Clinical trial NCT01967823
Conditions: Melanoma Meningioma Breast Cancer Non-Small Cell Lung Cancer Hepatocellular Cancer
Keywords: Metastatic Cancer Gene Therapy Immunotherapy Tumor Regression Melanoma
Sponsor: National Cancer Institute (NCI)
Start date: 2013-10-24; Completion date: 2020-04-06
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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 them, and then giving the cells back to the patient. In a previous study the NCI Surgery Branch used the anti-ESO-1 gene and a type of virus (retrovirus) to make these tumor fighting cells (anti-ESO-1 cells). About half of the patients who received this treatment experienced shrinking of their tumors. In this study, we are using a slightly different method of producing the anti-ESO-1 cells which we hope will be better in making the tumors shrink.

Objectives:

The purpose of this study is to see if these tumor fighting cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their surface can cause tumors to shrink and to see if this treatment is safe.

Eligibility:

\- Patients 15 years old and older with cancer that has the ESO-1 molecule on their tumors.

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 ESO-1 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-ESO-1 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:
PRECIS

Background:

* We have constructed a single retroviral vector that contains both and \<= chains of a murine T cell receptor (mTCR) that recognizes the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) (ESO) tumor antigen, which can be used to mediate genetic transfer of this T-cell receptor (TCR) with high efficiency.
* In co-cultures with human leukocyte antigen serotype within the HLA-A serotype group (HLA-A2) and ESO double positive tumors, anti-ESO mTCR transduced T cells secreted significant amounts of Interferons (IFN)- \>= with high specificity.

Primary objective:

\- To determine whether the administration of anti-ESO mTCR-engineered peripheral blood lymphocytes (PBL) plus high-dose aldesleukin following a non-myeloablative lymphoid depleting preparative regimen may result in objective tumor regression in patients with metastatic cancers including melanoma expressing the ESO antigen.

Eligibility:

* Age greater than or equal to 15 years and less than or equal to 70 years. Patients aged 15-17 years must weigh at least 50 kg.
* HLA-A\*0201 positive
* Metastatic cancer including melanoma whose tumors express the ESO antigen
* Previously received and have been a non-responder to or recurred after receiving standard care for metastatic disease
* No contraindications for high-dose aldesleukin administration

Design:

* Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in the presence of anti-CD3 monoclonal antibody (OKT3) and aldesleukin to stimulate T-cell growth.
* Transduction is initiated by exposure of cells to retroviral vector supernatant containing the anti-ESO mTCR genes. This mTCR targets the exact same epitope as the human T-cell receptor (hTCR).
* All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine.
* On day 0 patients will receive anti-ESO mTCR gene-transduced PBMC and then begin high dose aldesleukin.
* A complete evaluation of evaluable lesions will be conducted 6 weeks (+/- 2 weeks) following the administration of the cell product.
* The study will be conducted using a phase II optimal design (Simon R, Controlled Clinical Trials 10:1-10, 1989). The objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-ESO 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% Partial Response (PR) + Complete Response (CR) rate (p1=0.20).
* A total of up to 43 patients may be enrolled (41, plus allowing for up to 2 non-evaluable patients).

Arms: arm 1: Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-ESO murine T-cell receptor (TCR) transduced PBL + high-dose (HD) aldesleukin
Interventions: intervention 1: Anti-NY ESO-1 mTCR PBL intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: Aldesleukin
Intervention descriptions: intervention 1: Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes. intervention 2: Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenously (IV) in 250 mL dextrose 5% in water (D5W) infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days. intervention 3: Days -7 to -3: Fludarabine 25 mg /m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. intervention 4: Aldesleukin 720,000 IU/kg intravenously (IV) (based on total body weight) over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).

Protocol documents:
ICF_002.pdf: 
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY
 MEDICAL RECORD
 • Attach to NIH-2514-2, Consent to Participate in a Clinical Research Study
INSTITUTE:
 National Cancer Institute
STUDY NUMBER:
13-C-0214
PRINCIPAL INVESTIGATOR: Steven A. Rosenberg, M.D., Ph.D.
STUDY TITLE:
A Phase II Study of Metastatic Cancer that Expresses NY-ESO-1 Using 
Lymphodepleting Conditioning Followed by Infusion of Anti-NY ESO-1 Murine TCR-
Gene Engineered Lymphocytes
Continuing Review Approved by the IRB on 10/09/19
Amendment Approved by the IRB on 08/10/18 (N)
Date Posted to Web: 10/30/19
Assent (Ages 15-17 Years) 
PATIENT IDENTIFICATION
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4: Protocol Consent (2)
INTRODUCTION
We would like to invite you to take part in a research study at the National Institutes of Health 
(NIH). Before you decide about taking part in the study, we want you to know why we are doing 
the study and if it will help you. We also want you to know about any risks (what might go 
wrong) and what you will have to do. You can only be in the study if you and your parent(s) 
agree.
This form gives you information about the study. Your doctor will talk to you about the study 
and answer questions you have. If you would like to take part in this study, we will ask you to 
sign this form to show that you understand this study. We will give you a copy of this form to 
keep. It is important that you know:

You do not have to join the study.

You may change your mind and drop out of the study at any time.
If we make important changes to the study we will tell you about it and make sure you still want 
to be in the study.
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 them, and then giving the cells back to the patient. In a previous study, we used the 
anti-ESO-1 gene and a type of virus (retrovirus) to make these special cells (anti-ESO-1 cells). 
About half of the patients who received this treatment experienced shrinking of their tumors. In 
this study, we are using a slightly different way of producing the cells which we hope will work 
better in making the tumors shrink. The purpose of this study is to see if these tumor-fighting 
cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their 
surface cause tumors to shrink and to see if this treatment is safe.


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PATIENT IDENTIFICATIONMINOR PATIENT'S ASSENT TO PARTICIPATE IN A
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What will I be asked to do? What are my requirements? 
Before you Begin the Study
The following procedures are conducted under other Surgery Branch protocols, 99-C-0128 or 
03-C-0277, to which you have already enrolled.
Cell Harvest and Growth
You underwent a process called “apheresis” while enrolled on our companion protocol 03-C- 
0277. This process obtained certain types of blood cells from you. Some of these cells (anti- 
ESO-1) will be grown in the lab and genetically modified to recognize a protein on your tumor 
cells. 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 doctor who referred you to the NIH. 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 study doctor if you are allergic to any antibiotics.
Work-up
Prior to receiving the experimental treatment, you will undergo many tests. We will evaluate you 
for eligibility for participation on this trial with a physical examination, CT and/or MRI scans, x-
rays, EKG, heart and lung function tests, and blood tests. If you have received ipilimumab (also 
called Yervoy, MDX-010) or ticilimumab, and have experienced any gastrointestinal 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. 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 
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, a specific type of “apheresis”, 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 liquid component of blood), and lymphocytes (or white cells), 


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and then the plasma and red cells are returned to you through a second needle in your other arm. 
The white blood cells collected before treatment may be used to help grow the cells. In addition 
to the leukapheresis you will undergo as part of your work-up, we will also ask you to undergo 
one additional apheresis procedure between 4 and 6 weeks after you receive the cell infusion to 
see the impact of this therapy on the immune system and see if the cells we gave you are still 
active.
The leukapheresis procedure takes between 4-5 hours to complete. Rarely, people may 
experience lightheadedness or dizziness. We ask that you eat prior to the procedure to prevent 
this.
During the Study
Chemotherapy Regimen (Day -7 through Day -3)
After we have grown the anti-ESO-1 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-ESO-1 cells can work without any interference from the cells in your immune system. 
(These medicines will not treat your cancer. They may cause your tumor to shrink some, but this 
shrinkage is anticipated to be only partial and only for a short time.) The main purpose of the 
chemotherapy is to see if we can make the cells more effective in fighting cancer tumors. Animal 
experiments have indicated that this can make the cells more effective in fighting cancer tumors, 
and we think this is true in humans. You will receive the cyclophosphamide through your 
catheter over 1 hour for two days (Day -7 and Day -6) and the fludarabine will be given through 
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.
Cell Infusion and Aldesleukin (IL-2) Regimen (Day 0 through Day 5)
Two to four days after the last dose of chemotherapy, you will be given the anti-ESO-1 cells. 
The anti-ESO-1 cells will be given through your catheter over 20-30 minutes. Within 24 hours 
after the anti-ESO-1 cell infusion, you will be given high-dose aldesleukin through your catheter. 
Aldesleukin is approved by the FDA for treatment of metastatic melanoma and metastatic renal 
cell cancer. The purpose of giving aldesleukin with this therapy is to keep the cells we give you 
active for as long as possible so they will fight your tumor. 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 depending on how well you tolerate the 
infusion. The risks of the cells and aldesleukin are described on the following pages.
The day after you receive the anti-ESO-1 cells, we may give you G-CSF (filgrastim) as a shot or 
injection under the skin every day to stimulate your blood cells until they increase to a sufficient 
number. 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 


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medicines and treatments to prevent as many of these side effects and to make you as 
comfortable as we can.
When you are Finished with Treatment
Recovery
You will recover in the hospital until you are well enough to go home. This usually takes 7-21 
days after you have received cells or your last dose of aldesleukin; however, you may need to 
stay in the hospital for longer than this before you are well enough to go home. 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 1-9 
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 to prevent you from catching a certain type of pneumonia seen in patients who have 
low white blood cell counts. You may also need to take Valtrex, an anti-viral, for at least 6 
months following your treatment to prevent any type of herpes simplex virus, like shingles.
After you are discharged, we will ask you to return to the NIH Clinical Center approximately 6 
and 12 weeks following treatment, and then if you are responding to the treatment, every 3 
months x3, every 6 months for 2 years, and then as determined by your study doctor.
The first follow-up visit will probably take 2 days; the following visits may only take one day. 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 email 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 doctor 
who referred you to the NIH.
Sometimes things that don’t feel good happen in research studies. 
Some things that could happen, called side effects, may hurt you or make you feel upset. Some 
of the things might happen to you or they might not. Or things might happen that we don’t know 
about yet.
This experimental treatment can lead to long-term decrease in your immune function, which 
means it can lower your body’s ability to fight infections. It is also possible that you may lose 


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your fertility following this experimental treatment, meaning it may be harder for you to make a 
baby. It is possible, although unlikely, that this experimental treatment may cause your death.
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.
As this is a new experimental therapy, you may experience side effects that we do not expect that 
may cause your condition to worsen. Any new information that becomes available during the 
course of this study will be shared with you.
Anti-ESO-1 Cell Infusion (Gene Transfer)
The cells we will be giving you have a type of virus (retrovirus) put into them along with the 
anti-ESO-1 protein. Although this retrovirus is not active, there is the rare possibility that it may 
cause infection. The cells could also cause you to develop another type of cancer, such as 
leukemia or lymphoma. These specific gene-modified cells have been given only to a few 
individuals before so we do not have much information about the 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, which may progress to needing insertion of 
a breathing tube and treatment in the ICU.

Mental status changes

Abnormal kidney or liver function

Breathing problems, which may be severe

Decreased heart function

Electrolyte imbalances

Changes in your blood pressure

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.
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.


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Aldesleukin (IL-2)
When IL-2 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. 
In our experience giving IL-2 to over 2,000 patients, we have found that these side effects go 
away within a few days of stopping the IL-2.
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

Complications resulting 
from suppression of 
immune function, which 
can result in a severe 
infection and can be fatal.
Aldesleukin (IL-2) Side Effects
Common
Less Common
Rare

Fever, chills, and fatigue

Decrease in thyroid 

Bowel perforation (a 


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
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, diarrhea

Rash, itching

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.
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
hole) requiring longer 
hospitalization or 
surgery. This is more 
common in patients 
who have previously 
received anti-CTLA-4 
antibody (i.e., 
ipilimumab). You will 
have a colonoscopy and 
biopsy before treatment 
if you have previously 
received anti-CTLA-4 
antibody.

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.

