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.

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Page 1 of 123 
CLINICAL PROTOCOL 
A Phase 2, Multicenter, 3-Cohort Study to Assess the Safety and 
Efficacy of Autologous Tumor Infiltrating Lymphocytes (LN-144) 
for Treatment of Patients with Metastatic Melanoma  
PROTOCOL 
NUMBER:   
C-144-01
SPONSOR: 
Lion Biotechnologies, Inc. 
999 Skyway Rd, Suite 150 
San Carlos, CA 94070 
PROTOCOL 
VERSION: 
Final Version 5.0 (Incorporating 
Amendments 1-4) 
PROTOCOL 
DATE: 
4 February 2017 
IND NUMBER: 
16317 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of 
the Sponsor or their representatives, 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, 3-Cohort Study to Assess the 
Safety and Efficacy of Autologous Tumor Infiltrating 
Lymphocytes (LN-144) for Treatment of Patients with 
Metastatic Melanoma  
Protocol Number:  
C-144-01 
Sponsor: 
Lion Biotechnologies, Inc. 
Version / Date of Protocol: 
FINAL Version 5.0 (Incorporating Amendments 1-4), 
4 February 2017 
 
 
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, 3-Cohort Study to Assess the Safety and 
Efficacy of Autologous Tumor Infiltrating Lymphocytes (LN-144) for 
Treatment of Patients with Metastatic Melanoma  
Study Type: 
Phase 2  
Indication: 
Treatment of patients with metastatic melanoma that have progressed 
or not responded following prior systemic therapy 
Investigational 
Agent: 
LN-144: Autologous Tumor Infiltrating Lymphocytes (TIL) derived from 
the patient’s own tumor 
Study Objectives: 
Primary Objective 
• 
To characterize the safety profile of LN-144 in patients with 
metastatic melanoma. 
Secondary Objectives 
• 
To evaluate the efficacy of LN-144 in patients with metastatic 
melanoma using the objective response rate (ORR) and complete 
response rate (CR). 
• 
To evaluate efficacy parameters of LN-144 in patients with 
metastatic melanoma such as progression-free survival (PFS), 
duration of response (DOR), and overall survival (OS). 
Exploratory Objectives 
• 
To explore the persistence of LN-144 and potential immune 
correlates of response, outcome, and toxicity of the treatment. 
• 
To assess health-related quality of life (HRQoL). 
Study Design: 
Prospective, 3-cohort interventional study evaluating adoptive cell 
therapy (ACT) with autologous TIL infusion (LN-144) followed by 
interleukin-2 (IL-2) after a nonmyeloablative chemotherapy preparative 
regimen.  
Dose and Treatment 
Schedule: 
The cell transfer therapy used in this study involves patients receiving a 
lymphocyte-depleting preparative regimen, followed by infusion of 
autologous TIL (LN-144) and administration of a regimen of IL-2 at 
600,000 IU/kg approximately every 8 hours for up to a maximum of 
6 doses, starting 10-24 hours after cell infusion. Patients will be 
evaluated for response at approximately 6 weeks (Day 42) following the 
LN-144 therapy and every 6 weeks thereafter, for up to 6 months.  
After 6 months, patients will be evaluated as noted below: 
• 
At 9 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 
Patients will receive 1 course of LN-144 treatment in cohorts 1 and 2. 
Patients may be entered into a retreatment third cohort for a second 
treatment with TIL therapy.  
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Duration of Study 
Participation: 
Screening and tumor resection/TIL harvest: up to 6 weeks  
Lymphodepletion: 1 week  
Treatment period (LN-144 + IL-2): up to 5 days 
Long term Follow-up period: up to 2 years 
Overall Survival Follow-up: up to 3 years 
Number of Study 
Centers: 
Approximately 35 clinical sites 
Number of Planned 
Patients: 
Approximately 40 patients who complete treatment (approximately 
20 patients in Cohort 1 and 20 patients in Cohort 2). Complete 
treatment is defined as successful infusion with LN-144 followed by at 
least 1 dose of IL-2. Of the completed patients, up to 10 are allowed to 
enter a third treatment cohort (Cohort 3) where they can be retreated 
with TIL therapy. 
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 1 lesion that is resectable for TIL generation. Ideally, the 
lesion must be at least 1.5 cm in diameter post-prosection and 
can be surgically removed with minimal morbidity (defined as 
any operation for which expected hospitalization is less than or 
equal to 3 days).  
b. Patients must have undergone at least 1 prior systemic 
treatment for metastatic melanoma. 
c. Patients must have either progressive disease or no response 
(i.e., no PR or CR) 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. Enrollment of patients greater than 65 years of age 
can be done after consultation with the Medical Monitor. 
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 4 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 3 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). 
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 
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antigen, and hepatitis C antibody or antigen. 
k. Patients must be EBV viral capsid antigen (VCA) IgG positive 
and/or Epstein Barr nuclear antigen (EBNA) IgG positive, and 
have no clinical evidence of active EBV infection. 
l. 
Patients must not have received systemic chemotherapy or 
immunotherapy for 2 weeks (targeted therapies) and 4 weeks 
(all other anti-cancer treatment) at the time of enrollment, and 
there must be no intention of receiving any non-protocol 
systemic anti-cancer chemotherapy or immunotherapy during 
the study 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. Palliative 
radiation therapy is permitted between biopsy and 
lymphodepletion as long as it does not involve lesions being 
followed for response. There is no specific time window post 
radiation therapy, as long as all toxicities have recovered to 
Grade 1 or less or as specified in the eligibility criteria. 
Note: Patients may have undergone minor surgical procedures 
not involving general anesthesia within 3 weeks prior to 
enrollment. 
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 
been asymptomatic for at least 6 months or had a normal 
colonoscopy post anti-PD-1/anti-PD-L1 treatment, with 
uninflamed mucosa by visual assessment. 
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. 
Main Criteria for 
Exclusion: 
 
Patients who meet any of the following criteria will be excluded from the 
study: 
a. Patients with melanoma of uveal/ocular origin 
b. Patients who have received prior cell transfer therapy, which 
included a nonmyeloablative or myeloablative chemotherapy 
regimen (not applicable for patients in the retreatment 
Cohort 3). 
c. Patients who have 3 or more active brain metastases. 
Note: Patients with 1 or 2 untreated or inadequately treated 
brain lesions, or 3 or more adequately treated brain 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 1 month. Brain metastases with 
significant edema and or hemorrhage and metastases larger 
than 2 cm are excluded. 
d. Patients who are pregnant or breastfeeding. 
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e. Patients who are on a systemic steroid therapy regimen 
defined as the need for chronic steroid use for at least 7 or 
more days at a dose of greater than 10 mg of prednisone or 
equivalent per day.  
f. 
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. 
g. Patients who have any form of primary immunodeficiency (such 
as Severe Combined Immunodeficiency Disease and AIDS).   
h. Patients who have a history of severe immediate 
hypersensitivity reaction to cyclophosphamide, fludarabine, or 
IL-2.  
i. 
Patients who have a history of coronary revascularization or 
ischemic symptoms. 
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 a left ventricular ejection fraction (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 a documented FEV1 (forced expiratory 
volume in 1 second) of less than or equal to 60%. 
m. Patients who have had another primary malignancy within the 
previous 3 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 Cohorts: 
LN-144 (autologous TIL) followed by IL-2 after a lymphocyte-depleting 
preparative regimen as a 3-cohort, open-label treatment. 
Cohort 1: LN-144 process without cryopreservation of the final TIL 
product  
Cohort 2: LN-144 process with cryopreservation of the final TIL product  
Cohort 3: Retreatment cohort: Patients from Cohort 1 or 2 may 
rescreen for a second LN-144 harvest and treatment, if they meet all 
inclusion and exclusion criteria (except exclusion b). These patients will 
have a second tumor harvest and LN-144 treatment as per their prior 
cohort assignment. Nonexclusive examples of this cohort are prior 
responders who relapse, non-responders, and patients with 
manufacturing failures. 
Early Discontinuation 
from Study or 
Treatment: 
Criteria for early discontinuation from treatment: 
• 
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 
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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 Investigator 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. 
• 
Pregnancy. 
Criteria for early discontinuation from study: 
• 
Patient has become ineligible for study after tumor harvest and 
prior to LN-144 or IL-2 administration 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the 
patient 
Efficacy Assessment: 
The descriptive summary of the ORR, CR rate, DOR, PFS and OS will 
be used to determine the potential efficacy of LN-144.  
Safety Assessment: 
Treatment-emergent adverse events (TEAEs) and serious adverse 
events (SAEs) will be evaluated to assess the safety of this treatment. 
Overview of 
Statistical Plan: 
The primary statistical plan of analysis is based on use of descriptive 
methods.  
Patients meeting RECIST 1.1 criteria for a complete (CR) or partial 
(PR) response will be classified as responders in the analysis of the 
ORR. This rate will be summarized using both a point estimate and its 
2-sided 95% confidence limits. 
All time-to-event efficacy endpoints will use the Kaplan-Meier method 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 lymphodepletion.  
The assessment of safety data will be descriptive and based on the 
summarization of TEAEs, SAEs, AEs leading to discontinuation from 
treatment and the study, vital signs, physical examinations, and clinical 
laboratory tests. 
Sample Size 
Consideration: 
The per protocol sample size is approximately 40 patients treated with 
LN-144 followed by IL-2 administration, which is needed to detect 1 or 
more unique Grade 3 or 4 adverse event with >87, >80, and >70% 
probability when the true incidence rate is 5, 4 and 3%, respectively. 
DSMB Safety 
Assessments: 
A Data Safety Monitoring Board (DSMB) will evaluate cumulative safety 
data on the first 3 patients completing 12 weeks of assessment. 
Enrollment will not be halted during DSMB review. 
Additional evaluations of safety data may be specified in the DSMB 
charter. 
 
