A Phase 2, Multicenter Study to Assess the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN-144) for Treatment of Patients With Metastatic Melanoma
Phase: PHASE2
Conditions: Metastatic Melanoma
Sponsor: Iovance Biotherapeutics, Inc.

 
 
 
 
CLINICAL PROTOCOL 
 
 
A Phase 2, Multicenter, Single-arm Study to Assess the Safety, 
Feasibility, and Efficacy of Cell Transfer Therapy Using 
Autologous Tumor Infiltrating Lymphocytes (LN-144) Followed 
by IL-2 for Treatment of Metastatic Melanoma 
 
 
PROTOCOL 
NUMBER:   
C-144-01 
SPONSOR: 
Lion Biotechnologies, Inc. 
21900 Burbank Blvd., Third Floor 
Woodland Hills, CA 91367 
PROTOCOL 
VERSION: 
Version 3.0 
PROTOCOL 
DATE: 
July 16, 2015 
 
 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of 
The Sponsor or their representative and any unauthorized use or disclosure of 
such information without the prior written authorization of The Sponsor or their 
representative is expressly prohibited. 
 
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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
A Phase 2, Multicenter, Single-arm Study to Assess the 
Safety, Feasibility, and Efficacy of Cell Transfer Therapy 
Using Autologous Tumor Infiltrating Lymphocytes (LN-144) 
Followed by IL-2 for Treatment of Metastatic Melanoma 
Protocol Number:  
 
C-144-01 
Sponsor: 
Lion Biotechnologies, Inc. 
Version / Date of Protocol: 
Version 3.0 (July 16, 2015) 
 
 
I agree to conduct the study as detailed in the protocol and in compliance with ICH 
Guidelines for Good Clinical Practice. 
 
I acknowledge that I am responsible for overall study conduct, and I agree to personally 
conduct or supervise the described clinical study. 
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct 
of the study are informed about their obligations.  Mechanisms are in place to ensure 
that site staff receives the appropriate information throughout the study. 
 
 
 
 
Principal Investigator printed name 
 
 
 
 
 
 
 
 
Principal Investigator signature 
 
Date 
 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase 2, Multicenter, Single-arm Study to Assess the Safety, Feasibility, 
and Efficacy of Cell Transfer Therapy Using Autologous Tumor Infiltrating 
Lymphocytes (LN-144) Followed by IL-2 for Treatment of Metastatic 
Melanoma 
Study Type: 
Phase 2  
Indication: 
Treatment of metastatic melanoma that has progressed following prior 
systemic therapy. 
Investigational 
Agent: 
LN-144:  Autologous Tumor Infiltrating Lymphocytes (TIL) derived from 
the patient’s own tumor 
Study 
Objectives: 
Primary Objectives 
• 
To assess the safety and toxicities associated with the treatment 
regimen. 
• 
To assess the feasibility of TIL production, defined as the percentage of 
patients with tumor resected from which LN-144 is successfully produced 
(manufacture of more than 1.5 billion viable cells). 
Secondary Objectives 
• 
To assess the feasibility of LN-144 administration followed by IL-2 
(defined as the percentage of patients with tumor resected with LN-144 
subsequently infused). 
• 
To evaluate the anti-tumor activity defined by best overall response rate 
by RECIST 1.1 in patients who receive LN-144 followed by IL-2. 
Exploratory Objectives 
• 
To evaluate additional measures of efficacy for up to 24 months, 
including: progression-free survival (PFS), overall survival (OS), duration 
of response, and time to response. 
• 
To explore potential immune correlates of response, outcome, and 
toxicity of the treatment. 
Study Design: 
Prospective, single-arm interventional study evaluating adoptive cell therapy 
(ACT) with autologous TIL infusion (LN-144) followed by IL-2 after a non-
myeloablative chemotherapy preparative regimen.   
Rationale for 
Dose and 
Treatment 
Schedule: 
 
LN-144 is a cell transfer therapy and is based on current TIL therapy 
regimens originally developed by the NCI then further studied and modified at 
institutions in the United States and Europe.  
The cell transfer therapy used in this study involves patients receiving a 
lymphocyte depleting preparative regimen, followed by infusion of between 
1.5x109 and 150 x109 autologous TIL followed by the administration of a 
regimen of IL-2 at 600,000 IU/kg every eight hours for up to a maximum of six 
doses starting 12-24 hours after cell infusion.  Patients will be evaluated for 
response approximately 12 weeks following the LN-144 therapy.  Patients will 
receive one course of treatment.  
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Duration of 
Study 
Participation: 
Approximately 18 weeks (see Schedule of Events for details)   
Follow-up 
Period: 
Patients who experience stable disease, a partial response, or a complete 
response, or have unresolved toxicities at the 12-week post-treatment visit, 
will be evaluated as noted below: 
• 
At six months (+/- 1 week) following LN-144 treatment 
• 
At nine months (+/- 1 week) following LN-144 treatment 
• 
At 12 months(+/- 1 week)  following LN-144 treatment  
• 
At 18 months (+/- 3 weeks) following LN-144 treatment 
• 
At 24 months (+/- 3 weeks) following LN-144 treatment 
Number of 
Study Centers: 
Up to five clinical sites 
Number of 
Planned 
Patients: 
Twenty patients who complete treatment.  Complete treatment is defined as 
successful infusion with LN-144 followed by IL-2. 
Study 
Population: 
Diagnosis and 
Main Criteria 
for Inclusion: 
 
To be eligible for the study, patients must meet ALL of the following criteria 
prior to enrollment in the study: 
a. 
Patients must have measurable metastatic melanoma and at least one 
lesion that is resectable for TIL generation. The lesion must be of at least 
1.5 cm in diameter and can be surgically removed with minimal morbidity 
(defined as any operation for which expected hospitalization is less than 
or equal to three days).  
b. 
Patients must have undergone at least one prior systemic treatment for 
metastatic melanoma. 
c. 
Patients must have progressive disease while receiving or after 
completion of most recent prior treatment.   
d. 
Patients must be greater than 18 years of age at the time of consent.  
e. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1. 
f. 
In the opinion of the Investigator, patient must be capable of participating 
and completing study procedures.   
g. 
Patients of childbearing potential or with partners of childbearing 
potential must be willing to practice birth control during treatment and for 
four months after receiving all protocol related therapy. 
h. 
Patients must have a serum absolute neutrophil count (ANC) greater 
than 1000/mm3, hemoglobin greater than 9.0 g/dL, and platelet count 
greater than 100,000/mm3. 
i. 
Patients must have a serum ALT/SGPT and AST/SGOT  less than three 
times the upper limit of normal (<3x ULN), a calculated creatinine 
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clearance of greater than 50 mL/min (>50 mL/min), and a total bilirubin 
less than or equal to 2 mg/dL (≤ 2 mg/dL).  Patients with Gilbert’s 
Syndrome must have a total bilirubin less than 3 mg/dL (<3 mg/dL).  
j. 
Patients must be seronegative for the HIV antibody, hepatitis B antigen, 
and hepatitis C antibody or antigen. 
k. 
Patients must be EBV viral capsid antigen (VCA) IgG n positive, Epstein 
Barr nuclear antigen (EBNA) IgG positive, and D early antigen (EA-D) 
negative 
l. 
Patients must not be receiving any radiation therapy, systemic anti-
cancer chemo or immunotherapy for 2 weeks (targeted therapies) and 4 
weeks (all other treatment) at the time of enrollment, and there must be 
no intention of receiving any non-protocol systemic anti-cancer chemo or 
immuno- therapy during the trial period Additionally, all prior therapy-
related toxicities must have recovered to Grade 1 or less (CTCAE v4.03), 
except for alopecia or vitiligo  prior to enrollment . 
Note: Patients may have undergone minor surgical procedures not 
involving general anesthesia within three weeks prior to enrollment as 
long as all toxicities have recovered to Grade 1 or less or as specified in 
the eligibility criteria.Patients with documented Grade 2 or greater 
diarrhea or colitis as a result of previous treatment with ipilimumab, 
tremelimumab, anti-PD1 or anti-PD-L1 antibodies must have had a 
normal colonoscopy post treatment, including biopsy specimens.  
m. Patients must have the ability to understand the requirements of the 
study, have provided written informed consent as evidenced by signature 
on an informed consent form (ICF) approved by an institutional review 
board (IRB), and agree to abide by the study restrictions and return to 
the site for the required assessments. 
n. 
Patients have provided written authorization for use and disclosure of 
protected health information. 
Main 
Criteria for 
Exclusion: 
 
Patients who meet ANY of the following criteria will be excluded from the 
study: 
a. Patients who have received prior cell transfer therapy which included 
a non-myeloablative or myeloablative chemotherapy regimen. 
b. Patients who have more than three brain metastases.  Note:  Patients 
with fewer metastases may be eligible.  If lesions are symptomatic or 
greater than or equal to 1 cm each, these lesions must have been 
definitively treated and stable for one month. Brain metastases with 
significant edema and metastases larger than 2 cm are exclusionary. 
c. Patients who are pregnant or breastfeeding. 
d. Patients who are on a systemic steroid therapy regimen defined as 
the need for chronic steroid use for at least seven or more days at a 
dose of greater than 10 mg of prednisone or equivalent per day.  
e. Patients who have active systemic infections, coagulation disorders 
or other active major medical illnesses of the cardiovascular, 
respiratory or immune system, as evidenced in the medical history by 
a positive stress thallium or comparable test, myocardial infarction, 
cardiac arrhythmias, obstructive or restrictive pulmonary disease. 
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f. 
Patients who have any form of primary immunodeficiency (such as 
Severe Combined Immunodeficiency Disease and AIDS).   
g. Patients who have a history of severe immediate hypersensitivity 
reaction to cyclophosphamide, fludarabine, or IL-2.  
h. Patients who have a history of coronary revascularization or ischemic 
symptoms. 
i. 
Patients who have a history of a positive HIV test or active Hepatitis B 
or C.  
j. 
Patients who have an estimated glomerular filtration rate (eGFR) less 
than 40 mL/min using the Cockcroft Gault formula at Screening or 
have end-stage renal disorder requiring hemodialysis.  
k. Patients who have an LVEF less than 45%. (Older patients [60 – 70 
years] must have received an echocardiogram within the previous 60 
days demonstrating LVEF ≥ 45%). 
l. 
Patients who have history of cigarette smoking of at least 20 
packs/year within the past two years that have a documented FEV1 
(forced expiratory volume in one second) of less than or equal to 60%  
m. Patients who have had another primary malignancy within the 
previous three years (with the exception of carcinoma in situ of the 
breast, urothelial cancer in situ, and non-melanoma skin cancer that 
has been adequately treated). 
Treatment 
Groups: 
LN-144 (autologous TIL) followed by IL-2 after a lymphocyte-depleting 
preparative regimen as a single arm, open-label treatment. 
Discontinuation 
of Treatment: 
Criteria for early termination from study (removal from treatment) (CTCAE 
v4.03): 
• 
Grade 3 or greater autoimmunity that involves vital organs (heart, 
kidneys, brain, eye, liver, colon, adrenal gland, lungs) with symptoms 
emerging prior to first IL-2 administration.  
• 
Grade 3 or greater allergic reaction including bronchospasm or 
generalized urticaria that does not resolve after medical management 
in the opinion of the investigator.  
• 
Grade 3 or greater toxicity due to IL-2 that does not decrease to 
Grade 2 or less within 96 hours of management.   
• 
Determination by the PI that continued treatment is not in the best 
interest of the patient. 
• 
Withdrawal by patient. The patient may withdraw consent to treatment 
but continue consent for follow-up evaluations and/or survival status 
• 
Disease Progression prior to receipt of study drug (TIL followed by IL-
2) 
• 
Death 
• 
Study Terminated by sponsor 
• 
Pregnancy 
Efficacy 
Assessment: 
The descriptive summary of the clinical overall response rate and 
progression-free survival will be used to determine the potential efficacy of 
this treatment and to support the design of future clinical trials. 
Safety 
Assessment: 
Treatment-emergent adverse events and serious adverse events will be 
evaluated to assess the safety of this treatment. 
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Overview of 
Statistical Plan: 
The primary statistical plan of analysis is based on use of descriptive 
methods.  Point estimates of treatment effect will be derived from maximum 
likelihood methods.  All data will be listed. 
The feasibility endpoints are binomial proportions with the numerators defined 
as the number of patients successfully meeting pre-specified criteria of 
feasibility specific to each endpoint and the denominators comprised of all 
resected patients. These endpoints will be analyzed separately and will be 
summarized using both a point estimate and its two-sided, exact 95% 
confidence limits. 
Patients meeting RECIST 1.1 criteria for a complete (CR) or partial (PR) best 
overall response will be classified as responders in the analysis of best overall 
response (BOR) rate. The BOR rate is derived as the number of complete 
and partial responders divided by the number of patients infused with LN-144 
and IL-2. This rate will be summarized using both a point estimate and its two-
sided exact 95% confidence limits. 
All time-to-event efficacy endpoints will use Kaplan-Meier survival curve 
methods to summarize the data. The time origin for all such analyses (except 
for response duration) will be the date on which patients began treatment with 
IL-2 after infusion with LN-144.  
The assessment of safety data will be descriptive and based on the 
summarization of treatment-emergent adverse events, serious adverse 
events, adverse events leading to discontinuation from the study, vital signs, 
physical examinations, and clinical laboratory tests. 
Sample Size 
Determination: 
The sample size is driven by the need to obtain 20 patients who complete 
treatment.  Complete treatment is defined as successful infusion with LN-144 
followed by IL-2.This response parameter is assumed to be a binomial 
proportion, derived as the number of eligible patients divided by the number of 
resected patients x 100%. This percentage is expected to equal 60%. To 
achieve this target with 20 patients who complete treatment, roughly 33 
patients will need to be resected. A study accruing 20 patients who complete 
treatment allows adequate sensitivity to detect one or more Grade 3 or 4 
toxicities. This sample of 20 patients who complete treatment also provides a 
denominator number of patients for the anti-tumor efficacy measurements.   
Interim 
Analysis: 
The DSMB will perform safety evaluation of data analyzed when 3 patients 
have completed study.  A limited analysis will also be conducted reviewing all 
available data from these patients as specified in the DSMB charter. 
An additional interim analysis will be conducted after 10 patients have been 
treated to evaluate the feasibility of administering LN-144, including success 
of harvest of lymphocytes, propagation of TIL, and administration of TIL 
following preparative therapy. 
Study 
Discontinuation 
(study or site 
termination): 
Conditions may arise during the study that could prompt the study to be 
stopped or a study site to be closed.  Conditions that may prompt such 
considerations include, but are not limited to, the following: 
• 
The discovery of unexpected, serious, or unacceptable risk to 
subjects enrolled in the study; 
• 
A decision on the part of the Sponsor to suspend, discontinue, or 
shorten the study; 
• 
Study conduct at a study site may warrant termination under 
conditions that include the following:  
o 
Failure of the Investigator(s) to enroll eligible subjects into the 
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study 
o 
Failure of the Investigator(s) to comply with FDA or country-
specific regulations  
o 
Submission of false information from the research facility to 
the Sponsor, the Clinical Monitor, or a regulatory authority 
o 
Insufficient adherence to protocol requirements 
o 
A conflict of interest on the part of the Investigator, his/her 
institution, or site personnel that would negatively impact the 
integrity of the clinical trial 
o 
Institution or IRB under investigation for cause by a federal 
agency 
 
