Conditions: Breast Cancer Cervical Cancer Renal Cancer Melanoma Bladder Cancer
Keywords: Melanoma Immunotherapy Metastatic Cancer Gene Therapy T Cells
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 3
Healthy volunteers: no

Brief summary:
Background:

The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patients white blood cells with a retrovirus that has the gene for anti-MAGE-A3 incorporated in the retrovirus.

Objective:

The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-MAGE A3 cells) cause tumors to shrink and to be certain the treatment is safe

Eligibility:

\- Adults age 18-66 with cancer expressing the MAGE-A3 molecule.

Design:

* Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
* Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti MAGE-A3 cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}
* Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti MAGE-A3 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed description:
Background:

* We have constructed a single retroviral vector that contains both alpha and beta chains of a T cell receptor (TCR) that recognizes the human leukocyte antigen serotype within HLA-A "A" serotype group (HLA-A 01) restricted MAGE-A3 tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.
* In co-cultures with human leukocyte antigen serotype within HLA-A A serotype group (HLA-A 01) and MAGE-A3 double positive tumors, the anti-MAGE-A3- A 01 restricted (anti-MAGE-A3-01) TCR transduced T cells secreted significant amounts of Interferon (IFN)- \>= with high specificity.

Objectives:

Primary objectives:

* Determine a safe dose of administration of autologous T cells transduced with an anti- MAGE-A3 HLA-A 01-restricted TCR (MAGE-A3-01) TCR and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen.
* Determine if this approach will result in objective tumor regression in patients with metastatic cancer expressing MAGE-A3.
* Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are HLA-A 01 positive and 18 years of age or older must have

* Metastatic cancer whose tumors express the MAGE-A3 antigen
* Previously received and have been a non-responder to or recurred following at least one first line treatment for metastatic disease

Patients may not have:

\- Contraindications for high dose aldesleukin administration.

Design:

* Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be transduced with the retroviral vector supernatant encoding the anti-MAGE-A3 HLA-A 01-restricted TCR.
* The study will begin with a phase I dose escalation. After the maximum tolerated dose (MTD) cell dose has been determined, patients will be enrolled into the phase II portion of the trial at the MTD established during the phase I portion of the study. In the phase II portion, patients will be entered into two cohorts: cohort 2a will include patients with metastatic melanoma; cohort 2b will include patients with renal cancer and other types of metastatic cancer.
* Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR gene-transduced PBMC plus intravenous (IV) aldesleukin.
* Patients will undergo complete evaluation of tumor response every 1-6 months until off study criteria are met.
* For each of the two strata evaluated in the phase 2 portion, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled in that stratum.
* For both strata, the objective will be to determine if the treatment regimen is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modes 20% partial response (PR) + complete response (CR) rate (p1=0.20).
* In order to complete the dose escalation phase and both phase II cohorts, a total of up to 20+82=102 patients may be required (20 + 2 strata with a maximum of 41 apiece). Up to 6 patients enrolled at the MTD will count towards the accrual in the appropriate phase II strata if they are evaluable for response and if they would be fully eligible for enrollment in the phase II portion of the trial. Provided that about 4-5 patients per month will be able to be enrolled onto this trial, approximately 2 to 3 years may be needed to accrue the maximum number of required patients.

Arms:
arm 1: Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin arm 2: Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MAGE-A3- A1 transduced peripheral blood lymphocytes (PBL) + high-dose aldesleukin

Interventions: intervention 1: Aldesleukin intervention 2: Fludarabine intervention 3: Cyclophosphamide intervention 4: Anti-MAGE-A3 human leukocyte antigen serotype within HLA-A A serotype group (HLA-A* 01)-restricted T-cell receptor (TCR)
Intervention descriptions: intervention 1: Aldeskeukin 720,000 IU/kg (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses). intervention 2: Days -7 to -3: Fludarabine 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. intervention 3: Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr. intervention 4: Day 0: MAGE-A3-A1 transduced peripheral blood lymphocytes (PBL) will be infused intravenously on the Patient Care Unit over 20-30 minutes.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
1
Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
CC Protocol Number: 14-C-0110 I  
IBC Number: RD-14-III-03 
OSP Number: 1402-1293 
NCT Number: NCT02153905 
Version Date: May 21, 2018 
PROTOCOL TITLE 
A Phase I/II Study of the Treatment of Metastatic Cancer that Expresses MAGE-A3 Using 
Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-A*01-Restricted 
TCR-Gene Engineered Lymphocytes and Aldesleukin 
 
NIH Principal Investigator:  
Steven A. Rosenberg, M.D., Ph.D.  
 
 
 
 
 
Chief of Surgery, Surgery Branch, CCR, NCI 
 
Building 10, CRC, Room 3-3940 
 
9000 Rockville Pike, Bethesda, MD 20892 
 
 
 
 
 
Phone: 240-760-6218; Email: Steven.Rosenberg@nih.gov 
 
Investigational Agent: 
 
 
 
 
 
 
 
 
 
Commercial Agents: Cyclophosphamide, Fludarabine, and Aldesleukin 
 
Drug Name: 
Anti-MAGE-A3 HLA-A*01-Restricted TCR 
IND Number: 
15936 
Sponsor: 
Center for Cancer Research 
Manufacturer: Surgery Branch Cell Production Facility 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
2
PRÉCIS 
Background: 
• We have constructed a single retroviral vector that contains both α and β chains of a T 
cell receptor (TCR) that recognizes the HLA-A*01 restricted MAGE-A3 tumor antigen, 
which can be used to mediate genetic transfer of this TCR with high efficiency.  
• In co-cultures with HLA-A*01 and MAGE-A3 double positive tumors, the anti-MAGE-
A3-A*01 restricted (anti-MAGE-A3-01) TCR transduced T cells secreted significant 
amounts of IFN-γ with high specificity.  
Objectives: 
• Primary objectives:  
o Determine a safe dose of administration of autologous T cells transduced with an 
anti-MAGE-A3 HLA-A*01-restricted TCR (MAGE-A3-01) TCR and aldesleukin to 
patients following a nonmyeloablative but lymphoid depleting preparative regimen. 
o Determine if this approach will result in objective tumor regression in patients with 
metastatic cancer expressing MAGE-A3. 
o Determine the toxicity profile of this treatment regimen. 
Eligibility: 
• Patients who are HLA-A*01 positive and 18 years of age or older must have:  
o Metastatic cancer whose tumors express the MAGE-A3 antigen 
o Previously received and have been a non-responder to or recurred following at least 
one first line treatment for metastatic disease  
• Patients may not have: 
o Contraindications for high dose aldesleukin administration. 
Design: 
• PBMC obtained by leukapheresis will be transduced with the retroviral vector 
supernatant encoding the anti-MAGE-A3 HLA-A*01-restricted TCR.  
• The study will begin with a phase I dose escalation. After the MTD cell dose has been 
determined, patients will be enrolled into the phase II portion of the trial at the MTD 
established during the phase I portion of the study. In the phase II portion, patients will be 
entered into two cohorts: Cohort 2a will include patients with metastatic melanoma; 
Cohort 2b will include patients with renal cancer and other types of metastatic cancer.  
• Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen 
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex 
vivo tumor reactive, TCR gene-transduced PBMC plus IV aldesleukin.  
• Patients will undergo complete evaluation of tumor response every 1-6 months until off 
study criteria are met. 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
3
• For each of the two strata evaluated in the phase II portion, the study will be conducted 
using a phase II optimal design where initially 21 evaluable patients will be enrolled. For 
each of these two arms of the trial, if 0 or 1 of the 21 patients experiences a clinical 
response, then no further patients will be enrolled but if 2 or more of the first 21 
evaluable patients enrolled have a clinical response, then accrual will continue until a 
total of 41 evaluable patients have been enrolled in that stratum.  
• For both strata, the objective will be to determine if the treatment regimen is able to be 
associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a 
modest 20% PR + CR rate (p1=0.20).  
• In order to complete the dose escalation phase and both phase II cohorts, a total of up to 
20+82=102 patients may be required (20 + 2 strata with a maximum of 41 apiece). Up to 
6 patients enrolled at the MTD will count towards the accrual in the appropriate phase II 
strata if they are evaluable for response and if they would be fully eligible for enrollment 
in the phase II portion of the trial. Provided that about 4-5 patients per month will be able 
to be enrolled onto this trial, approximately 2 to 3 years may be needed to accrue the 
maximum number of required patients.  


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
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TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
1 
INTRODUCTION................................................................................................................. 8 
1.1 
Study Objectives ................................................................................................................. 8 
1.1.1 Primary Objectives.......................................................................................................... 8 
1.1.2 Secondary Objective ....................................................................................................... 8 
1.2 
Background and Rationale .................................................................................................. 8 
1.2.1 Surgery Branch Trials of Cell Transfer Therapy Using Transduction of Anti-Tumor 
Antigen TCR Genes into PBL .................................................................................................... 8 
1.2.2 MAGE-A3 as a Target for Cell Transfer Clinical Studies .............................................. 9 
1.2.3 Rationale for Targeting the MAGE-A3 HLA-A*01-Restricted 168-176 Epitope ....... 11 
1.2.4 Safety Considerations ................................................................................................... 12 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 12 
2.1 
Eligibility Criteria ............................................................................................................. 12 
2.1.1 Inclusion Criteria .......................................................................................................... 12 
2.1.2 Exclusion Criteria ......................................................................................................... 14 
2.2 
Screening Evaluation ........................................................................................................ 14 
2.2.1 Within 3 Months Prior to Enrollment ........................................................................... 14 
2.2.2 Within 8 Weeks Prior to Enrollment ............................................................................ 15 
2.2.3 Within 4 Weeks Prior to Enrollment ............................................................................ 15 
2.2.4 Within 14 Days Prior to Enrollment ............................................................................. 15 
2.2.5 Within 7 Days Prior to Enrollment ............................................................................... 15 
2.3 
Registration and Treatment Assignment Procedures ........................................................ 15 
2.3.1 Prior to Registration for this Protocol ........................................................................... 15 
2.3.2 Registration Procedure .................................................................................................. 16 
2.3.3 Treatment Assignment Procedures ............................................................................... 16 
3 
STUDY IMPLEMENTATION .......................................................................................... 16 
3.1 
Study Design ..................................................................................................................... 16 
3.1.1 Performed on 03-C-0277 .............................................................................................. 16 
3.1.2 Treatment Phase ............................................................................................................ 17 
3.1.3 Dose-Limiting Toxicity ................................................................................................ 17 
3.1.4 Phase I – Dose Escalation ............................................................................................. 18 
3.1.5 Phase II Portion ............................................................................................................. 18 
3.1.6 Protocol Stopping Rules ............................................................................................... 18 
3.2 
Drug Administration ......................................................................................................... 19 
3.2.1 Preparative Regimen with Cyclophosphamide and Fludarabine .................................. 19 
3.2.2 Cell Infusion and Aldesleukin Administration ............................................................. 20 
3.2.3 Treatment Schedule ...................................................................................................... 21 


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3.3 
On-Study Evaluations ....................................................................................................... 21 
3.3.1 Within 14 Days Prior to Starting the Preparative Regimen .......................................... 21 
3.3.2 During the Preparative Regimen (Daily) ...................................................................... 22 
3.3.3 After Cell Infusion ........................................................................................................ 22 
3.3.4 During Hospitalization (Every 1-2 Days) ..................................................................... 22 
3.4 
Retreatment ....................................................................................................................... 23 
3.5 
Post-Treatment Evaluation................................................................................................ 23 
3.5.1 Time-Period of Evaluations .......................................................................................... 23 
3.5.2 Scheduled Evaluations .................................................................................................. 23 
3.6 
Criteria for Removal from Protocol Therapy and Off-Study Criteria .............................. 24 
3.6.1 Criteria for Removal from Protocol Therapy................................................................ 24 
3.6.2 Off-Study Criteria ......................................................................................................... 24 
3.6.3 Off Protocol Therapy and Off-Study Procedure ........................................................... 25 
4 
CONCOMITANT MEDICATIONS/MEASURES .......................................................... 25 
4.1 
Infection Prophylaxis ........................................................................................................ 25 
4.1.1 Pneumocystis Jirovecii Pneumonia............................................................................... 25 
4.1.2 Herpes or Varicella Zoster Virus Prophylaxis .............................................................. 25 
4.1.3 Fungal Prophylaxis ....................................................................................................... 25 
4.1.4 Empiric Antibiotics ....................................................................................................... 25 
4.2 
Blood Product Support ...................................................................................................... 26 
4.3 
Other Concomitant Medications to Control Side Effects ................................................. 26 
5 
BIOSPECIMEN COLLECTION ...................................................................................... 26 
5.1 
Samples Sent to Dr. Figg’s Lab ........................................................................................ 26 
5.2 
Samples Sent to Surgery Branch Cell Processing laboratory ........................................... 27 
5.3 
Prior to Chemotherapy Administration ............................................................................. 27 
5.4 
Prior to Cell Infusion ........................................................................................................ 27 
5.5 
Post Cell Infusion Evaluations .......................................................................................... 27 
5.6 
Immunological Testing ..................................................................................................... 27 
5.7 
Monitoring Gene Therapy Trials: Persistence and RCR .................................................. 28 
5.8 
Sample Storage, Tracking and Disposition for SB Cell Processing Laboratory .............. 28 
5.9 
Sample Storage, Tracking and Disposition for Dr. Figg’s Lab ........................................ 29 
5.9.1 Sample Data Collection ................................................................................................ 29 
5.9.2 Sample Storage and Destruction ................................................................................... 29 
6 
DATA COLLECTION AND EVALUATION ................................................................. 30 
6.1 
Data Collection ................................................................................................................. 30 
6.1.1 Exclusions to Routine Adverse Event Recording ......................................................... 30 
6.2 
Data Sharing Plans ............................................................................................................ 31 
6.2.1 Human Data Sharing Plan ............................................................................................. 31 


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6.2.2 Genomic Data Sharing Plan .......................................................................................... 31 
6.3 
Response Criteria .............................................................................................................. 31 
6.3.1 Definitions..................................................................................................................... 31 
6.3.2 Disease Parameters ....................................................................................................... 31 
6.3.3 Methods for Evaluation of Measurable Disease ........................................................... 32 
6.3.4 Response Criteria .......................................................................................................... 33 
6.3.5 Confirmatory Measurement/Duration of Response Confirmation ............................... 34 
6.4 
Toxicity Criteria ................................................................................................................ 35 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN ............................................................................................................................................ 35 
7.1 
Definitions......................................................................................................................... 35 
7.1.1 Adverse Event ............................................................................................................... 35 
7.1.2 Suspected Adverse Reaction ......................................................................................... 35 
7.1.3 Unexpected Adverse Reaction ...................................................................................... 35 
7.1.4 Serious........................................................................................................................... 36 
7.1.5 Serious Adverse Event .................................................................................................. 36 
7.1.6 Disability ....................................................................................................................... 36 
7.1.7 Life-Threatening Adverse Drug Experience ................................................................. 36 
7.1.8 Protocol Deviation (NIH Definition) ............................................................................ 36 
7.1.9 Non-Compliance (NIH Definition) ............................................................................... 36 
7.1.10 
Unanticipated Problem.............................................................................................. 36 
7.2 
NCI-IRB and Clinical Director (CD) Reporting ............................................................... 37 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths . 37 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review ................................. 37 
7.2.3 NCI-IRB Reporting of IND Safety Reports.................................................................. 37 
7.3 
IND Sponsor Reporting Criteria ....................................................................................... 37 
7.3.1 Waiver of Expedited Reporting to CCR ....................................................................... 38 
7.3.2 Reporting Pregnancy ..................................................................................................... 38 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ............................................ 39 
7.4.1 Serious Adverse Event Reports to IBC ......................................................................... 39 
7.4.2 Annual Reports to IBC.................................................................................................. 39 
7.5 
Data and Safety Monitoring Plan ...................................................................................... 40 
7.5.1 Principal Investigator/Research Team .......................................................................... 40 
7.5.2 Sponsor Monitoring Plan .............................................................................................. 40 
7.5.3 Safety Monitoring Committee (SMC) .......................................................................... 41 
8 
STATISTICAL CONSIDERATIONS .............................................................................. 41 
9 
COLLABORATIVE AGREEMENTS.............................................................................. 43 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................ 43 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
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10.1 
Rationale For Subject Selection ........................................................................................ 43 
10.2 
Participation of Children ................................................................................................... 43 
10.3 
Participation of Subjects Unable to Give Consent ............................................................ 43 
10.4 
Evaluation of Benefits and Risks/Discomforts ................................................................. 44 
10.5 
Risks/Benefits Analysis .................................................................................................... 44 
10.6 
Consent Process and Documentation ................................................................................ 44 
10.6.1 
Informed Consent of Non-English Speaking Subjects ............................................. 44 
11 PHARMACEUTICAL INFORMATION ......................................................................... 45 
11.1 
Investigational Regimen ................................................................................................... 45 
11.1.1 
Cell Preparation (Anti-MAGE-A3 HLA-A*01-Restricted Transduced PBL) ......... 45 
11.1.2 
Interleukin-2 (Aldesleukin, Proleukin, Recombinant Human Interleukin 2) ........... 45 
11.1.3 
Fludarabine ............................................................................................................... 46 
11.1.4 
Cyclophosphamide .................................................................................................... 47 
11.2 
Supportive Medications .................................................................................................... 48 
11.2.1 
Mesna (Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891) ...... 48 
11.2.2 
Filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen)
 
