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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CLINICAL PROTOCOL 
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 
PROTOCOL NUMBER:  
C-144-01
SPONSOR: 
Lion Biotechnologies, Inc. 
999 Skyway Rd, Suite 150 
San Carlos, CA 94070 
United States 
PROTOCOL VERSION: 
Final Version 6.0 (Incorporating Amendments 1-5) 
PROTOCOL DATE: 
13 May 2017 
IND NUMBER: 
16317 
EudraCT NUMBER: 
2017-000760-15 
This study will be conducted in compliance with the protocol, Good Clinical Practice (CGP) and 
all other applicable regulatory requirements, including the archiving of essential documents. 
The specific contact details of the Lion Biotechnologies legal/regulatory entity within the relevant 
country are provided within the clinical trial agreement with the Investigator/Institution and in the 
Clinical Trial Application with the Competent Authority.
CONFIDENTIAL & PROPRIETARY INFORMATION 
This document contains confidential information, trade secrets and is the proprietary 
property of Lion Biotechnologies, Inc (Sponsor) or their representatives, and any 
unauthorized use or disclosure of such information without the prior written authorization 
of the Sponsor or their representative is expressly prohibited. 
 
 
  
 
 
 
 
 
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LEAD INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title:  
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  
Protocol Number:  
C-144-01 
IND Number 
16317 
EudraCT Number 
2017-000760-15 
Sponsor: 
Lion Biotechnologies, Inc. 
Version / Date of Protocol: 
FINAL Version 6.0 (Incorporating Amendments 1-5), 
13 May 2017 
By my signature, I acknowledge my review and approval of this protocol.  
 
 
___________________________________     
_________________________ 
Amod Sarnaik, MD 
 
 
 
Date 
Associate Professor, Cutaneous Oncology and Immunology 
Moffitt Cancer Center 
Tampa, FL  
United States  
 
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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title:  
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  
Protocol Number:  
C-144-01 
IND Number 
16317 
EudraCT Number 
2017-000760-15 
Sponsor: 
Lion Biotechnologies, Inc. 
Version / Date of Protocol: 
FINAL Version 6.0 (Incorporating Amendments 1-5), 
13 May 2017 
 
 
I agree to conduct the study as detailed in the protocol and in compliance with ICH Guidelines for 
Good Clinical Practice.  I received a copy of the Investigator’s Brochure. 
 
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. 
 
 
 
______________________________________ 
Investigator Printed Name 
 
 
 
 
______________________________________ 
 
_____________________ 
Investigator Signature  
 
 
 
Date 
 
 
 
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SPONSOR MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Name: 
 
Title: 
 
Address: 
999 Skyway Road, Suite 150 
San Carlos, CA  94070 
United States 
 
Direct Office: 
 
Toll-Free:  
 
E-mail: 
 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title: 
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  
Study Type: 
Phase 2  
Indication: 
Treatment of patients with metastatic melanoma who have progressed or not 
responded following prior systemic therapy 
Investigational Agent: 
LN-144: Autologous Tumor Infiltrating Lymphocytes (TIL) derived from the 
patient’s own tumor 
Study Objectives: 
Primary Objective 
• 
To evaluate the efficacy of LN-144 in patients with metastatic melanoma 
using the objective response rate (ORR) 
Secondary Objectives 
• 
To further evaluate efficacy of LN-144 in patients with metastatic 
melanoma such as complete response (CR) rate, duration of response 
(DOR), disease control rate (DCR), progression-free survival (PFS), and 
overall survival (OS) 
• 
To characterize the safety profile of LN-144 in patients with metastatic 
melanoma 
Exploratory Objectives 
• 
To explore the persistence of LN-144 and potential immune correlates of 
response, outcome, and toxicity of the treatment. 
• 
To explore efficacy based on irRECIST1 criteria as assessed by 
independent review 
• 
To assess health-related quality of life (HRQoL) 
Study Design: 
Prospective, interventional study evaluating adoptive cell therapy (ACT) with 
autologous TIL infusion (LN-144) followed by adjuvant interleukin-2 (IL-2) 
after a nonmyeloablative chemotherapy preparative regimen.  
Dose and Treatment 
Schedule: 
The cell transfer therapy used in this study involves patients receiving a 
nonmyeloablative lymphodepletion (NMA-LD) preparative regimen, 
consisting of cyclophosphamide IV (60 mg/kg x 2 doses) with mesna 15 
mg/kg and fludarabine IV (25 mg/m2 x 5 doses), followed by infusion of 
tumor-derived autologous TIL (LN-144) and administration of adjuvant IL-2 
at 600,000 IU/kg approximately every 8 hours for up to a maximum of 
6 doses, starting as soon as 3 hours, but no later than 24 hours after completion 
of LN-144 infusion.  
Patients will receive 1 course of LN-144 treatment in Cohort 1 and Cohort 2. 
Patients may be entered into a retreatment cohort (Cohort 3) for a second 
treatment with TIL therapy.  
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Duration of Study 
Participation: 
Screening and tumor resection/TIL harvest: up to 28 days  
Treatment Period: up to 12 days, including NMA-LD (7 days) and LN-144 
infusion followed by adjuvant IL-2 (up to 5 days) 
Patients will be evaluated for response at 6 weeks (Day 42 ± 3 days) following 
the LN-144 infusion and every 6 weeks thereafter, for up to 6 months.  
After 6 months, patients will be evaluated as noted below: 
• 
At 9 months (± 1 week) following LN-144 treatment 
• 
At 12 months (± 1 week) following LN-144 treatment  
• 
At 18 months (± 3 weeks) following LN-144 treatment 
• 
At 24 months (± 3 weeks) following LN-144 treatment 
Overall Survival Follow-up to collect subsequent anti-cancer therapy and 
survival status for 3 years from last patient receiving last dose of adjuvant IL-2 
or end of study (EOS) visit. 
Number of Study 
Centers: 
Approximately 35 clinical sites globally 
Number of Planned 
Patients: 
Approximately sixty (60) patients will complete treatment (approximately 
30 patients in Cohort 1 and 30 patients in Cohort 2). Complete treatment is 
defined as having received any volume of LN-144 infusion followed by at 
least 1 dose of adjuvant IL-2.  Patients who participate in initial TIL therapy in 
Cohort 1 or Cohort 2 may enter a third treatment cohort (Cohort 3) where 
approximately 10 patients will be retreated with a second 
manufacturing/administration of LN-144 (TIL therapy). 
Study Population: 
Diagnosis and Main 
Criteria for Inclusion: 
a. 
Patients with unresectable metastatic melanoma (Stage IIIc or Stage IV) 
who progressed following ≥1 line of prior systemic therapy, including 
immune checkpoint inhibitor (e.g., anti-PD-1), and if BRAF mutation-
positive, after BRAF inhibitor systemic therapy  
• 
At least one measurable target lesion as defined by RECIST 
version 1.1.2 Lesions in previously irradiated areas should not be 
selected as target lesion, unless treatment was ≥ 3 months prior, and 
there has been demonstrated progression in the lesion 
• 
At least one resectable lesion to generate TILs of a minimum 1.5 cm 
in diameter post-resection  
b. Patients must be ≥ 18 years and ≤ 70 years of age at the time of consent. 
Enrollment of patients > 70 years of age may be allowed after 
consultation with the Medical Monitor 
c. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1, and estimated life expectancy of ≥3 months 
d. In the opinion of the Investigator, patient must be able to complete all 
study-required procedures   
e. 
Patients of childbearing potential or their partners of childbearing 
potential must be willing to practice an approved method of birth control 
during treatment and for 4 months after receiving all protocol related 
therapy 
f. 
Patients must have the following hematologic parameters: 
• 
absolute neutrophil count (ANC) > 1000/mm3  
• 
hemoglobin > 9.0 g/dL 
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• 
platelet count > 100,000/mm3 
g. Patients must have adequate organ function: 
• 
serum ALT/SGPT and AST/SGOT < 3 times the upper limit of 
normal ULN), patients with liver metastasis < 5 times ULN 
• 
an estimated creatinine clearance (eCCr) ≥ 40 mL/min using the 
Cockcroft-Gault formula at Screening  
• 
total bilirubin ≤ 2 mg/dL 
o 
Patients with Gilbert’s Syndrome must have a total bilirubin 
< 3 mg/dL   
h. Patients must be seronegative for the HIV antibody, hepatitis B antigen, 
and hepatitis C antibody or antigen 
i. 
Patients must have recovered from all prior therapy-related AEs to 
Grade 1 or less (per CTCAE v4.03), except for alopecia or vitiligo, prior 
to enrollment (tumor resection) 
• 
A minimal washout period of 4 weeks is required prior to enrollment 
(tumor resection) 
• 
Palliative radiation therapy is permitted between biopsy and 
nonmyeloablative lymphodepletion if it does not involve lesions 
being selected as target or non-target lesions 
• 
Patients may undergo pre-planned procedures if within 2-3 weeks 
prior to the start of nonmyeloablative lymphodepletion 
j. 
Patients with documented Grade 2 or greater diarrhea or colitis as a result 
of previous treatment with immune checkpoint inhibitor(s) must have 
been asymptomatic for at least 6 months and/or had a normal 
colonoscopy post immune checkpoint inhibitor treatment by visual 
assessment, prior to start of nonmyeloablative lymphodepletion 
k. 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/Independent Ethics Committee (IRB/IEC), and agree to abide by 
the study restrictions and return to the site for the required assessments 
l. 
Patients have provided written authorization for use and disclosure of 
protected health information 
Main Criteria for 
Exclusion: 
 
a. 
Patients with melanoma of uveal/ocular origin 
b. Patients who have received prior cell transfer therapy that included a 
nonmyeloablative or myeloablative chemotherapy regimen (not 
applicable for patients in the retreatment Cohort 3) 
c. 
Patients with symptomatic and/or untreated brain metastases (of any size 
and any number) 
• 
Patients with definitively treated brain metastases, will be considered 
for enrollment after discussion with Medical Monitor, and must be 
stable for 2-4 weeks prior to the start of treatment (nonmyeloablative 
lymphodepletion) 
d. Patients who are pregnant or breastfeeding 
e. 
Patients who are on a systemic steroid therapy at a dose of > 10 mg of 
prednisone or equivalent per day 
• 
A short course of higher dose steroid therapy is allowed in cases of 
exacerbation of known disease or for treatments of new acute 
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symptoms 
f. 
Patients who have active medical illness(es) that in the opinion of the 
Investigator would pose increased risk for study participation, such as 
systemic infections requiring antibiotics, coagulation disorders or other 
active major medical illnesses of the cardiovascular, respiratory or 
immune system 
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 left ventricular ejection fraction (LVEF) < 45% at 
Screening  
j. 
Patients who have obstructive or restrictive pulmonary disease and have a 
documented FEV1 (forced expiratory volume in 1 second) of ≤ 60% 
k. Patients who have had another primary malignancy within the previous 
3 years (with the exception of carcinoma in situ of the breast, cervix, or 
bladder, localized prostate cancer and non-melanoma skin cancer that has 
been adequately treated) 
l. 
Patients with known allergic reaction to antibiotics of aminoglycoside 
group (i.e. streptomycin, gentamicin) 
m. Patients who have been shown to be BRAF mutation positive (V600), but 
have not received prior systemic therapy with a BRAF-directed kinase 
inhibitor 
Treatment Cohorts: 
LN-144 (autologous TIL) followed by IL-2 after a lymphocyte-depleting 
preparative regimen as an open-label treatment. 
Cohort 1: LN-144 process without cryopreservation of the final TIL product  
Cohort 2: LN-144 process with cryopreservation of the final TIL product  
Cohort 3: Retreatment cohort: patients from Cohort 1 or Cohort 2 may 
rescreen for a second tumor resection and LN-144 treatment, if they meet all 
Inclusion and Exclusion Criteria (except exclusion b). These patients will have 
a second tumor harvest and TIL (LN-144) therapy. Examples of patients who 
may be eligible for retreatment in Cohort 3 are prior responders to LN-144 
who relapse, non-responders, and patients with manufacturing failures. The 
Medical Monitor will have authority to adjudicate enrollment into Cohort 3 
(second TIL therapy). Prior to enrollment in Cohort 3, patients must undergo 
abbreviated screening procedures. 
Early Discontinuation 
from Study or 
Treatment: 
Criteria for early discontinuation from treatment: 
• 
Grade 3 or greater autoimmunity that involves vital organs (heart, 
kidneys, brain, eye, liver, colon, adrenal gland, lungs) with 
symptoms emerging prior to first IL-2 administration  
• 
Grade 3 or greater allergic reaction including bronchospasm or 
generalized urticaria that does not resolve after medical management 
in the opinion of the Investigator  
• 
Grade 3 or greater toxicity due to IL-2 that does not decrease to 
Grade 2 or less within 96 hours of management   
• 
Determination by the Investigator that continued treatment is not in 
the best interest of the patient 
 