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STUDY FLOWCHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Enrollment 
TIL  
Harvest 
TIL 
Expansion 
Lympho-
depletion 
TIL  
Release  
Infusion of TIL 
followed by IL-2  
Day 42 & 84 
Post-Treatment 
Evaluations 
Follow-up Evaluations: 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
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6.4 
Day -7 ...................................................................................................................... 37 
6.5 
Day -6 ...................................................................................................................... 39 
6.6 
Day -5 to Day -1 ...................................................................................................... 40 
6.7 
Day 0  (+2 days) ...................................................................................................... 40 
6.8 
Days 1 – 4 ............................................................................................................... 42 
6.9 
Day 14, 28 (+/- 1 day) .............................................................................................. 43 
6.10 
Day 42 ( +/- 3 days) ................................................................................................. 44 
6.11 
Day 84 ( +/- 3 days) ................................................................................................. 46 
6.12 
Months 6 (+/- 1 week), 9 (+/- 1 week), 12 (+/- 1 week), 18 (+/- 3 weeks), and 24 
(+/- 3 weeks) ............................................................................................................ 47 
6.13 
Discontinued Patients .............................................................................................. 48 
6.14 
Expected Toxicities and Treatment Guidelines ........................................................ 48 
6.14.1 
LN-144 
…………………………………………………………………...................48 
6.14.2 
IL-2 
……………………………………………………………………………….49 
6.14.3 
Treatment Guidelines for Toxicity Management ................................................... 50 
6.14.4 
Empiric Antibiotics ................................................................................................ 50 
6.14.5 
Blood Product Support ......................................................................................... 50 
6.14.6 
Renal Toxicity....................................................................................................... 51 
6.15 
Infection Prophylaxis ................................................................................................ 51 
6.15.1 
Pneumocystis Jiroveci Pneumonia ....................................................................... 51 
6.15.2 
Herpes Virus Prophylaxis ..................................................................................... 51 
6.15.3 
Fungal Prophylaxis (Fluconazole) ........................................................................ 52 
6.15.4 
Empiric Antibiotics ................................................................................................ 52 
6.15.5 
Blood Product Support ......................................................................................... 52 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF PATIENTS ................ 52 
7.1 
Study Completion .................................................................................................... 52 
7.2 
Criteria for Early Termination from Study (Removal from Treatment) ....................... 53 
7.3 
Criteria for Removal from Follow-Up ........................................................................ 54 
7.4 
Study Discontinuation (Study or Site Termination) ................................................... 54 
8 
STUDY DRUG INFORMATION .................................................................................... 55 
9 
STUDY ASSESSMENTS ............................................................................................. 57 
9.1 
Efficacy Assessments .............................................................................................. 57 
9.1.1 
Response Criteria ................................................................................................ 57 
10 STATISTICAL AND ANALYTICAL PLANS ................................................................... 60 
10.1 
Introduction .............................................................................................................. 60 
10.2 
Analysis Populations ................................................................................................ 61 
10.3 
Endpoints ................................................................................................................ 61 
10.3.1 
Primary 
……………………………………………………………………………….61 
10.3.2 
Secondary…………….............................................................................................61 
10.3.3 
Exploratory ……………………………………………………………………………….62 
10.4 
Sample Size Justification ......................................................................................... 63 
10.4.1 
Baseline Demographic and Clinical Characteristics .............................................. 64 
10.4.2 
Efficacy Analysis, Primary Endpoint ..................................................................... 64 
10.4.3 
Efficacy Analysis, Secondary Endpoints ............................................................... 64 
10.4.4 
Safety Analysis ..................................................................................................... 65 
10.4.5 
Other Planned Analyses ....................................................................................... 66 
11 CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS ....................................... 66 
11.1 
Drugs Administered during the Study....................................................................... 66 
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11.2 
TIL Treatment .......................................................................................................... 66 
11.3 
IL-2 Administration ................................................................................................... 66 
12 ADVERSE EVENTS ..................................................................................................... 67 
12.1 
Definitions ................................................................................................................ 67 
12.2 
Reporting Procedures for Adverse Events ............................................................... 69 
12.2.1 
All Adverse Events ............................................................................................... 69 
12.2.2 
Relationship to Study Drug ................................................................................... 70 
12.2.3 
Severity 
……………………………………………………………………………….71 
12.2.4 
Serious Adverse Events ....................................................................................... 71 
12.2.5 
Data Safety Monitoring Board .............................................................................. 72 
13 ADMINISTRATIVE REQUIREMENTS .......................................................................... 72 
13.1 
Protocol Modifications .............................................................................................. 72 
13.2 
Regulatory Documentation ...................................................................................... 73 
13.3 
Patient Identification Register .................................................................................. 74 
13.4 
Record Retention ..................................................................................................... 74 
13.5 
Data Quality Assurance ........................................................................................... 74 
13.6 
Data Handling and Recordkeeping .......................................................................... 75 
13.6.1 
Electronic Data ..................................................................................................... 75 
13.6.2 
Electronic Case Report Form (eCRF) Completion ................................................ 75 
13.7 
Study Completion/Termination ................................................................................. 76 
13.7.1 
Study Completion ................................................................................................. 76 
13.7.2 
Study Termination ................................................................................................ 76 
13.8 
Monitoring ................................................................................................................ 77 
14 INVESTIGATOR REGULATORY OBLIGATIONS ........................................................ 77 
14.1 
Institutional Review Board ....................................................................................... 77 
14.2 
Informed Consent .................................................................................................... 77 
14.3 
Declaration of Helsinki ............................................................................................. 78 
14.4 
Patient Data Protection ............................................................................................ 78 
14.5 
Adverse Event Reporting ......................................................................................... 79 
14.6 
Investigator .............................................................................................................. 79 
14.7 
Final Report ............................................................................................................. 79 
14.8 
Confidentiality .......................................................................................................... 80 
14.9 
Publications ............................................................................................................. 80 
15 REFERENCES ............................................................................................................. 81 
APPENDIX 1: SCHEDULE OF EVENTS ............................................................................. 86 
APPENDIX 2: ECOG SCALE .............................................................................................. 89 
APPENDIX 3: PRACTICAL WEIGHT .................................................................................. 90 
APPENDIX 4: HIGH-DOSE IL-2 TOXICITIES ..................................................................... 91 
APPENDIX 5: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT ........................ 92 
APPENDIX 6: COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS .................................................................................................................. 95 
APPENDIX 7: CYCLOPHOSPHAMIDE PACKAGE INSERT ............................................... 96 
APPENDIX 8: FLUDARABINE PACKAGE INSERT .......................................................... 114 
 
 
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LIST OF TABLES  
 
Table 1. 
Composition of LN-144........................................................................... 56 
Table 2. 
Time Point Response: Patients with Target (± Non-target) Disease ....... 59 
Table 3. 
Time Point Response: Patients with Non-target Disease Only ............... 59 
 
 
LIST OF FIGURES  
Figure 1. 
 LN-144 Manufacturing Process ............................................................. 24 
 
 
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LIST OF ABBREVIATIONS 
ACS 
American Cancer Society 
ACT 
Adoptive Cell Therapy 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate transaminase 
BOR 
Best Overall Response Rate 
BP 
Blood pressure 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
ClCR 
Calculated creatinine clearance 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events Version 4.03 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FEV 
Forced Expiratory Volume in the first second 
F/U 
Follow-up 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IL-2 
Interleukin-2 (also known as “aldesleukin”) 
IND 
Investigational New Drug (Application) 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition scan 
NCI 
National Cancer Institute 
NE 
In evaluable  
Non-CR 
Non-complete response 
Non-PD 
Non-progression 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive disease 
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PFS 
Progression-free survival 
PI 
Principal Investigator 
PFT 
Pulmonary Function Test  
PO 
Per Os (by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
(Taken) once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
T 
Body temperature 
TIL 
Tumor Infiltrating Lymphocyte 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit normal 
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1 
INTRODUCTION 
1.1 
Background  
There were an estimated 76,100 new cases of melanoma diagnosed in 2014, making 
it the 5th most common malignancy in men and the 7th most common malignancy in 
women, and unlike most malignancies, the incidence is increasing by greater than 2% 
per year in both sexes. While most melanoma is diagnosed early, up to 20% is 
regionally or distantly metastatic at the time of diagnosis.1 In advanced disease 
(Stage IV), prognosis is extremely poor with five-year survival of less than 5%.  
Numerous novel approaches, including chemotherapy, targeted therapy and 
immunotherapy have been developed as treatment with varying results.   
Chemotherapy regimens using dacarbazine or temozolomide have been reported to 
result in tumor regression in 10 – 20% of patients; however, the responses have been 
of limited duration and rarely result in a complete response.2   No chemotherapy 
regimen has, to date, demonstrated a survival benefit for patients with advanced 
melanoma.  As such, although chemotherapy was widely used in the past, it now has 
a secondary role and is currently reserved for melanoma that can no longer be 
controlled with immunotherapy or targeted therapy. 
Approved targeted therapies to date are limited to use in metastatic melanoma 
patients who have mutation in the V600 position of the gene encoding BRAF in the 
mitogen-activated protein kinase (MAPK) pathway.  This mutation results in the 
expression of a modified BRAF protein, which directs growth of cancer cells.  Two 
approved drugs, vemurafenib (Zelboraf) and dabrafenib (Tafinlar) directly inhibit the 
mutant BRAF gene.3 Vemurafenib has demonstrated a survival benefit over 
chemotherapy in patients, while dabrafenib has demonstrated a notable PFS benefit, 
with crossover blunting the effect on overall survival.4 Another gene product in the 
MAPK pathway being targeted is MEK which is downstream of BRAF. This gene 
product is being targeted in its wild-type or non-mutant form, as MEK mutations are 
not found in melanoma or are quite rare. MEK has been targeted by a kinase inhibitor 
called trametinib and has also demonstrated survival benefit over chemotherapy.5 
These targeted agents prolong the time until tumor growth and extend overall survival 
in patients with BRAF mutant melanoma. However, disease eventually progresses 
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despite continuation of treatment with such therapy. More recently, it has been 
demonstrated that combining a BRAF inhibitor and a MEK inhibitor increases both 
response rates and duration of response, and improves overall survival as compared 
to BRAF inhibition alone, though all cases still are ultimately expected to develop 
resistance.6 
While targeted therapies are noted to have high response rates but short durations of 
response, cancer immunotherapy tends to have fewer objective responses, but longer 
duration of response which may sometimes even translate to a cure, as defined when 
complete remission from disease has lasted for years after therapy with no evidence 
of recurrence after repeated follow-up. Cancer immunotherapy is categorized into 
three general treatment modalities: active immunization, non-specific immune 
stimulation, and adoptive cell transfer.  In the treatment of metastatic melanoma, 
active immunization with agents such as peptides, whole tumor cell vaccines, 
recombinant viruses encoding tumor-associated antigens, or dendritic cells have 
historically shown low tumor response rates of less than 5%,7-10 though more recently 
tested agents such as the oncolytic virus talimogene laherparepvec have shown 
promising response rates of up to 26%, with 16% lasting more than 6 months.11   
Nonspecific immune stimulation with high-dose interleukin-2 (IL-2) as a single agent 
or ipilimumab can lead to durable cancer regression, although the overall tumor 
response rates for each agent have been low.  The response rate for high-dose IL-2 
was reported at 16%, with only approximately half of these complete responses,12 and 
the response rate to ipilimumab was only 11%.7  Despite these low objective 
response rates, among complete responders to high-dose IL-2, 50% never 
experience disease recurrence.  Among patients treated with ipilimumab, up to 22% 
are still alive after three years, with some patients surviving beyond 10 years.13 A pilot 
trial of 36 patients with melanoma treated with ipilimumab combined with high-dose 
IL-2 had overall response (OR) rates of 25%, with 17% achieving a CR lasting more 
than eight years ongoing;14 however, IL-2 plus ipilimumab combination has not been 
further tested to confirm these results. Anti-PD1 and anti-PD-L1 antibodies have 
recently been reported to have OR rates of up to 38%,15, 16 and 17%,17 respectively, in 
patients with melanoma, and OR rates of up to 40% when combined with 
ipilimumab,18 although the long-term durability of the responses is not yet known. 
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Cancer immunotherapy with adoptive transfer of tumor infiltrating lymphocytes (TIL) 
presents a potentially effective treatment for patients with metastatic melanoma. 
Adoptive Cell Transfer (ACT) with TIL involves the ex vivo numerical expansion of 
antitumor lymphocytes that have infiltrated into tumors. These TIL are numerically 
expanded in culture using T-cell growth factor, IL-2, either from small cut tumor 
fragments from surgically-resected lesions or from single cell suspensions isolated 
from resected tumors. The expanded TIL are re-infused (“transferred”) back into the 
patient.  These cells can be activated ex vivo, free from the potentially suppressive 
tumor microenvironment that may prevent them from fully living up to their antitumor 
potential. ACT has theoretical and practical advantages over active immunization and 
nonspecific immune stimulation. These include: 1) ability to numerically expand and 
re-infuse much higher number of tumor-reactive T cells than is possible with these 
other approaches, 2) the ability to numerically expand tumor-specific T cells in the 
absence of the effects suppressive T-regulatory cells, 3) the wider array of tumor 
antigens, such as mutated tumor antigens, recognized by the expanded T cells 
intrinsic to the TIL product and 4) the ability to further manipulate these infused T cells 
using immune modulators such as IL-2, T-cell checkpoint blockade agents, or other 
active or non-specific immune stimulating agents.19, 20  Preparation of the host patient 
with lymphodepletion immediately prior to the transfer of the antitumor cells also 
eliminates potentially suppressive influences (such as regulatory T cells and cytokine 
sinks) to provide an optimal milieu for the transferred TIL to proliferate and become 
activated in vivo.  When combined with a preparative lymphodepleting regimen pre-
transfer, ACT using autologous TIL has demonstrated consistently high objective 
response rates, from 49% to 72%, with long-term durable and potentially curative CR 
rates of up to 20%.19, 21, 22   
1.2 
Overview of Adoptive Cell Transfer for Metastatic Melanoma 
The partial success of IL-2 therapy in the treatment of metastatic melanoma revealed 
that manipulation of the immune response could alter the clinical course of the 
disease.23 The induction of tumor regression by IL-2 is believed to be related to its 
immune regulatory effects, including the expansion of T lymphocytes following 
activation by specific antigen and NK cells.24-26  T cell recognition leading to tumor cell 
killing and/or the release of helper and other cytokines is due to the presence of 
specifically recognized antigens present on the tumor cells.27, 28  In the case of 
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melanoma, a number of antigens have now been identified that can be recognized by 
both CD8+ cytotoxic T cells and CD4+ T-helper cells, including MART-1, gp100, 
MAGE-1, tyrosinase, TRP-1, TRP-2 and NY-ESO-1.28, 29  The presence of these 
antigens on melanoma tumor cells has led to immunotherapy regimens that focused 
on the ability of effector T cells to mediate tumor destruction specially the 
development of adoptive cell transfer regimens using TIL.  
The identification of melanoma-specific antigens that are recognized by T cells and 
the ability to isolate and expand the tumor-reactive T cells population in vitro has led 
to the development of adoptive cell transfer regimens for treatment of metastatic 
melanoma.  TIL derived from resected melanoma tumors and expanded in vitro have 
been shown to be capable of specifically recognizing tumor antigens, particularly 
MART-1, in over two-thirds of melanoma patients.30, 31  In addition, recent studies 
have shown that TIL from melanoma tumors can recognize antigens derived from 
mutated gene products in the cancer cells recognized as “neo-antigens” by the T 
cells.  
The success of IL-2 therapy for metastatic melanoma and the discovery of tumor 
antigens recognized by TIL led to first attempts to isolate tumors, expand lymphocytes 
from tumor fragments, and re-infuse these expanded cells back into the patient. Some 
of the first clinical trials performed in different centers in the USA and Europe, such as 
the NCI, used TIL expanded for a number of weeks from tumor tissue with IL-2 alone 
followed by re-infusion into patients. This was followed up by low-dose IL-2 infusion or 
subcutaneous IL-2 administration.32-35 Although these protocols were found to be 
feasible, they had inconsistent and widely varying response rates ranging from 0% to 
66%, with the caveat that some of these trials were only on small numbers (<10) of 
patients (e.g., Tessier et al.).33  
During this time, the Surgery Branch at the National Cancer Institute (NCI, Bethesda, 
MD) also embarked on performing TIL trials for metastatic melanoma using a similar 
expansion method for TIL with IL-2 alone. The NCI however included a preparative 
chemotherapy regimen using low-dose cyclophosphamide (CY) before TIL infusion 
that resulted in a partial and transient depletion of host lymphocytes.  IL-2 was 
administered after TIL infusion. This led to more promising response rates in small 
pilot clinical trials of 30-60%.36-38 This prior CY pre-conditioning approach resulted 
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from work on murine tumor models at the NCI showing that the host immune 
environment may significantly impact the efficacy of adoptive T- cell therapy. In these 
studies an improved persistence and anti-tumor activity of transferred TIL expanded 
from implanted murine tumors was found when host mice were treated with CY or 
non-lethally irradiated to deplete endogenous lymphocytes.39, 40 Prior lymphodepletion 
with CY was later also found to remove a new subset of suppressive CD4+ T-
regulatory cells (CD4+Foxp3+ cells) that inhibit anti-tumor immune responses in mice. 
Higher T-regulatory cell frequencies in the blood are also correlated with an 
unfavorable prognosis in cancer patients.41-44  Alternatively, prior depletion of 
lymphocytes may create ‘space’ for the adoptively transferred cells within the 
lymphocyte compartment.45 Under this model, homeostatic lymphocyte survival may 
result in increased proliferation and enhanced survival of transferred T cells, perhaps 
through a mechanism involving increased access to endogenous cytokines like IL-7 
and IL-15.46 The success of prior lymphodepletion in animal models and the use of 
single agent CY preconditioning in initial TIL therapy trials, led to testing of more 
intensive pre-conditioning regimens yielding a complete depletion of host lymphocytes 
for a longer window of time than the prior CY alone regimens. 
The NCI first reported a study on 35 patients including this more intense 
lymphodepleting conditioning regimen to adoptive cell transfer therapy in patients with 
metastatic melanoma.47, 48  Patients received a lymphodepleting chemotherapy 
regimen consisting of high-dose cyclophosphamide and standard doses of fludarabine 
before administration of selected, expanded, tumor-reactive TIL and IL-2. The 
lymphodepletion step resulted in a transient myelosuppression and the elimination of 
all circulating lymphocytes for approximately one week, after which time patients 
recovered endogenous marrow function and reconstituted their lymphocyte 
compartments towards normal levels within two to three weeks.47, 48 
Because of the immunosuppression of fludarabine, one patient who had clonal 
repopulation from infused TIL and a complete response of metastatic melanoma, 
developed Epstein-Barr virus (EBV) - associated B cell lymphoma. This patient was 
EBV-naïve prior to treatment. The potential source of EBV was thought to be multiple 
blood products received after chemotherapy. The patient later died of complications 
from the treatment of the lymphoma. Another patient developed polyneuropathy 
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consisting of vision loss and motor and sensory defects approximately 2 months after 
chemotherapy. The etiology of this complication is unknown, but was possibly related 
to fludarabine.48 
Published clinical trials evaluating TIL therapy from several institutions using similar 
protocols as the NCI are reporting reproducible and promising results. Rosenberg et 
al.21 reported results of clinical trials conducted at NCI that used three different pre-
treatment regimens prior to TIL infusion for treatment of patients with melanoma. 
Objective responses were seen in 52/93 patients (56%) of which 20/93 (22%) were 
complete responses.  The complete responses were durable (defined as “ongoing 
after 64 -109 months of follow-up”) in 19/20 (95%) of the patients.  Radvanyi et al.49 
reported the MD Anderson Cancer Center experience with ACT using selected TIL for 
treatment of metastatic melanoma with objective clinical response in 15/31 (48.4%) 
patients with two resulting in a complete response (6.5%). Progression free survival of 
a duration of greater than 12 months was reported in 9/15 (60%) of the patients that 
responded to therapy. The H. Lee Moffitt Cancer Center also reported a 38% 
response rate in 13 treated patients with 2/13 (15%) achieving a complete response 
ongoing for more than 14 and 16 months at the time of publication, respectively.50 
Outside the U.S., Itzhaki et al.51 reported the experience from Sheba Medical Center 
in Israel using “young, unselected –TIL therapy.”  Of the 31 patients evaluated, 15 
(48%) of the patients achieved a clinical response including four patients (12.9%) with 
complete responses. In addition, a group in Denmark52 used low-dose IL-2 as an 
adjuvant after cell infusion to reduce treatment related toxicity in a small study (6 
patients).  They reported objective clinical responses in 2/6 patients (33%) with 
ongoing complete responses for more than 10 and 30 months (respectively), 2 
patients (33%) with stable disease for 4 and 5 months (respectively) and 2 patients 
(33%) whose disease progressed shortly after treatment.  
These collective results suggest that the non-myeloablative lymphodepleting chemo-
preparative regimen proposed in this current study can be tolerated and contributes to 
the potent efficacy of TIL for the treatment of advanced metastatic disease.  
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1.3 
Production and Expansion of Tumor Infiltrating Lymphocytes 
Generating LN-144 involves resecting a tumor deposit (generally > 1 cm, preferably 
1.5 cm in diameter) and culturing tumor fragments in media containing IL-2 to expand 
them in vitro (Figure 1).  Appropriately expanded TIL cultures should reach several 
million cells (combined) in two to three weeks. The cells can be screened at this stage 
for their capacity to kill autologous tumor cells if autologous tumor cells are available. 
Alternatively, the TIL can be screened using allogeneic HLA-A-matched tumor lines. 
Although anti-tumor reactivity assays were used to select TIL for further expansion in 
initial clinical trials, data from a number of studies indicates that both responding and 
non-responding patients have tumor-reactive TIL to similar extents (e.g., Radvanyi et 
al.).49 In addition, clinical trials using young, unselected TIL have as achieved 
relatively similar response rates.51, 53   In this trial TIL cultures will be selected on the 
basis of better growth and a higher proportion of CD8+ TIL.   TIL initially expanded 
from the tumor fragments then undergo a rapid expansion protocol (REP) using the T-
cell–stimulating antibody muromonab-CD3, resulting in billions of cells for patient 
infusion.  In a retrospective study evaluating surgical resections for TIL in 402 patients 
from 2002 to 2007 at the Surgery Branch of the National Cancer Institute, TIL were 
successfully generated in 677 (86%) of the 787 specimens from all tumor sites, 
although tumors from the gastrointestinal tract had a decreased rate of TIL growth 
(70%; P = 0.008).54 
 
