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 96 
 
 
 
 
CLINICAL PROTOCOL 
 
 
A Phase 2, Multicenter, Single-arm 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  
 
 
PROTOCOL 
NUMBER:   
C-144-01 
SPONSOR: 
Lion Biotechnologies, Inc. 
112 W 34th Street,  
New York, NY 10120 
PROTOCOL 
VERSION: 
Final Version 4.0 
PROTOCOL 
DATE: 
July 18, 2016 
 
 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of 
The Sponsor or their representative and any unauthorized use or disclosure of 
such information without the prior written authorization of The Sponsor or their 
representative is expressly prohibited. 
 
 
 
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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
A Phase 2, Multicenter, Single-arm Study to Assess the 
Safety and Efficacy of Cell Transfer Therapy Using 
Autologous Tumor Infiltrating Lymphocytes (LN-144) 
Followed by IL-2 for Treatment of Patients with 
Metastatic Melanoma  
Protocol Number:  
 
C-144-01 
Sponsor: 
Lion Biotechnologies, Inc. 
Version / Date of Protocol: 
Version 4.0 (July 18, 2016) 
 
 
I agree to conduct the study as detailed in the protocol and in compliance with ICH 
Guidelines for Good Clinical Practice. 
 
I acknowledge that I am responsible for overall study conduct, and I agree to personally 
conduct or supervise the described clinical study. 
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct 
of the study are informed about their obligations.  Mechanisms are in place to ensure 
that site staff receives the appropriate information throughout the study. 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase 2, Multicenter, Single-arm Study to Assess the Safety and 
Efficacy of Cell Transfer Therapy Using Autologous Tumor Infiltrating 
Lymphocytes (LN-144) Followed by IL-2 for Treatment of Patients 
with Metastatic Melanoma  
Study Type: 
Phase 2  
Indication: 
Treatment of metastatic melanoma that has progressed following 
prior systemic therapy 
Investigational 
Agent: 
LN-144:  Autologous Tumor Infiltrating Lymphocytes (TIL) derived 
from the patient’s own tumor 
Study Objectives: 
Primary Objectives 
 
To 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 best overall 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 persistence of LN-144 and potential immune 
correlates of response, outcome, and toxicity of the treatment.  
Study Design: 
Prospective, single-arm interventional study evaluating adoptive cell 
therapy (ACT) with autologous TIL infusion (LN-144) followed by IL-2 
after a non-myeloablative chemotherapy preparative regimen.   
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 administration of a regimen 
of IL-2 at 600,000 IU/kg approximately every eight hours for up to a 
maximum of six doses starting 12-24 hours after cell infusion.  
Patients will be evaluated for response approximately 12 weeks 
following the LN-144 therapy. Patients will receive one course of 
treatment.  
Duration of Study 
Participation: 
Screening and tumor resection/TIL harvest: up to 6 weeks  
Lymphodepletion: 1 week 
Treatment period: 12 weeks 
Long term Follow-up period: up to 2 years 
Follow-up Period: 
Patients will be evaluated as noted below: 
 
At six months (+/- 1 week) following LN-144 treatment 
 
At nine months (+/- 1 week) following LN-144 treatment 
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 
At 12 months (+/- 1 week) following LN-144 treatment  
 
At 18 months (+/- 3 weeks) following LN-144 treatment 
 
At 24 months (+/- 3 weeks) following LN-144 treatment 
Number of Study 
Centers: 
 Approximately ten clinical sites 
Number of Planned 
Patients: 
Twenty patients who complete treatment.  Complete treatment is 
defined as successful infusion with LN-144 followed by IL-2. 
Study Population: 
Diagnosis and Main 
Criteria for Inclusion: 
To be eligible for the study, patients must meet ALL of the following 
criteria prior to enrollment in the study: 
 
a. Patients must have measurable metastatic melanoma and at 
least one lesion that is resectable for TIL generation. 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 three days).  
b. Patients must have undergone at least one 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. 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.  
e. Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1. 
f. 
In the opinion of the Investigator, patient must be capable of 
participating and completing study procedures.   
g. Patients of childbearing potential or with partners of 
childbearing potential must be willing to practice birth control 
during treatment and for four months after receiving all 
protocol related therapy. 
h. Patients must have a serum absolute neutrophil count (ANC) 
greater than 1000/mm3, hemoglobin greater than 9.0 g/dL, 
and platelet count greater than 100,000/mm3. 
i. 
Patients must have a serum ALT/SGPT and AST/SGOT less 
than three times the upper limit of normal (<3x ULN), a 
calculated creatinine 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. 
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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 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           
 
Note: Patients may have undergone minor surgical 
 
procedures not involving general anesthesia within three 
 
weeks prior to enrollment as long as all toxicities have 
 
recovered to Grade 1 or less or as specified in the eligibility 
 
criteria. 
m. Patients with documented Grade 2 or greater diarrhea or 
colitis as a result of previous treatment with ipilimumab, 
tremelimumab, anti-PD1 for 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. 
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 non-myeloablative or myeloablative chemotherapy 
regimen. 
c. Patients who have three or more active brain metastases.  
Note:  Patients with one or two untreated or inadequately 
treated brain lesions or three 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 one month. Brain 
metastases with significant edema and or hemorrhage and 
metastases larger than 2 cm are excluded. 
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 seven 
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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 an LVEF less than 45%. (Older patients 
[60 – 70 years] must have received an echocardiogram within 
the previous 60 days demonstrating LVEF ≥ 45%). 
l. 
Patients who have a documented FEV1 (forced expiratory 
volume in one second) of less than or equal to 60%. 
m. Patients who have had another primary malignancy within the 
previous three years (with the exception of carcinoma in situ 
of the breast, urothelial cancer in situ, and non-melanoma 
skin cancer that has been adequately treated). 
Treatment Groups: 
LN-144 (autologous TIL) followed by IL-2 after a lymphocyte-
depleting preparative regimen as a single arm, open-label treatment. 
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 PI that continued treatment is not in the 
best interest of the patient 
 
Withdrawal by patient. The patient may withdraw consent to 
treatment but continue consent for follow-up evaluations 
and/or survival status 
 
Pregnancy 
Criteria for early discontinuation from study: 
 
Subject has become ineligible for study after enrollment and 
prior to LN-144 or IL2 administration 
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 
Progressive disease at 12 weeks or later 
 
Withdrawal of consent 
 
Death 
Efficacy 
Assessment: 
The descriptive summary of the best overall response rate (ORR), 
complete response rate (CR), duration of response (DOR), 
progression-free survival (PFS) and overall survival (OS) will be used 
to determine the potential efficacy of LN-144. These data will be used 
to support the design of future clinical trials. 
Safety Assessment: 
Treatment-emergent adverse events and serious adverse events will 
be evaluated to assess the safety of this treatment. 
Overview of 
Statistical Plan: 
The primary statistical plan of analysis is based on use of descriptive 
methods.  Point estimates of treatment effect will be derived from 
maximum likelihood methods.  All data will be listed. 
Patients meeting RECIST 1.1 criteria for a complete (CR) or partial 
(PR) response will be classified as responders in the analysis of the 
overall response rate (ORR). This rate will be summarized using both 
a point estimate and its two-sided exact 95% confidence limits. 
All time-to-event efficacy endpoints will use Kaplan-Meier survival 
curve methods to summarize the data. The time origin for all such 
analyses (except for response duration) will be the date on which 
patients began treatment with IL-2 after infusion with LN-144.  
The assessment of safety data will be descriptive and based on the 
summarization of treatment-emergent adverse events, serious 
adverse events, adverse events leading to discontinuation from the 
study, vital signs, physical examinations, and clinical laboratory tests. 
Sample Size 
Determination: 
The per protocol sample size is 20 patients treated with LN-144 
followed by IL-2 administration, which is considered minimum to 
detect one or more Grade 3 or 4 toxicities.  
DSMB Safety 
Assessments: 
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 charter. 
 
 
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STUDY FLOWCHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Enrollment 
TIL  
Harvest 
TIL 
Expansion 
Lympho-
depletion 
LN-144  
Release  
Infusion of LN-144 
followed by IL-2  
Day 42 & 84 
Post-Treatment 
Evaluations 
Follow-up Evaluations: 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
 
 
  
  
 
 
 
 
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TABLE OF CONTENTS 
INVESTIGATOR PROTOCOL SIGNATURE PAGE ________________________________ 3 
PROTOCOL SYNOPSIS ____________________________________________________ 4 
STUDY FLOWCHART _____________________________________________________ 9 
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 ____________________________________________________ 25 
2.1 
Description of the Study_______________________________________________ 25 
2.2 
Description of the Study Centers ________________________________________ 26 
3 
STUDY OBJECTIVES AND ENDPOINTS __________________________________ 26 
3.1 
Study Objectives _____________________________________________________ 26 
3.1.1 
Primary Objectives ________________________________________________________ 26 
3.1.2 
Secondary Objectives ______________________________________________________ 26 
3.1.3 
Exploratory Objectives _____________________________________________________ 26 
3.2 
Study Endpoints _____________________________________________________ 26 
3.2.1 
Primary Endpoints: ________________________________________________________ 26 
3.2.2 
Secondary Endpoints: ______________________________________________________ 27 
3.2.3 
Exploratory Endpoints: _____________________________________________________ 27 
4 
SELECTION OF PATIENT POPULATION __________________________________ 27 
4.1 
Inclusion Criteria_____________________________________________________ 27 
4.2 
Exclusion Criteria ____________________________________________________ 29 
4.3 
Number of Patients __________________________________________________ 31 
4.3.1 
Re-screening Patients ______________________________________________________ 31 
4.3.2 
Patient Cohorts ___________________________________________________________ 32 
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES
 