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TABLE OF CONTENTS 
INVESTIGATOR PROTOCOL SIGNATURE PAGE  ________________________________  3 
PROTOCOL SYNOPSIS ____________________________________________________  4 
LIST OF TABLES ________________________________________________________  14 
LIST OF FIGURES _______________________________________________________  14 
LIST OF ABBREVIATIONS  ________________________________________________  15 
1 
INTRODUCTION ___________________________________________________  17 
1.1 
Background  _________________________________________________________ 17 
1.2 
Overview of Adoptive Cell Transfer for Metastatic Melanoma ________________ 19 
1.3 
Production and Expansion of Tumor Infiltrating Lymphocytes  ________________ 23 
1.4 
LN‐144 TIL Therapy ___________________________________________________ 24 
2 
STUDY DESIGN ____________________________________________________  26 
2.1 
Description of the Study _______________________________________________ 26 
2.2 
Description of the Study Centers ________________________________________ 26 
3 
STUDY OBJECTIVES AND ENDPOINTS __________________________________  26 
3.1 
Study Objectives _____________________________________________________ 26 
3.1.1 
Primary Objective _________________________________________________________ 26 
3.1.2 
Secondary Objectives ______________________________________________________ 27 
3.1.3 
Exploratory Objectives _____________________________________________________ 27 
3.2 
Study Endpoints ______________________________________________________ 27 
3.2.1 
Primary Endpoints  ________________________________________________________ 27 
3.2.2 
Secondary Endpoints ______________________________________________________ 27 
3.2.3 
Exploratory Endpoints  _____________________________________________________ 27 
4 
SELECTION OF PATIENT POPULATION  _________________________________  27 
4.1 
Inclusion Criteria _____________________________________________________ 28 
4.2 
Exclusion Criteria _____________________________________________________ 30 
4.3 
Number of Patients ___________________________________________________ 31 
4.3.1 
Rescreening Patients  ______________________________________________________ 32 
4.3.2 
Patient Cohorts ___________________________________________________________ 32 
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND NON‐DRUG 
THERAPIES _______________________________________________________  33 
5.1 
Prior Treatment and Concomitant Medications ____________________________ 33 
5.2 
Prohibited and Permitted Medications during Study Treatment _______________ 34 
5.2.1 
Prohibited Treatment ______________________________________________________ 34 
5.2.2 
Permitted Medications – Use with Caution _____________________________________ 34 
6 
STUDY PROCEDURES _______________________________________________  34 
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6.1 
Screening ___________________________________________________________ 34 
6.2 
Enrollment and Tumor Resection ________________________________________ 36 
6.2.1 
Tumor Harvest and Processing Procedure ______________________________________ 37 
6.2.2 
Immune Monitoring and Sequencing of Tumor and Lymphocyte DNA  _______________ 37 
6.3 
Day ‐14 _____________________________________________________________ 38 
6.4 
Day ‐7 ______________________________________________________________ 39 
6.5 
Day ‐6 ______________________________________________________________ 40 
6.6 
Day ‐5 to Day ‐1 ______________________________________________________ 41 
6.7 
Day 0 (+2 days) _______________________________________________________ 42 
6.7.1 
Investigational Product _____________________________________________________ 42 
6.8 
Days 1 – 4 ___________________________________________________________ 44 
6.9 
Days 14, 28 (+/‐ 3 days) ________________________________________________ 45 
6.10 
Day 42 ( +/‐ 3 days) ___________________________________________________ 46 
6.11 
Day 84/ Week 12 and Day 126/ Week 18 ( +/‐ 3 days) _______________________ 48 
6.12 
Months 6 (+/‐ 1 week), 9 (+/‐ 1 week), 12 (+/‐ 1 week), 18 (+/‐ 3 weeks), and 
24 (+/‐ 3 weeks)  _____________________________________________________ 49 
6.13 
Patients Discontinued from Treatment ___________________________________ 51 
6.14 
Patients with Progressive Disease at Day 84 _______________________________ 51 
6.15 
Patients Who Do Not Receive a LN‐144 Infusion ____________________________ 51 
6.16 
Expected Toxicities and Treatment Guidelines _____________________________ 51 
6.16.1 
LN‐144 _______________________________________________________________ 51 
6.16.2 
IL‐2 __________________________________________________________________ 52 
6.16.3 
Blood Product Support  __________________________________________________ 53 
6.16.4 
Renal Toxicity __________________________________________________________ 53 
6.17 
Infection Prophylaxis __________________________________________________ 53 
6.17.1 
Pneumocystis jiroveci Pneumonia __________________________________________ 53 
6.17.2 
Herpes Virus Prophylaxis _________________________________________________ 54 
6.17.3 
Fungal Prophylaxis (Fluconazole)  __________________________________________ 54 
6.17.4 
Empiric Antibiotics ______________________________________________________ 55 
6.17.5 
Blood Product Support  __________________________________________________ 55 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF PATIENTS _______  55 
7.1 
Treatment Completion ________________________________________________ 55 
7.2 
Criteria for Early Discontinuation from Study or Treatment  __________________ 55 
8 
STUDY DRUG INFORMATION ________________________________________  56 
9 
STUDY ASSESSMENTS ______________________________________________  58 
9.1 
Tumor Assessments ___________________________________________________ 58 
9.1.1 
Response Criteria _________________________________________________________ 59 
10 
STATISTICAL AND ANALYTICAL PLANS _________________________________  61 
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10.1 
Introduction _________________________________________________________ 61 
10.2 
Study and Analysis Populations _________________________________________ 62 
10.3 
Endpoints ___________________________________________________________ 62 
10.3.1 
Primary _______________________________________________________________ 62 
10.3.2 
Secondary  ____________________________________________________________ 62 
10.3.3 
Exploratory ____________________________________________________________ 63 
10.4 
Sample Size Consideration _____________________________________________ 63 
10.4.1 
Baseline Demographics and Clinical Characteristics ____________________________ 64 
10.4.2 
Safety Analysis, Primary Endpoint __________________________________________ 64 
10.4.3 
Efficacy Analysis, Secondary Endpoints ______________________________________ 64 
10.4.4 
Safety Analysis _________________________________________________________ 64 
10.4.5 
Other Planned Analyses __________________________________________________ 65 
11 
CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS ___________________  65 
11.1 
Medications Administered during the Study _______________________________ 65 
11.2 
LN‐144 Treatment ____________________________________________________ 65 
11.3 
IL‐2 Administration ___________________________________________________ 65 
12 
ADVERSE EVENTS __________________________________________________  66 
12.1 
Definitions __________________________________________________________ 66 
12.2 
Reporting Procedures for Adverse Events _________________________________ 68 
12.2.1 
All Adverse Events ______________________________________________________ 68 
12.2.2 
Relationship to Study Drug _______________________________________________ 68 
12.2.3 
Severity  ______________________________________________________________ 69 
12.2.4 
Serious Adverse Events __________________________________________________ 70 
12.2.5 
Pregnancy Reporting ____________________________________________________ 71 
12.2.6 
Data Safety Monitoring Board _____________________________________________ 71 
13 
ADMINISTRATIVE REQUIREMENTS ____________________________________  72 
13.1 
Adherence to the Protocol _____________________________________________ 72 
13.2 
Regulatory Documentation _____________________________________________ 72 
13.3 
Record Retention _____________________________________________________ 73 
13.4 
Data Quality Assurance ________________________________________________ 74 
13.5 
Data Handling and Recordkeeping _______________________________________ 74 
13.5.1 
Electronic Data _________________________________________________________ 74 
13.5.2 
Electronic Case Report Form (eCRF) Completion ______________________________ 74 
13.6 
Study Completion/Termination _________________________________________ 75 
13.6.1 
Study Completion  ______________________________________________________ 75 
13.6.2 
Study Termination ______________________________________________________ 75 
13.7 
Monitoring __________________________________________________________ 75 
14 
INVESTIGATOR REGULATORY OBLIGATIONS ____________________________  76 
14.1 
Institutional Review Board _____________________________________________ 76 
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14.2 
Informed Consent ____________________________________________________ 76 
14.3 
Declaration of Helsinki  ________________________________________________ 77 
14.4 
Patient Data Protection ________________________________________________ 77 
14.5 
Adverse Event Reporting _______________________________________________ 78 
14.6 
Investigator _________________________________________________________ 78 
14.7 
Confidentiality _______________________________________________________ 78 
14.8 
Publications _________________________________________________________ 79 
15 
REFERENCES ______________________________________________________  80 
APPENDIX 1: SCHEDULE OF EVENTS  _______________________________________  85 
APPENDIX 2: ECOG SCALE  _______________________________________________  90 
APPENDIX 3: PRACTICAL WEIGHT _________________________________________  91 
APPENDIX 4: HIGH‐DOSE IL‐2 TOXICITIES ___________________________________  92 
APPENDIX 5: EXPECTED IL‐2 TOXICITIES AND THEIR MANAGEMENT  _____________  93 
APPENDIX 6: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  _________  96 
APPENDIX 7: CYCLOPHOSPHAMIDE PACKAGE INSERT _________________________  97 
APPENDIX 8: FLUDARABINE PACKAGE INSERT _______________________________  98 
APPENDIX 9: IL‐2 (ALDESLEUKIN) PACKAGE INSERT ___________________________  99 
APPENDIX 10: RECOMMENDED PROTOCOL FOR THAWING AND REINFUSION OF 
CRYOPRESERVED PRODUCT (COHORT 2) ______________________________  100 
APPENDIX 11: EORTC QLQ‐C30 (Version 3) _________________________________  101 
APPENDIX 12: SUMMARY OF CHANGES IN AMENDMENT 5  ___________________  104 
 
 
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LIST OF TABLES  
Table 1. 
Time Point Response: Patients with Target (± Non-target) Disease ....... 60 
Table 2. 
Time Point Response: Patients with Non-target Disease Only ............... 61 
 
LIST OF FIGURES  
Figure 1 
Study Flowchart ......................................................................................... 9 
Figure 2. 
LN-144 Manufacturing Process without Final Cryopreservation ............. 24 
Figure 3. 
LN-144 Manufacturing Process with Final Cryopreservation .................. 24 
 
 
 
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LIST OF ABBREVIATIONS 
ACT 
Adoptive Cell Therapy 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome  
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CR 
Complete response 
CT 
Computed tomography 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events Version 4.03 
CY 
Cyclophosphamide 
DOR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
EBNA 
Epstein-Barr nuclear antigen 
EBV 
Epstein-Barr virus 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
eGFR 
Estimated glomerular filtration rate 
EKG 
Electrocardiogram 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire - Core 30 instrument 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 second 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
HRQoL 
Human immunodeficiency virus 
Health related quality of life 
ICF 
Informed consent form 
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 
LN-144 
Autologous Tumor Infiltrating Lymphocytes 
LVEF 
Left ventricular ejection fraction 
MAPK 
Mitogen-activated protein kinase (pathway) 
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 
ORR 
Objective response rate 
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OS 
Overall survival 
PD 
Progression 
PE 
Physical exam 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PHI 
Personal health information 
PO 
Per Os (by mouth) 
PR 
Partial response 
QD 
(Taken) once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REP 
Rapid expansion protocol 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
TEAE 
Treatment-emergent adverse event 
TH 
Tumor Harvested patient population 
TIL 
Tumor infiltrating lymphocyte 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of 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. 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 patients with advanced disease 
(Stage IV), prognosis is extremely poor with 5-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 
3 general treatment modalities: active immunization, non-specific immune stimulation, 
and passive immunotherapy with targeted antibodies and/or adoptive cell transfer. In 
the treatment of patients with 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 
non-injected lesions 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 with the longest responses now over 25 years. Among patients treated 
with ipilimumab, up to 22% are still alive after 3 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 complete response (CR) lasting more than 8 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 
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up to 40% when combined with ipilimumab,18 although the long-term durability of the 
responses is not yet known. 
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 patients with advanced 
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 
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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 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 are 
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 patients with advanced 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 individual centers in the USA and 
Europe, such as the National Cancer Institute (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 conducted on small numbers (<10) of patients (e.g., Tessier et al).33  
During this time, the Surgery Branch at the National Cancer Institute (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 
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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 
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 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 such as IL-7, IL-15 
and IL-21.46 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 1 week, after which time patients 
recovered endogenous marrow function and reconstituted their lymphocyte 
compartments towards normal levels within 2 to 3 weeks. 47, 48 
Because of the immunosuppression of fludarabine, 1 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 
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blood products received after chemotherapy. The patient later died of complications 
from the treatment of the lymphoma. Another patient developed polyneuropathy 
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 al21 reported results of clinical trials conducted at NCI that used 3 individual 
pretreatment 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%) patients. Radvanyi et al49 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 2 resulting in a complete response (6.5%). Progression free survival of a 
duration of greater than 12 months was reported in 9/15 (60%) 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 al51 reported the experience from Sheba Medical Center in 
Israel using “young, unselected –TIL therapy.” Of the 31 patients evaluated, 15 (48%) 
patients achieved a clinical response including 4 patients (12.9%) with complete 
responses. In addition, a group in Denmark52 used decrescendo 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 nonmyeloablative lymphodepleting 
chemo-preparative regimen proposed in this current study can be tolerated and 
contributes to the potent efficacy of TIL for the treatment of patients with advanced 
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 
1.5-4.0 cm in diameter) and culturing tumor fragments in media containing IL-2 to 
expand them in vitro (Figure 2 and Figure 3). Appropriately expanded TIL cultures 
should reach several million cells (combined) in 2 to 3 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.49 In addition, clinical trials using young, unselected TIL have 
achieved relatively similar response rates.51, 53 In this trial, TIL cultures will not be 
selected but rather proceed when sufficient numbers are obtained to proceed. TIL 
isolated from the tumor fragments 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 NCI, TIL were 
successfully generated in 677 (86%) of the 787 specimens from all tumor sites, 
although tumors derived from the gastrointestinal tract had a decreased rate of TIL 
growth (70%; P = 0.008).54 
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Figure 2. 
LN-144 Manufacturing Process without Final Cryopreservation  
 