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Figure 1. 
 LN-144 Manufacturing Process 
 
1.4 
 LN-144 TIL Therapy 
LN-144 is an autologous, ready-to-infuse, TIL therapy and is almost identical to that 
developed by Dr. Steven Rosenberg at the National Cancer Institute.  TIL have 
demonstrated efficacy in the treatment of Stage IV melanoma, and Phase 2 clinical 
trials evaluating this product have shown an objective response rate of 49% or more, 
exceeding rates reported by other immunotherapies in melanoma.  The present study 
is being conducted to further evaluate: 1) the feasibility of a centralized mechanism for 
harvest, production, expansion, and infusion of TIL in metastatic melanoma, 2) the 
efficacy of TIL therapy, and 3) the safety of pre-treatment and TIL therapy regimens. 
Several treatment regimens have been used in conjunction with TIL therapy.  
Lymphodepleting regimens have included cyclophosphamide/fludarabine, total body 
irradiation or the combination of the two.  The lymphodepletion protocol used in the 
current study is based on the method developed and tested by the NCI and is also the 
most often used.  It involves two days of cyclophosphamide followed by five days of 
fludarabine as a lymphodepleting pre-treatment.  The treatment regimen includes 
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treatment with LN-144 (TIL therapy) followed by high-dose IL-2.  Protocols for the 
tumor harvest and LN-144 administration are provided in separate operating manuals. 
A range of between 1.5 to 150 x 109 total viable cells will be infused in this clinical trial. 
The final cell product is formulated in a minimum of 50% HypoThermosol™ in Plasma-
Lyte A™ (volume/volume) and up to 1% HSA (compatible for human infusion) containing 
300 IU/mL IL2. The final product will be available for administration in one of two  
volumes for infusion:  
1) 250 mL (in a 300-mL capacity infusion bag) when the total TIL harvested are 
≤ 75x109 
OR  
2)  500 mL (in a 600-mL capacity infusion bag) when the total TIL harvested are 
>75 x 109.  
The cell concentration range is   5.5 x 106 to 300 x 106/mL in the final product, with a 
dose range of 1.5 to 150 x 109 total viable cells.  
A number of factors indicate that this is a viable range of cells for TIL therapy for 
metastatic melanoma, including: 1) previous experience in published melanoma TIL 
therapy clinical trials where the total number of infused cells have been in this range, 
2) demonstrated safety when infusing cells within this range, and 3) demonstrated 
clinical responses in patients infused with TIL within this range of cell numbers.21, 47-50, 
52, 53, 55-59 
We cannot predict the total number of cells that will be generated for the final LN-144 
infusion product for each patient due to patient-to-patient variation in T-cell expansion 
rates during the REP step. The lower limit of the range (1.5 x 109 viable cells) is set 
based on the minimum number of cells needed on day 7 of the 14-day REP) in order 
to make a decision to lymphodeplete the patient using the CY plus FLUD 
chemotherapy regimen. Once we have begun lymphodepletion based on this minimal 
attained cell number, we are committed to treating the patient with whatever number 
of TIL we generate in the REP by day 14. The upper limit of the range for infusion 
(150 x 109 viable cells) is based on the known published upper limit safely infused 
where a clinical response has been attained.49 There is no evidence that moving 
beyond this upper limit will have more clinical benefit. 
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2 
STUDY DESIGN 
2.1 
Description of the Study 
This is a prospective single-arm interventional study evaluating patients who receive 
adoptive cell therapy (ACT) with LN-144 (autologous TIL).  Patients will receive 
between 1.5 x 109 and 150 x 109 LN-144 followed by the administration of a regimen 
of IL-2 at 600,000 IU/kg every eight hours starting 12 to 24 hours after the LN-144 
infusion and continuing for up to six doses.  Patients will be evaluated for response 
approximately 12 weeks following LN-144 therapy. 
Patients who experience stable disease, a partial response, or a complete response 
(per RECIST version 1.1) or have unresolved toxicities at the 12-week post-treatment 
visit, will be evaluated at six, nine, 12, 18 and 24 months following LN-144 treatment.  
Formal response evaluations will be per RECIST 1.1. 
2.2 
Description of the Study Centers 
Patients may be seen at the Investigators’ private offices or affiliated medical centers 
for evaluations prior to enrollment and during follow-up.  The patients will require 
hospitalization during the LN-144  infusion and IL-2 treatment.  
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 Primary Objectives 
• To assess the safety and toxicities associated with the treatment regimen. 
• To assess the feasibility of TIL production, defined as the percentage of 
patients with tumor resected from which TIL are successfully produced 
(manufacture of more than 1.5 billion viable cells). 
3.1.2 Secondary Objectives 
• To assess the feasibility of TIL administration (defined as the percentage of 
patients with tumor resected with TIL subsequently infused). 
• To evaluate the anti-tumor activity defined by response rate by RECIST 1.1 in 
patients who receive LN-144 followed by IL-2.  
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3.1.3 Exploratory Objectives 
• To evaluate additional measures of efficacy for up to 24 months including: 
progression-free survival (PFS), overall survival (OS), duration of response, 
and time to response. 
• To explore potential immune correlates of response, outcome, and toxicity of 
the treatment. 
3.2 
Study Endpoints  
3.2.1 Primary Endpoints: 
• Incidence and nature of AEs and SAEs related to TIL therapy followed by IL-2 
as defined by treatment-emergent adverse events, SAEs, therapy-related AEs, 
AEs of interest, AEs leading to early discontinuation from the study, and AEs 
resulting in deaths on study. 
• The proportion of resected patients from whom LN-144 is successfully 
produced (manufacture of more than 1.5 billion viable cells). 
3.2.2 Secondary Endpoints:  
• Percentage of resected patients who are infused with LN-144 followed by IL-2. 
• Efficacy of TIL therapy as defined by best overall response (BOR) rate over the 
study period in patients receiving TIL followed by IL-2 treatment. 
3.2.3 Exploratory Endpoints: 
• Evaluation of progression-free survival (PFS), overall survival (OS), duration of 
response, and time to response in patients receiving TIL followed by IL-2 
treatment up to 24 months after treatment. 
• Evaluation of immune correlates with respect to response, outcome, and/or 
toxicity of the treatment. 
4 
SELECTION OF PATIENT POPULATION 
Patients greater than 18 years of age, with a diagnosis of metastatic melanoma who 
have undergone at least one prior immunotherapy or chemotherapy regimen will be 
selected for this study. 
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Details about specific benefits and risks for patients participating in this clinical trial 
may be found in the accompanying Investigator’s Brochure and Informed Consent 
documents. 
4.1 
Inclusion Criteria  
To be eligible for the study, patients must meet ALL of the following criteria prior to 
enrollment 
a. 
Patients must have measurable metastatic melanoma and at least one lesion that is 
resectable for TIL generation. The lesion must be of at least 1.5 cm in diameter and 
can be surgically removed with minimal morbidity (defined as any operation for 
which expected hospitalization is less than or equal to three days).  
b. 
Patients must have undergone at least one prior systemic treatment for metastatic 
melanoma. 
c. 
Patients must have progressive disease while receiving or after completion of most 
recent prior treatment.   
d. 
Patients must be greater than 18 years of age at the time of consent.  
e. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 (Appendix 2). 
f. 
In the opinion of the Investigator, patient must be capable of participating and 
completing study procedures.   
g. 
Patients of child bearing age or potential must be willing to practice birth control 
during treatment and for four months after receiving all protocol related therapy. 
h. 
Patients must have a serum absolute neutrophil count (ANC) greater than 
1000/mm3, hemoglobin greater than 9.0 g/dL, and platelet count greater than 
100,000/mm3. 
i. 
Patients must have a serum ALT/SGPT and AST/SGOT less than three times the 
upper limit of normal (<3x ULN), a calculated creatinine clearance of greater than 50 
mL/min (>50 mL/min), and a total bilirubin less than or equal to 2 mg/dL (≤ 2 mg/dL).  
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Patients with Gilbert’s Syndrome must have a total bilirubin less than 3 mg/dL (<3 
mg/dL).  
j. 
Patients must be seronegative for the HIV antibody, hepatitis B antigen, and 
hepatitis C antibody or antigen. 
k. 
Patients must be EBV viral capsid antigen (VCA) IgG n positive, Epstein Barr 
nuclear antigen (EBNA) IgG positive, and D early antigen (EA-D) negative 
l. 
Patients must not have received systemic therapy for melanoma for a minimum of 
two weeks (targeted therapy) and four weeks (all other therapy) prior to the point of 
enrollment. Prior therapy-related toxicities must have recovered to Grade 1 or less 
(except for alopecia or vitiligo) according to CTCAE v4.03.   
Note:  Patients may have undergone minor surgical procedures not involving 
general anesthesia within three weeks prior to enrollment as long as all toxicities 
have recovered to Grade 1 or less or as specified in the eligibility criteria. 
m. Patients with documented Grade 2 or greater diarrhea or colitis as a result of 
previous treatment with ipilimumab, tremelimumab, anti-PD1 or anti-PD-L1 
antibodies must have had a normal colonoscopy, including normal biopsy 
specimens. 
n. 
Patients must have the ability to understand the requirements of the study, have 
provided written informed consent as evidenced by signature on an informed 
consent form (ICF) approved by an institutional review board (IRB), and agree to 
abide by the study restrictions and return to the site for the required assessments.   
o. 
Patients have provided written authorization for use and disclosure of protected 
health information. 
4.2 
Exclusion Criteria 
Patients who meet ANY of the following criteria will be excluded from the study: 
 