32 
5.1 
Prior Treatment and Concomitant Medications ____________________________ 32 
5.2 
Prohibited and Permitted Medications during Study Treatment _______________ 32 
5.2.1 
Prohibited Treatment ______________________________________________________ 32 
5.2.2 
Permitted Medications – Use with Caution _____________________________________ 33 
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6 
STUDY PROCEDURES _______________________________________________ 33 
6.1 
Screening __________________________________________________________ 33 
6.2 
Enrollment and Tumor Resection _______________________________________ 35 
6.2.1 
Tumor Harvest and Processing Procedure ______________________________________ 35 
6.2.2 
Immune Monitoring and Sequencing of Tumor and Lymphocyte DNA _______________ 37 
6.3 
Day -14 ____________________________________________________________ 37 
6.4 
Day -7 _____________________________________________________________ 38 
6.5 
Day -6 _____________________________________________________________ 39 
6.6 
Day -5 to Day -1 _____________________________________________________ 40 
6.7 
Day 0  (+2 days) _____________________________________________________ 41 
6.8 
Days 1 – 4 __________________________________________________________ 43 
6.9 
Day 14, 28 (+/- 1 day) _________________________________________________ 44 
6.10 
Day 42 ( +/- 3 days) ___________________________________________________ 45 
6.11 
Day 84/ Week 12 ( +/- 3 days) __________________________________________ 47 
6.12 
Months 6 (+/- 1 week), 9 (+/- 1 week), 12 (+/- 1 week), 18 (+/- 3 weeks), and 24 (+/- 
3 weeks) __________________________________________________________________ 48 
6.13 
Patients Discontinued from Treatment ___________________________________ 49 
6.14 
Expected Toxicities and Treatment Guidelines _____________________________ 50 
6.14.1 
LN-144 ________________________________________________________________ 50 
6.14.2 
IL-2 ___________________________________________________________________ 50 
6.14.3 
Treatment Guidelines for Toxicity Management ______________________________ 51 
6.14.4 
Empiric Antibiotics ______________________________________________________ 51 
6.14.5 
Blood Product Support ___________________________________________________ 51 
6.14.6 
Renal Toxicity __________________________________________________________ 52 
6.15 
Infection Prophylaxis _________________________________________________ 52 
6.15.1 
Pneumocystis Jiroveci Pneumonia __________________________________________ 52 
6.15.2 
Herpes Virus Prophylaxis _________________________________________________ 52 
6.15.3 
Fungal Prophylaxis (Fluconazole) ___________________________________________ 53 
6.15.4 
Empiric Antibiotics ______________________________________________________ 53 
6.15.5 
Blood Product Support ___________________________________________________ 53 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF PATIENTS ________ 54 
7.1 
Treatment Completion ________________________________________________ 54 
7.2 
Criteria for Early Discontinuation from Study or Treatment __________________ 54 
8 
STUDY DRUG INFORMATION _________________________________________ 55 
9 
STUDY ASSESSMENTS _______________________________________________ 57 
9.1 
Efficacy Assessments _________________________________________________ 57 
9.1.1 
Response Criteria __________________________________________________________ 57 
10 STATISTICAL AND ANALYTICAL PLANS __________________________________ 59 
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10.1 
Introduction ________________________________________________________ 59 
10.2 
Analysis Populations _________________________________________________ 60 
10.3 
Endpoints __________________________________________________________ 60 
10.3.1 
Primary _______________________________________________________________ 60 
10.3.2 
Secondary _____________________________________________________________ 60 
10.3.3 
Exploratory ____________________________________________________________ 61 
10.4 
Sample Size Justification ______________________________________________ 61 
10.4.1 
Baseline Demographic and Clinical Characteristics _____________________________ 62 
10.4.2 
Safety Analysis, Primary Endpoint __________________________________________ 62 
10.4.3 
Efficacy Analysis, Secondary Endpoints ______________________________________ 62 
10.4.4 
Safety Analysis _________________________________________________________ 62 
10.4.5 
Other Planned Analyses __________________________________________________ 63 
11 CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS____________________ 63 
11.1 
Drugs Administered during the Study ____________________________________ 63 
11.2 
LN-144 Treatment____________________________________________________ 63 
11.3 
IL-2 Administration ___________________________________________________ 63 
12 ADVERSE EVENTS __________________________________________________ 64 
12.1 
Definitions _________________________________________________________ 64 
12.2 
Reporting Procedures for Adverse Events _________________________________ 66 
12.2.1 
All Adverse Events ______________________________________________________ 66 
12.2.2 
Relationship to Study Drug ________________________________________________ 67 
12.2.3 
Severity _______________________________________________________________ 68 
12.2.4 
Serious Adverse Events __________________________________________________ 68 
12.2.5 
Data Safety Monitoring Board _____________________________________________ 69 
13 ADMINISTRATIVE REQUIREMENTS ____________________________________ 69 
13.1 
Protocol Modifications ________________________________________________ 69 
13.2 
Regulatory Documentation ____________________________________________ 70 
13.3 
Record Retention ____________________________________________________ 71 
13.4 
Data Quality Assurance _______________________________________________ 71 
13.5 
Data Handling and Recordkeeping ______________________________________ 72 
13.5.1 
Electronic Data _________________________________________________________ 72 
13.5.2 
Electronic Case Report Form (eCRF) Completion ______________________________ 72 
13.6 
Study Completion/Termination _________________________________________ 73 
13.6.1 
Study Completion _______________________________________________________ 73 
13.6.2 
Study Termination ______________________________________________________ 73 
13.7 
Monitoring _________________________________________________________ 73 
14 INVESTIGATOR REGULATORY OBLIGATIONS _____________________________ 74 
14.1 
Institutional Review Board ____________________________________________ 74 
14.2 
Informed Consent ____________________________________________________ 74 
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14.3 
Declaration of Helsinki ________________________________________________ 75 
14.4 
Patient Data Protection _______________________________________________ 75 
14.5 
Adverse Event Reporting ______________________________________________ 75 
14.6 
Investigator _________________________________________________________ 76 
14.7 
Confidentiality ______________________________________________________ 76 
14.8 
Publications ________________________________________________________ 76 
15 REFERENCES ______________________________________________________ 78 
APPENDIX 1: SCHEDULE OF EVENTS _______________________________________ 83 
APPENDIX 2: ECOG SCALE _______________________________________________ 87 
APPENDIX 3: PRACTICAL WEIGHT _________________________________________ 88 
APPENDIX 4: HIGH-DOSE IL-2 TOXICITIES ___________________________________ 89 
APPENDIX 5: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT _____________ 90 
APPENDIX 6: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS _________ 93 
APPENDIX 7: CYCLOPHOSPHAMIDE PACKAGE INSERT _________________________ 94 
APPENDIX 8: FLUDARABINE PACKAGE INSERT _______________________________ 95 
APPENDIX 9: IL-2 (ALDESLEUKIN) PACKAGE INSERT ___________________________ 96 
 
 
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LIST OF TABLES  
 
Table 1. 
Composition of LN-144........................................................................... 55 
Table 2. 
Time Point Response: Patients with Target (± Non-target) Disease ....... 58 
Table 3. 
Time Point Response: Patients with Non-target Disease Only ............... 59 
 
 
LIST OF FIGURES  
Figure 1. 
 LN-144 Manufacturing Process ............................................................. 24 
 