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• 
Withdrawal by patient. The patient may withdraw consent to 
treatment but continue consent for follow-up evaluations and/or 
survival status. 
• 
Pregnancy 
Criteria for early discontinuation from study: 
• 
Patient becomes ineligible for the study after tumor harvest or did not 
receive LN-144 infusion for any reason 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the patient 
Efficacy Assessment: 
The descriptive summary of the ORR, CR rate, DOR, DCR, and PFS per 
cohort will be used to determine the potential efficacy of LN-144, per RECIST 
1.1 criteria by Investigator review.  Estimation of OS will depend on the dates 
of death or the last known alive status.  
Safety Assessment: 
Treatment-emergent adverse events (TEAEs) and clinical laboratory data will 
be collected and evaluated to assess the safety of this treatment. Adverse 
events (AEs) will be collected from the time the patient signs the ICF up until 
6 month from their last dose of IL-2 or until the first dose of anti-cancer 
therapy, whichever occurs first. All AEs attributed to protocol-required 
procedures or treatment will be collected from signing of the ICF through 
Month 24 study visit. 
Overview of Statistical 
Plan: 
The primary statistical plan of analysis is based on use of descriptive methods 
and estimation of efficacy and safety parameters will be performed by cohort. 
There is no planned statistical comparison among cohorts.  
Patients meeting RECIST 1.1 criteria2 for a confirmed complete (CR) or 
partial (PR) response will be classified as responders in the analysis of the 
ORR. This rate will be summarized using both a point estimate and its 2-sided 
90% confidence limits. 
All time-to-event efficacy endpoints will use the Kaplan-Meier method to 
summarize the data. The time origin for all such analyses (except for response 
duration) will be the date on which patients began treatment with 
lymphodepletion.  
The assessment of safety data will be descriptive and based on the 
summarization of TEAEs, SAEs, AEs leading to discontinuation from 
treatment and the study, vital signs, physical examinations, and clinical 
laboratory tests. 
Sample Size 
Consideration: 
The planned number of all-treated patients (see Section 10.2) per Cohort 1 and 
Cohort 2 is approximately 30 (total 60, inclusive of Cohort 3 re-treated 
patients).  The hypotheses test of primary endpoint analysis per cohort in this 
study assumes an underlying ORR of 15% over best monotherapy available, as 
the historical control, for the treatment of patients with metastatic melanoma 
after progression on anti-PD-1 therapy.3 Assuming a true response rate of 30% 
for the LN-144 therapy, a sample size of 30 all-treated patients provides 
approximately 70% power to to reject the null hypothesis H0 ≤ 15% at 1-sided 
5% significance level. 
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DSMB Safety 
Assessments: 
A Data Safety Monitoring Board (DSMB) will evaluate cumulative safety data 
on the first 3 patients completing 12 weeks of assessment in Cohort 1 and in 
Cohort 2, respectively. Enrollment will continue while under DSMB review. 
Additional evaluations of safety data may be specified in the DSMB charter. 
 
 
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TABLE OF CONTENTS 
LEAD INVESTIGATOR PROTOCOL SIGNATURE PAGE .................................... 3 
INVESTIGATOR PROTOCOL SIGNATURE PAGE ................................................. 4 
SPONSOR MEDICAL MONITOR / EMERGENCY CONTACT  
INFORMATION ............................................................................................................... 5 
PROTOCOL SYNOPSIS ................................................................................................. 6 
LIST OF TABLES .......................................................................................................... 18 
LIST OF FIGURES ........................................................................................................ 18 
LIST OF ABBREVIATIONS ........................................................................................ 19 
1 
INTRODUCTION................................................................................................... 21 
1.1 
Background ................................................................................................................................. 21 
1.2 
Overview of Adoptive Cell Transfer for Metastatic Melanoma ................................................. 24 
1.3 
Production and Expansion of Tumor Infiltrating Lymphocytes ................................................ 27 
1.4 
LN-144 TIL Therapy ................................................................................................................... 29 
2 
STUDY DESIGN ..................................................................................................... 30 
2.1 
Description of the Study .............................................................................................................. 30 
2.2 
Description of the Study Centers ................................................................................................ 30 
3 
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 30 
3.1 
Study Objectives .......................................................................................................................... 30 
3.1.1 
Primary Objective ...................................................................................................................... 30 
3.1.2 
Secondary Objectives ................................................................................................................ 31 
3.1.3 
Exploratory Objectives .............................................................................................................. 31 
3.2 
Study Endpoints .......................................................................................................................... 31 
3.2.1 
Primary Endpoint ...................................................................................................................... 31 
3.2.2 
Secondary Endpoints ................................................................................................................. 31 
3.2.3 
Exploratory Endpoints ............................................................................................................... 31 
4 
SELECTION OF PATIENT POPULATION ...................................................... 32 
4.1 
Inclusion Criteria ........................................................................................................................ 32 
4.2 
Exclusion Criteria ........................................................................................................................ 34 
4.3 
Number of Patients ...................................................................................................................... 35 
4.3.1 
Rescreening Patients .................................................................................................................. 36 
4.3.2 
Patient Cohorts .......................................................................................................................... 36 
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5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND 
NON-DRUG THERAPIES ............................................................................................ 37 
5.1 
Prior Treatment and Concomitant Medications ......................................................................... 37 
5.2 
Prohibited and Permitted Medications during Study Treatment ............................................... 37 
5.2.1 
Prohibited Treatment ................................................................................................................. 37 
5.2.2 
Permitted Medications – Use with Caution ............................................................................... 38 
6 
STUDY PROCEDURES ........................................................................................ 38 
6.1 
Screening (up to 28 days from signing of informed consent form) ............................................. 38 
6.2 
Enrollment and Tumor Resection ............................................................................................... 40 
6.2.1 
Tumor Harvest and Processing Procedure ................................................................................. 40 
6.2.2 
Immune Monitoring and Phenotyping (Sequencing of Tumor and PBMC/Cell-Free DNA) .... 42 
6.3 
Baseline (Day -21 to Day -14) ...................................................................................................... 42 
6.4 
Patients Who Do Not Receive a LN-144 Infusion ....................................................................... 43 
6.5 
Early Treatment Discontinuation (prior to NMA-LD) ............................................................... 43 
6.6 
Day -7 ........................................................................................................................................... 43 
6.6.1 
Initiation of administration of the NMA-LD preconditioning medications ............................... 44 
6.7 
Day -6 ........................................................................................................................................... 45 
6.8 
Day -5 to Day -1 ........................................................................................................................... 46 
6.9 
Day 0 (Infusion day) .................................................................................................................... 47 
6.9.1 
Investigational Product .............................................................................................................. 47 
6.10 
Day 1, Day 2, Day 3 and Day 4................................................................................................ 48 
6.11 
Day 14 and 28 (both visits +/- 3 days) ..................................................................................... 50 
6.12 
Day 42 (Week 6) (+/- 3 days) ................................................................................................... 51 
6.13 
Day 84 (Week 12) and Day 126 (Week 18) (both visits +/- 3 days) ......................................... 52 
6.14 
Month 6, Month 9, Month 12, Month 18, and Month 24 (all visits +/- 1 week)...................... 54 
6.15 
Overall Survival Follow-Up .................................................................................................... 55 
6.16 
Late Treatment Discontinuation (following LN-144 infusion) ............................................... 56 
6.17 
Expected Toxicities and Treatment Guidelines ...................................................................... 56 
6.17.1 
LN-144 ................................................................................................................................. 56 
6.17.2 
IL-2 ....................................................................................................................................... 56 
6.17.3 
Blood Product Support ......................................................................................................... 57 
6.17.4 
Renal Toxicity ...................................................................................................................... 58 
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6.18 
Infection Prophylaxis .............................................................................................................. 58 
6.18.1 
Pneumocystis jiroveci Pneumonia ........................................................................................ 58 
6.18.2 
Herpes Virus Prophylaxis ..................................................................................................... 58 
6.18.3 
Fungal Prophylaxis (Fluconazole) ........................................................................................ 59 
6.18.4 
Empiric Antibiotics ............................................................................................................... 59 
6.18.5 
Blood Product Support ......................................................................................................... 59 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF 
PATIENTS....................................................................................................................... 59 
7.1 
Treatment Completion ................................................................................................................ 59 
7.2 
Criteria for Early Discontinuation from Treatment ................................................................... 60 
7.3 
Criteria for Early Discontinuation from Study........................................................................... 60 
8 
STUDY DRUG INFORMATION ......................................................................... 61 
8.1 
Investigational Product ............................................................................................................... 61 
8.2 
Qualitative Composition of LN-144 ............................................................................................ 61 
8.3 
Manufacturing Process ................................................................................................................ 61 
8.4 
Final Investigational Product Container ..................................................................................... 62 
8.5 
Transport ..................................................................................................................................... 62 
8.6 
Receipt at Clinical Site and Administration ................................................................................ 62 
9 
STUDY ASSESSMENTS ....................................................................................... 62 
9.1 
Tumor Assessments ..................................................................................................................... 62 
9.1.1 
Response Criteria ...................................................................................................................... 63 
9.2 
Biomarkers .................................................................................................................................. 65 
9.3 
Data Safety Monitoring Board .................................................................................................... 66 
10 STATISTICAL AND ANALYTICAL PLANS .................................................... 66 
10.1 
Introduction ............................................................................................................................ 66 
10.2 
Study and Analysis Populations .............................................................................................. 66 
10.2.1 
Efficacy Population .............................................................................................................. 66 
10.2.2 
Safety Population .................................................................................................................. 67 
10.3 
Endpoints ................................................................................................................................ 67 
10.3.1 
Primary ................................................................................................................................. 67 
10.3.2 
Secondary ............................................................................................................................. 67 
10.3.3 
Exploratory ........................................................................................................................... 68 
10.4 
Sample Size Consideration ..................................................................................................... 68 
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10.4.1 
Baseline Demographics and Clinical Characteristics ........................................................... 68 
10.4.2 
Primary Endpoint .................................................................................................................. 68 
10.4.3 
Secondary Endpoints ............................................................................................................ 69 
10.4.4 
Safety Analysis ..................................................................................................................... 69 
10.4.5 
Other Planned Analyses ........................................................................................................ 69 
11 CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS ...................... 70 
11.1 
Medications Administered during the Study .......................................................................... 70 
11.2 
LN-144 Treatment .................................................................................................................. 70 
11.3 
IL-2 Administration ................................................................................................................ 70 
12 ADVERSE EVENTS .............................................................................................. 70 
12.1 
Definitions ............................................................................................................................... 70 
12.1.1 
Adverse Event....................................................................................................................... 70 
12.1.2 
Serious Adverse Event .......................................................................................................... 72 
12.1.3 
Relationship to Study Drug .................................................................................................. 72 
12.1.4 
Severity ................................................................................................................................. 73 
12.2 
Reporting Procedures for Adverse Events ............................................................................. 73 
12.2.1 
Relationship to Study Drug .................................................................................................. 73 
13 ADMINISTRATIVE REQUIREMENTS ............................................................. 77 
13.1 
Adherence to the Protocol ....................................................................................................... 77 
13.2 
Regulatory Approval and Documentation .............................................................................. 77 
13.3 
Record Retention .................................................................................................................... 78 
13.4 
Data Quality Assurance .......................................................................................................... 79 
13.5 
Data Handling and Recordkeeping ........................................................................................ 80 
13.5.1 
Electronic Data ..................................................................................................................... 80 
13.5.2 
Data Handling and Recordkeeping ....................................................................................... 80 
13.6 
Study Completion/Termination .............................................................................................. 81 
13.6.1 
Study Completion ................................................................................................................. 81 
13.6.2 
Study Termination ................................................................................................................ 81 
13.7 
Monitoring .............................................................................................................................. 81 
14 INVESTIGATOR REGULATORY OBLIGATIONS ........................................ 81 
14.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ................................ 81 
14.2 
Informed Consent ................................................................................................................... 82 
14.3 
Patient Data Protection ........................................................................................................... 83 
14.4 
Adverse Event Reporting ........................................................................................................ 83 
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14.5 
Investigator ............................................................................................................................. 83 
14.6 
Confidentiality ........................................................................................................................ 84 
14.7 
Publications ............................................................................................................................. 84 
15 REFERENCES ........................................................................................................ 85 
APPENDIX 1: SCHEDULE OF EVENTS – FOR COHORT 1 AND  
COHORT 2 PATIENTS ................................................................................................. 91 
APPENDIX 2: SCHEDULE OF EVENTS – FOR COHORT 3 PATIENTS ............ 96 
APPENDIX 3: ECOG SCALE .................................................................................... 101 
APPENDIX 4: PRACTICAL WEIGHT ..................................................................... 102 
APPENDIX 5:  IL-2 TOXICITIES ............................................................................. 103 
APPENDIX 6: EXPECTED IL-2 TOXICITIES AND THEIR  
MANAGEMENT .......................................................................................................... 104 
APPENDIX 7: COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS......................................................................................................................... 107 
APPENDIX 8: CYCLOPHOSPHAMIDE PACKAGE INSERT ............................. 108 
APPENDIX 9: FLUDARABINE PACKAGE INSERT ............................................ 109 
APPENDIX 10: IL-2 (ALDESLEUKIN) PACKAGE INSERT ............................... 110 
APPENDIX 11: EORTC QLQ-C30 ............................................................................ 111 
APPENDIX 12: SUMMARY OF CHANGES (MAJOR/MINOR)  
IN PROTOCOL C-144-01 VERSION 6.0 (DATED, 13 mAY 2017) ........................ 114 
LIST OF TABLES  
Table 1. 
Time Point Response: Patients with Target (± Non-target) Disease .............. 65 
Table 2. 
Time Point Response: Patients with Non-Target Disease Only ..................... 65 
 