48 
11.2.3 
Trimethoprim and Sulfamethoxazole Double Strength (TMP / SMX DS) .............. 48 
11.2.4 
Herpes and Varicella Zoster Virus Prophylaxis........................................................ 49 
11.2.5 
Fluconazole ............................................................................................................... 50 
11.2.6 
Ondansetron Hydrochloride ...................................................................................... 50 
11.2.7 
Furosemide ................................................................................................................ 50 
12 REFERENCES .................................................................................................................... 51 
13 FIGURES, TABLES & APPENDICES ............................................................................ 54 
 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objectives  
• Determine a safe dose of the administration of autologous T cells transduced with an anti-
MAGE-A3 HLA-A*01 restricted (MAGE-A3-01) TCR and aldesleukin to patients 
following a nonmyeloablative but lymphoid depleting preparative regimen. 
• Determine if this approach will result in objective tumor regression in patients with 
metastatic cancer expressing MAGE-A3. 
• Determine the toxicity profile of this treatment regimen. 
1.1.2 Secondary Objective 
• Determine the in vivo survival of TCR gene-engineered cells. 
1.2 
BACKGROUND AND RATIONALE 
Studies in experimental animals have demonstrated that the cellular rather than the humoral arm 
of the immune response plays the major role in the elimination of murine tumors. Much of this 
evidence was derived from studies in which the adoptive transfer of T lymphocytes from 
immune animals could transfer resistance to tumor challenge or in some experiments, the 
elimination of established cancer. Thus, most strategies for the immunotherapy of patients with 
cancer have been directed at stimulating strong T cell immune reactions against tumor-associated 
antigens. 
In contrast to antibodies that recognize epitopes on intact proteins, T cells recognize short 
peptide fragments (8-18 amino acids) that are presented on surface class I or II major 
histocompatibility (MHC) molecules and it has been shown that tumor antigens are presented 
and recognized by T cells in this fashion. The molecule that recognizes these peptide fragments 
is the T-cell receptor (TCR). The TCR is analogous to the antibody immunoglobulin molecule in 
that, two separate proteins (the TCR alpha and beta chains) are brought together to form the 
functional TCR molecule. The goal of this protocol is to transfer MAGE-A3 reactive TCR genes 
into normal peripheral blood lymphocytes (PBL) derived from cancer patients and to return these 
engineered cells to patients with the intent of mediating regression of their tumors. 
1.2.1 Surgery Branch Trials of Cell Transfer Therapy Using Transduction of Anti-Tumor 
Antigen TCR Genes into PBL 
We have studied approaches to transduce genes encoding antigen specific TCRs genes into PBL 
as a method to generate large numbers of reactive anti-cancer T cells.   
In earlier studies we treated 24 patients with metastatic melanoma using autologous PBL 
transduced with high-avidity MART-1 F5 TCR following a non-myeolablative chemotherapy(1, 
2). Six patients (25%) achieved an objective partial response though 15 patients developed a 
transient mild anterior uveitis easily reversed by steroid eye drops and ten patients developed 
decreased hearing reversed by middle ear steroid injections. Transient rashes have also been 
seen. We have also conducted a clinical trial with a TCR that recognizes the gp100:154-162 
melanoma peptide(2). This TCR was raised in an HLA-A2 transgenic mouse immunized with 
this peptide15. We treated 21 patients with metastatic melanoma using autologous PBL 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
9
transduced with this gp100 TCR following a non-myeloablative chemotherapy. Four patients 
(19%) achieved an objective partial response. Seven patients developed a transient mild anterior 
uveitis reversed by steroid eye drops and ten patients developed decreased hearing reversed by 
middle ear steroid injections. There were no treatment related deaths in the trial. We are no 
longer using these TCRs in clinical studies. 
As of June 2013, we have performed several additional studies utilizing peripheral blood 
lymphocytes transduced with either TCR or chimeric antigen receptors (CAR) genes targeting 
putative tumor antigens following a non-myeloablative chemotherapy regimen. In protocol 08-C-
0121, 10 0f 19 patients (53%) with metastatic melanoma treated with autologous PBL 
genetically engineered to express an anti-NY-ESO-1 TCR experienced objective responses 
including four patients with complete responses, three of which are ongoing from 24 to 50 plus 
months(3). Similarly, 15 patients with metastatic synovial cell sarcoma also received autologous 
genetically engineered cells expressing the anti-NY-ESO-1 TCR and 10 (67%) experienced 
objective regressions including one ongoing complete regression at five months(3). In study 09-
C-0082, we have recently treated 12 patients with autologous PBL transduced with genes 
encoding an anti-CD19 CAR.  Four of these patients have ongoing complete regressions from 4 
to 19 plus months and five additional patients have ongoing partial responses at 2 to 20 plus 
months. In both of these protocols only patients that have been heavily pre-treated with standard 
therapy have been admitted (early results published in(4, 5)). 
Most toxicities observed in these studies were expected toxicities of the chemotherapy and 
aldesleukin administration. However, in 2 studies, we have observed serious adverse events 
related to the transduced cells. In 09-C-0041 (anti-Her2 CAR transduced PBL), the first patient, 
with metastatic colorectal cancer, was treated with 1010 autologous T cells transduced with the 
retrovirus encoding an anti-Her-2 CAR. This patient developed respiratory distress and died four 
days later. This toxicity was apparently due to a previously unrecognized ability of this CAR to 
recognize Her-2 expressed on lung epithelial cells although the exact explanation for the toxicity 
is not clear(6).  In 09-C-0047 (anti-CEA TCR transduced PBL), all three treated patients 
experienced diarrhea, and colitis and one patient experienced an objective response of liver 
metastases(7). All gastrointestinal side effects resolved in these patients and the patients had 
normal bowel function. Grade 3 diarrhea lasting longer than 72 hours is considered a DLT per 
protocol and this event was observed in two of three patients enrolled in protocol 09-C-0047, 
meeting the criteria for stopping protocol accrual. 
1.2.2 MAGE-A3 as a Target for Cell Transfer Clinical Studies 
Because of our success using the anti-NY-ESO-1 TCR we have explored targeting other cancer-
testes antigens. Cancer testis antigens (CTA) are proteins, which are normally only expressed in 
the placenta and in non-MHC expressing germ cells of testis, yet are aberrantly expressed in 
many tumors; thus CTA may represent ideal targets for tumor immunotherapy. More than 110 
CTA genes or gene families have been identified that are expressed in multiple tumor types(8-
10). These proteins are being vigorously pursued as targets for therapeutic cancer vaccines, and 
TCR based adoptive immunotherapy(11-13). In theory, targeting T cells against tumor associated 
CT antigens might selectively eliminate tumor cells while avoiding toxicity to normal tissue. 
Since the identification of the first human MAGE CT gene in 1991, the number of MAGE family 
genes has grown to over 25 members(14, 15). MAGE-A is a multigene family consisting of 12 
homologous genes, MAGE-A1 to A12 located at chromosome Xq28(10). Genomic clustering, 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
10
restricted expression pattern and single exon open reading frames of the MAGE genes are 
consistent with the possibility that these genes evolved from retrotransposition and subsequent 
duplication(16). The precise function and biological role of MAGE proteins are not completely 
elucidated. However, members of MAGE-A, B and C proteins have been implicated in the 
suppression of p53-dependent apoptosis(17, 18) and MAGE-A3 has been attributed to mediate 
fibronectin-controlled tumor progression and metastasis(19). Expression of CTAs including 
MAGE genes in tumor cells has been attributed to global DNA demethylation and other 
mechanisms that normally silences these genes in somatic cells(20). MAGE-A3 is one of the 
more frequently expressed CT antigens in human tumors, including melanoma(21), non-small 
cell lung carcinoma(22), head and neck squamous cell carcinoma(23), pancreatic cancer(24), 
hepatocellular carcinoma(25), non-Hodgkin lymphoma(26), and multiple myeloma(27). The 
expression of MAGE-A3 has been shown to be higher in more advanced stages of disease, and is 
associated with poor disease prognosis(28-30). Several antigenic peptides that bind to HLA class 
I or class II molecules on tumor cells have been reported(31-37). Because of its high expression 
in a wide array of tumor types, MAGE-A3 was chosen as the target for cancer immunotherapy.  
In a prior study, a high avidity Class I restricted TCR against MAGE-A3 was isolated using a 
transgenic mouse model that expressed the human HLA-A*0201 molecule. A retrovirus 
encoding the alpha and beta chains of this TCR that recognized the Class I restricted MAGE-A3 
epitope (aa112-120) was constructed. Nine cancer patients were treated with adoptive cell 
therapy using autologous anti-MAGE-A3 T-cell receptor (TCR) engineered T cells. Five patients 
experienced clinical regression of their cancers including 2 on-going responders. However, 
postinfusion, 3 patients experienced mental status changes, and of these 2 patients lapsed into 
comas and subsequently died(38). The TCR used in this study recognized epitopes in MAGE-
A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase 
chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was 
expressed in human brain and our TCR recognized an epitope in MAGE-A12 that was similar to 
the MAGE-A3 epitope being targeted. This previously unrecognized expression of MAGE-A12 
in human brain was possibly the initiating event of a TCR-mediated inflammatory response that 
resulted in neuronal cell destruction. There was no evidence of MAGE-A3 expressed in the brain 
by this same nanostring technology nor by deep sequencing of normal tissues.  
In a protocol at the University of Pennsylvania using a TCR that recognized the same HLA-A1 
Class I restricted epitope from MAGE-A3 that we are targeting in this protocol (aa 168-176), 
cardiac toxicity was seen that was attributed to changes introduced into the binding regions of 
the(39) TCR, which added new specificities resulting in cardiac rejection. In that protocol four 
amino acid changes were made in the CDR2 region of the alpha chain which led to the 
recognition of the titin protein. These changes were thought to be the cause of the off target 
toxicity. The unmodified TCR did not recognize titin and these investigators could find no 
MAGE-A3 expression in the heart. Our present study will use an unmodified receptor derived 
from a natural human T cell that has undergone negative selection in the thymus and thus we do 
not expect to see any off target toxicities. 
A Blast research of the NCBI human non-redundant protein sequence database revealed that the 
most closely related members of the MAGE gene family to the MAGE-A3 HLA-A1 epitope 
EVDPIGHLY were MAGE-A6 (EVDPIGHVY), which differed at one residue, and MAGE-A2 
(EVVPISHLY), which differed at two residues from the MAGE-A3 epitope, neither of which 
were recognized by T cells transduced with the MAGE-A3-reactive TCR. The most closely 


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related gene products that were not members of the MAGE gene family, RhoGEF and PH 
domain containing 5 (FDG5: EVGPIFHLY) and activating transcription factor 4 
(ATF4:TVNPIGHLP) differed at two and three positions from the MAGE-A3 epitope, 
respectively. 
Finally, MAGE-A3 has not been found to be expressed in any normal tissue except testis and 
thus the risk of on-target toxicity to normal tissue is minimal. 
1.2.3 Rationale for Targeting the MAGE-A3 HLA-A*01-Restricted 168-176 Epitope  
The [alpha] and [beta] chains encoding functional TCRs were isolated from 2 MAGE-A3-
reactive, HLA-A*01-restricted human T-cell clones, LAU147 CTL1 or 810/A10, referred to 
below as A10 and as 13–18. The A10 TCR expresses AV12–1/BV24–1 and 13–18 expresses 
AV12–3/BV15. 
Retroviral constructs were generated to encode the appropriate TCR [alpha] chain followed by a 
furin cleavage site, an SGSG spacer, the P2A “self-cleaving peptide, and the appropriate TCR 
[beta] chain. Two TCRs recognizing the MAGE-A3-restricted HLA-A*01-restricted epitope 
were designated A10 and 13–18. 
The results of coculture assays carried out with transduced PBMC demonstrated that TCR A10-
transduced T cells generated high levels of IFN-[gamma] in response to the HLA-A*01+/MAGE-
A3+ tumor-cell lines 397 mel, 2984 mel, and 2556 mel and cytokine levels that were between 5 
and 10 times those generated from TCR 13–18-transduced T cells (Figure 1A). The MAGE-A3+ 
but HLA-A*01- cell lines 562, 624, and 2359 mel, as well as the MAGE-A3- but HLA-A*01+ 
renal cancer cell line 2661 RCC, failed to stimulate significant levels of cytokine from either 
TCR A10 or 13–18-transduced T cells (Figure 1A). The levels of cell surface expression of the 
transduced A10 and 13–18 TCRs could not be quantitated due to a lack of detectable staining 
with a specific MAGE-A3:168–176 HLA-A*01 tetramer (data not shown) as well as a lack of 
antibodies against the AV12–1/BV24–1 and AV12–3/BV15 TCR [alpha] and [beta] chains that 
comprised the A10 and 13–18 TCRs, respectively. Nevertheless, the differences in activity of T 
cell transduced with the A10 and 13–18 TCRs did not appear to be due to differences in the 
frequency of transduction with the 2 TCRs, as they were roughly equivalent (Figure 1B). In 
addition, T cells transduced with the A10 TCR-recognized target cells incubated with a 
minimum concentration of 0.5 nM MAGE-A3 168–176 peptides, a 10-fold lower concentration 
than required for recognition by cells transduced with the 13–18 TCR (Figure 1C), indicating 
that the A10 TCR possessed a higher functional avidity than the 13–18 TCR. 
The T cells that were transduced with MAGE-A3-reactive TCR A10 and 13–18 recognized 5 of 
the 6 MAGE-A3+ and HLA-A*01+ fresh tumors (FrTu), FrTu 3178, 2767, 2823, 2830, and 3068, 
but did not recognize either FrTu 2685, an HLA-A*01+ fresh tumor that lacked expression of 
MAGE-A3 or the 3 MAGE-A3+ fresh tumors, FrTu 2181, 3242, and 2803, that lacked 
expression of HLA-A*01 (Figure 2A). The responses to the appropriate fresh tumors were 
relatively low, which may in part have been due to the reduced viability of many of these cells; 
however, the patterns of tumor recognition indicated that T cells transduced with these TCRs 
could mediate specific recognition of these targets. 
Although members of the MAGE-A family possess very similar amino acid sequences, previous 
studies have indicated that T cells recognizing the HLA-A*01-restricted MAGE-A3:168–176 
epitopes failed to recognize similar epitopes expressed by additional MAGE-A family members. 


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In agreement with previous results, T cells transduced with the MAGE-A3-reactive TCR A10 
recognize HLA-A1+ target cells transfected with MAGE-A3 but failed to recognize targets 
transfected with MAGE-A1, A2, A4, A6, A9, A10, or A12 constructs (Figure 3A) that encoded 
peptides that differed at between 1 and 3 positions from the MAGE-A3:170–178 epitope (Table 
1). 
The TCR A10-transduced T cells efficiently lysed the MAGE-A3+, HLA-A*01+ tumor targets 
397 and 2984 mel, whereas lower levels of lysis were observed with TCR 13–18-transduced T 
cells. The TCR A10-transduced and TCR 13–18-transduced T cells failed to lyse either the 
HLA-A*01- MAGE-A3+ target 624 mel or 2661 RCC, an HLA-A*01+ renal cancer cell line that 
lacked expression of MAGE-A3 (results not shown). 
The responses of separated populations of CD8+ and CD4+ T cells transduced with the 2 TCRs to 
tumor cell targets was then evaluated, as high-affinity class I–restricted TCRs possessed 
significant activity in CD4+ T cells. Highly purified CD4+ T cells transduced with TCR A10 
containing fewer than 1% contaminating CD8+ T cells released low but significant levels of IFN-
[gamma] in response to MAGE-A3+ tumor cell line 397 mel and the MAGE-A3+ tumor cell line 
1300A1 mel that was stably transfected with HLA-A*01, whereas CD4+ T cells transduced with 
TCR 13–18 failed to recognize antigen-positive targets (Figure 4). Based on this data we 
selected the TCR A10 for use in this protocol and a GMP retroviral vector was generated. 
1.2.4 Safety Considerations 
Several safety concerns regarding the infusion of large numbers of retrovirally modified tumor 
reactive T-cells have been addressed in our previous clinical studies as described below.  The 
non-myeloablative chemotherapy used in this protocol has been administered to over 300 
patients and all have reconstituted their hematopoietic systems.  
In other protocols we have administered over 3 X 1011 TIL with widely heterogeneous reactivity 
including CD4, CD8, and NK cells without difficulty. We do not believe the transfer of these 
gene modified cells has a significant risk for malignant transformation in this patient population. 
While the risk of insertional mutagenesis is a known possibility using retroviral vectors, this has 
only been observed in the setting of infants treated for XSCID, WAS, and X-CGD using 
retroviral vector-mediated gene transfer into CD34+ bone marrow cells. In the case of retroviral 
vector-mediated gene transfer into mature T-cells, there has been no evidence of long-term 
toxicities associated with these procedures since the first NCI sponsored gene transfer study in 
1989. Although continued follow-up of all gene therapy patients will be required, data suggest 
that the introduction of retroviral vectors transduced into mature T-cells is a safe procedure. 
While we believe the risk of insertional mutagenesis is extremely low, the proposed protocol 
follows all current FDA guidelines regarding testing and follow up of patients receiving gene 
transduced cells. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
a. Metastatic or locally advanced refractory/recurrent cancer that expresses MAGE-A3 as 
assessed by one of the following methods: RT-PCR on tumor tissue defined as 30,000 
copies of MAGE-A3 per 106 GAPDH copies, or by immunohistochemistry of resected 


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tissue defined as 10% or greater of tumor cells being 2-3+ for MAGE-A3, or serum 
antibody reactive with MAGE-A3. Metastatic cancer diagnosis will be confirmed by the 
Laboratory of Pathology at the NCI. 
b. Patients must have previously received prior first line standard therapy (or effective 
salvage chemotherapy regimens) for their disease, if known to be effective for that 
disease, and have been either non-responders (progressive disease) or have recurred. 
c. Patients must be HLA-A*01 positive. 
d. Greater than or equal to 18 years of age and less than or equal to age 70. 
e. Ability of subject to understand and the willingness to sign the Informed Consent 
Document 
f. Willing to sign a durable power of attorney 
g. Clinical performance status of ECOG 0 or 1 
h. Patients of both genders must be willing to practice birth control from the time of 
enrollment on this study and for up to four months after treatment. 
i. Serology:  
• Seronegative for HIV antibody. (The experimental treatment being evaluated in this 
protocol depends on an intact immune system. Patients who are HIV seropositive can 
have decreased immune-competence and thus be less responsive to the experimental 
treatment and more susceptible to its toxicities.)  
• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If 
hepatitis C antibody test is positive, then patient must be tested for the presence of 
antigen by RT-PCR and be HCV RNA negative.  
j. Women of child-bearing potential must have a negative pregnancy test because of the 
potentially dangerous effects of the treatment on the fetus.  
k. Hematology 
• Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim 
• WBC ≥ 3000/mm3 
• Platelet count ≥ 100,000/mm3 
• Hemoglobin > 8.0 g/dl 
l. Chemistry: 
• Serum ALT/AST ≤ to 2.5 times the upper limit of normal 
• Serum creatinine ≤ to 1.6 mg/dl 
• Total bilirubin ≤ to 1.5 mg/dl, except in patients with Gilbert’s Syndrome who must 
have a total bilirubin less than 3.0 mg/dl. 
m. More than four weeks must have elapsed since any prior systemic therapy at the time the 
patient receives the preparative regimen, and patients’ toxicities must have recovered to a 
grade 1 or less (except for toxicities such as alopecia or vitiligo). Patients must have 