 
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LIST OF ABBREVIATIONS 
ACS 
American Cancer Society 
ACT 
Adoptive Cell Therapy 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate transaminase 
BOR 
Best overall response rate 
BP 
Blood pressure 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
ClCR 
Calculated creatinine clearance 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE v4.03 
CY 
DLT 
DOR 
Common Terminology Criteria for Adverse Events Version 4.03 
Cyclophosphamide 
Dose limiting toxicity 
Duration of response 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FEV 
Forced Expiratory Volume in the first second 
F/U 
Follow-up 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IL-2 
Interleukin-2 (also known as “aldesleukin”) 
IND 
Investigational New Drug (Application) 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition scan 
NCI 
National Cancer Institute 
NE 
In evaluable  
Non-CR 
Non-complete response 
Non-PD 
Non-progression 
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ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
PE 
Progressive disease 
Physical exam 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PFT 
Pulmonary Function Test  
PO 
Per Os (by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
(Taken) once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
T 
TEAE 
Body temperature 
Treatment-emergent adverse event 
TIL 
Tumor infiltrating lymphocyte 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit normal 
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1 
INTRODUCTION 
1.1 
Background  
There were an estimated 76,100 new cases of melanoma diagnosed in 2014, making 
it the 5th most common malignancy in men and the 7th most common malignancy in 
women. 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 five-year survival of less than 5%.  
Numerous novel approaches, including chemotherapy, targeted therapy and 
immunotherapy have been developed as treatment with varying results.   
Chemotherapy regimens using dacarbazine or temozolomide have been reported to 
result in tumor regression in 10 – 20% of patients; however, the responses have been 
of limited duration and rarely result in a complete response.2  No chemotherapy 
regimen has, to date, demonstrated a survival benefit for patients with advanced 
melanoma.  As such, although chemotherapy was widely used in the past, it now has 
a secondary role and is currently reserved for melanoma that can no longer be 
controlled with immunotherapy or targeted therapy. 
Approved targeted therapies to date are limited to use in metastatic melanoma 
patients who have mutation in the V600 position of the gene encoding BRAF in the 
mitogen-activated protein kinase (MAPK) pathway.  This mutation results in the 
expression of a modified BRAF protein, which directs growth of cancer cells.  Two 
approved drugs, vemurafenib (Zelboraf) and dabrafenib (Tafinlar) directly inhibit the 
mutant BRAF gene.3 Vemurafenib has demonstrated a survival benefit over 
chemotherapy in patients, while dabrafenib has demonstrated a notable PFS benefit, 
with crossover blunting the effect on overall survival.4 Another gene product in the 
MAPK pathway being targeted is MEK which is downstream of BRAF. This gene 
product is being targeted in its wild-type or non-mutant form, as MEK mutations are 
not found in melanoma or are quite rare. MEK has been targeted by a kinase inhibitor 
called trametinib and has also demonstrated survival benefit over chemotherapy.5 
These targeted agents prolong the time until tumor growth and extend overall survival 
in patients with BRAF mutant melanoma. However, disease eventually progresses 
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despite continuation of treatment with such therapy. More recently, it has been 
demonstrated that combining a BRAF inhibitor and a MEK inhibitor increases both 
response rates and duration of response, and improves overall survival as compared 
to BRAF inhibition alone, though all cases still are ultimately expected to develop 
resistance.6 
While targeted therapies are noted to have high response rates but short durations of 
response, cancer immunotherapy tends to have fewer objective responses, but longer 
duration of response which may sometimes even translate to a cure, as defined when 
complete remission from disease has lasted for years after therapy with no evidence 
of recurrence after repeated follow-up. Cancer immunotherapy is categorized into 
three general treatment modalities: active immunization, non-specific immune 
stimulation, and passive immunotherapy/adoptive cell transfer.  In the treatment of 
metastatic melanoma, active immunization with agents such as peptides, whole tumor 
cell vaccines, recombinant viruses encoding tumor-associated antigens, or dendritic 
cells have historically shown low tumor response rates of less than 5%,7-10 though 
more recently tested agents such as the oncolytic virus talimogene laherparepvec 
have shown promising response rates of up to 26%, with 16% lasting more than 6 
months.11   
Nonspecific immune stimulation with high-dose interleukin-2 (IL-2) as a single agent 
or ipilimumab can lead to durable cancer regression, although the overall tumor 
response rates for each agent have been low.  The response rate for high-dose IL-2 
was reported at 16%, with only approximately half of these complete responses,12 and 
the response rate to ipilimumab was only 11%.7  Despite these low objective 
response rates, among complete responders to high-dose IL-2, 50% never 
experience disease recurrence.  Among patients treated with ipilimumab, up to 22% 
are still alive after three years, with some patients surviving beyond 10 years.13 A pilot 
trial of 36 patients with melanoma treated with ipilimumab combined with high-dose 
IL-2 had overall response (OR) rates of 25%, with 17% achieving a CR lasting more 
than eight years ongoing;14 however, IL-2 plus ipilimumab combination has not been 
further tested to confirm these results. Anti-PD1 and anti-PD-L1 antibodies have 
recently been reported to have OR rates of up to 38%,15, 16 and 17%,17 respectively, in 
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patients with melanoma, and OR rates of up to 40% when combined with 
ipilimumab,18 although the long-term durability of the responses is not yet known. 
Cancer immunotherapy with adoptive transfer of tumor infiltrating lymphocytes (TIL) 
presents a potentially effective treatment for patients with metastatic melanoma. 
Adoptive Cell Transfer (ACT) with TIL involves the ex vivo numerical expansion of 
antitumor lymphocytes that have infiltrated into tumors. These TIL are numerically 
expanded in culture using T-cell growth factor, IL-2, either from small cut tumor 
fragments from surgically-resected lesions or from single cell suspensions isolated 
from resected tumors. The expanded TIL are re-infused (“transferred”) back into the 
patient.  These cells can be activated ex vivo, free from the potentially suppressive 
tumor microenvironment that may prevent them from fully living up to their antitumor 
potential. ACT has theoretical and practical advantages over active immunization and 
nonspecific immune stimulation. These include: 1) ability to numerically expand and 
re-infuse much higher number of tumor-reactive T cells than is possible with these 
other approaches, 2) the ability to numerically expand tumor-specific T cells in the 
absence of the effects suppressive T-regulatory cells, 3) the wider array of tumor 
antigens, such as mutated tumor antigens, recognized by the expanded T cells 
intrinsic to the TIL product and 4) the ability to further manipulate these infused T cells 
using immune modulators such as IL-2, T-cell checkpoint blockade agents, or other 
active or non-specific immune stimulating agents.19, 20  Preparation of the host patient 
with lymphodepletion immediately prior to the transfer of the antitumor cells also 
eliminates potentially suppressive influences (such as regulatory T cells and cytokine 
sinks) to provide an optimal milieu for the transferred TIL to proliferate and become 
activated in vivo.  When combined with a preparative lymphodepleting regimen pre-
transfer, ACT using autologous TIL has demonstrated consistently high objective 
response rates, from 49% to 72%, with long-term durable and potentially curative CR 
rates of up to 20%.19, 21, 22   
1.2 
Overview of Adoptive Cell Transfer for Metastatic Melanoma 
The partial success of IL-2 therapy in the treatment of metastatic melanoma revealed 
that manipulation of the immune response could alter the clinical course of the 
disease.23 The induction of tumor regression by IL-2 is believed to be related to its 
immune regulatory effects, including the expansion of T lymphocytes following 
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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 metastatic melanoma and the discovery of tumor 
antigens recognized by TIL led to first attempts to isolate tumors, expand lymphocytes 
from tumor fragments, and re-infuse these expanded cells back into the patient. Some 
of the first clinical trials performed in individual centers in the USA and Europe, such 
as the NCI, used TIL expanded for a number of weeks from tumor tissue with IL-2 
alone followed by re-infusion into patients. This was followed up by low-dose IL-2 
infusion or subcutaneous IL-2 administration.32-35 Although these protocols were found 
to be feasible, they had inconsistent and widely varying response rates ranging from 
0% to 66%, with the caveat that some of these trials were only conducted on small 
numbers (<10) of patients (e.g., Tessier et al.).33  
During this time, the Surgery Branch at the National Cancer Institute (NCI, Bethesda, 
MD) also embarked on performing TIL trials for metastatic melanoma using a similar 
expansion method for TIL with IL-2 alone. The NCI however included a preparative 
chemotherapy regimen using low-dose cyclophosphamide (CY) before TIL infusion 
that resulted in a partial and transient depletion of host lymphocytes.  IL-2 was 
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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 a new subset of suppressive CD4+ T-
regulatory cells (CD4+Foxp3+ cells) that inhibit anti-tumor immune responses in mice. 
Higher T-regulatory cell frequencies in the blood are also correlated with an 
unfavorable prognosis in cancer patients.41-44  Alternatively, prior depletion of 
lymphocytes may create ‘space’ for the adoptively transferred cells within the 
lymphocyte compartment.45 Under this model, homeostatic lymphocyte survival may 
result in increased proliferation and enhanced survival of transferred T cells, perhaps 
through a mechanism involving increased access to endogenous cytokines like IL-7 
and IL-15.46 The success of prior lymphodepletion in animal models and the use of 
single agent CY preconditioning in initial TIL therapy trials, led to testing of more 
intensive pre-conditioning regimens yielding a complete depletion of host lymphocytes 
for a longer window of time than the prior CY alone regimens. 
The NCI first reported a study on 35 patients including this more intense 
lymphodepleting conditioning regimen to adoptive cell transfer therapy in patients with 
metastatic melanoma.47, 48  Patients received a lymphodepleting chemotherapy 
regimen consisting of high-dose cyclophosphamide and standard doses of fludarabine 
before administration of selected, expanded, tumor-reactive TIL and IL-2. The 
lymphodepletion step resulted in a transient myelosuppression and the elimination of 
all circulating lymphocytes for approximately one week, after which time patients 
recovered endogenous marrow function and reconstituted their lymphocyte 
compartments towards normal levels within two to three weeks.47, 48 
Because of the immunosuppression of fludarabine, one patient who had clonal 
repopulation from infused TIL and a complete response of metastatic melanoma, 
developed Epstein-Barr virus (EBV) - associated B cell lymphoma. This patient was 
EBV-naïve prior to treatment. The potential source of EBV was thought to be multiple 
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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 
al.21 reported results of clinical trials conducted at NCI that used three different pre-
treatment regimens prior to TIL infusion for treatment of patients with melanoma. 
Objective responses were seen in 52/93 patients (56%) of which 20/93 (22%) were 
complete responses.  The complete responses were durable (defined as “ongoing 
after 64 -109 months of follow-up”) in 19/20 (95%) of the patients.  Radvanyi et al.49 
reported the MD Anderson Cancer Center experience with ACT using selected TIL for 
treatment of metastatic melanoma with objective clinical response in 15/31 (48.4%) 
patients with two resulting in a complete response (6.5%). Progression free survival of 
a duration of greater than 12 months was reported in 9/15 (60%) of the patients that 
responded to therapy. The H. Lee Moffitt Cancer Center also reported a 38% 
response rate in 13 treated patients with 2/13 (15%) achieving a complete response 
ongoing for more than 14 and 16 months at the time of publication, respectively.50 
Outside the U.S., Itzhaki et al.51 reported the experience from Sheba Medical Center 
in Israel using “young, unselected –TIL therapy.”  Of the 31 patients evaluated, 15 
(48%) of the patients achieved a clinical response including four patients (12.9%) with 
complete responses. In addition, a group in Denmark52 used 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 non-myeloablative lymphodepleting chemo-
preparative regimen proposed in this current study can be tolerated and contributes to 
the potent efficacy of TIL for the treatment of advanced metastatic disease.  
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1.3 
Production and Expansion of Tumor Infiltrating Lymphocytes 
Generating LN-144 involves resecting a tumor deposit (generally > 1 cm, preferably 
1.5 cm in diameter) and culturing tumor fragments in media containing IL-2 to expand 
them in vitro (Figure 1).  Appropriately expanded TIL cultures should reach several 
million cells (combined) in two to three weeks. The cells can be screened at this stage 
for their capacity to kill autologous tumor cells if autologous tumor cells are available. 
Alternatively, the TIL can be screened using allogeneic HLA-A-matched tumor lines. 
Although anti-tumor reactivity assays were used to select TIL for further expansion in 
initial clinical trials, data from a number of studies indicates that both responding and 
non-responding patients have tumor-reactive TIL to similar extents (e.g., Radvanyi et 
al.).49 In addition, clinical trials using young, unselected TIL have 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 National Cancer Institute, TIL were successfully 
generated in 677 (86%) of the 787 specimens from all tumor sites, although tumors 
from the gastrointestinal tract had a decreased rate of TIL growth (70%; P = 0.008).54 
 
 
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Figure 1. 
 LN-144 Manufacturing Process 
 