 
Figure 3. 
LN-144 Manufacturing Process with Final Cryopreservation 
1.4 
 LN-144 TIL Therapy 
LN-144 is an autologous, ready-to-infuse TIL therapy and is comparable to that 
developed by Dr. Steven Rosenberg and colleagues at the NCI. TIL have 
demonstrated efficacy in the treatment of patients with advanced melanoma. Phase 2 
clinical trials evaluating this investigational product have shown an objective response 
rate of 49% or more, exceeding rates reported by other immunotherapies in 
melanoma. This study is being conducted to evaluate: 1) the safety of LN-144 
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therapy, 2) the efficacy of LN-144 therapy and 3) the efficacy of retreatment in 
responders who have progressed. 
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 2 days of cyclophosphamide followed by 5 days of 
fludarabine as a lymphodepleting pretreatment. The treatment regimen includes 
treatment with LN-144 (TIL therapy) followed by high-dose IL-2. Protocols for the 
tumor harvest and LN-144 administration as fresh or cryopreserved product are 
provided in separate operating manuals. 
Up to 150 x 109 viable cells will be infused in this clinical trial. The final cell 
investigational product is formulated in a minimum of 50% HypoThermosol™ in 
Plasma-Lyte A™ (volume/volume) and up to 0.5% HSA (compatible for human infusion) 
containing 300 IU/mL IL-2. The final investigational product will be available for 
administration in 1 of 3 volumes for infusion:  
Cohort 1 (LN-144 manufacturing process without final cryopreservation): 
1) 250 mL (in a 300-mL capacity infusion bag) when the total TIL harvested are 
≤75 x 109 
OR  
2) 500 mL (in a 600-mL capacity infusion bag) when the total TIL harvested are 
<150 x 109 
Cohort 2 (LN-144 manufacturing process with final cryopreservation):   
3) Up to five infusion bags containing up to approximately 100 mL of thawed 
cells. The number of infusion bags is dependent on the cell concentration 
We cannot predict the total number of cells that will be generated for the final LN-144 
infusion investigation product for each patient due to patient-to-patient variation in 
T-cell expansion rates during the REP step. A lower limit of cells is set based on the 
minimum number of cells needed in order to make a decision to lymphodeplete the 
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patient using the cyclophosphamide plus fludarabine chemotherapy regimen. Once 
we have begun lymphodepletion based on this minimal attained cell number, we are 
committed to treating the patient with the available number of TIL we generate in the 
REP. 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. 
2 
STUDY DESIGN 
2.1 
Description of the Study 
This is a prospective, 3-cohort interventional study evaluating patients who receive 
ACT with LN-144 (autologous TIL). Patients will receive LN-144 followed by the 
administration of a regimen of IL-2 at 600,000 IU/kg approximately every 8 hours 
starting 10 to 24 hours after the LN-144 infusion and continuing for up to 6 doses. 
Patients will be evaluated for response approximately 6 weeks following LN-144 
therapy and then every 6 weeks up to 6 months.  
After 6 months, patients will be evaluated at 9, 12, 18 and 24 months following 
LN-144 treatment. Formal response evaluations will be per RECIST 1.1.  
Patients who have completed the 24 months’ study and patients who have 
progressive disease after Day 84 will also be followed up for overall survival for up to 
3 years. 
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. 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 Objective 
• 
To characterize the safety profile of LN-144 in patients with metastatic 
melanoma  
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3.1.2 
Secondary Objectives 
• 
To evaluate the efficacy of LN-144 in patients with metastatic melanoma 
using the objective response rate (ORR) and complete response rate 
(CR).  
• 
To evaluate efficacy parameters of LN-144 in patients with metastatic 
melanoma such as progression-free survival (PFS), duration of response 
(DOR), and overall survival (OS).  
3.1.3 
Exploratory Objectives 
• 
To explore the persistence of LN-144 and potential immune correlates of 
response, outcome, and toxicity of the treatment. 
• 
To assess health-related quality of life (HRQoL). 
3.2 
Study Endpoints  
3.2.1 
Primary Endpoints 
• 
Incidence, severity, seriousness, relationship to study treatment, and 
characteristics of treatment-emergent AEs (TEAEs), including AEs 
leading to early discontinuation from treatment or withdrawal from the 
study, and AEs resulting in deaths while on the study. 
3.2.2 
Secondary Endpoints  
• 
Efficacy of LN-144 therapy as defined by ORR, CR rate, DOR, PFS, and 
OS. 
3.2.3 
Exploratory Endpoints 
• 
Evaluation of TIL persistence in the peripheral blood and immune 
correlates with respect to response, outcome, and/or toxicity of the 
treatment. These data will not be reported in the clinical study report but 
instead in a separate report. 
• 
EORTC QLQ-C30 HRQoL questionnaire 
4 
SELECTION OF PATIENT POPULATION 
Patients greater than 18 years of age, with a diagnosis of metastatic melanoma who 
have undergone at least 1 prior immunotherapy or chemotherapy regimen will be 
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selected for this study. Patients greater than 65 years of age may be allowed in the 
study after discussion between the Investigator and Medical Monitor regarding the 
patient’s ability to tolerate the high dose IL-2. 
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 1 lesion that is 
resectable for TIL generation.  Ideally the lesion must be of at least 1.5 cm in 
diameter post-prosection and can be surgically removed with minimal morbidity 
(defined as any operation for which expected hospitalization is less than or equal to 
3 days).  
b. 
Patients must have undergone at least 1 prior systemic treatment for metastatic 
melanoma. 
c. 
Patients must have either progressive disease or no response (i.e., no PR or CR) 
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. Enrollment of 
patients greater than 65 years of age can be done after consultation with the 
Medical Monitor.  
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.   
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g. 
Patients of childbearing potential or with partners of childbearing potential must be 
willing to practice birth control during treatment and for 4 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). 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 positive and/or Epstein Barr 
nuclear antigen (EBNA) IgG positive, and have no clinical evidence of active EBV 
infection. 
l. 
Patients must not have received systemic chemotherapy or immunotherapy for 
2 weeks (targeted therapy) and 4 weeks (all other anti-cancer treatment) at the time 
of enrollment, and there must be no intention of receiving any non-protocol systemic 
anti-cancer chemotherapy or immunotherapy during the study 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. Palliative radiation therapy 
is permitted between biopsy and lymphodepletion for LN-144 infusion as long as it 
does not involve lesions being followed for response. There is no specific time 
window post radiation therapy as long as all toxicities have recovered to Grade 1 or 
less or as specified in the eligibility criteria.  
Note: Patients may have undergone minor surgical procedures not involving 
general anesthesia within 3 weeks prior to enrollment.  
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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 been asymptomatic for at least 6 months or had a normal 
colonoscopy post anti-PD-1/anti-PD-L1 treatment, with uninflamed mucosa by visual 
assessment. 
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 with melanoma of uveal/ocular origin 
b. 
Patients who have received prior cell transfer therapy that included a 
nonmyeloablative or myeloablative chemotherapy regimen (not applicable for 
patients in the retreatment Cohort 3). 
c. 
Patients who have 3 or more active brain metastases. Note: Patients with 1 or 
2 untreated or inadequately treated brain lesions or 3 or more adequately treated 
brain 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 
1 month. Brain metastases with significant edema and or hemorrhage and 
metastases larger than 2 cm are exclusionary. 
d. 
Patients who are pregnant or breastfeeding. 
e. 
Patients who are on a systemic steroid therapy regimen defined as the need for 
chronic steroid use for at least 7 or more days at a dose of greater than 10 mg of 
prednisone or equivalent per day.  
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f. 
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. 
g. 
Patients who have any form of primary immunodeficiency (such as Severe 
Combined Immunodeficiency Disease and AIDS).   
h. 
Patients who have a history of severe immediate hypersensitivity reaction to IL-2, 
fludarabine or cyclophosphamide. 
i. 
Patients who have a history of coronary revascularization or ischemic symptoms. 
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 a left ventricular ejection fraction (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 a documented FEV1 (forced expiratory volume in 1 second) of 
less than or equal to 60%.   
m. Patients who have had another primary malignancy within the previous 3 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 and/or 
do not have tumor harvest within 6 weeks of signing the ICF are defined as screen 
failures.   
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The screening and tumor resection/TIL harvest period is up to 6 weeks. However, it 
can be extended, after discussion between the Investigator and the Medical Monitor, if 
there is delay in scheduling the tumor resection. 
The Investigator is to maintain a master screening log of all consented patients that 
documents all screen failures and the 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 electronic data capture (EDC) database as defined in the 
electronic case report form (eCRF) completion manual. 
Patients will be enrolled until approximately 40 patients have been successfully 
treated with LN-144 followed by at least 1 dose of IL-2. Screening may halt once it 
becomes likely that the full enrollment goal will be met. Patients from Cohorts 1 and 2 
may screen for the retreatment Cohort 3 as long as this study is open. 
4.3.1 
Rescreening Patients 
Patients who fail the initial screening process may be rescreened for eligibility. The 
Investigator and Medical Monitor will discuss the patient prior to any rescreening 
procedures and agree on which screening procedures need to be redone.  
Patients from Cohort 1 or 2 may also be rescreened and retreated if they meet all 
inclusion and exclusion criteria (except exclusion b), they will have a second tumor 
harvest for LN-144 treatment as per their prior cohort assignment. Nonexclusive 
examples of this group are prior responders who relapse, non-responders, and 
patients with manufacturing failures. 
4.3.2 
Patient Cohorts 
All patients treated with LN-144 followed by at least 1 dose of IL-2 are defined as the 
‘all-treated population’, and all patients resected for harvest will be defined as the 
Tumor Harvested (TH) population. 
Patients will be assigned to Cohorts 1 or 2 as follows. All patients will be assigned to 
Cohort 1 until Cohort 2 treatment is available from Lion. Subsequently, once patients 
qualify and approximately 15 patients receive TIL/IL-2 in Cohort 1, a new patient will 
be assigned to the cohorts in the following order to achieve an approximately 1:2 ratio 
between subsequent enrollment into Cohorts 1 and 2. The order is Cohort 2, then 
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Cohort 1, then Cohort 2, and then the sequence of these 3 repeats until the 
conclusion of the study. If a manufacturing slot for the specified cohort is not 
available, then the patient will be assigned to the other cohort and no attempt made to 
make up for the skipped cohort. If Cohort 1 approaches or passes the desired 
20-patient enrollment, the order of the subsequent enrollment into the cohorts may be 
adjusted to minimize over-enrollment into Cohort 1. 
A Data Safety Monitoring Board (DSMB) will evaluate safety data on the first 
3 patients completing 12 weeks of assessment. Additional analyses may be 
conducted as specified in the DSMB charter. 
The primary efficacy and safety analyses will take place after 12 weeks following the 
LN-144 administration of the last patient in the second cohort, and the final analysis 
will take place at the end of study. 
An additional third cohort will consist of patients who wish to rescreen for a second 
harvest of tumor for LN-144 manufacture and treatment. Nonexclusive examples of 
patients that may be eligible for retreatment (Cohort 3) are prior responders to LN-144 
who relapse, non-responders, and patients with manufacturing failures. These 
patients will need to be rescreened, meet all eligibility criteria (except exclusion 
criteria b) and will have all screening assessments redone except for the HLA typing. 
Of the 40 enrolled patients enrolled in Cohort 1 and 2, approximately 10 patients may 
rescreen for a second tumor harvest for LN-144 treatment in Cohort 3. 
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
5.1 
Prior Treatment and Concomitant Medications 
Use of all medications taken by the patient 30 days prior to consent will be recorded in 
the site’s source documentation and the patient’s electronic case report form (eCRF). 
All medications taken by the patient, or any changes in medications will also be 
recorded until completion of the study. 
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5.2 
Prohibited and Permitted Medications during Study Treatment 
5.2.1 
Prohibited Treatment 
Patients will enter a washout period prior to enrollment. Systemic chemotherapy or 
immunotherapy (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. Note: Palliative 
radiation therapy is permitted between biopsy and lymphodepletion as long as it 
does not involve lesions being followed for response. 
• 
Use of investigational drugs is not permitted 
5.2.2 
Permitted Medications – Use with Caution 
Concurrent 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 Investigator discretion.  
6 
STUDY PROCEDURES 
6.1 
Screening 
The following procedures should be performed after completion of Informed Consent: 
• 
Review of inclusion and exclusion criteria 
• 
Medical history including current medications 
• 
Physical exam including height and weight 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Evaluation and measurement of all skin and palpable lesions 
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• 
Slit Lamp eye exam. Prior evaluation within the past 30 days will fulfill this 
requirement.  
• 
Electrocardiogram (EKG). Prior evaluation within the past 60 days will fulfill this 
requirement. 
• 
Cardiac evaluation (stress thallium) for all patients. Echocardiogram or multiple 
gated acquisition scan (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. Prior evaluations within the past 6 months will fulfill this 
requirement. 
• 
Pulmonary function tests. Prior evaluations within the past 6 months will fulfill this 
requirement. 
• 
Computed tomography (CT) Exam 
• 
Chest (include neck if there is prior or suspected neck disease) 
• 
Abdomen 
• 
Pelvis 
• 
Magnetic resonance imaging (MRI) of brain 
• 
Blood and Urine Tests 
• 
Hematology – complete blood count (CBC) with differential 
• 
Chemistry - Sodium, Potassium, Chloride, Total CO2 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 childbearing potential 
• 
HIV antibody titer, HbsAG determination (HSV-1 IgG and HSV-2 IgG), CMV 
antigen assay, Anti HCV, Anti CMV IgG 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) 
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• 
HLA typing (to be shipped to central laboratory. Refer to central Laboratory 
Manual for details) 
• 
Urinalysis (complete urine culture if indicated) 
• 
Calculate creatinine clearance using Cockcroft-Gault formula 
Males:  
Creatinine CL = 
Weight (kg) x (140 – Age) 
(mL/min) 
 
 
72 x serum creatinine (mg/dL) 
Females:  
Creatinine CL = 
Weight (kg) x (140 – Age) x 0.85 
(mL/min) 
 
 
72 x serum creatinine (mg/dL) 
 
• 
ECOG performance status evaluation 
• 
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 been asymptomatic for at least 6 months or had a normal 
colonoscopy post treatment, with uninflamed mucosa by visual assessment 
• 
Assessment of adverse events (AEs) / serious AEs (SAEs) 
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 study.   
When the Medical Monitor has approved the patient to be enrolled into the study, 
tumor resection will take place. The patient is enrolled into the study when resection 
has started. The following procedures should be completed during this visit. 
• 
Verification of all ongoing concomitant medications (list only medications that are 
NOT part of the tumor harvest procedure) 
• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. Refer to 
Laboratory Manual) 
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• 
Tumor Harvest  
• 
Ten paraffin embedded slides created from the tumor resection for biomarker 
analyses and DNA sequencing 
• 
Assessment of AE/SAEs   
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 LN-144 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.  
 