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progressing disease after prior treatment. Note: Patients who have previously received 
ipilimumab and have documented GI toxicity must have a normal colonoscopy with 
normal colonic biopsies 
n. Subjects must be co-enrolled in protocol 03-C-0277. 
2.1.2 Exclusion Criteria 
a. Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the treatment on the fetus or infant. 
b. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders 
or any other active major medical illnesses. 
c. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease). 
d. Concurrent opportunistic infections (The experimental treatment being evaluated in this 
protocol depends on an intact immune system. Patients who have decreased immune 
competence may be less responsive to the experimental treatment and more susceptible to 
its toxicities). 
e. Concurrent systemic steroid therapy. 
f. History of severe immediate hypersensitivity reaction to any of the agents used in this 
study. 
g. History of any cardiac events including coronary revascularization or ischemic 
symptoms. 
h. Documented LVEF of less than or equal to 45%; testing is required in patients who are: 
• Age ≥ 65 years’ old 
• Clinically significant atrial and or ventricular arrhythmias including but not limited 
to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or 
have a history of ischemic heart disease, or chest pain. 
i. Patients with CNS metastases or symptomatic CNS involvement (including cranial 
neuropathies or mass lesions).  
j. Patients presenting with lesions that may harbor an occult infectious source. 
k. Documented FEV1 less than or equal to 60% predicted tested in patients with: 
• A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 
years). 
• Symptoms of respiratory dysfunction 
l. Patients who are receiving any other investigational agents. 
2.2 
SCREENING EVALUATION 
Note: Testing for screening evaluation is conducted under our companion protocol, 99-C-0128. 
2.2.1 Within 3 Months Prior to Enrollment 
a. HIV antibody titer and HBsAg determination, anti HCV  


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b. Confirmation of HLA-A*01 positivity. (Note: Testing is permitted to be conducted at any 
time prior to enrollment.) 
c. Confirmation of the diagnosis of cancer and MAGE A3 by the Laboratory of Pathology 
of the NCI. (Note: Testing is permitted to be conducted at any time prior to enrollment.) 
2.2.2 Within 8 Weeks Prior to Enrollment 
a. Pulmonary function testing for patients with a prolonged history of cigarette smoking (20 
pack/year of smoking within the past 2 years) or symptoms of respiratory dysfunction.  
b. Cardiac evaluation (stress thallium, echocardiogram, MUGA etc.,) in patients who are 
greater than or equal to age 65, or have a history of ischemic heart disease, chest pain, or 
clinically significant atrial and/or ventricular arrhythmias including but not limited to: 
atrial fibrillation, ventricular tachycardia, heart block. Patients with a LEVF of less than 
or equal to 45% will not proceed to treatment. Patients under the age of 65 who present 
with cardiac risk factors may undergo cardiac evaluation as noted above (e.g., diabetes, 
hypertension, obesity.) 
2.2.3 Within 4 Weeks Prior to Enrollment  
a. Complete history and physical examination, including weight, vital signs, and noting 
organ system involvement and any allergies/sensitivities to antibiotics. (Note: patient 
history may be obtained within 8 weeks.) 
b. Baseline evaluation to determine the status of disease. This may include CT, MRI, PET, 
or Photography. 
2.2.4 Within 14 Days Prior to Enrollment 
a. Screening blood tests  
• Chemistries: Creatinine, ALT/GPT, AST/GOT, and Total Bilirubin  
• CBC with differential and platelet count 
b. Urinalysis; urine culture, if indicated  
2.2.5 Within 7 Days Prior to Enrollment 
a. β-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
b. ECOG performance status of 0 or 1  
2.3 
 REGISTRATION AND TREATMENT ASSIGNMENT PROCEDURES 
2.3.1 Prior to Registration for this Protocol 
Patients will initially be registered on protocol 03-C-0277 (Cell Harvest and Preparation for 
Surgery Branch Adoptive Cell Therapy Protocols) prior to transduction of PBL cells (either fresh 
or cryopreserved samples), by the clinical fellow or research. Once cells exceed the potency 
requirement and are projected to exceed the minimum number specified in the Certificate of 
Analysis (COA), patients will sign the consent document for this protocol.   


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2.3.2 Registration Procedure 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office at ncicentralregistration-l@mail.nih.gov. 
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol. Verification of Registration will be 
forwarded electronically via e-mail to the research team. A recorder is available during non-
working hours. 
2.3.3 Treatment Assignment Procedures 
2.3.3.1 Cohorts 
Number Name 
Description 
1 
Phase I  
Patients with a MAGE-A3-expressing metastatic or locally advanced 
refractory/recurrent cancer 
2a 
Phase II - 
Melanoma 
Patients with a diagnosis of metastatic melanoma that express 
MAGE-A3 
2b 
Phase II – Renal 
and Other 
Patients with a diagnosis of renal cancer and other types of 
metastatic cancer that express MAGE-A3 
2.3.3.2 Arms 
Number Name 
Description 
1 
Phase I Arm 
Non-myeloablative, lymphodepleting preparative regimen of 
cyclophosphamide and fludarabine + escalating doses of MAGE-A3-A1 
transduced PBL + high-dose aldesleukin 
2 
Phase II Arm 
Non-myeloablative, lymphodepleting preparative regimen of 
cyclophosphamide and fludarabine + MTD of MAGE-A3-A1 
transduced PBL established in Phase I + high-dose aldesleukin 
2.3.3.3 Randomization and Arm Assignment 
This is a non-randomized study. All patients will be directly assigned based on cohort as follows: 
• Subjects in Cohort 1 will be directly assigned to Arm 1. 
• Subjects in Cohorts 2a and 2b will be directly assigned to Arm 2.  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
3.1.1 Performed on 03-C-0277 
PBMC will be obtained by leukapheresis (approximately 1x1010 cells) and cultured in the 
presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. Transduction 
is initiated by exposure of approximately 1x107 to 5x108 cells to supernatant containing the anti-
MAGE-A3 HLA-A*01 retroviral vector. The cells will then be further expanded in vitro prior to 
cell infusion. Successful TCR gene transfer will be tested by cytokine release as measured on 


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peptide pulsed HLA-A*01 cells and gamma-interferon secretion must be at least 200pg/ml and 
twice the background level. 
3.1.2 Treatment Phase 
Prior to receiving the engineered PBL cells, patients will receive a nonmyeloablative but 
lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine 
followed in one to four days by intravenous infusion of MAGE-A3-A1 transduced PBL and 
aldesleukin. Patients will receive no other experimental agents while on this protocol. 
The start date of the course will be the start date of the chemotherapy; the end date will be the 
day of the first post-treatment evaluation. Patients may undergo a second treatment as described 
in Section 3.4. 
Following administration of the cell product, neurological status will be closely monitored and 
urgently managed as described in Section 3.3.3. 
In addition, serum samples will be evaluated in an effort to identify the particular cytokines 
which may contribute to these toxicities. 
3.1.3 Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) is defined as follows:  
• Grade 3-5 allergic reactions related to the study cell infusion 
• Grades 3 and greater autoimmune reactions 
• Grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, 
pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying 
malignancy and occurring within 30 days of study cell infusion and does not resolve 
within 72 hours 
• Treatment-related death within 8 weeks of the study cell infusion 
The exceptions are as follows: 
• Myelosuppression, defined as lymphopenia, neutropenia, decreased hemoglobin, and 
thrombocytopenia, due to the chemotherapy preparative regimen  
• Aldesleukin expected toxicities as defined in Appendix 2 and Appendix 3. 
• Immediate hypersensitivity reactions occurring within 2 hours of cell infusion (related to 
cell infusion) that are reversible to a grade 2 or less within 24 hours of cell administration 
with standard therapy.  
• Expected chemotherapy toxicities as defined in Section 11. 
• Grade 3 Fever 
• Grade 3 Metabolic Laboratory abnormalities without significant clinical sequela that 
resolve to grade 2 within 7 days 
Patients who develop toxicity due to study agents will be followed until toxicity resolves to a 
grade 2 or less, regardless of disease progression.  


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3.1.4 Phase I – Dose Escalation 
Patients will be enrolled beginning with dose level 1. If a DLT is seen in this dose level, the dose 
will be de-escalated as shown in the table below. Initially, the protocol will enroll 1 patient in 
each dose level unless a patient experiences a DLT. The total number of anti-MAGE-A3 HLA-
A*01 engineered PBL cells transferred for each dose level will be: 
Dose Level 
Cell Dose 
De-Escalation 
Level -2d 
108 cells 
Level -1d 
3x108 cells 
Escalation 
Level 1 
109 cells 
Level 2 
3x109 cells 
Level 3 
1010 cells 
Level 4 
3x1010 cells 
Level 5 
1011 cells and up to 2x1011 cells 
In each dose level, if a patient experiences a DLT, a total of six patients will be treated at that 
dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next 
higher level. If a DLT is seen at any dose level, a minimum of 3 patients will be enrolled in 
subsequent dose levels, however, if escalation is permitted until dose level 5, it will be expanded 
to 6 patients unless it has 2 or more DLTs before the sixth patient has been evaluated.  
The maximum tolerated cell dose is the highest dose at which ≤1 of 6 patients experienced a 
DLT or the highest dose level studied if DLTs are not observed at any of the dose levels.  
A two-week safety assessment period following cell administration will be conducted between 
each dose level and before enrollment into the phase II portion of the protocol. 
3.1.5 Phase II Portion 
Similar to the Phase I portion, prior to receiving the engineered PBL cells, patients in the phase 
II portion will receive a nonmyeloablative but lymphocyte depleting preparative regimen 
consisting of cyclophosphamide and fludarabine followed in one to four days by intravenous 
infusion of MAGE-A3-HLA-A01 TCR transduced PBL.  
The phase II portion of the protocol will proceed using from 109 cells up to the MTD as 
determined in the phase I portion of the study. 
In the phase II portion of this study, patients will be entered into two cohorts based on histology: 
Cohort 2a will include patients with metastatic melanoma; Cohort 2b will include patients with 
renal cancer and other types of metastatic cancer. 
3.1.6  Protocol Stopping Rules 
The study will be temporarily halted pending discussions with the FDA and NCI IRB regarding 
safety and the need for protocol revisions if any of the following conditions are met: 


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• If 1 or more treatment related death occur due to the cell infusion, we will promptly 
discuss this with the NCI IRB and the FDA.  
• During the phase I portion of the study- if two or more patients develop a grade 3 or 
greater toxicity related to the cell product with the exception of 
o Grade 3 metabolic laboratory abnormalities without significant clinical sequela that 
resolve to grade 2 or less within 7 days 
o Grade 3 fever  
• If one of the first three patients (or 2 of the first 6 patients, or 3 of the first 9 patients, or 4 
of the first 12 patients) develop grade 3 autoimmunity, that cannot be resolved to less 
than or equal to a grade 2 autoimmune toxicity within 10 days, or any grade 4 or greater 
autoimmune toxicity. 
• During the phase II portion of the study- Once five or more patients have been enrolled, 
if more than 20% of patients cumulatively enrolled have developed a DLT, as described 
in Section 3.1.3. 
3.2 
DRUG ADMINISTRATION 
3.2.1 Preparative Regimen with Cyclophosphamide and Fludarabine 
Starting on day -6, study medication start times for drugs given once daily should be given 
within 2 hours of the scheduled time.  Administration of diuretics, electrolyte replacement, and 
hydration and monitoring of electrolytes should all be performed as clinically indicated. 
Chemotherapy infusions maybe slowed or delayed as medically indicated. 
Days -7 and -6  
Approximately 6 hours Prior to Cyclophosphamide 
Hydrate: Begin hydration with 0.9% Sodium Chloride Injection containing 10 meq/L of 
potassium chloride at 1.5 - 2.6 ml/kg/hr (starting approximately 6 hours pre-cyclophosphamide 
and continue hydration until 24 hours after last cyclophosphamide infusion). At any time during 
the preparative regimen, if urine output <1 ml/kg/hr or if body weight >2 kg over pre-
cyclophosphamide value, furosemide 10-20 mg IV maybe administered. The hydration rate will 
be capped at 250mL/hr. 
Approximately 1 hour pre-Cyclophosphamide  
Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose between 8 mg and 16 mg 
based on patient weight] IV every 8 hours X 3 days) will be given for nausea.  
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 
days over 1 hr. If patient is obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Appendix 1.  
A decreased dose of cyclophosphamide at 30mg/kg/day (x2 days) will be considered for patients 
who have a history of prolonged hematologic recovery from prior chemotherapy treatments. 
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Begin mesna infusion at 3 mg/kg/hour intravenously diluted in a suitable diluent (see Section 11) 
over 23 hours after each cyclophosphamide dose. If patient is obese (BMI > 35) drug dosage will 
be calculated using practical weight as described in Appendix 1.  
Days -7 to -3 
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days. If patient is obese (BMI > 35) 
drug dosage will be calculated using practical weight as described in Appendix 1. (The 
fludarabine will be started approximately 1-2 hours after the cyclophosphamide and mesna on 
Days -7 and -6) 
3.2.2 Cell Infusion and Aldesleukin Administration 
The patient’s PBL is delivered to the patient care unit by a staff member from the Tumor 
Immunology Cell Processing Laboratory. Prior to infusion, the cell product identity label is 
double-checked by two authorized staff (MD or RN), an identification of the product and 
documentation of administration are entered in the patient’s chart, as is done for blood banking 
protocols. The cell dose will be as described in Section 3.1.4 above and will be given over 20-30 
minutes or as clinically determined by an investigator for patient safety via non-filtered tubing, 
gently agitating the bag during infusion to prevent cell clumping.  
Aldesleukin will be administered at a dose of 720,000 IU/kg (based on total body weight) as an 
intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 
hours of cell infusion and continuing for up to 5 days (maximum 15 doses). Doses will be 
preferentially administered every eight hours; however, up to 24 hours may elapse between doses 
depending on patient tolerance. Aldesleukin dosing will be stopped if toxicities are not 
sufficiently recovered with supportive measures within 24 hours of the last dose of aldesleukin. 
Doses will be delayed or stopped if patients reach Grade 3 or 4 toxicity due to aldesleukin except 
for the reversible Grade 3 toxicities common to aldesleukin such as diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes as detailed in Appendix 2. Toxicities will be managed as outlined in 
Appendix 3. In addition, dosing may be held or stopped at the discretion of the treating 
investigator. (Appendix 4 lists the toxicities seen in patients treated with aldesleukin at the NIH 
Clinical Center). Because confusion is a possible side effect of aldesleukin administration, a 
Durable Power of Attorney will be signed by the patient to identify a surrogate to make decisions 
if a patient becomes unable to make decisions. 
Day 0 (one to four days after the last dose of fludarabine) 
 
o Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes 
or as clinically determined by an investigator for patient safety via non-filtered tubing, 
gently agitating the bag during infusion to prevent cell clumping.   
o Aldesleukin as described in Section 3.2.2.  
Days 0-4 (Day 0 is the day of cell infusion)  
o Beginning on day 1 or 2, filgrastim may be administered subcutaneously at a dose of 5 
mcg/kg/day (not to exceed 300 mcg/day). Filgrastim administration will continue daily 
until neutrophil count > 1.0 x109/L X 3 days or > 5.0 x109/L.  
o Aldesleukin as described in Section 3.2.2. 


