Conditions: Metastatic Ocular Melanoma Metastatic Uveal Melanoma
Keywords: Metastatic Ocular Melanoma Autologous Tumor-Infiltrating Lymphocytes Uveal Melanoma Adoptive Cell Therapy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
Background:

\- The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma. This study will use chemotherapy to prepare the immune system before this white blood cell treatment. After receiving the cells, the drug aldesleukin (IL-2) may be given to help the cells stay alive longer.

Objectives:

\- To see if chemotherapy and white blood cell therapy is a safe and effective treatment for advanced ocular melanoma.

Eligibility:

\- Individuals at least greater than or equal to 16 years to less than or equal to 75 years who have advanced ocular melanoma.

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.
* Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product.
* Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood 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 TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.
* Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed description:
Background:

* Metastatic ocular melanoma (OM) carries a poor prognosis with estimated survival of 4-6 months. There are no known effective systemic therapies. Metastatic OM is classified as an orphan disease and there are currently few clinical trial options for these patients. Thus, novel systemic approaches are desperately needed.
* Administration of autologous tumor infiltrating lymphocytes (TIL) generated from resected metastatic cutaneous melanoma can induce objective long-term tumor responses.
* Minimally invasive, safe, and effective surgical approaches have been developed in the Surgery Branch to procure liver tumor tissue for TIL generation.

Objectives:

* To determine whether autologous Young TIL infused with or without the administration of high-dose aldesleukin may result in clinical tumor regression in patients with metastatic ocular melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.
* To study immunologic correlates associated with Young TIL therapy for ocular melanoma.
* To determine the toxicity of this treatment regimen.

Eligibility:

* Patients with metastatic ocular melanoma who are greater than or equal to 16 years of age, and are physically able to tolerate non-myeloablative chemotherapy. Patients who can tolerate high-dose aldesleukin will receive it following cell infusion; those who cannot tolerate high-dose aldesleukin due to medical comorbidities or refuse high dose aldesleukin will receive cell infusion without aldesleukin.
* There is no requirement for prior systemic therapies, given the lack of known effective systemic treatments for metastatic OM.

Design:

* Patients will undergo biopsy or resection to obtain tumor for generation of autologous TIL cultures and autologous cancer cell lines.
* All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine.
* On day 0 patients will receive between 1x10\^9 to 2x10\^11 young TIL and then begin high dose aldesleukin (720,000 IU/kg intravenous (IV) every 8 hours for up to 15 doses) or no aldesleukin if they are not medically eligible to receive it.
* A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last dose of aldesleukin in the aldesleukin arm and 4-6 weeks after the cell administration in the no aldesleukin arm.
* Patients will be enrolled into two cohorts. The cohort receiving high-dose aldesleukin (cohort A) will be conducted using a small optimal two-stage Phase II design, initially 19 patients will be enrolled, and if 4 or more of the first 19 patients have a clinical response (partial response (PR) or complete response (CR), accrual will continue to 33 patients, targeting a 35% goal for objective response. For the cohort that will not receive aldesleukin (cohort B), the study will be conducted as a Minimax two-stage phase II trial. Initially 12 evaluable patients will be enrolled to this cohort, and if 1 or more the first 12 have a response, then accrual would continue until a total of 21 patients, targeting a 20% goal for objective response.

Arms:
arm 1: Patients receiving cells + high dose aldesleukin arm 2: Patients receiving cells and no high dose aldesleukin

Interventions: intervention 1: Aldesleukin intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: Young Tumor Infiltrating Lymphocytes (TIL)
Intervention descriptions: intervention 1: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses) (only for cohort A). intervention 2: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% water (D5W) with Mesna 15 mg/kg/day X 2 days over 1 hr. intervention 3: Fludarabine 25 mg/m\^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days. intervention 4: Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of young TIL and high dose aldesleukin (Cohort A) or no aldesleukin (Cohort B). On day 0,cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes.

Protocol document:
Prot_SAP_001.pdf: 
Amendment
Protocol Number:
13C0093-M
Principal Investigator: Steve Rosenberg 
NCI 
SB 
301.496.4164 
sar@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
370214
Protocol Title:
Phase II Study in Patients with Metastatic Ocular Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of 
Chemotherapy Followed by Infusion of Autologous Tumor-Infiltrating Lymphocytes with or without High Dose Aldesleukin
SIGNATURES
Principal Investigator (*): 
Steve Rosenberg - applied signature on 06/19/2017 12:20 PM EDT 
Udai Kammula - applied signature on 06/19/2017 12:21 PM EDT
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
Steve Rosenberg - applied signature on 06/19/2017 12:20 PM EDT
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 06/30/2017 10:09 AM EDT
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for 
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and 
used solely for those purposes.  Questions may be addressed to the Protrak System Owner. 
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
N/A
DEC Clearance Date:
N/A
Protocol Version Date:05/30/2017
Tonica Johnson
AM M
07/10/17


Abbreviated Title: Ocular Melanoma TIL 
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13-C-0093 
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Abbreviated Title:  Ocular Melanoma TIL 
CC Protocol Number: 13-C-0093 M 
Version Date: 05/30/2017 
NCT Number: NCT01814046 
 
PROTOCOL TITLE 
Phase II Study in Patients with Metastatic Ocular Melanoma Using a Non-Myeloablative 
Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Autologous 
Tumor-Infiltrating Lymphocytes with or without High Dose Aldesleukin 
 
NCI Principal Investigator: 
Steven A. Rosenberg, M.D., Ph.D. A, B, C, D, E 
 
 
 
Chief of Surgery, SB, CCR, NCI 
Building 10, CRC, Room 3-3940  
9000 Rockville Pike, Bethesda, MD 20892 
 
 
 
Phone: 240-760-6218  
 
 
 
Email: Steven.Rosenberg@nih.gov  
 
Study Coordinator: 
Christine McGowan, R.N., OCD, NCI A, B, C, E 
 
Telephone:  240-760-6221;  
 
Email:  Christine.McGowan@.nih.gov  
 
Collaborator:  
Steven Fischkoff, MD 
 
 
 
Lion Biotechnologies, Inc F, G 
 
Investigator Roles: 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens 
for research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research 
purposes 
G. Some/all research activities performed outside NIH 
Investigational Agents: 
Drug Name: 
Young TIL 
IND Number: 
IND 14265 
Sponsor: 
Center for Cancer Research 
Manufacturer 
Surgery Branch Cell Processing 
Facility 
 
Commercial Agents: Cyclophosphamide, Fludarabine, and Aldesleukin 
 
 


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PRÉCIS 
Background: 
• Metastatic ocular melanoma (OM) carries a poor prognosis with estimated survival of 4-6 
months. There are no known effective systemic therapies. Metastatic OM is classified as an 
“orphan” disease and there are currently few clinical trial options for these patients. Thus, 
novel systemic approaches are desperately needed. 
• Administration of autologous tumor infiltrating lymphocytes (TIL) generated from resected 
metastatic cutaneous melanoma can induce objective long-term tumor responses. 
• Minimally invasive, safe, and effective surgical approaches have been developed in the 
Surgery Branch to procure liver tumor tissue for TIL generation. 
 
Objectives: 
• To determine whether autologous Young TIL infused with or without the administration of 
high-dose aldesleukin may result in clinical tumor regression in patients with metastatic 
ocular melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.  
 
Eligibility:  
• Patients with metastatic ocular melanoma who are ≥ 16 years of age, and are 
physically able to tolerate non-myeloablative chemotherapy.  Patients who can 
tolerate high-dose aldesleukin will receive it following cell infusion; those who 
cannot tolerate high-dose aldesleukin due to medical comorbidities or refuse high-
dose aldesleukin will receive cell infusion without aldesleukin. 
• There is no requirement for prior systemic therapies, given the lack of known 
effective systemic treatments for metastatic OM. 
 
Design: 
• Patients will undergo biopsy or resection to obtain tumor for generation of autologous TIL 
cultures and autologous cancer cell lines.  
• All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of 
cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day IV) 
on days -5 through -1. 
• On day 0 patients will receive between 1x109 to 2x1011 young TIL and then begin high dose 
aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses) or no aldesleukin if they are 
not medically eligible to receive it. 
• A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last dose of 
aldesleukin in the aldesleukin arm and 4-6 weeks after the cell administration in the no 
aldesleukin arm.   
• Patients will be enrolled into two cohorts. The cohort receiving high-dose aldesleukin 
(cohort A) will be conducted using a small optimal two-stage Phase II design, initially 
19 patients will be enrolled, and if 4 or more of the first 19 patients have a clinical 
response (PR or CR), accrual will continue to 33 patients, targeting a 35% goal for 


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objective response.   For the cohort that will not receive aldesleukin (cohort B), the 
study will be conducted as a Minimax two-stage phase II trial. Initially 12 evaluable 
patients will be enrolled to this cohort, and if 1 or more the first 12 have a response, 
then accrual would continue until a total of 21 patients, targeting a 20% goal for 
objective response. 
 
 
 
 
 
 
 


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Table of Contents  
 
PRÉCIS .......................................................................................................................................... 2 
1 
INTRODUCTION................................................................................................................. 8 
1.1 Study Objectives.................................................................................................................... 8 
 Primary Objective: .......................................................................................................... 8 
 Secondary Objective(s): .................................................................................................. 8 
1.2 Background and Rationale: ................................................................................................. 8 
 Ocular (Uveal) melanoma (OM) ..................................................................................... 8 
 Adoptive Cell Transfer experience at the Surgery Branch, NCI .................................... 9 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 10 
2.1 Eligibility Criteria ............................................................................................................... 10 
 Inclusion Criteria .......................................................................................................... 10 
 Exclusion Criteria ......................................................................................................... 11 
2.2 Screening Evaluation .......................................................................................................... 11 
 Within 4 weeks prior to starting the chemotherapy regimen: ....................................... 11 
 Within 14 days prior to starting the chemotherapy regimen: ....................................... 12 
 Within 7 days prior to starting the chemotherapy regimen: ......................................... 12 
2.3 Registration Procedures ..................................................................................................... 12 
 Prior to Registration for this Protocol ........................................................................... 12 
 Registration Procedure .................................................................................................. 13 
3 
STUDY IMPLEMENTATION .......................................................................................... 13 
3.1 Study Design ........................................................................................................................ 13 
 Cell Preparation: ........................................................................................................... 13 
 Protocol Stopping Rules: .............................................................................................. 14 
3.2 Drug Administration .......................................................................................................... 14 
 Preparative Regimen with Cyclophosphamide and Fludarabine: ................................. 14 
 Cell Infusion and Aldesleukin Administration: ............................................................ 15 
 Study Calendar .............................................................................................................. 16 
3.3 On-Study Evaluations: ....................................................................................................... 16 
 Prior to starting the preparative regimen ...................................................................... 16 
 During the preparative regimen: DAILY ...................................................................... 16 
 After Cell Infusion: ....................................................................................................... 16 
 During Hospitalization: ................................................................................................. 17 