IL-2 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


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Common
Less Common
Rare
Filgrastim (To increase production of white blood cells)

Bone pain

Severe headache

Severe breathing 
problems

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
What benefit can I expect? 
People may also have good things happen to them when they are in research studies. The good 
things may be 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 receive personal, medical benefit from taking part in this 


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study, although what we learn from this study may help others in the future who also have 
cancer.
Can I refuse to be in the study? 
Please talk to your parents about this before you decide whether or not to be in this research 
study. We will also ask your parents to give their permission for you to be in this study. But even 
if your parents say “yes,” you can still decide not to be in this research study.
If you don’t want to be in this study, you don’t have to.
What other choices do I have if I do not take part in this study? 
If you don’t want to be in this study, there are other options for treatment of your cancer 
including:

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 study doctor about these and other options.
You may stop being in this any time. 
Remember, being in this study is up to you and no one will be upset if you don’t want to take 
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take part in this study, you will be free to return to the care of your doctor who referred you to 
the NIH.
Consenting 
Once you have turned 18, we will contact you to find out if you would still like to participate in 
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MEDICAL RECORD MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•  Attach to NIH-2514-2, Consent to Participate in a Clinical Research Study
STUDY NUMBER:  13-C-0214
CONTINUATION: page 10 of 10 pages
PATIENT IDENTIFICATIONMINOR PATIENT'S ASSENT TO PARTICIPATE IN A
CLINICAL RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4: Protocol Consent  
I have had this study explained to me in a way that I understand, and I have had the chance to ask 
questions. I agree to take part in this study.
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Prot_SAP_000.pdf: 
Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
1
Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
CC Protocol Number: 13-C-0214 N 
IBC Number: RD-13-VII-07 
OSP Number: 1308-1249 
NCT Number: NCT01967823 
Version Date: August 6, 2018 
PROTOCOL TITLE 
A Phase II Study of Metastatic Cancer that Expresses NY-ESO-1 Using Lymphodepleting 
Conditioning Followed by Infusion of Anti-NY-ESO-1 Murine TCR-Gene Engineered 
Lymphocytes 
 
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-ESO murine TCR transduced PBL 
IND Number: 
15698 
Sponsor: 
Center for Cancer Research 
Manufacturer 
Surgery Branch Cell Production Facility 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
2
PRÉCIS 
Background: 
• We have constructed a single retroviral vector that contains both α and β chains of a 
murine T-cell receptor (mTCR) that recognizes the NY-ESO-1 (ESO) tumor antigen, 
which can be used to mediate genetic transfer of this TCR with high efficiency. 
• In co-cultures with HLA-A2 and ESO double positive tumors, anti-ESO mTCR 
transduced T-cells secreted significant amounts of IFN-γ with high specificity. 
Objective:  
• Primary objective: 
o To determine whether the administration of anti-ESO mTCR-engineered peripheral 
blood lymphocytes (PBL) plus high-dose aldesleukin following a non-myeloablative, 
lymphodepleting preparative regimen may result in objective tumor regression in 
patients with metastatic cancer including melanoma expressing the ESO antigen.  
Eligibility: 
• Age ≥ 15 years and ≤ 70 years. Patients aged 15-17 years must weigh at least 50 kg. 
• HLA-A*0201 positive 
• Metastatic cancer including melanoma whose tumors express the ESO antigen 
• Previously received and have been a non-responder to or recurred after receiving standard 
care for metastatic disease 
• No contraindications for high-dose aldesleukin administration 
Design: 
• Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured 
in the presence of anti-CD3 (OKT3) and aldesleukin to stimulate T-cell growth. 
• Transduction is initiated by exposure of cells to retroviral vector supernatant containing 
the anti-ESO mTCR genes. This mTCR targets the exact same epitope as the hTCR.  
• All patients will receive a non-myeloablative, lymphodepleting preparative regimen of 
cyclophosphamide and fludarabine. 
• On Day 0, patients will receive anti-ESO mTCR gene-transduced PBMC and then begin 
high-dose aldesleukin. 
• A complete evaluation of evaluable lesions will be conducted 6 weeks (± 2 weeks) 
following the administration of the cell product. 
• The study will be conducted using a phase II optimal design. 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).  
• A total of up to 43 patients may be enrolled (41, plus allowing for up to 2 non-evaluable 
patients).  
 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
3
TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ............................................................................................................. 3 
1 
INTRODUCTION................................................................................................................. 7 
1.1 Study Objectives ......................................................................................................................7 
1.1.1 Primary Objective 
7 
1.1.2 Secondary Objectives 
7 
1.2 Background and Rationale .......................................................................................................7 
1.2.1 Adoptive Cell Transfer Experience at the NCI Surgery Branch 
7 
1.2.2 NY-ESO-1 T-Cell Receptor 
9 
1.2.3 NY-ESO-1 as a Target for Cell Transfer Clinical Studies 
9 
1.2.4 Murine TCR Directed Against NY-ESO-1 
11 
1.2.5 Safety Considerations 
15 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 15 
2.1 Eligibility Criteria ..................................................................................................................15 
2.1.1 Inclusion Criteria for Patients with Solid Tumor Cancers and Melanoma 
15 
2.1.2 Inclusion Criteria for Patients with Malignant Meningioma 
16 
2.1.3 Inclusion Criteria for all Patients 
16 
2.1.4 Exclusion Criteria 
17 
2.2 Screening Evaluation .............................................................................................................18 
2.2.1 Within 3 Months Prior to Starting the Preparative Regimen 
18 
2.2.2 Within 8 Weeks Prior to Starting the Preparative Regimen 
19 
2.2.3 Within 4 Weeks Prior to Starting the Preparative Regimen 
19 
2.2.4 Within 14 Days Prior to Starting the Preparative Regimen 
19 
2.2.5 Within 7 Days Prior to Starting the Preparative Regimen 
19 
2.3 Registration and Treatment Assignment Procedures .............................................................19 
2.3.1 Prior to Registration for this Protocol 
19 
2.3.2 Registration Procedure 
19 
2.3.3 Treatment Assignment Procedures 
20 
3 
STUDY IMPLEMENTATION .......................................................................................... 20 
3.1 Study Design ..........................................................................................................................20 
3.1.1 Pre-Treatment Phase: Cell Preparation Performed on 03-C-0277 
20 
3.1.2 Treatment Phase 
20 
3.2 Protocol Stopping Rules ........................................................................................................21 
3.3 Drug Administration ..............................................................................................................21 
3.3.1 Preparative Regimen with Cyclophosphamide and Fludarabine 
21 
3.3.2 Cell Infusion 
22 
3.3.3 Aldesleukin Administration 
22 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
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4
3.3.4 Treatment Schedule 
23 
3.4 Baseline Evaluation ...............................................................................................................23 
3.4.1 Within 14 Days Prior to Starting the Preparative Regimen 
23 
3.5 On-Study Evaluation ..............................................................................................................24 
3.5.1 During the Preparative Regimen (Daily) 
24 
3.5.2 Post-Cell Infusion 
24 
3.5.3 During Hospitalization (Every 1-2 Days) 
24 
3.6 Post-Treatment (Follow-Up) Evaluation ...............................................................................25 
3.6.1 Time-Period of Evaluations 
25 
3.6.2 Scheduled Evaluations 
25 
3.7 Study Assessment Calendar ...................................................................................................27 
3.8 Criteria for Removal from Protocol Therapy and Off-Study Criteria ...................................30 
3.8.1 Criteria for Removal from Protocol Therapy 
30 
3.8.2 Off-Study Criteria 
30 
3.8.3 Off Protocol Therapy and Off-Study Procedure 
30 
4 
CONCOMITANT MEDICATIONS/MEASURES .......................................................... 30 
4.1 Infection Prophylaxis .............................................................................................................30 
4.1.1 Pneumocystis Jirovecii Pneumonia 
31 
4.1.2 Herpes Simplex or Varicella Zoster Virus Prophylaxis 
31 
4.1.3 Fungal Prophylaxis (Fluconazole) 
31 
4.1.4 Empiric Antibiotics 
31 
4.2 Blood Product Support ...........................................................................................................31 
4.3 Other Concomitant Medications to Control Side Effects ......................................................32 
5 
BIOSPECIMEN COLLECTION ...................................................................................... 32 
5.1 Samples Sent to Figg Lab ......................................................................................................32 
5.2 Samples Sent to the Surgery Branch Cell Production Facility ..............................................32 
5.3 Prior to Chemotherapy Administration ..................................................................................32 
5.4 Prior to Cell Infusion (Baseline Sample for Cytokine Analysis) ...........................................33 
5.5 Post-Cell Infusion Evaluations ..............................................................................................33 
5.6 Samples Collection Schedule .................................................................................................33 
5.7 Immunological Testing ..........................................................................................................33 
5.8 Monitoring Gene Therapy Trials: Persistence and RCR .......................................................34 
5.9 Sample Storage, Tracking and Disposition for Surgery Branch Cell Production Facility ....34 
5.10 Sample Storage, Tracking and Disposition for Figg Lab ......................................................35 
5.10.1 Sample Data Collection 
35 
5.10.2 Sample Storage and Destruction 
35 
6 
DATA COLLECTION AND EVALUATION ................................................................. 36 
6.1 Data Collection ......................................................................................................................36 


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5
6.1.1 Exclusions to Routine Adverse Event Reporting 
36 
6.2 Data Sharing Plan ..................................................................................................................36 
6.2.1 Human Data Sharing Plan 
36 
6.2.2 Genomic Data Sharing Plan 
37 
6.3 Response Criteria ...................................................................................................................37 
6.3.1 Definitions 
37 
6.3.2 Disease Parameters 
37 
6.3.3 Methods for Evaluation of Measurable Disease 
38 
6.3.4 Response Criteria 
39 
6.4 Toxicity Criteria .....................................................................................................................41 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN ............................................................................................................................................ 41 
7.1 Definitions..............................................................................................................................41 
7.1.1 Adverse Event 
41 
7.1.2 Suspected Adverse Reaction 
41 
7.1.3 Unexpected Adverse Reaction 
42 
7.1.4 Serious 
42 
7.1.5 Serious Adverse Event 
42 
7.1.6 Disability 
42 
7.1.7 Life-Threatening Adverse Drug Experience 
42 
7.1.8 Protocol Deviation (NIH Definition) 
42 
7.1.9 Non-Compliance (NIH Definition) 
42 
7.1.10 Unanticipated Problem 
43 
7.2 IRB and Clinical Director (CD) Reporting ............................................................................43 
7.2.1 IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
43 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
43 
7.2.3 IRB Reporting of IND Safety Reports 
43 
7.2.4 Request for Waiver from IRB Reporting: Anticipated Protocol Deviations and 
Expected Non-UP Adverse Events 
44 
7.3 IND Sponsor Reporting Criteria ............................................................................................44 
7.3.1 Waiver of Expedited Reporting to CCR 
44 
7.3.2 Reporting Pregnancy 
45 
7.4 Institutional Biosafety Committee (IBC) Reporting Criteria .................................................45 
7.4.1 Serious Adverse Event Reports to IBC 
45 
7.4.2 Annual Reports to IBC 
46 
7.5 Data and Safety Monitoring Plan ...........................................................................................47 
7.5.1 Principal Investigator/Research Team 
47 
7.5.2 Sponsor Monitoring Plan 
47 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
6
7.5.3 Safety Monitoring Committee (SMC) 
47 
8 
STATISTICAL CONSIDERATIONS .............................................................................. 48 
9 
COLLABORATIVE AGREEMENTS.............................................................................. 48 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................ 48 
10.1 Rationale For Subject Selection .............................................................................................48 
10.2 Participation of Children ........................................................................................................49 
10.3 Participation of Subjects Unable to Give Consent .................................................................49 
10.4 Evaluation of Benefits and Risks/Discomforts ......................................................................49 
10.5 Risk/Benefit Analysis ............................................................................................................50 
10.6 Consent Process and Documentation .....................................................................................50 
10.6.1 Consent for Minors when they Reach the Age of Majority 
51 
10.6.2 Telephone Consent 
51 
10.6.3 Informed Consent of Non-English Speaking Subjects 
51 
11 PHARMACEUTICAL INFORMATION ......................................................................... 52 
11.1 Investigational Regimen ........................................................................................................52 
11.1.1 Anti-ESO TCR Transduced PBL 
52 
11.1.2 Interleukin-2 (Aldesleukin, Proleukin, Recombinant Human Interleukin 2) 
53 
11.1.3 Fludarabine 
53 
11.1.4 Cyclophosphamide 
54 
11.2 Support Medications ..............................................................................................................55 
11.2.1 Mesna (Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891) 
55 
11.2.2 Filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen) 56 
11.2.3 Trimethoprim and Sulfamethoxazole Double Strength (TMP/SMX DS) 
56 
11.2.4 Herpes and Varicella Zoster Virus Prophylaxis 
57 
11.2.5 Fluconazole 
58 
11.2.6 Ondansetron Hydrochloride 
58 
11.2.7 Furosemide 
58 
12 REFERENCES .................................................................................................................... 59 
13 APPENDICES ..................................................................................................................... 61 
13.1 Appendix A: Modification of Dose Calculations* in Patients Whose BMI is Greater than 35
 
61 
13.2 Appendix B: Adverse Events Occurring In ≥10% of Patients Treated With Aldesleukin 
(N=525)1 ........................................................................................................................................62 
13.3 Appendix C: Expected IL-2 Toxicities and Their Management ............................................63 
13.4 Appendix D: Interleukin-2 Toxicities Observed in Patients Treated at the NIH Clinical 
Center .............................................................................................................................................66 
13.5 Appendix E: Certificate of Analysis – Anti-NY-ESO-1 mTCR PBL ...................................67 
 
 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
7
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To determine whether the administration of anti-ESO mTCR-engineered peripheral blood 
lymphocytes plus high-dose aldesleukin following a non-myeloablative, lymphodepleting 
preparative regimen may result in objective tumor regression in patients with metastatic 
cancer including melanoma expressing the ESO antigen. 
1.1.2 Secondary Objectives 
• Determine the in vivo survival of TCR gene-engineered cells. 
• Determine the toxicity profile of this treatment regimen. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Adoptive Cell Transfer Experience at the NCI Surgery Branch 
The National Cancer Institute Surgery Branch (NCI-SB) has pioneered novel T-cell based cancer 
therapies for chemotherapy-refractory cancers and continues efforts to expand their application. 
This work has its foundation in the successful treatment of metastatic cutaneous melanoma with 
adoptive transfer of tumor infiltrating lymphocytes (TIL)(1). We have reported the results of 
adoptive transfer therapy in 93 patients with metastatic melanoma who received TIL following a 
lymphodepleting regimen plus aldesleukin administration, with or without total body irradiation 
(Figure 1)(2). Forty-three patients received a non-myeloablative chemotherapy consisting of 60 
mg/kg cyclophosphamide daily x 2 and 25mg/m2 fludarabine daily x 5 prior to cell transfer and 
aldesleukin administration. Twenty-five patients each also received the same chemotherapy 
agents in conjunction with either 200 or 1200 cGy total body irradiation (TBI) prior to cell 
infusion and aldesleukin administration. The overall objective response rate using RECIST 
criteria in these 93 patients was 56%. The clinical results in these three trials are shown in Table 
1. There was one treatment related death in these 93 patients, which occurred in a patient who 
received 200cGy TBI who had an undetected diverticular abscess prior to beginning therapy. Of 
the 52 responding patients in this trial, 42 had disease that was refractory to aldesleukin therapy 
and 22 had disease that was refractory to prior aldesleukin plus chemotherapy. Thus, TIL therapy 
shows promise as an effective treatment for chemotherapy refractory metastatic cutaneous 
melanoma. 
 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
8
 
Figure 1. Survival of patients with metastatic melanoma treated with autologous tumor-
infiltrating lymphocytes and IL-2 following three different lymphoconditioning regimens. 
 