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3.2.3 Treatment Schedule 
1One to four days after the last dose of fludarabine 
2Initiate within approximately 24 hours after cell infusion 
3Continue until neutrophils count > 1X109/L for 3 consecutive days or > 5x109/L. 
4The TMP/SMX schedule should be adjusted to QD three times per week (Monday, Wednesday, Friday) 
and continue for at least six months and until CD4 > 200 X 2, starting day 0 or within one week of 
anticipated lymphopenia 
5Continue until ANC > 1000/mm3 
6In patients positive for HSV or VZV continue until CD4 > 200 X 2 
3.3 
ON-STUDY EVALUATIONS 
Note: Please refer to Section 5 for research evaluations.  
3.3.1 Within 14 Days Prior to Starting the Preparative Regimen 
• Apheresis as indicated 
• Baseline blood test 
o Acute Care Panel (sodium, potassium, chloride, bicarbonate, creatinine, glucose, 
BUN), Hepatic Panel (alkaline phosphatase, AST, ALT, total bilirubin, direct 
bilirubin), Mineral Panel (albumin, calcium, magnesium, phosphorus), Uric Acid, 
Creatinine Kinase, Lactate Dehydrogenase, Protein, total  
o Complete Blood Count with differential 
o PT/PTT 
o TBNK 
o Thyroid Panel 
o Urinalysis 
Day 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide (60 mg/kg) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Fludarabine (25 mg/m2) 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Anti-MAGE-A3-A1 TCR PBL 
 
 
 
 
 
 
 
X1 
 
 
 
 
Aldesleukin 
 
 
 
 
 
 
 
X2 
X 
X 
X 
X 
Filgrastim3 (5 mcg/kg/day) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
TMP/SMX4 
160mg/800 mg (example) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Fluconazole5 (400 mg po) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Valacyclovir po or Acyclovir IV6 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 


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• Anti CMV antibody titer, HSV and VZV serology, and EBV panel. (may be 
performed within 3 months of chemotherapy) 
• Chest x-ray 
• EKG 
3.3.2 During the Preparative Regimen (Daily) 
• Complete Blood Count with differential 
• Acute Care Panel (sodium, potassium, chloride, bicarbonate, creatinine, glucose, 
BUN), Hepatic Panel (alkaline phosphatase, AST, ALT, total bilirubin, direct 
bilirubin), Mineral Panel (albumin, calcium, magnesium, phosphorus), Uric Acid, 
Creatinine Kinase, Lactate Dehydrogenase, Protein, total 
• Urinalysis as needed 
• Daily weight as indicated 
• PT/PTT (every 3 days) 
3.3.3 After Cell Infusion 
• Vital signs will be monitored hourly (+/- 15 minutes) for four hours and then 
routinely (every 4-6 hours) unless otherwise clinically indicated 
3.3.4 During Hospitalization (Every 1-2 Days) 
• A review of systems and physical exam as clinically indicated 
• CBC with differential 
• Acute Care Panel (sodium, potassium, chloride, bicarbonate, creatinine, glucose, 
BUN), Hepatic Panel (alkaline phosphatase, AST, ALT, total bilirubin, direct 
bilirubin), Mineral Panel (albumin, calcium, magnesium, phosphorus), Uric Acid, 
Creatinine Kinase, Lactate Dehydrogenase, Protein, total 
• Troponin levels on days 4 and 7 and as well as clinically indicated 
• Other tests will be performed as clinically indicated. 
• Neurological evaluations: If the patient experiences a grade 3 or greater neurological 
toxicity the following evaluations will be performed: 
o Neurology Consult – urgent 
o  MRI of the Brain 
o  Lumbar puncture to evaluate transduced cells in the CSF if the platelet count is 
greater than 50,000/mm3 
• Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood 
CD4 count will be drawn weekly (while the patients is hospitalized). Please refer to 
Section 5 for additional post cell infusion evaluations. 
• Vital signs and weight will be monitored as clinically indicated. 


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3.4 
RETREATMENT  
Patients experiencing a partial or complete response may receive a second treatment when 
progression by RECIST criteria is documented after evaluation by the Principal Investigator.  
Patients will be retreated at the currently enrolling dose level but will not count towards 
establishing the MTD. Patients who develop grade 3 or grade 4 toxicity due to cell infusion will 
not be retreated. Patients must continue to meet the original eligibility criteria to be considered 
for retreatment. Toxicity related to cyclophosphamide, fludarabine, or aldesleukin should be 
stable and resolved to less than grade 1 prior to retreatment. Retreatment benefits and risks will 
be carefully explained to the patient. A maximum of 1 retreatment course may occur.  
3.5 
POST-TREATMENT EVALUATION  
• All patients will return to the NIH Clinical Center for their 1st evaluation for response 6 
weeks (+/- 2 weeks) following the administration of the cell product 
• Patients who have received multiple transfusions during the treatment phase or have been 
discharged with grade 3 or greater significant adverse events should be evaluated by the 
referring physician within 2 weeks of discharge and repeat labs as appropriate to be faxed 
to the Research Nurse. Patients will receive appropriate treatment as determined by their 
treating physician. 
3.5.1 Time-Period of Evaluations 
• Patients who experience stable disease, a partial response, or a complete response or have 
unresolved toxicities will be evaluated as noted below: 
o Week 12 (+/- 2 weeks)  
o Every 3 months (+/- 1 month) x3 
o Every 6 months (+/- 1 month) x 2 years 
o As per PI discretion for subsequent years 
Note: Patients may be seen more frequently as clinically indicated 
 
3.5.2 Scheduled Evaluations 
At each scheduled evaluation patients will undergo: 
• Physical examination, including weight and vital signs  
• Acute Care Panel (sodium, potassium, chloride, bicarbonate, creatinine, glucose, BUN), 
Hepatic Panel (alkaline phosphatase, AST, ALT, total bilirubin, direct bilirubin), Mineral 
Panel (albumin, calcium, magnesium, phosphorus), Uric Acid, Creatinine Kinase, Lactate 
Dehydrogenase, Protein, total 
•  Complete blood count with differential 
• PT/PTT 
• Urinalysis as needed 
• Thyroid panel as clinically indicated 


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• TBNK, until CD4 > 200 x 2 
• Toxicity assessment, including a review of systems.  
• Imaging (CT, MRI, and/or PET) as performed at baseline. 
• A 5 liter apheresis may be performed. If a patient is unable to undergo apheresis, 
approximately 96 ml of blood may be obtained at the first follow up visit. Subsequently, 
60 ml of blood will be obtained at follow up visits for at least 3 months. Peripheral blood 
mononuclear cells will be cryopreserved so that immunologic testing may be performed. 
This will be performed on 03-C-0277.   
• Detection of RCR and persistence of gene transduced cells (Section 5.7) 
• Long-term follow up of patients receiving gene transfer: Physical examinations will be 
performed and documented annually for 5 years following cell infusion to evaluate long-
term safety. After 5 years, health status data will be obtained from surviving patients via 
telephone contact or mailed questionnaires. The long term follow up period for retroviral 
vectors is 15 years. This will be performed on 09-C-0161. 
Note: Patients who are unable or unwilling to return for follow up evaluations will be followed 
via phone or e-mail contacts. A request will be made to send laboratory, imaging and physician 
exam reports performed by their treating physician; and any outstanding toxicities will be 
reviewed with the patient.  
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete an evaluation 
safety visit approximately 6 weeks (± 2 weeks) following administration of the cell product (at 
the first follow-up evaluation). 
3.6.1 Criteria for Removal from Protocol Therapy 
Patients will be taken off treatment (and followed until progression of disease) for the following: 
• Completion of protocol therapy  
• Participant requests to be withdrawn from active therapy 
• Investigator discretion 
• Positive pregnancy test  
3.6.2 Off-Study Criteria 
Patients will be taken off-study for the following: 
• Completed study follow-up period 
• Participant requests to be withdrawn from study 
• Progressive disease, unless the patient is eligible for a second treatment 
• Lost to follow-up 
• Death 
Note: Once a subject is taken off study, no further data can be collected 


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Note: Patients who are taken off study for progressive disease or study closure maybe followed 
on Protocol 09-C-0161 “Follow up Protocol for Subjects Previously Enrolled in Surgery Branch 
Studies”.  
3.6.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to: NCI Central Registration Office 
<ncicentralregistration-l@mail.nih.gov>. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
INFECTION PROPHYLAXIS 
Note: Other anti-infective agents may be substituted at the discretion of the treating physician.  
4.1.1  Pneumocystis Jirovecii Pneumonia 
All patients will receive the fixed combination of trimethoprim and sulfamethoxazole 
(TMP/SMX) as double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) 
P.O. daily three times a week on non-consecutive days, beginning day 0 or within 1 week of 
lymphopenia.  
Dapsone (in G6PD sufficient patient), Atovaquone or Pentamidine may be substituted for 
TMP/SMX-DS in patients with sulfa allergies.  
4.1.2 Herpes or Varicella Zoster Virus Prophylaxis 
Patients with positive HSV or VZV serology will be given valacyclovir orally at a dose of 500 
mg daily starting on the day of cell infusion, or acyclovir, 250 mg/m2 IV every 12 hours if the 
patient is not able to take medication by mouth. Reversible renal insufficiency has been reported 
with IV but not oral acyclovir. Neurologic toxicity including delirium, tremors, coma, acute 
psychiatric disturbances, and abnormal EEGs has been reported with higher doses of acyclovir. 
Should this occur, a dosage adjustment will be made or the drug will be discontinued. Acyclovir 
will not be used concomitantly with other nucleoside analogs which interfere with DNA 
synthesis, e.g. ganciclovir. In renal disease, the dose is adjusted as per product labeling. 
Prophylaxis for Pneumocystis, Varicella Zoster and Herpes will continue for 6 months post 
chemotherapy. If the CD4 count is less than 200 at 6 months post chemotherapy, prophylaxis 
will continue for at least 6 months and until the CD4 count is greater than 200 for 2 consecutive 
measures. 
 
4.1.3 Fungal Prophylaxis 
Patients will start Fluconazole 400 mg p.o. starting on the day of cell infusion and continue until 
the absolute neutrophil count is greater than 1000/mm3. The drug may be given IV at a dose of 
400 mg in 0.9% sodium chloride USP daily in patients unable to take it orally. 
4.1.4 Empiric Antibiotics 
Patients will start on broad-spectrum antibiotics in accordance with current institutional 
guidelines for fever of 38.3°C once or two temperatures of 38.0°C or above at least one hour 


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apart, AND an ANC <500/mm3. Infectious disease consultation will be obtained for all patients 
with unexplained fever or any infectious complications. 
4.2 
BLOOD PRODUCT SUPPORT 
Using daily CBCs as a guide, the patient will receive platelets and packed red blood cells 
(PRBC’s) as needed. Attempts will be made to keep Hb >8.0 gm/dl, and platelets >10,000/mm3 
unless otherwise indicated. All blood products will be irradiated. Leukocyte filters will be 
utilized for all blood and platelet transfusions to decrease sensitization to transfused WBC’s and 
decrease the risk of CMV infection. 
4.3 
OTHER CONCOMITANT MEDICATIONS TO CONTROL SIDE EFFECTS 
Concomitant medications to control side effects of therapy may be given. Meperidine (25-50 mg) 
will be given intravenously if severe chilling develops. Other supportive therapy will be given as 
required and may include acetaminophen (650 mg q4h), indomethacin (50-75 mg q8h) and 
ranitidine (150 mg g12h). If patients require steroid therapy they will be taken off treatment. 
Patients who require transfusions will receive irradiated blood products. Ondansetron 0.15 
mg/kg/dose IV every 8 hours will be administered for nausea and vomiting. Additional 
antiemetics will be administered as needed for nausea and vomiting uncontrolled by 
ondansetron. Antibiotic coverage for central venous catheters may be provided at the discretion 
of the investigator. 
5 
BIOSPECIMEN COLLECTION  
Correlative Studies for Research: The amount of blood that may be drawn from adult patients for 
research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight- 
week period. 
Blood and tissue are tracked at the patient level and can be linked to all protocols on which the 
patient has been enrolled. Samples will be used to support the specific objectives listed in the 
treatment protocol(s), e.g., immunologic monitoring, cytokine levels, persistence, as well as to 
support long term research efforts within the Surgery Branch and with collaborators as specified 
in our companion protocol, 03-C-0277 (Cell Harvest and Preparation for Surgery Branch 
Adoptive Cell Therapy Protocols). 
5.1 
SAMPLES SENT TO DR. FIGG’S LAB 
• Venous blood samples will be collected in either a 4ml or an 8ml SST tube to be 
processed for serum and stored for future research. Record the date and exact time of 
draw on the tube. Blood tubes may be kept in the refrigerator until pickup. 
• For sample pickup, page 102-11964. 
• For immediate help, call 240-760-6180 (main blood processing core number) or, if no 
answer, 240-760-6190 (main clinical pharmacology lab number). 
• For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-
6044.  
• The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by 
the investigator. 


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5.2 
SAMPLES SENT TO SURGERY BRANCH CELL PROCESSING LABORATORY 
• Venous blood samples will be collected in 8ml CPT tubes to be processed and stored for 
future research. Record the date and exact time of draw on the tube. Blood tubes are kept 
at room temperature until pick up. 
• Samples will be pick-up by the research nurse or designee and transported to the SB Cell 
Processing Laboratory within 24 hours of blood draw. 
• The samples will be processed, barcoded, and stored in SB Cell Processing Laboratory. 
5.3 
PRIOR TO CHEMOTHERAPY ADMINISTRATION 
• CPT tubes (8 ml each) –SB’s lab 
• 1 SST tube (8 ml) – Figg’s lab 
• 1 SST tube (4 ml) daily; starting day of chemotherapy – Figg’s lab 
5.4 
PRIOR TO CELL INFUSION  
• Baseline blood sample for cytokine analysis (one 8mL SST) – Figg’s lab 
5.5 
POST CELL INFUSION EVALUATIONS 
• Once total lymphocyte count is greater than 200/mm3, the following samples will be 
drawn and sent to the TIL lab on Monday, Wednesday and Friday x5, then weekly (while 
the patient is hospitalized): 
o 5 CPT tubes (8 ml each) – SB’s lab 
o 1 SST tube (8 ml) – Figg’s lab 
5.6 
IMMUNOLOGICAL TESTING 
• Apheresis may be performed prior to and 4-6 weeks (+/- 2 weeks) following the 
administration of the cell product. At other time points, patient peripheral blood 
lymphocytes (PBL) will be obtained from whole blood by purification using 
centrifugation on a Ficoll cushion. Aliquots of these PBMC will be 1) cryopreserved for 
immunological monitoring of cell function and 2) subjected to DNA and RNA extraction 
for PCR analysis of TCR and vector copy number estimation. 
• Lymphocytes will be tested directly and following in vitro culture. Direct immunological 
monitoring will consist of quantifying T cells reactive with MAGE-A3/12 by FACS 
analysis using tetramer staining or reactivity against A1+ peptide pulsed targets. Ex vivo 
immunological assays will consist of cytokine release by bulk PBL (+/- peptide 
stimulation) and by other experimental studies such as cytolysis if sufficient cells are 
available. If cell numbers are limiting, preference will be given to the direct analysis of 
immunological activity. Immunological assays will be standardized by the inclusion of 1) 
pre-infusion PBMC and 2) an aliquot of the engineered PBL cryopreserved at the time of 
infusion. In general, differences of 2 to 3 fold in these assays are indicative of true 
biologic differences. Foxp3 levels will be analyzed by semiquantitative RT-PCR to 
evaluate for mRNA on PBL samples obtained prior to cell infusion and at the follow up 
time point. 


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5.7 
MONITORING GENE THERAPY TRIALS: PERSISTENCE AND RCR 
• Engineered cell survival. TCR and vector presence will be quantitated in PBMC samples 
using established PCR techniques.  Immunological monitoring using both tetramer 
analysis and staining for the TCR will be used to augment PCR-based analysis. This will 
provide data to estimate the in vivo survival of lymphocytes derived from the infused 
cells.  
• All patients will be co-enrolled on protocol 09-C-0161 “Follow up Protocol for Subjects 
Previously Enrolled in NCI Surgery Branch Studies”. Patients’ blood samples will be 
obtained and undergo analysis for detection of RCR by PCR prior to cell infusion and 
RCR PCR will be performed at 3 and 6 months, and at one year post cell administration. 
Blood samples will be archived annually thereafter if all previous testing has been 
negative with a brief clinical history. If a patient dies or develops neoplasms during this 
trial, efforts will be made to assay a biopsy sample for RCR. If any post-treatment 
samples are positive, further analysis of the RCR and more extensive patient follow-up 
will be undertaken, in consultation with the FDA. RCR PCR assays detect the GaLV 
envelope gene and are performed under contract by the Indiana University Vector 
Production Facility or other qualified testing facilities. The results of these tests are 
maintained by the contractor performing the RCR tests and by the Surgery Branch 
research team. 
5.8 
SAMPLE STORAGE, TRACKING AND DISPOSITION FOR SB CELL PROCESSING 
LABORATORY 
Blood and tissue collected during the course of this study will follow the Cell Tracking and 
Labeling System established by the Tumor Immunology Cell Processing Laboratory. The Cell 
Tracking and Labeling System is designed to unambiguously ensure that patient/data verification 
is consistent. The patients' cell samples (blood or tissue) are tracked by distinct identification 
labels that include a unique patient identifier and date of specimen collection. Cryopreserved 
blood and tissue samples also bear the date the sample was frozen. All cryopreserved samples are 
tracked for freezer location and storage criteria. All samples are stored in monitored 
freezers/refrigerators in 3NW Surgery Branch Laboratories at specified temperatures with alarm 
systems in place. Serum samples will be sent to the Blood Processing Core (BPC) for storage. 
Samples will be barcoded and stored on site or offsite at NCI Frederick Central Repository 
Services in Frederick, MD. All samples collected (blood or tissue) are entered into a central 
computer database with identification and storage location, and this database is backed up every 
night. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed and reported as such to the IRB. Any samples lost (in transit or by a 
researcher) or destroyed due to unknown sample integrity (i.e. broken freezer allows for 
extensive sample thawing, etc.) will be reported as such to the IRB. 
Note: Blood and tissue collected during the course of this study will be stored, tracked and 
disposed of as specified in our companion protocol 03-C-0277, (Cell Harvest and Preparation for 
Surgery Branch Adoptive Cell Therapy Protocols). 


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5.9 
SAMPLE STORAGE, TRACKING AND DISPOSITION FOR DR. FIGG’S LAB 
5.9.1 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC, and data will be updated to the 
Surgery Branch central computer database weekly. This is a secure program, with access to 
LABrador limited to defined Figg lab personnel, who are issued individual user accounts. 
Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen. All Figg lab personnel with access to patient information 
annually complete the NIH online Protection of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
5.9.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed and reported as such to the IRB. Any samples lost (in transit or by a 
researcher) or destroyed due to unknown sample integrity (i.e. broken freezer allows for 
extensive sample thawing, etc.) will be reported as such to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
Note: Blood and tissue collected during the course of this study will be stored, tracked, and 
disposed of as specified in our companion protocol, 03-C-0277 (Cell Harvest and Preparation for 
Surgery Branch Adoptive Cell Therapy Protocols).  


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6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. Data will be entered into the NCI CCR 
C3D database.  
All adverse events (AEs), including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event. Patients will be followed for adverse events until their first week 6 follow-up evaluation or 
until off-study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization.  
• Is judged by the Investigator to be of significant clinical impact 
• 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. 
All AEs must be recorded on the AE case report form unless otherwise noted below in Section 
6.1.1. 
End of study procedures: Data will be stored according to HHS and FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
6.1.1 Exclusions to Routine Adverse Event Recording 
Patients will be receiving multiple agents which include commercially available agents 
(fludarabine, cyclophosphamide, aldesleukin and supportive medications) in combination with 
the investigational agents; therefore, all grade 1 events not related to the cell product will not be 
reported/recorded. 