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3.4 Retreatment ......................................................................................................................... 17 
3.5 Post Study Evaluation (Follow-up) ................................................................................... 17 
3.6 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA................................................................................................................................... 18 
 Criteria for removal from protocol therapy .................................................................. 18 
 Off Study Criteria ......................................................................................................... 18 
 Off Protocol Therapy and Off-study procedure ............................................................ 19 
4 
CONCOMITANT MEDICATIONS/MEASURES .......................................................... 19 
4.1 Infection Prophylaxis: ........................................................................................................ 19 
 Pneumocystis Jirovecii Pneumonia............................................................................... 19 
 Herpes Virus Prophylaxis ............................................................................................. 19 
 Fungal Prophylaxis ....................................................................................................... 19 
 Empiric Antibiotics ....................................................................................................... 19 
4.2 Blood Product Support ....................................................................................................... 20 
4.3 Other Concomitant medications to control side effects................................................... 20 
5 
BIOSPECIMEN COLLECTION ...................................................................................... 20 
5.1 Samples Sent to Dr. Figg’s Lab ......................................................................................... 20 
5.2 Samples Sent to Surgery Branch Cell Processing laboratory ......................................... 21 
5.3 Sample Storage, Tracking and Disposition for SB Cell Processing Laboratory........... 21 
5.4 Sample Storage, Tracking and Disposition For Dr. Figg’s lab ....................................... 21 
 Sample Data Collection ................................................................................................ 21 
 Sample Storage and Destruction ................................................................................... 22 
5.5 Prior to chemotherapy administration ............................................................................. 23 
5.6 Prior to cell infusion............................................................................................................ 23 
5.7 Post cell infusion evaluations: ............................................................................................ 23 
5.8 Immunological Testing: ...................................................................................................... 23 
6 
DATA COLLECTION AND EVALUATION ................................................................. 23 
6.1 Data Collection .................................................................................................................... 23 
 Routine Adverse Event Reporting ................................................................................ 24 
 Exclusions to Routine Adverse Event Reporting: ........................................................ 24 


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 Reporting of laboratory events...................................................................................... 24 
 Reporting of non-laboratory events .............................................................................. 24 
 Reporting Infections...................................................................................................... 25 
6.2 Data sharing Plans .............................................................................................................. 25 
 Human Data Sharing Plan ............................................................................................. 25 
 Genomic Data Sharing Plan .......................................................................................... 25 
6.3 Response Criteria ................................................................................................................ 25 
 Evaluation of target lesions1 ......................................................................................... 25 
 Evaluation of non-target lesions2 .................................................................................. 25 
 Evaluation of best overall response .............................................................................. 26 
 Confirmatory Measurement/Duration of Response ...................................................... 26 
6.4 Toxicity Criteria .................................................................................................................. 27 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN ............................................................................................................................................ 28 
7.1 Definitions ............................................................................................................................ 28 
 Adverse Event ............................................................................................................... 28 
 Suspected adverse reaction ........................................................................................... 28 
 Unexpected adverse reaction ........................................................................................ 28 
 Serious........................................................................................................................... 29 
 Serious Adverse Event .................................................................................................. 29 
 Disability ....................................................................................................................... 29 
 Life-threatening adverse drug experience ..................................................................... 29 
 Protocol Deviation (NIH Definition) ............................................................................ 29 
 Non-Compliance (NIH Definition) ............................................................................... 29 
 
Unanticipated Problem.............................................................................................. 29 
7.2 NCI-IRB and Clinical Director Reporting ....................................................................... 30 
 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths . 30 
 NCI-IRB Requirements for PI Reporting at Continuing Review ................................. 30 
 NCI-IRB Reporting of IND Safety Reports.................................................................. 30 
7.3 IND sponsor reporting criteria .......................................................................................... 30 
 Reporting Pregnancy ..................................................................................................... 31 
7.4 Data and Safety Monitoring Plan ...................................................................................... 31 
 Principal Investigator/Research Team .......................................................................... 31 
 Sponsor Monitoring Plan .............................................................................................. 32 
8 
STATISTICAL CONSIDERATIONS .............................................................................. 32 
9 
COLLABORATIVE AGREEMENTS.............................................................................. 33 


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10 HUMAN SUBJECTS PROTECTIONS ............................................................................ 33 
10.1 
Rationale For Subject Selection ..................................................................................... 33 
10.2 
Participation of Children ............................................................................................... 34 
10.3 
Participation of Subjects Unable to Give Consent ....................................................... 34 
10.4 
Evaluation of Benefits and Risks/Discomforts ............................................................. 34 
10.5 
Risks/Benefits Analysis ................................................................................................... 34 
10.6 
Consent and Assent Process and Documentation ........................................................ 34 
10.7 
Additional Considerations for participation of sixteen and seventeen-year-old 
patients ......................................................................................................................................... 35 
11 PHARMACEUTICAL INFORMATION ......................................................................... 35 
11.1 
Interleukin-2 (Aldesleukin, Proleukin, Recombinant Human Interleukin 2) ........... 35 
11.2 
Fludarabine: .................................................................................................................... 36 
11.3 
Cyclophosphamide .......................................................................................................... 37 
11.4 
Young TIL Preparation .................................................................................................. 38 
11.5 
Mesna ............................................................................................................................... 38 
11.6 
Filgrastim ......................................................................................................................... 38 
11.7 
Trimethoprim and Sulfamethoxazole Double Strength (TMP / SMX DS): .............. 39 
11.8 
Aerosolized Pentamidine in Place of TMP/SMX DS: .................................................. 39 
11.9 
Herpes Virus Prophylaxis: ............................................................................................. 39 
 
Valacyclovir (Valtrex): ............................................................................................. 39 
 
Acyclovir................................................................................................................... 39 
11.10 Fluconazole: ..................................................................................................................... 40 
11.11 Support Medications ....................................................................................................... 40 
12 REFERENCES .................................................................................................................... 41 
13 FIGURES, TABLES & APPENDICES ............................................................................ 43 
 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
 Primary Objective: 
• To determine whether autologous Young TIL infused with or without the administration 
of high-dose aldesleukin may result in clinical tumor regression in patients with 
metastatic ocular melanoma receiving a non-myeloablative lymphoid depleting 
preparative regimen.   
 Secondary Objective(s): 
• To study immunologic correlates associated with Young TIL therapy for ocular 
melanoma. 
• To determine the toxicity of this treatment regimen. 
 
1.2 
BACKGROUND AND RATIONALE: 
This is a clinical protocol aimed at treating patients with metastatic ocular (uveal) melanoma 
(OM) with adoptive transfer of autologous young tumor infiltrating lymphocytes (young TIL). 
OM is the most common primary intraocular cancer in adults. Nearly half of primary uveal 
melanoma tumors will metastasize, but there are currently no effective therapies for metastatic 
OM. The potential of TIL to mediate complete and durable responses in metastatic cutaneous 
melanoma has been established by work from the Surgery Branch1. We are now seeking to 
determine if this therapeutic approach can mediate objective tumor regression in patients with 
metastatic OM.  
 Ocular (Uveal) melanoma (OM) 
OM is the most frequent tumor of the eye. It arises from the pigmented uveal tract of the eye in 
97% of the cases (choroid, ciliary body, iris) but can also rarely appear in the conjunctiva (3%). 
Its annual incidence is 5.1 per million  and has remained stable over the past 30 years in the US2. 
Based on these statistics OM represents a “rare disease” as defined by The Rare Disease Act of 
2002 (HR 4013) and the US Orphan Drug Act. Approximately half of patients diagnosed with 
primary OM will develop metastatic disease3. Although there are effective therapies to eradicate 
and prevent local recurrence of primary OM within the eye (radioplaque, proton beam, and 
enucleation), there are currently no effective therapies for metastatic uveal melanoma3. The most 
common sites of OM metastases metastasizes are liver (95%), lungs (24%), bone (16%), and 
skin (11%)4. The clinical course of patients with uveal melanoma is highly dependent on disease 
progression in the liver. The median survival after diagnosis of patients with liver metastases is 
approximately 4 to 6 months with a 1-year survival of approximately 10% to 15%5.   
Because the liver is the main site of metastases in up to 90% of the patients, efforts to develop 
loco-regional therapies for hepatic metastases, including surgical resection6,7 chemo-
embolization8,9, immune-embolization10,11, radioembolization12, intra-arterial chemotherapy13-15 
and  hepatic arterial perfusion16,17 have been explored. Unfortunately, to date there is no clinical 
evidence that these loco-regional therapies improve overall survival for patients with metastatic 
OM.   
The development of effective systemic therapies for patients with metastatic OM has similarly 
shown limited success. There are currently no standard systemic therapies for the treatment of 
metastatic OM.  Various chemotherapy agents, alone or in combination, have been studied 


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without evidence of significant anti-tumor activity18. Promising small molecule inhibitors that 
have shown clinical responses in metastatic cutaneous melanoma19,20 have not translated to the 
successful treatment of OM due to significant differences in the expression of common driver 
mutations (ie BRAF and NRAS) in OM21. Further recently approved immune modulating agents 
such as anti-CTLA-4 antibody have shown initial limited activity in patients with OM22,23. Given 
the poor prognosis and lack of effective therapies for patients with metastatic OM, novel 
effective systemic approaches are desperately needed. 
 Adoptive Cell Transfer experience at the Surgery Branch, NCI 
The 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).  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)24. Forty-three 
patients received a non-myeloablative chemotherapy consisting of 60 mg/kg cyclophosphamide 
q daily x 2 and 25mg/m2 fludarabine q 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, and the 
toxicities shown in Table 2 for the TBI studies (04-C-0288, 06-C-0136) and Table 3 for the 
initial study without TBI (99-C-0158). There was one treatment related death in these 93 patients 
which occurred in a patient 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. 
In the Surgery Branch, work is underway to extend TIL therapy to non-cutaneous melanoma 
cancers. In an ongoing protocol we are targeting digestive tract tumors with young TIL. Most of 
the toxicities observed in this study were expected toxicities of the non-myeloablative 
chemotherapy and the IL-2. TIL was grown successfully in 14 of 15 attempts from resected GI 
tumors (Table 4), demonstrating our ability to reliably generate a cell product from a variety of 
cancers.  This work has been further supported by the successful generation of TIL from patients 
with cervical cancer (Table 5) in another ongoing clinical effort in the Surgery Branch. Based 
upon these findings, we believe that the generation of young TIL from OM metastases should be 
readily feasible with our current cell production methodologies. 
A significant and unique challenge associated with this clinical trial is the ability to successfully 
obtain metastatic tumor tissue from patients with OM, given that the majority of patients will 
have only liver metastases. We recently reported on our series of cutaneous melanomas patients 
in which we performed minimally invasive laparoscopic liver metastasectomy to obtain tumor 
tissue for the generation of TIL. In this report we demonstrated the safety and feasibility of 
performing minimally invasive laparoscopic liver resection to obtain tumor tissue to generate 
TIL for therapy25. Median hospital stay was 3 days for patients undergoing laparoscopic liver 
resection. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL 
procured in this manner, with one patient experiencing an ongoing complete response (32+ 


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months). Thus, laparoscopic liver resection can be performed with minimal morbidity and serve 
as an effective means to procure tumor to generate therapeutic TIL for patients with metastatic 
cutaneous melanoma. We now aim to evaluate this therapeutic strategy in patients with 
metastatic OM. 
In summary, we are uniquely qualified to procure tumor tissue from patients with ocular 
melanoma and to generate young TIL for experimental therapy. We believe that the current 
proposed clinical administration of TIL to patients with metastatic OM represents a novel and 
desperately needed treatment strategy for investigation in patients with this disease.  
 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
 Inclusion Criteria 
a. Measurable metastatic ocular melanoma.   
b. Confirmation of diagnosis of metastatic ocular melanoma by the Laboratory of Pathology 
of the NCI.  
c. 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.  
d. Greater than or equal to 16 years of age and less than or equal to age 75 
e. Able to understand and sign the Informed Consent Document 
f. Willing to sign a durable power of attorney 
g. Clinical performance status of ECOG 0 or 1 
h. Life expectancy of greater than three months 
i. Patients of both genders must be willing to practice birth control from the time of 
enrollment on this study and for up to four months after receiving the treatment. 
j. Serology:  
• Seronegative for HIV antibody.  (The experimental treatment being evaluated in 
this protocol depends on an intact immune system.  Patients who are HIV 
seropositive can have decreased immune-competence and thus be less responsive 
to the experimental treatment and more susceptible to its toxicities.)  
• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If 
hepatitis C antibody test is positive, then patient must be tested for the presence of 
antigen by RT-PCR and be HCV RNA negative.  
k. Women of child-bearing potential must have a negative pregnancy test because of the 
potentially dangerous effects of the treatment on the fetus.  
l. Hematology 
• Absolute neutrophil count greater than 1000/mm3 without the support of 
filgrastim 
• WBC ≥ 3000/mm3 
• Platelet count ≥ 100,000/mm3 
• Hemoglobin > 8.0 g/dl 
m. Chemistry: 
• Serum ALT/AST ≤ to 3.5 times the upper limit of normal 
• Serum creatinine ≤ to 1.6 mg/dl 