a. 
Patients who have received prior cell transfer therapy which included a non-
myeloablative or myeloablative chemotherapy regimen. 
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b. 
Patients who have more than three brain metastases.  Note:  Patients with fewer 
metastases may be eligible.    If lesions are symptomatic or greater than or equal to 
1 cm each, these lesions must have been definitively treated and stable for one 
month.   Brain metastases with significant edema and metastases larger than 2 cm 
are exclusionary. 
c. 
Patients who are pregnant or breastfeeding. 
d. 
Patients who are on a systemic steroid therapy regimen defined as the need for 
chronic steroid use for at least seven or more days at a dose of  greater than 10 mg 
of prednisone or equivalent per day.  
e. 
Patients who have active systemic infections, coagulation disorders or other active 
major medical illnesses of the cardiovascular, respiratory or immune system, as 
evidenced in the medical history by a positive stress thallium or comparable test, 
myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary 
disease. 
f. 
Patients who have any form of primary immunodeficiency (such as Severe 
Combined Immunodeficiency Disease and AIDS).   
g. 
Patients who have a history of severe immediate hypersensitivity reaction to IL-2, 
fludarabine, cyclophosphamide. 
h. 
Patients who have a history of coronary revascularization or ischemic symptoms. 
i. 
Patients who have a history of a positive HIV test or active Hepatitis B or C. 
j. 
Patients who have an estimated glomerular filtration rate (eGFR) less than 40 
mL/min using the Cockcroft-Gault formula at Screening or have end-stage renal 
disorder requiring hemodialysis. 
k. 
Patients who have an LVEF less than 45%. (Older patients [60 – 70 years], must 
have received an echocardiogram within the previous 60 days demonstrating LVEF 
≥ 45%). 
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l. 
Patients who have history of cigarette smoking of at least 20 packs/year within the 
past two years that have a documented FEV1 (forced expiratory volume in one 
second) of less than or equal to 60%   
m. Patients who have had another primary malignancy within the previous three years 
(with the exception of carcinoma in situ of the breast, urothelial cancer in situ, and 
non-melanoma skin cancer that has been adequately treated). 
4.3 
Number of Patients 
Patients that meet all of the inclusion criteria and do not meet any of the exclusion 
criteria will be enrolled in the study.   
Patients who sign an ICF and fail to meet the inclusion and/or exclusion criteria are 
defined as screen failures.  For all screen failures, the Investigator is to maintain a 
screening log that documents, at a minimum, the patient initials, or other identifier 
used by site, patient date of birth and reason(s) for screen failure.  A copy of the log 
should be retained in the Investigator's study files.  Minimum data for screen failures 
will be captured in the EDC database as defined in the data management plan and 
eCRF completion manual. 
Patients will be enrolled until 20 patients have been successfully treated with TIL 
followed by IL-2 administration.  Enrollment may halt once it becomes likely that the 
full accrual goal will be met. 
4.3.1 Re-screening Patients 
Patients who fail the initial screening process may be re-screened for eligibility.  The 
Principal Investigator and Medical Monitor will discuss the patient prior to any 
rescreening procedures.  
4.3.2 Patient Cohorts 
All patients who are resected for LN-144 production will be included in the intent-to-
treat cohort.  
The DSMB will perform a safety evaluation of data analyzed when 3 patients have 
completed study.  A limited analysis will also be conducted reviewing all data 
available from these patients as specified in the DSMB charter. 
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An additional interim analysis will be conducted after 10 patients have been treated to 
evaluate the feasibility of administering LN-144 , including success of harvest of 
lymphocytes, propagation of TIL, and administration of TIL following preparative 
therapy. 
The primary efficacy and toxicity analyses will take place after 12 weeks following the 
LN-144 administration of the 20th patient treated.   
The final analysis will occur at the point at which all  patients have either withdrawn 
from follow-up, died, or have been followed 24 months after the final patient is treated 
with LN-144 followed by IL-2.  
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
5.1 
Prior Treatment 
Use of all medications taken by the patient 30 days prior to enrollment will be 
recorded in the site’s source documentation and the patient’s electronic case report 
form (eCRF).  Any changes in concomitant medications also will be recorded in the 
site’s source documentation and the patient’s eCRF until completion of the 12-week 
post treatment evaluation (Day 84) period. 
5.2 
Prohibited and Permitted Medications during Study Treatment 
5.2.1 Prohibited Treatment 
Patients will enter a washout period prior to enrollment.  Targeted therapy must be 
stopped at least 2 weeks prior to enrollment and all other anti-cancer treatments must 
be stopped at least 4 weeks prior to enrollment.   
The following guidelines should be used regarding concomitant medications: 
 
• Systemic therapies intended to treat melanoma are not permitted while the 
patient is on study 
• Use of tumor directed therapy (including radiation therapy) during the study 
must be discussed with the Medical Monitor on a case by case basis 
• Use of investigational drugs is not permitted 
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5.2.2 Permitted Medications – Use with Caution 
Current medications for conditions other than their metastatic melanoma are 
permitted with the exception of any medications that may have an anti-tumor effect.  
Although prohibited for study entry, systemic steroid therapy greater than 10 mg/day 
prednisone or equivalent may be initiated on study per PI discretion.  
6 
STUDY PROCEDURES 
6.1 
Screening 
The following procedures should be completed after completion of Informed Consent: 
• Medical history including current medications 
• Physical Exam including Height, Weight 
• Vital signs - Pulse, Respirations, Blood Pressure and Temperature 
• Evaluation and measurement of all skin and palpable lesions 
• Slit Lamp Eye exam (noting in detail, the exact size and location of any lesions) 
• 
EKG  
 
• 
Cardiac evaluation (stress thallium) for all patients. Echocardiogram or 
MUGA) for patients ≥ 60 years or patients who have a history of ischemic 
heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias.  Stress thallium must show normal LVEF and unimpaired 
wall movement 
 
• Pulmonary Function tests if indicated (ie: patients with a prolonged history of 
smoking (20 packs/year))   
• CT Exam 
• Chest (include neck there is prior or suspected neck disease) 
• Abdomen 
• Pelvis 
• MRI of brain 
• Blood and Urine Tests 
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• Hematology - CBC with Differential 
• Chemistry - Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel (to include TSH and free 
T4) 
• Serum pregnancy test for all women of child bearing potential 
• HIV antibody titer, HbsAG determination (HSV-1 IgG and HSV-2 
IgG), CMV antigen assay ,Anti HCV, Anti CMV antibody titer, HSV 
serology and EBV panel (VCA-IgM, VCA-IgG, EA-D IgG, EBNA, 
IgG) (may be within previous 3 months as of enrollment) 
• HLA typing (to be shipped to central lab.  Refer to central lab 
manual for details) 
• Urinalysis (complete urine culture if indicated) 
• Calculate Creatinine Clearance using Cockcroft-Gault formula 
• ECOG performance status evaluation 
• Colonoscopy, with biopsy, (required in patients who previously have had 
documented Grade 2 or greater colitis or diarrhea due to prior receipt of 
ipilimumab, tremelimumab, anti-PD1 or anti PD-L1 antibodies) 
• No symptoms and negative biopsies post treatment are required for patient to 
continue if patient had experienced immune-related colitis as above. 
6.2 
Enrollment and Tumor Resection  
Following confirmation of patient eligibility, the medical monitor, or designee, will 
either approve or not approve patient for enrollment into the clinical trial.   
If enrolled, tumor resection will take place.  The date of tumor resection is expected to 
occur approximately 44 days prior to the TIL infusion (Day 0) and is dependent on the 
rate of cell growth at the central TIL manufacturing facility.  The following procedures 
should be completed during this visit. 
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• Verification of all ongoing medications 
• ECOG performance status evaluation 
• Obtain blood for Immune monitoring (50 mL of blood to be obtained.  Refer to 
lab manual) 
• Tumor Harvest  
• Six paraffin embedded slides created from the tumor resection for biomarker 
analyses.   
6.2.1 Tumor Harvest and Processing Procedure 
A detailed Tumor Procurement Manual will be provided to each clinical site and 
training will be performed on the procedures for collecting and shipping of the tumor to 
the TIL Manufacturing Facility.  
Tumors will be harvested at the investigational centers participating in the trial 
according to their respective institutional protocols for sterile harvest for TIL 
preparation.  
The tumor (minimum 1.5 cm in diameter) will be surgically resected from the patient.  
The resected tumor sample will be handled aseptically at all times.  Care will be taken 
to keep the tumor hydrated by adding Hank’s Balanced Salt Solution (HBSS) to the 
tissue, as needed, to keep it hydrated through drop-wise addition. Using sterile 
tweezers and a scalpel or other suitable sterile instruments, the tumor is trimmed to 
remove extraneous non-tumor tissue by a trained surgeon or pathologist or otherwise 
qualified personnel. Using sterile forceps the trimmed tumor is placed into a sterile, 
previously sealed and unopened sterile 100 mL bottle of HypoThermosol®.  The lid 
should be screwed on tightly. The bottle containing the tumor will be placed in a 
plastic sealable bag secondary container containing absorbent tissue or paper towels.  
This secondary container is placed in an activated NanoCool™ shipper adjacent to a 
TempTale® 4 temperature monitor.  The NanoCool™ shipper is then closed and 
packaged as instructed in the Tumor Procurement Manual.  The package will be 
shipped overnight to the central TIL manufacturing facility).  The NanoCool™ shipper 
will be supplied to the site with address labels affixed for shipment to the 
manufacturing facility as well as all appropriate labels for shipping. 
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Further details and additional instructions are available in the Tumor Procurement 
Manual. 
 
 
 
6.2.2 Biomarker Collection and Processing 
 
A total of 50 mL of blood will be collected from the patient for biomarker analysis 
utilizing vacutainer blood collection vials.  Refer to the study Lab Manual for the 
complete procedure details.    
6.3 
Day -14 
The following procedures should be completed during this visit, which is 
approximately 2 weeks prior to the treatment date: 
• Physical Exam including Weight 
• Vital signs - Pulse, Respirations, Blood Pressure and Temperature 
• Evaluation and measurement of all skin and palpable lesions 
• Verification of all ongoing medications 
• EKG  
LN-144 is an autologous product which is procured and delivered 
by means which have more in common with autologous blood 
product delivery than those of traditional drug production.  It is 
imperative that only the patient’s own (autologous) study treatment (LN-
144) be administered to the same individual patient. For these reasons, 
the patient specimen must be procured and handled according to a strict 
protocol to ensure optimal quality of the specimen and minimum 
transport time to and from the processing facility, as well as to ensure 
the unique identification of the specimen at all times including injection 
back into the patient. 
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• 
Cardiac evaluation (stress thallium) for all patients.  Echocardiogram or MUGA) 
for patients ≥ 60 years or patients who have a history of ischemic heart disease, 
chest pain, or clinically significant atrial and/or ventricular arrhythmias.  Stress 
thallium must show normal LVEF and unimpaired wall movement 
 