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6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
De-identified human data generated for use in future and ongoing research will be shared 
through a NIH-funded or approved repository (ClinicalTrials.gov) and BTRIS. At the completion 
of data analysis, data will be submitted to ClinicalTrials.gov either before publication or at the 
time of publication or shortly thereafter. Data may also be used to support long term research 
efforts within the Surgery Branch and de-identified data may also be shared with collaborators as 
specified in our companion protocol, 03-C-0277 (Cell Harvest and Preparation for Surgery 
Branch Adoptive Cell Therapy Protocols). 
6.2.2 Genomic Data Sharing Plan 
The NIH Genomic Data Sharing Policy does not apply to this study.  
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response at 6 and 12 weeks 
(+/- 2 weeks), then every 3 months (+/- 1 month) x3, then every 6 months’ (+/- 1 month) x 2 
years. In addition to a baseline scan, confirmatory scans should also be obtained approximately 4 
(not less than 4) weeks following initial documentation of objective response. 
Clinical Response will be determined using the Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.0).  
6.3.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with Cyclophosphamide. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable non-target disease response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
6.3.2 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as: 
• By chest x-ray: ≥ 20 mm  
• By CT scan:  
o Scan slice thickness 5 mm or under: ≥ 10 mm 
o Scan slice thickness > 5 mm: double the slice thickness  
• With calipers on clinical exam: ≥ 10 mm 


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All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
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 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 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), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. 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. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 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. 
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. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). Ideally, the same type of 


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scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 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:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. 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. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.4 Response Criteria 
6.3.4.1  Evaluation of Target Lesions1  
• 
Complete Response (CR): Disappearance of all target lesions 
• 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions taking as reference the baseline sum LD. 
• 
Progression (PD): At least a 20% increase in the sum of LD of target lesions 
taking as reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions. 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD. 
6.3.4.2 Evaluation of Non-Target Lesions2  
• 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
• 
Non-Complete Response: Persistence of one or more non-target lesions 


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• 
Progression (PD): Appearance of one or more new lesions. Unequivocal 
progression of existing non-target lesions 
----------------------------------------------------------------------------------- 
1 
All measurable lesions up to a maximum of 10 lesions 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 their suitability for accurate repetitive measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference to further characterize the objective tumor response of the measurable 
dimension of the disease. 
2 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required, and these lesions 
should be followed as “present” or “absent.” 
6.3.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
6.3.5 Confirmatory Measurement/Duration of Response Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed at least 4 weeks after the criteria for response are first 
met. In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6-8 weeks. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 


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The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
Response Criteria for Non-Melanoma Tumors 
For patients with breast cancer or other chemotherapy-sensitive tumors (i.e. sarcoma), only 
responses seen on or after day 28 and maintained at 4 months will be considered a positive 
response for accrual to the second phase of this study. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in research, whether or not 
considered related to the subject’s participation in the research.  
7.1.2 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, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected Adverse Reaction 
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. 
"Unexpected”, 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 
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7.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• Death 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.  
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-Threatening Adverse Drug Experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9 Non-Compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
b. the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 


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• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• 
All deaths, except deaths due to progressive disease 
• 
All protocol deviations 
• 
All unanticipated problems 
• 
All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
Note: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA 
Up until the first follow-up evaluation (6 weeks (± 2 weeks) following the administration of the 
cell product), the investigator must immediately report to the sponsor, using the mandatory 
MedWatch Form FDA 3500A or equivalent, any serious adverse event, whether or not 
considered drug related, including those listed in the protocol or investigator brochure and must 
include an assessment of whether there is a reasonable possibility that the drug caused the event. 
For serious adverse events that occur after the first follow-up evaluation, only those events that 
have an attribution of at least possibly related to the agent/intervention will be reported. 
Required timing for reporting per the above guidelines: 


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• Death (except death due to progressive disease) must be reported via email within 24 
hours. A complete report must be submitted within one business day.  
• Other serious adverse events as well as deaths due to progressive disease must be 
reported within one business day 
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov 
and to the CCR PI and study coordinator.mailto: 
7.3.1 Waiver of Expedited Reporting to CCR 
The investigators are requesting a waiver from reporting specific events in an expedited manner 
to the CCR. Patients will be receiving commercially available agents, such as fludarabine, 
cyclophosphamide, and aldesleukin. The majority of toxicities observed on Surgery Branch 
Adoptive Cell Therapy protocols are expected toxicities of the non-myeloablative chemotherapy 
regimen or IL-2 and occur in approximately 95% of the patients enrolled, therefore, we are 
requesting a waiver from reporting the following events in an expedited manner to the CCR.  
• Grade 3 or greater myelosuppression, defined as lymphopenia, neutropenia, decreased 
hemoglobin, and thrombocytopenia. 
• Grade 3 or greater nausea, vomiting, mucositis - oral, anorexia, diarrhea, fever, chills, 
fatigue, and rash maculo-papular. 
• Grade 3 hypoxia, dyspnea, hematuria, hypotension, sinus tachycardia, urine output 
decreased, confusion, infections, and febrile neutropenia. 
The PI will submit a summary table of all grade 3-5 events, whether or not considered related to 
the product, every 6 months.  The report shall include the number of patients treated in the 
timeframe, the number of events per AE term per grade which occurred in the 6-month 
timeframe and in total since the start of the study, attribution, and type/category of serious. 
Reports will be submitted to the Center for Cancer Research (CCR) at: 
CCRsafety@mail.nih.gov. 
7.3.2 Reporting Pregnancy  
7.3.2.1 Maternal Exposure 
If a patient becomes pregnant during the first four months following treatment the pregnancy 
should be reported to the Sponsor. The potential risk of exposure of the fetus to the 
investigational agent(s) or chemotherapy agents (s) should be documented in box B5 of the 
Medwatch form “Describe Event or Problem”. 
Pregnancy itself is not regarded as an SAE unless there is a suspicion that the study treatment 
under study may have interfered with the effectiveness of a contraceptive medication. However, 
as patients who become pregnant on study risk intrauterine exposure of the fetus to agents which 
may be teratogenic, the CCR is requesting that pregnancy should be reported in an expedited 
manner as Grade 3 “Pregnancy, puerperium and perinatal conditions - Other (pregnancy)” under 
the Pregnancy, puerperium and perinatal conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 


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outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.3.2.2 Paternal Exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
120 days after the last dose of aldesleukin. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 120 days after the last dose 
should, if possible, be followed up and documented. 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of anti-MAGE-A3 HLA-A*01-restricted TCR as 
soon as possible but in no event later than 7 calendar days of initial receipt of the information. 
Serious adverse events that are unexpected and associated with the use of the anti-MAGE-A3 
HLA-A*01-restricted TCR, but are not fatal or life-threatening, must be reported to the NIH IBC 
as soon as possible, but not later than 15 calendar days after the investigator’s initial receipt of 
the information. Adverse events may be reported by using the FDA Form 3500a. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report. Please include the 
IBC protocol number on the report. 
7.4.2.1 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information for each trial:  
• the title and purpose of the trial  
• clinical site 
• the Principal Investigator 
• clinical protocol identifiers  


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• participant population (such as disease indication and general age group, e.g., adult or 
pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  
• if the trial has been completed, a brief description of any study results.  
7.4.2.2 Progress Report and Data Analysis 
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• a summary of all serious adverse events submitted during the past year 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
• if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death 
• a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.  
7.5 
DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about enrollment will be made based on the 
toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Sponsor Monitoring Plan 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 


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affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subject’s protection. This is done through independent verification of study 
data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
7.5.3 Safety Monitoring Committee (SMC) 
This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial 
review will occur as soon as possible after the annual NCI-IRB continuing review date.  
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.  For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 
8 
STATISTICAL CONSIDERATIONS  
Following an initial portion of the study in which the safety of the cells used in this protocol will 
be determined, the primary objective of this trial is to determine whether the combination of high 
dose aldesleukin, lymphocyte-depleting chemotherapy, and an infusion of anti-MAGE-A3 HLA-
A*01-restricted TCR-gene engineered lymphocytes is able to be associated with a modest 
fraction of patients that can experience a clinical response (PR +CR) to therapy. A secondary 
objective is to have sufficient patients in order to do exploratory evaluations of survival of cells.  
 The study will begin by evaluating the safety of escalating doses of cells from 109 to 1011. Once 
a safe dose has been confirmed, patients will be enrolled into the phase II portion of the trial 
using the cell dose found to be safe in the first phase of this protocol.  
Following the determination of a safe cell dose, the following describes the phase II portion of 
the study.  
Patients who express MAGE-A3 will be enrolled into individual strata depending on their 
specific histology. This stratification is being used to separate patients who have been shown 
historically to be aldesleukin sensitive (melanoma) from those who have not. In each case, the 
MAGE-A3 expression is expected to be so dominant in regulating potential for response that 
differences in clinical response according to histology will not be expected but will be evaluated 
in an exploratory manner to help assess this, in a pilot sense.  


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For each of the 2 strata, the study will be conducted using a phase II optimal design (Simon R, 
Controlled Clinical Trials 10:1-10, 1989). For both strata, the objective will be to determine if 
the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-MAGE-
A3 HLA-A*01-restricted TCR -gene engineered lymphocytes is able to be associated with a 
clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate 
(p1=0.20).  
In patients in each of the two strata (melanoma vs. other histologies or renal carcinoma), the 
following design will be used. For each strata, with alpha=0.05 (5% probability of accepting a 
poor therapy) and beta=0.10 (10% probability of rejecting a good therapy), initially 21 evaluable 
patients will be enrolled. If 0 or 1 of the 21 patients experiences a clinical response, then no 
further patients will be enrolled. If 2 or more of the first 21 evaluable patients enrolled have a 
clinical response, then accrual will continue until a total of 41 evaluable patients have been 
enrolled. As it may take several weeks to determine if a patient has experienced a clinical 
response, a temporary pause of up to 6 months in the accrual to the trial may be necessary to 
ensure that enrollment to the second stage is warranted. If 2 to 4 of the 41 have a clinical 
response, then this will be considered inadequate for further investigation. If 5 or more of 41 
patients have a clinical response, then this will indicate that this strategy provides a new 
approach that may be worthy of further consideration. Under the null hypothesis (5% response 
rate), the probability of early termination is 72%. 
Further, to help ensure that mal-distribution of patients who are either particularly responsive or 
unresponsive in the first stage does not materially interfere with the intended use of the two-stage 
design, we will aim to enroll 4-5 patients of each allowed histology among the first 21 enrolled 
in the ‘other histology’ arm. Although this has its own inherent issues due to limited sample size, 
since we believe that these ‘other histologies’ will behave the same clinically, it will permit us to 
evaluate the different response rates in a limited number of subjects and determine if they differ 
markedly or not. Since this would merely be an exploratory analysis, we will also look at minor 
response as well to help evaluate for hints of efficacy. If the response rates do seem to potentially 
differ markedly by histology, despite our hypothesis that this will not happen, we may consider 
amending the protocol when appropriate to try to restrict enrollment to those histologies with 
stronger evidence of responsiveness. For patients with breast cancer or other chemotherapy-
sensitive tumors (i.e. sarcoma), only responses seen at day 28 and maintained at 4 months will be 
considered a positive response for accrual to the second phase of this study. 
The dose escalation portion of the study may require 6 patients per dose level. For purposes of 
sample size estimation, we will assume that as few as 9 and no more than 20 patients will be 
required to perform the initial safety evaluation. In order to complete the dose escalation phase 
and both phase II cohorts, a total of up to 20+82=102 patients may be required (20 + 2 strata 
with a maximum of 41 apiece). Up to 6 patients enrolled at the MTD will count towards the 
accrual in the appropriate phase II strata if they are evaluable for response and if they would be 
fully eligible for enrollment in the phase II portion of the trial. Provided that about 4-5 patients 
per month will be able to be enrolled onto this trial, approximately 2 to 3 years may be needed to 
accrue the maximum number of required patients. However, as adequate responses to proceed to 
the second stage of accrual may not occur, the trial may end up accruing as few as 9+42=51 
patients if no arm demonstrates sufficient patients to accrue a second stage.  


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9 
COLLABORATIVE AGREEMENTS  
We have established a Cooperative Research and Development Agreement (CRADA #02716) 
with Kite Pharma, Inc., and will be sharing data with them. 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
The patients to be entered in this protocol have metastatic cancer which is refractory to standard 
therapy, and limited life expectancies. 
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria. To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another. Efforts 
will be made to extend accrual to a representative population, but in this preliminary study, a 
balance must be struck between patient safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the 
need to explore gender and ethnic aspects of clinical research on the other hand. If differences in 
outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a 
follow-up study may be written to investigate those differences more fully. 
10.2 PARTICIPATION OF CHILDREN 
The use of the nonmyeloablative regimen in this protocol is a major procedure which entails 
serious discomforts and hazards for the patient, such that fatal complications are possible. It is 
therefore only appropriate to carry out this experimental procedure in the context of life 
threatening metastatic cancer. Since the efficacy of this experimental procedure is unknown, it 
does not seem reasonable to expose children to this risk without further evidence of benefit. 
Should results of this study indicate efficacy in treating metastatic cancer, which is not 
responsive to other standard forms of therapy, future research can be conducted in the pediatric 
population to evaluate potential benefit in that patient population. 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 10.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. The PI or AI will contact the NIH Ability 
to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do 
not have pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 
for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, 
and (b) who do not have a legal guardian or durable power of attorney, will be followed. 


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10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has a chance to provide clinical benefit though it is not known if it 
will do so. The risks in this treatment are detailed in Section 11. The success of this effort cannot 
be predicted at this time.  
10.5 RISKS/BENEFITS ANALYSIS 
Because all patients in this protocol have metastatic cancer, which is refractory to standard 
therapy and limited life expectancies, the potential benefit is thought to outweigh the potential 
risks. 
10.6 CONSENT PROCESS AND DOCUMENTATION 
 Patients are initially consented on protocol 03-C-0277, Cell Harvest and Preparation for Surgery 
Branch Adoptive Cell Therapy Protocols, if the patient is HLA-A*01 positive and has a tumor 
that is found to be MAGE-A3- positive by immunohistochemistry. If the lymphocytes can be 
generated for infusion and the patient meets the thorough screening for eligibility, while enrolled 
on 99-C-0128, the patient, with family members or friends at the request of the patient, will be 
presented with a detailed description of this protocol treatment. The specific requirements, 
objectives, and potential advantages and disadvantages will be presented. The Informed Consent 
document is given to the patient, who is requested to review it and to ask questions prior to 
agreeing to participate in the treatment portion of this protocol. The patient is reassured that 
participation on trial is entirely voluntary and that he/she can withdraw or decide against 
treatment at any time without adverse consequences. The PI, associate investigator, or clinical 
fellow is responsible for obtaining written consent from the patient. 
10.6.1 Informed Consent of Non-English Speaking Subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary 
that will be used is the English version of the extant IRB approved consent document. Signed 
copies of both the English version of the consent and the translated short form will be given to 
the subject or their legally authorized representative and the signed original will be filed in the 
medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 


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11 PHARMACEUTICAL INFORMATION  
11.1 INVESTIGATIONAL REGIMEN 
11.1.1 Cell Preparation (Anti-MAGE-A3 HLA-A*01-Restricted Transduced PBL) 
The procedure for expanding the human PBL and the certificate of analysis are similar to those 
approved by the Food and Drug Administration and used at the NCI in ongoing protocols 
evaluating cell therapy in the surgery branch. The certificate of analysis is included in Appendix 
5. The PBL will be transduced with retroviral supernatant containing the alpha chain and beta 
chain genes of the Anti-MAGE-A3-A1. Note: Penicillin, Streptomycin, and gentamycin will not 
be used in the manufacture of products for patients with documented allergies to these drugs.  
11.1.1.1 Retroviral Vector Containing the anti-MAGE-A3-A1-Restricted Gene 
The retroviral vector supernatant [PG13-MAGE-A3 TCR encoding a T cell receptor directed 
against MAGE-A3-A1, was prepared and preserved following cGMP conditions in the Surgery 
Branch Vector Production Facility (SBVPF). The retroviral vector, PG13-MAGE-A3-A1 
consists of the 5' LTR from the murine stem cell virus (promoter), packaging signal including the 
splicing donor (SD) and splicing acceptor sites, alpha chain and beta chain genes of the anti- 
anti-MAGE-A3 HLA-A*01-restricted TCR. The alpha and beta chains are linked by a P2A 
peptide. For clone selection, the physical titer will be determined by RNA dot blot. The physical 
titer of the clinical vector will be measured in transducing units per mL following a titration on 
human PBL according to sponsor protocols. The supernatant has been stored at the SBVPF upon 
the completion of production at –80 °C. A portion of the supernatant will be shipped on dry ice 
and stored –80 °C at Fisher Bioservices, Rockville, MD. This storage facility is equipped with 
around-the-clock temperature monitoring. Upon request, supernatant will be delivered on dry ice 
to be used in in vitro transduction. There will be no re-use of the same unit of supernatant for 
different patients. Retroviral titer has been shown to be stable after immediate thawing and 
immediate administration (coating the tissue culture wells previously coated with Retronectin). 
Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-2).  The specific 
guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm. 
11.1.2 Interleukin-2 (Aldesleukin, Proleukin, Recombinant Human Interleukin 2) 
How Supplied: Interleukin-2 (aldesleukin) will be provided by the NIH Clinical Pharmacy 
Department from commercial sources.  
Formulation/Reconstitution: Aldesleukin, NSC #373364, is provided as single-use vials 
containing 22 million IU (−1.3 mg) IL-2 as a sterile, white to off-white lyophilized cake plus 50 
mg mannitol and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg 
monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The vial is 
reconstituted with 1.2 mL of Sterile Water for Injection, USP, and the resultant concentration is 
18 million IU/ml or 1.1 mg/mL. Diluent should be directed against the side of the vial to avoid 
excess foaming. Swirl contents gently until completely dissolved. Do not shake. Since vials 
contain no preservative, reconstituted solution should be used with 24 hours. 
Storage: Intact vials are stored in the refrigerator (20 - 80C) protected from light. Each vial bears 
an expiration date. 
Dilution/Stability: Reconstituted aldesleukin should be further diluted with 50 mL of 5% Human 
Serum Albumin (HSA). The HSA should be added to the diluent prior to the addition of RIL-2. 