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• Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert’s Syndrome who 
must have a total bilirubin less than 3.0 mg/dl. 
n. 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 3 weeks, as long 
as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria in 
Section 2.1.1. 
 Exclusion Criteria 
a. Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the treatment on the fetus or infant. 
b. Active systemic infections, coagulation disorders or other active major medical illnesses 
of the cardiovascular, respiratory or immune system, as evidenced by a positive stress 
thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or 
restrictive pulmonary disease. 
c. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease). 
d. Concurrent opportunistic infections (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who have decreased immune 
competence may be less responsive to the experimental treatment and more susceptible to 
its toxicities). 
e. Concurrent systemic steroid therapy. 
f. History of severe immediate hypersensitivity reaction to any of the agents used in this 
study. 
g. The following patients will be excluded from the high-dose aldesleukin arm (but may be 
eligible for cells alone arm): 
• History of coronary revascularization or ischemic symptoms 
• Documented LVEF of less than or equal to 45%. Testing is required in patients with: 
o Clinically significant atrial and/or ventricular arrhythmias including but not 
limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart 
block 
o Age ≥ 60 years’ old 
• Clinically significant patient history which in the judgment of the Principal Investigator 
would compromise the patient’s ability to tolerate aldesleukin 
 
2.2 
SCREENING EVALUATION 
 Within 4 weeks prior to starting the chemotherapy regimen:  
a. Complete history physical examination, including weight, ECOG, and vital signs noting 
in detail the exact size and location of any lesions that exist and any allergies/sensitivities 
to antibiotics. (Note: patient history may be obtained within 8 weeks.) 
b. Chest x-ray 
c. EKG  
d. Baseline imaging (CT, MRI, and/or PET) to evaluate the status of disease.  
e. Patients with a prolonged history of cigarette smoking or symptoms of respiratory 
dysfunction will undergo Pulmonary Function Testing.  Patients with an FEV1 of less 


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than or equal to 60% predicted for age will not be eligible to receive high-dose 
aldesleukin, but may be eligible to receive cells without aldesleukin (may be performed 
within 8 weeks of treatment).  Note: Pulmonary function testing will not be required for 
patients who are not candidates to receive high-dose aldesleukin due to medical 
judgment or patient refusal.  
f. Patients who are greater than or equal to age 60, or have a history of ischemic heart 
disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including 
but not limited to: atrial fibrillation, ventricular tachycardia, heart block, will undergo 
cardiac evaluation (stress thallium, echocardiogram, MUGA etc.,).  Patients with a LEVF 
of less than or equal to 45% will not be eligible to receive high-dose aldesleukin but, may 
be eligible to receive cells without aldesleukin (may be performed within 8 weeks of 
treatment).  Patients under the age of 60 who have cardiac risk factors may also undergo 
cardiac evaluations as noted above (e.g., diabetes, hypertension, obesity) Note: Cardiac 
evaluation will not be required for patients who are not candidates to receive high-dose 
aldesleukin due to medical judgment or patient refusal. 
g. HIV antibody titer and HbsAG determination, anti HCV (may be performed within 3 
months of chemotherapy start date). 
h. Anti CMV antibody titer, HSV serology, and EBV panel. (Note:  Patients who are known 
to be positive for any of the above do not need to be retested - may be performed within 3 
months of chemotherapy start date.)  
i. Verification that HLA typing is completed (testing is permitted to be conducted at any 
time prior to this point)  
 
 Within 14 days prior to starting the chemotherapy regimen: 
a. Baseline blood tests  
• Chemistries: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, 
ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total 
CK, Uric Acid) 
• Thyroid panel  
• CBC with differential and platelet count 
• PT/PTT 
b. Urinalysis; urine culture, if indicated  
 
  Within 7 days prior to starting the chemotherapy 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 PROCEDURES 
 Prior to Registration for this Protocol 
Patients will be registered on protocol 03-C-0277 (Cell Harvest and Preparation for Surgery 
Branch Adoptive Cell Therapy Protocols) prior to tumor resection for young TIL generation, by 
the clinical fellow or research nurse within 24 hours of the patient signing the consent and 
sending the completed Eligibility Checklist via encrypted email to: NCI Central Registration 


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Office (HOIS) ncicentralregistration-l@mail.nih.gov. 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.   
 Registration Procedure 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol.  Verification of 
Registration will be forwarded electronically via e-mail to the research team. A recorder is 
available during non-working hours.  
 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
The study will be conducted using a Phase II design. Young TIL will be generated from tumor 
fragments and/or digests according to standard operating procedure.  
There will be two cohorts of patients depending on eligibility to receive high-dose aldesleukin 
(see 2.1.2 g) 
• Cohort A - Patients who are eligible will receive high-dose aldesleukin following the cell 
product; 
• Cohort B - Patients who are not eligible to receive high-dose aldesleukin will receive cells 
alone. 
Each cohort will accrue independently of the other. Patients will receive no other experimental 
agents while on this protocol. 
Patients will receive the standard NCI Surgery Branch non-myeloablative, lymphodepleting 
preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of 
Young TIL +/- 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. Patients may undergo a second treatment as described in Section 3.4. 
 Cell Preparation: 
Patients with evaluable metastatic ocular melanoma who have lesions that can be resected with 
minimum morbidity will undergo resection of tumor.  TIL will be obtained while enrolled on the 
Surgery Branch protocol 03-C-0277, “Cell Harvest and Preparation for Surgery Branch Adoptive 
Cell Therapy Protocols”.  Separate tumor biopsies may be performed under protocol 03-C-0277 
to obtain TIL if initial tumor biopsy could not successfully generate TIL. Young TIL will be 
grown and expanded for this trial according to standard operating procedures submitted in the 
IND.  Young TIL will be assessed for potency by interferon-gamma release as specified in the 
Certificate of Analysis shown in Appendix 4.  Once cells exceed the potency requirement and 
are projected to exceed the minimum number specified in the COA, the patient will be registered 
on this study and receive the lymphocyte depleting preparative regimen consisting of fludarabine 
and cyclophosphamide, followed by infusion of cells and administration of high-dose 


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aldesleukin.  It is anticipated that Young TIL that meet the COA will not be achievable in 
approximately 20% of patients who undergo resection.  These patients may undergo a second 
resection to grow Young TIL, if another suitable lesion exists.   
 Protocol Stopping Rules: 
The study will be temporarily halted pending discussions with the FDA and NCI IRB regarding 
safety and the need for protocol revisions if any of the following conditions are met: 
• Two or more patients develop a grade 3 or greater toxicity at any point in the study not 
attributable to the chemotherapy preparative regimen or aldesleukin (or circumstances 
unrelated to the study). 
• 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 of the first four patients (or 2 of the first 6 patients, or 3 of the first 9 patients, or 4 
of the first 12 patients) develops a grade 3 or greater non-hematologic toxicity due to the 
prior conditioning regimen, aldesleukin or the cell product that does not resolve in 72 
hours, or experiences a toxicity requiring intubation, pressors or CVVH. 
• If one or more treatment related deaths occur due to the cell infusion, we will promptly 
discuss this with the NCI IRB and FDA. 
 
3.2 
DRUG ADMINISTRATION 
 Preparative Regimen with Cyclophosphamide and Fludarabine: 
(Times are offered as examples and may be changed as long as a similar time relationship 
between administration of the drugs is maintained. Study medication start times for drugs given 
once daily should be given within 2 hours of the scheduled time.  All other medications should 
be given +/- one hour of the scheduled time; the length of administration is all +/- 15 minutes.  
Administration of diuretics, electrolyte replacement, and hydration and monitoring of 
electrolytes should all be performed as clinically indicated – the times noted below are offered 
only as examples. Chemotherapy infusions maybe slowed or delayed as medically indicated) 
DAYS -7 and -6 
6 AM 
Hydrate: Begin hydration with 0.9% Sodium Chloride Injection containing 10 meq/L of 
potassium chloride at 2.6 ml/kg/hr (starting 11 hours pre-cyclophosphamide and continue 
hydration until 24 hours after last cyclophosphamide infusion).  At any time during the 
preparative regimen, if urine output <1.5 ml/kg/hr or if body weight >2 kg over pre-
cyclophosphamide value, furosemide 10-20 mg IV maybe administered. Serum potassium should 
be monitored and treated as indicated following administration of furosemide. 
4 PM 
Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose between 8 mg and 16 mg 
based on patient weight] IV every 8 hours X 3 days) will be given for nausea.  
5 PM 


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Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 
days over 1 hr. If patient is obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Table 6.  
6 PM 
Begin mesna infusion at 3 mg/kg/hour intravenously diluted in a suitable diluent (see 
pharmaceutical section 11) over 23 hours after each cyclophosphamide dose. If patient is obese 
(BMI > 35) drug dosage will be calculated using practical weight as described in Table 6.  
DAYS -5 to -1 
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 Table 6.  
 Cell Infusion and Aldesleukin Administration: 
The patient’s Young TIL are delivered to the patient care unit by a staff member from the Tumor 
Immunology Cell Processing Laboratory.  Cells will be administered at a dose of between 1x109 
to 2x1011 lymphocytes over 20-30 minutes.  Prior to infusion, the cell product identity label is 
double-checked by two authorized staff (MD or RN), an identification of the product and 
documentation of administration are entered in the patient’s chart, as is done for blood banking 
protocols.  The cells are to be infused intravenously over 20-30 minutes via non-filtered tubing, 
gently agitating the bag during infusion to prevent cell clumping. 
Aldesleukin Administration (Cohort A):  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 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.  Dosing 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 1.  Toxicities will be managed as outlined in Appendix 2.  In addition, dosing may be 
held or stopped at the discretion of the treating investigator.  (Appendix 3 lists the toxicities seen 
in patients treated with aldesleukin at the NIH Clinical Center26). Because confusion is a possible 
side effect of aldesleukin administration, a Durable Power of Attorney will be signed by the 
patient to identify a surrogate to make decisions if a patient becomes unable to make decisions. 
DAY 0 (one to four days after the last dose of fludarabine): 
 
• Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes 
(between one and four days after the last dose of fludarabine). 
• Aldesleukin as described in Section 3.2.2above (only for cohort A). 
DAY 1-4 (Day 0 is the day of cell infusion):  
• Beginning on day 1 or 2, filgrastim may be administered subcutaneously at a dose of 5 
mcg/kg/day (not to exceed 300 mcg/day).  Filgrastim administration will continue daily 
until neutrophil count > 1.0 x109/L X 3 days or > 5.0 x109/L.  
• Aldesleukin as described in section 3.2.2above (only for cohort A). 
 


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 Study Calendar 
1One to four days after the last dose of fludarabine 
2Initiate within approximately 24 hours after cell infusion 
3Continue until neutrophils count > 1X109/L for 3 consecutive days or > 5x109/L. 
4The TMP/SMX schedule should be adjusted to QD three times per week (Monday, Wednesday, Friday) and 
continue for at least six months and until CD4 > 200 X 2 
5Continue until ANC > 1000/mm3 
6In patients positive for HSV continue until CD4 > 200 X 2 
 
3.3 
ON-STUDY EVALUATIONS: 
 Prior to starting the preparative regimen 
• Apheresis as indicated 
• Within 14 days prior to starting the preparative regimen, patients will have a complete 
blood count, serum chemistries performed including electrolytes, BUN, creatinine, liver 
function tests, and TBNK.  If any results are beyond the criteria established for eligibility, 
the patient will not proceed until the abnormalities can be resolved.  
 