 
6.2.2 
Immune Monitoring and Sequencing of Tumor and Lymphocyte DNA 
A total of 50 mL of blood will be collected from the patient for immune monitoring 
(biomarker analysis) and sequencing of lymphocyte DNA utilizing vacutainer blood 
collection vials. Refer to the study Laboratory Manual for the complete procedure 
details. In addition, DNA from tumor tissue will be sequenced.    
LN-144 is an autologous investigational product, which is procured 
and delivered by means that 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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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 rate, respiratory rate, blood pressure and temperature 
• 
Evaluation and measurement of all skin and palpable lesions 
• 
Verification of all concomitant medications 
• 
EKG  
• 
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. At the 
Investigator’s discretion, this can be done as early as Day -21. 
• 
Blood and urine tests 
• 
Hematology - CBC with differential 
• 
Chemistry - Sodium, Potassium, Chloride, Total CO2 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 childbearing potential 
• 
Urinalysis (complete urine culture if indicated) 
• 
ECOG performance status evaluation 
• 
Assessment of AE/SAEs 
• 
EORTC QLQ-C30 HRQoL questionnaire 
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6.4 
Day -7  
Prior to the start of lymphodepletion, verification of sufficient LN-144 expansion at this 
time point will be confirmed. In Cohort 2, the REP may be extended an additional 
7 days if growth is inadequate in which case, the Day -7 and subsequent visits would 
be delayed 1 week.  
In addition, prior to beginning the lymphodepletion for all Cohorts, the Investigator 
should assess whether the patient has had any clinical deterioration, which would put 
him/her at increased risk when subsequently receiving the high-dose IL-2. 
Specifically, the Investigator should consider whether a worsening of ECOG status 
and/or a deterioration of laboratory values is such that the patient no longer meets the 
requirements of the inclusion and exclusion criteria. If this deterioration is believed to 
be reversible, the LN-144 investigational product may remain frozen at the 
appropriate stage and the schedule adjusted to allow recovery and subsequent 
LN-144 administration. If the deterioration is believed irreversible and of sufficient 
magnitude to increase the risk of high-dose IL-2 administration, the patient should not 
proceed to lymphodepletion and subsequent therapy and be followed as per 
Section 6.15:  
• 
Physical exam including weight, calculated BSA and BMI 
• 
Verification of all concomitant medications 
• 
ECOG performance status evaluation 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to cyclophosphamide administration) 
• 
Hematology - CBC with differential 
• 
Chemistry - Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, Creatinine, 
Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, Alkaline 
Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total 
protein, Total CK  
• 
Urinalysis (complete Urine culture if indicated) 
• 
CMV antigen assay, as clinically indicated 
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• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. Refer to 
Laboratory Manual) 
• 
Administration of the following medications: 
• 
Cyclophosphamide 60 mg/kg intravenously (IV) in 250 mL D5W with mesna 
15 mg/kg are infused over approximately 2 hours. If the patient is obese 
(BMI >35) drug dosage will be calculated using practical weight as 
described in Appendix 3 
• 
Mesna infusion will continue to be infused at a rate of 3 mg/kg/hour in a 
suitable diluent over 22 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 8 hours X 
3 days) will be given for nausea, or as per standard of care at the treating 
institution. (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 
• 
Assessment of AE/SAEs 
6.5 
Day -6 
The following procedures should be performed: 
• 
Verification of all concomitant medications 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to cyclophosphamide administration) 
• 
Hematology - CBC with differential 
• 
Chemistry - Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, Creatinine, 
Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, Alkaline 
Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total 
protein, Total CK 
• 
CMV antigen assay, as clinically indicated 
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• 
Urinalysis (complete urine culture if indicated) 
• 
Administration of the following medications 
• 
Cyclophosphamide 60 mg/kg IV in 250 mL D5W with mesna15 mg/kg are infused 
over approximately 2 hours. If the patient is obese (BMI >35) drug dosage will be 
calculated using practical weight as described in Appendix 3 
• 
Mesna infusion will continue to be infused at a rate of 3 mg/kg/hour in a suitable 
diluent over 22 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 8 hours X 3 days) will be 
given for nausea, or as per standard of care at the treating institution. 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 
• 
Assessment of AE/SAEs 
6.6 
Day -5 to Day -1 
The following procedures should be performed: 
• 
Physical exam including weight (Day -1 only) 
• 
Verification of all concomitant medications 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to fludarabine administration) 
• 
Hematology - CBC with Differential 
• 
Chemistry - Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, 
Creatinine, Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, 
Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct 
Bilirubin, LDH, Total protein, Total CK 
• 
CMV antigen assay, as clinically indicated 
• 
Urinalysis (complete urine culture if indicated) 
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• 
The following medication should be administered: 
• 
Fludarabine 25 mg/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 
• 
Assessment of AE/SAEs 
6.7 
Day 0 (+2 days) 
Day 0 is the day of LN-144 infusion.   
Upon completion of the manufacturing process, the investigational 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 investigational 
product will then be released for shipment from the manufacturing facility.  
6.7.1 
Investigational Product  
The investigational product will be shipped overnight by courier to the clinical site 
pharmacy in a shipping container validated to maintain the appropriate investigational 
product temperature. The product temperature will be continuously monitored by a 
TempTale 4™, which will be placed in the container in contact with the investigational 
product.  
The investigational product will be received by the appropriate clinical pharmacy for 
the particular patient. After verification and labeling at the pharmacy, the 
investigational product will be returned to the shipper to maintain temperature as the 
investigational product is transferred to the patient bedside. Upon receipt by the 
infusing physician and double verification for identity the investigational product may 
be prepared for infusion. See the LN-144 Pharmacy and Administration Manual for 
precise details for handling of LN-144 for Cohort 1 (non-cryopreserved cells) or 
Cohort 2 (cryopreserved cells).  
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 
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hospitalized until the completion of the IL-2 therapy, as per institutional standards. 
The following procedures should be performed: 
• 
Physical exam including weight  
• 
Verification of all concomitant medications 
• 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
• 
Vital signs will be monitored every 30 minutes during infusion then hourly  
(+/-15 minutes) for 4 hours and then routinely (every 4 to 6 hours), unless 
otherwise clinically indicated, for up to approximately 24 hours post LN-144 
infusion  
• 
Blood and urine tests (to be drawn prior to LN-144 infusion) 
• 
Hematology – CBC with differential 
• 
Chemistry - Sodium, Potassium, Chloride, Total CO2 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) 
• 
The following medications will be administered: 
• 
Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg will be given 
as per standard of care 
• 
LN-144 Infusion:  Autologous TIL (LN-144) will be administered intravenously. 
The investigational product will be administered (by gravity) within approximately 
45 minutes. If interruption of infusion is required for medical reasons, the 
investigational product infusion should be completed within 3 hours of beginning 
infusion. Investigational Product not infused within 3 hours should be discarded. 
During periods of infusion interruption, the LN-144 fresh or thawed product 
should be refrigerated. Further details of the administration procedure are 
provided in the LN-144 Pharmacy and Administration Manual 
• 
Assessment of AE/SAEs 
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6.8 
Days 1 – 4 
During these days, while patient remains hospitalized, the following procedures 
should be performed: 
• 
Physical exam including weight (physical exam Days 1 and 4 only) 
• 
Verification of all concomitant medications 
• 
Vital signs - pulse rate, respiratory rate, 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 CO2 or Bicarbonate, Creatinine, 
Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, Alkaline 
Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total 
protein, Total CK 
• 
CMV antigen assay - required only on Days 1 and 3 
• 
Urinalysis (complete urine culture if indicated) 
• 
Obtain blood for immune monitoring on Days 1 and 4 only (50 mL of blood to be 
obtained. Refer to Laboratory Manual) 
• 
Assessment of AE/SAEs 
• 
The following medications will be administered: 
• 
IL-2 – begin infusion 10-24 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 infusion at a frequency not greater than every 8 hours 
as per institutional standard of care. Continue for up to a maximum of 6 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 
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• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. Refer to 
Laboratory Manual) (Day 14 only) 
• 
If required, the following medications will continue to be administered 
• 
Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each day 
until the absolute neutrophil count reaches >1000/mm3 for 3 consecutive days, or 
as per standard of care at the treating institution 
• 
Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute neutrophil 
count reaches >1000/mm3 or as per standard of care at the treating institution 
• 
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 as per standard of 
care at the treating institution. Valacyclovir PO or acyclovir IV will be 
administered daily, and continued until CD4 >200 cells/mm3 or as per standard of 
care at the treating institution 
• 
Assessment of AE/SAEs 
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 concomitant medications 
• 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
• 
Assessment of AE/SAEs 
• 
Blood tests 
• 
Hematology- CBC with differential 
• 
Chemistry- Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, 
Creatinine, Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, 
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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 
• 
CD4 count 
• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. Refer to 
Laboratory Manual) 
• 
CT Exam as clinically indicated 
• 
Chest (include neck if there is prior or suspected neck disease) 
• 
Abdomen 
• 
Pelvis 
• 
MRI of brain as clinically indicated 
• 
If required, the following medications will continue to be administered 
• 
Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
day until the absolute neutrophil count reaches >1000/mm3 for 
3 consecutive days or as per standard of care at the treating institution  
• 
Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3, or as per standard of care at the 
treating institution  
• 
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 as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until CD4 >200 cells/mm3 or as 
per standard of care at the treating institution 
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6.11 Day 84/ Week 12 and Day 126/ Week 18 ( +/- 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 concomitant medications 
• 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
• 
Assessment of AE/SAEs 
• 
Slit lamp eye exam (Day 84 only) 
• 
Blood tests 
• 
Hematology- CBC with Differential 
• 
Chemistry- Sodium, Potassium, Chloride, Total CO2 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 
• 
CD4 count 
• 
Calculate Creatinine Clearance using Cockcroft-Gault formula (Day 84 only) 
• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. Refer to 
Laboratory Manual) (Day 84 only) 
• 
CT Exam as clinically indicated 
• 
Chest (include neck if there is prior or suspected neck disease) 
• 
Abdomen 
• 
Pelvis 
• 
MRI of brain as clinically indicated 
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• 
EORTC QLQ-C30 HRQoL questionnaire (Day 84 only) 
• 
If required, the following medications will continue to be administered 
• 
Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
day until the absolute neutrophil count reaches >1000/mm3 for 
3 consecutive days, or as per standard of care at the treating institution 
• 
Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3, or as per standard of care at the 
treating institution  
• 
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 as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until CD4 >200 cells/mm3, or as 
per standard of care at the treating institution 
6.12 Months 6 (+/- 1 week), 9 (+/- 1 week), 12 (+/- 1 week), 18 (+/- 3 weeks), and 
24 (+/- 3 weeks) 
The following procedures will be performed during these visits: 
• 
Physical exam including weight 
• 
ECOG performance status evaluation 
• 
Verification of all concomitant medications 
• 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
• 
Evaluation and measurement of all skin and palpable lesions 
• 
Blood tests 
• 
Hematology- CBC with Differential 
• 
Chemistry- Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, 
Creatinine, Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, 
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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) 
• 
CD4 count (Month 6 only) 
• 
CMV antigen assay, as clinically indicated 
• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. Refer to 
Laboratory Manual) (Months 6, 9 and 12 only) 
• 
CT Exam, as clinically indicated 
• 
Chest (include neck if there is prior or suspected neck disease) 
• 
Abdomen 
• 
Pelvis 
• 
MRI of brain, as clinically indicated 
• 
If required, the following medications will continue to be administered (Month 6) 
• 
Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each day 
until the absolute neutrophil count reaches >1000/mm3 for 3 consecutive days, or 
as per standard of care at the treating institution 
• 
Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute neutrophil 
count reaches >1000/mm3, or as per standard of care at the treating institution  
• 
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 as per standard of 
care at the treating institution. Valacyclovir PO or acyclovir IV will be 
administered daily, and continued until CD4 >200 cells/mm3, or as per standard 
of care at the treating institution 
• 
Assessment of AEs/SAEs (see Section 12.2 for future guidance on AE/SAE 
reporting requirements during the follow-up period) 
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• 
EORTC QLQ-C30 HRQoL questionnaire (Months 6, 12, and 24 only) 
6.13 Patients Discontinued from Treatment 
Patients who are discontinued from treatment should stay on the study and continue 
with all scheduled study visit assessments.  
6.14 Patients with Progressive Disease at Day 84 
Patients with progressive disease at Day 84 should remain on study but the data 
collection will be reduced to survival status and other anti-cancer medications. This 
data will be collected every 3 months and may be done by telephone contact. 
6.15 Patients Who Do Not Receive a LN-144 Infusion 
Some patients may undergo harvest and LN-144 manufacture but do not receive the 
infusion of investigational product. If this is due to a potentially treatable medical 
event, the pre-REP cells (Cohort 1) or the REP cells (Cohort 2) may remain frozen for 
a period of time agreed between the Investigator and Medical Monitor to see if the 
patient recovers and meets criteria to receive the TILs. If a decision is taken that the 
patient will not receive their TILs, then the patient should remain on study but the data 
collection will be reduced to survival status and other anti-cancer medications. This 
data will be collected every 3 months and may be done by telephone contact. 
6.16 Expected Toxicities and Treatment Guidelines 
6.16.1 
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 that 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 Section 6.16.2.) The use of the 
nonmyeloablative regimen prior to cell administration increases the toxicity of this 
treatment as profound myelosuppression occurs in all patients. 
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6.16.2 
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 is to continue dosing 
until grade 3 or 4 events occur but this study calls for 1 to 6 doses based on 
tolerance. 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, almost 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.  
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 
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(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. 
Treatment will be given as per Investigator discretion and can be given as per 
institutional standard of care. Additional guidelines for toxicity management are as 
below.  
6.16.3 
Blood Product Support  
Using daily CBCs as a guide, the patient will receive platelets and packed red blood 
cells (PRBCs) as needed as per standard of care at the treating institution. 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. 
6.16.4 
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. 
6.17 Infection Prophylaxis 
Note: Other anti-infective agents may be substituted at the discretion of the treating 
Investigator as per standard of care at the treating institution.    
6.17.1 
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 3 times a week on non-consecutive days, beginning 
on the first Monday, Wednesday, or Friday on or after the first dose of chemotherapy 
or as per standard of care at the treating institution.  
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Pentamidine will be substituted for TMP/SMX DS in patients with sulfa allergies. It will 
be administered aerosolized at 300 mg per nebulizer within 1 week prior to receiving 
study treatment and continued monthly until CD4 count is above 200/mm3 and for at 
least 6 months post chemotherapy, or as Investigator deems appropriate as per 
standard of care at the treating institution. 
Pneumonia prophylaxis will continue for 6 months post chemotherapy. If the CD4 
count is less than 200/mm3 at 6 months post chemotherapy, or as Investigator deems 
appropriate as per standard of care at the treating institution, prophylaxis will continue 
until the CD4 count is greater than 200/mm3. 
6.17.2 
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 as per standard of care 
at the treating institution. Reversible renal insufficiency has been reported with IV but 
not oral acyclovir. Neurologic toxicity including delirium, tremors, coma, acute 
psychiatric disturbances, and abnormal EEGs has been reported with higher doses of 
acyclovir. Should this occur, a dosage adjustment will be made or the drug will be 
discontinued. Acyclovir will not be used concomitantly with other nucleoside analogs, 
which interfere with DNA synthesis, e.g. ganciclovir. In renal disease, the dose is 
adjusted as per product labeling. 
Herpes prophylaxis will continue for 6 months post-chemotherapy, or as long as 
Investigator deems necessary. If the CD4 count is less than 200/mm3 at 6 months 
post chemotherapy, prophylaxis will continue until the CD4 count is greater than 
200/mm3, or as per standard of care of the treating institution. 
6.17.3 
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 or as per 
standard of care of the treating institution. 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 as per 
standard of care at the treating institution. 
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6.17.4 
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, 1 or 2 temperatures of 
38.0°C or above at least 1 hour apart, AND an absolute neutrophil count (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 standard of care at the 
treating institution. 
6.17.5 
Blood Product Support 
Using CBCs as a guide, the patient will receive platelets and packed red blood cells 
(PRBCs) as needed as per standard of care at the treating institution. 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 
 Treatment Completion 
Completion of treatment is defined as successful infusion with LN-144 followed by a 
minimum of 1 dose of IL-2.  
7.2 
Criteria for Early Discontinuation from Study or Treatment  
Criteria for early discontinuation from treatment:  
• 
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 Investigator that continued treatment is not in the best 
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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 
• 
Pregnancy 
Criteria for early discontinuation from study 
• 
Patient has become ineligible for study after tumor harvest and prior to LN-144 or 
IL-2 administration 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the patient  
8 
STUDY DRUG INFORMATION 
Investigational Product Name: LN-144 
Active Investigational Product Components: Autologous, viable, tumor infiltrating 
lymphocytes (TIL) 
Dosage Form: Live cell suspension either non-cryopreserved (Cohort 1) or 
cryopreserved (Cohort 2) 
Qualitative Composition:   
LN-144 is a cellular investigational 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 either formulated in either HypoThermosol™ transport medium 
(non-cryopreserved product) or Cryostor medium (cryopreserved product) with 
Plasma-Lyte® A as diluent, with 0.5% HSA (human serum albumin) and 300 IU/mL of 
IL-2. The suspension volume will be between 250 to 500 mL. Only one LN-144 dose 
is given intravenously after lymphodepletion chemotherapy followed by high dose IL-2 
therapy 10-24 hours after infusion. The total volume to be infused will be 
approximately 250 mL (300 mL transfer bag for Cohort 1) for cell concentrations 
≤75 x 109 LN-144 or 500 mL (up to 600 mL transfer bag for Cohort 1) for cell 
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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 under quarantine. 
Receipt is defined as the moment the LN-144 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 released by Lion and transferred to the patient bedside. The investigational 
product is infused by gravity within approximately 45 minutes. If interruption of 
infusion is required for medical reasons, the investigational product infusion should 
complete within 3 hours of beginning infusion. Refer to the LN-144 Pharmacy and 
Administration Manual for additional details. 
9 
STUDY ASSESSMENTS 
9.1 
Tumor Assessments 
Tumor assessment will be performed by clinical exam (skin lesions) and by conventional 
or spiral CT scans of the chest, abdomen, pelvis and MRI of brain conducted at 
Screening, Day -14 and 6 weeks (Day 42) following the LN-144 therapy and every 
6 weeks thereafter, up to 6 months, at which time the tumor assessments will follow the 
schedule below:  
• 
At 9 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 
CT scans of additional anatomical locations will be conducted at the above referenced 
visits if prior or suspected disease is clinically indicated. Assessments should be made 
and recorded by the Investigator or an individual authorized by the Investigator.  
MRI or positron emission tomography (PET) scans in lieu of CT scans will be allowed for 
patients who have an intolerability to contrast media. The imaging modality used must 
be uniform for the duration of the study.  
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9.1.1 
Response Criteria 
Tumor response will be determined using RECIST version 1.1 with a modification to 
require confirmation of PD. Refer to Table 1 and Table 2 for RECIST 1.1 response 
criteria definitions. 
CT and MRI (PET) scans will be forwarded to a central imaging facility for adjudicated 
centralized read. Evaluations done by the central reviewers will prevail over locally 
generated assessments in the evaluation of the patient’s efficacy results. Local 
assessments should be used for clinical treatment decisions, however. An 
independent central response adjudication committee will perform an assessment of 
tumor responses.  
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 1 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. 
                                            