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Dilutions of the reconstituted solution over a 1000-fold range (i.e., 1 mg/mL to 1 mcg/mL) are 
acceptable in either glass bottles or polyvinyl chloride bags. Aldesleukin is chemically stable for 
48 hours at refrigerated and room temperatures, 20 – 300C. 
Administration: The dosage will be calculated based on total body weight. The final dilution of 
aldesleukin will be infused over 15 minutes. Aldesleukin will be administered as an inpatient.  
Toxicities: Expected toxicities of aldesleukin are listed in the product label and in Appendix 2 
and Appendix 3. Grade 3 toxicities common to aldesleukin include diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes as detailed in Appendix 2. Additional grade 3 and 4 toxicities seen with 
aldesleukin are detailed in Appendix 3.  
11.1.3 Fludarabine 
(Please refer to package insert for complete product information)  
Description: Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic 
nucleosides in that the sugar moiety is arabinose instead of ribose or deoxyribose. Fludarabine is 
a purine antagonist antimetabolite.  
How Supplied: It will be purchased by the NIH Clinical Pharmacy Department from commercial 
sources. Fludarabine is supplied in a 50 mg vial as a fludarabine phosphate powder in the form of 
a white, lyophilized solid cake.  
Stability: Following reconstitution with 2 mL of sterile water for injection to a concentration of 
25 mg/ml, the solution has a pH of 7.7. The fludarabine powder is stable for at least 18 months at 
2-8°C; when reconstituted, fludarabine is stable for at least 16 days at room temperature. 
Because no preservative is present, reconstituted fludarabine will typically be administered 
within 8 hours. Specialized references should be consulted for specific compatibility 
information. Fludarabine is dephosphorylated in serum, transported intracellularly and converted 
to the nucleotide fludarabine triphosphate; this 2-fluoro-ara-ATP molecule is thought to be 
required for the drug’s cytotoxic effects. Fludarabine inhibits DNA polymerase, ribonucleotide 
reductase, DNA primase, and may interfere with chain elongation, and RNA and protein 
synthesis. 
Storage: Intact vials should be stored refrigerated (2-8°C). 
Administration: Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium chloride, 
USP over 15 to 30 minutes. The doses will be based on body surface area (BSA). If patient is 
obese (BMI > 35) drug dosage will be calculated using practical weight as described in 
Appendix 1.  
Toxicities: At doses of 25 mg/m2/day for 5 days, the primary side effect is myelosuppression; 
however, thrombocytopenia is responsible for most cases of severe and life-threatening 
hematologic toxicity. Serious opportunistic infections have occurred in CLL patients treated with 
fludarabine. Hemolytic anemia has been reported after one or more courses of fludarabine with 
or without a prior history of a positive Coomb’s test; fatal hemolytic anemia has been reported. 
In addition, bone marrow fibrosis has been observed after fludarabine therapy. Other common 
adverse effects include malaise, fever, chills, fatigue, anorexia, nausea and vomiting, and 
weakness. Irreversible and potentially fatal central nervous system toxicity in the form of 
progressive encephalopathy, blindness, and coma is only rarely observed at the currently 


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administered doses of fludarabine. More common neurologic side effects at the current doses of 
fludarabine include weakness, pain, malaise, fatigue, paresthesia, visual or hearing disturbances, 
and sleep disorders. Adverse respiratory effects of fludarabine include cough, dyspnea, allergic 
or idiopathic interstitial pneumonitis. Tumor lysis syndrome has been rarely observed in 
fludarabine treatment of CLL. Treatment on previous adoptive cell therapy protocols in the 
Surgery Branch have caused persistently low (below 200) CD4 counts, and one patient 
developed polyneuropathy manifested by vision blindness, and motor and sensory defects. 
11.1.4 Cyclophosphamide 
 (Refer to FDA-approved package insert for complete product information) 
Description: Cyclophosphamide is a nitrogen mustard-derivative alkylating agent. Following 
conversion to active metabolites in the liver, cyclophosphamide functions as an alkylating agent; 
the drug also possesses potent immunosuppressive activity. The serum half-life after IV 
administration ranges from 3-12 hours; the drug and/or its metabolites can be detected in the 
serum for up to 72 hours after administration.  
How Supplied: Cyclophosphamide will be obtained from commercially available sources by the 
NIH Clinical Center Pharmacy Department.   
Stability: Following reconstitution as directed with sterile water for injection, cyclophosphamide 
is stable for 24 hours at room temperature or 6 days when kept at 2-8°C.  
Administration: It will be diluted in 250 ml D5W and infused over one hour. The dose will be 
based on the patient’s body weight. If patient is obese (BMI > 35) drug dosage will be calculated 
using practical weight as described in Appendix 1. 
Toxicities: Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia 
and thrombocytopenia. Anorexia, nausea and vomiting, rash and alopecia occur, especially after 
high-dose cyclophosphamide; diarrhea, hemorrhagic colitis, infertility, and mucosal and oral 
ulceration have been reported. Sterile hemorrhagic cystitis occurs in about 20% of patients; 
severity can range from microscopic hematuria to extensive cystitis with bladder fibrosis. 
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide appears to be 
lower than that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has been 
used prophylactically as a uroprotective agent in patients receiving cyclophosphamide. 
Prophylactic mesna is not effective in preventing hemorrhagic cystitis in all patients. Patients 
who receive high dose cyclophosphamide may develop interstitial pulmonary fibrosis, which can 
be fatal. Hyperuricemia due to rapid cellular destruction may occur, particularly in patients with 
hematologic malignancy. Hyperuricemia may be minimized by adequate hydration, 
alkalinization of the urine, and/or administration of allopurinol. If allopurinol is administered, 
patients should be watched closely for cyclophosphamide toxicity (due to allopurinol induction 
of hepatic microsomal enzymes). At high doses, cyclophosphamide can result in a syndrome of 
inappropriate antidiuretic hormone secretion; hyponatremia with progressive weight gain without 
edema occurs. At high doses, cyclophosphamide can result in cardiotoxicity. Deaths have 
occurred from diffuse hemorrhagic myocardial necrosis and from a syndrome of acute 
myopericarditis; in such cases, congestive heart failure may occur within a few days of the first 
dose. Other consequences of cyclophosphamide cardiotoxicity include arrhythmias, potentially 
irreversible cardiomyopathy, and pericarditis. Other reported adverse effects of 
cyclophosphamide include headache, dizziness, and myxedema; faintness, facial flushing, and 


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diaphoresis have occurred following IV administration. Mesna (sodium 2-
mercaptoethanesulphonate; given by IV injection) is a synthetic sulfhydryl compound that can 
chemically interact with urotoxic metabolites of cyclophosphamide (acrolein and 4-
hydroxycyclophosphamide) to decrease the incidence and severity of hemorrhagic cystitis.  
11.2 SUPPORTIVE MEDICATIONS 
11.2.1 Mesna (Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891)  
(Please refer to the FDA-approved package insert for complete product information) 
Description: Mesna will be obtained commercially by the Clinical Center Pharmacy Department 
and is supplied as a 100 mg/ml solution.  
Storage: Intact ampoules are stored at room temperature.  
Stability: Diluted solutions (1 to 20 mg/mL) are physically and chemically stable for at least 24 
hours under refrigeration. Mesna is chemically stable at room temperature for 48-72 hours in 
D5W, 48-72 hour in D5W/0.45% NaCl, or 24 hours in 0.9% NaCl. 
Administration: Dilute to concentrations less than or equal to 20 mg mesna/ml fluid in D5W or 
0.9% NaCl and to be administered intravenously as a continuous infusion. If patient is obese 
(BMI > 35) drug dosage will be calculated using practical weight as described in Appendix 1. 
Toxicities include nausea, vomiting and diarrhea.  
11.2.2 Filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen) 
Filgrastim will be obtained commercially by the Clinical Center Pharmacy Department and is 
supplied in 300 ug/ml and 480 ug/1.6 ml vials. G-CSF should be refrigerated and not allowed to 
freeze. The product bears the expiration date. The product should not be shaken. It is generally 
stable for at least 10 months when refrigerated. The appropriate dose is drawn up into a syringe. 
G-CSF will be given as a daily subcutaneous injection. The side effects of G-CSF are skin rash, 
myalgia and bone pain, an increase of preexisting inflammatory conditions, enlarged spleen with 
occasional associated low platelet counts, alopecia (with prolonged use) elevated blood 
chemistry levels. 
11.2.3 Trimethoprim and Sulfamethoxazole Double Strength (TMP / SMX DS) 
TMP/SMX DS will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used for the prevention of PCP pneumonia. The oral dose is 1 tablet PO daily 
three times a week (MUST be on non-consecutive days) beginning on day 0 or within one week 
of anticipated lymphopenia and continuing for at least 6 months and until the CD4 count is 
greater than 200 on 2 consecutive lab studies.  
Like other sulfa drugs, TMP/SMX DS can cause allergies, fever, photosensitivity, nausea, and 
vomiting. Allergies typically develop as a widespread itchy red rash with fever eight to fourteen 
days after beginning the standard dose. Neutropenia, a reduction in the number of neutrophils, 
can also occur. Should allergies develop, the following medications may be used in place of 
TMP/SMX DS. 
11.2.3.1 Dapsone 
Dapsone will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used for the prevention of Pneumocystis pneumonia. The dose is 100mg by 


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mouth daily, starting on day 0 (± 7 days) and continuing at least 6 months and until the CD4+ 
count is > 200 on two consecutive lab studies. It is supplied as 25mg and 100mg tablets. 
Dapsone contains a sulfa group, although the cross reactivity in patients with sulfa allergies is 
quite low. Dapsone may be considered in patients with mild to moderate sulfa allergies. Dapsone 
should be avoided in patients with severe (i.e., a history of anaphylaxis or other equally serious 
reaction) reactions to sulfa drugs. Additionally, dapsone has been reported to cause hemolytic 
anemia is patients with G6PD deficiency. It is recommended that patients be tested for G6PD 
deficiency prior to the initiation of dapsone therapy. Dapsone is generally well tolerated, but may 
cause a number of hematologic adverse reactions, including increased reticulocyte counts, 
hemolysis, decreased hemoglobin, methemoglobinemia, agranulocytosis, anemia, and 
leukopenia. Other rare but serious adverse reactions include bullous exfoliative dermatitis, 
Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, interstitial pneumonitis, and 
pulmonary eosinophilia. For more detailed information about adverse reactions, consult the 
package insert. 
11.2.3.2 Atovaquone 
Atovaquone will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used for the prevention of Pneumocystis pneumonia in patients who cannot 
tolerate or are allergic to sulfamethoxazole/trimethoprim, dapsone, or pentamidine. Atovaquone 
may be given as a single daily dose of 1500mg orally or the dose may be split into 750mg given 
orally twice daily. Atovaquone will be started on day 0 (± 7 days), and will continue for at least 6 
months and until the CD4+ count is > 200 on two consecutive lab studies. Atovaquone is 
supplied as an oral suspension containing 150mg/mL. Common adverse reactions to atovaquone 
include: headache, rash, diarrhea, nausea, vomiting, abdominal pain, cough, and fever. Rare but 
serious adverse reactions include acute renal failure, hepatitis and hepatic failure, angioedema, 
pancreatitis, and Stevens-Johnson syndrome. For more detailed information about adverse 
reactions, consult the package insert. 
11.2.3.3 Aerosolized Pentamidine  
Patients with sulfa allergies will receive aerosolized Pentamidine 300 mg per nebulizer within 
one week prior to admission and continued monthly until the CD4 count is above 200 on two 
consecutive follow up lab studies and for at least 6 months post chemotherapy. Pentamidine 
Isethionate will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used to prevent the occurrence of PCP infections. It is supplied in 300 mg vials 
of lyophilized powder and will be administered via nebulizer. Toxicities reported with the use of 
Pentamidine include metallic taste, coughing, bronchospasm in heavy smokers and asthmatics; 
increased incidence of spontaneous pneumothorax in patients with previous PCP infection or 
pneumatoceles, or hypoglycemia.  
11.2.4 Herpes and Varicella Zoster Virus Prophylaxis 
11.2.4.1 Valacyclovir (Valtrex) 
Valacyclovir will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used orally to prevent the occurrence of herpes virus infections in patients with 
positive HSV serology.  It is supplied in 500 mg tablets. Valcyclovir will be started at a dose of 
500 mg orally daily if the patient is able to tolerate oral intake. See package insert for dosing 
adjustments in patients with renal impairment. Common side effects include headache, upset 


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stomach, nausea, vomiting, diarrhea or constipation. Rare serious side effects include hemolytic 
uremic syndrome and thrombotic thrombocytopenic purpura.  
11.2.4.2 Acyclovir 
Acyclovir will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used to prevent the occurrence of herpes virus infections in patients who 
cannot take oral medications. It is supplied as powder for injection in 500 mg/vials. Reconstitute 
in 10 mL of sterile water for injection to a concentration of 50 mg/mL. Reconstituted solutions 
should be used within 12 hours. IV solutions should be diluted to a concentration of 7mg/mL or 
less and infused over 1 hour to avoid renal damage. Reversible renal insufficiency has been 
reported with IV but not oral acyclovir. Neurologic toxicity including delirium, tremors, coma, 
acute psychiatric disturbances, and abnormal EEGs have been reported with higher doses of 
acyclovir. Should this occur, a dosage adjustment will be made or the drug will be discontinued. 
Stomach upset, headache or nausea, rash or hives; peripheral edema; pain, elevated liver function 
tests; and leukopenia, diarrhea, lymphadenopathy, myalgias, visual abnormalities and elevated 
creatinine have been reported. Hair loss from prolonged use has been reported. Acyclovir will 
not be used concomitantly with other nucleoside analogs which interfere with DNA synthesis, 
e.g. ganciclovir. In renal disease, the dose is adjusted as per product labeling.  
 
11.2.5 Fluconazole 
Fluconazole will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used to prophylax against fungal infections. It is available in 200 mg tablets. It 
can cause headache, nausea, vomiting, diarrhea or abdominal pain, and liver damage which may 
be irreversible. It can cause rashes and itching, which in rare cases has caused Stevens Johnson 
Syndrome. It has several significant drug interactions. The package insert should be consulted 
prior to prescribing. For IV administration in patients who cannot tolerate the oral preparation, 
Fluconazole comes in 2 MG/ML solution for injection, and prepared according to Clinical Center 
Pharmacy standard procedures. It should be administered at a maximum IV rate of 200 mg/hr. 
11.2.6 Ondansetron Hydrochloride 
Ondansetron hydrochloride will be obtained by the Clinical Center Pharmacy Department from 
commercial sources. It will be used to control nausea and vomiting during the chemotherapy 
preparative regimen. It can cause headache, dizziness, myalgias, drowsiness, malaise, and 
weakness. Less common side effects include chest pain, hypotension, pruritus, constipation and 
urinary retention. Consult the package insert for specific dosing instructions. 
11.2.7 Furosemide 
Furosemide will be obtained by the Clinical Center Pharmacy Department from commercial 
sources. It will be used to enhance urine output during the chemotherapy preparative regimen 
with cyclophosphamide. Adverse effects include dizziness, vertigo, paresthesias, weakness, 
orthostatic hypotension, photosensitivity, rash and pruritus. Consult the package insert for a 
complete list of all side effects. 
 