 During the preparative regimen: DAILY 
• Complete Blood Count 
• Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid 
• Urinalysis as needed. 
 
 After Cell Infusion: 
• Vital signs will be monitored hourly x4 and then routinely (every 4-6 hours) unless 
otherwise clinically indicated 
• Once total lymphocytes count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly (while the patient is hospitalized).  Refer to section 5 for 
additional post cell infusion evaluations.  
 
Day 
-7 -6 
-5 
-4 
-3 
-2 
-1 
01 
1 
2 
3 
4 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide (60 mg/kg) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Fludarabine (25 mg/m2) 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Young TIL 
 
 
 
 
 
 
 
X1 
 
 
 
 
Aldesleukin 
 
 
 
 
 
 
 
X2 
X 
X 
X 
X 
Filgrastim3 (5 mcg/kg/day) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
TMP/SMX4 
160mg/800 mg (example) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluconazole5 (400 mg po) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Valacyclovir po or Acyclovir IV6 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 


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 During Hospitalization:  
Every 1-2 days 
• A review of systems and physical exam as clinically indicated 
• CBC 
• Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid 
• Other tests will be performed as clinically indicated. 
 
3.4 
RETREATMENT  
Patients experiencing a sustained stable disease, partial or complete response may receive 
a second treatment when progression by RECIST criteria is documented after evaluation 
by the principal investigator.  Retreatment will consist of the same regimen that they had 
been given safely previously.  Patients who develop grade 3 or grade 4 toxicity due to 
cell infusion will not be retreated. Patients must continue to meet the original eligibility 
criteria to be considered for retreatment.  Toxicity related to cyclophosphamide, 
fludarabine, or aldesleukin should be stable and resolved to less than grade 1 prior to 
retreatment.  Retreatment benefits and risks will be carefully explained to the patient.  A 
maximum of 1 retreatment course may occur.  
3.5 
POST STUDY EVALUATION (FOLLOW-UP) 
• All patients will return to the NIH Clinical Center for evaluation 6 weeks (+/- 2 weeks) 
following the administration of the cell product. 
 
• Patients who have received multiple transfusions during the treatment phase or have been 
discharged with grade 3 or greater significant adverse events should be evaluated by the 
referring physician within 2 weeks of discharge and repeat labs drawn as appropriate to be 
faxed to the Research Nurse.  Patients will receive appropriate treatment as determined by 
their treating physician.  
 
• Patients who experience stable disease, a partial response, or a complete response or have 
unresolved toxicities will be evaluated as noted below: 
o Week 12 (+/- 2 weeks)  
o Every 3 months (+/- 1 month) x3 
o Every 6 months (+/- 1 month) x 2  
o As per PI discretion for subsequent years 
Note: Patients may be seen more frequently as clinically indicated 
 
• At each scheduled evaluation patients will undergo: 
o Physical examination  
o Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid  


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o Complete blood count 
o Thyroid panel as clinically indicated 
o TBNK, until CD4 > 200 x 2 
o Toxicity assessment, including a review of systems.  
o CT of the chest, abdomen and pelvis. If clinically indicated, other scans or x-rays may 
be performed, e.g. brain MRI, bone scan. 
o Visual symptoms will be evaluated and if changes have occurred from baseline, i.e. 
changes in visual acuity, an ophthalmologic consult will be performed. 
o A 5 liter apheresis may be performed.  If the patient is unable to undergo apheresis, 
approximately 96 ml of blood may be obtained at the first follow up visit.  
Subsequently, 60 ml of blood will be obtained at follow up visits for at least 3 
months. Peripheral blood mononuclear cells will be cryopreserved so that 
immunologic testing may be performed.    
 
• Patients who are unable or unwilling to return for follow up evaluations will be followed 
via phone or e-mail contacts.  Patients may be asked to send laboratory, imaging and 
physician exam reports performed be their treating physician.  
 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
Prior to removal from study, effort must be made to have all subjects compete a safety visit 
approximately 30 days following the last dose of study therapy.   
 Criteria for removal from protocol therapy 
Patients will be taken off treatment (and followed until progression of disease) for the following: 
• Completion of protocol therapy  
• Participant requests to be withdrawn from active therapy 
• Investigator discretion 
• Positive pregnancy test 
 
 Off Study Criteria 
Patients will be taken off study for the following: 
• Completed study follow-up period 
•  Participant requests to be withdrawn from study  
• Progressive disease, unless the patient is eligible for a second treatment 
• Death 
 
Note: Patients who are taken off study for progressive disease or study closure may be followed 
on Protocol 09-C-0161 “Follow up Protocol for Subjects Previously Enrolled in Surgery Branch 
Studies”. 
Note:  Once a subject is taken off study, no further data can be collected. 


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 Off Protocol Therapy and Off-study procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov. 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
INFECTION PROPHYLAXIS: 
Note: Appropriate anti-infective agents may be substituted at the discretion of the treating 
physician.  
 Pneumocystis Jirovecii Pneumonia 
All patients will receive the fixed combination of trimethoprim and sulfamethoxazole 
(TMP/SMX) as double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) 
P.O. daily three times a week on non-consecutive days, beginning between days -5 and -8.  
Pentamidine will be substituted for TMP/SMX-DS in patients with sulfa allergies. It will be 
administered aerosolized at 300 mg per nebulizer within one week prior to admission and 
monthly thereafter. 
 Herpes Virus Prophylaxis 
Patients with positive HSV serology will be given valacyclovir orally at a dose of 500 mg daily 
the day after chemotherapy ends, or acyclovir, 250 mg/m2 IV every 12 hrs 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 Pneumocystitis and Herpes will continue for 6 months post chemotherapy.  If the 
CD4 count is less than 200 at 6 months post chemotherapy, prophylaxis will continue until the 
CD4 count is greater than 200. 
 
 Fungal Prophylaxis 
Patients will start Fluconazole 400 mg p.o. the day after chemotherapy concludes and continue 
until the absolute neutrophil count is greater than 1000/mm3.  The drug may be given IV at a 
dose of 400 mg in 0.9% sodium chloride USP daily in patients unable to take it orally. 
 Empiric Antibiotics 
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation cephalosporin or a 
quinolone for fever of 38.3°C once or two temperatures of 38.0°C or above 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 


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4.2 
BLOOD PRODUCT SUPPORT 
Using daily CBC’s as a guide, the patient will receive platelets and packed red blood cells 
(PRBC’s) as needed.  Attempts will be made to keep Hb >8.0 gm/dl, and plts >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 WBC’s and decrease the risk of CMV 
infection. 
4.3 
OTHER CONCOMITANT MEDICATIONS TO CONTROL SIDE EFFECTS 
Concomitant medications to control side effects of therapy may be given.  Meperidine (25-50 
mg) will be given intravenously if severe chilling develops.  Other supportive therapy will be 
given as required and may include acetaminophen (650 mg q4h), indomethacin (50-75 mg q6h) 
and ranitidine (150 mg g12h). If patients require steroid therapy, they will be taken off treatment.  
Patients who require transfusions will receive irradiated blood products.  Ondansetron 0.15 
mg/kg/dose IV every 8 hours will be administered for nausea and vomiting.  Additional 
antiemetics will be administered as needed for nausea and vomiting uncontrolled by 
ondansetron.  Antibiotic coverage for central venous catheters may be provided at the discretion 
of the investigator. 
 
5 
BIOSPECIMEN COLLECTION  
Correlative Studies for Research: The amount of blood that may be drawn from adult patients for 
research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-
week period. 
Blood and tissue are tracked at the patient level and can be linked to all protocols on which the 
patient has been enrolled.  Samples will be used to support the specific objectives listed in the 
treatment protocol(s), e.g., immunologic monitoring, cytokine levels, persistence, as well as to 
support long term research efforts within the Surgery Branch and with collaborators as specified 
in our companion protocol, 03-C-0277 (Cell Harvest and Preparation for Surgery Branch 
Adoptive Cell Therapy Protocols). 
 
5.1 
SAMPLES SENT TO DR. FIGG’S LAB 
• Venous blood samples will be collected in either a 4ml or an 8ml SST tube to be 
processed for serum and stored for future research. Record the date and exact time of 
draw on the tube.  
• For sample pickup, page 102-11964. 
• For immediate help, call 240-760-6180 (main blood processing core number) or, if no 
answer, 240-760-6190 (main clinical pharmacology lab number). 
• For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-
6044. 
• The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by 
the investigator. 
 


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5.2 
SAMPLES SENT TO SURGERY BRANCH CELL PROCESSING LABORATORY 
• Venous blood samples will be collected in 8ml CPT tubes to be processed and stored for 
future research. Record the date and exact time of draw on the tube. 
• Samples will be picked -up by the research nurse or designee and transported to the SB 
Cell Processing Laboratory. 
• The samples will be processed, barcoded, and stored in SB Cell Processing Laboratory. 
 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION FOR SB CELL PROCESSING 
LABORATORY 
Blood and tissue collected during the course of this study will follow the Cell Tracking and 
Labeling System established by the Tumor Immunology Cell Processing Laboratory.  The Cell 
Tracking and Labeling System is designed to unambiguously ensure that patient/data verification 
is consistent.  The patients' cell samples (blood or tissue) are tracked by distinct identification 
labels that include a unique patient identifier and date of specimen collection.  Cryopreserved 
blood and tissue samples also bear the date the sample was frozen.  All cryopreserved samples 
are tracked for freezer location and storage criteria.  All samples are stored in monitored 
freezers/refrigerators in 3NW Surgery Branch Laboratories at specified temperatures with alarm 
systems in place.  Serum samples will be sent to the Blood Processing Core (BPC) for storage.    
Samples will be barcoded and stored on site or offsite at NCI Frederick Central Repository 
Services in Frederick, MD.  All samples collected (blood or tissue) are entered into a central 
computer database with identification and storage location, and this database is backed up every 
night. 
 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
 
Note:  Blood and tissue collected during the course of this study will be stored, tracked and 
disposed of as specified in our companion protocol 03-C-0277, (Cell Harvest and Preparation for 
Surgery Branch Adoptive Cell Therapy Protocols). 
 
5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION FOR DR. FIGG’S LAB 
 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC, and data will be updated to the 
Surgery Branch central computer database weekly. This is a secure program, with access to 
LABrador limited to defined Figg lab personnel, who are issued individual user accounts. 
Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have 


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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.). 
 
 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), 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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Note:  Blood and tissue collected during the course of this study will be stored, tracked and 
disposed of as specified in our companion protocol 03-C-0277, (Cell Harvest and Preparation for 
Surgery Branch Adoptive Cell Therapy Protocols). 
 
5.5 
PRIOR TO CHEMOTHERAPY ADMINISTRATION 
• 5 CPT tubes (8 ml each) – SB’s lab 
• 1 SST tube (8 ml) – Figg’s lab 
• 1 SST tube (4 ml) daily; starting on the day of chemotherapy – Figg’s lab 
5.6 
PRIOR TO CELL INFUSION 
• Blood samples for cytokine analysis (one 8 ml tube) – Figg’s lab 
5.7 
POST CELL INFUSION EVALUATIONS: 
• Once total lymphocyte count is greater than 200/mm3, the following samples will be 
drawn and sent to the TIL lab on Monday, Wednesday and Friday x5, then weekly (while 
the patient is hospitalized): 
o 5 CPT tubes (8 ml each) – SB’s lab 
o 1 SST tube (8 ml) – Figg’s lab 
 
5.8 
IMMUNOLOGICAL TESTING: 
o Apheresis may be performed prior to and 4-6 weeks after the treatment.  At other time 
points, patient peripheral blood lymphocytes (PBL) will be obtained from whole 
blood by purification using centrifugation on a Ficoll cushion. Aliquots of these 
PBMC will be cryopreserved for immunological monitoring of cell function. 
o Lymphocytes will be tested directly and following in vitro culture using some or all 
of the following tests. Direct immunological monitoring will consist of quantifying T 
cells reactive with targets FACS analysis using tetramer staining.  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 TIL cryopreserved at the 
time of infusion. In general, differences of 2 to 3 fold in these assays are indicative of 
true biologic differences.  Foxp3 levels will be analyzed by semiquantitative RT-PCR 
to evaluate for mRNA on PBL samples obtained prior to cell infusion and at the 
follow up time point. 
 