1 All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured 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. 
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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 1 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. (Note: 
the appearance of 1 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 1. 
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 
                                            
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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Table 2. 
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 
 
9.1.1.4 Confirmatory Measurement/Duration of Response 
9.1.1.4.1 Confirmation 
To be assigned a status of response, changes in tumor measurements must be 
confirmed by a subsequent assessment that should be performed at least 4 weeks 
after the criteria for response are first met. In the case of SD, follow-up measurements 
must have met the SD criteria at least once after study entry at a minimum interval of 
6 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 progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started) or death. 
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 2-sided, 
95% criteria and implement exact methods. Missing data will not be imputed unless 
defined in the statistical analysis plan (SAP). If inferential statistics are calculated 
(e.g., p-values), they will be used in a descriptive manner.   
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A more detailed description of the analyses and reporting plan of the data will be 
provided in the SAP.  
10.2 Study and Analysis Populations 
The 2 study cohorts (Cohort 1 and Cohort 2) comprise the Tumor Harvested (TH) 
population defined as all resected patients. The TH population is further divided into 
the following analysis populations: 
• 
The primary safety population consists of subjects in the TH population who 
received at least one component of the study treatment; cyclophosphamide, 
fludarabine, LN-144 or IL-2.  The TH population is the secondary safety analysis 
population. 
• 
The All-Treated population consists of subjects in the safety population who have 
been successfully treated with LN-144 followed by IL-2 (at least 1 dose) 
subsequent to treatment of the patient with nonmyeloablative chemotherapy. 
• 
The non-treated population is the rest of patients in the TH who did not receive 
any component of the study treatment. 
Responders (PR or CR) among the All-Treated will be used to summarize the 
duration of response. Patients who are rescreened, re-harvested, and retreated 
(Cohort 3) will have their safety and efficacy data tabulated separately. There will be 
no formal comparisons among cohorts. 
10.3 Endpoints 
10.3.1 
Primary 
The 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.  
10.3.2 
Secondary 
The secondary endpoints are the ORR, CR using RECIST 1.1 criteria. The ORR is 
derived as the sum of the number of patients with a CR or partial response (PR) 
divided by the number of patients in the All-Treated population x 100%.  
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The other secondary endpoints will be PFS, DOR and OS. The definition of each of 
these endpoints follows. 
PFS is defined as the time (in months) from the start date of lymphodepletion to PD or 
death due to any cause, whichever event is earlier. Patients not experiencing PD or 
death at the time of data cut or end of study (i.e., database lock) will have their event 
times censored on the last adequate tumor assessment date.  
DOR 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 progressive disease (PD) 
or death occurs. Patients not experiencing PD or death prior to the time of data cut or 
end of study will have their event times censored on the last adequate tumor 
assessment date.  
OS is defined as the time (in months) from the start date of the lymphodepletion to 
death due to any cause. Patients not having expired at the time of data cut or end of 
study will have their event times censored on the last date of their known survival 
status. 
10.3.3 
Exploratory 
The exploratory endpoints include measures of LN-144 persistence in the peripheral 
blood as well as immune response with the objective to evaluate their correlation with 
response, outcome, and toxicity of the treatment; ir-RECIST will also be assessed in 
addition to RECIST. HRQoL will be assessed using the EORTC QLQ-C30 instrument 
and analyzed per the Evaluation Manual. 
10.4 Sample Size Consideration 
A sample size of approximately 20 patients per cohort (Cohort 1 and Cohort 2) who 
completed treatment, will be able to observe at least 1 unique Grade 3 or 4 adverse 
event with >70, >80, and >87% probability when the true incidence rate is 3, 4, and 5% or 
higher, respectively.  
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10.4.1 
Baseline Demographics and Clinical Characteristics 
Baseline demographic and clinical (disease) characterized will be summarized 
descriptively for the Safety and the All-Treated patient populations if they are not 
identical. Age will be derived as a function of the date of informed consent. 
10.4.2 
Safety Analysis, Primary Endpoint 
The primary safety variable is a binomial proportion and will be summarized using 
both a point estimate and its 2-sided 95% confidence limits. 
10.4.3 
Efficacy Analysis, Secondary Endpoints 
The secondary efficacy (ORR and CR) variables are binomial proportions and will be 
summarized using both a point estimate and its 2-sided 95% confidence limits based 
on the Wilson’s score method.  
PFS, OS, durations of overall are time-to-event variables subjected to right censoring. 
Kaplan-Meier probabilities and related summary statistics will be provided for the 
entire time-to-event curve as well as for the following landmark event-free rates: 
6 months, 12 months, 18, months, and 24 months. The landmark analyses will be 
applied to the PFS and OS data.  
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. Treatment emergent is considered to start the time of 
lymphodepletion for the Safety and All-Treated populations. Adverse event 
summaries will be based on patient incidence counts and their related percentages; 
the number of events will be displayed as appropriate. In addition to an overall 
summary of adverse events, separate displays will be made by severity and 
relationship. Certain safety data will be amenable to summary by use of toxicity 
grades, and all such analyses will evaluate the worst grade observed per patient 
during the treatment-emergent period. These toxicity grade summaries will be derived 
separately based on the current version of CTCAE for each measure under 
consideration (e.g., ANCs for neutropenia; platelets for thrombocytopenia). 
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10.4.5 
Other Planned Analyses 
No additional analyses are planned. Should exploratory analyses other than those 
described in the study protocol, the SAP, or the DSMB charter be performed, their 
details will be described in the Clinical Study Report. 
11 CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS 
11.1 Medications 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 LN-144 Treatment  
Early toxicities related specifically to the infusion of the cells (those seen immediately 
following cell infusion and prior to IL-2 administration) are generally mild and include 
fevers, chills, headache, and malaise. Toxicities that occur following administration of 
IL-2 but 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 Section 6.16.2). The use of the nonmyeloablative 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 6.16.2 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 
14 June 2010.  
12.1 Definitions 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
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. 
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Events that do not meet the definition of an AE include: 
• 
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 intensive care unit (ICU) 
specifically for administration of study treatment is not considered a serious adverse 
event.  
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12.2 Reporting Procedures for Adverse Events 
12.2.1 
All Adverse Events 
All AEs occurring after signature of informed consent and either observed by the 
Investigator or reported by the patient (whether or not attributed to the use of IL-2 or 
LN-144 treatment), will be reported on the eCRF. Monitoring and reporting of AEs will 
be conducted through 12 months from the last dose date of IL-2 or until the first dose 
date of the next line of anti-cancer therapy, whichever occurs first. 
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, LN-144, 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 while on the study, the Investigator will inform the Sponsor as 
soon as possible. (Note: Death due to disease progression should not be reported as 
an 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. 
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 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: 
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• 
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 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 
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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 while on the 
study (from signature of informed consent until last study visit). 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 v 4.03 
guidelines. 
All SAEs that occur during the study 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. All AEs and SAEs will be captured in the eCRF within the 
timelines outlined in the eCRF completion guidelines. SAEs will also be reported 
using the paper SAE report form. 
SAE reports will be reported to Drug Safety Solutions, Inc., via 
 
or 
 
Reporting to Regulatory Agencies and Institutional Review Boards (IRBs): 
In the event of a suspected unexpected serious adverse reaction (SUSAR), 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 potential serious risks from clinical trials or any other source 
based on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations and the EU Clinical Trial Directive (2001/20/EC) and 
relevant updates. The Sponsor will notify participating sites of relevant SUSAR reports 
and other applicable serious safety findings, which occur during the trial.  
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12.2.5 
Pregnancy Reporting 
Any pregnancy that occurs while on the study (including the post study drug follow-up 
period) must be reported using the Pregnancy Questionnaire form within 24 hours of 
becoming aware of the pregnancy. The pregnancy itself is not considered an AE nor is 
an induced abortion to terminate a pregnancy without medical reasons. Any premature 
termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic abortion 
due to complications or other medical reasons) must be reported within 24 hours as an 
AE or SAE. The underlying medical reason for this procedure should be recorded as the 
AE or SAE term. A spontaneous abortion is always considered an SAE and will be 
reported as described in Section 12.2.4.  
The patient should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Drug Safety Solutions, Inc. via 
 
 
 using the Pregnancy 
Outcome form. Any SAE occurring in association with a pregnancy, brought to the 
Investigator’s attention after the patient has completed the study must be promptly 
reported to the Sponsor or their representative. In addition, pregnancies of female 
partners of male study patients enrolled in the study and exposed to study drugs must 
also be reported, with relevant information submitted to the Sponsor or their 
representative within 24 hours. Monitoring of the female partners should continue until 
the conclusion of the pregnancy to determine the outcome and status of mother and 
child. 
12.2.6 
Data Safety Monitoring Board  
An independent DSMB will monitor patient safety during the study. The DSMB will 
evaluate safety data on the first 3 patients completing 12 weeks of assessment. A 
limited analysis may also be conducted reviewing all data available from these 
patients as specified in the DSMB charter. 
The DSMB’s roles, responsibilities, and conduct are described in an independent 
charter. 
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13 ADMINISTRATIVE REQUIREMENTS 
13.1 Adherence to the Protocol  
The Investigator is responsible for ensuring the study is conducted in accordance with 
the procedures and evaluations described in the protocol. The Investigator will not 
deviate from this protocol without obtaining the concurrence of the Sponsor, 
specifically without discussion with the Medical Monitor. 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. 
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 
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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. 
13.3 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. 
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13.4  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/designee. Electronic CRFs will be reviewed for accuracy and 
completeness by Clinical Research Monitors during on- site monitoring visits and after 
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.  
Representatives of the Sponsor’s Clinical Quality Assurance department/designee 
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. 
13.5 Data Handling and Recordkeeping 
13.5.1 
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. 
13.5.2 
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 
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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 study. 
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 study.  
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/designee to determine their acceptability. If necessary, Data 
Correction Requests will be generated for resolution by the study site. 
13.6 Study Completion/Termination 
13.6.1 
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. 
13.6.2 
Study Termination 
The Sponsor reserves the right to temporarily suspend or terminate the study at any 
time. Reasons for such action taken by the Sponsor include, but are not limited to: 
• 
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 
13.7 Monitoring 
On-site monitoring visits will be performed by the Sponsor as frequently as necessary. 
At these visits the monitor will compare the data entered into the eCRFs with the 
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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 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, 
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. 
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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 
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, the Sponsor’s collaborators, 
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 
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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 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 
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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. 
14.8 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 metastatic 
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Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term 
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
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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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Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:122-133. 
19. 
Wu R, Forget MA, Chacon J, et al. Adoptive T-cell therapy using autologous tumor-
infiltrating lymphocytes for metastatic melanoma: current status and future outlook. 
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Sim GC, Chacon J, Haymaker C, et al. Tumor-infiltrating lymphocyte therapy for 
melanoma: rationale and issues for further clinical development. BioDrugs 
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21. 
Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily 
pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. 
Clin Cancer Res 2011;17:4550-4557. 
22. 
Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with 
metastatic synovial cell sarcoma and melanoma using genetically engineered 
lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011;29:917-924. 
23. 
Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high-dose 
interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989;210:474-484; 
discussion 484-475. 
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Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-
dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for 
the treatment of patients with advanced cancer. J Natl Cancer Inst 1993;85:622-
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25. 
Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to 
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Royal RE, Steinberg SM, Krouse RS, et al. Correlates of response to IL-2 therapy 
in patients treated for metastatic renal cancer and melanoma. Cancer J Sci Am 
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27. 
Misko IS, Moss DJ, Pope JH. HLA antigen-related restriction of T lymphocyte 
cytotoxicity to Epstein-Barr virus. Proc Natl Acad Sci U S A 1980;77:4247-4250. 
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28. 
Le AX, Bernhard EJ, Holterman MJ, et al. Cytotoxic T cell responses in HLA-A2.1 
transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a 
restriction element. J Immunol 1989;142:1366-1371. 
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Kirkin AF, Dzhandzhugazyan K, Zeuthen J. Melanoma-associated antigens 
recognized by cytotoxic T lymphocytes. APMIS 1998;106:665-679. 
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Kawakami Y, Eliyahu S, Sakaguchi K, et al. Identification of the immunodominant 
peptides of the MART-1 human melanoma antigen recognized by the majority of 
HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med 1994;180:347-352. 
31. 
Seiter S, Monsurro V, Nielsen MB, et al. Frequency of MART-1/MelanA and 
gp100/PMel17-specific T cells in tumor metastases and cultured tumor-infiltrating 
lymphocytes. J Immunother 2002;25:252-263. 
32. 
Kradin RL, Kurnick JT, Lazarus DS, et al. Tumour-infiltrating lymphocytes and 
interleukin-2 in treatment of advanced cancer. Lancet 1989;1:577-580. 
33. 
Tessier MH, Pandolfino MC, Jotereau F, et al. Home therapy with autologous 
tumour-infiltrating lymphocytes and subcutaneous interleukin-2 in metastatic 
melanoma. Eur J Cancer 1996;32A:735-736. 
34. 
Goedegebuure PS, Douville LM, Li H, et al. Adoptive immunotherapy with tumor-
infiltrating lymphocytes and interleukin-2 in patients with metastatic malignant 
melanoma and renal cell carcinoma: a pilot study. J Clin Oncol 1995;13:1939-
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Ravaud A, Legrand E, Delaunay MM, et al. A phase I trial of repeated tumour-
infiltrating lymphocyte (TIL) infusion in metastatic melanoma. Br J Cancer 
1995;71:331-336. 
36. 
Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating 
lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic 
melanoma. A preliminary report. N Engl J Med 1988;319:1676-1680. 
37. 
Topalian SL, Solomon D, Avis FP, et al. Immunotherapy of patients with advanced 
cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot 
study. J Clin Oncol 1988;6:839-853. 
38. 
Aebersold P, Hyatt C, Johnson S, et al. Lysis of autologous melanoma cells by 
tumor-infiltrating lymphocytes: association with clinical response. J Natl Cancer Inst 
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39. 
Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive 
immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 
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Alexander RB, Rosenberg SA. Long-term survival of adoptively transferred tumor-
infiltrating lymphocytes in mice. J Immunol 1990;145:1615-1620. 
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41. 
Song S, Zhang K, You H, et al. Significant anti-tumour activity of adoptively 
transferred T cells elicited by intratumoral dendritic cell vaccine injection through 
enhancing the ratio of CD8(+) T cell/regulatory T cells in tumour. Clin Exp Immunol 
2010;162:75-83. 
42. 
Poehlein CH, Haley DP, Walker EB, et al. Depletion of tumor-induced Treg prior to 
reconstitution rescues enhanced priming of tumor-specific, therapeutic effector T 
cells in lymphopenic hosts. Eur J Immunol 2009;39:3121-3133. 
43. 
Wang W, Lau R, Yu D, et al. PD1 blockade reverses the suppression of melanoma 
antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol 
2009;21:1065-1077. 
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Ahmadzadeh M, Felipe-Silva A, Heemskerk B, et al. FOXP3 expression accurately 
defines the population of intratumoral regulatory T cells that selectively accumulate 
in metastatic melanoma lesions. Blood 2008;112:4953-4960. 
45. 
Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with 
metastatic melanoma. Curr Opin Immunol 2009;21:233-240. 
46. 
Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine 
sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-
specific CD8+ T cells. J Exp Med 2005;202:907-912. 
47. 
Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and 
autoimmunity in patients after clonal repopulation with antitumor lymphocytes. 
Science 2002;298:850-854. 
48. 
Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following 
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients 
with refractory metastatic melanoma. J Clin Oncol 2005;23:2346-2357. 
49. 
Radvanyi LG, Bernatchez C, Zhang M, et al. Specific lymphocyte subsets predict 
response to adoptive cell therapy using expanded autologous tumor-infiltrating 
lymphocytes in metastatic melanoma patients. Clin Cancer Res 2012;18:6758-
6770. 
50. 
Pilon-Thomas S, Kuhn L, Ellwanger S, et al. Efficacy of Adoptive Cell Transfer of 
Tumor-infiltrating Lymphocytes After Lymphopenia Induction for Metastatic 
Melanoma. Journal of Immunotherapy 2012;35:615-620 
610.1097/CJI.1090b1013e31826e31828f31825f. 
51. 
Itzhaki O, Hovav E, Ziporen Y, et al. Establishment and large-scale expansion of 
minimally cultured "young" tumor infiltrating lymphocytes for adoptive transfer 
therapy. J Immunother 2011;34:212-220. 
52. 
Ellebaek E, Iversen TZ, Junker N, et al. Adoptive cell therapy with autologous 
tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma 
patients. J Transl Med 2012;10:169. 
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53. 
Besser MJ, Shapira-Frommer R, Treves AJ, et al. Clinical responses in a phase II 
study using adoptive transfer of short-term cultured tumor infiltration lymphocytes 
in metastatic melanoma patients. Clin Cancer Res 2010;16:2646-2655. 
54. 
Goff SL, Smith FO, Klapper JA, et al. Tumor infiltrating lymphocyte therapy for 
metastatic melanoma: analysis of tumors resected for TIL. J Immunother 
2010;33:840-847. 
 