 


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Dhodapkar MV, Osman K, Teruya-Feldstein J, Filippa D, Hedvat CV, Iversen K, et al. 
Expression of cancer/testis (CT) antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7, and NY-
ESO-1 in malignant gammopathies is heterogeneous and correlates with site, stage and risk 
status of disease. Cancer Immun. 2003;3:9. 
31. 
Valkmori D, Lienard D, Waanders G. Analysis of MAGE-3-specific cytolytic T 
lymphocytes in human leukocyte antigen-A2 melanoma patients. Cancer Res. 1997;57:735-41. 
32. 
Chaux P, Vantomme V, Stroobant V, Thielemans K, Corthals J, Luiten R, et al. 
Identification of MAGE-3, epitopes presened by HLA-DR molecules to CD4+ T lymphocytes. J 
Exp Med. 1999;189:767-77. 
33. 
Manici ST, Sturniolo T, Imro MA, Hammer J, Sinigaglia F, Noppen C, et al. Melanoma 
cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with 
histocompatibility leukocyte antigen DR11. J Exp Med. 1999;189:871-6. 
34. 
Schultz ES, Lethe B, Cambiaso CL, Van Snick J, Chaux P, Corthals J, et al. A MAGE-
A3 peptide presented by HLA-DP4 is recognized on tumore cells by CD4+ cytolytic T 
lymphocytes. Cancer Res. 2000;60:6272-5. 
35. 
Kobayashi H, Song Y, Hoon DS, Appella E, Celis E. Tumor-reactive T helper 
lymphocytes recognize a promiscuous MAGE-A3 epitope presented by various major 
histocompatibility complex class II alleles. Cancer Res. 2001;61:4773-8. 
36. 
Kawashima I, Hudson SJ, Tsai V. The multi-epitope approach for immunotherapy for 
cancer: identification of several CTL epitopes from various tumor-associated antigens expressed 
on solid epithelial tumors. Hum Immunol. 1998;59:1-14. 
37. 
Graff-Dubois S, Faure O, Gross DA, Alves P, Scardino A, Chouaib S, et al. Generation 
of CTL recognizing an HLA-A*0201-restricted epitope shared by MAGE-A1, -A2, -A3, -A4, -
A6, -A10, and -A12 tumor antigens: implication in a broad-spectrum tumor immunotherapy. J 
Immunol. 2002;169:575-80. 
38. 
Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, et al. Cancer 
regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 
2013;36:133-51. 
39. 
Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, et al. Identification 
of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE 
A3-directed T cells. Sci Transl Med. 2013;5(197):197ra03. 
 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
54
13 FIGURES, TABLES & APPENDICES 
Figure 1 
 
 
Figure 1. Responses of TCR-
transduced T cells to tumor cell 
lines. Anti-CD3-stimulated 
PBMC were transduced with 
TCR A10 or 13-18, which 
recognized the MAGE-A3:168-
176 HLA-A*01-restricted 
epitope (A-C). The TCR-
transduced T cells, as well as 
untransduced control T cells, 
were evaluated for their ability to 
release IFN-γ in response to a 
panel of tumor cell lines in an 
overnight coculture assay. 
Estimates of relative transduction 
frequencies of PBMC used for 
the experiments are shown in 
(B). Representative results from 
2 of 3 independent experiments 
assessing responses of T cells 
transduced with these TCRs are 
presented. IFN indicates 
interferon; PBMC, peripheral 
blood mononuclear cells; TCR, 
T-cell receptor. 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
55
Figure 2 
 
Figure 2. Responses of TCR-transduced T cells to fresh uncultured melanomas. Patient 
PBMC that were transduced with TCR A10, 13-18, were assayed for their ability to release 
IFN-γ in response to a panel of fresh uncultured melanomas that either did or did not 
express HLA-A*01+/MAGE-A3+ tumor cell line 397 mel stimulated the release of 17,400 
and 4200 pg/mL of IFN-γ from TY cells transduced with TCR A10 and 13-18, respectively. 
Representative results from one of 3 independent experiments assessing responses of T cells 
transduced with these TCRs are presented. IFN indicates interferon; PBMC, peripheral 
blood mononuclear cells; TCR, T-cell receptor. 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
56
Figure 3 
 
 
 
 
Figure 3. Ability of TCR-transduced T cells to recognize target cells transfected with 
MAGE-A gene family members. The monkey kidney cell line COS-7 was transiently 
transfected with HLA-A*01plus MAGE-A3, A1, A2, A4, A6, A9, A10 or A12 
overnight. The following day T cells transduced with either TCR A10, 13-18, or 
untransduced control cells were added and the release of soluble IFN-γ was evaluated 
after an overnight coculture by ELISA. ELISA indicates enzyme-linked 
immunosorbent assay; IFN, interferon; TCR, T-cell receptor. 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
57
Figure 4 
 
 
   
 
Figure 4. Cytolytic activity of TCR transduced T cells. Following stimulation with anti-CD3 
antibody, PMBC from a single donor were transduced with TCRs that recognize the MAGE-3 and 
MAGE-A12 tumor antigens. Thirteen days after stimulation, transduced T cells were incubated 
with the indicated tumor targets in a standard 4 hour 51Cr release assay. 
Representative results from one of two independent experiments are presented.  
 
A       C 
B       D 
Cell line HLA-A*01 HLA-C *07: MAGE-A3 MAGE-A12 
397 mel   +  01 
+   + 
624 mel   -   02 
+   + 
2984 mel   +   -  
+   + 
2661 RCC   +   - 
 -   - 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
58
 
Table 1 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
59
Appendix 1 
Modification of Dose Calculations* in patients whose BMI is greater than 35 
Unless otherwise specified in this protocol, actual body weight is used for dose 
calculations of treatment agents.  In patients who are determined to be obese (BMI > 
35), the practical weight (see 3 below) will be used. 
 
 
1. BMI Determination: 
 
BMI = weight (kg) / [height (m)]2 
 
 
2. Calculation of ideal body weight 
 
Male = 50 kg + 2.3 (number of inches over 60 inches) 
Example: ideal body weight of 5’10’’ male 
50 + 2.3 (10) = 73 kg 
 
Female = 45.5 kg + 2.3 (number of inches over 60 inches) 
Example: ideal body weight of 5’3’’ female 
45.5 + 2.3 (3) = 57 kg 
 
3. Calculation of “practical weight” 
 
Calculate the average of the actual and the ideal body weights. This is the 
practical weight to be used in calculating the doses of chemotherapy and 
associated agents designated in the protocol. 
 
 
 
 
 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
60
 
 
Appendix 2 
Adverse Events Occurring In ≥10% Of Patients Treated With Aldesleukin (N=525)1 
Body System  
% Patients  
 
Body System  
  % Patients 
Body as a Whole  
 
 
 
Metabolic and Nutritional Disorders 
Chills   
 
 
52  
 
Bilirubinemia   
 
40 
Fever   
 
 
29  
 
Creatinine increase  
 
33 
Malaise  
 
 
27  
 
Peripheral edema  
 
28 
Asthenia  
 
 
23 
 
 SGOT increase  
 
23 
Infection  
 
 
13  
 
Weight gain   
 
16 
Pain   
 
 
12  
 
Edema  
 
 
15 
Abdominal pain  
 
11  
 
Acidosis  
 
 
12 
Abdomen enlarged  
 
10  
 
Hypomagnesemia  
 
12 
Cardiovascular  
 
 
 
Hypocalcemia  
 
11 
Hypotension   
 
71  
 
Alkaline phosphatase incr 
10 
Tachycardia   
 
23 
 
Nervous 
Vasodilation   
 
13  
 
Confusion  
 
 
34 
Supraventricular tachycardia  12  
 
Somnolence   
 
22 
Cardiovascular disordera  
11  
 
Anxiety  
 
 
12 
Arrhythmia  
 
 
10  
 
Dizziness  
 
 
11 
Digestive  
 
 
 
 
Respiratory 
Diarrhea  
 
 
67  
 
Dyspnea  
 
 
43 
Vomiting  
 
 
50  
 
Lung disorderb  
 
24 
Nausea  
 
 
35  
 
Respiratory disorderc   
11 
Stomatitis  
 
 
22  
 
Cough increase  
 
11 
Anorexia  
 
 
20  
 
Rhinitis  
 
 
10 
Nausea and vomiting   
19  
 
Skin and Appendages 
Hemic and Lymphatic  
 
 
Rash   
 
 
42 
Thrombocytopenia  
 
37 
 
 Pruritus  
 
 
24 
Anemia  
 
 
29  
 
Exfoliative dermatitis  
18 
Leukopenia 
 
 
16  
 
Urogenital 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
61
Oliguria  
 
 
63 
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
1Source: Proleukin® Prescribing Information – June 2007 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
62
Appendix 3 
Expected IL-2 Toxicities and their Management 
Expected toxicity 
Expected 
grade 
Supportive Measures 
Stop Cycle* 
 
Stop 
Treatment ** 
Chills 
3 
IV Meperidine 25-50 
mg, IV q1h, prn, 
No 
No 
Fever 
3 
Acetaminophen 650 
mg, po, q4h; 
Indomethicin 50-75 
mg, po, q8h 
No 
No 
Pruritis 
3 
Hydroxyzine HCL 
10-20 mg po q6h, 
prn; 
Diphenhydramine 
HCL25-50 mg, po, 
q4h, prn 
No 
No 
Nausea/ Vomiting/ 
Anorexia 
3 
Ondansetron 10 mg, 
IV, q8h, prn; 
Granisetron 0.01 
mg/kg IV daily prn; 
Droperidol 1 mg, IV 
q4-6h, prn; 
Prochlorperazine 25 
mg prn or 10 mg IV 
q6h prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg, po, 
q3h, prn; 
Diphenoxylate HCl 
2.5 mg and atropine 
sulfate 25 mcg, po, 
q3h, prn; codeine 
sulfate 30-60 mg, po, 
q4h, prn 
If uncontrolled after 24 
hours despite all 
supportive measures 
No 
Malaise 
3 or 4 
Bedrest 
If other toxicities occur 
simultaneously 
No 
Hyperbilirubinemia 
3 or 4 
Observation 
If other toxicities occur 
simultaneously 
No 
Anemia 
3 or 4 
Transfusion with 
PRBCs 
If uncontrolled despite 
all supportive measures 
No 
Thrombocytopenia 
3 or 4 
Transfusion with 
platelets 
If uncontrolled despite 
all supportive measures 
No 
Edema/Weight gain 3 
Diuretics prn 
No 
No 
Hypotension 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled despite 
all supportive measures 
No 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
63
Dyspnea 
3 or 4 
Oxygen or 
ventilatory support 
If requires ventilatory 
support 
No 
Oliguria 
3 or 4 
Fluid boluses or 
dopamine at renal 
doses 
If uncontrolled despite 
all supportive measures 
No 
Increased creatinine 3 or 4 
Observation 
Yes (grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 
Pleural effusion 
3 
Thoracentesis 
If uncontrolled despite 
all supportive measures 
No 
Bowel perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid 
and electrolyte 
imbalances; chemical 
conversion or 
electrical conversion 
therapy 
If uncontrolled despite 
all supportive measures 
No 
Elevated Troponin 
levels 
3 or 4 
Observation 
Yes 
If changes in 
LV function 
have not 
improved to 
baseline by 
next dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
Elevated 
transaminases 
3 or 4 
Observation 
For grade 4 without 
liver metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Hyperbilirubinemia 
3 or 4 
Observation 
For grade 4 without 
liver metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Electrolyte 
imbalances 
3 or 4 
Electrolyte 
replacement 
If uncontrolled despite 
all supportive measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to grade 2 or less by next treatment. 
 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
64
 
 
Appendix 4 
Interleukin-2 toxicities observed in patients treated at the NIH Clinical Center 
 
 
 
 
 
 
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
65
Appendix 5 
 
 
Certificate of Analysis 
Infused T cells transduced with anti-MAGE-A3 HLA-A*01-restricted TCR 
Date of preparation of final product: 
Patient: 
Tests performed on final product: 
 
Test 
 
Method 
Limits 
Result 
Test 
Performe
d by  
Initials/ 
Date 
Cell viability1 
trypan blue exclusion 
>70% 
 
 
 
Total viable cell 
number1 
visual microscopic 
count 
>1 x107 
 
 
 
Tumor 
reactivity2 
-IFN release vs. 
peptide pulsed A1+ 
cells 
>200 pg/ml, and > 
2 times background 
 
 
 
TCR 
Expression2 
FACS analysis of the 
transduced cells 
PBL, >10% 
 
 
 
Microbiological 
studies  
gram stain1,3,  
no micro-organisms 
seen 
 
 
 
 
aerobic culture3,4 
no growth 
 
 
 
 
fungal culture3,4 
no growth 
 
 
 
 
anaerobic culture3,4 
no growth 
 
 
 
 
mycoplasma test5 
negative 
 
 
 
Endotoxin  
limulus assay1 
<5 E.U./kg 
 
 
 
RCR 
S+L- Assay4 
RCR-PCR6 
negative 
 
 
 
1 Performed on sample of the final product immediately prior to infusion. Results are available at 
the time of infusion. 
2 Performed 2-10 post transduction. Results are available at the time of infusion.  
3 Performed 2-4 days prior to infusion. Results are available at the time of infusion but may not 
be definitive. 
4 Sample collected from the final product prior to infusion. Results will not be available before 
cells are infused into the patient. 
5 Performed 2-10 days prior to infusion. Results are available at the time of infusion. 
6 Performed on sample approximately 1-4 days prior to infusion. Results are available at the time 
of infusion.  
 


Abbreviated Title: Anti-MAGE-A3 A*01 TCR PBL 
Version Date: May 21, 2018 
 
66
Prepared by: _______________________________________ 
Date: 
____________________ 
 
 
QC sign-off: _______________________________________ 
Date: 
____________________ 
Qualified Clinical or Laboratory Supervisor 
 
 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
14-C-0110 
PRINCIPAL INVESTIGATOR: 
Steven A. Rosenberg, M.D., Ph.D 
STUDY TITLE:  
  
A Phase I/II Study of the Treatment of Metastatic Cancer that Expresses MAGE-A3 
Using Lymphodepleting Conditioning Followed by Infusion of Anti-MAGE-A3 HLA-
A*01-Restricted TCR-Gene Engineered Lymphocytes and Aldesleukin 
 
Continuing Review Approved by the IRB on 06/28/18 
   
Amendment Approved by the IRB on 05/31/18 (I) 
   Date posted to Web:  07/04/18 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time. In 
either case, you will not lose any benefits to which you are otherwise entitled. However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part. The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions). If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study. Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.  
Why is this study being done?  
We have developed an experimental therapy for treating patients with cancer that involves taking 
white blood cells from the patient, growing them in the laboratory in large numbers, genetically 
modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and 
then giving the cells back to the patient. This type of therapy is called gene transfer.  In this 
protocol we are modifying the patient’s white blood cells with a retrovirus that has the gene for 
anti-MAGE-A3 incorporated in the retrovirus. So far, MAGE-A3 has been found only on tumor 
cells. The purpose of this study is to see if these particular tumor-fighting cells can cause tumors 
to shrink and to be certain the treatment is safe. However, it is possible that these cells will not 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 2 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
have this effect. The first few patients enrolled will participate in the Phase I portion of the study, 
called the “dose escalation” phase. The purpose of dose escalation is to determine the most 
effective yet safe dose of anti-MAGE-A3 cells. There will be 5 dose levels of anti-MAGE-A3 
cells. The first patients enrolled get the smallest dose and the dose is increased when a level has 
been determined to be safe. If the first dose has too many side effects, patients enrolled will 
receive smaller doses. Discuss with your doctor which dose of anti-MAGE-A3 cells you will be 
receiving. This is the first time these cells will be given to humans. Since this is a phase I/II trial, 
it is unlikely that you will receive any benefit. 
Why are you being asked to take part in this study? 
You are being asked to participate in this study because you have been diagnosed with cancer 
that has the MAGE-A3 molecule on the surface of the tumors. 
How many people will take part in this study?  
Up to 102 patients will be enrolled in this study.  
Description of Research Study 
This study has several stages as outlined below: 
• Stage 1 is performed under the companion protocol, 99-C-0128 (Evaluation for NCI 
Surgery Branch Clinical Research Protocols), to which you have already enrolled. 
• Stage 2 is performed under the companion protocol, 03-C-0277 (Cell Harvest and 
Preparation for Surgery Branch Adoptive Cell Therapy Protocols), to which you have 
already enrolled. 
• Stages 3-6 are performed under this protocol. 
 
Stage 
Timeframe 
Location 
Comments & Instructions 
1. Work-up 
1-4 weeks 
Inpatient or 
outpatient  
Scans, x-rays, labs, other tests as 
needed 
2. Cell 
Manufacturing 
4-6 weeks 
Inpatient or 
Outpatient 
Leukapheresis 
3. Chemotherapy 
(Days -7 to -3) 
5 days 
Inpatient 
Receive IV chemotherapy to 
prepare your immune system for 
the cells 
4. Cells and 
aldesleukin 
(Days 0-5) 
1-5 days 
Inpatient and 
possibly ICU 
 