 
Table 1. Cell Transfer Therapy (11/1/2012). Response rates and duration in patients with 
melanoma treated with tumor-infiltrating lymphocytes plus high-dose IL-2 following three 
different lymphoconditioning regimens. 
 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
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9
1.2.2 NY-ESO-1 T-Cell Receptor 
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 the surface of 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 tumor-associated antigen 
(TAA)-reactive TCR genes isolated from mice immunized against the NY-ESO-1 cancer testis 
antigen into normal peripheral blood lymphocytes (PBL) derived from cancer patients and to 
return these engineered cells to patients aimed at mediating regression of their tumors. This trial 
is similar to previous NCI-SB TCR gene transfer adoptive immunotherapy protocols using 
human and mouse TCRs. 
1.2.3 NY-ESO-1 as a Target for Cell Transfer Clinical Studies 
The NY-ESO-1 molecule, which was initially identified by screening a cDNA expression library 
with an antiserum from a patient with esophageal squamous cell carcinoma, represents a tumor 
antigen that can be targeted in patients bearing a wide variety of malignancies(3). Expression of 
NY-ESO-1 protein has been observed in approximately one third of melanoma, breast, prostate, 
lung ovarian, thyroid and bladder cancer, but is limited in normal tissues to germ cells and 
trophoblasts(4). A related cancer/testis antigen, LAGE-1, has also been identified and shown to 
possess 84% amino acid similarity to the NY-ESO-1 protein(5). Further studies resulted in the 
identification of an identical peptide corresponding to amino acids 157 to 165 of the NY-ESO-1 
and LAGE-1 proteins SLLMWITQC as a dominant epitope recognized by HLA-A2 restricted, 
NY-ESO-1 reactive T-cells(6). An HLA-A2 restricted epitope representing the first eleven amino 
acids of an alternative open reading frame of the NY-ESO-1 and LAGE-1 transcripts has also 
been described(7) and epitopes derived from the normal as well as alternative open reading frames 
of both gene products in the context of HLA-A31 have been described(8). In addition, NY-ESO-1 
epitopes are recognized in the context of multiple HLA class II restriction elements(9-11).  
Utilizing modifications to a human anti-ESO TCR directed against the dominant NY-ESO-
1:157-165 T-cell epitope, a Phase II clinical trial (08-C-0121) was opened for accrual in April 
2008 and as of December 20, 2012, has accrued 34 evaluable patients treated for the first time 
with the anti-ESO TCR. Patients were entered into 4 cohorts. Cohorts 1 and 3 include patients 
with metastatic melanoma or renal cell cancer; cohorts 2 and 4 include patients with other types 
of metastatic cancer. In cohorts 3 and 4, patients also received the ALVAC-NY-ESO-1 vaccine. 
Thus, to date, we have enrolled 18 patients with metastatic melanoma, 16 patients with synovial 
sarcoma, and 1 patient with breast cancer. The vaccine was supplied by Sanofi Pasteur who then 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
10
withdrew the supply. There were no apparent effects of the vaccine and it is no longer available. 
The combined responses to therapy are shown in Table 2.  
 
Table 2. Response to therapy with NY-ESO-1 TCR (4/1/13) 
 
Total 
PR (%) 
CR (%) 
OR (%) 
Melanoma 
21 
5 (29%) 
 
α (20+, 10**, 8, 5, 3+, 3) 
4 (19%) 
 
(51+, 39+, 25, 
23+**) 
10 (48%) 
Synovial Cell 
Sarcoma 
18 
12 (67%) 
 
(31+**, 12**, 10, 8, 7, 6, 5, 4+, 4, 
3, 3**, 1*) 
0 
12 (67%) 
α Durations of response in months are in parenthesis under the number of responders. “+” 
indicates on ongoing response. 
* Meets criteria for response at first follow-up, but not official response  
** Plus ALVAC vaccine 
 
This regimen (08-C-0121) resulted in objective cancer regression in 50% (9/18) patients with 
melanoma, 4 of whom are ongoing, and in 63% (10/16) patients with synovial sarcoma 3 of 
which are ongoing. Non-hematologic and hematologic toxicities were those expected from IL-2 
and the myelosuppressive chemotherapy and none were attributed to any off-tumor target 
toxicity due to recognition of NY-ESO-1. Grade 2, 3 and 4 toxicities attributable to the anti-ESO 
TCR are shown in Table 3. There were no mortalities related to the cell therapy; one patient died 
from sepsis secondary to myelosuppression from the chemotherapy, a second patient developed 
renal failure due to aldesleukin.  
 
Table 3. Adverse events possibly related to anti-NY-ESO-1. 
Adverse Event 
Grade 
number of events  
Rash/desquamation 
2 
1 
Bilirubin (hyperbilirubinemia)* 
3 
4 
Dyspnea (shortness of breath) 
2 
1 
Dyspnea (shortness of breath) 
3 
3 
Renal failure* 
4 
1 
* likely due to aldesleukin 
 


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Version Date: August 6, 2018 
 
11
Robbins et al. reported preliminary results from this protocol in March of 2011(12). The clinical 
responses observed in the 34 patients receiving anti-ESO TCR-engineered peripheral blood 
lymphocytes to date show a combined response rate by RECIST criteria for all arms of this study 
of 4 complete responses and 15 partial responses.  
1.2.4 Murine TCR Directed Against NY-ESO-1 
By introducing a TCR targeting the NY-ESO-1 antigen, large numbers of T-cells with a defined 
antigen specificity can be generated, resulting in the clinical responses seen in our past clinical 
trial targeting this antigen. However, given the short duration of some responses seen in the 
current clinical trial, methods to increase the potential efficacy of the TCR were investigated. 
One possible reason for decreased efficacy is that by introducing a TCR, mixed TCR dimers can 
be formed, which could harbor potentially harmful specificities and off-target effects, as well as 
decreasing the TCR expression of both the introduced and endogenous TCRs(13). Studies have 
shown that the pairing of endogenous and introduced TCR chains in TCR gene-modified T-cells 
can lead to the formation of self-reactive TCRs, leading to cytokine-driven autoimmune 
pathology in mouse models(14). These toxicities have not been seen in our prior studies targeting 
the same epitope as in the proposed trial. Murine-human hybrid TCRs have been investigated as 
a method to improve the expression of the transduced TCR. These studies demonstrated that by 
constructing TCRs with a murine constant region in place of the human constant region, a higher 
expression of the receptors were found on the surface of the human lymphocytes, caused by the 
preferential pairing of the murine constant regions(15). The murine-human TCRs mediated higher 
levels of cytokine secretion and cell lysis, which was associated with improved CD3 stability(15).  
To generate high avidity mTCRs against NY-ESO-1 antigen, we employed a transgenic mouse 
model that expresses the human HLA-A*0201 molecule. Transgenic mice expressing the full-
length HLA-A*0201 molecule were immunized with a previously identified naturally processed 
and presented HLA-A*0201 restricted peptide from NY-ESO-1 (SLLMWITQC). Following two 
immunizations, murine T-cells were harvested from the spleen and stimulated in vitro with the 
respective peptide and IL-2. Bulk T-cell cultures were tested for specific reactivity using LPS-
blast cells and T2 cells both pulsed with the relevant peptide after three in vitro stimulations. 
Reactive T-cells from positive wells from both the first and the third bulk stimulations were then 
cloned by limiting dilution and tested for antigen specific reactivity.  
TCR α- and β-chains from each tumor reactive T-cell clone were cloned using SMARTTM RACE 
cDNA amplification kit with gene specific primers in the constant region of mouse TCR α and β-
chains. After the identification of the variable regions of α- and β-chains and the specific 
constant region of the β-chain, specific primers were used to amplify the full length TCR α and 
β-chains from cDNA. The TCR α- and β-chains that showed the highest level of specific 
reactivity were then cloned into an MSGV1-based retroviral vectors with expression cassettes 
consisting of MSGV1 ESO-157muTCRA2aB and MSGV1 ESO-157 muTCRB2aA (Figure 2A). 
The TCR expression in this vector is driven by the viral LTR, α and β chains are expressed as a 
single open reading frame using the 2A linker peptide(16, 17). Human PBL were stimulated for 3 
days and then transduced twice. FACS analysis of transduced PBL using the anti-mouse TCR-β 
chain revealed that both CD8+ and CD4+ cells had been transduced with these TCR vectors 
(Figure 2B). These transduced PBL were then expanded using our rapid expansion protocol 
(REP), along with the human NY-ESO-1 TCR used in our current clinical trial for comparison. 
The percentage of transduced cells was evaluated after one stimulation and after REP (Figure 
2C), which showed an increase in the percentage of positively transduced mTCR cells after REP.  


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
12
 
 
Figure 2. (A) Schematic illustration of the MSGV1 based retroviral vector encoding anti ESO-
157 mu T cell receptor expression cassette. TCR α and β chains are linked with furin- -spacer 
(SGSG)-P2A ribosomal skip peptide sequence. (B) Flow cytometric analysis of ESO mTCR 
transduced PBL, representative of eleven different donors. (C) Percentage of TCR positive cells 
(ESO TCR vs ESO mTCR) after stimulation with OKT3 (S1) and after a rapid expansion 
protocol (R1), representative of four different donors. 


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13
To evaluate the recognition by the respective NY-ESO-1 TCRs, transduced PBL were subjected 
to co-culture assay with peptide pulsed T2 cells. mTCR transduced PBL specifically secreted 
IFN-γ upon encounter with the antigenic peptide in a dose dependent manner (Figure 3), and at 
higher levels after REP. PBL transduced with the ESO mTCR recognized T2 cells pulsed with as 
little as 0.1 ng/ml NY-ESO-1 peptide indicating that the TCR was a relatively high avidity 
receptor. To assess the specific recognition of tumor cells, TCR engineered PBL were co-
cultured with a panel of HLA-A*0201+ and HLA-A*0201- melanoma and lung tumor derived 
cell lines. Specific release of IFN-γ was observed when the TCR engineered PBL were co-
cultured with HLA- A*0201+/NY-ESO-1+ cell lines but not HLA-A*0201-/NY-ESO-1+ or HLA- 
A*0201+/NY-ESO-1- cell lines (Figure 4). Higher levels of IFN-γ were secreted by the mTCR 
when compared with the current human TCR in use. These cells were also capable of specific 
cell lysis of HLA-A*0201+/NY-ESO-1+ tumor cell lines (Figure 5). 
 
 
Figure 3. Recognition of peptide pulsed T2 cells by the ESO TCR and ESO mTCR transduced 
PBL. Human PBL expressing TCR and mTCR against NY-ESO-1, GFP (negative control) and 
untransduced PBL (negative control) were co-cultured for 16 hours with T2 cells that were 
previously pulsed with different concentrations of peptide, representative of four different 
donors. 
 


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Figure 4. Recognition of NY-ESO-1+, A2+ tumor cell lines (H1299-A2, 624.38 and 1300) and 
NY-ESO-1+, A2- tumor cell lines (938). ESO TCR and ESO mTCR transduced PBL were co-
cultured for 16 hours with tumor target cell lines (H1299-A2=non-small cell lung cancer, ESO+, 
A2+, 624.38= melanoma, ESO+, A2+, 1300= melanoma, ESO+, A2+, 938= melanoma, ESO+, 
A2-) and IFN gamma levels were then measured, representative of 8 different donors. 
 
 
 
Figure 5. Cell lysis assay comparing cell-specific lysis activity of the ESO TCR transduced PBL 
with ESO mTCR transduced PBL. Effector cells were co-cultured with an ESO+, A2+ tumor 
target (624.38, + control) and an ESO+, A2- tumor target (938, - control), representative of four 
different donors. 