LIST OF FIGURES  
Figure 1 
Cohort 1 or Cohort 2 Study Flowchart ............................................................ 12 
Figure 2 
Cohort 3 Study Flowchart ................................................................................. 13 
Figure 3 
LN-144 Manufacturing Process without Final Cryopreservation ................. 28 
Figure 4 
LN-144 Manufacturing Process with Final Cryopreservation ....................... 28 
 
 
 
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LIST OF ABBREVIATIONS 
ACT 
Adoptive Cell Therapy 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome  
ALC 
Absolute lymphocyte count 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APC 
Antigen presenting cell 
AST 
Aspartate transaminase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMO 
Contract Manufacturing Organization  
CR 
Complete response 
CT 
Computed tomography 
CTL 
Cytotoxic T lymphocyte 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events Version 4.03 
CY 
Cyclophosphamide 
DC 
Dendritic cell 
DCR 
Disease control rate 
DOR 
Duration of response 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein-Barr virus 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
EKG 
Electrocardiogram 
EOS 
End of study 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire - Core 30 instrument 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 second 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
HRQoL 
Human immunodeficiency virus 
Health related quality of life 
HSA 
Human serum albumin 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IL-2 
Interleukin-2 (also known as “aldesleukin”) 
IND 
Investigational New Drug (Application) 
IP 
Investigational product 
irRECIST 
Immune-Related Response Evaluation Criteria in Solid Tumors 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
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IV 
Intravenous 
LD 
Lymphodepletion 
LN-144 
Autologous Tumor Infiltrating Lymphocytes 
LPLD 
Last patient last dose 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NMA 
Nonmyeloablative 
Non-CR 
Non-complete response 
Non-PD 
Non-progression 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PE 
Physical exam 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PHI 
Personal health information 
PO 
Per Os (by mouth) 
PR 
Partial response 
QD 
(Taken) once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REP 
Rapid expansion protocol 
RPR 
Rapid plasma reagin  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
T½ 
Half life 
TEAE 
Treatment-emergent adverse event 
TH 
Tumor Harvested patient population 
TIL 
Tumor infiltrating lymphocyte 
TME 
Tumor microenvironment 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
VDRL 
Venereal disease research laboratory 
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1 
INTRODUCTION 
1.1 
Background 
There are an estimated 232,000 newly diagnosed cases of melanoma skin cancers occurring 
globally each year, making it the fifth most common malignancy in men and the sixth most 
common malignancy in women.4 Unlike other malignancies, the incidence of melanoma is 
increasing by greater than 3.2% and 2.4% per year in males and females, respectively.5 Globally, 
the incidence rate varies with 20-30 new melanoma cases per 100,000 inhabitants in the US, 
compared to <10-25 new melanoma cases per 100,000 inhabitants in EU, and with the highest 
incidence of 50-60 per 100,000 inhabitants in Australia.6 One estimate predicted 112,000 new 
cases of invasive melanoma in 2030 if the current trend continues, showing relative increases in 
new melanoma cases in ranging from 291% in Australia to 585% in the UK.7,8 Of interest, 
individuals under age 45 account for 25% of all new melanoma cases.4    
The National Cancer Institute’s Surveillance, Epidemiology, and End Results uptake (SEER) 
Program estimates that there will be 10,130 deaths due to melanoma in 2016 in the US, despite 
the approvals of ipilimumab in 2011, and pembrolizumab and nivolumab in 2014, and the rapid 
uptake of these immunotherapeutic agents.5 Five-year survival depends on the stage at diagnosis. 
Between 2005 and 2011, 98% of patients with local disease survived 5 years as opposed to 63% 
with regional lymph node disease and 17% with distant spread at the time of diagnosis.7  
Current melanoma treatment guidelines are similar in Europe, the US, Canada, Australia and New 
Zealand.9 Approved first line treatments for metastatic melanoma include immunotherapeutic 
strategies blocking PD-1 (pembrolizumab, nivolumab), or combining nivolumab with the anti-
CTLA-4 blocker ipilimumab, or chemotherapy with agents targeting specific activating mutations 
in the BRAF pathway (e.g., vemurafenib, dabrafenib, trametinib). Following disease progression, 
patients can receive additional treatment with anti-PD-1 monotherapy; nivolumab/ipilimumab 
combination therapy; ipilimumab monotherapy; BRAF and/or MEK inhibitors, if BRAF mutant; 
high-dose aldesleukin (interleukin-2; IL-2); cytotoxic agents (e.g., dacarbazine, temozolomide, 
paclitaxel, cisplatin, carboplatin, vinblastine); or imatinib for KIT-mutant melanoma (NCCN 
Guidelines Version 2.2016).10,11 In 2015, talimogene laherparepvec, a live oncolytic virus 
therapy, was approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal 
lesions in patients with melanoma recurrent after initial surgical excision. This product has not 
been shown to improve overall survival or to have an effect on visceral metastases.12 
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Until recently, high-dose aldesleukin was the only FDA-approved systemic therapy for metastatic 
melanoma capable of inducing durable objective cancer responses, with an overall objective 
response rate (ORR) of 16% and durable complete tumor regressions (CRs) observed in up to 6% 
of treated patients [Proleukin® (aldesleukin) Label, FDA, July 2012; Alva 2016].13,14 The recently 
approved PD-1 immune checkpoint inhibitors pembrolizumab and nivolumab approximately 
double the rate of durable responses in metastatic melanoma relative to IL-2 treatment.15,16 
In previously treated patients, the ORR for nivolumab is 32%, with higher and more durable 
responses correlated with higher levels of PD-1 ligand expression by tumors; and the ORR for 
pembrolizumab following prior therapy with ipilimumab is 21%. In treatment naïve patients, 
durable objective responses are achieved in 50% of patients when nivolumab and ipilimumab 
administered in combination, although the CR rate remains low at 8.9% [Opdivo® (nivolumab) 
Label, FDA, October 2016].17  Retreatment of patients who progressed post anti-PD-1 therapy 
with additional checkpoint inhibitors has been one method of therapy, however, overall response 
rates of 16% and 21% are the best noted in use of ipilimumab or ipilimumab plus nivolumab, 
respectively.3    
Use of the immune checkpoint inhibitors is associated with a spectrum of immune-related adverse 
events, including pneumonitis, colitis, hepatitis, nephritis and renal dysfunction.18,19 Increased 
toxicity is observed in patients treated with nivolumab and ipilimumab combination therapy: 
Treatment-related adverse events leading to discontinuation of therapy occurred in 36.4%, 7.7% 
and 14.8% of patients receiving the combination therapy, nivolumab alone or ipilimumab alone, 
respectively.16,18 
Although the targeted therapies and immune checkpoint inhibitors can achieve dramatic 
responses in patients with metastatic melanoma, death rates for this cancer are projected to 
remain stable through 2030. The overall age-adjusted melanoma death rate was 2.7 per 100000 
in 2011 and remained at this level in 2015.20  
Cell transfer therapy with autologous TIL appears able to mediate durable complete responses 
in patients with metastatic melanoma and other solid tumors irrespective of prior treatment, so 
that even heavily pretreated patients can show dramatic and durable responses.21,22,23 At 
present, however, only a limited number of clinical centers in the US with access to suitable 
GMP manufacturing facilities are able to offer investigational therapy with autologous TIL. 
Furthermore, each institution follows its own procedure for production of TIL, distinct from 
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other institutions. Lion is utilizing the TIL manufacturing method developed by Dr. Steven A. 
Rosenberg’s team at NCI as a starting point in developing a robust GMP process for the 
production of LN-144, and in parallel, to execute a clinical development program designed to 
evaluate the efficacy and safety of LN-144 in the treatment of double-refractory melanoma. 
The scientific and pharmacologic rationale for developing adoptive transfer of TIL as an anti-
cancer therapeutic is based on observations that 1) The immune system is adept at producing 
antigen-specific anti-tumor cytotoxic T cell responses which have demonstrated anti-tumor 
reactivity both in vitro and in vivo, the latter having also demonstrated therapeutic efficacy. 
2) such autologous cellular therapies represent the terminal engagement of Ag-specific effector 
mechanisms mediated by the pro-inflammatory immunologic cascade, which are subject to 
significantly fewer adverse autoimmune sequalae than more broad-spectrum, non-specific, 
upstream immunologic interventions, such as checkpoint blockade. 3) T cells isolated and 
expanded from the tumor microenvironment (TME), as opposed to elsewhere in the body, are 
enriched for reactivity against tumor cells,24,25 and 4) increased frequencies of TIL in the TME 
of melanoma and other solid tumors are correlated with improved prognosis both at the primary 
tumor stage setting as well as in later stage metastatic disease settings.26,27,28 5) While the TME 
appears to limit the capacity of TIL to overcome tumor cell growth, TIL isolated from the 
patient’s TME, expanded to large numbers (109 to 1011) ex vivo, and then infused back into the 
patient have demonstrated potent anti-tumor activity.21 
TIL isolated from melanoma and other solid tumors are a heterogeneous mixture primarily 
consisting of CD4+ and CD8+ T cells at different stages of differentiation. CD8+ cytotoxic 
T-lymphocytes (CTL) comprise the most numerous and the most active component with anti-
tumor cell killing properties.29,30,31 Antigens recognized by TIL result from the overexpression 