• Pulmonary Function tests if indicated (ie: patients with a prolonged history of 
smoking (20 pack/yr) 
• CT Exam 
• Chest (include neck there is prior or suspected neck disease) 
• Abdomen 
• Pelvis 
• MRI- Brain in patients who had brain abnormalities on screening exam 
• Blood and Urine Tests 
• Hematology - CBC with Differential 
• Chemistry - Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free T4) 
• Serum pregnancy test for all women of child bearing potential 
• Urinalysis (complete urine culture if indicated) 
• ECOG performance status evaluation 
6.4 
Day -7  
Prior to the start of lymphodepletion, verification of successful TIL production and 
expansion will be confirmed.  Successful production and expansion will be evidenced 
by expansion to at least 50 fold over original cells. 
• Physical Exam including Weight (calculate BSA using DuBois formula and BMI) 
• Verification of all ongoing medications 
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• ECOG performance status evaluation 
• Vital signs - Pulse, Respirations, Blood Pressure and Temperature 
• Blood and Urine Tests (to be drawn prior to cyclophosphamide administration) 
• Hematology - CBC with Differential 
• Chemistry - Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free 
T4) 
• Urinalysis (complete Urine culture if indicated) 
• CMV antigen assay, as clinically indicated 
• Obtain blood for Immune monitoring (50 mL of blood to be obtained.  Refer to 
lab manual) 
• Administration of the following medications: 
• Cyclophosphamide 60 mg/kg IV in 250 mL D5W – infuse at a rate 
of 15 mg/kg over 2hr. (If the patient is obese (BMI > 35) drug 
dosage will be calculated using practical weight as described in 
Appendix 3.) 
• Mesna - Begin mesna infusion at a rate of 3 mg/kg/hour 
intravenously diluted in a suitable diluent (see pharmaceutical 
section) over 23 hours after each cyclophosphamide dose. 
• 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 
eight hours X 3 days) will be given for nausea. (If the patient is 
obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Appendix 3). 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
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6.5 
Day -6 
The following procedures should be performed: 
• Physical Exam including Weight (calculate BSA using DuBois formula and BMI) 
• Verification of all ongoing medications 
• Vital signs - Pulse, Respirations, Blood Pressure and Temperature 
• Blood and Urine Tests (to be drawn prior to cyclophosphamide administration) 
• Hematology - CBC with Differential 
• Chemistry - Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free 
T4) 
• CMV antigen assay, as clinically indicated 
• Urinalysis (complete urine culture if indicated) 
• Administration of the following medications 
• Cyclophosphamide 60 mg/kg IV in 250 mL D5W – infuse at a rate 
of 15 mg/kg over 2hr. (If the patient is obese (BMI > 35) drug 
dosage will be calculated using practical weight as described in 
Appendix 3.) 
• Mesna - Begin mesna infusion at a rate of 3 mg/kg/hour 
intravenously diluted in a suitable diluent (see pharmaceutical 
section) over 23 hours after each cyclophosphamide dose. 
• 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 
eight hours X 3 days) will be given for nausea. (If the patient is 
obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Appendix 3). 
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• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
6.6 
Day -5 to Day -1 
The following procedures should be performed: 
• Physical Exam including Weight (calculate BSA using DuBois formula and BMI) 
• Verification of all ongoing medications 
• Vital signs - Pulse, Respirations, Blood Pressure and Temperature 
• Blood and Urine Tests (to be drawn prior to fludarabine administration) 
• Hematology - CBC with Differential 
• Chemistry - Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel on days -4 and -1(to include 
TSH and free T4) 
• CMV antigen assay, as clinically indicated 
• Urinalysis (complete urine culture if indicated) 
• The following medication should be administered: 
• Fludarabine 25mg/ m2 to be given IV over approximately 30 
minutes once daily each day. 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
6.7 
Day 0  (+2 days) 
Day 0 is the day of LN-144 infusion.   
Upon completion of the manufacturing process the product will be labeled with a 
patient specific label.  A certificate of authenticity verifying the result of the release 
testing and the accuracy of the labels will be issued.  The product will then be 
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released for shipment from the manufacturing facility. The product will be shipped 
overnight by courier to the clinical site pharmacy in a NanoCool™ shipper validated to 
maintain a product temperature of 2-8oC. The product temperature will be 
continuously monitored by a TempTale 4™ which will be placed in the container in 
contact with the product. 
The product will be received by the appropriate clinical pharmacy for the particular 
patient.  After verification and labeling at the pharmacy, the product will be returned to 
the NanoCool™ shipper to maintain temperature as the product is transferred to the 
patient bedside. Upon receipt by the infusing physician and double verification for 
identity the product may be removed from the NanoCool™ shipper and prepared for 
infusion. 
If not already hospitalized, the patient will be admitted 1-2 days prior to planned LN-
144 administration and prepared for study drug administration. Patients will remain 
hospitalized until the completion of the IL-2 therapy, as per institutional standards. 
The following procedures should be performed: 
• Physical exam including Weight (calculate BSA using DuBois formula and BMI) 
• Verification of all ongoing medications 
• ECOG performance status evaluation 
• Vital signs- Pulse, Respirations, Blood Pressure and Temperature 
• Vital signs to be measured every 30 minutes during infusion and hourly for up 
to 4 hours post LN-144 infusion. 
• Following the completion of 4 hour post infusion assessments, routine vital 
signs monitoring (every 4-6 hours for up to approximately 24 hours post TIL 
infusion) unless a higher frequency is clinically indicated  
• The following medications will be administered: 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care 
• LN-144 Infusion:  Between 1.5 x 109 and 150 X 109 autologous TIL (LN-144) 
will be administered intravenously. The product will be administered (by gravity) 
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within 45 minutes. If interruption of infusion is required for medical reasons, the 
product infusion should complete within 3 hours of beginning infusion. The total 
volume to be infused will be approximately 250 mL for cell concentrations ≤ 75 
x 109 LN-144 or 500 mL for cell concentrations >75 x 109 LN-144  . Further 
details of the administration procedure will be provided in the Pharmacy 
Manual. 
6.8 
Days 1 – 4 
During these days, while patient remains hospitalized, the following procedures 
should be performed: 
• Physical Exam including weight (calculate BSA using DuBois formula and BMI) 
• Verification of all ongoing medications 
• Vital signs- Pulse, Respirations, Blood Pressure and Temperature 
• Blood and Urine Tests (to be drawn prior to the first IL-2 administration of each 
calendar day) 
• Hematology- CBC with Differential 
• Chemistry- Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free 
T4) 
• CMV antigen assay - required only on days 1 and 3 
• Urinalysis (complete Urine culture if indicated) 
• Conduct Toxicity Assessment 
• The following medications will be administered: 
• IL-2 – begin infusion on Day1: 12 - 24 hours after conclusion of 
the LN-144 infusion. IL-2 will be administered at a dose of 600,000 
IU/kg (based on total body weight). Administer by intravenous 
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infusion at a frequency not greater than every 8 hours as per 
institutional standard of care   Continue for up to a maximum of six 
doses.  IL-2 doses will be skipped if patient experiences a Grade 3 
or 4 toxicity due to IL-2 except: reversible Grade 3 toxicities 
common to IL-2 such as diarrhea, nausea, vomiting, hypotension, 
skin changes, anorexia, mucositis, dysphagia, or constitutional 
symptoms and laboratory changes as detailed in Appendix 4. 
Toxicities will be managed as outlined in Appendix 5.  If these 
toxicities can be easily reversed within 24 hours by supportive 
measures, then additional doses may be given.  If greater than 2 
doses of IL-2 are skipped, IL-2 administration will be stopped.  In 
addition, dosing may be held or stopped at the discretion of the 
treating investigator.  Refer to Appendix 5 for guidance. 
• Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days. The 
maximum filgrastim dose should not exceed 300 mcg per day. 
• Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3  
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care 
• Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
6.9 
Day 14, 28 (+/- 1 day) 
The following procedures will be performed: 
• Physical Exam including weight  
• ECOG performance status evaluation  Day 14 only 
• Verification of all ongoing medications 
• Vital signs- Pulse, Respirations, Blood Pressure and Temperature 
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• Blood and Urine Tests 
• Hematology- CBC with Differential 
• Chemistry- Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free T4) 
• Conduct Toxicity Assessment 
• Obtain blood for Immune monitoring (50 mL of blood to be obtained.  Refer to 
lab manual).  Day 14 only 
• If required, the following medications will continue to be administered 
• Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days. The 
maximum filgrastim dose should not exceed 300 mcg per day. 
• Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
• Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
6.10 
Day 42 ( +/- 3 days) 
The following procedures will be performed: 
• Physical Exam including Weight 
• Evaluation and measurement of all skin and palpable lesions 
• Verification of all ongoing medications 
• Vital signs- Pulse, Respirations, Blood Pressure and Temperature 
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• Conduct Toxicity Assessment 
• Blood and Urine Tests 
• Hematology- CBC with Differential 
• Chemistry- Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free T4) 
• CMV antigen assay, as clinically indicated 
• Obtain blood for Immune monitoring (50 mL of blood to be obtained.  Refer to 
lab manual) 
• CT Exam 
• Chest (include neck if there is prior or suspected neck disease) 
• Abdomen 
• Pelvis 
• MRI of brain 
• If required, the following medications will continue to be administered 
• Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days. The 
maximum filgrastim dose should not exceed 300 mcg per day. 
• Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
• Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
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6.11 
Day 84 ( +/- 3 days) 
The following procedures will be performed during this post treatment evaluation visit: 
• Physical Exam including Weight 
• ECOG performance status evaluation 
• Evaluation and measurement of all skin and palpable lesions 
• Verification of all ongoing medications 
• Vital signs- Pulse, Respirations, Blood Pressure and Temperature 
• Conduct Toxicity Assessment 
• Slit lamp eye exam (noting in detail, the exact size and location of any lesions) 
• Calculate Creatinine Clearance using Cockcroft-Gault formula 
• Blood and Urine Tests 
• Hematology- CBC with Differential 
• Chemistry- Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free T4) 
• CMV antigen assay, as clinically indicated 
• Obtain blood for Immune monitoring (50 mL of blood to be obtained.  Refer to 
lab manual) 
• CT Exam 
• Chest ( include neck if there is prior or suspected neck disease) 
• Abdomen 
• Pelvis 
• MRI of brain 
• If required, the following medications will continue to be administered 
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• Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days. The 
maximum filgrastim dose should not exceed 300 mcg per day. 
• Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
• Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
6.12 
Months 6 (+/- 1 week), 9 (+/- 1 week), 12 (+/- 1 week), 18 (+/- 3 weeks), and 24 (+/- 
3 weeks) 
Patients who experience stable disease, a partial response, or complete response, or 
those with unresolved toxicities noted at day 84 visit will be evaluated. The following 
procedures will be performed during these visits: 
• Physical Exam including Weight 
• ECOG performance status evaluation 
• Vital signs- Pulse, Respirations, Blood Pressure and Temperature 
• Evaluation and measurement of all skin and palpable lesions 
• Blood and Urine Tests 
• Hematology- CBC with Differential 
• Chemistry- Sodium, Potassium, Chloride, Total C02,or 
Bicarbonate, Creatinine, Glucose, BUN, Albumin, Calcium, 
Magnesium, Phosphorus, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
Total CK, Uric Acid, and thyroid panel(to include TSH and free T4) 
• CMV antigen assay , as clinically indicated 
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• Obtain blood for Immune monitoring (50 mL of blood to be obtained..  Refer to 
lab manual) Month 6 only 
• CT Exam 
• Chest ( include neck if there is prior or suspected neck disease) 
• Abdomen 
• Pelvis 
6.13 
Discontinued Patients 
Patients who discontinue during the Day 84 visit due to progressive disease, or 
unwillingness or inability to return for follow up evaluations will be followed via phone 
or email contact. The following information will be requested from the patient: 
• Summary of treatment received, including adverse events, since the previous 
contact 
• Estimation of performance status 
• Any additional imaging studies, physical exam or laboratory reports which the 
patient can provide 
• Survival status 
Patients who develop progressive disease during the follow up period, or are unwilling 
to return for follow up evaluations will be followed via phone or email contact. The 
following information will be requested from the patient: 
• Summary of treatment received, since the previous contact 
• Estimation of performance status 
• Survival status 
6.14 
Expected Toxicities and Treatment Guidelines 
6.14.1 LN-144  
Early toxicities related specifically to the infusion of the cells (those which are seen 
immediately following the cell infusion and prior to IL-2 administration are generally 
mild and include fevers, chills, headache, and malaise. Toxicities which occur 
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following administration of IL-2 but are thought to be related to the cells include 
immune mediated events such as vitiligo transient uveitis, hearing loss and vestibular 
dysfunction. (IL-2 specific toxicity is discussed in 6.14.2) The use of the non-
myeloablative regimen prior to cell administration increases the toxicity of this 
treatment as profound myelosuppression occurs in all patients. 
6.14.2  IL-2 
IL-2 administration has been associated with capillary leak syndrome (CLS) which is 
characterized by a loss of vascular tone and extravasation of plasma proteins and 
fluid into the extravascular space. CLS results in hypotension and reduced organ 
perfusion which may be severe and can result in death. CLS may be associated with 
cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, 
respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, 
renal insufficiency, edema, and mental status changes.  
IL-2 treatment is also associated with impaired neutrophil function (reduced 
chemotaxis) and with an increased risk of disseminated infection, including sepsis and 
bacterial endocarditis. Consequently, preexisting bacterial infections should be 
adequately treated prior to initiation of IL-2 therapy. Patients with indwelling central 
lines are particularly at risk for infection with gram positive microorganisms. Antibiotic 
prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated 
with a reduced incidence of staphylococcal infections. IL-2 administration should be 
withheld in patients developing moderate to severe lethargy or somnolence; continued 
administration may result in coma. 
The standard approach to the administration of high-dose IL-2 in all studies is to 
continue dosing until grade 3 or 4 events occur. The most commonly seen grade 4 
events are pulmonary and renal impairment, and mental status changes.  These 
toxicities may sometimes require intubation for protection of the patient’s airway.  It is 
important to note that although these patients require significant supportive measures 
during this period, all toxicities are reversible and the overwhelming majority of 
patients have suffered no long term sequelae following this treatment 
regimen.  However, fatal complications are possible and it is therefore only 
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appropriate to carry out this experimental treatment in the context of life threatening 
metastatic cancer. 
6.14.3 Treatment Guidelines for Toxicity Management   
Concomitant medications to control side effects of therapy will be given.  Meperidine 
(25-50 mg), or other medication per site standard of care may be given intravenously 
if severe chills develop.  Other supportive therapy shall be given as required. 
Supportive therapy includes acetaminophen (650 mg q4h), indomethacin (50-75 mg 
q6h) and ranitidine (150 mg q12h).  The investigator should use supportive therapies 
as per institutional standard of care.   Additional antiemetic therapy will be 
administered for breakthrough nausea and vomiting.  Patients shall receive supportive 
care as indicated for IL-2 toxicities as listed in Appendix 5.   
Expected toxicities with cyclophosphamide and fludarabine administration are listed in 
the package inserts (See Appendix 7 and 8 respectively). Also included in the 
package inserts is information on supportive care and management of toxicities.  
Additionally, Sections 6.5 and 6.6 provide some guidance on management of 
common adverse effects..  Treatment will be given as per investigator discretion. 
Additional guidelines for toxicity management are as below: 
6.14.4  Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation 
cephalosporin or a quinolone for fever – defined as 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. 
6.14.5  Blood Product Support  
Using daily CBCs as a guide, the patient will receive platelets and packed red blood 
cells (PRBCs) as needed.  Attempts will be made to keep hemoglobin >7.5 g/dL, and 
platelets >10,000/mm3.  All blood products will be irradiated.  Leukocyte filters will be 
utilized for all blood and platelet transfusions to decrease sensitization to transfused 
WBCs and decrease the risk of CMV infection. 
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6.14.6 Renal Toxicity 
Renal toxicity defined by rapid rise in creatinine levels or clinical symptoms is a risk. If 
patients exhibit signs or symptoms of renal toxicity, manage as per institutional 
standard of care. 
6.15 
Infection Prophylaxis 
Note: Other anti-infective agents may be substituted at the discretion of the treating 
Investigator.    
6.15.1 Pneumocystis Jiroveci Pneumonia 
All patients will receive the fixed combination of trimethoprim (TMP) and 
sulfamethoxazole [SMX] as double strength (DS) tab (DS tabs = TMP 160 mg/tab, 
and SMX 800 mg/tab) (PO) daily three times a week on non-consecutive days, 
beginning on the first Monday, Wednesday, or Friday on or after the first dose of 
chemotherapy.  
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 
receiving study treatment and continued monthly until CD4 count is above 200/mm3 
and for at least six months post chemotherapy, or as Investigator deems appropriate.
 
 
Pneumonia prophylaxis will continue for six months post chemotherapy.  If the CD4 
count is less than 200/mm3 at six months post chemotherapy, or as Investigator 
deems appropriate, prophylaxis will continue until the CD4 count is greater than 
200/mm3. 
 
6.15.2 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 hours 
if the patient is not able to take medication by mouth.  Reversible renal insufficiency 
has been reported with IV but not oral acyclovir.  Neurologic toxicity including delirium, 
tremors, coma, acute psychiatric disturbances, and abnormal EEGs has been 
reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will 
be made or the drug will be discontinued.  Acyclovir will not be used concomitantly 
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with other nucleoside analogs which interfere with DNA synthesis, e.g. ganciclovir.  In 
renal disease, the dose is adjusted as per product labeling. 
Herpes prophylaxis will continue for six months post-chemotherapy, or as long as 
Investigator deems necessary.  If the CD4 count is less than 200/mm3 at six months 
post chemotherapy, prophylaxis will continue until the CD4 count is greater than 
200/mm3. 
6.15.3 Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg (PO) 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. 
6.15.4 Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation 
cephalosporin or a quinolone for fever – defined as 38.3°C once or two temperatures 
of 38.0°C or above at least one hour apart, AND an ANC <500/mm3.  
Aminoglycosides should be avoided unless there is clear evidence of sepsis. 
Infectious disease consultation will be obtained for all patients with unexplained fever 
or any infectious complications as per institutional standard of care. 
6.15.5  Blood Product Support 
Using CBCs  as a guide, the patient will receive platelets and packed red blood cells 
(PRBCs) as needed.  Attempts will be made to keep hemoglobin >7.5 g/dL, and 
platelets >10,000/mm3.  All blood products will be irradiated.  Leukocyte filters will be 
utilized for all blood and platelet transfusions to decrease sensitization to transfused 
WBCs and decrease the risk of CMV infection 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF PATIENTS 
7.1 
Study Completion 
Patients will be considered to have completed the study if they complete the tumor 
harvest, receive chemotherapy, LN-144 and IL-2 and complete the post treatment Day 
14,  28, 42 & 84 Visits.   
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7.2 
Criteria for Early Termination from Study (Removal from Treatment)  
The Investigator will document on the appropriate eCRF page the 
reasons/circumstances for discontinuation.  A subject may be removed from further 
study drug administration for the following medical or administrative reasons:  
• Withdrawal of consent (subjects may voluntarily withdraw at any time during 
the course of the study.  Subject’s “withdrawing consent” should be carefully 
assessed to confirm the reason for withdrawal is not an AE) 
• Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, 
brain, eye, liver, colon, adrenal gland, lungs) with symptoms emerging prior to 
first IL-2 administration.  
• Grade 3 or greater allergic reaction including bronchospasm or generalized 
urticaria that does not resolve after medical management in the opinion of the 
investigator.  
• Grade 3 or greater toxicity due to IL-2 that does not decrease to Grade 2 or 
less within 96 hours of management.   
• Determination by the PI that continued treatment is not in the best interest of 
the patient. 
•  Withdrawal by patient. The patient may withdraw consent to treatment but 
continue consent for follow-up evaluations and/or survival status 
•  Disease Progression prior to receipt of study drug (TIL followed by IL-2) 
• Death 
• Study Terminated by sponsor 
•  Pregnancy 
• Subject has become ineligible for study after enrollment and prior to TIL  or IL2 
administration 
Efforts will be made to follow all subject who discontinue study drug for any reason 
(except those who withdraw consent).  Such follow-up will include all relevant 
evaluations for safety including clinical assessments and collection of laboratory study 
results as set out in this protocol.  Subjects can only be considered to have a final 
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disposition “lost to follow-up” after 3 documented attempts to contact the subject.  
 