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1.2.5 Safety Considerations 
The eligibility, design, treatment, and evaluation of patients in this protocol is the same as that 
already used to treat 40 patients using the human TCR. We saw no off-tumor toxicities when 
targeting this NY-ESO-1 epitope. Several safety concerns regarding the infusion of large 
numbers of retrovirally-modified tumor reactive T-cells have been addressed in our previous 
clinical studies. The non-myeloablative, lymphodepleting preparative regimen and the 
administration of high-dose aldesleukin have expected toxicities, which are discussed in Section 
7.3.1 of this study. The non-myeloablative, lymphodepleting preparative regimen used in this 
protocol has been administered to over 500 patients and all have reconstituted their 
hematopoietic systems. In October 2017, one patient enrolled to this protocol diagnosed with 
synovial cell sarcoma and extensive lung disease experienced a constellation of toxicities after 
receiving 69.1x109 anti-ESO-1 murine TCR-gene engineered lymphocytes and one dose 
aldesleukin. Toxicities included mental status changes (somnolence, depressed consciousness), 
kidney and liver abnormalities, respiratory failure, and altered heart functioning. The events were 
determined to be possibly related to anti-ESO-1 cell infusion, aldesleukin infusion, and 
pulmonary compromise from tumor and prior surgeries. 
In other protocols, we have administered up to 1.5x1011 TIL with widely heterogeneous 
reactivity including CD4, CD8, and NK cells without difficulty. As discussed above, the 
expansion of tumor reactive cells is a desirable outcome following the infusion of antigen 
reactive T-cells. 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+ hematopoietic stem 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. Murine 
TCRs have been used in four previous TCR gene therapy trials at the Surgery Branch (04-C-
0241, 07-C-0174, 09-C-0047,11-C-0062). The introduction of murine or murinized TCRs and 
the possibility of immune responses against murine antigens has been studied in two of our 
clinical trials in which cancer patients were treated with murine TCRs specific for the antigens 
p53 and gp100; this study found that 23% of patients treated with the mTCRs developed 
antibodies directed towards the murine variable regions and not to the constant region common 
to all mTCR(18). These antibodies were not detected for 3-4 months after cell transfer and the 
production of these antibodies was not associated with the level of transduced cell persistence or 
response to therapy. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria for Patients with Solid Tumor Cancers and Melanoma 
 Measurable (per RECIST v1.0 criteria) metastatic cancer or locally advanced 
refractory/recurrent malignancy including melanoma that expresses ESO as assessed by 


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one of the following methods: RT-PCR on tumor tissue, immunohistochemistry of 
resected tissue, or serum antibody reactive with ESO.  
 Confirmation of diagnosis of metastatic cancer including melanoma by the NCI 
Laboratory of Pathology.  
 Patients must have previously received first-line standard therapy (or effective salvage 
chemotherapy regimens) for metastatic disease, if known to be effective for that disease, 
and have been either non-responders (progressive disease) or have recurred. 
 Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and 
asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery 
must be clinically stable for 1 month after treatment for the patient to be eligible. 
Patients with surgically resected brain metastases are eligible.  
 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). 
Note: Patients may have undergone minor surgical procedures within the past three 
weeks, as long as all toxicities have recovered to grade 1 or less. 
Note: Patients who have previously received ipilimumab and have documented GI 
toxicity must have a normal colonoscopy with normal colonic biopsies.  
2.1.2 Inclusion Criteria for Patients with Malignant Meningioma 
 Histologically proven recurrent meningioma or aggressive meningioma. 
Note: Confirmation of ESO expression and pathology is not required in patients with 
definitive radiologic evidence of meningioma who are unresectable, and in whom 
radiation therapy without biopsy is the standard treatment.  
 Recurrent disease/progression after receiving all standard treatments, which must 
include the following: 
• Surgical resection, if possible.  
• Definitive radiation therapy for unresectable meningioma, or for recurrent meningioma 
after resection.  
 At least 4 weeks post-surgery, and must be at least 3 months post-radiation therapy, 
with resolution of related toxicities.  
 Measurable disease on MRI scan.  
 No history of intracranial hemorrhage. 
 Patients with a history of neurofibromatosis (NF) may have other stable CNS tumors, 
such as schwannoma, acoustic neuroma, or ependymoma only if those lesions have 
been stable for the past 6 months.  
 Patients must be on stable dose of steroids for at least 5 days prior to baseline imaging. 
2.1.3 Inclusion Criteria for all Patients 
 Age ≥ 15 years and ≤ 70 years. 


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 Patient, or their parent(s)/legal guardian(s) (if the patient is < 18 years of age), is able to 
understand and willing to sign a written informed consent. Written assent will be 
obtained for participants under the age of 18 as appropriate, as stated in Section 10.6. 
 All participants ≥ 18 years of age must be willing to sign a durable power of attorney. 
 Clinical performance status of ECOG 0 or 1. 
 Patients aged 15-17 years weigh ≥ 50 kg. 
 HLA-A*0201 positive. 
 Patients of both genders must be willing to practice birth control from the time of 
enrollment on this study and for four months after treatment.  
 Women of child-bearing potential must have a negative pregnancy test because of the 
potentially dangerous effects of the treatment on the fetus. 
 Serology 
• Seronegative for HIV antibody. (The experimental treatment being evaluated in this 
protocol depends on an intact immune system. Patients who are HIV seropositive may 
have decreased immune-competence and thus may 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.  
 Hematology 
• ANC > 1000/mm3 without the support of filgrastim 
• WBC ≥ 3000/mm3 
• Platelet count ≥ 100,000/mm3 
• Hemoglobin > 8.0 g/dL. Subjects may be transfused to reach this cut-off. 
 Chemistry 
• Serum ALT/AST ≤ 2.5 x ULN 
• Serum creatinine ≤ 1.6 mg/dL 
• Total bilirubin ≤ 1.5 mg/dL, except in patients with Gilbert’s Syndrome, who must 
have a total bilirubin < 3.0 mg/dL. 
 Subject must be co-enrolled on protocol 03-C-0277. 
2.1.4 Exclusion Criteria 
 Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the treatment on the fetus or infant. 
 Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease). 
 Active systemic infections requiring anti-infective treatment, coagulation disorders, or 
any other active or uncompensated major medical illnesses. 


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 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). 
 Concurrent systemic steroid therapy. 
 History of severe immediate hypersensitivity reaction to cyclophosphamide, 
fludarabine, or aldesleukin. 
 History of coronary revascularization or ischemic symptoms. 
 Documented LVEF ≤ 45% tested in patients: 
• Age ≥ 65 years 
• With 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 and/or chest pain. 
 Documented FEV1 ≤ 60% predicted tested in patients with: 
• A prolonged history of cigarette smoking (≥ 20 pack-year smoking history, with 
cessation within the past two years). 
• Symptoms of respiratory dysfunction. 
 Patients who are receiving any other investigational agents. 
2.2 
SCREENING EVALUATION 
Note: Testing for screening evaluation is conducted under the NCI-SB companion protocol, 99-
C-0128 (Evaluation for NCI Surgery Branch Clinical Research Protocols). 
2.2.1 Within 3 Months Prior to Starting the Preparative Regimen 
• HIV antibody titer, HBsAg determination, and anti-HCV  
• Anti-CMV antibody titer, HSV and VZV serology, and EBV panel (Note: Patients who 
are known to be positive do not need to be retested.) 
• One of the following methods will be used to assess ESO expression: RT-PCR analysis 
of tumor biopsy, immunohistochemistry of resected tissue, or analysis of serum to 
evaluate for expression of ESO-1 antibody reactive with ESO. Immunohistochemistry 
verification of ESO expression will be carried out in a CLIA-approved pathology 
laboratory, while RT-PCR and ELISA assay for ESO-1 antibody will be conducted in Dr. 
Rosenberg’s laboratory using CLIA-approved methods. (Note: Testing is permitted to be 
conducted at any time prior to starting the preparative regimen.) 
• Confirmation of diagnosis of metastatic cancer including melanoma by the NCI 
Laboratory of Pathology. (Note: Testing is permitted to be conducted at any time prior to 
starting the preparative regimen.) 


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2.2.2 Within 8 Weeks Prior to Starting the Preparative Regimen 
• Pulmonary function testing for patients with a prolonged history of cigarette smoking (≥ 
20 pack-year smoking history, with cessation within the past two years), symptoms of 
respiratory dysfunction, or other clinical indications which may include thoracic 
surgeries.  
• Cardiac evaluation commensurate to patients’ history and clinical presentation (e.g., 
stress thallium, echocardiogram, MUGA) for patients who are ≥ 65 years of age, or who 
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 LVEF ≤ 45% will not be eligible. Patients < 65 
years of age with cardiac risk factors (e.g., diabetes, hypertension, obesity) may undergo 
cardiac evaluations as noted above.  
2.2.3 Within 4 Weeks Prior to Starting the Preparative Regimen  
• Complete history and physical examination, including weight and vital signs, noting 
organ system involvement and any allergies/sensitivities to antibiotics. (Note: Patient 
history may be obtained within 8 weeks prior to starting the preparative regimen.) 
• Patients with meningioma must undergo a neurological examination (Section 6.3.4.6). 
• Baseline evaluation to determine disease status. This may include CT, MRI, PET, and/or 
photography. Note: CT scans are not required for patients with meningioma. 
2.2.4 Within 14 Days Prior to Starting the Preparative Regimen 
• Screening blood tests:  
o CBC w/differential 
o Chemistries: Creatinine, ALT/GPT, AST/GOT, Total bilirubin   
• Urinalysis, with culture if indicated  
2.2.5 Within 7 Days Prior to Starting the Preparative Regimen 
• β-HCG pregnancy test (serum or urine) on all women of child-bearing potential. 
• 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 sign the consent for and enroll on the NCI-SB companion protocol 03-C-0277 (Cell 
Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols), prior to 
leukapheresis for generation of the cell product. 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.  
2.3.2 Registration Procedure 
Authorized staff must register an eligible candidate with the NCI Central Registration Office 
(CRO) within 24 hours of signing consent. A registration Eligibility Checklist from the website 


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20
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to the NCI-CRO at ncicentralregistration-l@mail.nih.gov. After confirmation of 
eligibility at the NCI-CRO, 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 email to 
the research team. A recorder is available during non-working hours.  
2.3.3 Treatment Assignment Procedures 
 Cohorts  
Number 
Name 
Description 
1 
ESO-Expressing Cancers 
Patients with metastatic, solid tumor cancers (including 
melanoma and meningioma) that expresses the ESO antigen 
 Arms 
Number 
Name 
Description 
1 
Experimental Therapy 
Non-myeloablative, lymphodepleting preparative regimen of 
cyclophosphamide and fludarabine + anti-ESO murine TCR 
transduced PBL + high-dose aldesleukin 
 Randomization and Arm Assignment 
This is a non-randomized study. All patients will be directly assigned based on cohort as follows: 
• Patients in Cohorts 1-2 will be directly assigned to Arm 1. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
3.1.1 Pre-Treatment Phase: Cell Preparation Performed on 03-C-0277 
PBMC will be obtained by leukapheresis (approximately 1x1010 cells). Whole PBMC will be 
cultured in the presence of anti-CD3 (OKT3) and aldesleukin to stimulate T-cell growth. 
Transduction is initiated by exposure of approximately 1x107 to 5x108 cells to supernatant 
containing the anti-ESO retroviral vector. These transduced cells will be expanded and tested for 
their anti-tumor activity. Successful TCR gene transfer will be determined by FACS analysis for 
the TCR protein and anti-tumor reactivity will be tested by cytokine release as measured on 
peptide pulsed T2 cells. Successful TCR gene transfer for each transduced PBL population will 
be defined as >10% TCR positive cells and for biological activity, gamma-interferon secretion 
must be at least 200 pg/mL. Cells will be administered at a dose of between 1x109 to 2x1011 
lymphocytes and will be given over 20-30 minutes. 
3.1.2 Treatment Phase 
The study will be conducted using a Phase II design. Patients will receive up to 2x1011 anti-ESO 
mTCR engineered PBL. A minimum of approximately 1x109 cells will be given. The cells 
administered vary depending on their growth characteristic. The percent of TCR+ cells will be 
recorded for each patient and the number of TCR+ cells administered per kg will be calculated 
for each patient at the time of the IRB continuing review, the annual report to the FDA, and in 
the event of any serious adverse events related to the cell product.  
Patients will receive no other experimental agents while on this protocol. 


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Patients will receive the standard NCI-SB non-myeloablative, lymphodepleting preparative 
regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of anti-ESO 
mTCR engineered PBL and aldesleukin. All patients will receive one course of treatment. 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. 
3.2 
PROTOCOL STOPPING RULES 
New subject enrollment to the protocol will be temporarily halted if any of the following 
conditions are met, and discussions will be had with the FDA or IRB regarding safety and the 
need for protocol revisions if applicable: 
• Two or more patients develop a grade 3 or greater toxicity at any point in the study 
attributable to the cell infusion that does not resolve to grade 2 within 10 days. 
• 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. 
• If one or more treatment-related deaths occur due to the cell infusion, we will promptly 
discuss this with the IRB and the FDA. 
3.3 
DRUG ADMINISTRATION 
3.3.1 Preparative Regimen with Cyclophosphamide and Fludarabine 
Treatment will be according to the schedule described below and in Section 3.3.4. Starting on 
Day -6, study medication start times for drugs given once daily should be given within 2 hours of 
the scheduled time. Chemotherapy infusions may be slowed or delayed as medically indicated. 
Administration of diuretics, electrolyte replacement, and hydration and monitoring of 
electrolytes should all be performed as clinically indicated.  
Days -7 and -6 
Approximately 6 Hours Prior to Cyclophosphamide 
Hydrate: Begin hydration with 0.9% Sodium Chloride Injection containing 20 mEq/L of 
potassium chloride at 1.5-2.0 mL/kg/hour (starting approximately 6 hours pre-cyclophosphamide 
and continuing until 24 hours after last cyclophosphamide infusion). Rate and composition of 
fluid may be altered based on clinical indications. The hydration rate will be capped at 250 
mL/hour. At any time during the preparative regimen, if urine output is < 1.0 mL/kg/hour or if 
body weight > 2 kg over pre-cyclophosphamide value, furosemide 10-20 mg IV may be 
administered.  
Approximately 1 Hour Prior to Cyclophosphamide 
Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose between 8-16 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 infused simultaneously with 
mesna 15 mg/kg/day over 1 hour x 2 days. If patient is obese (BMI > 35), drug dosage will be 
calculated using practical weight as described in Appendix A.  