of genes that are either specific to melanoma, or members of oncogene, growth factor gene, or 
signaling gene families, or from the expression of neo-epitopes resulting from mutated genes in 
the tumor cell.32 The latter are now thought to be the key type of antigen recognized by TIL 
mediating enhanced tumor eradication during TIL therapy.33 In addition, TIL are expected to 
facilitate a pro-inflammatory environment conducive to increased trafficking of dendritic cells 
(DCs) and other antigen presenting cells (APCs) to further drive anti-tumor responses by taking 
up antigen from dying tumor cells and stimulating other T-cell clones in the infused or 
endogenous T-cells.34-38 
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Ex vivo expansion of TIL is key to the development of a product with therapeutic value. 
Protocols have varied somewhat across treatment centers. The current procedure used in LN-144 
production follows the most widely adopted process per the NCI’s publications, whereby TIL are 
sourced from cut tumor fragments then expanded in two stages. Lion has worked closely with 
Dr. Rosenberg’s team in understanding and recreating the details of the TIL growth process and 
further in transferring the procedure to our own GMP manufacturing facilities. In both processes, 
the TIL first undergo an initial 3-week culture in the presence of IL-2, termed the pre-Rapid 
Expansion Protocol (pre-REP), then they are further cultured within a REP protocol that includes 
IL-2 the OKT3 (anti-CD3 monoclonal antibody) and irradiated peripheral blood mononuclear 
cells (PBMC; as feeder cells). 
Current methods for the expansion of autologous TIL from excised tumors are well-established 
and are robust enough to ensure a high degree of success in consistently generating sufficient 
numbers of high-quality therapeutic cells. Key advances in TIL therapy include the introduction 
of a more intensive, two-agent nonmyeloablative (NMA) lymphodepletion (LD) preconditioning 
regimen, post-infusion IL-2 (up to a maximum of 6 doses), and the use of minimally cultured 
(so-called “young”) TIL that undergo REP without selection for particular attributes. 
The NCI has contributed a substantial body of preclinical and clinical research that supports 
the development of TIL-based therapies for cancer. Across clinical studies conducted by the 
NCI, immunotherapy of patients with advanced melanoma with autologous TIL infusion has 
induced durable objective responses (ORs) by RECIST criteria in 54% (54/101) of patients, 
including heavily pretreated patients, with 24 of the 101 patients (24%) achieving a complete 
response (CR). Nineteen of the 24 CRs were ongoing beyond 3 years of follow-up.17,18 
1.2 
Overview of Adoptive Cell Transfer for Metastatic Melanoma 
The efficacy of IL-2 therapy in the treatment of patients with advanced melanoma revealed 
that manipulation of the immune response could alter the clinical course of the disease.39 
The induction of tumor regression by IL-2 is believed to be related to its immune regulatory 
effects, including the expansion of T lymphocytes following activation by specific antigen and 
NK cells.40–42 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.43, 44 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, 
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gp100, MAGE-1, tyrosinase, TRP-1, TRP-2 and NY-ESO-1.44,45 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.46, 47 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 initial efficacy reported for IL-2 therapy in patients with advanced melanoma and the 
discovery of tumor antigens recognized by TIL inspired the first attempts to expand 
lymphocytes from isolated tumor fragments, and the re-infusion of these expanded cells as a 
potential therapeutic back into the patient. Some of the first clinical trials performed in 
individual centers in the USA and Europe, such as the National Cancer Institute (NCI), used 
TIL expanded ex vivo 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.48–51 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.).49  
During this time, the Surgery Branch at the National Cancer Institute (Bethesda, MD) also 
embarked on performing TIL trials for metastatic melanoma using a similar expansion method 
for TIL with IL-2 alone. The NCI however included a preparative chemotherapy regimen 
using low-dose cyclophosphamide (CY) before TIL infusion that resulted in a partial and 
transient depletion of host lymphocytes. IL-2 was administered after TIL infusion. This led to 
more promising response rates in small pilot clinical trials of 30%-60%.52–54 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 
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non-lethally irradiated to deplete endogenous lymphocytes.55, 56 Furthermore, this prior 
lymphodepletion preconditioning regimen with CY was also later found to remove suppressive 
CD4+ T-regulatory cells (CD4+Foxp3+ cells) that inhibit anti-tumor immune responses in mice. 
Higher T-regulatory cell frequencies in the blood of cancer patients have also been correlated 
with an unfavorable prognosis in cancer patients.57–60 Alternatively, prior depletion of 
lymphocytes may create ‘space’ for the adoptively transferred cells within the lymphocyte 
compartment.61 Under this model, homeostatic lymphocyte survival may result in increased 
proliferation and enhanced survival of transferred T cells, perhaps through a mechanism 
involving increased access to endogenous cytokines such as IL-7, IL-15 and IL-21.62 
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 monotherapy 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.63,64 Patients received a lymphodepleting chemotherapy regimen consisting of high-
dose cyclophosphamide and standard doses of fludarabine before administration of selected, 
expanded, tumor-reactive TIL and IL-2. The lymphodepletion step resulted in a transient 
myelosuppression and the elimination of all circulating lymphocytes for approximately 
1 week, after which time patients recovered endogenous marrow function and reconstituted 
their lymphocyte compartments towards normal levels within 2 to 3 weeks.63,64 
Because of the immunosuppression exhibited by fludarabine, 1 patient who had clonal 
repopulation from infused TIL and a complete objective tumor response to therapy, developed 
Epstein-Barr virus (EBV) - associated B cell lymphoma. This patient was EBV-naïve prior to 
treatment. The potential source of EBV was thought to be multiple blood products received 
after chemotherapy. The patient later died from complications of the treatment for 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.64 
Published clinical trials evaluating TIL therapy from several institutions using similar protocols 
as the NCI are reporting reproducible and promising results. Across clinical studies conducted by 
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the NCI, immunotherapy of patients with advanced melanoma with autologous TIL therapy has 
induced durable objective response rates (ORR) by RECIST 1.0 criteria in 54% (54/101) of 
patients, including heavily pretreated patients, with 24 of the 101 patients (24%) achieving a 
complete response (CR). Nineteen of the 24 CRs were ongoing beyond 3 years of follow-up.15,16 
Radvanyi et al.65 reported the MD Anderson Cancer Center experience with ACT using 
selected TIL for treatment of metastatic melanoma with objective clinical response in 15/31 
(48.4%) patients with 2 resulting in a complete response (6.5%). Progression-free survival of 
greater than 12 months duration was reported in 9/15 (60%) patients that responded to therapy. 
The H. Lee Moffitt Cancer Center also reported a 38% response rate in 13 treated patients with 
2/13 (15%) achieving a complete response ongoing for more than 14 and 16 months at the 
time of publication, respectively.66 Outside the U.S., Itzhaki et al67 reported the experience 
from Sheba Medical Center in Israel using “young, unselected –TIL therapy.” Of the 
31 patients evaluated, 15 (48%) patients achieved a clinical response including 4 patients 
(12.9%) with complete responses. In addition, a group in Denmark68 used decrescendo 
low-dose IL-2 as an adjuvant after cell infusion to reduce treatment related toxicity in a small 
study (6 patients). This study reported objective clinical responses in 2/6 patients (33%) with 
ongoing complete responses of 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.  
1.3 
Production and Expansion of Tumor Infiltrating Lymphocytes 
The LN-144 active biologic is composed of viable TILs derived from an individual patient’s 
own tumor (autologous cell product). The process for manufacturing LN-144 begins at the 
clinical site with the surgical resection of primary or secondary metastatic tumor material of 
≥1.5 cm from the patient.  The tumor specimen is placed in biopreservation transport media 
and shipped (at 2-8°C), by overnight transport to a GMP manufacturing facility. Upon arrival 
at the GMP manufacturing facility, the tumor specimen is dissected into fragments of 2 mm3 
to 3 mm3, which are cultured in a pre-rapid expansion protocol (pre-REP) with human 
recombinant interleukin 2 (IL-2, Proleukin®) for 11 to 21 days to generate ≥1 x 108 total viable 
cells. The small-scale, pre-REP cells can then be cryopreserved allowing for flexibility in the 
subsequent scheduling of TIL therapy administration into the patient from which they were 
originally derived. The pre-REP cells are then further expanded in a rapid expansion protocol 
(REP), in which they are cultured for ~14 days in the presence of IL-2, and OKT3 
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(muromonab-CD3, murine monoclonal antibody to human CD3) with irradiated allogenic 
mononuclear cells as feeder cells. The REP expanded cells (TILs) are then harvested, washed, 
and formulated in a blood transport and infusion bag for shipment by courier to the clinical 
site. The dosage form of the investigational product is a live cell suspension of either non-
cryopreserved or cryopreserved autologous TIL for intravenous infusion into the patient from 
which they were derived.  Diagrams of the production processes for the non-cryopreserved and 
cryopreserved LN-144 investigational products are provided in Figure 3 and Figure 4, 
respectively. 
Figure 3 
LN-144 Manufacturing Process without Final Cryopreservation  
 