7.3 
Criteria for Removal from Follow-Up 
Patients will be removed from follow-up in the following situations: 
• The patient voluntarily withdraws (the reason patient withdraws consent will be 
collected).   
• There is significant noncompliance with protocol required activities. 
• General or specific changes in the patient’s condition render continued 
participation the patient unacceptable for further participation in the judgment of 
the Investigator. 
• Death. 
• Lost to Follow-Up 
• Study Terminated by Sponsor 
7.4 
Study Discontinuation (Study or Site Termination) 
Conditions may arise during the study that could prompt the study to be stopped or a 
study site to be closed.  Conditions that may prompt such considerations include, but are 
not limited to, the following: 
• The discovery of unexpected, serious, or unacceptable risk to subjects enrolled 
in the study; 
• A decision on the part of the Sponsor to suspend, discontinue, or shorten the 
study; 
• Study conduct at a study site may warrant termination under conditions that 
include the following:  
• Failure of the Investigator(s) to enroll eligible subjects into the study 
• Failure of the Investigator(s) to comply with FDA or country-specific regulations  
• Submission of false information from the research facility to the Sponsor, the 
Clinical Monitor, or a regulatory authority 
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• Insufficient adherence to protocol requirements 
• A conflict of interest on the part of the Investigator, his/her institution, or site 
personnel that would negatively impact the integrity of the clinical trial 
• Institution or IRB under investigation for cause by a federal agency 
8 
STUDY DRUG INFORMATION 
Product Name:  LN-144 
Active Product Components:  Autologous, viable, tumor infiltrating lymphocytes (TIL) 
Dosage Form: Live cell suspension 
Quantitative Composition: Refer to Table 1 
 
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Table 1. 
Composition of LN-144 
Ingredient 
Unit and/or
Percentage Formula 
Function 
% v/v
Per mL
Tumor Infiltrating 
Lymphocytes 
1.5  x 109  to 150 x 109 
Active Ingredient 
Interleukin 2 
Not applicable 300 IU 
Lymphocyte growth factor 
Human Serum Albumin 
0.5 
Not applicable 
Stabilizer 
Plasma-Lyte® A 
≤50 
Not applicable 
Diluent 
HypoThermosol™ 
≥50 
Not applicable 
Transport medium 
 
Qualitative Composition:  LN-144 is a cell product of autologous tumor-infiltrating 
lymphocytes (TIL) derived from the patient's own tumor.  LN-144 is an autologous cell 
therapy for the treatment of patients with advanced melanoma.  LN-144 is a live cell 
suspension that is formulated in HypoThermosol™ transport medium, Plasma-Lyte® A 
with 1% HSA (human serum albumin) and 300 IU/mL of IL2.  The suspension volume 
will be between 250 to 500 mL.  Only one TIL cell dose is given intravenously after 
lymphodepletion chemotherapy followed by high dose IL-2 therapy 12-24 hours after 
infusion.  Each dose contains a range between 1.5 to 150 x 109 total viable 
lymphocytes. The total volume to be infused will be approximately 250 mL (300 mL 
transfer bag) for cell concentrations ≤ 75 x 109 LN-144 or 500 mL (600mL transfer 
bag) for cell concentrations >75 x 109 LN-144.  
Manufacturing Process:  The overall process of tumor shipping, TIL manufacturing, 
and TIL product shipping, and infusion was shown above in Figure 1.  The TIL product 
is manufactured ex vivo using autologous tumor as starting material.  The key 
manufacturing steps include: 
• Surgical removal of autologous metastatic tumor and shipment to 
manufacturing facility 
• Culture of small 2-3 mm (length x width x height) fragments of autologous 
tumor in IL-2 for up to three weeks to expand TIL. 
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• Harvesting and cryopreservation of TIL for further scheduling of patient and 
expansion in a rapid expansion protocol (REP) 
• REP culture for 14 days in the presence of IL-2, OKT3, and irradiated 
allogeneic MNC feeder cells 
• Harvesting and formulation of REP expanded product in transport medium and  
overnight shipment to clinical site for infusion 
Final Product Container: The live suspension of LN-144 is stored in a 300 mL blood 
transfer pack (Baxter) for cell concentrations ≤ 75 x 109 LN-144 or 600 mL blood 
transfer pack (Baxter) for cell concentrations >75 x 109 LN-144.  
Transport:  Each dose of the live suspension LN-144 will be shipped/sent by courier 
to the clinical site from the TIL Manufacturing Facility the day before administration 
using a method that is intended to support 24-hour delivery.  The live suspension 
product will be packaged in a protective bag containing absorbent padding then 
placed into an insulated container (Therapak NanoCool™ shipper), designed to 
maintain transit temperature between 2 - 8oC. A temperature monitoring device will be 
included to monitor the temperature inside the container during shipping. 
Receipt at Clinical Site and Administration:  The dose of LN-144 will be received at 
the clinical site in the pharmacy on the day of administration. Receipt is defined as the 
moment the TIL package is signed for by site personnel and released from courier’s 
custody.  After receiving, verification, and labelling with the clinical sites specific labels 
at the pharmacy, the investigational product, LN-144, will be transferred to the patient 
bedside.  The product is infused by gravity within 45 minutes. If interruption of infusion 
is required for medical reasons, the product infusion should complete within 3 hours of 
beginning infusion.  Refer to Product Administration Manual for additional details. 
9 
STUDY ASSESSMENTS 
9.1 
Efficacy Assessments 
9.1.1 Response Criteria 
Clinical response will be determined using RECIST version 1.1 with a modification to 
require confirmation of PD.  Refer to Table 2 and Table 3 for RECIST 1.1 response 
criteria definitions. 
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9.1.1.1 
Evaluation of Target Lesions1 
• Complete Response (CR):  Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have a reduction 
in short axis to <10 mm). 
• Partial Response (PR):  At least a 30% decrease in the sum of the diameter of 
target lesions taking as reference the baseline sum diameters. 
• Progression (PD):  At least a 20% increase in the sum of diameters of target 
lesions taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum diameters 
while on study. 
9.1.1.2 
Evaluation of Non-target Lesions2 
• Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
• Non-Complete Response:  Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above normal limits. 
• Progression (PD):  Unequivocal progression of existing non-target lesions. 
                                            
1 All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured during screening. A sum of the diameters  (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum diameters will be used as reference by which to characterize any 
objective tumor regression in the measurable dimension of the disease. If lymph nodes are to 
be included in the sum, only the short axis will contribute. 
 
2 All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.   
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(Note: the appearance of one or more new lesions is also considered 
progression).   
9.1.1.3 
Evaluation of Best Overall Response 
The best overall response is determined once all the data for the patient is known. 
The best overall response is the best response recorded from the start of treatment 
until disease progression/recurrence, the initiation of new anti-cancer therapy, death 
or 24 months whichever comes first.  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.   
Table 2. 
Time Point Response: Patients with Target (± Non-target) Disease 
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 3. 
Time Point Response: Patients with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
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9.1.1.4 
Confirmatory Measurement/Duration of Response 
9.1.1.4.1 Confirmation 
To be assigned a status of PD, 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 six-eight weeks. 
9.1.1.4.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are 
first met for either CR/PR 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. 
9.1.1.4.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are first met, taking as reference the smallest measurements recorded 
since the treatment started.  
10 STATISTICAL AND ANALYTICAL PLANS  
10.1 
Introduction  
The primary statistical plan of analysis is based on use of descriptive methods unless 
mentioned otherwise. Continuous data will be summarized as the number of patients 
with non-missing data (N), mean, standard deviation, median, minimum, and 
maximum values. Categorical data will be summarized as counts and their related 
percentages, where applicable. Point estimates of treatment effect will be derived 
from maximum likelihood methods. Estimation of confidence limits will use two-sided, 
95% criteria and implement exact methods. Missing data will not be imputed unless 
mentioned otherwise. For cases that inferential statistics will be calculated (e.g., p-
values), they will be used in a descriptive manner.  All data will be listed. 
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An overview of the main analysis strategy is provided in the following sections. A 
more detailed description of the analyses and reporting plan of the data will be 
provided in the Statistical Analysis Plan (SAP).  
10.2 
Analysis Populations 
Three analysis populations will be defined to summarize the data. The Intent-to-Treat 
population (ITT) will consist of all resected patients. The Safety Population is based 
on all resected patients who have been successfully infused with LN-144 followed by 
IL-2 (at least one dose). A subset of the Per Protocol dataset will be used to 
summarize the duration of overall response and is limited to those patients achieving 
a complete or partial overall response. The primary Safety dataset used for analysis is 
based on the number of patients infused with LN-144. A limited amount of safety data 
is collected at the time of resection until infusion with LN-144 followed by IL-2. These 
data will be summarized as needed, but separately from the primary Safety dataset. 
10.3 
Endpoints 
10.3.1 Primary 
Two endpoints are of primary interest. The first primary endpoint is based on 
summarizing the safety and toxicity data. Safety and toxicity will be based on the 
assessment of multiple clinical evaluations and will mainly include adverse events, 
clinical laboratory tests, vital signs, and physical examinations. The second primary 
endpoint is a feasibility measure defined as the number of patients from which LN-144 
is successfully produced (manufacture of > 1.5 x 109 viable cells) divided by the 
number of resected patients x 100%.  Patients not meeting numerator criteria for this 
definition of feasibility will be classified as failures. This is an ITT based analysis. 
10.3.2 Secondary 
Several secondary and exploratory endpoints are of interest. The first secondary 
endpoint is an additional feasibility measure and is defined as the number of patients 
successfully infused with LN-144 followed by IL-2 divided by the number of resected 
patients x 100%. Patients not meeting numerator criteria for feasibility will be 
classified as failures. This is an ITT based analysis. 
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The second endpoint is based on the assessment of anti-tumor activity by 
measurement of the best overall response and subsequent estimation of the best 
overall response (BOR) rate using RECIST 1.1 criteria. The BOR rate is derived as 
the number of patients with a complete response (CR) or partial response (PR) 
divided by the number of patients successfully infused with LN-144 followed by IL-2 
(at least one dose) x 100%. Patients failing to achieve a CR or PR among the 
denominator patient population (i.e., the PP dataset) will be classified as non-
responders. 
10.3.3 Exploratory 
The remaining endpoints are exploratory. The first set of such endpoints is used to 
evaluate additional measures of efficacy up to 24 months, including: progression-free 
survival (PFS), overall survival (OS), duration of response (overall, CR, and stable 
disease), and time to response. The definition of each of these endpoints follows. 
PFS is defined as the time (in days) from the start of IL-2 therapy to PD, relapse, or 
death due to any cause, whichever event is earlier. Patients not experiencing PD or 
having expired at the end of the follow-up period will have their event times censored 
on the last date that a valid assessment of tumor status is made. One day will be 
added to each patient’s derived event time. 
OS is defined as the time (in days) from the start of IL-2 therapy to death due to any 
cause. Patients not having expired at the end of the follow-up period will have their 
event times censored on the last date of their known survival status.  One day will be 
added to each patient’s derived event time. 
Duration of overall response is measured from the first time measurement criteria are 
met for a CR or PR, whichever response is observed first, until the first date that 
recurrent or progressive disease (PD) occurs. The time is measured in days. Patients 
not experiencing recurrent or PD prior to the end of the follow-up period will have their 
event times censored on the last date that a valid assessment of tumor status is 
made. One day will be added to each patient’s derived event time. 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 or PD is objectively documented. 
The duration of stable disease is measured from the start of the treatment until the 
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criteria for progression are first met, taking as reference the smallest measurements 
recorded since the treatment started. 
Time to response will be defined as the time (in days) from the start of IL-2 therapy 
until achievement of a CR or PR. The analysis will be limited to just those patients 
with a CR or PR; no observations will be censored in the analysis.  One day will be 
added to each patient’s derived event time. 
The second set of exploratory endpoints includes measures of immune response with 
the objective to evaluate their correlation with response, outcome, and toxicity of the 
treatment. 
10.4 
Sample Size Justification 
The sample size is driven by the need to obtain 20 patients who complete treatment; 
the number of resected patients is not the sampling target. Complete treatment is 
defined as successful infusion with LN-144 followed by IL-2This response parameter 
is assumed to be a binomial proportion, with the percentage (proportion x 100%) 
derived as the number of eligible patients divided by the number of resected patients 
x 100%. This percentage is expected to equal 60%. Based on this percentage value, 
roughly 33 patients will need to be resected in order to yield a sample size of 20 
patients who complete treatment. Two-sided 95% confidence limits estimated on a 
binomial proportion of 60% and 33 resected patients are associated with a maximum 
half width value of 16.7%: the lower confidence limit bound not to be less than 43.3%. 
Estimating the sample size in this manner yields a small oversampling for the primary 
feasibility objective since the number of patients who complete treatment is a subset 
of the number of patients that LN-144 is successfully produced (manufacture of more 
than 1.5 billion viable cells).. It is expected that at least 80% of the resected patients 
will achieve the primary study endpoint. As such, a trial accruing 33 resected patients 
to net 20 eligible patients will be associated with two-sided 95% confidence limits with 
bounds of ± 13.6% for an 80% rate: the lower bound value no less than 66.3%. It is 
assumed that percentage values < 50% for the primary feasibility endpoint are not 
desirable, and hence, should the observed rate equal or exceed 80%, a sampling of 
33 resected patients will have adequate sensitivity for the confidence bounds to 
exclude this undesired target. A smaller number of resected patients will likewise net 
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sufficient confidence limit bounds to exclude values ≤50%.These values appear 
reasonable for a study whereby an objective is to meet a pre-stated threshold in the 
number of manufactured TIL before receiving infusion with LN-144 followed by IL-2. 
A sample size of 20 patients who completed treatment is associated with acceptable 
cumulative probabilities of observing at least one Grade 3 or 4 toxicity. Assuming an 
underlying rate of observing a Grade 3 or 4 toxicity is 0.05, 0.10, or 0.15, the 
probability of observing at least 1 such toxicity in a sample of 20 patients who 
completed treatment is 0.642, 0.898, and 0.961, respectively. 
The 20 patient sample size also provides a denominator number of patients for the 
anti-tumor efficacy measurements. Since these assessments are of a secondary or 
exploratory nature, such a sample size seems reasonable. 
The upper sampling limit of patients in this study is 20 patients who completed 
treatment as previously defined. While it is estimated that about 33 resected patients 
are needed to achieve this target, an additional limit of 40 resected patients is placed 
on patient sampling.   
10.4.1 Baseline Demographic and Clinical Characteristics 
Baseline demographic and clinical (disease) characterized will be summarized 
descriptively for the ITT and Safety patient populations. Age will be derived as a 
function of the date of informed consent. 
10.4.2 Efficacy Analysis, Primary Endpoint 
The primary efficacy variable is a binomial proportion and will be summarized using 
both a point estimate and its two-sided, exact 95% confidence limits. 
10.4.3 Efficacy Analysis, Secondary Endpoints 
The first (feasibility as a function of successful infusion with LN-144) and third 
secondary efficacy (BOR rate) variables are binomial proportions and will be 
summarized using both a point estimate and its two-sided, exact 95% confidence 
limits. A separate analysis of the BOR rate will be performed for just those patients 
achieving a CR as their best overall response. 
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PFS, OS, durations of overall and complete response, and time to response are time-
to-event (i.e., survival analysis) variables subjected to right censoring (except for time 
to response). Kaplan-Meier probabilities and related summary statistics will be 
provided for the entire survival curve as well as for the following landmark times 
following the initial dose of IL-2: 6 months, 9 months, 18, months, and 24 months 
duration. The landmark analyses will be applied to just the PFS and OS data. For 
duration of response, a supportive analysis will include death as an event for patients 
not having recurrent disease or PD at the time of death. Separate analyses of 
duration of response will be performed for the durations of CR and stable disease, if 
warranted. 
Analysis methods employing graphical techniques and simple statistics (e.g., 
Spearman’s rho) will be used to explore the potential immune correlates of response, 
outcome, and toxicity of treatment. More complex methods based may be used, if 
warranted by the data. These methods will be detailed in the SAP. 
10.4.4 Safety Analysis 
The assessment of safety data will be descriptive and based on the summarization of 
treatment-emergent adverse events, serious adverse events, adverse events leading 
to discontinuation from the study, vital signs, physical examinations, and clinical 
laboratory tests. Adverse event summaries will be based on patient incidence counts 
and their related percentages; the number of events will be displayed as appropriate. 
In additional to an overall summary of adverse events, separate displays will be made 
by intensity and relationship. Certain safety data will be amenable to summary by use 
of toxicity grades, and all such analyses will evaluate the distribution of grades over 
time in addition to the worst grade observed per patient while on study. These toxicity 
grade summaries will be derived separately for each measure under consideration 
(e.g., ANCs for neutropenia; platelets for thrombocytopenia). 
A limited amount of safety data is collected at the time of resection until infusion with 
LN-144 followed by IL-2. These data will be summarized as needed, but separately 
from the primary safety analyses. 
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10.4.5 Other Planned Analyses 
No additional analyses are planned. Should analyses other than those described in 
the study protocol be performed, their details will be described in the SAP and Clinical 
Study Report, wherever applicable. 
11 CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS 
11.1 
Drugs Administered during the Study 
Please refer to the Information for Use package insert provided with all drugs used in 
this study to understand the contraindications, precautions and warning relative to a 
specific drug. 
11.2 
TIL Treatment  
Early toxicities related specifically to the infusion of the cells (those which are seen 
immediately following cell infusion and prior to IL-2 administration) are generally mild 
and include fevers, chills, headache, and malaise.  Toxicities which occur following 
administration of IL-2 but are thought to be related to the cells include immune 
mediated events such as vitiligo, transient uveitis, hearing loss and vestibular 
dysfunction. (IL-2 specific toxicity is discussed in 6.14.2).  The use of the non-
myeloablative regimen prior to cell administration increases the toxicity of this 
treatment as profound myelosuppression occurs in all patients.   
11.3 
IL-2 Administration 
See section 6.14.2 for IL-2 toxicity considerations. The standard approach to the 
administration of high-dose IL-2 in all studies is to continue dosing without putting the 
patient at risk for severe or irreversible toxicities. The most commonly seen Grade 4 
events are pulmonary and renal impairment, and mental status changes.  It is 
important to note that although these patients require significant supportive measures 
during this period, most toxicities are reversible and the overwhelming majority of 
patients have suffered no long term sequelae following this treatment regimen.  
However, fatal complications are possible and it is therefore only appropriate to carry 
out this experimental treatment in the context of life threatening metastatic cancer. 
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12 ADVERSE EVENTS 
Toxicities will be recorded as AEs and SAEs in the patient’s source documents and 
on the Adverse Event eCRF and must be graded using the NCI’s CTCAE v4.03 dated 
June 14, 2010. Safety will be assessed in all patients after enrollment in the study 
through the day 84 assessment.   
12.1 
Definitions 
Adverse Event 
An AE is defined as any untoward medical occurrence that occurs during a clinical 
investigation regardless of causal relationship with the investigational product.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease assessed in eligible patients after enrollment 
in the study. 
Events meeting the definition of an AE include: 
• Adverse event temporally associated with the use of any of the study drugs or 
TIL treatment whether or not considered related to the use of any of the study 
drugs or TIL treatment. 
• Any abnormal laboratory test results (e.g. hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., EKGs, radiological scans, vital 
signs measurements), that worsen from baseline, and are felt to be clinically 
significant in the medical and scientific judgment of the Investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after investigational product 
administration. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction with 
investigational product. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication. 
Events that do not meet the definition of an AE include: 
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• Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the patient’s condition.  
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
During clinical trials, AEs can be spontaneously reported or elicited during open-
ended questioning, examination, or evaluation of a patient.   
Serious Adverse Event 
An AE is considered ‘serious” if, in the view of either the Investigator or the Sponsor, it 
results in any of the following outcomes:  
• Death 
• Is Life Threatening 
• Inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not directly result in death, be life-threatening, or 
require hospitalization may be considered serious when, based on Investigator 
decision, they may jeopardize the patient and may require intervention to prevent one 
of the above outcomes as listed in this definition. 
Hospitalization including admission to a telemetry unit or ICU specifically for 
administration of study treatment is not considered a serious adverse event.  
 