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A decreased dose of cyclophosphamide at 30 mg/kg/day (x 2 days) will be considered for 
patients who have a history of prolonged hematologic recovery from prior chemotherapy 
treatments. 
Immediately Following the End of Cyclophosphamide  
Begin mesna infusion at 3 mg/kg/hour intravenously diluted in a suitable diluent (see Section 
11.2.1) 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 A.  
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 A. 
(Fludarabine will be started approximately 1-2 hours after the cyclophosphamide and mesna on 
Days -7 and -6.) 
3.3.2 Cell Infusion 
Day 0 (2-4 Days After the Last Dose of Fludarabine) 
The patient’s PBMC transduced cells are delivered to the Patient Care Unit by a staff member 
from the Surgery Branch Cell Production Facility (SB-CPF). Cells will be administered at a dose 
of between 1x109 to 2x1011 lymphocytes. Prior to infusion, the cell product identity label is 
double-checked by two authorized staff (MD or RN), and an identification of the product and 
documentation of administration are entered in the patient’s chart. The cells are to be infused 
intravenously on the Patient Care Unit 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. 
3.3.3 Aldesleukin Administration 
Days 0-5 (Day 0 = Day of Cell Infusion)  
• Beginning on Day 1 or 2, filgrastim will be administered subcutaneously at a dose of 300 
mcg/day (dose may be adjusted as clinically indicated). Filgrastim administration will 
continue daily until neutrophil count > 1x109/L x 3 days or > 5x109/L.  
• Aldesleukin will be given as described below. 
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 B. Toxicities will be managed as outlined in 
Appendix C. Dosing may be held or stopped at the discretion of the treating investigator. 
(Appendix D lists the toxicities seen in patients treated with aldesleukin at the NIH Clinical 
Center.)  


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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 about their 
medical care if the patient becomes incapacitated or cognitively impaired. 
3.3.4 Treatment Schedule 
1Two to four days after the last dose of fludarabine. 
2Initiate within 24 hours after cell infusion. 
3Continue until neutrophil 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 x2, starting Day 0 or within one week of 
anticipated lymphopenia. 
5Continue until ANC > 1000/mm3 
6In patients positive for HSV or VZV, continue for at least 6 months and until CD4 > 200 x2. 
3.4 
BASELINE EVALUATION 
Note: Refer to Section 5 for research evaluations. 
3.4.1 Within 14 Days Prior to Starting the Preparative Regimen 
• Apheresis, as indicated 
• Baseline blood tests: 
o CBC w/differential 
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, Total protein 
o PT-INR/PTT 
o TBNK 
Day 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide (60 mg/kg) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine (25 mg/m2) 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Anti-ESO mTCR transduced PBL 
 
 
 
 
 
 
 
X1 
 
 
 
 
 
Aldesleukin (720,000 IU/kg) 
 
 
 
 
 
 
 
X2 
X 
X 
X 
X 
X 
Filgrastim3 (5 mcg/kg) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
TMP/SMX4 
160 mg/800 mg (example) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Fluconazole5 (400 mg PO) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Valacyclovir PO or Acyclovir IV6 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 


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o Thyroid Panel 
o Anti-CMV antibody titer, HSV and VZV serology, and EBV panel (may be 
performed within 3 months prior to starting the preparative regimen) 
• Urinalysis, with culture if indicated 
• Chest x-ray 
• EKG 
3.5 
ON-STUDY EVALUATION 
3.5.1 During the Preparative Regimen (Daily) 
• CBC w/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, Total protein 
• PT-INR/PTT (every 3 days) 
• Urinalysis, as needed 
• Weight, as indicated 
3.5.2 Post-Cell Infusion 
• Vital signs (with neuro checks for patients with meningioma) will be monitored hourly (± 
15 minutes) for four hours and then routinely (every 4-6 hours) unless otherwise 
clinically indicated. 
Note: Neuro checks do not need to be continued after the first 4 hours if they are normal. 
3.5.3 During Hospitalization (Every 1-2 Days) 
• Physical examination, including weight and vital signs, as clinically indicated 
• Toxicity assessment, including a review of systems, as clinically indicated 
• CBC w/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, Total protein 
• Once total lymphocyte count is > 200/mm3, TBNK for peripheral blood CD4 count will 
be drawn weekly (while the patient is hospitalized). See Section 5.5 for post-cell infusion 
evaluations.  
• Other tests will be performed as clinically indicated. 


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3.6 
POST-TREATMENT (FOLLOW-UP) EVALUATION  
• All patients will return to the NIH Clinical Center for their first follow-up 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 two weeks of discharge and repeat labs as appropriate to be 
faxed to the research team. Patients will receive appropriate treatment as determined by 
their treating physician. 
• Patients who are unable or unwilling to return for follow-up evaluations may be followed 
via phone or email contact. A request will be made to send laboratory, imaging, and 
physician exam reports performed by their treating physician. Any outstanding toxicities 
will be reviewed with the patient.  
3.6.1 Time-Period of Evaluations 
Patients who experience stable disease, a partial response, or a complete response, or have 
unresolved toxicities after their first follow-up evaluation, will return to the NIH Clinical Center 
as noted below: 
• Week 12 (± 2 weeks)  
• Every 3 months (± 1 month) x3 
• Every 6 months (± 1 month) x 2 years 
• As per PI discretion for subsequent years 
Note: Patients may be seen more frequently as clinically indicated. 
3.6.2 Scheduled Evaluations 
At each scheduled evaluation for response, patients will undergo: 
• Physical examination, including ECOG 
• Weight and vital signs  
• Toxicity assessment, including a review of systems 
• CBC w/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, Total protein 
• PT-INR/PTT 
• Urinalysis, as needed 
• Thyroid Panel, as clinically indicated 
• TBNK 


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• Imaging studies as per baseline assessment. If clinically indicated, other scans or x-rays 
may be performed, e.g. CT, MRI, and/or PET. 
• A 5-liter apheresis may be performed at the first follow-up visit. If the patient is unable to 
undergo apheresis, approximately 96 mL of blood may be obtained. Subsequently, 
approximately 60 mL of blood will be obtained at follow-up visits for at least 3 months. 
PBMC will be cryopreserved so that immunologic testing may be performed. This will be 
performed on protocol 03-C-0277.  
• Detection of RCR and persistence of TCR gene transduced cells (see Section 5.8). This 
will be performed on the NCI-SB long-term follow-up protocol 09-C-0161 (Follow up 
Protocol for Subjects Previously Enrolled in NCI Surgery Branch Studies). 
• 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 protocol 09-C-0161. 


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3.7 
STUDY ASSESSMENT CALENDAR  
Assessments 
Prior to Starting Preparative Regimen 
Prior to 
Preparative 
Regimen 
During 
Preparative 
Regimen (Daily) 
Prior to Cell 
Infusion 
Post-Cell 
Infusion 
During 
Hospitalization 
(Every 1-2 Days) 
Post-
Treatment 
Follow-up1 
Within 3 
Months 
Within 8 
Weeks 
Within 4 
Weeks 
Within 
14 Days 
Within 7 
Days 
Confirmation of diagnosis 
by NCI Lab of Pathology2 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of ESO 
expression3 
X 
 
 
 
 
 
 
 
 
 
 
Medical history4 
 
 
X 
 
 
 
 
 
 
 
 
Physical exam 
 
 
X 
 
 
 
 
 
 
X5 
X6 
Neurological exam7 
 
 
X 
 
 
 
 
 
X8 
 
 
                                                 
1 All patients will return to the NIH Clinical Center for their first follow-up evaluation for response 6 weeks (± 2 weeks) following the 
administration of the cell product. Patients who experience stable disease, a partial response, or a complete response, or have unresolved toxicities 
after their first follow-up evaluation, will return to the NIH Clinical Center at week 12 (± 2 weeks), every 3 months (± 1 month) x 3, every 6 
months (± 1 month) x 2 years, and then per PI discretion for subsequent years. Patients may be seen more frequently as clinically indicated. See 
Section 3.6. 
2 Confirmation of diagnosis of metastatic cancer including melanoma. Testing is permitted to be conducted at any time prior to starting the 
preparative regimen. 
3 One of the following methods will be used to assess ESO expression: RT-PCR analysis of tumor biopsy, immunohistochemistry of resected 
tissue, or analysis of serum to evaluate for expression of ESO-1 antibody reactive with ESO. Immunohistochemistry verification of ESO 
expression will be carried out in a CLIA-approved pathology laboratory, while RT-PCR and ELISA assay for ESO-1 antibody will be conducted 
in Dr. Rosenberg’s laboratory using CLIA-approved methods. Testing is permitted to be conducted at any time prior to starting the preparative 
regimen. 
4 Note organ system involvement and any allergies/sensitivities to antibiotics. Patient history may be obtained within 8 weeks prior to starting the 
preparative regimen. 
5 As needed or clinically indicated. 
6 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 protocol 09-C-0161. 
7 For patients with meningioma. 
8 Neuro checks for patients with meningioma will be done hourly (± 15 minutes) for four hours and then routinely (every 4-6 hours) unless 
otherwise clinically indicated. Neuro checks do not need to be continued after the first 4 hours if they are normal. 


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Assessments 
Prior to Starting Preparative Regimen 
Prior to 
Preparative 
Regimen 
During 
Preparative 
Regimen (Daily) 
Prior to Cell 
Infusion 
Post-Cell 
Infusion 
During 
Hospitalization 
(Every 1-2 Days) 
Post-
Treatment 
Follow-up1 
Within 3 
Months 
Within 8 
Weeks 
Within 4 
Weeks 
Within 
14 Days 
Within 7 
Days 
Performance score 
(ECOG)9 
 
 
 
 
X 
 
 
 
 
 
X 
Weight 
 
 
X 
 
 
 
X5 
 
 
X 
X 
Vital signs 
 
 
X 
 
 
 
 
 
X10 
X 
X 
β-HCG pregnancy test11 
 
 
 
 
X 
 
 
 
 
 
 
Urinalysis12 
 
 
 
X 
 
 
X 
 
 
 
X 
Pulmonary function test13 
 
X 
 
 
 
 
 
 
 
 
 
Cardiac evaluation14 
 
X 
 
 
 
 
 
 
 
 
 
EKG 
 
 
 
X 
 
 
 
 
 
 
 
Toxicity assessment15 
 
 
 
 
 
 
 
 
 
X5 
X 
Serology 
HIV antibody, HBsAg, 
anti-HCV 
X 
 
 
 
 
 
 
 
 
 
 
Anti-CMV, HSV and 
VZV serology, EBV 
panel16 
X 
 
 
X 
 
 
 
 
 
 
 
Laboratory Procedures 
CBC w/differential 
 
 
 
X 
 
 
X 
 
 
X 
X 
                                                 
9 ECOG of 0 or 1. 
10 Vital signs will be monitored hourly (± 15 minutes) for four hours and then routinely (every 4-6 hours) unless otherwise clinically indicated. 
11 Serum or urine; on all women of child-bearing potential. 
12 With culture if indicated. 
13 For patients with a prolonged history of cigarette smoking (≥ 20 pack-year smoking history, with cessation within the past two years), 
symptoms of respiratory dysfunction, or other clinical indications which may include thoracic surgeries. 
14 Commensurate to patients’ history and clinical presentation (e.g., stress thallium, echocardiogram, MUGA) for patients who are ≥ 65 years of 
age, or who 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 LVEF ≤ 45% will not be eligible. Patients < 65 years of age with 
cardiac risk factors (e.g., diabetes, hypertension, obesity) may undergo cardiac evaluation as noted above. 
15 Including a review of systems. 
16 Patients who are known to be positive do not need to be retested. May be performed within 3 months prior to starting the preparative regimen. 


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Assessments 
Prior to Starting Preparative Regimen 
Prior to 
Preparative 
Regimen 
During 
Preparative 
Regimen (Daily) 
Prior to Cell 
Infusion 
Post-Cell 
Infusion 
During 
Hospitalization 
(Every 1-2 Days) 
Post-
Treatment 
Follow-up1 
Within 3 
Months 
Within 8 
Weeks 
Within 4 
Weeks 
Within 
14 Days 
Within 7 
Days 
Blood chemistries17 
 
 
 
X 
 
 
X 
 
 
X 
X 
PT-INR/PTT 
 
 
 
X 
 
 
X18 
 
 
 
X 
TBNK 
 
 
 
X 
 
 
 
 
 
X19 
X 
Thyroid Panel 
 
 
 
X 
 
 
 
 
 
 
X5 
Additional apheresis20 
 
 
 
X5 
 
 
 
 
 
 
X 
Persistence and RCR21 
 
 
 
 
 
 
 
 
 
 
X 
Correlatives22 
CPT tubes (SB-CPF) 
 
 
 
 
 
X 
 
 
X 
 
 
SST tubes (Figg Lab) 
 
 
 
 
 
X 
 
X 
X 
 
 
Imaging 
CT, MRI, PET, and/or 
photography 
 
 
X23 
 
 
 
 
 
 
 
X24 
Chest x-ray 
 
 
 
X 
 
 
 
 
 
 
 
 
                                                 
17 Screening: Creatinine, ALT/GPT, AST/GOT, Total bilirubin. All other times: 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, Total protein. 
18 Every 3 days. 
19 Once total lymphocyte count is > 200/mm3, TBNK for peripheral blood CD4 count will be drawn weekly (while the patient is hospitalized). 
20 Apheresis may be performed prior to and 6 weeks (± 2 weeks) following the administration of the cell product. If the patient is unable to 
undergo apheresis, approximately 96 mL of blood may be obtained. Subsequently, approximately 60 mL of blood will be obtained at follow-up 
visits for at least 3 months. PBMC will be cryopreserved so that immunologic testing may be performed. This will be performed on protocol 03-C-
0277. 
21 Detection of RCR and persistence of TCR gene transduced cells (see Section 5.8). This will be performed on protocol 09-C-0161. 
22 Research samples, as described in Section 5. 
23 Baseline evaluation to determine disease status. CT scans are not required for patients with meningioma. 
24 Imaging studies as per baseline assessment. If clinically indicated, other scans or x-rays may be performed. 