1.4 
 LN-144 TIL Therapy 
LN-144 is an autologous, ready-to-infuse, TIL therapy and is almost identical to that 
developed by Dr. Steven Rosenberg and colleagues at the National Cancer Institute.  
TIL have demonstrated efficacy in the treatment of Stage IV melanoma, and Phase 2 
clinical trials evaluating this product have shown an objective response rate of 49% or 
more, exceeding rates reported by other immunotherapies in melanoma.  The present 
study is being conducted to further evaluate: 1) the safety of LN-144 therapy and 2) 
the efficacy of LN-144 therapy. 
Several treatment regimens have been used in conjunction with TIL therapy.  
Lymphodepleting regimens have included cyclophosphamide/fludarabine, total body 
irradiation or the combination of the two.  The lymphodepletion protocol used in the 
current study is based on the method developed and tested by the NCI and is also the 
most often used.  It involves two days of cyclophosphamide followed by five days of 
fludarabine as a lymphodepleting pre-treatment.  The treatment regimen includes 
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treatment with LN-144 (TIL therapy) followed by high-dose IL-2.  Protocols for the 
tumor harvest and LN-144 administration are provided in separate operating manuals. 
Up to 150 x 109 viable cells will be infused in this clinical trial. The final cell product is 
formulated in a minimum of 50% HypoThermosol™ in Plasma-Lyte A™ (volume/volume) 
and up to 0.5% HSA (compatible for human infusion) containing 300 IU/mL IL2. The final 
product will be available for administration in one of two volumes for infusion:  
1) 250 mL (in a 300-mL capacity infusion bag) when the total TIL harvested are 
≤ 75x109 
OR  
2)  500 mL (in a 600-mL capacity infusion bag) when the total TIL harvested are 
< 150 x 109   
We cannot predict the total number of cells that will be generated for the final LN-144 
infusion product for each patient due to patient-to-patient variation in T-cell expansion 
rates during the REP step. A lower limit of cells on day 7 of the 14-day REP is set 
based on the minimum number of cells needed in order to make a decision to 
lymphodeplete the 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 by day 14. The upper limit of the range for 
infusion (150 x 109 viable cells) is based on the known published upper limit safely 
infused where a clinical response has been attained.49 There is no evidence that 
moving beyond this upper limit will have more clinical benefit. 
2 
STUDY DESIGN 
2.1 
Description of the Study 
This is a prospective single-arm interventional study evaluating patients who receive 
adoptive cell therapy (ACT) with LN-144 (autologous TIL).  Patients will receive LN-
144 followed by the administration of a regimen of IL-2 at 600,000 IU/kg 
approximately every eight hours starting 12 to 24 hours after the LN-144 infusion and 
continuing for up to six doses.  Patients will be evaluated for response approximately 
12 weeks following LN-144 therapy. 
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Patients will be evaluated at six, nine, 12, 18 and 24 months following LN-144 
treatment.  Formal response evaluations will be per RECIST 1.1. 
2.2 
Description of the Study Centers 
Patients may be seen at the Investigators’ private offices or affiliated medical centers 
for evaluations prior to enrollment and during follow-up.  The patients will require 
hospitalization during the LN-144 infusion and IL-2 treatment.  
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 Primary Objectives 
 
To characterize the safety profile of LN-144 in patients with metastatic 
melanoma  
3.1.2 Secondary Objectives 
 
To evaluate the efficacy of LN-144 in patients with metastatic melanoma 
using the best overall response rate (ORR) and complete response rate 
(CR).  
 
To evaluate the 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. 
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. 
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3.2.2 Secondary Endpoints:  
 
Efficacy of LN-144 therapy as defined by: 
 Best overall response rate (ORR) 
 Complete response rate (CR) as best overall 
 Duration of response (DOR) 
 Progression free survival (PFS) 
 Overall survival (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 its own report. 
4 
SELECTION OF PATIENT POPULATION 
Patients greater than 18 years of age, with a diagnosis of metastatic melanoma who 
have undergone at least one prior immunotherapy or chemotherapy regimen will be 
selected for this study. 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 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 one 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 
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(defined as any operation for which expected hospitalization is less than or equal to 
three days).  
b. 
Patients must have undergone at least one prior systemic treatment for metastatic 
melanoma. 
c. 
Patients must have 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. 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 the high dose IL-2. 
e. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 (Appendix 2). 
f. 
In the opinion of the Investigator, patient must be capable of participating and 
completing study procedures.   
g. 
Patients of child bearing potential or with partners of childbearing potential must be 
willing to practice birth control during treatment and for four months after receiving 
all protocol related therapy. 
h. 
Patients must have a serum absolute neutrophil count (ANC) greater than 
1000/mm3, hemoglobin greater than 9.0 g/dL, and platelet count greater than 
100,000/mm3. 
i. 
Patients must have a serum ALT/SGPT and AST/SGOT less than three times the 
upper limit of normal (<3x ULN), a calculated creatinine 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. 
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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 trial period. Additionally, all 
prior therapy-related toxicities must have recovered to Grade 1 or less (CTCAE 
v4.03), except for alopecia or vitiligo prior to enrollment. 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.   
Note:  Patients may have undergone minor surgical procedures not involving 
general anesthesia within three weeks prior to enrollment as long as all toxicities 
have recovered to Grade 1 or less or as specified in the eligibility criteria. 
m. Patients with documented Grade 2 or greater diarrhea or colitis as a result of 
previous treatment with ipilimumab, tremelimumab, anti-PD1 or anti-PD-L1 
antibodies must have been asymptomatic for at least 6 months or had a normal 
colonoscopy post 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 
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b. 
Patients who have received prior cell transfer therapy which included a non-
myeloablative or myeloablative chemotherapy regimen. 
c. 
Patients who have three or more active brain metastases.  Note: Patients with one 
or two untreated or inadequately treated brain lesions or three 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 one 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 seven 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 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 an LVEF less than 45%. (Older patients [60 – 70 years], must 
have received an echocardiogram within the previous 60 days demonstrating LVEF 
≥ 45%). 
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l. 
Patients who have a documented FEV1 (forced expiratory volume in one second) of 
less than or equal to 60%.   
m. Patients who have had another primary malignancy within the previous three years 
(with the exception of carcinoma in situ of the breast, urothelial cancer in situ, and 
non-melanoma skin cancer that has been adequately treated). 
4.3 
Number of Patients 
Patients that meet all of the inclusion criteria and do not meet any of the exclusion 
criteria will be enrolled in the study.   
Patients who sign an ICF and fail to meet the inclusion and/or exclusion criteria are 
defined as screen failures.   
The screening and tumor resection/TIL harvest period is up to 6 weeks. However, it 
can be extended, after approval by the Medical Monitor, if there is delay in scheduling 
the tumor resection. 
For all screen failures, the Investigator is to maintain a screening log that documents, 
at a minimum, the patient initials, or other identifier used by site, patient date of birth 
and reason(s) for screen failure.  A copy of the log should be retained in the 
Investigator's study files.  Minimum data for screen failures will be captured in the 
EDC database as defined in the data management plan and eCRF completion 
manual. 
Patients will be enrolled until 20 patients have been successfully treated with LN-144 
followed by IL-2 administration.  Screening may halt once it becomes likely that the 
full accrual goal will be met. 
4.3.1 Re-screening Patients 
Patients who fail the initial screening process may be re-screened for eligibility.  The 
Principal Investigator and Medical Monitor will discuss the patient prior to any 
rescreening procedures and agree on which screening procedures need to be redone.  
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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 
modified Intention to Treat population. Efficacy and safety analyses will be performed 
on both populations. 
DSMB will evaluate safety data on first 3 patients completing 12 weeks of 
assessment. A 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 20th patient treated.   
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. 
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 
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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 
Current medications for conditions other than their metastatic melanoma are 
permitted with the exception of any medications that may have an anti-tumor effect.  
Although prohibited for study entry, systemic steroid therapy greater than 10 mg/day 
prednisone or equivalent may be initiated on study per PI discretion.  
6 
STUDY PROCEDURES 
6.1 
Screening 
The following procedures should be completed after completion of Informed Consent: 
 
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 
 
Slit Lamp eye exam  
 
EKG 
 
Cardiac evaluation (stress thallium) for all patients. Echocardiogram or 
MUGA) for patients ≥ 60 years or patients who have a history of ischemic 
heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias.  Stress thallium must show normal LVEF and unimpaired 
wall movement 
 
 
Pulmonary function tests if indicated  
 
CT Exam 
 Chest (include neck if there is prior or suspected neck disease) 
 Abdomen 
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 Pelvis 
 
MRI of brain 
 
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 child bearing 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) 
 HLA typing (to be shipped to central lab.  Refer to central lab 
manual for details) 
 Urinalysis (complete urine culture if indicated) 
 
Calculate creatinine clearance using Cockcroft-Gault formula 
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 
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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 AE/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.   
If enrolled, tumor resection will take place.  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 medications 
 
ECOG performance status evaluation 
 
Obtain blood for Immune monitoring (50 mL of blood to be obtained.  
Refer to lab manual) 
 
Tumor Harvest  
 
Six paraffin embedded slides created from the tumor resection for 
biomarker analyses 
 
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.  
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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. Using sterile 
tweezers and a scalpel or other suitable sterile instruments, the tumor is trimmed to 
remove extraneous non-tumor tissue by a trained surgeon or pathologist or otherwise 
qualified personnel. Using sterile forceps the trimmed tumor is placed into a sterile, 
previously sealed and unopened sterile 100 mL bottle of HypoThermosol®.  The lid 
should be screwed on tightly. The bottle containing the tumor will be placed in a 
plastic sealable bag secondary container containing absorbent tissue or paper towels.  
This secondary container is placed in an activated NanoCool™ shipper adjacent to a 
TempTale® 4 temperature monitor.  The NanoCool™ shipper is then closed and 
packaged as instructed in the Tumor Procurement Manual.  The package will be 
shipped overnight to the central LN-144 manufacturing facility).  The NanoCool™ 
shipper will be supplied to the site with address labels affixed for shipment to the 
manufacturing facility as well as all appropriate labels for shipping. 
Further details and additional instructions are available in the Tumor Procurement 
Manual. 
 
 
LN-144 is an autologous product which is procured and delivered 
by means which have more in common with autologous blood 
product delivery than those of traditional drug production.  It is 
imperative that only the patient’s own (autologous) study treatment (LN-
144) be administered to the same individual patient. For these reasons, 
the patient specimen must be procured and handled according to a strict 
protocol to ensure optimal quality of the specimen and minimum 
transport time to and from the processing facility, as well as to ensure 
the unique identification of the specimen at all times including injection 
back into the patient. 
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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 Lab Manual for the complete procedure details. In 
addition, DNA from tumor tissue will be sequenced.    
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 ongoing 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 
 
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) 
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 Serum pregnancy test for all women of child bearing potential 
 Urinalysis (complete urine culture if indicated) 
 
ECOG performance status evaluation 
 
Assessment of AE/SAEs 
6.4 
Day -7  
Prior to the start of lymphodepletion, verification of sufficient LN-144 expansion at this 
timepoint will be confirmed.   
 