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Any pregnancy that occurs from enrollment through the day 84 assessment must be 
reported to the Sponsor or their representative.  The pregnancy must be followed up 
until discharge following delivery or premature termination to determine outcome and 
status of mother and child.  Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE.  Spontaneous abortions must be 
reported as an SAE.  Any SAE occurring in association with a pregnancy, brought to 
the Investigator’s attention after the patient has completed the study and considered 
by the Investigator as possibly related to the investigational product, must be promptly 
reported to the Sponsor or their representative.  In addition, the Investigator must 
attempt to collect pregnancy information on any female partners of male study 
patients who become pregnant while the patient is enrolled in the study. Pregnancy 
information must be reported to the Sponsor or their representative. 
12.2 
Reporting Procedures for Adverse Events 
12.2.1  All Adverse Events 
All AEs occurring after enrollment in the study and either observed by the Investigator 
or reported by the patient (whether or not attributed to the use of IL-2 or TIL 
treatment), will be reported on the eCRF.    Monitoring and reporting AEs will be 
conducted through the last on-study visit (i.e., the 12-Week Post Treatment 
Evaluation Visit).   
Medically significant AEs considered related to the investigational product by the 
Investigator or the Sponsor will be followed until resolved or resolved with sequelae.  
The Investigator shall categorize the cause of the AE as chemotherapy, TIL, IL-2 or 
other and must assign the following attributes:  description; dates of onset and 
resolution; severity; assessment of relatedness to investigational product, and action 
taken.  The Investigator may be asked to provide follow-up information. 
If any patient should die during the trial or within 12 weeks of completing or stopping 
study treatment, the Investigator will inform the Sponsor as soon as possible.  (Note: 
Death due to disease progression should not be reported as a SAE unless it is 
deemed to be related to the use of study treatment.)  The cause of death should be 
recorded in detail on the SAE Report Form. 
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Each site will be responsible for reporting SAEs occurring at the site to the applicable 
IRB per the IRB’s reporting guidelines.  Sites that are required to utilize a local IRB 
will be responsible for their own local IRB submissions.   
It will be left to the Investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the patient’s removal from the study treatment.  A patient may also 
voluntarily discontinue treatment due to what he or she perceives as an intolerable 
AE. This should be captured in the eCRF.    If either of these occurs, the patient must 
undergo an end-of-treatment visit and be given appropriate care under medical 
supervision until symptoms cease or the condition becomes stable and returns for a 
safety Follow-up visit.  If the patient was permanently removed from the study or 
investigational product due to an SAE, this information must be included in either the 
initial or follow-up SAE Report Form and in the eCRF. 
12.2.2 Relationship to Study Drug 
The following categories and definitions of causal relationship to study drug should be 
considered: 
• Definite There is a known causal relationship between the study drug and the 
AE/SAE.  The event responds to withdrawal of study drug (de-challenge), and 
recurs with re-challenge when clinically feasible. (>95% certainty of 
relatedness). 
• Probable: There is reasonable causal relationship between the study drug and 
the AE/SAE.  The event responds to de-challenge. Re-challenge is not 
required. (65%-95% probability of relatedness). 
• Possible: There is reasonable causal relationship between the study drug and 
the AE/ SAE.  De-challenge information is lacking or unclear. (35%-65% 
probability of relatedness). 
• Not likely: There is temporal relationship to study drug administration, but there 
is not a reasonable causal relationship between the study drug and the 
AE/SAE. (5-35% probability of relatedness). 
• Not related: There is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is known causal 
relationship between the AE/SAE and another drug, concurrent disease, or 
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other circumstance. (<5% chance of relatedness). 
12.2.3  Severity 
The severity of an event describes the degree of impact and/or the need for medical 
care necessary to treat an event.   
AE grading will be defined by the CTCAE v 4.03.  In the event the CTCAE v 4.03 does 
not apply, the severity descriptions below will be used. 
Mild: 
Asymptomatic; clinical or diagnostic observations only; intervention 
not indicated 
Moderate:  
Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate activities of daily life 
Severe:  
Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization may be required; 
disabling; limiting activities of daily life 
Life-threatening: Urgent intervention is required 
12.2.4 Serious Adverse Events 
Investigator Reporting to Sponsor: 
All SAEs, regardless of relationship to study treatment, must be collected beginning 
after informed consent until six weeks after completion or discontinuation of treatment.  
In addition, the Investigator must notify the Sponsor of any SAE that may occur after 
this time period which (s)he believes to be certainly, probably, or possibly related 
study treatment.   
SAE terminology and severity grading will be based on the NCI’s CTCAE v4.03 
guidelines. 
All SAEs that occur during the course of the investigation must be reported by the 
Investigator to the Sponsor or designee within 24 hours of learning of the event.  The 
initial notification should be as complete as is possible with the information available 
and include the Investigator’s assessment of whether there is a reasonable possibility 
that the study drug caused the event.   
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SAE reports will be reported to Drug Safety Solutions, Inc. via 
 
 
Reporting to Regulatory Agencies and Institutional Review Boards (IRBs): 
In the event of a serious adverse event, the Sponsor, or their designee, will notify the 
appropriate regulatory authorities and all appropriate parties as per the regulations.  In 
addition, the Sponsor must submit expedited reports of an increased rate of 
occurrence of serious adverse events over that listed in the protocol or Investigational 
Brochure. Sponsor will notify participating sites of any serious adverse events which 
occur during trial.  
12.2.5 Data Safety Monitoring Board  
An independent DSMB will monitor patient safety during the study.  The DSMB’s roles, 
responsibilities, and conduct are described in an independent charter. 
13 ADMINISTRATIVE REQUIREMENTS 
13.1 
Protocol Modifications 
Neither the Investigator nor Sponsor will modify this protocol without obtaining the 
concurrence of the other.  All protocol amendments must be issued by the Sponsor, 
signed and dated by the Investigator, and should not be implemented without prior 
IRB approval, except where necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the trial 
(e.g., change in monitor[s], change of telephone number[s]).  Responsibilities for 
reporting protocol amendments to any Regulatory Authority (if applicable) and/or IRB 
are further described in the Ethical Aspects section of the protocol. 
In situations requiring a departure from the protocol, the Investigator or other 
physician in attendance will contact the site manager or other appropriate Sponsor 
representative by fax or telephone (see the Contact Information page).  If possible, 
this contact will be made before implementing any departure from protocol.  In all 
cases, contact with the Sponsor must be made as soon as possible in order to 
discuss the situation and agree on an appropriate course of action. The eCRF and 
source documents will describe any departure from the protocol and the 
circumstances requiring it. 
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13.2 
Regulatory Documentation 
 