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3.8 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects compete an evaluation 
safety visit approximately 6 weeks (± 2 weeks) following administration of the cell product (at 
the first follow-up evaluation).  
3.8.1 Criteria for Removal from Protocol Therapy 
Patients will be taken off treatment for the following: 
• Completion of first follow-up evaluation 
• Progression of disease 
• Patient requests to be withdrawn from protocol therapy 
• Investigator discretion 
• Positive pregnancy test 
3.8.2 Off-Study Criteria 
Patients will be taken off-study for the following: 
• Completion of study follow-up period 
• Progression of disease 
• Patient begins a new therapy for their cancer 
• Patient requests to be withdrawn from the study 
• Significant noncompliance 
• Investigator discretion 
• Patient lost to follow-up 
• Death 
All patients will be co-enrolled on protocol 09-C-0161. Patients who are taken off-study for 
progressive disease or study closure on this treatment protocol may be followed on protocol 09-
C-0161. 
Once a subject is taken off study, no further data can be collected on this treatment protocol. 
3.8.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify the NCI-CRO when a subject is taken off protocol therapy and 
when a subject is taken off-study. A Participant Status Update Form from the website 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to the NCI-CRO at 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 investigator. 


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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) PO 
daily three times a week on non-consecutive days, beginning Day 0 or within one week of 
anticipated 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 Simplex 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 have 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, HSV, and VZV will continue for 6 months post-chemotherapy. If 
the CD4 count is < 200 at 6 months post-chemotherapy, prophylaxis will continue for at least 6 
months and until the CD4 count is > 200 for two consecutive measures. 
Note: A missed prophylactic dose will not be considered a protocol deviation, and thus a 
deviation will not be reported to the IRB (see sections 7.1.8 and 7.2), if the patient is compliant 
with taking at least 75 percent of their required dose.  
4.1.3 Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg PO starting on the day of cell infusion and continue until 
the absolute neutrophil count is > 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 ≥ 38.0°C at least one hour 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 
(PRBCs) as needed. As a general guideline, patients may be transfused for: 
• Hemoglobin < 8 gm/dL 
• Platelets < 10,000/mm3 
All blood products will be irradiated. Leukocyte filters will be utilized for all blood and platelet 
transfusions to decrease sensitization to transfused WBCs and decrease the risk of CMV infection. 


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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 every 4 hours), indomethacin (50-75 mg every 
8 hours), and ranitidine (150 mg every 12 hours). 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  
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 NCI-SB and with collaborators as specified in 
protocol 03-C-0277. 
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. 
5.1 
SAMPLES SENT TO FIGG LAB 
• Venous blood samples will be collected in either a 4-mL or an 8-mL 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 pick-up.  
• For sample pick-up, 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 email or at 240-760-
6044. 
• The samples will be processed, barcoded, and stored in the Figg Lab until requested by 
the investigator. 
5.2 
SAMPLES SENT TO THE SURGERY BRANCH CELL PRODUCTION FACILITY 
• Venous blood samples will be collected in 8-mL 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 picked up by the research nurse or designee and transported to the SB-
CPF within 24 hours of blood draw. 
• The samples will be processed, barcoded, and stored in SB-CPF. 
5.3 
PRIOR TO CHEMOTHERAPY ADMINISTRATION 
• 5 CPT tubes (8 mL each): SB-CPF 


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• 1 SST tube (8 mL): Figg Lab 
• 1 SST tube (4 mL): Daily, starting first day of chemotherapy through day of discharge. 
Send to Figg Lab. 
5.4 
PRIOR TO CELL INFUSION (BASELINE SAMPLE FOR CYTOKINE ANALYSIS) 
• 1 SST tube (8 mL): Figg Lab  
5.5 
POST-CELL INFUSION EVALUATIONS 
Once total lymphocyte count is > 200/mm3, the following samples will be drawn and sent to the 
SB-CPF on Monday, Wednesday, and Friday x5, and then weekly (while the patient is 
hospitalized): 
• 5 CPT tubes (8 mL each): SB-CPF 
• 1 SST tube (8 mL): Figg Lab 
5.6 
SAMPLES COLLECTION SCHEDULE 
Test 
Volume Blood 
Type of Tube 
Collection Point 
Disposition 
Research blood 
52 mL 
CPT and SST 
Prior to chemo 
Deliver SST tubes to Figg Lab. 
Deliver CPT tubes to SB-CPF. 
Research blood 
8 mL 
SST 
Prior to cell 
infusion 
Deliver to Figg Lab. 
Research blood 
48 mL 
CPT and SST 
Post-cell infusion 
and at follow-up 
visits1 
Deliver SST tubes to Figg Lab. 
Deliver CPT tubes to SB-CPF 
1 Research blood will be obtained at follow-up visits for at least 3 months. 
5.7 
IMMUNOLOGICAL TESTING 
• Apheresis may be performed prior to and 6 weeks (± 2 weeks) following the 
administration of the cell product. At other time points, patient PBL will be obtained 
from whole blood by purification using centrifugation on a Ficoll cushion. Aliquots of 
these PBMC will be cryopreserved for immunological monitoring of cell function and 
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 using some or all the 
following tests. Direct immunological monitoring will consist of quantifying T-cells 
reactive with targets FACS analysis using mouse V-beta antibody. 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 transduced PBMC cryopreserved at the time 
of infusion. In general, differences of 2- to 3-fold in these assays are indicative of true 
biologic differences.  


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5.8 
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. In addition, measurement of CD4 and CD8 T-cells will be conducted and studies of 
these T-cell subsets in the circulation will be determined by using specific PCR assays 
capable of detecting the unique DNA sequence for each retroviral vector engineered T-
cell. Note: Samples will be batched and assayed at the conclusion of the study. 
• Patients will be co-enrolled on protocol 09-C-0161 and will adhere to the follow-up 
schedule described in that protocol. 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 envelop gene and are 
performed under contract by the Indiana University Vector Production Facility. The 
results of these tests are maintained by the contractor performing the RCR tests and by 
the NCI-SB research team. 
5.9 
SAMPLE STORAGE, TRACKING AND DISPOSITION FOR SURGERY BRANCH CELL 
PRODUCTION FACILITY 
Blood and tissue collected during the course of this study will follow the Cell Tracking and 
Labeling System established by the SB-CPF. 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 NCI-SB 
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. 
Blood and tissue collected during the course of this study will be stored, tracked, and disposed of 
as specified in protocol 03-C-0277. 


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5.10 SAMPLE STORAGE, TRACKING AND DISPOSITION FOR FIGG LAB 
5.10.1 Sample Data Collection 
All samples sent to the 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 NCI-SB 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.). 
5.10.2 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 
(PI) 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. 


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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 PI, 
associate investigators (AI), 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 AEs until their first follow-up evaluation (6 weeks (± 2 
weeks) following administration of the cell product) 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 Reporting 
Patients will be receiving multiple agents, which include commercially available agents 
(fludarabine, cyclophosphamide, aldesleukin, and supportive medications) in combination with 
the investigational agents; therefore, grade 1 events not related to the cell product will not be 
reported/recorded.  
6.2 
DATA SHARING PLAN 
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 


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37
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 NCI-SB, and de-identified data may also be shared with collaborators as specified in 
protocol 03-C-0277. 
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 
following administration of the cell product, then as per PI discretion. In addition to a baseline 
scan, confirmatory scans should also be obtained at least 4 weeks (but not less than 4 weeks) 
following initial documentation of objective response. 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised 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 course 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 course 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 course 
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 
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 


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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 based on 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 
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. 


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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 based on FDG-PET 
imaging can be identified according to the following algorithm:  
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing based on the anatomic images, this is not PD. 
• 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 
 Evaluation of Target Lesions 
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 based on 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.  
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. 


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 Evaluation of Non-Target Lesions 
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.” 
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. 
Progression (PD): Appearance of one or more new lesions. Unequivocal progression of existing 
non-target lesions. 
 
 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 
 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). 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.  


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 Central Radiology Review  
We will centrally (NCI) review all MRI scans that have been designated as a partial or complete 
response. Dr. John Butman of NIH Neuro-Radiology or his designee will assist in the review of 
all MRI scans. 
 Neurological Examination 
Since it is not used for determining response, an objective assessment of the neurological exam 
will not be required data. Nevertheless, the neurological exam could be useful as a corollary 
piece of data to support or refute the validity of subtle MRI changes. Thus, we will request (but 
not require) that the following information will be recorded at each follow-up visit: 
• Normal versus abnormal neurologic exam 
• Status of neurologic exam compared to last exam: 
o Definitely better 
o Possibly better 
o Stable 
o Possibly worse 
o Definitely worse 
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 
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. 


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7.1.3 Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the Investigator’s Brochure or is not listed at the specificity or severity that has been observed; 
or, if an Investigator’s 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’s Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
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 
• Persistent or significant disability/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.  


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7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
1.  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 
2. Is related or possibly related to participation in the research; AND 
3. 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 
IRB AND CLINICAL DIRECTOR (CD) REPORTING 
7.2.1 IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the 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 IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the 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 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 IRB.  


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7.2.4 Request for Waiver from IRB Reporting: Anticipated Protocol Deviations and Expected 
Non-UP Adverse Events 
Patients may receive prophylaxis for pneumocystis, HSV, and VZV for at least 6 months post-
chemotherapy (see Section 4.1.2). The investigators are requesting a waiver from IRB reporting 
for a missed prophylactic dose. A missed prophylactic dose will not be considered a protocol 
deviation, and thus a deviation will not be reported to the IRB, if the patient is compliant with 
taking at least 75 percent of their required dose.  
If the rate of these events exceeds the rate anticipated in the protocol (i.e., the patient takes less 
than 75 percent of their required dose), the events will be classified and reported as though they 
are unanticipated problems. 
7.3 
IND SPONSOR REPORTING CRITERIA 
From the time the subject receives the investigational agent/intervention to the time of 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’s 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: 
• 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. 
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 NCI-SB adoptive cell 
therapy (ACT) protocols are expected toxicities of the non-myeloablative, lymphodepleting 
preparative 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. 


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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  
 Maternal Exposure 
If a patient becomes pregnant during treatment and for the first four months following treatment, 
the study treatment should be discontinued immediately and 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. 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 
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 during the course of the study, then the investigator should inform the 
Sponsor within one 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. 
 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 PI (or delegate) will notify IBC of any unexpected fatal or life-threatening experience 
associated with the use of the cell product 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 


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associated with the use of the cell product, but are not fatal or life-threatening, much 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 MedWatch Form 
FDA 3500A or equivalent. 
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 PI (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. 
 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:  
• Title and purpose of the trial  
• Clinical site 
• Principal Investigator 
• Clinical protocol identifiers  
• Participant population (such as disease indication and general age group, e.g., adult or 
pediatric)  
• 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  
• 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.  
 Progress Report and Data Analysis  
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• Narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• Summary of all serious adverse events submitted during the past year 
• 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 


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• 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 PI or AI. 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 reported to the IRB 
using iRIS. 
The PI will review adverse event and response data on each patient to ensure safety and data 
accuracy. The PI 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 
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 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 PI and Clinical 
Director or Deputy Clinical Director, CCR, NCI. 


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8 
STATISTICAL CONSIDERATIONS  
The primary objective of this trial is to determine whether the combination of high-dose 
aldesleukin, lymphodepleting chemotherapy, and an infusion of anti-ESO mTCR-gene 
engineered lymphocytes is associated with a modest fraction of patients who express ESO that 
can experience a clinical response (PR + CR) to therapy.  
The study will be conducted using a phase II optimal design(19). The objective will be to 
determine if the combination of high-dose aldesleukin, lymphodepleting chemotherapy, and anti-
ESO 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).  
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%. 
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. 
A total of up to 43 patients may be required (41 plus up to 2 inevaluable patients). Provided that 
about 2-4 patients per month will be able to be enrolled onto this trial, approximately 2 years 
may be needed to accrual 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 21 patients. 
9 
COLLABORATIVE AGREEMENTS  
We have established a Cooperative Research and Development Agreement (CRADAs #02716 
and #03168) 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 


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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 non-myeloablative, lymphodepleting preparative 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 under the 
age of 15 to this risk without further evidence of benefit. We will only treat adolescents who are 
of adult stature (must be ≥ 50 kg) and thus can safely receive the protocol treatment regimen; we 
do not anticipate the need for consultation with the pediatric oncology service although this will 
always remain an option. 
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 younger 
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 (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have a 
pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 and 
OHSRP SOP 14E 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. 
10.4  EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has a chance to provide clinical benefit though this is unknown. The 
NCI-SB has extensive experience with ACT following treatment with high-dose aldesleukin, 
however, this experimental treatment is only available at a very few centers throughout the 
country. Although we have seen responses to this treatment, we do not know if this change in our 
process will improve patient outcome. The risks associated with ACT are substantial, including a 
delay in treatment due to the need to harvest and grow the cells; a surgical procedure (possibly 
major) to obtain tumor for the cell product; the possibility that a cell product cannot be 
generated; infection and sepsis due to the non-myeloablative, lymphodepleting preparative 
regimen; intubation; renal toxicities due to aldesleukin; and death. The risks in this treatment are 
detailed in Section 11.   