 
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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.  
2. 
Medical History including melanoma disease history, prior radiotherapy, prior cancer related surgery and prior systemic therapy (with start/stop 
dates). In addition, date of most recent disease progression, if applicable should be documented. 
3. 
List only medications that are NOT part of the tumor harvest procedure. 
4. 
Vital signs will include pulse rate, respiratory rate, blood pressure, and temperature. On Day 0 (LN-144 infusion), vital signs will be monitored 
every 30 minutes during infusion then hourly (+/-15 minutes) for 4 hours and then routinely (every 4 to 6 hours), unless otherwise clinically 
indicated, for up to approximately 24 hours post LN-144 infusion. 
5. 
CMV assay if clinically indicated. Required on Days 1 and 3. 
6. 
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. 
7. 
Required for Screening, then imaging as clinically indicated. If screening image shows abnormalities, obtain at Day -14. At Investigator 
discretion, the repeat brain MRI may be done as early as day -21. Include neck if there is prior or suspected neck disease. MRI or PET scans 
will be allowed in lieu of CT for patients who have an intolerability to contrast media. The imaging modality used must be uniform for the 
duration of the study.  
8. 
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]. Uric acid not collected on Days -7 through -1 and Day 1 through 4 
9. 
Thyroid panel: TSH and Free T4. Obtain only as clinically indicated beginning at Day 84/Week 12 and during Follow-up. 
10. Complete blood count with differential 
11. Dipstick urinalysis with culture, if indicated 
12. Calculate creatinine clearance using Cockcroft-Gault calculation 
13. Serum pregnancy test for women of childbearing potential   
14. HLA typing to be sent to central laboratory 
15. Pulmonary evaluation for all patients   
16. Patients with documented Grades 2 or greater diarrhea or colitis as a result of previous treatment with ipilimumab, tremelimumab, or anti-PD1 
or anti-PD-L1 antibodies must have been asymptomatic for at least 6 months or had a normal colonoscopy post treatment, with uninflamed 
mucosa by visual assessment.  
17. One to 2 days after the last dose of agent in the preparative regimen 
18. Initiate within approximately 10-24 hours after TIL infusion and continue every 8 hours for up to 6 doses. IL-2 dosing is allowed for up to 
4 days post LN-144 infusion for proper management of IL-2 toxicity, if necessary. 
19. Continue until neutrophils count >1000/mm3 X 3 consecutive days or per standard of care at the institution.   
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20. The TMP/SMX DS schedule should be adjusted to QD 3 times per week (Monday, Wednesday, Friday) and continue for at least 6 months and 
until CD4 >200/mm3 or per standard of care at the institution 
21. Continue until ANC >1000/mm3 or per standard of care at the institution  
22. In patients positive for HSV continue until CD4 > 200/mm3 or per standard of care at the institution    
23. 50 mL of blood drawn using vacutainers (refer to the Laboratory Manual). To be sent to central laboratory. There is a -/+ 2-days window for the 
Immune Monitoring samples. If the scheduled visit is on a Friday, the Immune Monitoring sample should be collected on the prior Thursday. If 
the scheduled visit is on a Saturday or Sunday, the Immune Monitoring sample should be collected on the following Monday. 
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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 
Hyperbilirubinemia 
3 or 4 
Observation 
If other toxicities 
occur 
simultaneously 
No 
Anemia  
3 or 4 
Transfusion with PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytopenia 3 or 4 
Transfusion with 
platelets 
If uncontrolled 
despite all 
supportive 
measures 
No 
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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 
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Expected toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
Stop Treatment 
** 
Elevated 
transaminases 
3 or 4 
Observation 
For Grade 4 
without liver 
metastases 
If changes have 
not improved to 
baseline by next 
dose 
Electrolyte 
imbalances 
3 or 4 
Electrolyte replacement 
If uncontrolled 
despite all 
supportive 
measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to Grade 2 or less by next 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 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012
142s112lbl.pdf 
 
 
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APPENDIX 8: FLUDARABINE PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020038s032lbl.p
df 
 
 
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APPENDIX 9: IL-2 (ALDESLEUKIN) PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.
pdf 
 
 
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APPENDIX 10: RECOMMENDED PROTOCOL FOR THAWING AND REINFUSION OF 
CRYOPRESERVED PRODUCT (COHORT 2) 
Thawing Protocol 
1. Wearing appropriate personal protective equipment, obtain frozen cassette from 
dry shipper or LN2 storage unit. 
2. Open cassette and carefully transfer the frozen product bag into a sealable 
plastic thaw bag. Do not unfold label flap. 
3. Gently squeeze excess air out of thaw bag and seal. 
4. Record start time of thaw of (first) bag. 
5. Submerse thaw bag in a 37°C water bath and gently rock underwater until most 
of the product is thawed, with only a few small ice crystals remaining 
(approximately 3-5 minutes). 
6. Dry off any excess moisture from the outside of the thaw bag. Remove product 
bag from thaw bag. 
7. Wipe with 70% isopropanol disinfectant and transfer to laminar flow hood or 
glove box. 
8. Repeat steps 1 - 7 for each additional bag thaw. 
 
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APPENDIX 11: EORTC QLQ-C30 (VERSION 3) 
 
 
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APPENDIX 12: SUMMARY OF CHANGES IN AMENDMENT 5  
The main purposes for revising the C-144-01 protocol are to: 
• Addition of cohort of patients receiving LN-144 produced with a shortened 
process 
• Addition of cohort of patients harvested and treated a second time 
• Addition of an additional assessment time point 
• Addition of exploratory endpoint of HRQoL 
• Numerous clarifications to statistical section and minor operational 
changes addressing operational issues 
• Numerous typographical changes were made for clarity and consistency. 
This Summary of Changes outlines noteworthy changes from Amendment 4 to 
Amendment 5, and includes rationales for the changes. 
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SUMMARY OF CHANGES 
Notable changes are described in the table below. Deletions of text are presented in strikethrough format. Added/new text is 
presented in bold format.   
Section  
Changed to 
Rationale 
Protocol Title - Cover Page; 
Sponsor and Investigator 
Signature Pages; Synopsis 
A Phase 2, Multicenter, Single arm 3-Cohort Study to Assess the Safety 
and Efficacy of Cell Transfer Therapy Using Autologous Tumor Infiltrating 
Lymphocytes (LN-144) Followed by IL 2 for Treatment of Patients with 
Metastatic Melanoma 
Updated protocol title to reflect 
current design. 
Cover Page 
Lion Biotechnologies, Inc. 
112 W. 34th Street, 
New York, NY 10120 
999 Skyway Rd, Suite 150 
San Carlos, CA 94070 
Updated to reflect Sponsor’s current 
mailing address. 
Synopsis - Indication 
Treatment of patients with metastatic melanoma that has progressed 
following prior system therapy 
Updated for clarity. 
Synopsis – Study 
Objectives; Section 6.3 
Exploratory Objectives 
• 
To explore the persistence of LN-144 and potential immune correlates 
of response, outcome, and toxicity of the treatment. 
• 
Health-related quality of life (HRQoL). 
Added an exploratory endpoint to 
assess any effects on health-related 
quality of life. 
Synopsis - Study Design; 
Section 2.1 
Prospective, single-arm 3-cohort interventional study evaluating adoptive 
cell therapy (ACT) with autologous TIL infusion (LN-144) followed by IL-2 
after a nonmyeloablative chemotherapy preparative regimen.   
Updated to reflect current study 
design. 
Synopsis - Dose and 
Treatment Schedule  
The cell transfer therapy used in this study involves patients receiving a 
lymphocyte-depleting preparative regimen, followed by infusion of 
autologous TIL (LN-144) followed by the and administration of a regimen of 
IL-2 at 600,000 IU/kg approximately every 8 hours for up to a maximum of 
6 doses, starting 1210-24 hours after cell infusion. Patients will be 
evaluated for response at approximately 12 weeks 6 weeks (Day 42) 
following the LN-144  
Clarification of timing of 
assessments for efficacy endpoints 
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therapy and at which time the tumor assessments will follow the schedule 
below: every 6 weeks thereafter, for up to 6 months.  
After 6 months, patients will be evaluated as noted below: 
• 
At 9 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 
Patients will receive 1 course of LN-144 treatment in cohorts 1 and 2. 
Patients may be re-entered into a retreatment third cohort for a 
second treatment with TIL therapy.  
 
Synopsis - Duration of Study 
Participation  
Screening and tumor resection/TIL harvest: up to 6 weeks 
Lymphodepletion: 1 week 
Treatment period (LN-144 + IL-2): up to 5 days 12 weeks 
Long term Follow-up period: up to 2 years 
Overall Survival Follow-up: up to an additional 3 years for a total Follow up 
of 5 years following LN-144 therapy (under separate protocol). 
Clarification of treatment periods 
with addition of long term survival 
follow up 
Synopsis - Number of Study 
Centers  
Approximately ten 35 clinical sites 
Provision for additional sites to 
accommodate patients in additional 
cohorts 
Synopsis - Number of 
Planned Patients 
Approximately 40 twenty patients who complete treatment 
(approximately 20 patients in Cohort 1 and 20 patients in Cohort 2). 
Complete treatment is defined as successful infusion with LN-144 followed 
by at least 1 dose of IL-2. Of the completed patients, up to 10 are 
allowed to enter a third treatment cohort where they can be retreated 
with TIL therapy. 
Addition of cohort will allow clinical 
experience with LN-144 produced 
with shortened process and 
cryopreserved. 
Synopsis - Diagnosis and 
Main Criteria for Inclusion; 
Section 4.1 Criteria d, l, m 
d. Patients must be greater than 18 years of age at the time of consent. 
Enrollment of patients greater than 65 years of age can be done 
after consultation with the Medical Monitor. Patients greater than 65 
years of age may be allowed in the study after discussion between the 
Principle Investigator and Medical Monitor regarding the patient’s ability 
to tolerate high dose IL-2. 
Clearer language. No change in 
intent. 
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l. 
Patients must not have received systemic chemotherapy or 
immunotherapy for 2 weeks (targeted therapies) and 4 weeks (all other 
anti-cancer treatment) at the time of enrollment, and there must be no 
intention of receiving any non-protocol systemic anti-cancer 
chemotherapy or immunotherapy during the trial study 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. Palliative radiation therapy is permitted between biopsy and 
lymphodepletion as long as it does not involve lesions being followed 
for response. There is no specific time window post radiation 
therapy, as long as all toxicities have recovered to Grade 1 or less 
or as specified in the eligibility criteria. 
 