Figure 4 
LN-144 Manufacturing Process with Final Cryopreservation 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.4 
 LN-144 TIL Therapy 
LN-144 is an autologous, ready-to-infuse TIL therapy which is comparable to that developed 
by Dr. Steven Rosenberg and colleagues at the NCI.  
Several pre-conditioning 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. It involves 2 days of 
cyclophosphamide followed by 5 days of fludarabine as a lymphodepleting pretreatment. 
The TIL therapy includes infusion with LN-144 (investigational product) followed by adjuvant 
IL-2. Details for the tumor harvest and LN-144 administration as fresh or cryopreserved 
product are provided in the Pharmacy & Investigational Product Administration Manual. 
The final investigational product will be available for administration in 1 of several volumes for 
infusion, as described in the Pharmacy & Investigatotional Product Administration Manual.  
Cohort 1 (LN-144 manufacturing process without final cryopreservation). This final cellular 
investigational product is formulated in a minimum of 50% HypoThermosol™ in Plasma-Lyte 
A™ (volume/volume) and up to 0.5% HSA (compatible for human infusion) containing 
300 IU/mL IL-2. 
1) 250 mL (in a 300-mL capacity infusion bag) when the total TIL harvested are 
≤75 x 109 
or 
2) 500 mL (in a 600-mL capacity infusion bag) when the total TIL harvested are 
≤150 x 109 
Cohort 2 (LN-144 manufacturing process with final cryopreservation). This final cellular 
investigational product is formulated in 50% CryoStor10™ in Plasma-Lyte A™.   
1) Up to five infusion bags containing up to approximately 100 mL of thawed cells. The 
number of infusion bags is dependent on the total cell number 
Cohort 3 patients will have their TILs manufactured per the same process for the second 
LN-144 infusion as used for the original TIL manufacturing if the first LN-144 infusion was 
completed (either non-cryopreserved TIL or cryopreserved TIL), alternatively if no prior 
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LN-144 therapy/infusion was received, treatment in Cohort 3 will by which ever 
manufacturing process has the first availability.  
2 
STUDY DESIGN 
2.1 
Description of the Study 
This is a prospective, multicenter interventional study evaluating patients who receive ACT 
with LN-144 (autologous TIL). Patients will receive a single infusion of LN-144 followed by 
the administration of a regimen of adjuvant IL-2 at 600,000 IU/kg approximately every 
8 hours starting as soon as 3 hours, but no later than 24 hours after the LN-144 infusion and 
continuing for up to 6 doses. Patients will be evaluated for objective response approximately 
6 weeks following LN-144 infusion and then every 6 weeks up to 6 months.  
After 6 months, patients will be evaluated for objective response at 9, 12, 18 and 24 months 
following LN-144 treatment. Formal response evaluations will follow RECIST 1.1 criteria.2 
Overall Survival (OS) Follow-Up will continue until the last patient treated in the study has 
finished 3 years FU following their last dose of IL-2 or end of study (EOS) visit. It is the intent 
that all patients will be followed for OS for a minimum of 3 years. 
2.2 
Description of the Study Centers 
Patients may be seen at the Investigators’ private offices or affiliated medical centers for 
evaluations prior to enrollment and during follow-up. Patients will require hospitalization 
during the mesna administration in the NMA-lymphodepletion pretreatment regimen and then 
also just prior to the LN-144 infusion through the adjuvant IL-2 administration.  
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
• 
To evaluate the efficacy of LN-144 in patients with metastatic melanoma using the 
objective response rate (ORR) 
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3.1.2 
Secondary Objectives 
• 
To further evaluate efficacy of LN-144 in patients with metastatic melanoma by 
assessing complete response (CR) rate, duration of response (DOR), disease control 
rate (DCR), progression free survival (PFS) and overall survival (OS) 
• 
To characterize the safety profile of LN-144 in patients with metastatic melanoma  
3.1.3 
Exploratory Objectives 
• 
To explore the persistence of LN-144 and potential immune correlates of response, 
outcome, and toxicity of the treatment 
• 
To explore efficacy based on irRECIST criteria1 as assessed by independent review 
• 
To assess health-related quality of life (HRQoL) 
3.2 
Study Endpoints  
3.2.1 
Primary Endpoint 
• 
Objective response rate (ORR) 
3.2.2 
Secondary Endpoints  
• 
Complete response (CR) rate, duration of response (DOR), disease control rate 
(DCR), progression free survival (PFS) and overall survival (OS) per RECIST 1.1 
criteria2 by independent and Investigator review 
• 
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 
3.2.3 
Exploratory Endpoints 
• 
TIL persistence in the peripheral blood and immune correlates with respect to 
response, outcome, and/or toxicity of the treatment, utilizing peripheral blood 
mononuclear cells (PBMC), serum, plasma and tumor specimens to test for cellular 
and soluble factors via immunological assays and molecular assays related to exome 
sequencing 
• 
ORR, CR rate, DCR, and PFS using irRECIST1 as assessed by independent review 
• 
Patient-reported outcomes based on the EORTC QLQ-C30 HRQoL questionnaire 
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4 
SELECTION OF PATIENT POPULATION 
4.1 
Inclusion Criteria  
a. Patients with unresectable or metastatic melanoma (Stage IIIc or Stage IV), who 
progressed following ≥1 line of prior systemic therapy, including immune checkpoint 
inhibitor (e.g., anti-PD-1), and if BRAF mutation-positive, after BRAF inhibitor systemic 
therapy 
• 
At least one measurable target lesion by RECIST version 1.1.2 Lesions in previously 
irradiated areas should not be selected as target lesion, unless treatment was 
≥ 3 months prior, and there has been demonstrated progression in the lesion   
• 
At least one resectable lesion to generate TILs of minimum 1.5 cm in diameter post-
resection; surgical removal with minimal morbidity (defined as any procedure for 
which expected hospitalization is less than or equal to 3 days)  
b. Patients must be ≥ 18 years and ≤ 70 years of age at the time of consent. Enrollment of 
patients > 65 years of age may be allowed after consultation with the Medical Monitor  
c. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1 (Appendix 3) and an estimated life expectancy of ≥ 3 months 
d. In the opinion of the Investigator, patient must be able to complete all study-required 
procedures   
e. Patients of childbearing potential or their partners of childbearing potential must be 
willing to practice an approved method of birth control during treatment and for 4 months 
after receiving all protocol related therapy 
Approved methods of birth control are as follows: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral; intravaginal; transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral; injectable; implantable 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
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• 
bilateral tubal occlusion 
• 
vasectomized partner 
• 
sexual abstinence 
f. Patients must have the following hematologic parameters: 
• 
absolute neutrophil count (ANC) > 1000/mm3 
• 
hemoglobin > 9.0 g/dL 
• 
platelet count > 100,000/mm3 
g. Patients must have adequate organ function: 
• 
ALT/SGPT and AST/SGOT < 3 times the upper limit of normal (ULN); patients with 
liver metastasis < 5 times ULN 
• 
an estimated creatinine clearance (eCCr) ≥ 40 mL/min using the Cockcroft-Gault 
formula at Screening  
• 
total bilirubin ≤2 mg/dL  
o Patients with Gilbert’s Syndrome must have a total bilirubin < 3 mg/dL  
h. Patients must be seronegative for the HIV antibody, hepatitis B antigen, and hepatitis C 
antibody or antigen 
i. 
Patients must have recovered from all prior therapy-related AEs to Grade 1 or less 
(per CTCAE v4.03), except for alopecia or vitiligo prior to enrollment (tumor resection) 
• 
A minimal washout period of 4 weeks is required prior to enrollment (tumor 
resection) 
• 
Palliative radiation therapy is permitted between biopsy and nonmyeloablative 
lymphodepletion for LN-144 infusion if it does not involve lesions selected as target 
or non-target lesions 
• 
Patients may undergo pre-planned procedures if 2-3 weeks prior to the start of 
nonmyeloablative lymphodepletion  
j. 
Patients with documented Grade 2 or greater diarrhea or colitis as a result of previous 
treatment with immune checkpoint inhibitor(s) must have been asymptomatic for at least 
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6 months and/or had a normal colonoscopy postimmune checkpoint inhibitor treatment, 
by visual assessment, prior to the start of nonmyeloablative lymphodepletion 
k. 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/Independent Ethics Committee (IRB/IEC), 
and agree to abide by the study restrictions and return to the site for the required 
assessments   
l. 
Patients have provided written authorization for use and disclosure of protected health 
information 
4.2 
Exclusion Criteria 
a. Patients with melanoma of uveal/ocular origin 
b. Patients who have received prior cell transfer therapy that included a nonmyeloablative 
or myeloablative chemotherapy regimen (not applicable for patients in the retreatment 
Cohort 3) 
c. Patients with symptomatic and/or untreated brain metastases (of any size and any 
number)  
• 
Patients with definitively treated brain metastases, who can be considered for 
enrollment after discussion with Medical Monitor, must be stable for 2-4 weeks prior 
to the start of treatment (nonmyeloablative lymphodepletion) 
d. Patients who are pregnant or breastfeeding 
e. Patients who are on a systemic steroid therapy at a dose of > 10 mg of prednisone or 
equivalent per day 
• 
Short course of higher dose steroid therapy is allowed in case of exacerbation of 
known disease or for treatment of new acute symptoms  
f. Patients who have active medical illness(es) that in the opinion of the Investigator would 
pose increased risk for study participation, such as systemic infections requiring 
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antibiotics, coagulation disorders or other active major medical illnesses of the 
cardiovascular, respiratory or immune system 
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 left ventricular ejection fraction (LVEF) < 45%  
j. 
Patients who have obstructive or restrictive pulmonary disease and a documented FEV1 
(forced expiratory volume in 1 second) of ≤ 60%  
k. Patients who have had another primary malignancy within the previous 3 years (with the 
exception of carcinoma in situ of the breast, cervix or bladder, localized prostate cancer 
and non-melanoma skin cancer that has been adequately treated) 
l. 
Patients with known allergic reaction to antibiotics of aminoglycoside group 
(i.e. streptomycin, gentamicin) 
m. Patients who have been shown to be BRAF mutation positive (V600), but have not 
received prior systemic therapy with a BRAF-directed kinase inhibitor 
4.3 
Number of Patients 
Patients that meet all inclusion criteria and do not meet any exclusion criteria will be enrolled 
in the study.   
Patients who sign an ICF and fail to meet the inclusion and/or exclusion criteria will be defined as 
a Screen Failure, However, patients who do not have tumor resection within 4 weeks (28 days) of 
signing the ICF may be reconsented after a discussion with the Medical Monitor, if there is delay 
in scheduling the tumor resection.   
The Investigator is to maintain a master screening log of all consented patients that documents all 
screen failures and the reason(s) for screen failure. A copy of the log should be retained in the 
Investigator's study files. Minimum data for screen failures will be captured in the electronic data 
capture (EDC) database as defined in the electronic case report form (eCRF) completion manual. 
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Patients will be enrolled until approximately 60 patients across both Cohort 1 and Cohort 2 have 
received any volume of LN-144 infusion followed by at least 1 dose of adjuvant IL-2, and 
approximately 10 patients may enter the third cohort (Cohort 3) where they will be retreated with 
a second administration of LN-144 (second TIL therapy). Screening may halt once it becomes 
likely that the full enrollment goals for Cohort 1 and Cohort 2 will be met. Patients from Cohorts 
1 and 2 may screen for the retreatment Cohort 3 as long as this study is open. Prior to enrollment 
in Cohort 3, patients must undergo abbreviated screening evaluation and procedures. 
4.3.1 
Rescreening Patients 
Patients who fail the initial screening process will be deemed a Screen Failure, but may be 
reconsented and rescreened at a later date. Patients who exceed the 4 weeks (28 days) in 
Screening without tumor resection (Enrollment) may resign the informed consent form and be 
reassessed for eligibility following a discussion between the Investigator and Medical Monitor to 
agree on which screening procedures need to be redone.  
Patients from Cohort 1 or Cohort 2 may also be rescreened, have a second tumor resected, and be 
retreated in Cohort 3 with a second LN-144 infusion if they meet all inclusion and exclusion 
criteria (except exclusion b). Cohort 3 patients will have a second tumor harvest for TIL 
manufacturing by the same process (either Cohort 1 [fresh TILs] or Cohort [cryopreserved TILs]) 
as their prior cohort assignment, unless they did not receive an LN-144 infusion from the initial 
tumor resected, in which case the most immediately available manufacturing slot will be 
assigned. Examples of patients who may be eligible for retreatment in Cohort 3 are prior 
responders to LN-144 who relapse, non-responders, and patients with manufacturing failures. The 
Medical Monitor will have authority to adjudicate enrollment into Cohort 3 (second TIL therapy). 
4.3.2 
Patient Cohorts 
All patients who receive any volume of LN-144 infusion followed by at least 1 dose of adjuvant 
IL-2 are defined as the ‘all-treated population’, and all patients resected for harvest will be 
defined as the Tumor Harvested (TH) population. 
Patients will be assigned to Cohort 1 or Cohort 2 based on IRB/IEC approval of appropriate 
protocol/ICF versions at the site and the most immediately available manufacturing slot. If either 
Cohort 1 or Cohort 2 approaches or passes the desired 30-patient enrollment, assignment will be 
adjusted to minimize over-enrollment. 
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The primary efficacy and safety analyses will take place after the last patient in Cohort 2 has an 
opportunity to reach the 6-month tumor assessment, and the final analysis will take place at the 
end of the 2-year (24 month) post-treatment follow-up. 
Cohort 3 will consist of patients who wish to rescreen for a second tumor harvest of tumor for 
TIL manufacture and LN-144 treatment as per their prior cohort assignment. Examples of patients 
who may be eligible for retreatment in Cohort 3 are prior responders to LN-144 who relapse, non-