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10.5  RISK/BENEFIT ANALYSIS 
Because all patients in this protocol have metastatic cancer and limited life expectancies, the 
potential benefit is thought to outweigh the potential risks. The risk/benefit analysis for adults 
with the capacity to consent, as well as for adults who may become unable to provide consent, is 
greater than minimal risk but presenting the prospect of direct benefit to individual subjects 
based on the risks and potential benefits described in Section 10.4. The risk/benefit analysis for 
pediatric patients falls under Category 2, 45 CFR 46.405, which is greater than minimal risk but 
presenting the prospect of direct benefit to the individual child subjects involved in the research. 
10.6  CONSENT PROCESS AND DOCUMENTATION 
Patients are initially consented on protocols 99-C-0128 and 03-C-0277. If the patient has a tumor 
that is found to be NY-ESO-1 positive by immunohistochemistry, and if the lymphocytes can be 
generated for infusion and the patient meets the thorough screening for eligibility, the patient and 
their parent(s) or legal guardian(s) if applicable, with family members or friends at the request of 
the patient, will be presented with a detailed description of the protocol treatment. The specific 
requirements, objectives, and potential advantages and disadvantages will be presented. If the 
patient is under 18 years of age, the consent process includes both the patient and the 
parent(s)/guardian(s), and a signed informed consent document will be obtained prior to entry 
onto the study. The informed consent document is given to the patient, and the 
parent(s)/guardian(s) if applicable, who is requested to review it and to ask questions prior to 
agreeing to participate in receiving treatment on 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, AI, or clinical fellow is responsible 
for completing the consent process and a copy of the consent is offered to the patient, and the 
parent(s)/guardian(s), if applicable. 
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
informed consent to enter a child on the protocol. Because many patients must travel to the NIH 
from long distances at substantial expense, requiring both parents to be present for the consent 
process could be a financial hardship for many families. When guardianship status of the child is 
uncertain, documentation of custody status must be obtained. In situations where there is joint 
custody of a child, both parents must sign consent. If only one parent can be present at NIH, the 
other parent’s consent can be obtained by telephone via the procedure described in Section 
10.6.2. 
Where deemed appropriate by the clinician and the child’s parent(s) or legal guardian(s), the 
child will also be included in all discussions about the trial and age-appropriate language will be 
used to describe the procedures and tests involved in this study, along with the risks, discomforts 
and benefits of participation. The parent(s)/guardian(s) will sign and date the informed consent to 
provide permission for the child to take part in the study. Written assent will be obtained from 
children as the study holds out the prospect of direct benefit that is important to the health and 
well-being of the child and is available only in the context of the research. Written assent will be 
obtained as appropriate for children ages 15-17, and the parent(s)/guardian(s) will sign on the 
designated line on the informed consent attesting to the fact that the child has given assent. The 
consent/assent process will be documented in the child’s medical record, including the 
assessment of the child’s ability to provide written assent, as applicable. All children will be 


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contacted after they have reached the age of 18 (see Section 10.6.1) to determine whether they 
wish to continue on the trial and informed consent will be obtained from them at that time. 
10.6.1 Consent for Minors when they Reach the Age of Majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require consenting of the now 
adult with the standard protocol consent document to ensure legally effective informed consent 
has been obtained. We request waiver of informed consent for those individuals who become lost 
to follow-up during their participation in the research study. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
1. The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to subjects. 
2. The waiver or alteration will not adversely affect the rights and welfare of the subjects. 
a. Retention of these samples or data does not affect the welfare of subjects.  
3. The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between the minor’s last contact with the research 
team and their age of majority, it will likely be very difficult to locate them again. A 
significant reduction in the number of samples analyzed is likely to impact the quality 
of the research.  
4. Whenever appropriate, the subjects will be provided with additional pertinent information 
after participation. 
a. We request a waiver of consent for those subjects who have been lost to follow-up or 
who have been taken off-study before reaching the age of majority. 
10.6.2 Telephone Consent 
In situations where the second parent is unable to be physically present to give consent, the 
informed consent document will be sent to that parent or legally authorized representative. An 
explanation of the study will be provided over the telephone after the second parent or legally 
authorized representative has had the opportunity to read the consent form. The second parent or 
legally authorized representative will sign and date the informed consent. A witness to the 
second parent or legally authorized representative’s signature will sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.  
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
10.6.3 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 PI and/or those authorized to obtain informed 


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consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, 
OHSRP 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 (24-48 
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. 
11 PHARMACEUTICAL INFORMATION  
Cyclophosphamide, fludarabine, and aldesleukin, the commercial drugs used in this study, will 
not alter labeling of the FDA-approved drugs. The investigation is not intended to support a new 
indication for use or any other significant changes to labeling or advertising in 
cyclophosphamide, fludarabine, or aldesleukin. The investigation does not involve a route of 
administration or dosage level in use in a patient population or other factor that significantly 
increases the risks (or decreases the acceptability of the risks) associated with the use of the drug 
products. 
11.1 INVESTIGATIONAL REGIMEN 
11.1.1 Anti-ESO TCR Transduced PBL 
The procedure for expanding the human PBL and the CoA are similar to those approved by the 
Food and Drug Administration, and used at the NCI in ongoing protocols evaluating cell therapy 
in the NCI-SB. The CoA is included in Appendix E. The PBL will be transduced with retroviral 
supernatant containing the α-chain and β-chain genes of the anti-ESO mTCR.  
 Retroviral Vector Containing the anti-ESO TCR Gene 
The retroviral vector supernatant (PG13-ESO-157m TCR (C1) encoding a T-cell receptor 
directed against NY-ESO-1, was prepared and preserved following cGMP conditions in the 
Indiana University Vector Production Facility (IUVPF). Transgenic mice expressing full-length 
human HLA-A*0201 gene were obtained from the Jackson Laboratory (Bar Harbor, ME) and 
immunized with human NY-ESO-1 peptide (SLLMWITQC). Murine T-cells reactive to this 
peptide were used as a source to isolate the TCR alpha and beta chain genes (TCR alpha chain 
TRAV6D and beta chain TRBV26). Based on the DNA sequence of the TCR alpha and beta 
chains, a DNA sequence was chemically synthesized to link the beta and alpha TCR genes using 
a peptide linker. This synthetic DNA was then inserted into the gamma-retroviral vector MSGV1 
to produce the murine anti-NY-ESO-1 TCR vector, (MSGV1 ESO-157 muTCR B2aA). Plasmid 
DNA for this vector was used to make the PG13 virus producer cell clone. The alpha and beta 
chains are linked by a T2A peptide.  


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The physical titer will be determined by transduction of PBL with serial dilutions of the vector. 
TCR expression on the cell surface will be measured using FACS following staining with an 
anti-mouse constant region antibody. The titer will be measured as transducing units per 
milliliter. Portions of the supernatant will be stored at -80°C at NCI-SB, as well as at Fisher 
Bioservices in 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 ex 
vivo transduction of patient PBL. 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. 
Note: Penicillin, streptomycin, and gentamycin will not be used in the manufacture of products 
for patients with documented allergies to these drugs. 
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 (2-8°C) 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. 
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, 2-30°C. 
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 B 
and Appendix C. 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 B. Additional grade 3 and 4 toxicities seen with 
aldesleukin are detailed in Appendix C.  
11.1.3  Fludarabine 
(Please refer to the FDA-approved package insert for complete product information)  


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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, ribnucleotide 
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 15-30 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 A.  
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 
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 ACT protocols in the NCI-SB 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 
(Please refer to the 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 alkyating 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.  


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How Supplied: Cyclophosphamide will be obtained from commercially available sources by the 
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 A. 
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 
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 SUPPORT 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 (1-20 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. 


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Administration: Dilute to concentrations ≤ 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 A. 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 µg/mL and 480 µg/1.6 mL vials. Filgrastim 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. 
Filgrastim will be given as a daily subcutaneous injection. The side effects of filgrastim 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 Day 0 or within one week of 
anticipated lymphopenia and continuing for at least 6 months and until the CD4 count is > 200 
on two 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 8-14 days after beginning the standard dose. Neutropenia, a reduction in the 
number of neutrophils, can also occur.  
Dapsone (in G6PD sufficient patient), atovaquone, or pentamidine will may be substituted for 
TMP/SMX-DS in patients with sulfa allergies. 
 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 100 mg by 
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 25 mg and 100 mg 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. 


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 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 1500 mg orally or the dose may be split into 750 mg 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 150 mg/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. 
  Aerosolized Pentamidine  
Patients with sulfa allergies will receive aerosolized pentamidine 300 mg per nebulizer with 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 
 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 
stomach, nausea, vomiting, diarrhea or constipation. Rare serious side effects include hemolytic 
uremic syndrome and thrombotic thrombocytopenic purpura.  
 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 7 mg/mL or 
less and infused over one 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 


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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 is prepared according to Clinical Center 
Pharmacy standard procedures. It should be administered at a maximum IV rate of 200 mg/hour. 
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, pruritis, 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 pruritis. Consult the package insert for a 
complete list of all side effects. 
 


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expanding family of targets for cancer immunotherapy. Immunol Rev. 2002;188:22-32. 
5. 
Lethe B, Lucas S, Michaux L, De SC, Godelaine D, Serrano A, et al. LAGE-1, a new 
gene with tumor specificity. Int J Cancer. 1998;76(6):903-8. 
6. 
Jager E, Chen YT, Drijfhout JW, Karbach J, Ringhoffer M, Jager D, et al. Simultaneous 
humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of 
human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med. 
1998;187(2):265-70. 
7. 
Aarnoudse CA, van den Doel PB, Heemskerk B, Schrier PI. Interleukin-2-induced, 
melanoma-specific T cells recognize CAMEL, an unexpected translation product of LAGE-1. Int 
J Cancer. 1999;82(3):442-8. 
8. 
Wang RF, Johnston SL, Zeng G, Topalian SL, Schwartzentruber DJ, Rosenberg SA. A 
breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated 
from different open reading frames. J Immunol. 1998;161(7):3598-606. 
9. 
Chen Q, Jackson H, Parente P, Luke T, Rizkalla M, Tai TY, et al. Immunodominant 
CD4+ responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with 
ISCOMATRIX adjuvant. Proc Natl Acad Sci U S A. 2004;101(25):9363-8. 
10. 
Jager E, Jager D, Karbach J, Chen YT, Ritter G, Nagata Y, et al. Identification of NY-
ESO-1 epitopes presented by human histocompatibility antigen (HLA)-DRB4*0101-0103 and 
recognized by CD4(+) T lymphocytes of patients with NY-ESO-1-expressing melanoma. J Exp 
Med. 2000;191(4):625-30. 
11. 
Zeng G, Touloukian CE, Wang X, Restifo NP, Rosenberg SA, Wang RF. Identification 
of CD4+ T cell epitopes from NY-ESO-1 presented by HLA-DR molecules. J Immunol. 
2000;165(2):1153-9. 
12. 
Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor 
regression in patients with metastatic synovial sarcoma and melanoma using genetically 
engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917-24. 
13. 
van Loenen MM, de Boer R, Amir AL, Hagedoorn RS, Volbeda GL, Willemze R, et al. 
Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad 
Science,USA. 2010;107:10972-7. 
14. 
Bendle GM, Linnemann C, Hooijkaas AI, Bies L, de Witte MA, Jorritsma A, et al. Lethal 
graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med. 
2010;16(5):565-70, 1p. 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
60
15. 
Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA. Enhanced antitumor activity of 
murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved 
pairing and TCR/CD3 stability. Cancer Res. 2006;66:8878-86. 
16. 
Wargo JA, Robbins PF, Li Y, Zhao Y, El-Gamil M, Caragacianu D, et al. Recognition of 
NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and 
epigenetic modulation of tumor antigen expression. Cancer Immunol Immunother. 
2009;58(383):394. 
17. 
Yang S, Cohen CJ, Peng PD, Zhao Y, Cassard L, Yu Z, et al. Development of optimal 
bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell 
recognition. Gene Ther. 2008;15:1411-23. 
18. 
Davis JL, Theoret MR, Zheng Z, Lamers CH, Rosenberg SA, Morgan RA. Development 
of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients 
enrolled in TCR gene therapy trials. Clin Cancer Res. 2011;16:5852-61. 
19. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. 
 
 
 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
61
13 APPENDICES 
13.1 APPENDIX A: 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. 
 
*Practical weight will NOT be used in the calculation of dose for aldesleukin. 
 