Physical exam including weight, calculated BSA and BMI 
 
Verification of all ongoing 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, Uric Acid, and thyroid panel (to include TSH and free 
T4) 
 Urinalysis (complete Urine culture if indicated) 
 CMV antigen assay, as clinically indicated 
 
Obtain blood for immune monitoring (50 mL of blood to be obtained.  
Refer to lab manual) 
 
Administration of the following medications: 
 Cyclophosphamide 60 mg/kg IV in 250 mL D5W with mesna 15 
mg/kg are infused over 2hr. (If the patient is obese (BMI > 35) 
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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 (see pharmaceutical section) 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 
eight hours X 3 days) will be given for nausea. (If the patient is 
obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Appendix 3) 
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care 
 Assessment of AE/SAEs 
6.5 
Day -6 
The following procedures should be performed: 
 
Physical exam including weight  
 
Verification of all ongoing 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, Uric Acid, and thyroid panel (to include TSH and free 
T4) 
 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 2hr. (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 (see pharmaceutical section) 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 
eight hours X 3 days) will be given for nausea. (If the patient is 
obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Appendix 3) 
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care 
 
Assessment of AE/SAEs 
6.6 
Day -5 to Day -1 
The following procedures should be performed: 
 
Physical exam including weight  
 
Verification of all ongoing 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, 
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Total CK, Uric Acid, and thyroid panel on Days -5, -4 and -1 only 
(to include TSH and free T4) 
 CMV antigen assay, as clinically indicated 
 Urinalysis (complete urine culture if indicated) 
 
The following medication should be administered: 
 Fludarabine 25mg/ m2 to be given IV over approximately 30 
minutes once daily each day 
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care 
 
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 product will be labeled with a 
patient specific label.  A certificate of authenticity verifying the result of the release 
testing and the accuracy of the labels will be issued.  The product will then be 
released for shipment from the manufacturing facility. The product will be shipped 
overnight by courier to the clinical site pharmacy in a NanoCool™ shipper validated to 
maintain a product temperature of 2-8oC. The product temperature will be 
continuously monitored by a TempTale 4™ which will be placed in the container in 
contact with the product. 
The product will be received by the appropriate clinical pharmacy for the particular 
patient.  After verification and labeling at the pharmacy, the product will be returned to 
the NanoCool™ shipper to maintain temperature as the product is transferred to the 
patient bedside. Upon receipt by the infusing physician and double verification for 
identity the product may be removed from the NanoCool™ shipper and prepared for 
infusion. 
If not already hospitalized, the patient will be admitted 1-2 days prior to planned LN-
144 administration and prepared for study drug administration. Patients will remain 
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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 ongoing medications 
 
ECOG performance status evaluation 
 
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 four hours and then routinely (every four to six 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 
may be given as clinically indicated, per standard of care 
 LN-144 Infusion:   Autologous TIL (LN-144) will be administered 
intravenously. The product will be administered (by gravity) within 
45 minutes. If interruption of infusion is required for medical 
reasons, the product infusion should complete within 3 hours of 
beginning infusion. 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 
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of the administration procedure will be provided in the Pharmacy 
Manual 
 
Assessment of AE/SAEs 
6.8 
Days 1 – 4 
During these days, while patient remains hospitalized, the following procedures 
should be performed: 
 
Physical exam including weight  
 
Verification of all ongoing 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, Uric Acid, and thyroid panel (to include TSH and free 
T4) 
 CMV antigen assay - required only on Days 1 and 3 
 Urinalysis (complete Urine culture if indicated) 
 
Obtain blood for immune monitoring on Days 1 and 4 only (50 mL to 
blood to be obtained. Refer to lab manual) 
 
Assessment of AE/SAEs 
 
The following medications will be administered: 
 IL-2 – begin infusion on Day1: 12 - 24 hours after conclusion of 
the LN-144 infusion. IL-2 will be administered at a dose of 600,000 
IU/kg (based on total body weight). Administer by intravenous 
infusion at a frequency not greater than every 8 hours as per 
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institutional standard of care.  Continue for up to a maximum of six 
doses.  IL-2 doses will be skipped if patient experiences a Grade 3 
or 4 toxicity due to IL-2 except: reversible Grade 3 toxicities 
common to IL-2 such as diarrhea, nausea, vomiting, hypotension, 
skin changes, anorexia, mucositis, dysphagia, or constitutional 
symptoms and laboratory changes as detailed in Appendix 4. 
Toxicities will be managed as outlined in Appendix 5.  If these 
toxicities can be easily reversed within 24 hours by supportive 
measures, then additional doses may be given.  If greater than 2 
doses of IL-2 are skipped, IL-2 administration will be stopped.  In 
addition, dosing may be held or stopped at the discretion of the 
treating investigator.  Refer to Appendix 5 for guidance. 
 Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days.  
 Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3  
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care 
 Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
 
Assessment of AE/SAEs 
6.9 
Day 14, 28 (+/- 1 day) 
The following procedures will be performed: 
 
Physical exam including weight  
 
ECOG performance status evaluation - Day 14 only 
 
Blood tests 
 Hematology- CBC with differential 
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 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) 
 CD4 count – Day 28 only 
 
Obtain blood for Immune monitoring (50 mL of blood to be obtained.  
Refer to lab manual) – Day 14 only 
 
If required, the following medications will continue to be administered 
 Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days.  
 Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
 Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
 
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 ongoing medications 
 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
 
Assessment of AE/SAEs 
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 
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 
 
Obtain blood for immune monitoring (50 mL of blood to be obtained.  
Refer to lab manual) 
 
CT Exam 
 Chest (include neck if there is prior or suspected neck disease) 
 Abdomen 
 Pelvis 
 
MRI of brain 
 
If required, the following medications will continue to be administered 
 Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days. The 
maximum filgrastim dose should not exceed 300 mcg per day. 
 Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
 Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
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continued until CD4 > 200 cells/mm3.  
6.11 
Day 84/ Week 12 ( +/- 3 days) 
The following procedures will be performed during this post treatment evaluation visit: 
 
Physical exam including weight 
 
ECOG performance status evaluation 
 
Evaluation and measurement of all skin and palpable lesions 
 
Verification of all ongoing medications 
 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
 
Assessment of AE/SAEs 
 
Slit lamp eye exam  
 
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 
 
Obtain blood for immune monitoring (50 mL of blood to be obtained.  
Refer to lab manual) 
 
CT Exam 
 Chest (include neck if there is prior or suspected neck disease) 
 Abdomen 
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 Pelvis 
 
MRI of brain 
 
If required, the following medications will continue to be administered 
 Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days.  
 Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
 Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
6.12 
Months 6 (+/- 1 week), 9 (+/- 1 week), 12 (+/- 1 week), 18 (+/- 3 weeks), and 24 
(+/- 3 weeks) 
The following procedures will be performed during these visits: 
 
Physical exam including weight 
 
ECOG performance status evaluation 
 
Verification of all ongoing 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, Alkaline Phosphatase, ALT/SGPT, 
AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total protein, 
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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 lab manual) - Month 6, 9 and 12 only 
 
CT Exam 
 Chest (include neck if there is prior or suspected neck disease) 
 Abdomen 
 Pelvis 
 
MRI of brain 
 
If required, the following medications will continue to be administered 
 Filgrastim 5 mcg/kg/day administered by subcutaneous injection. 
This will be administered each day until the absolute neutrophil 
count reaches >1000/mm3 for three consecutive days.  
 Fluconazole 400 mg PO daily. This should be administered each 
day until the absolute neutrophil count reaches >1000/mm3.  
 Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg 
may be given as clinically indicated, per standard of care. 
 Herpetic treatment will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and 
continued until CD4 > 200 cells/mm3.  
 
Assessment of AE/SAEs 
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.  
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6.14 
Expected Toxicities and Treatment Guidelines 
6.14.1 LN-144  
Early toxicities related specifically to the infusion of the cells (those which are seen 
immediately following the cell infusion and prior to IL-2 administration are generally 
mild and include fevers, chills, headache, and malaise. Toxicities which occur 
following administration of IL-2 but are thought to be related to the cells include 
immune mediated events such as vitiligo, transient uveitis, hearing loss and vestibular 
dysfunction. (IL-2 specific toxicity is discussed in 6.14.2) The use of the non-
myeloablative regimen prior to cell administration increases the toxicity of this 
treatment as profound myelosuppression occurs in all patients. 
6.14.2  IL-2 
IL-2 administration has been associated with capillary leak syndrome (CLS) which is 
characterized by a loss of vascular tone and extravasation of plasma proteins and 
fluid into the extravascular space. CLS results in hypotension and reduced organ 
perfusion which may be severe and can result in death. CLS may be associated with 
cardiac arrhythmias (supraventricular and ventricular), angina, myocardial infarction, 
respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, 
renal insufficiency, edema, and mental status changes.  
IL-2 treatment is also associated with impaired neutrophil function (reduced 
chemotaxis) and with an increased risk of disseminated infection, including sepsis and 
bacterial endocarditis. Consequently, preexisting bacterial infections should be 
adequately treated prior to initiation of IL-2 therapy. Patients with indwelling central 
lines are particularly at risk for infection with gram positive microorganisms. Antibiotic 
prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated 
with a reduced incidence of staphylococcal infections. IL-2 administration should be 
withheld in patients developing moderate to severe lethargy or somnolence; continued 
administration may result in coma. 
The standard approach to the administration of high-dose IL-2 in all studies is to 
continue dosing until grade 3 or 4 events occur. The most commonly seen grade 4 
events are pulmonary and renal impairment, and mental status changes.  These 
toxicities may sometimes require intubation for protection of the patient’s airway.  It is 
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important to note that although these patients require significant supportive measures 
during this period, all toxicities are reversible and the overwhelming majority of 
patients have suffered no long term sequelae following this treatment 
regimen.  However, fatal complications are possible and it is therefore only 
appropriate to carry out this experimental treatment in the context of life threatening 
metastatic cancer. 
6.14.3 Treatment Guidelines for Toxicity Management   
Concomitant medications to control side effects of therapy will be given.  Meperidine 
(25-50 mg), or other medication per site standard of care may be given intravenously 
if severe chills develop.  Other supportive therapy shall be given as required. 
Supportive therapy includes acetaminophen (650 mg q4h), indomethacin (50-75 mg 
q6h) and ranitidine (150 mg q12h).  The investigator should use supportive therapies 
as per institutional standard of care.   Additional antiemetic therapy will be 
administered for breakthrough nausea and vomiting.  Patients shall receive supportive 
care as indicated for IL-2 toxicities as listed in Appendix 5.   
Expected toxicities with cyclophosphamide and fludarabine administration are listed in 
the package inserts (See Appendix 7 and 8 respectively). Also included in the 
package inserts is information on supportive care and management of toxicities.  
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.  
6.14.4  Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation 
cephalosporin or a quinolone for fever – defined as 38.3°C once or two temperatures 
of 38.0°C or above at least one hour apart, AND an ANC <500/mm3. Infectious 
disease consultation will be obtained for all patients with unexplained fever or any 
infectious complications. 
6.14.5  Blood Product Support  
Using daily CBCs as a guide, the patient will receive platelets and packed red blood 
cells (PRBCs) as needed.  Attempts will be made to keep hemoglobin >7.5 g/dL, and 
platelets >10,000/mm3.  All blood products will be irradiated.  Leukocyte filters will be 
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utilized for all blood and platelet transfusions to decrease sensitization to transfused 
WBCs and decrease the risk of CMV infection. 
6.14.6 Renal Toxicity 
Renal toxicity defined by rapid rise in creatinine levels or clinical symptoms is a risk. If 
patients exhibit signs or symptoms of renal toxicity, manage as per institutional 
standard of care. 
6.15 
Infection Prophylaxis 
Note: Other anti-infective agents may be substituted at the discretion of the treating 
Investigator.    
6.15.1 Pneumocystis Jiroveci Pneumonia 
All patients will receive the fixed combination of trimethoprim (TMP) and 
sulfamethoxazole [SMX] as double strength (DS) tab (DS tabs = TMP 160 mg/tab, 
and SMX 800 mg/tab) (PO) daily three times a week on non-consecutive days, 
beginning on the first Monday, Wednesday, or Friday on or after the first dose of 
chemotherapy.  
Pentamidine will be substituted for TMP/SMX DS in patients with sulfa allergies. It will 
be administered aerosolized at 300 mg per nebulizer within one week prior to 
receiving study treatment and continued monthly until CD4 count is above 200/mm3 
and for at least six months post chemotherapy, or as Investigator deems appropriate.
 