responders, and patients with manufacturing failures. The Medical Monitor will have authority to 
adjudicate enrollment into Cohort 3 (second TIL therapy). These Cohort 3 patients will need to be 
rescreened and meet all eligibility criteria (except exclusion criteria b). Of the approximate 
60 enrolled patients enrolled across Cohort 1 and Cohort 2, and approximately 10 patients may 
rescreen for a second tumor harvest for LN-144 treatment in Cohort 3. 
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
5.1 
Prior Treatment and Concomitant Medications 
Use of all medications taken by the patient 30 days prior to consent will be recorded in the site’s 
source documentation and the patient’s electronic case report form (eCRF). All medications taken 
by the patient, or any changes in medications will also be recorded throughout the course of the 
study until completion of the post-treatment follow-up phase. 
5.2 
Prohibited and Permitted Medications during Study Treatment 
5.2.1 
Prohibited Treatment 
The following guidelines should be used regarding concomitant medications/concomitant 
therapies: 
• 
Systemic therapies intended to treat melanoma are not permitted  
• 
Patients who complete the NMA-LD should not receive a live or attenuated vaccine 
until ANC is ≥ 1000/mm3 
• 
Use of investigational drugs (other than the LN-144 investigational therapy), is not 
permitted 
• 
Palliative radiation therapy is permitted between biopsy and lymphodepletion as long 
as it does not involve selected target or non-target lesions  
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• 
Patients may undergo pre-planned procedures if 2-3 weeks prior to the start of 
lymphodepletion 
5.2.2 
Permitted Medications – Use with Caution 
Concurrent medications for conditions other than their metastatic melanoma are permitted with 
the exception of any medications that may have an anti-tumor effect. Although prohibited at 
study entry, at > 10 mg/day prednisone or equivalent may be initiated in cases of exacerbation of 
known disease or for treatment of new symptoms on study per Investigator discretion.  
6 
STUDY PROCEDURES 
6.1 
Screening (up to 28 days from signing of informed consent form) 
The following procedures should be performed after signing of informed consent form (ICF): 
• 
Review of inclusion and exclusion criteria 
• 
Medical history 
• 
Melanoma medical history, including prior therapies, response to prior therapies and 
BRAF mutational status 
• 
Concurrent medications within 30 days prior to signing of ICF 
• 
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. Prior evaluation within 30 days prior to signing of ICF is 
allowed 
• 
Electrocardiogram (EKG). Prior evaluation within 60 days prior to signing of ICF is 
allowed 
• 
Cardiac evaluation (stress thallium) for all patients. Echocardiogram or multiple 
gated acquisition scan (MUGA) for patients ≥60 years or patients who have a history 
of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias. Stress thallium must show normal LVEF and unimpaired wall 
movement. Prior evaluations within 6 months of signing of ICF is allowed. 
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• 
Pulmonary function tests. Prior evaluations within 6 months prior to signing ICF is 
allowed. 
• 
Computed tomography (CT), of anatomic regions per disease history and clinical 
symptoms, including:  
o Chest (include neck if there is prior or suspected neck disease) 
o Abdomen 
o Pelvis 
• 
Magnetic resonance imaging (MRI) of brain 
• 
Blood and Urine Tests 
o Hematology – complete blood count (CBC) with differential 
o Chemistry - Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, 
Creatinine, Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, 
Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct 
Bilirubin, LDH, Total protein, Total CK, Uric Acid, and thyroid panel 
(to include TSH and free T4) 
• 
Serum pregnancy test for all women of childbearing potential 
• 
CMV serology (IgG and IgM, as per local standard) 
• 
Syphilis screening (as per local standard; e.g., Rapid Plasma Reagin [RPR] venereal 
disease research laboratory [VDRL] or other) at Screening, and thereafter as 
clinically indicated 
• 
HIV antibody titer, HbsAG determination (HSV-1 IgG and HSV-2 IgG), Anti HCV, 
HSV serology and EBV serology (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 laboratory). Refer to central Laboratory Manual 
for details. 
• 
Urinalysis (complete urine culture if indicated) 
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• 
Calculate estimated creatinine clearance (eCCr) 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 immune checkpoint inhibitor(s) must have been asymptomatic for at 
least 6 months or had a normal colonoscopy post immune checkpoint inhibitor 
treatment, with uninflamed mucosa by visual assessment, prior to the start of 
nonmyeloablative lymphodepletion 
• 
Assessment of adverse events (AEs) / serious AEs (SAEs) 
6.2 
Enrollment and Tumor Resection  
Following confirmation of patient eligibility, the Medical Monitor, or designee, will either 
approve or decline patient for enrollment into the clinical study.   
When the Medical Monitor has approved the patient to be enrolled into the study, tumor 
resection will take place. The patient is enrolled into the study when resection has started. 
The following procedures should be completed during this visit. 
• 
Verification of all ongoing concomitant medications (list only medications that are 
NOT part of the tumor harvest procedure) 
• 
Obtain blood for immune monitoring/phenotyping (refer to Laboratory Manual) 
• 
Tumor Harvest (see Section 6.2.1) 
• 
Assessment of AE/SAEs   
6.2.1 
Tumor Harvest and Processing Procedure 
Detailed Tumor Procurement & Shipping Manuals 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. Ideally, the resected tumor specimen for TIL manufacturing 
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should be ≥ 1.5 cm, but no more than 4.0 cm in diameter, of viable solid tumor tissue. Viable 
solid tumor tissue is tissue that has necrotic, hemorrhagic and fatty tissue removed. Tumor tissue 
is to be sent to the Manufacturing Facility. 
If after completion of preparation of tumor tissue for TIL manufacturing, a portion of the viable 
tumor tissue is still available, up to 5 mm x 5 mm x 5 mm is to be placed in formalin and sent to 
the Central Lab (refer to central Laboratory Manual for details). Provision of adequate amount 
of tumor tissue for TIL manufacturing is priority over tumor tissue to be sent to the Central Lab. 
When tumor tissue is limiting, a single 2 mm punch biopsy from the center of the resected tumor 
will be placed into formalin and sent to the Central Lab (refer to central Laboratory Manual for 
details). Every effort should be made to obtain adequate tumor tissue for both TIL manufacturing 
and to be sent to the Central Lab.    
Tumor tissue sent to the Central Lab will be used as follows 1) for immunohistochemistry to 
identify different immune cell populations 2) for isolation of DNA, which will be used for 
“exome” (not whole genome) sequencing as a part of neoepitopes interrogation. The patient will 
be requested to sign the optional consent (e.g. Genetic Research ICF) for exome sequencing. 
Tumors will be harvested at the investigational sites participating in the trial according to their 
respective institutional protocols for sterile harvest for TIL preparation.  
LN-144 is an autologous investigational product which is procured and delivered by means that 
have more in common with autologous blood product delivery than those of traditional drug 
production.  
It is imperative that only the patient’s own (autologous) study treatment (LN-144) be 
administered to that same individual patient. For these reasons, the patient specimen must be 
procured and handled per a strict protocol to ensure optimal quality of the specimen and 
minimum transport time to and from the processing Contract Manufacturing Organization (CMO) 
facility, as well as to ensure the unique identification of the specimen at all time including 
infusion back into the patient. 
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6.2.2 
Immune Monitoring and Phenotyping (Sequencing of Tumor and 
PBMC/Cell-Free DNA) 
Peripheral blood will be collected from the patient for immune monitoring (biomarker analysis) 
and sequencing (exome and TCR sequencing) of lymphocyte DNA utilizing vacutainer blood 
collection vials. Refer to the study Laboratory Manual for the complete procedure details. 
In addition, exome sequencing of DNA collected from the tumor will be performed.  
6.3 
Baseline (Day -21 to Day -14) 
The following procedures should be completed during this visit: 
• 
Physical exam including weight 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Evaluation and measurement of all skin and palpable lesions 
• 
Verification of all concomitant medications 
• 
EKG  
• 
CT Exam, include anatomic regions per disease history and clinical symptoms, 
(the same CT series as completed at Baseline [Day -21 to Day -14] is to be repeated 
at all post-treatment disease assessments, [scheduled and unscheduled]) 
o Chest (include neck there is prior or suspected neck disease) 
o Abdomen 
o Pelvis 
• 
MRI – Brain in patients who had brain abnormalities at Screening. For those patients 
who had negative brain scans at Screening, the Baseline assessment should be done 
only if clinically indicated. These Baseline scans can be done as early as Day -21 
(the same MRI series to be repeated at all post-treatment disease assessments 
[scheduled and unscheduled]). 
• 
Blood and urine tests 
o Hematology - CBC with differential 
o Chemistry - Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, 
Creatinine, Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, 
Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct 
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Bilirubin, LDH, Total protein, Total CK, Uric Acid, and thyroid panel 
(to include TSH and free T4, only if clinically indicated) 
o Serum pregnancy test for all women of childbearing potential 
o Urinalysis (complete urine culture if indicated) 
• 
ECOG performance status evaluation 
• 
Assessment of AE/SAEs 
• 
EORTC QLQ-C30 HRQoL questionnaire 
• 
Re-check of abbreviated Inclusion/Exclusion Criteria in order to ensure that patient 
performance status and main eligibility criteria have not changed from time of 
Screening, a re-confirmation is to be perform and approved by Sponsor or designee 
6.4 
Patients Who Do Not Receive a LN-144 Infusion 
Some patients may undergo tumor harvest and LN-144 manufacture but will not receive the 
infusion of investigational product. Early Treatment Discontinuation (prior to NMA-LD). 
6.5 
Early Treatment Discontinuation (prior to NMA-LD) 
If the patient does not receive any volume of LN-144 infusion and this is prior to NMA-LD, 
due to a potentially treatable medical event, the pre-REP cells (for Cohort 1 patients) or the 
REP cells (for Cohort 2 patients) may remain frozen for a period of time agreed upon between 
the Investigator and Medical Monitor, to see if the patient recovers and meets criteria to 
receive LN-144 infusion. If a decision is take that the patient will not receive their TILs, then 
the patient should remain on study, but the data collection will be reduced to survival status 
and start of any new anticancer therapy. 
6.6 
Day -7  
Prior to the start of lymphodepletion, verification of sufficient LN-144 expansion at this time 
point will be confirmed by the Sponsor with the manufacturing facility. In Cohort 2, the REP 
may be extended an additional 7 days if growth is inadequate in which case, the Day -7 and 
subsequent visits will be delayed by 1 week.  
Prior to beginning the lymphodepletion for all cohorts, the Investigator should assess whether 
the patient has had any clinical deterioration, which would put them at increased risk when 
subsequently receiving the adjuvant IL-2. Specifically, the Investigator should consider 
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whether a worsening of ECOG status and/or a deterioration of laboratory values is such that 
the patient no longer meets the requirements of the inclusion and exclusion criteria. If this 
deterioration is believed to be reversible, the LN-144 investigational product may remain 
frozen at the appropriate stage and the schedule adjusted to allow recovery and subsequent 
LN-144 administration. If the deterioration is believed irreversible and of sufficient magnitude 
to increase the risk of adjuvant IL-2 administration, the patient should not proceed to 
lymphodepletion and subsequent therapy and be followed as per Section 1.1.  
The following procedures/assessments should be completed during this visit: 
• 
Physical exam including weight, calculated BSA and BMI 
• 
Verification of all concomitant medications 
• 
ECOG performance status evaluation 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to cyclophosphamide administration) 
o Hematology - CBC with differential 
o 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  
o Urinalysis (complete Urine culture if indicated) 
o CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated 
• 
Obtain blood for immune monitoring (refer to Laboratory Manual) 
6.6.1 
Initiation of administration of the NMA-LD preconditioning medications 
• 
Cyclophosphamide 60 mg/kg intravenously (IV) in 250 mL D5W with mesna 
15 mg/kg are infused over approximately 2 hours. If the patient is obese (BMI >35) 
drug dosage will be calculated using practical weight as described in Appendix 4 
• 
Mesna infusion will continue to be infused at a rate of 3 mg/kg/hour in a suitable 
diluent over 22 hours after each cyclophosphamide dose. Patient may be hospitalized 
overnight during the mesna administration. 
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• 
Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose between 8 mg 
and 16 mg based on patient weight] IV every 8 hours X 3 days) will be given for 
nausea, or as per standard of care at the treating institution. (If the patient is obese 
(BMI >35) drug dosage will be calculated using practical weight as described in 
Appendix 4) 
• 
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 -6 
The following procedures should be performed: 
• 
Verification of all concomitant medications 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to cyclophosphamide administration) 
o Hematology - CBC with differential 
o 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 
o CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated 
o Urinalysis (complete urine culture if indicated) 
• 
Administration of the following medications 
o Cyclophosphamide 60 mg/kg IV in 250 mL D5W with mesna15 mg/kg are 
infused over approximately 2 hours. If the patient is obese (BMI >35) drug 
dosage will be calculated using practical weight as described in 
Appendix 4 
o Mesna infusion will continue to be infused at a rate of 3 mg/kg/hour in a 
suitable diluent over 22 hours after each cyclophosphamide dose. Patient 
may be discharged following completion of the mesna administration. 
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o Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose 