Note: Patients may have undergone minor surgical procedures not 
involving general anesthesia within 3 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 
for anti-PD-L1 antibodies must have been asymptomatic for at least 6 
months or had a normal colonoscopy post anti-PD-1/anti-PD-L1 
treatment, with uninflamed mucosa by visual assessment. 
Clarifications with no change in 
intent. 
Synopsis – Main Criteria for 
Exclusion; Section 4.2 
Criterion b 
b. Patients who have received prior cell transfer therapy, which included a 
nonmyeloablative or myeloablative chemotherapy regimen (not 
applicable for patients in the retreatment Cohort 3).  
Retreatment cohort is exempted 
from this criterion. 
Synopsis – Treatment 
Cohorts Groups 
LN-144 (autologous TIL) followed by IL-2 after a lymphocyte-depleting 
preparative regimen as a 3-cohort single arm, open-label treatment. 
Cohort 1: LN-144 process without cryopreservation of the final TIL 
product  
Cohort 2: LN-144 process with cryopreservation of the final TIL 
product  
Cohort 3: Retreatment cohort: Patients from Cohort 1 or 2 may 
rescreen for a second LN-144 harvest and treatment, if they meet all 
inclusion and exclusion criteria (except exclusion b). These patients 
will have a second tumor harvest and LN-144 treatment as per their 
Provides definition of new cohorts. 
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prior cohort assignment. Nonexclusive examples of this cohort are 
prior responders who relapse, non-responders, and patients with 
manufacturing failures. 
Synopsis – Early 
Discontinuation from Study 
or Treatment 
Criteria for early discontinuation from study: 
• 
Patient Subject has become ineligible for study after tumor harvest 
enrollment and prior to LN-144 or IL-2 administration 
• 
Progressive disease at 12 weeks or later 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the 
patient 
Allow follow up for survival of 
patients who do not respond.  
1.3 (Production and 
Expansion of TIL), Figures 1 
and 2 
Updated figure titles to reflect the LN-144 manufacturing process with and 
without cryopreservation. 
Updated for clarity. 
1.4 (LN-144 TIL Therapy) 
LN-144 is an autologous, ready-to-infuse, TIL therapy and is almost 
identical comparable to that developed by Dr. Steven Rosenberg and 
colleagues at the National Cancer Institute NCI. TIL have demonstrated 
efficacy in the treatment of patients with Stage IV advanced melanoma. , 
and Phase 2 clinical trials evaluating this investigational product have 
shown an objective response rate of 49% or more, exceeding rates 
reported by other immunotherapies in melanoma.  The present This study 
is being conducted to further evaluate: 1) the safety of LN-144 therapy and 
2) the efficacy of LN-144 therapy and 3) the efficacy of retreatment in 
responders who have progressed. 
Minor clarifications plus addition of 
retreatment cohort. 
 
The final investigational product will be available for administration in 1 of 
3 volumes for infusion:  
Cohort 1 (LN-144 manufacturing process without final 
cryopreservation): 
4) 250 mL (in a 300-mL capacity infusion bag) when the total TIL 
harvested are ≤75 x 109 
Adds description of cryopreserved 
product. 
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OR  
5) 500 mL (in a 600-mL capacity infusion bag) when the total TIL 
harvested are <150 x 109 
Cohort 2 (LN-144 manufacturing process with final cryopreservation): 
6) Up to five infusion bags containing up to approximately 
100 mL of thawed cells. The number of infusion bags is 
dependent on the cell concentration 
2.1 (Description of the 
Study) 
This is a prospective 3-cohort single arm interventional study 
evaluating patients who receive ACT with LN-144 (autologous TIL). 
Patients will receive LN-144 followed by the administration of a regimen 
of IL-2 at 600,000 IU/kg approximately every 8 hours starting 12 10 to 
24 hours after the LN-144 infusion and continuing for up to 6 doses. 
Patients will be evaluated for response approximately 6 12 weeks 
following LN-144 therapy and then every 6 weeks up to 6 months.  
After 6 months, patients will be evaluated at 6, 9, 12, 18 and 24 months 
following LN-144 treatment. Formal response evaluations will be per 
RECIST 1.1.  
Patients who have completed the 24 months’ study and patients who 
have progressive disease after Day 84 will also be followed up for 
overall survival for up to 3 years. 
Updated to reflect current study 
design, and clarify follow-up period 
3.2.3 (Exploratory 
Endpoints) 
• 
Evaluation of TIL persistence in the peripheral blood and immune 
correlates with respect to response, outcome, and/or toxicity of the 
treatment. These data will not be reported in the clinical study report 
but instead in a separate report. 
• 
EORTC QLQ-C30 HRQoL questionnaire 
Added the EORTC QLQ-C30 
HRQoL questionnaire as a measure 
of the health-related quality of life 
assessment 
4.3 (Number of Patients) 
Patients who sign an ICF and fail to meet the inclusion and/or exclusion 
criteria and/or do not have tumor harvest within 6 weeks of signing 
the ICF are defined as screen failures. 
The screening and tumor resection/TIL harvest period is up to 6 weeks. 
However, it can be extended, after discussion between the Investigator 
and approval by the Medical Monitor, if there is delay in scheduling the 
tumor resection. 
Clarification of timings and provision 
for new cohorts 
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For all screen failures, tThe Investigator is to maintain a master screening 
log of all consented patients screening log that documents all screen 
failures at a minimum, the patient initials, or other identifier used by site, 
patient date of birth and the 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 electronic data capture (EDC) 
database as defined in the electronic case report form (eCRF) 
completion manual. 
Patients will be enrolled until approximately 40 20 patients have been 
successfully treated with LN-144 followed by at least 1 dose of IL-2 
administration. Screening may halt once it becomes likely that the full 
enrollment accrual goal will be met. Patients from Cohorts 1 and 2 may 
screen for the retreatment Cohort 3 as long as this study is open. 
4.3.1 (Re-screening 
Patients) 
Patients who fail the initial screening process may be rescreened for 
eligibility. The Principal Investigator and Medical Monitor will discuss the 
patient prior to any rescreening procedures and agree on which screening 
procedures need to be redone.  
Patients from Cohort 1 or 2 may also be rescreened and retreated if 
they meet all inclusion and exclusion criteria (except exclusion b), 
they will have a second tumor harvest for LN-144 treatment as per 
their prior cohort assignment. Nonexclusive examples of this group 
are prior responders who relapse, non-responders, and patients with 
manufacturing failures. 
Provision for new cohorts 
4.3.2 (Patient Cohorts) 
All patients treated with LN-144 followed by at least 1 dose of IL-2 are 
defined as the ‘all-treated population’, and all patients resected for harvest 
will be defined as the Tumor Harvested population 
Patients will be assigned to Cohorts 1 or 2 as follows. All patients will 
be assigned to Cohort 1 until Cohort 2 treatment is available from 
Lion. Subsequently, once patients qualify and approximately 15 
patients receive TIL/IL-2 in Cohort 1, a new patient will be assigned to 
the cohorts in the following order to achieve an approximately 1:2 
ratio between subsequent enrollment into Cohorts 1 and 2. The order 
is Cohort 2, then Cohort 1, then Cohort 2, and then the sequence of 
these 3 repeats until the conclusion of the study. If a manufacturing 
slot for the specified cohort is not available, then the patient will be 
assigned to the other cohort and no attempt made to make up for the 
Statistical clarifications to 
accommodate new cohorts 
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skipped cohort. If Cohort 1 approaches or passes the desired 
20-patient enrollment, the order of the subsequent enrollment into the 
cohorts may be adjusted to minimize over-enrollment into Cohort 1. 
The A Data Safety Monitoring Board (DSMB) will evaluate safety data on 
the first 3 patients completing 12 weeks of assessment. Additional 
analyses may limited analysis will also be conducted reviewing all data 
available from these patients as specified in the DSMB charter. 
The primary efficacy and safety analyses will take place after 12 
weeks following the LN-144 administration of the last patient in the 
second cohort, and the final analysis will take place at the end of 
study. 
An additional third cohort will consist of patients who wish to 
rescreen for a second harvest of tumor for LN-144 manufacture and 
treatment. Nonexclusive examples of patients that may be eligible for 
retreatment (Cohort 3) are prior responders to LN-144 who relapse, 
non-responders, and patients with manufacturing failures. These 
patients will need to be rescreened, meet all eligibility criteria (except 
exclusion criteria b) and will have all screening assessments redone 
except for the HLA typing. Of the 40 enrolled patients enrolled in 
Cohort 1 and 2, approximately 10 patients may rescreen for a second 
tumor harvest for LN-144 treatment in Cohort 3. 
6.1 (Screening) 
• Slit Lamp eye exam. Prior evaluation within the past 30 days will 
fulfill this requirement.  
• Electrocardiogram (EKG). Prior evaluation within the past 60 days 
will fulfill this requirement. 
• Cardiac evaluation (stress thallium) for all patients. Echocardiogram or 
multiple gated acquisition scan (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. Prior 
evaluations within the past 6 months will fulfill this requirement. 
• Pulmonary function tests if indicated. Prior evaluations within the 
past 6 months will fulfill this requirement. 
Clarifies screening assessments for 
which recently conducted 
assessments/tests may be used for 
screening purposes, including the 
timing of such prior assessments. 
6.2 (Enrollment and Tumor 
Resection) 
If enrolled When the Medical Monitor has approved the patient to be 
enrolled into the study, tumor resection will take place. The patient is 
Minor clarifications and operational 
changes 
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enrolled into the study when resection has started. The date of tumor 
resection is expected to occur approximately 44 days prior to the LN 144 
infusion (Day 0) and is dependent on the rate of cell growth at the central 
LN-144 manufacturing facility. The following procedures should be 
completed during this visit. 
• 
Verification of all ongoing concomitant medications (list only 
medications that are NOT part of the tumor harvest procedure) 
• 
ECOG performance status evaluation 
• 
Obtain blood for immune monitoring (50 mL of blood to be obtained. 
Refer to Laboratory Manual) 
• 
Tumor Harvest  
• 
Ten Six paraffin embedded slides created from the tumor resection 
for biomarker analyses and DNA sequencing 
• 
Assessment of AE/SAEs   
6.2.1 (Tumor Harvest and 
Processing Procedure) 
The tumor (ideally 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. … 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. 
Further details and additional instructions are available in the Tumor 
Procurement Manual. 
Details of harvest removed from 
protocol and referred to the specific 
manual 
6.3 (Day -14); 6.11 (Day 84/ 
Week 12 and Day 126/ 
Week 18 ( +/- 3 days) 
[Day 84 only]); 6.12 (Months 
6 (+/- 1 week), 9 (+/- 1 
week), 12 (+/- 1 week), 18 
(+/- 3 weeks), and 24  
(+/- 3 weeks) (Months 6, 12, 
24 only) 
Added the EORTC QLQ-C30 HRQoL questionnaire to the respective visit 
assessments. 
Added the EORTC QLQ-C30 
HRQoL questionnaire as a measure 
of the health-related quality of life 
assessment 
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6.4 (Day -7) 
Prior to the start of lymphodepletion, verification of sufficient LN-144 
expansion at this time point will be confirmed. In Cohort 2, the REP may 
be extended an additional 7 days if growth is inadequate in which 
case, the Day -7 and subsequent visits would be delayed 1 week.  
In addition, prior to beginning the lymphodepletion for all Cohorts, 
the Investigator should assess whether the patient has had any 
clinical deterioration, which would put him/her at increased risk when 
subsequently receiving the high-dose IL-2. Specifically, the 
Investigator should consider whether a worsening of ECOG status 
and/or a deterioration of laboratory values is such that the patient no 
longer meets the requirements of the inclusion and exclusion criteria. 
If this deterioration is believed to be reversible, the LN-144 
investigational product may remain frozen at the appropriate stage 
and the schedule adjusted to allow recovery and subsequent LN-144 
administration. If the deterioration is believed irreversible and of 
sufficient magnitude to increase the risk of high-dose IL-2 
administration, the patient should not proceed to lymphodepletion 
and subsequent therapy and be followed as per Section 6.15: 
Addition of recheck of ability to 
tolerate high dose IL-2 based on 
recommendation from DSMB 
6.4 (Day -7); 6.5 (Day -6); 
6.6 (Day -5 to Day -1) 
• 
Verification of all ongoing concomitant medications 
• 
Chemistry – Sodium, Potassium, Chloride, Total CO2 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) 
Specified that concomitant 
medications will be recorded and 
verified; also removed uric acid and 
thyroid panel from the serum 
chemistry assessments at these 
visits. 
6.7.1 (Investigational 
Product) 
6.7.1 
Investigational Product Cohort 1 
The investigational product will be shipped overnight by courier to the 
clinical site pharmacy in a Nanocool™ shipper shipping container 
validated to maintain an the appropriate investigational product 
temperature of 2-8°C. The product temperature will be continuously 
monitored by a TempTale 4™, which will be placed in the container in 
contact with the investigational product.  
The investigational product will be received by the appropriate clinical 
pharmacy for the particular patient. After verification and labeling at the 
pharmacy, the investigational product will be returned to the shipper to 
maintain temperature as the investigational product is transferred to the 
Clarification that supportive 
medications may be given as per 
institutional practice. Clarification of 
use of shipping container. 
 
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patient bedside. Upon receipt by the infusing physician and double 
verification for identity the investigational product may be removed from 
the Nanocool™ shipper and prepared for infusion. See the LN-144 
Pharmacy and Administration Manual for precise details for handling 
of LN-144 for Cohort 1 (non-cryopreserved cells) or Cohort 2 
(cryopreserved cells). … 
• 
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 will be given as per 
standard of care 
 
• 
LN-144 Infusion:  Autologous TIL (LN-144) will be administered 
intravenously. The investigational product will be administered (by 
gravity) within approximately 45 minutes. If interruption of infusion is 
required for medical reasons, the investigational product infusion 
should be completed within 3 hours of beginning infusion. 
Investigational Product not infused within 3 hours should be 
discarded. During periods of infusion interruption, the LN-144 
fresh or thawed product should be refrigerated. returned to the 
Nanocool 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 < 150 x 109 LN 144. Further details of the 
administration procedure will be are provided in the LN-144 Pharmacy 
and Administration Manual. 
 