 
Pneumonia prophylaxis will continue for six months post chemotherapy.  If the CD4 
count is less than 200/mm3 at six months post chemotherapy, or as Investigator 
deems appropriate, prophylaxis will continue until the CD4 count is greater than 
200/mm3. 
 
6.15.2 Herpes Virus Prophylaxis 
Patients with positive HSV serology will be given valacyclovir orally at a dose of 500 
mg daily the day after chemotherapy ends, or acyclovir, 250 mg/m2 IV every 12 hours 
if the patient is not able to take medication by mouth.  Reversible renal insufficiency 
has been reported with IV but not oral acyclovir.  Neurologic toxicity including delirium, 
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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 six months post-chemotherapy, or as long as 
Investigator deems necessary.  If the CD4 count is less than 200/mm3 at six months 
post chemotherapy, prophylaxis will continue until the CD4 count is greater than 
200/mm3. 
6.15.3 Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg (PO) the day after chemotherapy concludes and 
continue until the absolute neutrophil count is greater than 1000/mm3.  The drug may 
be given IV at a dose of 400 mg in 0.9% sodium chloride USP daily in patients unable 
to take it orally. 
6.15.4 Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation 
cephalosporin or a quinolone for fever – defined as 38.3°C once or two temperatures 
of 38.0°C or above at least one hour apart, AND an ANC <500/mm3.  
Aminoglycosides should be avoided unless there is clear evidence of sepsis. 
Infectious disease consultation will be obtained for all patients with unexplained fever 
or any infectious complications as per institutional standard of care. 
6.15.5  Blood Product Support 
Using CBCs as a guide, the patient will receive platelets and packed red blood cells 
(PRBCs) as needed.  Attempts will be made to keep hemoglobin >7.5 g/dL, and 
platelets >10,000/mm3.  All blood products will be irradiated.  Leukocyte filters will be 
utilized for all blood and platelet transfusions to decrease sensitization to transfused 
WBCs and decrease the risk of CMV infection 
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7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF PATIENTS 
7.1 
 Treatment Completion 
Completion of treatment is defined as successful infusion with LN-144 followed by the 
12-week 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 PI that continued treatment is not in the best interest 
of the patient. 
 
 Withdrawal by patient. The patient may withdraw consent to treatment 
but continue consent for follow-up evaluations and/or survival status 
 
Pregnancy 
Criteria for early discontinuation from study 
 
Subject has become ineligible for study after enrollment and prior to TIL 
or IL2 administration 
 
Withdrawal of consent 
 
Death 
 
Lost to follow-up after 3 documented attempts to contact the subject.  
 
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8 
STUDY DRUG INFORMATION 
Product Name:  LN-144 
Active Product Components:  Autologous, viable, tumor infiltrating lymphocytes (TIL) 
Dosage Form: Live cell suspension 
 
Table 1. 
Composition of LN-144 
Ingredient 
Unit and/or 
Percentage Formula 
Function 
% v/v 
Per mL 
Tumor Infiltrating 
Lymphocytes  
Up to 150 x 109 
Active Ingredient 
Interleukin 2 
Not applicable 300 IU 
Lymphocyte growth factor 
Human Serum Albumin 
0.5 
Not applicable 
Stabilizer 
Plasma-Lyte® A 
≤50 
Not applicable 
Diluent 
HypoThermosol™ 
≥50 
Not applicable 
Transport medium 
 
Qualitative Composition:  LN-144 is a cell product of autologous tumor-infiltrating 
lymphocytes (TIL) derived from the patient's own tumor.  LN-144 is an autologous cell 
therapy for the treatment of patients with advanced melanoma.  LN-144 is a live cell 
suspension that is formulated in HypoThermosol™ transport medium, Plasma-Lyte® A 
with 0.5% HSA (human serum albumin) and 300 IU/mL of IL2.  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 12-24 hours 
after infusion. The total volume to be infused will be approximately 250 mL (300 mL 
transfer bag) for cell concentrations ≤ 75 x 109 LN-144 or 500 mL (600mL transfer 
bag) for cell concentrations < 150 x 109 LN-144.  
Manufacturing Process:  The overall process of tumor shipping, LN-144 
manufacturing, and LN-144 product shipping, and infusion was shown above in 
Figure 1.  The LN-144 product is manufactured ex vivo using autologous tumor as 
starting material.  The key manufacturing steps include: 
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 
Surgical removal of autologous metastatic tumor and shipment to 
manufacturing facility 
 
Culture of small 2-3 mm (length x width x height) fragments of autologous 
tumor in IL-2 for up to three weeks to expand TIL. 
 
Harvesting and cryopreservation of TIL for further scheduling of patient 
and expansion in a rapid expansion protocol (REP) 
 
REP culture for 14 days in the presence of IL-2, OKT3, and irradiated 
allogeneic MNC feeder cells 
 
Harvesting and formulation of REP expanded product in transport 
medium and overnight shipment to clinical site for infusion 
Final Product Container: The live suspension of LN-144 is stored in a 300 mL blood 
transfer pack (Baxter) for cell concentrations ≤ 75 x 109 LN-144 or 600 mL blood 
transfer pack (Baxter) for cell concentrations < 150 x 109 LN-144.  
Transport:  Each dose of the live suspension LN-144 will be shipped/sent by courier 
to the clinical site from the LN-144 Manufacturing Facility the day before 
administration using a method that is intended to support 24-hour delivery.  The live 
suspension product will be packaged in a protective bag containing absorbent 
padding then placed into an insulated container (Therapak NanoCool™ shipper), 
designed to maintain transit temperature between 2 - 8oC. A temperature monitoring 
device will be included to monitor the temperature inside the container during 
shipping. 
Receipt at Clinical Site and Administration:  The dose of LN-144 will be received at 
the clinical site in the pharmacy on the day of administration 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 product is infused 
by gravity within 45 minutes. If interruption of infusion is required for medical reasons, 
the product infusion should complete within 3 hours of beginning infusion.  Refer to 
Product Administration Manual for additional details. 
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9 
STUDY ASSESSMENTS 
9.1 
Efficacy Assessments 
9.1.1 Response Criteria 
Clinical response will be determined using RECIST version 1.1 with a modification to 
require confirmation of PD.  Refer to Table 2 and Table 3 for RECIST 1.1 response 
criteria definitions. 
9.1.1.1 
Evaluation of Target Lesions1 
 
Complete Response (CR):  Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have a 
reduction in short axis to <10 mm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 
diameter of target lesions taking as reference the baseline sum 
diameters. 
 
Progression (PD):  At least a 20% increase in the sum of diameters of 
target lesions taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study).  In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as references the smallest sum 
                                            
 
1 All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured during screening. A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum diameters will be used as reference by which to characterize any 
objective tumor regression in the measurable dimension of the disease. If lymph nodes are to 
be included in the sum, only the short axis will contribute. 
 
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diameters while on study. 
9.1.1.2 
Evaluation of Non-target Lesions2 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Non-Complete Response:  Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above normal limits. 
 
Progression (PD):  Unequivocal progression of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also 
considered progression).   
9.1.1.3 
Evaluation of Best Overall Response 
The best overall response is determined once all the data for the patient is known. 
The best overall response is the best response recorded from the start of treatment 
until disease progression/recurrence, the initiation of new anti-cancer therapy, death 
or 24 months whichever comes first.  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.   
Table 2. 
Time Point Response: Patients with Target (± Non-target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
 
 
 