Note: The collection and analysis of research labs will be monitored by the TIL lab and not by 
Harris. 
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 and ensuring data accuracy, consistency and timeliness. The principal 


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investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant.  Data will be entered into the NCI CCR 
C3D database.  
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
 Routine Adverse Event Reporting  
Following registration through 30 days after cell infusion, adverse will be recorded in the source 
documents, reviewed by the designated data manager or research nurse or principle investigator 
and captured in Surgery Branch Immunotherapy database. All events occurring during the 
treatment phase of the study will be followed until resolution to grade 2 or baseline.  During the 
follow up period, only grade 3 and 4 and unexpected grade 2 events that are related the treatment 
will be captured in C3D. 
 Exclusions to Routine Adverse Event Reporting: 
Patients will be receiving multiple agents which include commercially available agents 
(fludarabine, cyclophosphamide and supportive medications) in combination with the 
investigational agents.  Therefore, Grade 2 adverse events ‘unrelated’ or ‘unlikely related’ to the 
investigational agent, and ‘possibly’, ‘probably’ or ‘definitely’ related to the commercially 
available agents as specified in the package inserts do not require reporting/recording.  In 
addition, all grade 1 events and all expected grade 2 events unrelated to the cell product will not 
be reported/recorded.  
 Reporting of laboratory events 
Laboratory results will be uploaded in C3D however only those events (including grade 3 and 4 
events) that support the diagnosis of a reportable adverse event or that reflect major organ 
function will be considered adverse events. For example, grade 3 and 4, creatinine, liver function 
tests, hemoglobin, ANC, ALC, platelets, and lipase and amylase as indicated will be captured as 
adverse events; electrolytes, BUN, albumin, total protein, uric acid etc., and the remainder of the 
CBC differential will not be captured as adverse events. 
For reportable adverse events: the adverse event start date will be the date the event reaches a 
grade 3; the event will be considered resolved once it reaches grade 2.  The highest grade the 
event reaches in that period will be considered the grade of the event.  For hematological 
toxicities, the event will not be considered resolved until it reaches grade 2 without the support 
of transfusions or growth factors. 
 Reporting of non-laboratory events 
For reportable expected adverse events: the adverse event start date will be the date the event 
reaches a grade 3; the event will be considered resolved once it reaches grade 2.  The highest 
grade the event reaches in that period will be considered the grade of the event.   


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For unexpected adverse events, the adverse event start date will be the date the event reaches a 
grade 2; the event will be considered resolved once it reaches grade 1 or baseline. 
 Reporting Infections 
• Febrile neutropenia will be captured as follows:  The start date will be the date the fever 
of 38.5 or greater was first recorded.  The end date will be the date the patient has been 
afebrile greater than 48 hours or the date the patient develops a clinically significant 
infection. 
• If a patient has a positive culture during the period of febrile neutropenia, the event will 
be captured as “infection with neutropenia” with the start date as the date the fever of 
38.5 was first recorded.   
• Infection will only be captured once in any given period regardless of the number of 
organisms cultured or sites involved. 
• Positive cultures seen on routine surveillance cultures with no clinical symptoms will not 
be captured as infections regardless of whether anti-infective agents are given. 
6.2 
DATA SHARING PLANS 
 Human Data Sharing Plan 
De-identified human data generated for use in future and ongoing research will be shared 
through a NIH-funded or approved repository (ClinicalTrials.gov) and BTRIS.  At the 
completion of data analysis, data will be submitted to ClinicalTrials.gov either before publication 
or at the time of publication or shortly thereafter. Data may also be used to support long term 
research efforts within the Surgery Branch and de-identified data may also be shared with 
collaborators as specified in our companion protocol, 03-C-0277 (Cell Harvest and Preparation 
for Surgery Branch Adoptive Cell Therapy Protocols). 
 Genomic Data Sharing Plan 
The NIH Genomic Data Sharing Policy does not apply to this study. 
6.3 
RESPONSE CRITERIA 
Clinical Response will be determined using the Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.0).   
  Evaluation of target lesions1  
• 
Complete Response (CR):  Disappearance of all target lesions 
• 
Partial Response (PR):  At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions taking as reference the baseline sum LD. 
• 
Progression (PD):  At least a 20% increase in the sum of LD of target lesions 
taking as reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions. 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD. 
 Evaluation of non-target lesions2  
• 
Complete Response (CR): Disappearance of all non-target lesions and 
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• 
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 
----------------------------------------------------------------------------------- 
1 
All measurable lesions up to a maximum of 10 lesions representative of all involved organs should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repetitive measurements (either by imaging techniques or clinically).  
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD.  The 
baseline sum LD will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease. 
2 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required, and these lesions should be followed as “present” or “absent.” 
 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 


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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.  
6.4 
TOXICITY CRITERIA 
This study will utilize the CTCAE version 3.0 for toxicity and adverse event reporting.  A copy 
of the CTCAE v3.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All 
appropriate treatment areas should have access to a copy of the CTCAE 3.0.   
 
Over 150 patients have been treated in the Surgery Branch, NCI with tumor infiltrating 
lymphocytes.  Early toxicities related specifically to the infusion of the cells (those which are 
seen immediately following cell infusion and prior to aldesleukin administration) are generally 
mild and include fevers, chills, headache, and malaise.  Toxicities which occur following 
administration of cells can include immune mediated events such as vitiligo, transient uveitis, 
hearing loss and vestibular dysfunction.  The use of the non-myeloablative regimen prior to cell 
administration increases the toxicity of this treatment as profound myelosuppression occurs in all 
patients.  In 93 patients treated with TIL using the non-myeloablative chemotherapy regimen 
with or without total body irradiation, there was one treatment related death (NMA + 200 cGY 
TBI) due to an unexpected but preexisting diverticular abscess.   
To ensure safety using this treatment, the NCI SB will review safety data on all protocols semi-
annually at the time of continuing review.  Data will be presented for both the recent 6 month 
period and for the entire length of time the protocol has been open.  The toxicity data for review 
will include all toxicities captured on the protocol and will be presented in individual tables as 
follows:  
• all toxicities attributed to the cells,  
• all incidences of intubation including the duration of and reason for intubation, 
• all grade 2 unexpected adverse events, and all grade 3 or greater events regardless of 
attribution except those due to myelosuppression or IL-2.    
Toxicities seen on protocols using this non-myeloablative regimen that occur during the follow 
up period are rare but have included EBV lymphoma following prolonged lymphopenia, herpes 
zoster infection, and sensory neuropathy likely related to fludarabine.   
The major discomforts of the research are those of nausea, mucositis, anorexia, diarrhea, fever 
and malaise.  Side effects of common drugs used in this nonmyeloablative regimen include: 
 
Cyclophosphamide: Marrow suppression, nausea, mucositis, rash, hemorrhagic cystitis, 
myocardial damage, alopecia, infertility, nausea and vomiting, SIADH.   
Fludarabine: Myelosuppression, fever and chills, nausea and vomiting, malaise, fatigue, 
anorexia, weakness, neurologic toxicity including sensory neuropathies and blindness, and 
interstitial pneumonitis.  Serious opportunistic infections have occurred in CLL patients treated 
with fludarabine. 
Antimicrobials in general: Allergic reactions, renal impairment, nausea, vomiting, hepatic 
damage, marrow suppression.  
High-dose aldesleukin: a variety of side effects have been associated with high-dose aldesleukin 
administration. A listing of these side effects in 525 patients treated with high-dose aldesleukin is 
listed in Appendix 1. 


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7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted above in 
Section 6. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per sections 7.2 and 7.3. 
An abnormal laboratory value will be considered an AE 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. 
 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. 
 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application.  
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 


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 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.  
 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• Death 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant 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. 
 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
 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. 
 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
 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.  
 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, 
and 
b. the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• 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. 


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7.2 
NCI-IRB AND CLINICAL DIRECTOR REPORTING 
 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
 NCI-IRB Requirements for PI Reporting at Continuing Review 
 
The protocol PI will report to the NCI-IRB:  
• 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. 
• A summary of any instances of non-compliance. 
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.  
 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA 
An investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a, any serious adverse event, whether or not considered drug related, including those listed 
in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event.  
• All Grade 5 (fatal) events (except death due to progressive disease) must be reported via 
email within 24 hours.  A complete report must be submitted within one business day.  
• All other serious adverse events including deaths due to progressive disease must be 
reported within one business day 
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor. 


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Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov 
and to the CCR PI and study coordinator. 
 Reporting Pregnancy  
7.3.1.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy 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 in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.3.1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
120 days after the last dose of aldesleukin or pembrolizumab. 
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 
DATA AND SAFETY MONITORING PLAN 
 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about enrollment will be made based on the 
toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator. Adverse 
events will be reported as required above. Any safety concerns, new information that might 


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affect either the ethical and or scientific conduct of the trial, or protocol deviations will be 
reported to the IRB using iRIS. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
 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 an NCI 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.  
8 
STATISTICAL CONSIDERATIONS   
The primary objective of this pilot trial is to determine whether adoptive transfer of Young TIL 
will result in objective clinical responses. Patients may be enrolled on this protocol with 
insufficient cardiac or pulmonary capability to be able to receive high-dose aldesleukin, but in all 
other aspects are eligible for enrollment.  These patients will be assigned to receive cells (PBL) 
alone.  The results obtained, if suggestive of benefit, will provide direction for larger 
confirmatory studies to increase applicability of this potentially successful treatment modality.  
For the cohort who will receive high dose aldesleukin, the study will be conducted as an optimal 
two-stage phase II trial (Simon R, Controlled Clinical Trials 10:1-10, 1989), in order to rule out 
an unacceptably low 15% clinical response rate (PR+CR; p0=0.15) in favor of a higher response 
rate of 35% (p1=0.35). With alpha=0.10 (probability of accepting a poor treatment=0.10) and 
beta = 0.10 (probability of rejecting a good treatment=0.10), the study will initially enroll 19 
evaluable patients and if 0-3 of the 19 have a clinical response, then no further patients will be 
accrued. If 4 or more of the first 19 have a response, then accrual would continue until a total of 
33 patients have 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 there are 4-7 responses in 
33 patients, this would be an uninterestingly low response rate, while if there were 8 or more 
responses in 33 patients, then this would be sufficiently interesting to warrant further study in 


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later trials. Under the null hypothesis (15% response rate), the probability of early termination is 
68%. 
For the cohort who will receive cells alone, the study will be conducted as a Minimax two-stage 
phase II trial (Simon R, Controlled Clinical Trials 10:1-10, 1989), in order to rule out an 
unacceptably low 5% clinical response rate (PR+CR; p0=0.05) in favor of a modest response rate 
of 20% (p1=0.20). With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 
0.20 (probability of rejecting a good treatment=0.20), the study will initially enroll 12 evaluable 
patients and if 0 of the 12 have a clinical response, then no further patients will be accrued in this 
category.  If 1 or more the first 12 have a response, then accrual would continue until a total of 
21 patients receiving cells alone have 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 there are 
1-2 responses in 21 patients, this would be an uninterestingly low response rate, while if there 
were 3 or more responses in 21 patients, then this would be sufficiently interesting to warrant 
further study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 54%. 
 If only the first stages of both cohorts are required to enroll patients, then a minimum of 31 
patients will enroll. If both cohorts require accrual to a second stage, then accrual of up to 54 
evaluable patients may be required.  It is anticipated that up to 2 patients per month may be 
enrolled onto this trial, and thus approximately 3 years may be required to enroll the maximum 
number of required patients. To allow for the possibility of a small number of unevaluable 
patients, the accrual ceiling for the trial will be set at 57. 
 