 
 
 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
62
13.2 APPENDIX B: 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 increased 
10 
Tachycardia   
 
 
23 
 
Nervous 
Vasodilation   
 
 
13  
 
Confusion  
 
 
 
34 
Supraventricular tachycardia   
12  
 
Somnolence   
 
 
22 
Cardiovascular disorder a  
 
11  
 
Anxiety  
 
 
 
12 
Arrhythmia  
 
 
 
10  
 
Dizziness  
 
 
 
11 
Digestive  
 
 
 
 
 
Respiratory 
Diarrhea  
 
 
 
67  
 
Dyspnea  
 
 
 
43 
Vomiting  
 
 
 
50  
 
Lung disorder b  
 
 
24 
Nausea  
 
 
 
35  
 
Respiratory disorder c  
 
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 
 
 
 
 
 
 
 
Oliguria  
 
 
 
63 
 
Legend: 
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-NY-ESO-1 mTCR PBL 
Version Date: July 5, 2018 
 
63 
 
13.3 APPENDIX C: 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 q4h PO, 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 interspersed 
with activity 
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 
No 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
64
supportive 
measures 
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 
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 


Abbreviated Title: Anti-NY-ESO-1 mTCR PBL 
Version Date: August 6, 2018 
 
65
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-NY-ESO-1 mTCR PBL 
Version Date: July 5, 2018 
 
66 
 
13.4 APPENDIX D: INTERLEUKIN-2 TOXICITIES OBSERVED IN PATIENTS TREATED AT 
THE NIH CLINICAL CENTER 
 
 


A b brevi ate d Title:  A nti -N Y -E S O - 1 m T C R P B L  
Versi o n D ate: A u g ust 6, 2 0 1 8  
 
6 7  
1 3. 5  A P P E N DI X E:  C E R TI FI C A T E O F A N A L Y SI S –  A N TI -N Y -E S O - 1 MT C R  P B L  
 
Date of pre parati o n of fi nal pr o d uct:  
Patie nt:  
T ests perf or me d o n fi nal pr o d uct: 
 
Test  
 
Met h o d 
Li mits  
Res ult  
Tests 
perf or me d by  
I niti als/
D ate  
Cell via bilit y 1 
tr y pa n bl ue e xcl usi o n 
> 7 0 % 
 
 
 
T otal via ble cell 
n u m ber 1 
vis ual micr osc o pic c o u nt  
> 1 x 1 0 8 
 
 
 
T u m or reacti vit y 2 
IF N release vs. pe pti de 
p ulse d T 2 cells  
> 2 0 0 p g/ m L 
 
 
 
T C R e x pressi o n 2 
F A C S a nal ysis of t he 
tra ns d uce d cells 
P B L, > 1 0 % 
 
 
 
Micr o bi ol o gical 
st u dies  
gra m stai n 1, 3,  
n o micr o-
or ga nis ms see n  
 
 
 
 
aer o bic c ult ure 3, 4 
n o gr o wt h 
 
 
 
 
f u n gal c ult ure3, 4 
n o gr o wt h 
 
 
 
 
a naer o bic c ult ure 3, 4 
n o gr o wt h 
 
 
 
 
m yc o plas ma test 5 
ne gati ve  
 
 
 
E n d ot o xi n  
li m ul us assa y1 
< 5 E. U./ k g 
 
 
 
R C R  
S + L - Assa y 4 
R C R -P C R 6 
ne gati ve  
 
 
 
1 P erf or me d o n sa m ple of t h e fi n al pr o d u ct i m me diatel y pri or t o i nf usi o n.  Res ults are a vaila ble at t h e ti me of i nf usi o n.  
2 P erf or me d 2 -1 0 p ost tra ns d u cti o n. Res ults are a vaila ble at t h e ti me of i nf usi o n.  
3 P erf or me d 2 -4 d a ys pri or t o i nf usi o n.  Res ults are a vaila ble at t h e ti me of i nf usi o n b ut ma y n ot b e d efi niti ve.  
4 Sa m ple c ollecte d fr o m t h e fi n al pr o d u ct pri or t o i nf usi o n.  Res ults will n ot b e a vaila ble b ef ore cells are i nf use d i nt o t he 
patie nt.  
5 P erf or me d 2 -1 0 d a ys pri or t o i nf usi o n.  Res ults are a vaila ble at t h e ti me of i nf usi o n.  
6 P erf or me d o n sa m ple a p pr o xi matel y 1 -4 d a ys pri or t o i nf usi o n.  Res ults are a vaila ble at t h e ti me of i nf usi o n.  
 
Pre pare d b y:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
Q C si g n -off:   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Q ualifie d Cli nical or La b orat or y S u per vis or 

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:
13-C-0214
PRINCIPAL INVESTIGATOR: 
Steven A. Rosenberg, M.D., PhD.
STUDY TITLE: 
A Phase II Study of Metastatic Cancer that Expresses NY-ESO-1 Using 
Lymphodepleting Conditioning Followed by Infusion of Anti-NY-ESO-1 Murine TCR-
Gene Engineered Lymphocytes
Continuing Review Approved by the IRB on 10/09/19
Amendment Approved by the IRB on  08/10/18 (N)
Date posted to web: 10/30/19
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. 
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document.


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: 13-C-0214
CONTINUATION: page 2 of 17 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 
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 them, and then giving the cells back to the patient. In a previous study, we used the 
anti-ESO-1 gene and a type of virus (retrovirus) to make these special cells (anti-ESO-1 cells). 
About half of the patients who received this treatment experienced shrinking of their tumors. In 
this study, we are using a slightly different way of producing the cells which we hope will work 
better in making the tumors shrink. The purpose of this study is to see if these tumor-fighting 
cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their 
surface cause tumors to shrink and to see if this treatment is safe.
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 ESO-1 molecule on the surface of the tumors.
How many people will take part in this study? 
Up to 43 patients will be enrolled in this study.
Description of Research Study
This study has several stages outlined below:

Stage 1 is performed under the screening protocol, 99-C-0128 (Evaluation for NCI 
Surgery Branch Clinical Research Protocols), to which you have already enrolled.

Stage 2 is performed under the cell harvest 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
1-2 weeks
Inpatient and/or 
outpatient
Scans, x-rays, blood tests, and other 
tests as needed
2.  Cell 
Manufacturing
4-6 weeks
Inpatient and/or 
outpatient
Leukapheresis
3.  Chemotherapy
1 week
Inpatient
Receive IV chemotherapy to prepare 
your immune system for the cells.
4.  Cells and 
aldesleukin 
(IL-2)
1-5 days
Inpatient and 
possibly ICU
Receive anti-ESO-1 cells IV, and 
then high-dose aldesleukin (IL-2) 
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: 13-C-0214
CONTINUATION: page 3 of 17 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 
5. Recovery
1-3 weeks
Inpatient 
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, and scans 
approximately 6 and 12 weeks 
following treatment, and then every 3 
months x 3, every 6 months for 2 
years, and then as determined by your 
study doctor.
What will happen if you take part in this research study? 
Before you Begin the Study
The following procedures are conducted under protocols 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. This process obtained certain types of blood cells from you. Some of these cells (anti- 
ESO-1) will be grown in the lab and genetically modified to recognize a protein on your tumor 
cells. 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. We will evaluate you 
for eligibility for participation on this trial with a physical examination, CT and/or MRI scans, x-
rays, EKG, heart and lung function tests, and blood tests. Patients who have a positive HIV blood 
test will not be eligible for this protocol because it may put them at higher risk of developing 
infections. If you have received ipilimumab (also called Yervoy, MDX-010) or ticilimumab, and 
have experienced any gastrointestinal 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.


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: 13-C-0214
CONTINUATION: page 4 of 17 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 
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 
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, a specific type of “apheresis”, 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 liquid component of blood), 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 collected before treatment may be used to help grow the cells. In addition 
to the leukapheresis you will undergo as part of your work-up, we will also ask you to undergo 
one additional apheresis procedure between 4 and 6 weeks after you receive the cell infusion to 
see the impact of this therapy on the immune system and see if cells we gave you are still active.
The leukapheresis procedure takes between 4-5 hours to complete. Rarely, people may 
experience lightheadedness or dizziness. We ask that you eat prior to the procedure to prevent 
this.
During the Study
Chemotherapy Regimen (Day -7 through Day -3)
After we have grown the anti-ESO-1 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-ESO-1 cells can work without any interference from the cells in your immune system. 
(These medicines will not treat your cancer. They may cause your tumor to shrink some, but this 
shrinkage is anticipated to be only partial and only for a short time.) The main purpose of the 
chemotherapy is to see if we can make the cells more effective in fighting cancer tumors. Animal 
experiments have indicated that this can make the cells more effective in fighting cancer tumors, 
and we think this is true in humans. You will receive the cyclophosphamide through your 
catheter over 1 hour for two days (Day -7 and Day -6) and the fludarabine will be given through 
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.


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: 13-C-0214
CONTINUATION: page 5 of 17 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 
Cell Infusion and Aldesleukin (IL-2) Regimen (Day 0 through Day 5)
Two to four days after the last dose of chemotherapy, you will be given the anti-ESO-1 cells. 
The anti-ESO-1 cells will be given through your catheter over 20-30 minutes. Within 24 hours 
after the anti-ESO-1 cell infusion, you will be given high-dose aldesleukin through your catheter. 
Aldesleukin is approved by the FDA for treatment of metastatic melanoma and metastatic renal 
cell cancer. The purpose of giving aldesleukin with this therapy is to keep the cells we give you 
active for as long as possible so they will fight your tumor. 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 depending on how well you tolerate the 
infusion. The risks of the cells and aldesleukin are described on the following pages.
The day after you receive the anti-ESO-1 cells, we may give you G-CSF (filgrastim) as a shot or 
injection under the skin every day to stimulate your blood cells until they increase to a sufficient 
number. 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 and to make you as 
comfortable as we can.
When you are Finished with Treatment
Recovery
You will recover in the hospital until you are well enough to go home. This usually takes 7-21 
days after you have received the cells or your last dose of aldesleukin; however, you may need to 
stay in the hospital for longer than this before you are well enough to go home. 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 1-9 
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 to prevent you from catching a certain type of pneumonia seen in patients who have 
low white blood cell counts. You may also need to take Valtrex, an anti-viral, for at least 6 
months following your treatment to prevent any type of herpes simplex virus, like shingles.
After you are discharged, we will ask you to return to the NIH Clinical Center approximately 6 
and 12 weeks following treatment, and then if you are responding to the treatment, every 3 
months x3, every 6 months for 2 years, and then as determined by your study doctor.


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: 13-C-0214
CONTINUATION: page 6 of 17 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 first follow-up visit will probably take 2 days; the following visits may only take one day. 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 email 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.
Birth Control
If you are a woman who is breast feeding or pregnant, you may not participate in the study 
because we do not 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 you finish study treatment. Males 
should also refrain from sperm donation during this time-period. If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse as soon as possible. 
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) post-cell administration. 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 


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: 13-C-0214
CONTINUATION: page 7 of 17 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 
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. These long-term follow-up evaluations will be 
conducted under our companion protocol 09-C-0161, “Follow up Protocol for Subjects 
Previously Enrolled in NCI Surgery Branch Studies”, to which you will be enrolled following 
treatment.
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.
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.
As this is a new experimental therapy, you may experience side effects that we do not expect that 
may cause your condition to worsen. Any new information that becomes available during the 
course of this study will be shared with you.
Anti-ESO-1 Cell Infusion (Gene Transfer)
The cells we will be giving you have a type of virus (retrovirus) put into them along with the 
anti-ESO-1 protein. Although this retrovirus is not active, there is the rare possibility that it may 
cause infection. The cells could also cause you to develop another type of cancer, such as 
leukemia or lymphoma. These specific gene-modified cells have been given only to a few 
individuals before so we do not have much information about the 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, which may progress to needing insertion of 
a breathing tube and treatment in the ICU.

Mental status changes

Abnormal kidney or liver function

Breathing problems, which may be severe


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: 13-C-0214
CONTINUATION: page 8 of 17 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 

Decreased heart function

Electrolyte imbalances

Changes in your blood pressure

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.
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.
Aldesleukin (IL-2)
When IL-2 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 IL-2 to over 2,000 patients, we have found that these side 
effects go away within a few days of stopping the IL-2.
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 

Bleeding

Infection

Bladder irritation with 
bloody urine

Severe allergic reaction 
(difficulty 
breathing/swelling)

Headache or 
dizziness

Sweating

Swelling of arms or 

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 


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: 13-C-0214
CONTINUATION: page 9 of 17 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 
treatment)

Loss of appetite, 
nausea, vomiting

Diarrhea, stomach pain

Mouth sores

Hair loss

Fatigue

Muscle or joint aches
legs

Skin changes, rash, 
blisters

Weakness

Hearing loss
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

Complications resulting 
from suppression of 
immune function, which 
can result in a severe 
infection and can be fatal.
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, diarrhea

Rash, itching

Changes in skin or hair 
pigmentation, called 

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. This is more 
common in patients 
who have previously 
received anti-CTLA-4 
antibody (i.e., 
ipilimumab). You will 
have a colonoscopy and 
biopsy before treatment 
if you have previously 
received anti-CTLA-4 
antibody.

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 


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: 13-C-0214
CONTINUATION: page 10 of 17 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 
vitiligo

Changes in mental 
status, including 
confusion, difficulty 
sleeping or vivid 
dreams; this can be 
severe and require 
sedation and monitoring 
in the ICU
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.

IL-2 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

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


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: 13-C-0214
CONTINUATION: page 11 of 17 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 
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
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 
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 protocol 09-C-0161.
Potential Benefits of Participation
Are there benefits to taking part in this study?
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 benefit 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? 
Instead of being in this study, you have the following options:

Taking part in another study

Getting treatment or care for your cancer without being in a study


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: 13-C-0214
CONTINUATION: page 12 of 17 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 

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 take you off this study if:

He/she believes that it is in your best interest

Your disease comes back during treatment

You become pregnant

You experience side effects from the treatment that your doctor thinks are too severe

New information becomes available that shows another treatment would be better for you
In this case, you will be informed of the reason for the decision to take you off the study.
You can stop participating in the study at any time. However, if you decide to stop participating 
in the study, we encourage you to talk to the study doctor and your regular doctor first. If you 
refuse to participate or withdraw from the protocol or at the completion of the protocol, we will 
attempt to offer you participation in other NIH protocols if these are available, or will refer you 
to your home physician for further management.
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.


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: 13-C-0214
CONTINUATION: page 13 of 17 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 

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

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 website will not include information that can identify you. At most the 
website will include a summary of the results. You can search this website 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. 


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: 13-C-0214
CONTINUATION: page 14 of 17 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 
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.
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 NIH and the research team for this study are working with Kite Pharma, Inc. to see if this 
type of study could be done at institutions other than the NIH Clinical Center. Kite Pharma, Inc. 
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.
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 


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: 13-C-0214
CONTINUATION: page 15 of 17 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 
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: 13-C-0214
CONTINUATION: page 16 of 17 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. You may also call the Clinical Center Patient Representative at 301-496-2626. 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.
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: 13-C-0214
CONTINUATION: page 17 of 17 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 OCTOBER 10, 2019 THROUGH APRIL 08, 2020.
Signature of Investigator
Date
Signature of Witness
Date
Print Name
Print Name