6.14 (Patients with PD at 
Day 84) 
6.14 
Patients with Progressive Disease at Day 84 
Patients with progressive disease at Day 84 should remain on study 
but the data collection will be reduced to survival status and other 
anti-cancer medications. This data will be collected every 3 months 
and may be done by telephone contact. 
Adds long term survival follow up for 
all patients 
6.14.4 (Empiric Antibiotics) 
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. 
Deleted to reduce redundancy 
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6.15 (Patients who do not 
Receive a LN-144 Infusion) 
6.15 
Patients Who Do Not Receive a LN-144 Infusion 
Some patients may undergo harvest and LN-144 manufacture but do 
not receive the infusion of investigational product. If this is due to a 
potentially treatable medical event, the pre-REP cells (Cohort 1) or the 
REP cells (Cohort 2) may remain frozen for a period of time agreed 
between the Investigator and Medical Monitor to see if the patient 
recovers and meets criteria to receive the TILs. If a decision is taken 
that the patient will not receive their TILs, then the patient should 
remain on study but the data collection will be reduced to survival 
status and other anti-cancer medications. This data will be collected 
every 3 months and may be done by telephone contact. 
Provides a mechanism to delay 
treatment for patients who develop a 
reversible clinical deterioration which 
prevents them from receiving the 
LN-144 on time but could be given 
later 
7.1 (Treatment Completion) 
Completion of treatment is defined as successful infusion with LN-144 
followed by the 12 week a minimum of 1 dose of IL-2. 
Clarifies the definition of study 
completion 
7.2 (Criteria for Early 
Discontinuation from Study 
or Treatment) 
Criteria for early discontinuation from study 
Patient Subject has become ineligible for study after enrollment tumor 
harvest and prior to LN-144 TIL or IL-2 administration 
Changed for clarity 
8 (Study Drug Information) 
Investigational Product Name: LN-144 
Active Investigational Product Components: Autologous, viable, tumor 
infiltrating lymphocytes (TIL) 
Dosage Form: Live cell suspension either non-cryopreserved fresh 
(Cohort 1) or cryopreserved (Cohort 2) 
Describes the cryopreserved product 
from the shortened process used in 
Cohort 2 
 
Qualitative Composition:  LN-144 is a cellular investigational 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 
either formulated in HypoThermosol™ transport medium, Plasma-Lyte® A 
with 0.5% HSA (human serum albumin) or Cryostor 5% and 
HypoThermasol for Cohort 2 and 300 IU/mL of IL-2. The suspension 
volume will be between 250 to 500 mL. Only 1 LN-144 dose is given 
intravenously after lymphodepletion chemotherapy followed by high dose 
IL-2 therapy 1012-24 hours after infusion. 
The total volume to be infused will be approximately 250 mL (300 mL 
transfer bag for Cohort 1) for cell concentrations ≤75 x 109 LN-144 or 
500 mL (up to 600 mL transfer bag for Cohort 1) for cell concentrations 
<150 x 109 LN-144. Patients on Cohort 2 will have up to 5 bags containing 
 
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up to approximately 100 mL of thawed cells. 
Manufacturing Process: The overall process of tumor shipping, LN-144 
manufacturing, and LN-144 investigational product shipping, and infusion 
is shown in Figure 2 (Cohort 1) and Figure 3 (Cohort 2). The LN-144 
investigational product is manufactured ex vivo using autologous tumor as 
starting material. The key manufacturing steps include: 
Surgical resection 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. 
Harvesting and cryopreservation of TIL for further scheduling of patient and 
expansion in a rapid expansion protocol (REP) 
A rapid expansion protocol (REP) culture for 14 days in the presence of IL-
2, OKT3, and irradiated allogeneic MNC feeder cells 
Harvesting and formulation of REP expanded investigational product in 
transport medium or cryopreserved (as above) and overnight shipment to 
clinical site for infusion 
Final Investigational Product Container: The live suspension of LN-144 for 
Cohort 1 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 <150 x 109 LN-144. Alternatively, in Cohort 2, TILs 
will be received cryopreserved in up to 5 bags containing up to 
approximately 100 mL of thawed cells. 
Transport: Each dose of the live suspension LN-144 will be shipped/sent 
by courier to the clinical site from the LN-144 Manufacturing Facility the 
day before administration using a method that is intended to support 24-
hour delivery. The live suspension investigational 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 (Cohort 1). For Cohort 2, a dry cryoshipper 
will be utilized. 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 
 
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under quarantine. Receipt is defined as the moment the LN-144 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 released by Lion 
and transferred to the patient bedside. The investigational product is 
infused by gravity within approximately 45 minutes. If interruption of 
infusion is required for medical reasons, the investigational product 
infusion should complete within 3 hours of beginning infusion. Refer to 
Investigational Product the LN-144 Pharmacy and Administration Manual 
for additional details. 
9.1 Efficacy Tumor 
Assessments 
Tumor assessment will be performed by clinical exam (skin lesions) 
and by conventional or spiral CT scans of the chest, abdomen, pelvis 
and MRI of brain conducted at Screening, Day -14 and 6 weeks (Day 
42) following the LN-144 therapy and every 6 weeks thereafter, up to 6 
months, at which time the tumor assessments will follow the 
schedule below:  
At 9 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 
CT scans of additional anatomical locations will be conducted at the 
above referenced visits if prior or suspected disease is clinically 
indicated. Assessments should be made and recorded by the 
Investigator or an individual authorized by the Investigator.  
MRI or positron emission tomography (PET) scans in lieu of CT scans 
will be allowed for patients who have an intolerability to contrast 
media. The imaging modality used must be uniform for the duration 
of the study. 
An additional assessment at 4.5 
months has been added to better 
define time to response 
9.1.1 (Response Criteria) 
Clinical Tumor 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. 
CT and MRI (PET) scans will be forwarded to a central imaging facility 
for adjudicated centralized read. Evaluations done by the central 
reviewers will prevail over locally generated assessments in the 
evaluation of the patient’s efficacy results. Local assessments should 
Describes new central reading 
process 
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be used for clinical treatment decisions, however. An independent 
central response adjudication committee will perform an assessment 
of tumor responses. 
10.2 (Analysis Populations) 
Two analysis populations will be defined to summarize the data. The 
modified Intention to Treat population (ITT) will consist of all resected 
patients. The All-Treated population is based on all resected patients who 
have been successfully treated with LN 144 followed by IL 2 (at least one 
dose).  Responders (PR or CR) among both populations will be used to 
summarize the duration of overall response. The 2 study cohorts (Cohort 
1 and Cohort 2) comprise the Intent-to-Treat (TH) population defined 
as all resected patients. The TH population is further divided into the 
All-Treated and non-treated populations where the All-Treated 
population consists of patients who have been successfully treated 
with LN-144 followed by IL-2 (at least 1 dose). The non-treated 
population is the rest of patients in the TH who are not a part of the 
All-Treated population. 
Responders (PR or CR) among both populations will be used to 
summarize the duration of response. Patients who are rescreened, re-
harvested, and retreated (Cohort 3) will have their safety and efficacy 
data tabulated separately. There will be no formal comparisons 
among cohorts. 
Clarifies definition of analysis 
populations 
10.3.2 (Secondary 
Endpoints) 
The secondary endpoints are the objective response rate (ORR), 
complete response rate (CR) using RECIST 1.1 criteria. …  
Patients not having expired at the time of data cut or end of study will 
have their event times censored on the last date of their known 
survival status. 
The secondary endpoints are the objective response rate (ORR), 
complete response rate (CR) using RECIST 1.1 criteria. The ORR is 
derived as the number of patients with a complete response (CR) or 
partial response (PR) divided by the number of patients in the All-
Treated population x 100%. Patients failing to achieve a CR and PR 
among the denominator patient population will be classified as non-
responders. 
The other secondary endpoints will be progression-free survival 
(PFS), duration of response (DOR) and overall survival (OS). The 
definition of each of these endpoints follows. 
Clarifies secondary endpoint 
statistical methods 
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PFS is defined as the time (in months) from the start date of 
lymphodepletion to PD or death due to any cause, whichever event is 
earlier. Patients not experiencing PD or death at the time of data cut 
or end of study (i.e., database lock) will have their event times 
censored on the last adequate assessment of tumor status.  
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 progressive disease (PD) or 
death occurs. Patients not experiencing PD or death prior to the time 
of data cut or end of study will have their event times censored on the 
last adequate disease assessment date.  
OS is defined as the time (in months) from the start date of the 
lymphodepletion to death due to any cause. Patients not having 
expired at the time of data cut or end of study will have their event 
times censored on the last date of their known survival status. 
10.4 (Sample Size 
Justification) 
The sample size of 20 patients is based on the All Treated population 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 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. 
A sample size of approximately 20 patients per cohort (Cohort 1 and 
Cohort 2) who completed treatment, will be able to observe at least 1 
Grade 3 or 4 toxicity with the true incidence rate of 4% or higher with 
>80% probability. 
Changes sample size for new cohort 
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10.4.3 (Efficacy Analysis, 
Secondary Endpoints) 
The secondary efficacy (ORR and CR) variables are binomial proportions 
and will be summarized using both a point estimate and its 2-sided, exact 
95% confidence limits based on the Wilson’s score method.  
PFS, OS, durations of overall are time-to-event variables subjected to right 
censoring. Kaplan-Meier probabilities and related summary statistics will 
be provided for the entire survival time-to-event curve as well as for the 
following landmark times following the initial dose of lymphodepletion: 
event-free rates: 6 months, 12 months, 18, months, and 24 months 
duration. The landmark analyses will be applied to the PFS and OS data. 
Clarifies sample size calculation but 
does not change original intent 
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. Treatment 
emergent is considered to start the time of harvest surgery (Tumor 
Harvested population) and lymphodepletion (All-Treated population). 
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 severity intensity and relationship. … 
A limited amount of safety data are is collected at the time of resection until 
lymphodepletion. These data will be summarized as needed for both all-
treated and non-treated populations within the TH, but separately from the 
primary safety analyses. 
Minor clarification  
12.1 (Definitions - Adverse 
Event) 
An AE is defined as any untoward medical occurrence in a patient or 
clinical trial subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE is 
defined as any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the 
medicinal product. assessed in eligible patients after enrollment in the 
study. 
Change to new standard safety 
language but does not change 
original intent 
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12.1 (Definitions – Serious 
Adverse Event) 
Any pregnancy that occurs while on the study must be reported to the 
Sponsor or their representative. … Pregnancy information must be 
reported to the Sponsor or their representative. 
Deleted to reduce redundancy 
12.2.1 (All Adverse Events) 
All AEs occurring after signature of informed consent and either observed 
by the Investigator or reported by the patient (whether or not attributed to 
the use of IL-2 or LN-144 treatment), will be reported on the eCRF. 
Monitoring and reporting of AEs will be conducted through the last study 
visit 12 months from the LN-144 infusion or until the first dose date of 
the next line of anti-cancer therapy, whichever occurs first.  
Clarifies the period for reporting 
AEs/SAEs 
12.2.4 (Serious Adverse 
Events) 
All SAEs that occur during the study 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. All AEs and 
SAEs will be captured in the eCRF within the timelines outlined in the 
eCRF completion guidelines. SAEs will also be reported using the 
paper SAE report form. 
Clarifies the reporting of AEs and 
SAEs 
12.2.4 (Serious Adverse 
Events – Regulatory 
Reporting) 
In the event of a serious adverse event suspected unexpected serious 
adverse reaction (SUSAR), 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 
potential serious adverse events over that listed in the protocol or 
investigational Brochure risks from clinical trials or any other source 
based on relevant local legislation or regulations, including the 
applicable US FDA Code of Federal Regulations and the EU Clinical 
Trial Directive (2001/20/EC) and relevant updates. The Sponsor will 
notify participating sites of relevant SUSAR reports and other 
applicable serious safety findings which occur during trial. 
Change to new standard safety 
language but does not change 
original intent 
12.2.5 (Pregnancy 
Reporting) 
Any pregnancy that occurs while on the study … The underlying medical 
reason for this procedure should be recorded as the AE or SAE term. A 
spontaneous abortion is always considered an SAE and will be reported as 
described in Section 12.2.4.  
The patient should receive appropriate monitoring and care until the 
conclusion of the pregnancy. The outcome should be reported to 
Drug Safety Solutions, Inc. via 
 
 using the Pregnancy Outcome form. Any 
Change to new standard safety 
language but does not change 
original intent 
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SAE occurring in association with a pregnancy, brought to the 
Investigator’s attention after the patient has completed the study 
must be promptly reported to the Sponsor or their representative. In 
addition, pregnancies of female partners of male study patients 
enrolled in the study and exposed to study drugs must also be 
reported, with relevant information submitted to the Sponsor or their 
representative within 24 hours. Monitoring of the female partners 
should continue until the conclusion of the pregnancy to determine 
the outcome and status of mother and child. 
12.2.6 (Data Safety 
Monitoring Board) 
An independent DSMB will monitor patient safety during the study. The 
DSMB will evaluate safety data on the first 3 patients completing 
12 weeks of assessment. A limited analysis may also be conducted 
reviewing all data available from these patients as specified in the 
DSMB charter. 
The DSMB’s roles, responsibilities, and conduct are described in an 
independent charter. 
Minor clarification which does not 
change original intent 
13.1 (Adherence to the 
Protocol Modifications) 
The Investigator is responsible for ensuring the study is conducted in 
accordance with the procedures and evaluations described in the 
protocol. The Investigator will not modify deviate from this protocol 
without obtaining the concurrence of the Sponsor, specifically without 
discussion with the Medical Monitor. 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 source 
Minor clarification which does not 
change original intent 
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documents will describe any departure from the protocol and the 
circumstances requiring it. 
Appendix 11 
EORTC QLQ-C30 (Version 4) 
Added the EORTC QLQ-C30 
HRQoL questionnaire to the 
appendices. 
Appendix 12 
SUMMARY OF CHANGES IN AMENDMENT 5 
Added the Summary of Changes 
effective with Amendment 5 
 
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