 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
                                            
 
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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Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 3. 
Time Point Response: Patients with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
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 six 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 
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from maximum likelihood methods. Estimation of confidence limits will use two-sided, 
95% criteria and implement exact methods. Missing data will not be imputed unless 
defined in the statistical analysis plan (SAP). If inferential statistics are calculated 
(e.g., p-values), they will be used in a descriptive manner.   
A more detailed description of the analyses and reporting plan of the data will be 
provided in the SAP.  
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.  
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 best overall response (ORR), complete response 
rate (CR) as best overall 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 either resected (modified Intention to Treat population) and 
successfully infused with LN-144 followed by IL-2 (at least one dose, 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. 
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PFS is defined as the time (in months) from the start of IL-2 therapy 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 of the lymphodepletion therapy 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 includes 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. 
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. 
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10.4.1 Baseline Demographic and Clinical Characteristics 
Baseline demographic and clinical (disease) characterized will be summarized 
descriptively for the All-Treated patient populations. 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 two-sided, exact 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 two-sided, exact 95% confidence 
limits.  
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 curve as well as for the following landmark times following the initial 
dose of lymphodepletion: 6 months, 12 months, 18, months, and 24 months duration. 
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 harvest surgery 
(modified Intention to Treat population) or 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 intensity 
and relationship. Certain safety data will be amenable to summary by use of toxicity 
grades, and all such analyses will evaluate the distribution of grades over time in 
addition to the worst grade observed per patient while on study. These toxicity grade 
summaries will be derived separately for each measure under consideration (e.g., 
ANCs for neutropenia; platelets for thrombocytopenia). 
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A limited amount of safety data is collected at the time of resection until infusion with 
LN-144 followed by IL-2. These data will be summarized as needed, but separately 
from the primary safety analyses. 
10.4.5 Other Planned Analyses 
No additional analyses are planned. Should 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 
Drugs Administered during the Study 
Please refer to the Information for Use package insert provided with all drugs used in 
this study to understand the contraindications, precautions and warning relative to a 
specific drug. 
11.2 
LN-144 Treatment  
Early toxicities related specifically to the infusion of the cells (those which are seen 
immediately following cell infusion and prior to IL-2 administration) are generally mild 
and include fevers, chills, headache, and malaise.  Toxicities which occur following 
administration of IL-2 but are thought to be related to the cells include immune 
mediated events such as vitiligo, transient uveitis, hearing loss and vestibular 
dysfunction. (IL-2 specific toxicity is discussed in 6.14.2).  The use of the non-
myeloablative regimen prior to cell administration increases the toxicity of this 
treatment as profound myelosuppression occurs in all patients.   
11.3 
IL-2 Administration 
See section 6.14.2 for IL-2 toxicity considerations. The standard approach to the 
administration of high-dose IL-2 in all studies is to continue dosing without putting the 
patient at risk for severe or irreversible toxicities. The most commonly seen Grade 4 
events are pulmonary and renal impairment, and mental status changes.  It is 
important to note that although these patients require significant supportive measures 
during this period, most toxicities are reversible and the overwhelming majority of 
patients have suffered no long term sequelae following this treatment regimen.  
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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. 
12 ADVERSE EVENTS 
Toxicities will be recorded as AEs and SAEs in the patient’s source documents and 
on the Adverse Event eCRF and must be graded using the NCI’s CTCAE v4.03 dated 
June 14, 2010.  
12.1 
Definitions 
Adverse Event 
An AE is defined as any untoward medical occurrence that occurs during a clinical 
investigation regardless of causal relationship with the investigational product.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease assessed in eligible patients after enrollment 
in the study. 
Events meeting the definition of an AE include: 
 
Adverse event temporally associated with the use of any of the study 
drugs or TIL treatment whether or not considered related to the use of 
any of the study drugs or TIL treatment. 
 
Any abnormal laboratory test results (e.g. hematology, clinical chemistry, 
or urinalysis) or other safety assessments (e.g., EKGs, radiological scans, 
vital signs measurements), that worsen from baseline, and are felt to be 
clinically significant in the medical and scientific judgment of the 
Investigator. 
 
Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after investigational product 
administration. 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction with 
investigational product. 
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 
Signs, symptoms, or the clinical sequelae of a suspected overdose of 
either investigational product or a concomitant medication. 
Events that do not meet the definition of an AE include: 
 
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 
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decision, they may jeopardize the patient and may require intervention to prevent one 
of the above outcomes as listed in this definition. 
Hospitalization including admission to a telemetry unit or ICU specifically for 
administration of study treatment is not considered a serious adverse event.  
Any pregnancy that occurs while on the study must be reported to the Sponsor or 
their representative.  The pregnancy must be followed up until discharge following 
delivery or premature termination to determine outcome and status of mother and 
child.  Pregnancy complications and elective terminations for medical reasons must 
be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.  
Any SAE occurring in association with a pregnancy, brought to the Investigator’s 
attention after the patient has completed the study and considered by the Investigator 
as possibly related to the investigational product, must be promptly reported to the 
Sponsor or their representative.  In addition, the Investigator must attempt to collect 
pregnancy information on any female partners of male study patients who become 
pregnant while the patient is enrolled in the study. Pregnancy information must be 
reported to the Sponsor or their representative. 
12.2 
Reporting Procedures for Adverse Events 
12.2.1  All Adverse Events 
All AEs occurring after 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.   
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 
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a SAE unless it is deemed to be related to the use of study treatment.)  The cause of 
death should be recorded in detail on the SAE Report Form. 
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: 
 
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, 
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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 
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 v4.03 
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.   
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SAE reports will be reported to Drug Safety Solutions, Inc. via 
 
 
Reporting to Regulatory Agencies and Institutional Review Boards (IRBs): 
In the event of a serious adverse event, the Sponsor, or their designee, will notify the 
appropriate regulatory authorities and all appropriate parties as per the regulations.  In 
addition, the Sponsor must submit expedited reports of an increased rate of 
occurrence of serious adverse events over that listed in the protocol or Investigational 
Brochure. Sponsor will notify participating sites of any serious adverse events which 
occur during trial.  
12.2.5 Data Safety Monitoring Board  
An independent DSMB will monitor patient safety during the study.  The DSMB’s roles, 
responsibilities, and conduct are described in an independent charter. 
13 ADMINISTRATIVE REQUIREMENTS 
13.1 
Protocol Modifications 
The Investigator will not modify this protocol without obtaining the concurrence of the 
sponsor.  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 
documents will describe any departure from the protocol and the circumstances 
requiring it. 
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13.2 
Regulatory Documentation 
 
Documents that must be provided to the Sponsor prior to study drug shipment are as 
follows: 
 
Up-to-date curriculum vitae for each Investigator.  
 
Signed and dated Investigator Agreement.  
 
Applicable local regulatory documentation (e.g., FDA 1572 Form). 
 
A copy of the formal written notification to the Investigator regarding 
approval of the protocol by an IEC/IRB that is in compliance with 
regulatory guidelines. The written notification is to be signed by the 
chairman or authorized designee and must identify the specific protocol.  
In cases where an IEC/IRB member has a known conflict of interest, 
abstention of that individual from voting should be documented; an 
Investigator may be a member of the IEC/IRB, but may not vote on any 
research in which he or she is involved. 
 
Name and address of the IRB with a statement that it is organized and 
operates according to GCP and the applicable laws and regulations, and 
a current list of the IRB members. If accompanied by a letter of 
explanation from the IRB, a general statement may be substituted for this 
list. 
 
A copy of the IRB approved informed consent and other adjunctive 
materials (e.g., advertising) to be used in the study, including written 
documentation of IEC approval of these items. 
 
Name and address of any local laboratory conducting tests for the study, 
a dated copy of the laboratory reference values for tests to be performed 
during the study and a copy of the certification or other documentation 
establishing adequacy of the facility. 
 
Required financial agreement. 
In addition to the documents required prior to the study, other documentation may be 
required during the course of the study. 
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13.3 
Record Retention 
In compliance with the ICH/GCP guidelines the Investigator/institution will be 
responsible for all information in the eCRF and will maintain the source documents 
that support the data collected from each patient, and all trial documents as specified 
in Essential Documents for the Conduct of a Clinical Trial and as specified by the 
applicable regulatory requirement(s). The Investigator/Institution will take measures to 
prevent accidental or premature destruction of these documents.  Essential 
documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the 
Sponsor to inform the Investigator/institution as to when these documents no longer 
need to be retained. If the responsible Investigator retires, relocates, or for other 
reasons withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person who will accept the responsibility.  The Sponsor must be 
notified in writing of the name and address of the new custodian. 
13.4 
 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. On-Site 
Audits 
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, 
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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 
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. 
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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. 
Visits are usually made at intervals of at least four to twelve weeks.  The dates of the 
visits will be recorded by the monitor in a trial center visit log to be kept at the site. 
The first post-initiation visit will usually be made as soon as possible after enrollment 
has begun.  At these visits the monitor will compare the data entered into the eCRFs 
with the hospital or clinic records (source documents). At a minimum, source 
documentation must be available to substantiate proper informed consent procedures, 
adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, administration of concomitant medication, drug receipt/dispensing/return 
records, and study drug administration information.  Specific items required as source 
documents will be reviewed with the Investigator prior to the study.  Findings from this 
review of eCRFs and source documents will be discussed with the Investigator. The 
Sponsor expects that, during monitoring visits, the Investigator (and as appropriate 
the Study Coordinator) will be available, the source documentation will be available, 
and a suitable environment will be provided for review of study-related documents. 
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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.  
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 
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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 
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. 
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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 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. 
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The Investigator shall not submit a publication to journals or professional societies 
without the prior written approval of the Sponsor.  
 
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15 REFERENCES 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 
Jan-Feb;66(1):7-30. doi: 10.3322/caac.21332. Epub 2016 Jan 7. PubMed PMID: 
26742998. 
 
2. 
Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: 
time for a change? Cancer 2007;109:455-464. 
3. 
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib 
in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516. 
4. 
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated 
metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled 
trial. Lancet 2012;380:358-365. 
5. 
Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in 
BRAF-mutated melanoma. N Engl J Med 2012;367:107-114. 
6. 
Robert C. COMBI-v: A randomised, open-label, phase III study comparing the 
combination of dabrafenib (D) and trametinib (T) to vemurafenib (V) as first-line 
therapy in patients (pts) with unresectable or metastatic BRAF V600E/K 
mutation-positive cutaneous melanoma.  European Society for Medical Oncology 
Congress. Madrid, Spain: September 26-30, 2014. 
7. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med 2010;363:711-723. 
8. 
Sondak VK, Sabel MS, Mule JJ. Allogeneic and autologous melanoma vaccines: 
where have we been and where are we going? Clin Cancer Res 2006;12:2337s-
2341s. 
9. 
Church SE, Jensen SM, Twitty CG, et al. Multiple vaccinations: friend or foe. 
Cancer J 2011;17:379-396. 
10. 
Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond 
current vaccines. Nat Med 2004;10:909-915. 
11. 
Kaufman H, Lutzky J, Clark J, et al. Safety and efficacy of ipilimumab in 
melanoma patients who received prior immunotherapy on phase III study 
MDX010-020. J Clin Oncol 2013;31. 
12. 
Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 
therapy for patients with metastatic melanoma: analysis of 270 patients treated 
between 1985 and 1993. J Clin Oncol 1999;17:2105-2116. 
13. 
Hodi FS. Advanced melanoma patients treated with ipilimumab live as long as 10 
years.  European Cancer Congress. Amsterdam, The Netherlands: September 
27-October 1, 2013. 
1008 of 1468

Lion Biotechnologies, Inc. 
 