Documents that must be provided to the Sponsor prior to study drug shipment are as 
follows: 
• Up-to-date curriculum vitae for each Investigator.  
• Signed and dated Investigator Agreement.  
• Applicable local regulatory documentation (e.g., FDA 1572 Form). 
• A copy of the formal written notification to the Investigator regarding approval of 
the protocol by an IEC/IRB that is in compliance with regulatory guidelines. The 
written notification is to be signed by the chairman or authorized designee and 
must identify the specific protocol.  In cases where an IEC/IRB member has a 
known conflict of interest, abstention of that individual from voting should be 
documented; an Investigator may be a member of the IEC/IRB, but may not 
vote on any research in which he or she is involved. 
• Name and address of the IRB with a statement that it is organized and 
operates according to GCP and the applicable laws and regulations, and a 
current list of the IRB members. If accompanied by a letter of explanation from 
the IRB, a general statement may be substituted for this list. 
• A copy of the IRB approved informed consent and other adjunctive materials 
(e.g., advertising) to be used in the study, including written documentation of 
IEC approval of these items. 
• Name and address of any local laboratory conducting tests for the study, a 
dated copy of the laboratory reference values for tests to be performed during 
the study and a copy of the certification or other documentation establishing 
adequacy of the facility. 
• Required financial agreement. 
In addition to the documents required prior to the study, other documentation may be 
required during the course of the study. 
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13.3 
Patient Identification Register 
The Investigator agrees to complete a patient identification register, which will be 
used for the purpose of long-term follow-up, if needed. This form will be treated as 
confidential, and will be filed by the Investigator in the Trial Center File.  Otherwise, all 
reports and communications relating to the study will identify patients by initials and 
assigned number only. 
13.4 
Record Retention 
In compliance with the ICH/GCP guidelines the Investigator/institution will be 
responsible for all information in the eCRF and will maintain the source documents 
that support the data collected from each patient, and all trial documents as specified 
in Essential Documents for the Conduct of a Clinical Trial and as specified by the 
applicable regulatory requirement(s). The Investigator/Institution will take measures to 
prevent accidental or premature destruction of these documents.  Essential 
documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the 
Sponsor to inform the Investigator/institution as to when these documents no longer 
need to be retained. If the responsible Investigator retires, relocates, or for other 
reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person who will accept the responsibility.  The Sponsor must be 
notified in writing of the name and address of the new custodian. 
13.5 
 Data Quality Assurance  
Steps to be taken to assure the accuracy and reliability of data include; the selection 
of qualified Investigators and appropriate study centers, review of protocol procedures 
with the Investigator and associated personnel prior to the study, periodic monitoring 
visits by the Sponsor and direct transmission of clinical laboratory data from a central 
laboratory into the database.  Electronic CRFs will be reviewed for accuracy and 
completeness by Clinical Research Monitors during on- site monitoring visits and after 
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their return from the site, and any discrepancies will be resolved with the Investigator 
or designees, as appropriate. The data will be verified for accuracy. 
Agreements made by the Sponsor with the Investigator/Institution and any other 
parties involved in the clinical trial will be in writing as a separate agreement. On-Site 
Audits 
Representatives of the Sponsor’s Clinical Quality Assurance department may visit the 
site to carry out an audit of the study in compliance with regulatory guidelines and 
company policy.  Such audits will require access to all study records, including source 
documents, for inspection and comparison with the eCRFs.  Patient privacy must, 
however, be respected.  Sufficient prior notice will be provided to allow the 
Investigator to prepare properly for the audit. 
Similar auditing procedures may also be conducted by agents of any regulatory body 
reviewing the results of this study in support of a Licensing Application. The 
Investigator should immediately notify the Sponsor if they have been contacted by a 
regulatory agency concerning an upcoming inspection. 
13.6 
Data Handling and Recordkeeping 
13.6.1   Electronic Data 
When using electronic data handling, the Sponsor or their designee will ensure that 
systems comply with 21CFR Part 11 requirements.  Documentation regarding the 
electronic data systems used in this protocol is located in the study-specific plans or 
SOPS for that particular task. 
13.6.2   Electronic Case Report Form (eCRF) Completion 
Electronic data capture (EDC) will be used for this study.  The site will be suitably 
trained on the use of the eCRF and appropriate site personnel will be provided 
electronic signatures.  Data must be entered into the eCRF screens in English. The 
eCRFs are to be completed at the time of the patient's visit, with the exception of 
results of tests performed outside the Investigator's office, so that they always reflect 
the latest observations on the patients participating in the trial. 
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Data must be recorded first on a source document that can be verified before it is 
entered in the EDC system.  Completed eCRFs are to be signed off by the 
Investigator as per the data completion guidelines written for this trial.  
All eCRF corrections are to be made by the Investigator or other authorized study site 
personnel. The Investigator must authorize changes to the recorded safety and 
efficacy data. 
Completed eCRFs will be submitted according to the Sponsor's instructions, and 
reviewed by the Sponsor to determine their acceptability.  If necessary, Data 
Correction Requests will be generated for resolution by the study site. 
13.7 
Study Completion/Termination 
13.7.1 Study Completion 
The Investigator will complete the study and submit all eCRFs in satisfactory 
compliance with the protocol after study completion. Continuation of this study beyond 
this time must be agreed upon by both the Investigator and Sponsor and may be 
implemented without amendment to the protocol. 
13.7.2 Study Termination 
An initiative for center closure or trial termination can be taken at any time either by 
the Sponsor or by the Investigator, provided there is reasonable cause and sufficient 
notice is given in advance of the intended termination. Reasons for such action taken 
by the Sponsor include, but are not limited to: 
• Successful completion of the trial at the center  
• The required number of patients for the trial has been recruited  
• Failure of the Investigator to comply with the protocol, the Sponsor's 
procedures or GCP guidelines  
• Safety concerns  
• Sufficient data suggesting lack of efficacy  
• Inadequate recruitment of patients by the Investigator 
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13.8 
Monitoring 
On-site monitoring visits will be performed by the Sponsor as frequently as necessary. 
Visits are usually made at intervals of at least four to twelve weeks.  The dates of the 
visits will be recorded by the monitor in a trial center visit log to be kept at the site. 
The first post-initiation visit will usually be made as soon as possible after enrollment 
has begun.  At these visits the monitor will compare the data entered into the eCRFs 
with the hospital or clinic records (source documents). At a minimum, source 
documentation must be available to substantiate proper informed consent procedures, 
adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, administration of concomitant medication, drug receipt/dispensing/return 
records, and study drug administration information.  Specific items required as source 
documents will be reviewed with the Investigator prior to the study.  Findings from this 
review of eCRFs and source documents will be discussed with the Investigator. The 
Sponsor expects that, during monitoring visits, the Investigator (and as appropriate 
the Study Coordinator) will be available, the source documentation will be available, 
and a suitable environment will be provided for review of study-related documents. 
14 INVESTIGATOR REGULATORY OBLIGATIONS 
14.1 
Institutional Review Board 
This trial will be undertaken only after full approval of the protocol and addenda has 
been obtained from an IRB and a copy of this approval has been received by the 
Sponsor.  The IRB must be informed of all subsequent protocol amendments issued 
by the Sponsor.  Reports on, and reviews of, the trial and its progress will be 
submitted to the IRB by the Investigator at intervals stipulated in their guidelines. 
The IRB must meet all regulatory requirements governing IRBs (CFR, Title 21, Part 56). 
14.2 
Informed Consent 
Each patient (or a legally authorized representative) must give written consent (and 
sign other locally required documents) according to local requirements after the 
nature of the study has been fully explained. The consent form must be signed prior to 
performance of any study-related activity.  The consent form that is used must be 
approved both by the Sponsor and by the reviewing IRB.  The informed consent 
should be in accordance with the current revision of the Declaration of Helsinki, 
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current International Conference on Harmonization (ICH) and Good Clinical Practice 
(GCP) guidelines, and the Sponsor’s policies. 
The Investigator must explain to potential patients or their legal representatives the 
aims, methods, reasonably anticipated benefits and potential hazards of the trial, and 
any discomfort it may entail.  Patients will be informed that they are free not to 
participate in the trial and that they may withdraw consent to participate at any time.  
They will be told which alternative treatments are available if they refuse to take part 
and that such refusal will not prejudice future treatment. Finally, they will be told that 
their records may be examined by competent authorities and authorized persons but 
that personal information will be treated as strictly confidential and will not be publicly 
available. Patients must be given the opportunity to ask questions. After this 
explanation and before entry into the trial, consent should be appropriately recorded 
by means of the patient's or his/her legal representative's dated signature.  If a patient 
and his/her legal representative are unable to read, an impartial witness must be 
present during the entire informed consent discussion. The signature of the impartial 
witness will certify the patient's consent. The patient should receive a signed and 
dated copy of the informed consent. The informed consent process should be 
documented in the patient’s medical record. 
In accordance with HIPAA, the written Informed Consent Form must include a patient 
authorization to release medical information to the Sponsor or their representative 
and/or allow the Sponsor or their representative, a regulatory authority, or IRB access 
to patient’s medical information that includes all hospital records relevant to the study, 
including a patient’s medical history. 
14.3 
Declaration of Helsinki 
The study will be performed in accordance with ethical principles that have their origin 
in the Declaration of Helsinki and are consistent with ICH GCP, applicable regulatory 
requirements. 
14.4 
Patient Data Protection 
The Principal Investigator at each site and designees, employees, and agents 
involved with this study will comply with relevant state and federal laws relating to the 
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confidentiality, privacy, and security of patient’s personal health information (PHI). 
They will only create, maintain, use, or disclose any data that is generated by this 
study or other information disclosed to the Principal Investigator or their employees or 
agents during the course of the study to the Sponsor, IRB, FDA, or other authorized 
recipients as appropriate for the execution, analysis, review, and reporting of this 
study. Such information shall not be used for any other purposes and will remain 
confidential. Patient records are only to be identified by initials and patient ID 
numbers. 
14.5 
Adverse Event Reporting 
The Investigator agrees to report all AEs to the Sponsor as described in the Adverse 
Events section.  Furthermore, the Investigator is responsible for ensuring that any co-
Investigator or sub-Investigator promptly bring AEs to the attention of the Investigator.  
If applicable, the Investigator also is responsible for informing the participating 
IRB/IEC of any SAEs. 
14.6 
Investigator 
The Investigator will permit study-related monitoring, audits, IEC/IRB review, and 
regulatory inspections by providing direct access to source data and documents. The 
Investigator must notify the Sponsor when contacted by a regulatory authority 
regarding inspection of her/his study site. 
All required data will be recorded in the eCRFs in a timely manner.  All eCRF data 
must be submitted to the Sponsor throughout and at the end of the study. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, 
the Investigator must notify the Sponsor to agree upon an acceptable storage 
solution. Regulatory authorities will be notified with the appropriate documentation 
detailing the person to whom the responsibility has been transferred. 
14.7 
Final Report 
The Investigator must complete a report notifying the IRB/IEC of the conclusion of the 
clinical study.  This report should be made within 3 months of completion or 
termination of the study.   
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14.8 
Confidentiality 
Unless otherwise specified in the clinical study agreement, the following process shall 
occur: The Investigator must assure that patients’ anonymity will be maintained and 
that their identities are protected from unauthorized parties.  In the eCRFs or other 
documents submitted to the Sponsor, patients should not be identified by their names, 
but by an identification code. The Investigator should keep a site enrollment log 
showing codes, names, and addresses.  Documents not for submission to the 
Sponsor (e.g., patients’ written consent forms) should be maintained by the 
Investigator in strict confidence, in accordance with all applicable local and national 
regulations.  All information provided to the Investigator prior to the study, as well as 
all data developed during the study, is confidential and remains the property of the 
Sponsor.  The Investigator agrees that no information based on the conduct of this 
study (including the protocol, the data resulting from this study, or the fact that this 
study is/was conducted) will be released without prior written consent of the Sponsor 
unless this requirement is superseded by local or national regulations. 
14.9 
Publications 
The Sponsor will be responsible for determining when the study results should be 
published. The Sponsor will work jointly with the Investigators to publish information. 
The Investigator shall not submit a publication to journals or professional societies 
without the prior written approval of the Sponsor.  
 
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Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated 
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Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond 
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Kaufman H, Lutzky J, Clark J, et al. Safety and efficacy of ipilimumab in 
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Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 
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Hodi FS. Advanced melanoma patients treated with ipilimumab live as long as 10 
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Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-
term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates 
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Hamid O, Robert C, Daud A, et al. Safety and tumor responses with 
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134-144. 
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Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 
antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-2465. 
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34. 
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selectively accumulate in metastatic melanoma lesions. Blood 2008;112:4953-
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with metastatic melanoma. Curr Opin Immunol 2009;21:233-240. 
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47. 
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autoimmunity in patients after clonal repopulation with antitumor lymphocytes. 
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of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-
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Besser MJ, Shapira-Frommer R, Treves AJ, et al. Clinical responses in a phase 
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Ullenhag GJ, Sadeghi AM, Carlsson B, et al. Adoptive T-cell therapy for 
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1. 
Physical examination (PE) will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, 
respiratory system, skin, psychiatric (mental status), general nutrition. PE conducted during follow-up will be symptom directed.  Post TIL infusion 
PE should occur three times a week until discharge. 
2. 
List only medications that are NOT part of the tumor harvest procedure. 
3. 
Vital signs will include heart rate, respiratory rate, blood pressure, and temperature.  On Day 0 (TIL infusion), vital signs will be monitored every 
30 minutes during infusion then hourly (+/-15 minutes) for four hours and then routinely (every four to six hours), unless otherwise clinically 
indicated, for up to approximately 24 hours post TIL infusion. 
4. 
CMV assay if clinically indicated 
5. 
Cardiac evaluation (stress thallium) for all patients (per current package insert for IL2).  Echocardiogram or MUGA for patients ≥ 60 years or 
patients who have a history of ischemic heart disease, chest pain, or clinical significant atrial and/or ventricular arrhythmias.  Stress thallium must 
show normal LVEF and unimpaired wall movement. 
6. 
Required for Screening and Pre-Study, then imaging as clinically indicated.  If screening image shows abnormalities, obtain at day -14.   Include 
neck there is prior or suspected neck disease 
7. 
Chem 20: [Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Magnesium total (Mg), Phosphorus, Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, 
Total CK, Uric Acid]  
8. 
Thyroid panel: TSH and Free T4.  Obtain only as clinically indicated beginning at Day 84/EOS and during Follow-up. 
9. 
Complete blood count with differential 
10. With culture, if indicated 
11. Calculate creatinine clearance using Cockcroft-Gault calculation 
12. HLA typing to be sent to central laboratory.   
13. Serum pregnancy test 
14. Pulmonary evaluation for patients with a prolonged history of cigarette smoking (ie: 20 packs/year of smoking in the last two years)  
15. Only required for documented Grades 2 or greater diarrhea or colitis as a result of previously received ipilimumab, tremelimumab, or anti-PD1 or 
anti-PD-L1 antibodies. As per standard clinical age-appropriate screening 
16. One to two days after the last dose of agent in the preparative regimen 
17. Initiate within approximately 12-24 hours after TIL infusion and continue every eight hours for up to six doses 
18. Continue until neutrophils count > 1000/mm3 X 3 days.   
19. The TMP/SMX DS schedule should be adjusted to QD three times per week (Monday, Wednesday, Friday) and continue for at least six (6) 
months and until CD4 > 200/mm3 
20. Continue until ANC > 1000/mm3   
21. In patients positive for HSV continue until CD4 > 200/mm3     
22. 50 mL of blood drawn using vacutainers (refer to the Lab Manual) 
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APPENDIX 2: ECOG SCALE 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead. 
Adapted from Oken MM, Creech RH, Tormey DC, et al.  Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol.  1982;5:649-655. 
 
 
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APPENDIX 3: PRACTICAL WEIGHT 
Modification of Dose Calculations* in Patients whose BMI is > 35 
 Unless otherwise specified in this protocol, actual body weight is used for dose calculations 
of treatment agents.   In patients who are determined to be obese (BMI > 35), the practical 
weight (see 3 below) will be used. 
 1.  BMI Determination: 
 BMI = weight (kg) / [height (m)]2 
 2.  Calculation of ideal body weight 
 Male = 50 kg + 2.3 (number of inches over 60 inches) 
Example:  ideal body weight of 5’10’’ male 
     50 + 2.3 (10) = 73 kg 
 Female = 45.5 kg + 2.3 (number of inches over 60 inches) 
Example:  ideal body weight of 5’3’’ female 
     45.5 + 2.3 (3) = 57 kg 
 3.  Calculation of “practical weight” 
 Calculate the average of the actual and the ideal body weights.  This is the practical weight 
to be used in calculating the doses of chemotherapy and associated agents designated in 
the protocol. 
 *Practical weight will NOT be used in the calculation of dose for IL-2. 
 
 
 
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APPENDIX 4: HIGH-DOSE IL-2 TOXICITIES 
Adverse Events occurrence in > 10% of patients treated with IL-2 (n=525) 
  
Body System/Events 
% patients 
Body System/Events 
% 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 
Enlarged Abdomen 
10 
Hypomagnesemia 
12 
Cardiovascular System 
Hypocalcemia 
11 
Hypotension 
71 
Alkaline Phosphatase Increase
10 
Tachycardia 
23 
Nervous System 
Vasodilation 
13 
Confusion 
34 
Supraventricular Tachycardia 
12 
Somnolence 
22 
Cardiovascular disordera 
11 
Anxiety 
12 
Arrhythmia 
10 
Dizziness 
11 
Digestive System 
Respiratory System 
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 
Hematologic and Lymphatic 
Rash 
42 
Thrombocytopenia 
37 
Pruritus 
24 
Anemia 
29 
Exfoliative dermatitis 
18 
Leukopenia 
16 
Urogenital System 
  
  
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. 
Source: Proleukin® Prescribing Information – June 2007 
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APPENDIX 5: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT 
 
Expected 
toxicity 
Expected 
grade 
Supportive Measures
suggested 
Stop Cycle*
 
Stop Treatment 
** 
Chills 
3 
IV Meperidine 25-50 mg, IV 
q1h, prn, 
No 
No 
Fever 
3 
Acetaminophen 650 mg, po, 
q4h; Indomethacin 50-75 
mg, po, q8h 
No 
No 
Pruritus 
3 
Hydroxyzine HCl 10-20 mg 
po q6h, prn; 
Diphenhydramine HCl 25-50 
mg, po, q4h, prn 
No 
No 
Nausea/ 
Vomiting/ 
Anorexia 
3 
Ondansetron 10 mg, IV, q8h, 
prn; Granisetron 0.01 mg/kg 
IV daily prn; Droperidol 1 
mg, IV q4-6h, prn; 
Prochlorperazine 25 mg q4h 
p.r., 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 
µg, po, q3h, prn; codeine 
sulfate 30-60 mg, po, q4h, 
prn 
If uncontrolled after 
24 hours despite all 
supportive 
measures 
No 
Malaise 
3 or 4 
Bedrest interspersed with 
activity 
If other toxicities 
occur 
simultaneously 
No 
Hyperbilirubine
mia 
3 or 4 
Observation 
If other toxicities 
occur 
simultaneously 
No 
Anemia  
3 or 4 
Transfusion with PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytope
nia 
3 or 4 
Transfusion with platelets 
If uncontrolled 
despite all 
supportive 
measures 
No 
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Expected 
toxicity 
Expected 
grade 
Supportive Measures
suggested 
Stop Cycle*
 
Stop Treatment 
** 
Edema/Weight 
gain 
3  
Diuretics prn 
No 
No 
Hypotension 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled 
despite all 
supportive 
measures 
No 
Dyspnea 
3 or 4 
Oxygen or ventilatory 
support 
If requires 
ventilatory support 
No 
Oliguria 
3 or 4 
Fluid boluses or dopamine at 
renal doses 
If uncontrolled 
despite all 
supportive 
measures 
No 
Increased 
creatinine 
3 or 4 
Observation 
Yes (Grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 
Pleural effusion  
3 
Thoracentesis 
If uncontrolled 
despite all 
supportive 
measures 
No 
Bowel 
perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion therapy 
If uncontrolled 
despite all 
supportive 
measures 
No 
Elevated 
Troponin levels 
3 or 4 
Observation 
Yes 
If changes in LV 
function have 
not improved to 
baseline by next 
dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
Elevated 
3 or 4 
Observation 
For Grade 4 
without liver 
If changes have 
not improved to 
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Expected 
toxicity 
Expected 
grade 
Supportive Measures
suggested 
Stop Cycle*
 
Stop Treatment 
** 
transaminases 
metastases 
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 re-treatment. 
 
 
 
 
 
 
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APPENDIX 6: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 5x7.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 7: CYCLOPHOSPHAMIDE PACKAGE INSERT
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APPENDIX 8: FLUDARABINE PACKAGE INSERT
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CONFIDENTIAL 
Page 123 of 125 
1149 of 1468

Lion Biotechnologies, Inc. 
 
LN-144 
Protocol C-144-01 
 
Version 3.0 
 
 
CONFIDENTIAL 
Page 124 of 125 
1150 of 1468

Lion Biotechnologies, Inc. 
 
LN-144 
Protocol C-144-01 
 
Version 3.0 
 
 
CONFIDENTIAL 
Page 125 of 125 
 
1151 of 1468