between 8 mg and 16 mg based on patient weight] IV every 8 hours 
X 3 days) will be given for nausea, or as per standard of care at the treating 
institution. If the patient is obese (BMI >35) drug dosage will be calculated 
using practical weight as described in Appendix 4 
o 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 
6.8 
Day -5 to Day -1 
The following procedures should be performed: 
• 
Physical exam including weight (Day -1 only) 
• 
Verification of all concomitant medications 
• 
Vital signs – pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to fludarabine administration) 
o Hematology - CBC with Differential 
o 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 
o CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated 
o Urinalysis (complete urine culture if indicated) 
• 
The following medication should be administered: 
o Fludarabine 25 mg/m2 to be given IV over approximately 30 minutes once 
daily each day 
o 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 
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6.9 
Day 0 (Infusion day) 
Day 0 is the day of LN-144 infusion.   
Upon completion of the manufacturing process, the investigational product, LN-144, will be 
labeled with a patient specific label. The investigational product will then be shipped from the 
manufacturing facility to the respective clinical site for infusion, as described in the 
Pharmacy & Investigational Product Administration manual. All visits following LN-144 
infusion (Day 0) are calculated from that date forward. 
6.9.1 
Investigational Product  
The investigational product, LN-144, will be shipped overnight by courier to the clinical site 
pharmacy in a shipping container validated to maintain the appropriate investigational product 
temperature.  
The investigational product will be received by the appropriate clinical pharmacy or designee 
for subsequent administration into the specific patient from whom the TILs were derived. See 
the LN-144 Pharmacy & Administration Manual for precise details for handling of LN-144 for 
Cohort 1 (non-cryopreserved cells) or Cohort 2 (cryopreserved cells).  
If not already hospitalized, the patient will be admitted the day prior to the planned LN-144 
infusion. Patients will remain hospitalized until completion of the adjuvant IL-2 
administration, as per institutional standards. The following procedures should be performed: 
• 
Physical exam including weight  
• 
Verification of all concomitant medications 
• 
Vital signs - pulse rate, respiratory rate, blood pressure and temperature 
• 
Vital signs will be monitored every 30 minutes during infusion then hourly  
(± 15 minutes) for 4 hours and then routinely (every 4 to 6 hours), unless otherwise 
clinically indicated, for up to approximately 24-hours post LN-144 infusion  
• 
Blood and urine tests (to be drawn prior to LN-144 infusion) 
o Hematology – CBC with differential 
o Chemistry - Sodium, Potassium, Chloride, Total CO2 or Bicarbonate, 
Creatinine, Glucose, BUN, Albumin, Calcium, Magnesium, Phosphorus, 
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Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct 
Bilirubin, LDH, Total protein, Total CK, Uric Acid, and thyroid panel 
(to include TSH and free T4, only if clinically indicated) 
o Urinalysis (complete urine culture if indicated) 
• 
The following medications will be administered: 
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg will be 
given as per standard of care 
6.9.1.1 
LN-144 Infusion   
• 
Autologous TIL (LN-144) will be administered intravenously. The fresh LN-144 
investigational product for Cohort 1 patients) will be administered (by gravity) within 
approximately 45 minutes. If interruption of infusion is required for medical reasons, 
the infusion should be restarted when appropriate and completed within 3 hours of 
the initial start of the infusion. During periods of infusion interruption, the remaining 
LN-144 fresh (Cohort 1) investigational product should be refrigerated.  
• 
The frozen LN-144 investigational product (for Cohort 2 patients) will be thawed in a 
37oC water bath and each infusion bag will be administered sequentially. During 
periods of infusion interruption, the remaining cryobags of frozen TILs (Cohort 2) 
should be kept in the cryoshipper. 
• 
Further details of the administration procedure are provided in the LN-144 Pharmacy 
and Administration Manual 
• 
Assessment of AE/SAEs 
6.10 Day 1, Day 2, Day 3 and Day 4 
While the patient remains hospitalized, the following procedures should be performed: 
• 
Physical exam including weight (physical exam Day 1 and Day 4 only) 
• 
Verification of all concomitant medications 
• 
Vital signs - pulse rate, respiratory rate, blood pressure and temperature 
• 
Blood and urine tests (to be drawn prior to the first IL-2 administration of each 
calendar day) 
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o Hematology - CBC with differential 
o 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 
o CMV serology (IgG and IgM, as per local standard) - required only once 
from Day 1 through Day 3 
o Urinalysis (complete urine culture if indicated) 
• 
Obtain blood for immune monitoring on Day 1 and Day 4 only (Refer to Laboratory 
Manual) 
• 
Assessment of AE/SAEs 
• 
The following medications will be administered: 
o Adjuvant IL-2 – the first adjuvant IL-2 administration can begin as soon as 
3 hours, but no later than 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). Adjuvant IL-2 is to be administered by intravenous infusion at a 
frequency not greater than every 8 hours, as per institutional standard of 
care, up to the protocol-defined maximum of 6 doses. Continue for up to a 
maximum of 6 doses. IL-2 doses will be skipped if patient experiences a 
Grade 3 or 4 toxicity due to IL-2 except: reversible Grade 3 toxicities 
common to IL-2 such as diarrhea, nausea, vomiting, hypotension, skin 
changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes as detailed in Appendix 5. Toxicities will be managed 
as outlined in Appendix 6. If these toxicities can be easily reversed within 
24 hours by supportive measures, then the additional doses of adjuvant 
IL-2 up to the protocol-defined maximum of 6 doses may be given. 
If greater than 2 doses of IL-2 are skipped, IL-2 administration will be 
discontinued. In addition, adjuvant IL-2 dosing may be held or stopped at 
the discretion of the treating Investigator. Refer to Appendix 6 for guidance 
o Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
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day until the absolute neutrophil count reaches >1000/mm3 for 
3 consecutive days or as per standard of care at the treating institution  
o Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3 or as per standard of care at the 
treating institution 
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be 
given as clinically indicated, per standard of care 
o Herpetic treatment will be initiated in patients positive for HSV as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until absolute lymphocyte count 
(ALC) >1000/mm3 or as per standard of care at the treating institution  
• 
Assessment of AE/SAEs 
6.11 Day 14 and 28 (both visits +/- 3 days) 
The following procedures will be performed: 
• 
Physical exam including weight  
• 
ECOG performance status evaluation (Day 14 only) 
• 
Blood tests 
o Hematology - CBC with differential 
o 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). Thyroid panel only to be done at Day 14 
• 
Obtain blood for immune monitoring (Refer to Laboratory Manual) (Day 14 only) 
• 
If required, the following medications will continue to be administered 
o Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
day until the absolute neutrophil count reaches >1000/mm3 for 
3 consecutive days, or as per standard of care at the treating institution 
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o Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3 or as per standard of care at the 
treating institution 
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be 
given as clinically indicated, per standard of care 
o Herpetic treatment will be initiated in patients positive for HSV as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until ALC > 1000/mm3 or as per 
standard of care at the treating institution 
• 
Assessment of AE/SAEs 
6.12 Day 42 (Week 6) (+/- 3 days) 
The following procedures will be performed: 
• 
Physical exam including weight 
• 
Evaluation and measurement of all skin and palpable lesions 
• 
Verification of all concomitant medications 
• 
Vital signs- pulse rate, respiratory rate, blood pressure and temperature 
• 
Assessment of AE/SAEs 
• 
Blood tests 
o Hematology - CBC with differential 
o 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, only if clinically indicated) 
o CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated 
• 
Obtain blood for immune monitoring (Refer to Laboratory Manual) 
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• 
CT Exam (repeat the same CT series for post-treatment tumor assessment [scheduled 
and unscheduled] as completed at Baseline [Day -21 to Day -14]) 
o Chest (include neck if there is prior or suspected neck disease) 
o Abdomen 
o Pelvis 
• 
MRI of brain if positive CNS involvement at Screening or Baseline, or as clinically 
indicated (repeat the same MRI series for post-treatment tumor assessment 
[scheduled and unscheduled] as completed at Baseline [Day -21 to Day -14]) 
• 
If required, the following medications will continue to be administered 
o Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
day until the absolute neutrophil count reaches >1000/mm3 for 
3 consecutive days or as per standard of care at the treating institution  
o Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3, or as per standard of care at the 
treating institution  
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be 
given as clinically indicated, per standard of care 
o Herpetic treatment will be initiated in patients positive for HSV as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until ALC > 1000/mm3 or as per 
standard of care at the treating institution 
6.13 Day 84 (Week 12) and Day 126 (Week 18) (both visits +/- 3 days) 
The following procedures will be performed during this post treatment evaluation visit: 
• 
Physical exam including weight 
• 
ECOG performance status evaluation 
• 
Evaluation and measurement of all skin and palpable lesions 
• 
Verification of all concomitant medications 
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• 
Vital signs - pulse rate, respiratory rate, blood pressure and temperature 
• 
Assessment of AE/SAEs 
• 
Slit lamp eye exam (Day 84 only) 
• 
Blood tests 
o Hematology - CBC with Differential 
o 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, only if clinically indicated) 
o CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated 
• 
Calculate Creatinine Clearance using Cockcroft-Gault formula (Day 84 only) 
• 
Obtain blood for immune monitoring (Refer to Laboratory Manual) (Day 84 only) 
• 
CT Exam (repeat the same CT series for post-treatment tumor assessment [scheduled 
and unscheduled] as completed at Baseline [Day -21 to Day -14])  
o Chest (include neck if there is prior or suspected neck disease) 
o Abdomen 
o Pelvis 
• 
MRI of brain if positive for CNS involvement at Screening or Baseline, or as 
clinically indicated (repeat the same MRI series for post-treatment tumor assessment 
[scheduled and unscheduled] as completed at Baseline [Day -21 to Day -14]) 
• 
EORTC QLQ-C30 HRQoL questionnaire (Day 84 only) 
• 
If required, the following medications will continue to be administered 
o Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
day until the absolute neutrophil count reaches >1000/mm3 for 
3 consecutive days, or as per standard of care at the treating institution 
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o Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3, or as per standard of care at the 
treating institution  
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be 
given as clinically indicated, per standard of care 
o Herpetic treatment will be initiated in patients positive for HSV as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until ALC > 1000/mm3, or as per 
standard of care at the treating institution 
6.14 Month 6, Month 9, Month 12, Month 18, and Month 24 (all visits +/- 1 week) 
The following procedures will be performed during these visits: 
• 
Physical exam including weight 
• 
ECOG performance status evaluation 
• 
Verification of all concomitant medications 
• 
Vital signs - pulse rate, respiratory rate, blood pressure and temperature 
• 
Evaluation and measurement of all skin and palpable lesions 
• 
Blood tests 
o Hematology - CBC with Differential 
o 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 at Month 24 or if clinically indicated at other 
timepoints) 
o CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated 
• 
Obtain blood for immune monitoring (Refer to Laboratory Manual) (Months 6, 9 and 
12 only) 
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• 
CT Exam (repeat the same CT series for post-treatment tumor assessment [scheduled 
and unscheduled] as completed at Baseline [Day -21 to Day -14]) 
o Chest (include neck if there is prior or suspected neck disease) 
o Abdomen 
o Pelvis 
• 
MRI of brain if positive for CNS involvement at Screening or Baseline or as 
clinically indicated (repeat the same MRI series for post-treatment tumor assessment 
[scheduled and unscheduled] as completed at Baseline [Day -21 to Day -14]) 
• 
If required, the following medications will continue to be administered (Month 6) 
o Filgrastim 5 mcg/kg/day administered by subcutaneous injection, or as per 
standard of care at the treating institution. This will be administered each 
day until the absolute neutrophil count reaches >1000/mm3 for 3 
consecutive days, or as per standard of care at the treating institution 
o Fluconazole 400 mg PO daily, or as per standard of care at the treating 
institution. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3, or as per standard of care at the 
treating institution  
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be 
given as clinically indicated, per standard of care 
o Herpetic treatment will be initiated in patients positive for HSV as per 
standard of care at the treating institution. Valacyclovir PO or acyclovir IV 
will be administered daily, and continued until ALC > 1000/mm3, or as per 
standard of care at the treating institution 
• 
Assessment of AEs/SAEs (see Section 12 for future guidance on AE/SAE reporting 
requirements during the follow-up period) 
• 
EORTC QLQ-C30 HRQoL questionnaire (Months 6, 12, and 24 only) 
6.15 Overall Survival Follow-Up 
Patients are to be followed in Overall Survival (OS) Follow-up to collect subsequent anti-
cancer therapy and survival status for 3 years from last patient receiving last dose of adjuvant 
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IL-2 or end of study (EOS) visit.  It is the intent that all patients will be followed for OS for a 
minimum of 3 years. 
6.16 Late Treatment Discontinuation (following LN-144 infusion) 