LN-144 
Protocol C-144-01 
 
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14. 
Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-
term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 
2012;18:2039-2047. 
15. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates 
of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454. 
16. 
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. 
17. 
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. 
18. 
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. Cancer J 2012;18:160-175. 
20. 
Sim GC, Chacon J, Haymaker C, et al. Tumor-infiltrating lymphocyte therapy for 
melanoma: rationale and issues for further clinical development. BioDrugs 
2014;28:421-437. 
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. 
24. 
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-
632. 
25. 
Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path 
to effective cancer immunotherapy. Nat Rev Cancer 2008;8:299-308. 
26. 
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 1996;2:91-98. 
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. 
1009 of 1468

Lion Biotechnologies, Inc. 
 
LN-144 
Protocol C-144-01 
 
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CONFIDENTIAL 
Page 80 of 96 
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. 
29. 
Kirkin AF, Dzhandzhugazyan K, Zeuthen J. Melanoma-associated antigens 
recognized by cytotoxic T lymphocytes. APMIS 1998;106:665-679. 
30. 
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-
1949. 
35. 
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 1991;83:932-937. 
39. 
Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive 
immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 
1986;233:1318-1321. 
40. 
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. 
44. 
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. 
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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. 
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. 
55. 
Besser MJ, Shapira-Frommer R, Itzhaki O, et al. Adoptive transfer of tumor-
infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat 
analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res 
2013;19:4792-4800. 
56. 
Besser MJ, Shapira-Frommer R, Treves AJ, et al. Minimally cultured or selected 
autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy 
regimen in metastatic melanoma patients. J Immunother 2009;32:415-423. 
57. 
Dudley ME, Gross CA, Langhan MM, et al. CD8+ enriched "young" tumor 
infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin 
Cancer Res 2010;16:6122-6131. 
58. 
Dudley ME, Gross CA, Somerville RP, et al. Randomized selection design trial 
evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for 
adoptive cell therapy for patients with melanoma. J Clin Oncol 2013;31:2152-
2159. 
59. 
Ullenhag GJ, Sadeghi AM, Carlsson B, et al. Adoptive T-cell therapy for 
malignant melanoma patients with TILs obtained by ultrasound-guided needle 
biopsy. Cancer Immunol Immunother 2012;61:725-732. 
 
 
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1. 
Physical examination (PE) will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, 
respiratory system, skin, psychiatric (mental status), general nutrition. PE conducted during follow-up will be symptom directed.  Post LN-144 
infusion PE should occur three times a week until discharge. 
2. 
List only medications that are NOT part of the tumor harvest procedure. 
3. 
Vital signs will include 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 four hours and then routinely (every four to six hours), unless otherwise clinically 
indicated, for up to approximately 24 hours post LN-144 infusion. 
4. 
CMV assay if clinically indicated 
5. 
Cardiac evaluation (stress thallium) for all patients (per current package insert for IL2).  Echocardiogram or MUGA for patients ≥ 60 years or 
patients who have a history of ischemic heart disease, chest pain, or clinical significant atrial and/or ventricular arrhythmias.  Stress thallium must 
show normal LVEF and unimpaired wall movement. 
6. 
Required for Screening, then imaging as clinically indicated.  If screening image shows abnormalities, obtain at day -14.   Include neck if there is 
prior or suspected neck disease 
7. 
Chem 20: [Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Magnesium total (Mg), Phosphorus, Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, 
Total CK, Uric Acid]  
8. 
Thyroid panel: TSH and Free T4.  Obtain only as clinically indicated beginning at Day 84/Week 12 and during Follow-up. 
9. 
Complete blood count with differential 
10. Dipstick urinalysis with culture, if indicated 
11. Calculate creatinine clearance using Cockcroft-Gault calculation 
12. Serum pregnancy test for women of child bearing potential   
13. HLA typing to be sent to central laboratory 
14. Pulmonary evaluation for all patients   
15. 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.  
16. One to two days after the last dose of agent in the preparative regimen 
17. Initiate within approximately 12-24 hours after TIL infusion and continue every eight hours for up to six doses 
18. Continue until neutrophils count > 1000/mm3 X 3 days.   
19. The TMP/SMX DS schedule should be adjusted to QD three times per week (Monday, Wednesday, Friday) and continue for at least six (6) 
months and until CD4 > 200/mm3 
20. Continue until ANC > 1000/mm3   
21. In patients positive for HSV continue until CD4 > 200/mm3     
22. 50 mL of blood drawn using vacutainers (refer to the Lab Manual). To be sent to central laboratory 
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APPENDIX 2: ECOG SCALE 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead. 
Adapted from Oken MM, Creech RH, Tormey DC, et al.  Toxicity and Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol.  1982;5:649-655. 
 
 
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APPENDIX 3: PRACTICAL WEIGHT 
Modification of Dose Calculations* in Patients whose BMI is > 35 
 Unless otherwise specified in this protocol, actual body weight is used for dose calculations 
of treatment agents.   In patients who are determined to be obese (BMI > 35), the practical 
weight (see 3 below) will be used. 
 1.  BMI Determination: 
 BMI = weight (kg) / [height (m)]2 
 2.  Calculation of ideal body weight 
 Male = 50 kg + 2.3 (number of inches over 60 inches) 
Example:  ideal body weight of 5’10’’ male 
     50 + 2.3 (10) = 73 kg 
 Female = 45.5 kg + 2.3 (number of inches over 60 inches) 
Example:  ideal body weight of 5’3’’ female 
     45.5 + 2.3 (3) = 57 kg 
 3.  Calculation of “practical weight” 
 Calculate the average of the actual and the ideal body weights.  This is the practical weight 
to be used in calculating the doses of chemotherapy and associated agents designated in 
the protocol. 
 *Practical weight will NOT be used in the calculation of dose for IL-2. 
 
 
 
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APPENDIX 4: HIGH-DOSE IL-2 TOXICITIES 
Adverse Events occurrence in > 10% of patients treated with IL-2 (n=525) 
 
 
  
 
Body System/Events 
% patients 
Body System/Events 
% patients 
Body as a whole 
Metabolic and Nutritional Disorders 
Chills 
52 
Bilirubinemia 
40 
Fever 
29 
Creatinine Increase 
33 
Malaise 
27 
Peripheral Edema 
28 
Asthenia 
23 
SGOT increase 
23 
Infection 
13 
Weight gain 
16 
Pain 
12 
Edema 
15 
Abdominal pain 
11 
Acidosis 
12 
Enlarged Abdomen 
10 
Hypomagnesemia 
12 
Cardiovascular System 
Hypocalcemia 
11 
Hypotension 
71 
Alkaline Phosphatase Increase 
10 
Tachycardia 
23 
Nervous System 
Vasodilation 
13 
Confusion 
34 
Supraventricular Tachycardia 
12 
Somnolence 
22 
Cardiovascular disordera 
11 
Anxiety 
12 
Arrhythmia 
10 
Dizziness 
11 
Digestive System 
Respiratory System 
Diarrhea 
67 
Dyspnea 
43 
Vomiting 
50 
Lung Disorderb 
24 
Nausea 
35 
Respiratory Disorderc 
11 
Stomatitis 
22 
Cough increase 
11 
Anorexia 
20 
Rhinitis 
10 
Nausea and Vomiting 
19 
Skin and Appendages 
Hematologic and Lymphatic 
Rash 
42 
Thrombocytopenia 
37 
Pruritus 
24 
Anemia 
29 
Exfoliative dermatitis 
18 
Leukopenia 
16 
Urogenital System 
  
  
Oliguria 
63 
a  Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b  Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c  Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
Source: Proleukin® Prescribing Information – June 2007 
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APPENDIX 5: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT 
 
Expected 
toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
 
Stop Treatment 
** 
Chills 
3 
IV Meperidine 25-50 mg, IV 
q1h, prn, 
No 
No 
Fever 
3 
Acetaminophen 650 mg, po, 
q4h; Indomethacin 50-75 
mg, po, q8h 
No 
No 
Pruritus 
3 
Hydroxyzine HCl 10-20 mg 
po q6h, prn; 
Diphenhydramine HCl 25-50 
mg, po, q4h, prn 
No 
No 
Nausea/ 
Vomiting/ 
Anorexia 
3 
Ondansetron 10 mg, IV, q8h, 
prn; Granisetron 0.01 mg/kg 
IV daily prn; Droperidol 1 
mg, IV q4-6h, prn; 
Prochlorperazine 25 mg q4h 
p.r., prn or 10 mg IV q6h prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg, po, q3h, 
prn; Diphenoxylate HCl 2.5 
mg and atropine sulfate 25 
µg, po, q3h, prn; codeine 
sulfate 30-60 mg, po, q4h, 
prn 
If uncontrolled after 
24 hours despite all 
supportive 
measures 
No 
Malaise 
3 or 4 
Bedrest interspersed with 
activity 
If other toxicities 
occur 
simultaneously 
No 
Hyperbilirubine
mia 
3 or 4 
Observation 
If other toxicities 
occur 
simultaneously 
No 
Anemia  
3 or 4 
Transfusion with PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytope
nia 
3 or 4 
Transfusion with platelets 
If uncontrolled 
despite all 
supportive 
measures 
No 
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Expected 
toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
 
Stop Treatment 
** 
Edema/Weight 
gain 
3  
Diuretics prn 
No 
No 
Hypotension 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled 
despite all 
supportive 
measures 
No 
Dyspnea 
3 or 4 
Oxygen or ventilatory 
support 
If requires 
ventilatory support 
No 
Oliguria 
3 or 4 
Fluid boluses or dopamine at 
renal doses 
If uncontrolled 
despite all 
supportive 
measures 
No 
Increased 
creatinine 
3 or 4 
Observation 
Yes (Grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 
Pleural effusion  
3 
Thoracentesis 
If uncontrolled 
despite all 
supportive 
measures 
No 
Bowel 
perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion therapy 
If uncontrolled 
despite all 
supportive 
measures 
No 
Elevated 
Troponin levels 
3 or 4 
Observation 
Yes 
If changes in LV 
function have 
not improved to 
baseline by next 
dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
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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/2013/012141s090,012142 
s112lbl.pdf 
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APPENDIX 8: FLUDARABINE PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda docs/label/2009/020038s032lbl.pdf 
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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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