1.2; 4.1; 5.3 
Text edited to more accurately reflect process 
1.5 
1.5 
Editorial change 
1.4.2; 3.3.1 
1.4.2; 3.3.1 
Study progress updated to reflect current status 
3.1 
3.1 
Inclusion criteria for antigen expression edited to 
change the threshold and reflect standard 
protocol template language as determination of 
positive expression managed by central laboratory  
3.3.4 
3.3.4 
Text edited to reflect current inclusion wording  
4.5.2 
4.5.2 
Additional storage detail added 
5.12 
5.12 
Text edited to more accurately reflect process 
15 
15 
Missing references added 
 
 
 

 
 
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