9 
COLLABORATIVE AGREEMENTS  
We have established a Cooperative Research and Development Agreement (CRADA) with Lion 
Biotechnologies, 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 or recurrent/refractory locally 
advanced ocular melanoma-associated cancer which is refractory to standard therapy, and limited 
life expectancies. 
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another.  Efforts 
will be made to extend accrual to a representative population, but in this preliminary study, a 
balance must be struck between patient safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the 
need to explore gender and ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a 
follow-up study may be written to investigate those differences more fully. 


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10.2 PARTICIPATION OF CHILDREN 
The use of the nonmyeloablative regimen in this protocol is a major procedure which entails 
serious discomforts and hazards for the patient, such that fatal complications are possible.  It is 
therefore only appropriate to carry out this experimental procedure in the context of life 
threatening metastatic cancer.  Since the efficacy of this experimental procedure is unknown, it 
does not seem reasonable to expose children under the age of 16 to this risk without further 
evidence of benefit.  Should results of this study indicate efficacy in treating metastatic cancer, 
which is not responsive to other standard forms of therapy, future research can be conducted in 
the 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. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has a chance to provide clinical benefit though it is not known if it 
will do so. The risks of this treatment are detailed in section 6.4. The success of this effort cannot 
be predicted at this time. Because all patients in this protocol have incurable metastatic or 
recurrent/refractory locally advanced ocular melanoma-associated cancers the potential benefit is 
thought to outweigh the risks. 
10.5 RISKS/BENEFITS ANALYSIS 
Because all patients in this protocol have metastatic or recurrent/refractory locally advanced 
ocular melanoma-associated cancer and limited life expectancies the potential benefit is thought 
to outweigh the potential risks. 
10.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
Patients initially signs a consent when they agree to have TIL obtained for study and growth on 
protocol 03-C-0277, Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy 
Protocols.  If the Young TIL can be generated for infusion and the patient meets the thorough 
screening for eligibility, the patient, 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 as well as risks and 
potential benefits will be presented.  The Informed Consent document is given to the patient, and 
the parents if applicable, who are requested to review it and to ask questions prior to agreeing to 
participate in the treatment portion of this protocol.  The patient is reassured that participation on 


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trial is entirely voluntary and that he/she can withdraw or decide against treatment at any time 
without adverse consequences. The research nurse, principal investigator, associate investigator, 
or clinical associate is responsible for obtaining written consent from the patient or the parents. 
Informed consent of non-English speaking subjects: 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 
given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
10.7 ADDITIONAL CONSIDERATIONS FOR PARTICIPATION OF SIXTEEN AND SEVENTEEN-YEAR-
OLD PATIENTS 
In addition to the specific requirements, risks and benefits noted above, any particular risks 
specific to this age group will be discussed with both the patient and their parents.  The parents 
and the patient will be given the opportunity to ask questions; both parents will be asked to sign 
the informed consent document.  Patients will be treated on 3NW. 
 
11 PHARMACEUTICAL INFORMATION   
Cyclophosphamide, fludarabine, and aldesleukin, the commercial drugs used in this study will 
not alter labelling 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 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 


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mg mannitol and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg 
monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8).  The vial is 
reconstituted with 1.2 mL of Sterile Water for Injection, USP, and the resultant concentration is 
18 million IU/ml or 1.1 mg/mL.  Diluent should be directed against the side of the vial to avoid 
excess foaming.  Swirl contents gently until completely dissolved.  Do not shake.  Since vials 
contain no preservative, reconstituted solution should be used with 24 hours. 
Storage: Intact vials are stored in the refrigerator (20 - 80C) protected from light.  Each vial bears 
an expiration date. 
Dilution/Stability: Reconstituted aldesleukin should be further diluted with 50 mL of 5% Human 
Serum Albumin (HSA).  The HSA should be added to the diluent prior to the addition of RIL-2.  
Dilutions of the reconstituted solution over a 1000-fold range (i.e., 1 mg/mL to 1 mcg/mL) are 
acceptable in either glass bottles or polyvinyl chloride bags.  Aldesleukin is chemically stable for 
48 hours at refrigerated and room temperatures, 20 – 300C. 
Administration:  The dosage will be calculated based on total body weight.  The final dilution of 
aldesleukin will be infused over 15 minutes.  Aldesleukin will be administered as an inpatient.   
Toxicities:  Expected toxicities of aldesleukin are listed in the product label and in Appendix 1 
and Appendix 2.  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 1.  Additional grade 3 and 4 toxicities seen with 
aldesleukin are detailed in Appendix 2. 
11.2 FLUDARABINE: 
(Please refer to package insert for complete product information)   
Description: Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic 
nucleosides in that the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is 
a purine antagonist antimetabolite.  
How Supplied:  It will be purchased by the NIH Clinical Pharmacy Department from commercial 
sources. Fludarabine is supplied in a 50 mg vial as a fludarabine phosphate powder in the form of 
a white, lyophilized solid cake.   
Stability:  Following reconstitution with 2 mL of sterile water for injection to a concentration of 
25 mg/ml, the solution has a pH of 7.7.  The fludarabine powder is stable for at least 18 months 
at 2-8°C; when reconstituted, fludarabine is stable for at least 16 days at room temperature.  
Because no preservative is present, reconstituted fludarabine will typically be administered 
within 8 hours.  Specialized references should be consulted for specific compatibility 
information.  Fludarabine is dephosphorylated in serum, transported intracellularly and converted 
to the nucleotide fludarabine triphosphate; this 2-fluoro-ara-ATP molecule is thought to be 
required for the drug’s cytotoxic effects.  Fludarabine inhibits DNA polymerase, 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 to 30 minutes.  The doses will be based on body surface area (BSA).  If patient is 
obese (BMI > 35) drug dosage will be calculated using practical weight as described in Table 6.  


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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 adoptive cell therapy protocols in the 
Surgery Branch have caused persistently low (below 200) CD4 counts, and one patient 
developed polyneuropathy manifested by vision blindness, and motor and sensory defects. 
11.3 CYCLOPHOSPHAMIDE 
 (Refer to FDA-approved package insert for complete product information): 
Description:  Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following 
conversion to active metabolites in the liver, cyclophosphamide functions as an 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.   
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 Table 6. 
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, 


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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.  
11.4 YOUNG TIL PREPARATION 
The Certificate of Analysis is similar to those approved by the Food and Drug Administration 
and used in other Surgery Branch, NCI TIL clinical studies.  The autologous Young TIL product 
will be provided for investigational use only under a sponsor-investigator IND.  The Certificate 
of Analysis is in Appendix 4 and the Standard Operating Procedures for the growth of the 
Young TIL are included in the IND. For all cohorts, cells will be administered at a dose of 
between 1x109 to 2x1011 lymphocytes.  Note: Penicillin, Streptomycin, and gentamycin will not 
be used in the manufacture of products for patients with documented allergies to these drugs.    
 
11.5 MESNA  
(Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891):  
(Please refer to the FDA-approved package insert for complete product information) 
Description:  Mesna will be obtained commercially by the Clinical Center Pharmacy Department 
and is supplied as a 100 mg/ml solution.   
Storage:  Intact ampoules are stored at room temperature.   
Stability:  Diluted solutions (1 to 20 mg/mL) are physically and chemically stable for at least 24 
hours under refrigeration.  Mesna is chemically stable at room temperature for 48-72 hours in 
D5W, 48-72 hour in D5W/0.45% NaCl, or 24 hours in 0.9% NaCl. 
Administration:  Dilute to concentrations less than or equal to 20 mg mesna/ml fluid in D5W or 
0.9% NaCl and to be administered intravenously as a continuous infusion.  If patient is obese 
(BMI > 35) drug dosage will be calculated using practical weight as described in Table 6.  
Toxicities include nausea, vomiting and diarrhea.  
11.6 FILGRASTIM  
(Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen): 
Filgrastim will be obtained commercially by the Clinical Center Pharmacy Department and is 
supplied in 300 ug/ml and 480 ug/1.6 ml vials.  G-CSF should be refrigerated and not allowed to 
freeze.  The product bears the expiration date.  The product should not be shaken.  It is generally 
stable for at least 10 months when refrigerated.  The appropriate dose is drawn up into a syringe.  
G-CSF will be given as a daily subcutaneous injection.  The side effects of G-CSF are skin rash, 


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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. 
11.7 TRIMETHOPRIM AND SULFAMETHOXAZOLE DOUBLE STRENGTH (TMP / SMX DS): 
TMP/SMX DS will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It will be used for the prevention of PCP pneumonia.  The oral dose is 1 tablet PO daily 
three times a week (MUST be on non-consecutive days) beginning on day -7 and continuing for 
at least 6 months and until the CD4 count is greater than 200 on 2 consecutive lab studies.  Like 
other sulfa drugs, TMP/SMX DS can cause allergies, fever, photosensitivity, nausea, and 
vomiting. Allergies typically develop as a widespread itchy red rash with fever eight to fourteen 
days after beginning the standard dose. Neutropenia, a reduction in the number of neutrophils, 
can also occur. 
11.8 AEROSOLIZED PENTAMIDINE IN PLACE OF TMP/SMX DS:   
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.  
11.9 HERPES 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 the 
day after the last dose of fludarabine 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 7mg/mL or less and infused over 1 hour to avoid renal damage.  Reversible 
renal insufficiency has been reported with IV but not oral acyclovir.  Neurologic toxicity 
including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs have been 
reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will be made or 


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the drug will be discontinued. Stomach upset, headache or nausea, rash or hives; peripheral 
edema; pain, elevated liver function tests; and leukopenia, diarrhea, lymphadenopathy, myalgias, 
visual abnormalities and elevated creatinine have been reported. Hair loss from prolonged use 
has been reported. Acyclovir will not be used concomitantly with other nucleoside analogs which 
interfere with DNA synthesis, e.g. ganciclovir. In renal disease, the dose is adjusted as per 
product labeling.  
 
11.10 FLUCONAZOLE: 
Fluconazole will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It will be used to prophylax against fungal infections.  It is available in 200 mg tablets.  
It can cause headache, nausea, vomiting, diarrhea or abdominal pain, and liver damage which 
may be irreversible.  It can cause rashes and itching, which in rare cases has caused Stevens 
Johnson Syndrome.  It has several significant drug interactions.  The package insert should be 
consulted prior to prescribing.  For IV administration in patients who cannot tolerate the oral 
preparation, Fluconazole comes in 2 MG/ML solution for injection, and prepared according to 
Clinical Center Pharmacy standard procedures.  It should be administered at a maximum IV rate 
of 200 mg/hr. 
Note: Appropriate anti-infective agents may be substituted at the discretion of the treating 
physician.  
11.11 SUPPORT MEDICATIONS 
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. 
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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metastatic melanoma. World J Surg Oncol 2012;10:113. 
26. 
Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high-dose 
interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989;210:474-84. 
 
 


Abbreviated Title: Ocular Melanoma TIL 
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13 FIGURES, TABLES & APPENDICES 
Table 1 
Response rates and duration in patients with melanoma treated with tumor infiltrating 
lymphocytes plus high-dose aldesleukin following three different lymphoconditioning regimens. 
 
 


Abbreviated Title: Ocular Melanoma TIL 
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Table 2 
Transfusions and grade 3 and 4 non-hematologic toxicities associated with NMA plus 
TBI lymphodepleting preparative regimens. 
 
 
 


Abbreviated Title: Ocular Melanoma TIL 
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Table 3 
Time in hospital and non-hematological grade 3 and 4 toxicities related to lymphodepleting 
chemotherapy and cell transfer. 
 