Receive the anti-MAGE-A3 cells 
IV and then high dose 
aldesleukin about every 8 hours 
for up to 15 doses 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 3 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
Stage 
Timeframe 
Location 
Comments & Instructions 
5. Recovery 
1-3 weeks 
Inpatient unit 
Recover from the effects of 
treatment 
6. Follow -up 
Ongoing 
until disease 
progression 
Outpatient 
Return to clinic for physical 
exam, review of side effects, labs, 
scans every 1-3 months for the 
first year. 
What will happen if you take part in this research study?  
Before you Begin the Study 
The following procedures are conducted under 99-C-0128 or 03-C-0277. 
Cell Harvest and Growth 
You underwent a process called “apheresis”, while enrolled on our companion protocol 03-C-
0277 (Cell harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols). This 
process obtained certain types of blood cells from you. Some of these cells will be grown in the 
lab and genetically modified to recognize a protein on your tumor cells (anti-MAGE-A3). If your 
cells do not grow, unfortunately you will not be able to receive the cell infusion. If that happens, 
we will look at alternative experimental treatments at the NIH Clinical Center or refer you to the 
care of your referring physician. We usually know after about 4 weeks whether the cells will 
grow well enough to be used as an experimental treatment on this protocol. At the time we 
determine that your cells are not growing, we will inform you and discuss your options with you. 
Several medications are used during the preparation of your cell product, be sure to tell your 
doctor if you are allergic to any antibiotics. 
Work-up 
Prior to receiving the experimental treatment, you will undergo many tests. These include 
imaging procedures, heart and lung function tests, eye exams, and laboratory tests. If you have 
received ipilimumab (also called Yervoy, MDX-010) or any antibody therapy that could affect 
an anti cancer immune response and have experienced any GI toxicities, you will have a 
colonoscopy and biopsies to make sure your colon is normal since these drugs may have caused 
damage to your colon that may worsen with aldesleukin treatment. If you are a woman, you will 
undergo a pregnancy test. You may be admitted to the hospital for these tests. However, you will 
be allowed to leave on pass on the days that you are not having tests performed. 
Catheter Insertion 
Prior to beginning the experimental treatment, you will have an intravenous (IV) catheter placed 
in your upper chest. The area will be numbed with an anesthetic before the catheter is put in. 
Although rare, putting these catheters in can sometimes cause collapse of a lung or cause 
bleeding. Lung collapse is treated by putting a tube into your chest for a few days to allow your 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 4 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
lung to expand. Pressure is placed on any area that might bleed. Other IVs may be needed in one 
or both of your arms if we need to give you extra fluids, medicines, or nutrition. 
Leukapheresis 
Leukapheresis is a procedure that allows us to remove certain types of blood cells from you and 
return the rest of your blood. It is a very common procedure that is done routinely here at the 
NIH with very few risks. During leukapheresis, blood is removed from you through a needle in 
your arm, circulated through a machine that divides whole blood into red cells, plasma (the 
serum part), and lymphocytes (or white cells), and then the plasma and red cells are returned to 
you through a second needle in your other arm. The white blood cells may be used to help grow 
the cells and after the treatment, you will have leukapheresis so that we can test your cells. In 
addition to the leukapheresis you will undergo as part of your work up, we will also ask you to 
undergo one additional pheresis procedure between 4 and 6 weeks after your cell regimen to see 
the impact of this therapy on the immune system and see if cells we gave you are still active. 
During the Study 
The following procedures will be performed under this protocol: 
Chemotherapy Regimen (Day -7 through Day -3) 
After we have grown the anti-MAGE-A3 cells to large numbers in the laboratory, you will be 
admitted to the hospital to begin your experimental treatment. You will be given two 
chemotherapy medicines, cyclophosphamide and fludarabine, to suppress your immune system 
so the anti-MAGE-A3 cells can work without any interference from the cells in your immune 
system. (These medicines will not treat your cancer; although they may cause your tumor to 
shrink for a short period of time.) Animal experiments have indicated that this can make the cells 
more effective in fighting cancer tumors, but it is not known whether this is true in humans. The 
cyclophosphamide will be given into your catheter over 1 hour for two days (Day -7 and Day -6) 
and the fludarabine will be given into your catheter for 30 minutes every day for five days (Day -
7 through Day -3). The side effects of these medicines are described on the following pages. 
After you have completed the chemotherapy regimen you will receive the cell infusion.  
Cell Infusion and Aldesleukin Regimen (Day 0 through Day 5)  
One to four days after the last dose of chemotherapy, you will be given the anti-MAGE-A3 cells. 
The anti-MAGE-A3 cells will be given in your intravenous catheter over 30 minutes. Within 24 
hours after the anti-MAGE-A3 cell infusion, you will be given high dose aldesleukin through 
your intravenous catheter. Aldesleukin is approved by the FDA for treatment of metastatic 
melanoma and metastatic renal cell cancer. The purpose of giving the aldesleukin with this 
therapy is to keep the cells we give you active for as long as possible so they will fight your 
tumor. The aldesleukin will be given as a 15-minute infusion about every 8 hours for up to five 
days after the cell infusion (maximum number of doses is 15). Doses may be skipped or delayed 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 5 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
depending on how well you tolerate the doses. The risks of the cells and aldesleukin are 
described on the following pages. 
The day after you receive the anti-MAGE-A3 cells, we will give you G-CSF (filgrastim) as a 
shot or injection under the skin. This will continue until your white blood cell counts begin to 
return to normal. We will watch you closely during this entire time for any side effects of this 
experimental regimen. We will discuss the side effects below and we will include in your care all 
the medicines and treatments to prevent as many of these side effects as we can and to make you 
as comfortable as we can.  
When You are Finished Taking the Drugs (Treatment) 
Recovery 
After your last dose of aldesleukin, you will recover in the hospital until you are well enough to 
go home. This usually takes 7 to 21 days; however, you may need to stay in the hospital for 
longer than this. We will continue to give you support medications, do laboratory tests, and 
watch you closely for any side effects until we feel your condition is stable.  
In addition to the laboratory tests to monitor your condition, we will remove approximately 9 
teaspoons of blood three times per week to study the effects of this regimen on your immune 
system. The maximum amount of blood for research is approximately 2.3 cups in 8 weeks. 
Follow-up and Evaluation of Experimental Regimen  
You will need to continue to take Bactrim, an antibiotic, for at least 6 months following your 
treatment. We will ask you to return to the NIH Clinical Center frequently after you are 
discharged approximately 6 and 12 weeks following treatment and then if you are responding to 
the treatment, every 3 months x 3, then every 6 months x 2 years and then as determined by your 
physician. The follow up visits will probably take 1-2 days. At each visit you will have lab tests, 
imaging studies and a physical examination. At some of your follow up visits, you may undergo 
leukapheresis or have about 8 tubes of blood drawn (4 tablespoons) so that we can see the effect 
this therapy has had on your immune system and if the cells we gave you are still alive. If you 
are unwilling or unable to travel to the NIH Clinical Center we will contact you by phone or e-
mail and we may ask you to send us lab, imaging, and physical exam reports. If your tumor 
appears to be growing, we will look for other investigational therapies you may be eligible for, or 
refer you back to the care of your local physician. 
Retreatment 
If your tumor shrinks or disappears following the initial treatment and then stops shrinking or 
recurs, you may receive additional treatments if you tolerated the treatment well and if all the 
side effects have resolved. The second treatment will not begin prior to 6- 8 weeks after your last 
dose of aldesleukin.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 6 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for four months after your blood tests show no evidence of the cells. In 
addition, male participants should not donate sperm during this time period. If you think that you 
or your partner is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include: 
• Abstinence  
• Intrauterine device (IUD) 
• Hormonal [birth control pills, injections, or implants]  
• Tubal ligation 
• Vasectomy 
Gene Therapy Long-Term Follow-up (Retroviral Vectors)  
Because we do not know the long-term side effects of gene therapy, we will collect your blood 
over the next several years, frequently at first and then less frequently. If you return to your 
referring physician after treatment here we will ask you to have your physician send your blood 
specimens here for this testing.  This testing will determine if the cells have grown or changed in 
your body. We will test your blood immediately after you receive the cells, and then at 3, 6 and 
12 months (2 teaspoons each time). If all of the tests are normal and show no change, we will 
collect blood from you every year after that to store in case you develop symptoms later. 
According to FDA requirements, we need you to return annually to the NIH for a physical 
examination for five years after you receive the cells. After that time, we will be sending you a 
questionnaire to get information regarding your health for the next ten years, for a total follow up 
time period of 15 years. For this reason, we ask that you continue to provide us with a current 
address and telephone number, even after you complete this research study.  At the time of your 
death, no matter the cause, we may request permission for an autopsy in order to obtain vital 
information concerning the safety of this experimental treatment approach. Please discuss this 
with your family to inform them of this request. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
The risks and discomforts of this research study can be significant. This experimental treatment 
can lead to long-term decrease in your immune function. It is also possible that you may lose 
your fertility following this experimental treatment. It is possible, although unlikely, that this 
experimental treatment may cause your death.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 7 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
We will discuss the side effects of this experimental treatment with you. You will be given 
medicines, transfusions, and treatments to prevent or treat the side effects including drugs to 
prevent and/or treat different types of infections. We will try to make you as comfortable as 
possible. You should talk to your study doctor about any symptoms that you experience while 
taking part in the study. 
Cell Infusion 
The cells we will be giving you have been modified with a retrovirus that has the gene for anti-
MAGE-A3 incorporated in the retrovirus. The cells could cause you to develop another type of 
cancer, such as leukemia or lymphoma, although this has never been seen in any gene therapy 
trial involving lymphocytes. These specific gene-modified cells have not been given to patients 
and thus we do not know what the specific side effects will be. In 2 prior studies using different 
parts of the MAGE gene, four patients died. In one of these studies, two patients of 9 who 
received this treatment died from neurological toxicities, probably due to the treatment. We 
stopped that study but continued research to try to determine the cause of the side effects from 
the treatment. In the other study which took place at another institution 2 patients died from 
cardiac toxicities.  The anti-MAGE-A3 is different from the MAGE used in the earlier trials and 
we do not anticipate that this anti-MAGE-A3 will cause the same side effects.  
Potential risks include:  
• Fever, chills and shortness of breath, which may last for a few hours (common) 
• Lung congestion causing shortness of breath  
• Autoimmune reaction such as loss of skin pigment (known as vitiligo) or inflammation of 
the eye (uveitis) which may require the use of steroid eye drops.  
• As this is a new experimental therapy which has not been given to patients, side effects 
that we do not anticipate that may cause your condition to deteriorate may be 
encountered. Any new information that becomes available during the course of this study 
will be shared with you. 
• You will be treated on this gene transfer protocol with a viral vector that was 
manufactured at the NCI Surgery Branch Vector Production Facility before May 2016. 
 An internal review of the facility that made the vector for this protocol determined that 
the facility needed to be closed due to manufacturing issues. We know of no additional 
risks related to the previously produced vector for patients who have received cells with 
vectors made in this facility as the vectors were extensively tested by outside experts. 
Therefore, the IRB has determined that the potential benefit to you outweighs the 
potential risks. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 8 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
Aldesleukin (IL-2)  
When aldesleukin is given through an intravenous catheter, it can make you feel like you have 
the flu. It can also cause confusion and mental status changes making you unable to make sound 
decisions. Prior to beginning treatment, we will ask you to complete a Durable Power of 
Attorney so that a person of your choosing can make health care decisions for you in case you 
develop these side effects. In our experience giving aldesleukin to over 2,000 patients we have 
found that these side effects go away within a few days of stopping the aldesleukin. 
Medications 
The side effects of cyclophosphamide, fludarabine, high dose aldesleukin and some of the other 
medications you will receive are listed below:  
Cyclophosphamide and Fludarabine Side Effects 
Common 
Less Common 
Rare 
 
Changes in blood counts 
including: low red cell 
count (causing fatigue and 
shortness of breath), low 
platelet count (increasing 
the risk of bleeding and 
bruising), decrease in 
white blood cells 
(increasing the risk of 
infection and the need for 
treatment with antibiotics 
or other treatment)  
 
Loss of appetite, nausea, 
vomiting,  
 
Diarrhea, stomach pain 
 
Mouth sores 
 
Hair loss 
 
Fatigue 
 
Muscle or joint aches  
 
Bleeding 
 
Infection 
 
Bladder irritation with 
bloody urine 
 
Severe allergic reaction 
(difficulty 
breathing/swelling) 
 
Headache or dizziness 
 
Sweating 
 
Swelling of arms or legs 
 
Skin changes, rash, blisters  
 
Weakness 
 
Hearing loss 
 
Heart damage 
 
Lung damage 
 
Kidney damage 
 
Inflammation of the eye 
resulting in blindness 
 
Inflammation of nervous 
system resulting in death 
 
Epstein Barr Virus 
Lymphoma. This can be 
fatal (Two patients on 
other studies in the 
Surgery Branch developed 
EBV lymphoma, and both 
died as a result of this 
disease.) 
 
Loss of fertility 
 
Death due to 
complications resulting 
from suppression of the 
immune function which 
resulted in a severe 
infection  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 9 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
Aldesleukin (IL-2) Side Effects 
Common 
Less Common  
Rare 
 
Fever, chills, and fatigue  
 
Lowered platelet and red 
blood cell levels that may 
require transfusions  
 
Significant fluid retention 
causing weight gain (as 
much as 20 pounds).  
 
Low blood pressure 
 
Increased heart rate 
 
Shortness of breath 
 
Low urine output 
 
Swelling in your 
extremities,  
 
Fluid in your lungs that 
can require oxygen  
 
Dry mouth, nausea, 
vomiting and diarrhea; 
 
Rash, itching; and changes 
in skin or hair 
pigmentation, called 
vitiligo;  
 
Changes in mental status, 
including confusion, 
difficulty sleeping or vivid 
dreams; this can be severe 
and require sedation and 
monitoring in the ICU 
 
 
Decrease in thyroid 
function that may require 
daily thyroid hormone 
replacement. 
 
Abnormal kidney and liver 
function that can be 
severe.  
 
Abnormal heartbeats or 
low blood pressure that 
may require treatment in 
the ICU.  
 
Breathing problems which 
may need monitoring in 
ICU and insertion of a 
breathing tube.  
 
 
Bowel perforation (a hole) 
requiring longer 
hospitalization or surgery. 
 
Autoimmune disease, 
where your immune 
system attacks cells in 
organs of your body. 
Should this occur, you will 
be treated with steroids to 
stop the immune response. 
 
Damage to the heart 
muscle or heart attack 
 
Loss of blood flow to the 
extremities due to 
medicines used to treat 
very low blood pressure 
and shock. In one instance 
a patient had to have her 
lower arm amputated after 
treatment with these 
medicines. 
 
Aldesleukin is mixed with 
human albumin which 
could cause an allergic 
reaction or potentially 
transmit viral infections, 
although we have not had 
this occur. 
  
Support Medications – Side Effects 
Common 
Less Common 
Rare 
Filgrastim (To increase production of white blood cells) 
 
Bone Pain 
 
Severe headache 
 
Severe breathing problems 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 10 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
 
Rupture of your spleen 
Bactrim (To prevent a specific type of pneumonia) 
 
 
Fever 
 
Nausea, vomiting  
 
Skin rash with itching 
 
Reduced number of white 
blood cells  
 
Allergic reaction 
 
Fluconazole (To prevent fungal infections)  
 
Headache 
 
Nausea, vomiting, diarrhea, 
abdominal pain 
 
Itching  
 
 
A skin disorder called 
Stevens Johnson Syndrome, 
which can be fatal 
 
Liver damage which may 
be permanent 
Acyclovir and Valacyclovir 
 
 
Temporary decrease in 
kidney function which may 
not cause any symptoms 
 
Nausea, vomiting, diarrhea, 
constipation  
 
Pain and irritation at place 
of injection 
 
Skin rash, hives, itching  
 
Tremors, dizziness, 
Confusion, seizures 
 
Fatigue  
 
Blood in the urine 
Prior to and throughout this study you will undergo many tests to determine the size and extent 
of your tumor, as well as the impact of the treatment. Multiple blood tests will be performed and 
some of your serum and lymphocytes will be stored for future testing. Blood and tissue samples 
collected from you may be stored and used in the future to study scientific questions related to 
this protocol. If there are any risks to you or your family associated with these future scientific 
studies which are not covered in this consent form, your consent will be obtained before such 
studies are performed. 
If your disease progresses or recurs after this experimental treatment, then you will no longer 
receive treatment in this protocol, though you may be eligible to be considered for other 
protocols at the National Cancer Institute, NIH or referred elsewhere for treatment.  
Gene Therapy Risk of Cancer and Other Diseases  
We are unsure if this type of gene therapy will cause you to become sick in the future. It is 
possible that it may cause your immune system or nerves not to work well or cause a sickness of 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 11 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
your blood cells or even a cancer (for example leukemia). We do not know if you will develop 
any of these disorders, but you need to be aware of this possible risk. Children in France and 
England received gene therapy for a particular disease of the immune system. Most of the 
children were cured, but 5 children out of 22 later developed leukemia and one died. Experts 
who looked at these cases thought that the gene therapy caused the leukemia in these children. 
To monitor you for this risk we will be testing your blood 3 months after cell infusion, then at 6 
and 12 months, and then annually thereafter. If we find that the cells we have given you grow out 
of control, chemotherapy will be given to you to kill the cells, given their risk of causing 
leukemia or a second cancer. This testing will be conducted on our protocol 09-C-0161, “Follow 
up Protocol for Subjects Previously Enrolled in NCI Surgery Branch Studies” to which you will 
be enrolled following treatment. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink. 
We do not know if you will receive personal, medical benefit from taking part in this study. 
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer. Because there is not much information about the 
effect of this treatment on cancer, we do not know if you will benefit from taking part in this 
study, although the knowledge gained from this study may help others in the future who have 
cancer.  
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Other options for treatment of your cancer include: 
• Taking part in another study 
• Getting treatment or care for your cancer without being in a study 
• Getting no treatment or getting comfort care, which is also called palliative care. This 
type of care helps reduce pain, tiredness, appetite problems, and other problems caused 
by cancer. It does not treat the cancer directly, but instead tries to improve how you feel. 
Comfort care tries to keep you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 12 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
• if you become pregnant 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Sponsor. If you 
withdraw your consent and leave the trial, any samples of yours that have been obtained for the 
study and stored at the NCI can be destroyed upon request. However, any samples and data 
generated from the samples that have already been distributed to other researchers or placed in 
the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside 
the Clinical Center, NIH if the study related treatment is not available at the NIH.  
• There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH. You may have to pay for these costs if they 
are not covered by your insurance company. 
• Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH. 
• Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Organizations that may look at and/or 
copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• NCI Institutional Review Board 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 13 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
• The study Sponsor, Center for Cancer Research or their agents 
• Our research collaborator, Kite Pharma, Inc. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most the 
Website will include a summary of the results. You can search this Web site at any time.  
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide. You may ask your research team 
for a copy of the Protocol Review Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:14-C-0110 
CONTINUATION: page 14 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent 
 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using the cell product 
developed by the NCI Surgery Branch through a joint study with your researchers and the 
company (Kite Pharma, Inc.). The company also provides financial support for this study.  
Use of Specimens and Data for Future Research 
Blood and tissue collected during the course of this study will be used for future research and 
will be stored, tracked and disposed of under our companion protocol 03-C-0277, (Cell Harvest 
and Preparation for Surgery Branch Adoptive Cell Therapy Protocols) on which you have 
already been enrolled.  
In addition, to advance science, it is helpful for researchers to share information they get from 
studying human samples. They do this by putting it into one or more scientific databases, where 
it is stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved. Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses. These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you. It is also possible that the stored specimens and data may never be used. Results 
of research done on your specimens and data will not be available to you or your doctor. It might 
help people who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 14-C-0110 
CONTINUATION: page 15 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.: 09-25-0099 
 
File in Section 4: Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality. When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified. In most cases, 
the NIH will not release any information about your research involvement without your written 
permission. However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record. This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries. The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here. In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government. However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
3. 
Payments. The amount of payment to research volunteers is guided by the National 
Institutes of Health policies. In general, patients are not paid for taking part in research studies at 
the National Institutes of Health. Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions. If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Steven A. Rosenberg, M.D., Ph.D., Building 10, Room 3-3940, Telephone: 240-
760-6218. If you have any questions about the use of your specimens or data for future research 
studies, you may also contact the Office of the Clinical Director, Telephone: 240-760-6070. You 
may also call the Clinical Center Patient Representative at 301-496-2626.  
5. 
Consent Document. Please keep a copy of this document in case you want to read it 
again. 
 
 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 14-C-0110 
CONTINUATION: page 16 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.: 09-25-0099 
 
File in Section 4: Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions. I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions. I hereby give 
permission for my child to take part in this 
study.  
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 28, 2018 THROUGH DECEMBER 27, 2018.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name