 


Abbreviated Title: Ocular Melanoma TIL 
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Table 4 
 
 
 
Patient characteristics and success at generating tumor infiltrating lymphocytes from non-cutaneous 
melanoma tumors (digestive tract cancers). 
Patients 
Age, 
gender 
Prior 
chemo-
therapy 
regimens 
Metastatic adenocarcinoma    
(site of TIL harvest) 
Technique for 
growing TIL 
Successful 
first 
outgrowth 
Total cell 
count, end of 
REP (x e9) 
Preclinical studies 
 
 
 
 
 
1) 
R. W. 
63, M 
2 
Colon (liver) 
GMACS,     O/N 
digest
yes 
47.5 
2) 
A. S. 
44, F 
3 
Gastric (liver) 
GMACS,     O/N 
digest
yes 
38.3 
3) 
T. H. 
45, M 
1 
Colon (liver) 
GMACS,     O/N 
digest
yes 
25.1 
Clinical studies 
 
 
 
 
 
4) 
M. L. 
45, F 
3 
Colon (liver) 
GMACS,     O/N 
digest
yes 
18.5 
5) 
D. A. 
57, M 
3 
Biliary tract (omentum) 
GMACS,     O/N 
digest
yes 
no REP 
6) 
J.F. L. 
42, M 
1 
Colon (retro-peritoneum) 
Fragments 
yes 
32.1 
7) 
J. M. 
51, M 
4 
Rectal (lung) 
Fragments, GMACS 
yes 
20.0 
8) 
M. M. 
51, M 
2 
Colon (lung) 
Fragments, GMACS 
yes 
no REP 
9) 
M. S. 
53, F 
2 
Colon (abdominal wall) 
Fragments, GMACS 
no 
- 
11) 
S.M. 
57, F 
3 
Colon (liver) 
Fragments, GMACS 
yes 
no REP 
12) 
J. R. 
51, F 
1 
Colon (liver, omental nodule) 
Fragments, GMACS 
yes 
30.3 
13) 
A. H. 
52, F 
6 
Colon (lung) 
Fragments, GMACS 
yes 
69.5 
14) 
B. D. 
41, M 
5 
Colon (Axillary node) 
Fragments, GMACS 
yes 
no REP 
15) 
M. W. 
37, F 
2 
Colon (liver) 
Fragments, GMACS 
yes 
75.0 


Abbreviated Title: Ocular Melanoma TIL 
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Table 5 
 
Characteristics of tumor infiltrating lymphocytes grown from non-cutaneous melanoma tumors 
(cervical cancer) 
 
Frequency of cells in the 
lymphocyte gate 
Patient 
Prior 
therapy 
Growth positive 
wells/total wells1 
Autologous 
tumor 
reactivity2 
Fragments 
for REP 
CD3+ 
CD4+ 
CD8+ 
CD3-
CD56+ 
REP fold 
expansion 
1 
none 
8/24 
n/a 
F1 
97 
73 
24 
3 
1216 
F2 
96 
9 
85 
2 
1110 
F3 
79 
35 
38 
18 
1326 
F4 
62 
9 
93 
6 
1890 
2 
chemo/RT 
5/24 
positive 
F1 
80 
10 
42 
19 
344 
F2 
78 
31 
36 
19 
1752 
F3 
86 
70 
10 
11 
1224 
F4 
78 
8 
71 
21 
816 
3 
none 
17/26 
negative 
F1 
99 
75 
24 
0 
2226 
 
 
 
 
F2 
99 
15 
84 
1 
1632 
F3 
93 
35 
32 
3 
2240 
F4 
99 
90 
7 
0 
3 
4 
none 
2/19 
n/a 
F1 
95 
69 
8 
3 
2737 
F2 
95 
11 
84 
5 
1968 
5 
none 
13/13 
n/a 
n/a 
n/a 
n/a 
n/a 
n/a 
n/a 
1 Growth positive defined as lymphocyte confluence in 4 wells of a 24-well plate, approximately 10e6 cells. 
2Autologous tumor reactivity was determined by IFN-γ production in overnight coculture with cryopreserved autologous 
tumor targets. Positive recognition was defined as two times the negative control and greater than 200 pg/mL of IFN-γ. 
3Pooled with F3 for the REP. 
n/a = not tested 
 


Abbreviated Title: Ocular Melanoma TIL 
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Table 6 
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. 
 
 
 
 
Figure 1 


Abbreviated Title: Ocular Melanoma TIL 
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Survival of patients with metastatic melanoma treated with autologous tumor infiltration 
lymphocytes and IL-2 following three different lymphoconditioning regimens. 
 
 
 


Abbreviated Title: Ocular Melanoma TIL 
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Appendix 1 
Adverse Events Occurring In ≥10% Of Patients Treated With Aldesleukin (N=525)1 
Body System  
% Patients  
 
Body System  
   % Patients 
Body as a Whole  
 
 
 
Metabolic and Nutritional Disorders 
Chills   
 
 
52  
 
Bilirubinemia   
 
40 
Fever   
 
 
29  
 
Creatinine increase   
33 
Malaise  
 
 
27  
 
Peripheral edema  
 
28 
Asthenia  
 
 
23 
 
 SGOT increase  
 
23 
Infection  
 
 
13  
 
Weight gain   
 
16 
Pain   
 
 
12  
 
Edema  
 
 
15 
Abdominal pain  
 
11  
 
Acidosis  
 
 
12 
Abdomen enlarged  
 
10  
 
Hypomagnesemia  
 
12 
Cardiovascular  
 
 
 
Hypocalcemia  
 
11 
Hypotension   
 
71  
 
Alkaline phosphatase incr 
10 
Tachycardia   
 
23 
 
Nervous 
Vasodilation   
 
13  
 
Confusion  
 
 
34 
Supraventricular tachycardia  12  
 
Somnolence   
 
22 
Cardiovascular disordera  
11  
 
Anxiety  
 
 
12 
Arrhythmia  
 
 
10  
 
Dizziness  
 
 
11 
Digestive  
 
 
 
 
Respiratory 
Diarrhea  
 
 
67  
 
Dyspnea  
 
 
43 
Vomiting  
 
 
50  
 
Lung disorderb  
 
24 
Nausea  
 
 
35  
 
Respiratory disorderc   
11 
Stomatitis  
 
 
22  
 
Cough increase  
 
11 
Anorexia  
 
 
20  
 
Rhinitis  
 
 
10 
Nausea and vomiting   
19  
 
Skin and Appendages 
Hemic and Lymphatic  
 
 
Rash   
 
 
42 
Thrombocytopenia  
 
37 
 
 Pruritus  
 
 
24 
Anemia  
 
 
29  
 
Exfoliative dermatitis   
18 
Leukopenia 
 
 
16  
 
Urogenital 
Oliguria  
 
 
63 
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
1Source: Proleukin® Prescribing Information – June 2007 


Abbreviated Title: Ocular Melanoma TIL 
Version Date: 5/30/2017 
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Appendix 2 
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 pr, prn or 10 mg 
IV q6h prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg, po, 
q3h, prn; 
Diphenoxylate HCl 
2.5 mg and atropine 
sulfate 25 mcg, po, 
q3h, prn; codeine 
sulfate 30-60 mg, po, 
q4h, prn 
If uncontrolled after 24 
hours despite all 
supportive measures 
No 
Malaise 
3 or 4 
Bedrest 
If other toxicities occur 
simultaneously 
No 
Hyperbilirubinemia 
3 or 4 
Observation 
If other toxicities occur 
simultaneously 
No 
Anemia 
3 or 4 
Transfusion with 
PRBCs 
If uncontrolled despite 
all supportive measures 
No 
Thrombocytopenia 
3 or 4 
Transfusion with 
platelets 
If uncontrolled despite 
all supportive measures 
No 
Edema/Weight gain 3 
Diuretics prn 
No 
No 
Hypotension 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled despite 
all supportive measures 
No 
Dyspnea 
3 or 4 
Oxygen or 
ventilatory support 
If requires ventilatory 
support 
No 


Abbreviated Title: Ocular Melanoma TIL 
Version Date: 5/30/2017 
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52
Oliguria 
3 or 4 
Fluid boluses or 
dopamine at renal 
doses 
If uncontrolled despite 
all supportive measures 
No 
Increased creatinine 3 or 4 
Observation 
Yes (grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 
Pleural effusion 
3 
Thoracentesis 
If uncontrolled despite 
all supportive measures 
No 
Bowel perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid 
and electrolyte 
imbalances; chemical 
conversion or 
electrical conversion 
therapy 
If uncontrolled despite 
all supportive measures 
No 
Elevated Troponin 
levels 
3 or 4 
Observation 
Yes 
If changes in 
LV function 
have not 
improved to 
baseline by 
next dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
Elevated 
transaminases 
3 or 4 
Observation 
For grade 4 without 
liver metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Hyperbilirubinemia 
3 or 4 
Observation 
For grade 4 without 
liver metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Electrolyte 
imbalances 
3 or 4 
Electrolyte 
replacement 
If uncontrolled despite 
all supportive measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to grade 2 or less by next treatment. 
 
 
 


Abbreviated Title: Ocular Melanoma TIL 
Version Date: 5/30/2017 
13-C-0093 
53
Appendix 3 
 
Interleukin-2 toxicities observed in patients treated at the NIH Clinical 
Center 
 
 
 
 
 
 


Abbreviated Title: Ocular Melanoma TIL 
Version Date: 5/30/2017 
13-C-0093 
54
Appendix 4 
Certificate of Analysis:                     
Young TIL from Ocular Melanoma 
Patient: 
Date of preparation of final product: 
Unique TIL identifier (tumor and culture number): 
Tests performed on final product: 
Test 
Method 
Limits 
Result 
Test performed 
by 
Initials/Date 
Cell viability1 
trypan blue 
exclusion 
>70% 
 
 
 
Total viable 
cell number1 
visual microscopic 
count 
between 109 and  
2 X 1011 
 
 
 
Identity 
FACs  
> 80 % CD3+ on 
REP cells 
 
 
 
TIL potency2 
OKT3-stimulated 
IFN release  
>200 pg/ml per 105 
cells and > 2 times 
background 
 
 
 
Microbiologica
l studies  
aerobic culture5  
no growth 
 
 
 
 
anaerobic culture5 
no growth 
 
 
 
 
gram stain1,3 
no micro-organisms 
seen 
 
 
 
 
aerobic culture3,4 
no growth 
 
 
 
 
fungal culture3,4 
no growth 
 
 
 
 
anaerobic culture3,4 
no growth 
 
 
 
 
mycoplasma test2 
negative 
 
 
 
Endotoxin1  
limulus assay 
<5 E.U./kg 
 
 
 
Presence of 
tumor cells2 
Cytopathology 
No tumor cells per 
200 cells examined 
 
 
 
1 Performed on the final product prior to infusion.  Results are available at the time of infusion. 
2 Performed 2 - 10 days prior to infusion (test performed prior to final manipulation).  Results are available at the 
time of infusion. 
3 Performed 2-4 days prior to infusion.  Results are available at the time of infusion but may not be definitive. 
4 Sample for test collected on the final product prior to infusion.  Results will not be available before cells are 
infused into the patient. 
5 Sample for test collected on the in process cells prior to the REP.  Results will be available before cells are infused 
into the patient. 
Prepared by: 
_________________________________________ 
Date:  ____________________ 
 
QC sign-off: 
__________________________________________ 
Date:  ____________________ 
Qualified Laboratory or Clinical Supervisor 

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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-0093 
CONTINUATION: page 2 of 14 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 
 
 
drugs to temporarily suppress the immune system to improve the chances that the tumor fighting 
cells will be able to survive in the body.  The Surgery Branch has pioneered and successfully 
used this therapy in cancers such as metastatic melanoma, cervical and gastro-intestinal cancers 
and we now would like to try this therapy in metastatic ocular melanoma.   After the cells are 
given, patients who agree and are medically eligible may receive aldesleukin (IL-2) to help the 
tumor fighting cells stay alive longer.   
The purpose of this study is to see if these tumor fighting cells (young TIL) with or without the 
administration of aldesleukin can cause metastatic ocular melanoma tumors to shrink and to 
evaluate the toxicity of this treatment. 
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 metastatic 
ocular melanoma.  
How many people will take part in this Study?  
Up to 54 patients will be enrolled in this study. 
Description of Research Study 
Research Study Overview 
The Cell protocol has several stages: 
 
Stage 
Timeframe 
Location 
Comments & Instructions 
Work up 
1-2 weeks 
Inpatient 
and 
out patient   
Scans, x-rays, labs leukapheresis 
other tests as needed 
Chemotherapy 
(day -7 to -1) 
1 week 
Inpatient 
Receive IV chemotherapy to prepare 
your immune system for the cells 
Cells 
and 
aldesleukin 
(Day 0-4) 
1-5 days 
Inpatient 
and 
possibly ICU 
Receive the TIL cells IV and then 
high dose aldesleukin about every 8 
hours for up to 15 doses 
Recovery 
1-2 weeks 
Inpatient unit 
Recover from the effects of treatment 
Follow -up 
Ongoing until 
disease 
progression 
Outpatient 
Return to clinic for physical exam, 
review of side effects, labs, scans 
every 1-3 months for the first year. 
 


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-0093 
CONTINUATION: page 3 of 14 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 
 
 
What will happen if you take part in this research study?   
Before you begin the study 
Cell harvest and growth 
You underwent a procedure, either surgery or a biopsy, to obtain pieces of your tumor so that we 
can grow the Young TIL from your tumor cells in the laboratory while enrolled on our 
companion protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell 
Therapy Protocols). The surgical procedure may involve liver resection either by laparoscopic or 
open surgical approaches. In 1 out of 5 patients, we are not able to successfully grow the cells for 
this procedure.  If your cells do not grow, you will not be able to receive the cell infusion.  If that 
happens, we will look at alternative treatments for you (best available care) or return you to the 
care of your referring physician.  We usually know after about 4 weeks whether the cells will 
grow well enough to be used as an experimental treatment on this protocol.  At the time we 
determine that your cells are not growing, we will inform you and discuss your options with you. 
Several medications are used during the preparation of your cell product, be sure to tell your 
doctor if you are allergic to any antibiotics. 
Work up 
Prior to receiving the experimental treatment, you will undergo many tests. These include 
imaging procedures, heart and lung function tests, and laboratory tests.  If you are a woman, you 
will undergo a pregnancy test.  You will also have a large catheter inserted into a vein and 
leukapheresis will be performed (see below).  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 is a procedure that allows us to remove certain types of blood cells from you and 
return the rest of your blood.  It is a very common procedure that is done routinely here at the 
NIH with very few risks.  During leukapheresis, blood is removed from you through a needle in 
your arm, circulated through a machine that divides whole blood into red cells, plasma (the 
serum part), and lymphocytes (or white cells), and then the plasma and red cells are returned to 
you through a second needle in your other arm.  The procedure takes between 3-4 hours to 
complete. The white blood cells may be used to help grow the cells. In addition to the 


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-0093 
CONTINUATION: page 4 of 14 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 
 
 
leukapheresis you will undergo as part of your work up, we will also ask you to undergo one 
additional pheresis procedure between 4 and 6 weeks after your cell treatment to see the impact 
of this therapy on the immune system and see if the cells we gave you are still active. 
During the Study 
Chemotherapy Regimen (Day -7 through Day -1) 
After we have grown the Young TIL 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 make space in your immune 
system so the Young TIL can work without any interference from the cells in your immune 
system. These medicines may cause your tumor to shrink some, but this shrinkage is anticipated 
to be only partial and of small duration.  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 chemotherapy can make the cells more effective in fighting cancer tumors, but it is not 
known whether this is true in humans.  The cyclophosphamide will be given into your catheter 
over 1 hour for two days (Day -7 and Day -6) and the fludarabine will be given into your catheter 
for 30 minutes every day for the next five days (Day -5 through Day -1).  The side effects of 
these medicines are described on the following pages. 
Cell Infusion and Aldesleukin Regimen (Day 0 through Day 5) 
All patients will be given the cells through their IV over 20-30 minutes one to four days after the 
last dose of chemotherapy.  Within 24 hours after your cell infusion you will be given high dose 
aldesleukin through one of the IVs.  It will be given as a 15-minute infusion about every 8 hours 
for up to five days after the cell infusion.  Aldesleukin is a cell growth factor and it is thought 
that it will help the cells live longer in your body.  No aldesleukin will be given if you refuse it or 
are not medically eligible to receive it. 
The day after your cells are infused, we will give you G-CSF (filgrastim) as a shot or injection 
under the skin every day to stimulate your bone marrow to produce blood cells until they 
increase to a sufficient number.  We will watch you closely during this entire time for any side 
effects of this experimental regimen.  We will discuss the side effects below and we will include 
in your care all the medicines and treatments to prevent as many of these side effects as we can 
and to make you as comfortable as we can.   
When you are finished taking the drugs (treatment) 
Recovery 
You will recover in the hospital until you are well enough to go home.  This usually takes 7-12 
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.  


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-0093 
CONTINUATION: page 5 of 14 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 to the laboratory tests to monitor your condition, we will remove between 1 and 9 
teaspoons of blood daily to study the effects of this regimen on your immune system.  If you 
experience side effects in your kidneys, we will collect 1 additional teaspoon of blood and about 
6 teaspoons of urine to see if we can determine the cause of these side effects.  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. We will ask you to return to the NIH Clinical Center frequently 
after you are discharged approximately 6 and 12 weeks following treatment and then if you are 
responding to the treatment, every 3 months for the first year following treatment, every 6 
months for the second year and then as determined by your physician.  The first 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 e-mail and we may ask you to send us lab, imaging, and physical exam reports. 
Retreatment 
If you have sustained stable disease or your tumor shrinks or disappears following the initial 
treatment and then recurs you may receive one additional treatment if you tolerated the treatment 
well and if all the side effects have resolved.  You will receive the same medications and cell 
infusion on the same schedule as with the first treatment. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for four months after you finish study treatment.  If you think that you or 
your partner is pregnant, you should tell your study doctor or nurse at once.   
• Effective forms of birth control include: 
• Abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants]  
• tubal ligation 
• vasectomy 
 


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-0093 
CONTINUATION: page 6 of 14 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 
 
 
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. 
Leukapheresis 
During the leukapheresis procedure, you may have some tingling in your face and lips due to the 
medicine used to keep your blood from clotting during the procedure.  The nurses may give you 
a calcium-containing antacid to chew that takes away this tingling.  Rarely, people may 
experience lightheadedness or dizziness.  We ask that you eat prior to the procedure to prevent 
this.  Rare complications of this procedure are lowered blood pressure, bleeding or bruising 
where the needles are put in your arms. 
Young TIL Cell Infusion  
All Young TIL cells will be given through your catheter while we keep you in the patient care 
unit so we can watch you closely.  
 Potential risks include:  
• Fever, chills and shortness of breath, which are common and may last for a few hours 
• Lung congestion causing shortness of breath 
• Immune-type reaction, such as pharyngitis and vaginitis. Note: In similar clinical 
trials with cells targeting a melanoma protein, we have observed the following 
immune-mediated toxicities: loss of skin pigment (known as vitiligo), and 
inflammation of the eye (uveitis).  The skin and the eye are all sites where that 
targeted melanoma protein is known to exist.   
• As this is a new experimental therapy, side effects that we do not anticipate that may 
cause your condition to deteriorate may be encountered.  Any new information that 
becomes available during the course of this study will be shared with you. 
Medications 
The side effects of cyclophosphamide, fludarabine, high dose aldesleukin and some of the other 
medications you will receive are listed below:  
 


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-0093 
CONTINUATION: page 7 of 14 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 
 
 
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/swellin
g) 
 
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 one 
died as a result of this disease.) 
 
Loss of fertility 
 
Two out of the first 81 patients 
enrolled on the initial young TIL study 
died from complications resulting from 
suppression of the immune function 
which resulted in a severe infection 
(one of these patients also received 
radiation as part of their treatment 
regimen).   
 
IL-2 (aldesleukin) 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 
 
Low urine output 
 
Swelling in your 
extremities,  
 
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 
 
Bowel perforation (a hole) 
requiring longer hospitalization 
or surgery. 
 
Autoimmune disease, where your 
immune system attacks cells in 
organs of your body.  Should this 
occur, you will be treated with 
steroids to stop the immune 
response. 
 
Damage to the heart muscle or 
heart attack 
 
Loss of blood flow to the 
extremities due to medicines used 


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-0093 
CONTINUATION: page 8 of 14 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 
 
 
 
Fluid in your lungs that 
can require oxygen  
 
Dry mouth, nausea, 
vomiting and diarrhea; 
 
Rash, itching; and 
changes in skin or hair 
pigmentation, called 
vitiligo;   
 
Changes in mental 
status, including 
confusion, difficulty 
sleeping or vivid 
dreams; this can be 
severe and require 
sedation and monitoring 
in the ICU 
 
monitoring in ICU and 
insertion of a 
breathing tube.   
 
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 
Acyclovir and Valacyclovir 


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-0093 
CONTINUATION: page 9 of 14 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 
 
 
 
 
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 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this new experimental treatment will cause your tumors to 
shrink. We do not know if you will receive personal medical benefit from taking part in this 
study. These potential benefits could include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.  Because there is not much information 
about the Young TIL therapy effect on your type of 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?  
If there are effective salvage regimens (regimens used when standard regimens have failed), you 
will be directed to undergo these regimens before participating in this protocol. 
Instead of being on this study, you have these options for treatment: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another 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. Instead it 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.  
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: 


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-0093 
CONTINUATION: page 10 of 14 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 
 
 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• NCI Institutional Review Board 
• The study Sponsor (Center for Cancer Research) or their agent(s) 
• Lion Biotechnologies 
 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time. 
Stopping the Study  
Your doctor may decide to take you off this study under the following circumstances: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you become pregnant 
• if you experience side effects from the treatment that are considered too severe 
• if new information becomes available that shows that another treatment would be better for 
you 
In this case, you will be informed of the reason for that decision. 
 
You can stop participating 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 


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-0093 
CONTINUATION: page 11 of 14 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 
 
 
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. 
 
Conflict of Interest 
The National Institutes of Health 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 additional information or a copy of the Protocol Review Guide.  Members of the research 
team who do not work for the NIH are expected to follow these guidelines but they do not need 
to report their personal finances to the NIH.  The NIH and 2 of the investigators on the research 
team have developed the cell process being used in this research and have a patent pending.  This 
means that it is possible that the results of this study could lead to payments to NIH scientists and 
to the NIH.  By law, government scientists are required to receive such payments for their 
inventions.   
 
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.  
 
Use of Specimens and Data for Future Research 
Specimens and data collected during the course of this study will be used for future research and 
will be stored, tracked and disposed of under our companion protocol 03-C-0277, (Cell Harvest 
and Preparation for Surgery Branch Adoptive Cell Therapy Protocols) on which you have 
already been enrolled.   
 
In addition, to advance science, it is helpful for researchers to share information they get from 
studying human samples.  They do this by putting it into one or more scientific databases, where 
it is stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   


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-0093 
CONTINUATION: page 12 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0093 
CONTINUATION: page 13 of 14 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, Udai S. Kammula, M.D., Building 10, Room 3-5930, Telephone:  240-
760-6216. If you have any questions about the use of your specimens or data for future research 
studies, you may also contact the Office of the Clinical Director, Telephone:  240-760-6070.  
You may also call the Clinical Center Patient Representative at 301-496-2626.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0093 
CONTINUATION: page 14 of 14 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 17, 2016 THROUGH OCTOBER 16, 2017.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name