A patient who is discontinued from treatment, after receiving LN-144 should remain on the 
study and continue with all scheduled study visit assessments. 
• 
However, if a patient must initiate anti-cancer therapy or exhibits disease progression 
after LN-144 infusion they will remain in the study, but the data collection will be 
reduced to survival status and other anti-cancer therapy 
6.17 Expected Toxicities and Treatment Guidelines 
6.17.1 
LN-144  
Early toxicities related specifically to the infusion of the cells (those which are seen 
immediately following the cell infusion and prior to IL-2 administration) are generally mild 
and include fevers, chills, headache, and malaise. Toxicities that occur following 
administration of IL-2, but are thought to be related to the cells include immune mediated 
events such as vitiligo, transient uveitis, hearing loss and vestibular dysfunction. (IL-2 specific 
toxicity is discussed in Section 6.17.2)  
6.17.2 
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 
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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 IL-2 is to continue dosing until grade 3 or 
4 events occur but this study calls for 1 to 6 doses based on tolerance. The most commonly 
seen grade 4 events are pulmonary and renal impairment, and mental status changes. These 
toxicities may sometimes require intubation for protection of the patient’s airway. It is 
important to note that although these patients require significant supportive measures during 
this period, almost all toxicities are reversible, and the overwhelming majority of patients have 
suffered no long-term sequelae following this treatment regimen. However, fatal 
complications are possible.  
Treatment Guidelines for Toxicity Management   
Concomitant medications to control side effects of therapy will be given. Meperidine 
(25-50 mg), or other medication per site standard of care may be given intravenously if severe 
chills develop. Other supportive therapy shall be given as required. Supportive therapy 
includes acetaminophen (650 mg q4h), indomethacin (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 6.  
Expected toxicities with cyclophosphamide and fludarabine administration are listed in the 
package inserts (see Appendix 8 and 9, 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.  
6.17.3 
Blood Product Support  
Using daily CBCs as a guide, the patient will receive platelets and packed red blood cells 
(PRBCs) as needed as per standard of care at the treating institution. Attempts will be made to 
keep hemoglobin >7.5 g/dL, and platelets >10,000/mm3. All blood products will be irradiated. 
Leukocyte filters will be utilized for all blood and platelet transfusions to decrease 
sensitization to transfused WBCs and decrease the risk of CMV infection. 
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6.17.4 
Renal Toxicity 
Renal toxicity defined by rapid rise in creatinine levels or clinical symptoms is a risk. 
If patients exhibit signs or symptoms of renal toxicity, manage as per institutional standard 
of care. 
6.18 Infection Prophylaxis 
Other anti-infective agents may be substituted at the discretion of the Investigator as per 
standard of care at the treating institution.    
6.18.1 
Pneumocystis jiroveci Pneumonia 
All patients will receive the fixed combination of trimethoprim (TMP) and sulfamethoxazole 
[SMX] as double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) (PO) 
daily 3 times a week on non-consecutive days, beginning on the first Monday, Wednesday, or 
Friday on or after the first dose of chemotherapy or as per standard of care at the treating 
institution.  
Pentamidine will be substituted for TMP/SMX DS in patients with sulfa allergies. It will be 
administered aerosolized at 300 mg per nebulizer within 1 week prior to receiving study 
treatment and continued monthly until ALC is above 1000/mm3 and for at least 6 months post 
chemotherapy, or as Investigator deems appropriate as per standard of care at the treating 
institution. 
Pneumonia prophylaxis will continue for 6 months post chemotherapy. If the ALC is less than 
1000/mm3 at 6 months post chemotherapy, or as Investigator deems appropriate as per 
standard of care at the treating institution, prophylaxis will continue until the CD4 count is 
greater than 200/mm3. 
6.18.2 
Herpes Virus Prophylaxis 
Patients with positive HSV serology will be given valacyclovir orally at a dose of 500 mg 
daily the day after chemotherapy ends, or acyclovir, 250 mg/m2 IV every 12 hours if the 
patient is not able to take medication by mouth as per standard of care at the treating 
institution. Reversible renal insufficiency has been reported with IV but not oral acyclovir. 
Neurologic toxicity including delirium, tremors, coma, acute psychiatric disturbances, and 
abnormal EEGs has been reported with higher doses of acyclovir. Should this occur, a dosage 
adjustment will be made or the drug will be discontinued. Acyclovir will not be used 
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concomitantly with other nucleoside analogs, which interfere with DNA synthesis, 
e.g. ganciclovir. In renal disease, the dose is adjusted as per product labeling. 
Herpes prophylaxis will continue for 6 months post-chemotherapy, or as long as Investigator 
deems necessary. If the ALC count is less than 1000/mm3 at 6 months post chemotherapy, 
prophylaxis will continue until the ALC count is greater than 1000/mm3, or as per standard 
of care of the treating institution. 
6.18.3 
Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg (PO) the day after chemotherapy concludes and 
continue until the ALC is greater than 1000/mm3 or as per standard of care of the treating 
institution. The drug may be given IV at a dose of 400 mg in 0.9% sodium chloride USP daily 
in patients unable to take it orally as per standard of care at the treating institution. 
6.18.4 
Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation cephalosporin 
or a quinolone for fever – defined as 38.3°C, 1 or 2 temperatures of 38.0°C or above at least 
1 hour apart, AND an ANC <500/mm3 or receiving IL-2 administration. Aminoglycosides 
should be avoided unless there is clear evidence of sepsis. Infectious disease consultation will 
be obtained for all patients with unexplained fever or any infectious complications as per 
standard of care at the treating institution. 
6.18.5 
Blood Product Support 
Using CBCs as a guide, the patient will receive platelets and packed red blood cells (PRBCs) 
as needed as per standard of care at the treating institution. Attempts will be made to keep 
hemoglobin >7.5 g/dL, and platelets >10,000/mm3. All blood products will be irradiated. 
Leukocyte filters will be utilized for all blood and platelet transfusions to decrease 
sensitization to transfused WBCs and decrease the risk of CMV infection. 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF PATIENTS 
7.1 
 Treatment Completion 
Completion of treatment is defined as having received any volume of LN-144 infusion followed 
by at least 1 dose of adjuvant IL-2.  
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7.2 
Criteria for Early Discontinuation from 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 LN-144 infusion  
• 
Grade 3 or greater allergic reaction including bronchospasm or generalized urticaria 
that does not resolve after medical management in the opinion of the Investigator  
• 
Grade 3 or greater toxicity due to IL-2 that does not decrease to Grade 2 or less 
within 96 hours of management   
• 
Determination by the Investigator that continued treatment is not in the best interest 
of the patient 
• 
Withdrawal by patient. The patient may withdraw consent to treatment but continue 
consent for follow-up evaluations and/or survival status 
• 
Pregnancy 
• 
Criteria for early discontinuation from study 
• 
Patient has become ineligible for study after tumor harvest and prior to LN-144 or 
IL-2 administration 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the patient  
7.3 
Criteria for Early Discontinuation from Study  
• 
Withdrawal by patient.  The patient may withdraw consent.  All efforts should be 
made to continue consent for survival status follow-up 
• 
Patient has become ineligible for study after tumor harvest  
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the patient 
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8 
STUDY DRUG INFORMATION 
8.1 
Investigational Product 
Investigational Product Name: LN-144 
Active Investigational Product Components: Autologous, viable, tumor infiltrating 
lymphocytes (TIL) 
Dosage Form: Live cell suspension either non-cryopreserved (Cohort 1) or cryopreserved 
(Cohort 2) 
8.2 
Qualitative Composition of LN-144   
LN-144 is a cellular investigational product of autologous tumor-infiltrating lymphocytes 
(TIL) derived from the patient's own tumor. LN-144 is an autologous cell therapy for the 
treatment of patients with advanced melanoma. LN-144 is a live cell suspension that is either 
formulated in either HypoThermosol™ transport medium (non-cryopreserved product) or 
Cryostor medium (cryopreserved product) with Plasma-Lyte® A as diluent, with 0.5% HSA 
(human serum albumin) and 300 IU/mL of IL-2. The suspension volume will be between 
250 to 500 mL. Only one LN-144 dose is given intravenously a NMA-LD lymphodepletion 
preconditioning regimen followed by adjuvant IL-2 therapy starting as soon as 3 hours, but not 
later than 24 hours after completion of LN-144 infusion. The total volume of LN-144 to be 
infused will be approximately 250 mL (300 mL transfer bag for Cohort 1) for cell 
concentrations ≤75 x 109 LN-144 or 500 mL (up to 600 mL transfer bag for Cohort 1) for cell 
concentrations ≤150 x 109 LN-144. Patients on Cohort 2 will have up to 5 bags containing up 
to approximately 100 mL of thawed cells. 
8.3 
Manufacturing Process 
The overall process of tumor shipping, LN-144 manufacturing, and LN-144 investigational 
product shipping, and infusion is shown in Figure 3 (Cohort 1) and Figure 4 (Cohort 2). 
The LN-144 investigational product is manufactured ex vivo using autologous tumor as 
starting material. The key manufacturing steps include: 
• 
Surgical resection of autologous metastatic tumor and shipment to manufacturing 
facility 
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• 
Culture of small 2-3 mm (length x width x height) fragments of autologous tumor 
in IL-2 to expand TIL 
• 
A rapid expansion protocol (REP) in the presence of IL-2, OKT3, and irradiated 
allogeneic MNC feeder cells 
• 
Harvesting and formulation of REP expanded investigational product in transport 
medium or cryopreserved and overnight shipment to clinical site for infusion 
8.4 
Final Investigational Product Container 
The live suspension of LN-144 for Cohort 1 is stored in a 300-mL blood transfer pack (Baxter) 
for cell concentrations ≤75 x 109 LN-144 or 600 mL blood transfer pack (Baxter) for cell 
concentrations ≤150 x 109 LN-144. Alternatively, in Cohort 2, TILs will be received 
cryopreserved in up to 5 bags containing up to approximately 100 mL of thawed cells. 
8.5 
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 by a method that is intended to support 24-hour 
delivery. The live suspension investigational product will be packaged in a protective bag 
containing absorbent padding then placed into an insulated container (Therapak NanoCool™ 
shipper), designed to maintain transit temperature between 2-8oC (Cohort 1). For Cohort 2, a 
dry cryoshipper will be utilized. A temperature monitoring device will be included to monitor 
the temperature inside the container during shipping. 
8.6 
Receipt at Clinical Site and Administration 
The dose of LN-144 investigational product will be received at the clinical site on or prior 
to Day 0. Refer to the LN-144 Pharmacy and Administration Manual for additional details. 
9 
STUDY ASSESSMENTS 
9.1 
Tumor Assessments 
Tumor assessment will be performed by clinical exam (skin lesions) and by conventional or spiral 
CT scans of the chest, abdomen, pelvis and MRI of brain conducted at Screening, Day -14 and 
Day 42 (6 weeks, ± 3 days) following the LN-144 infusion and every 6 weeks thereafter, up to 
6 months post-LN-144 infusion, at which time the tumor assessments will follow the schedule 
below:  
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• 
At 9 months (± 1 week) following LN-144 treatment 
• 
At 12 months (± 1 week) following LN-144 treatment  
• 
At 18 months (± 3 weeks) following LN-144 treatment 
• 
At 24 months (± 3 weeks) following LN-144 treatment 
CT scans of additional anatomical locations will be conducted at the above referenced visits if 
prior or suspected disease is clinically indicated (the same CT series and brain MRI as completed 
at Baseline [Day -21 to Day -14] is to be repeated at all post-treatment disease assessments, 
[scheduled and unscheduled]). Assessments should be made and recorded by the Investigator 
or an individual authorized by the Investigator.  
MRI or positron emission tomography (PET) scans in lieu of CT scans will be allowed for 
patients who have an intolerability to contrast media. The imaging modality used must be 
uniform for the duration of the study.  
9.1.1 
Response Criteria 
Tumor response will be determined using RECIST version 1.12 with a modification to require 
confirmation of PD. Refer to Table 1 and Table 2 for RECIST 1.1 response criteria2 
definitions. Images (CT scans and/or MRI) obtained at Baseline Visit (Day -21 to Day -14) are 
to be utilized for RECIST 1.1 response assessments throughout the study. 
Local tumor assessments should be used for clinical treatment decisions, and may include 
photographic/caliper measurement of superficial dermal and subcutaneous lesion.  
All locally-obtained images will be forwarded to a central imaging facility for independent 
assessment of tumor responses.  
9.1.1.1 
Evaluation of Target Lesions1 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have a reduction in short axis to <10 mm). 
                                            
1 All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured during screening. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as 
reference by which to characterize any objective tumor regression in the measurable dimension of the 
disease. If lymph nodes are to be included in the sum, only the short axis will contribute. 
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• 
Partial Response (PR): At least a 30% decrease in the sum of the diameter of target 
lesions taking as reference the baseline sum diameters. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or 
more new lesions is also considered progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as references the smallest sum diameters while on study. 
9.1.1.2 
Evaluation of Non-target Lesions2 
• 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
• 
Non-Complete Response: Persistence of 1 or more non-target lesion(s) and/or 
maintenance of tumor marker level above normal limits. 
• 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of 1 or more new lesions is also considered progression).   
9.1.1.3 
Evaluation of Best Overall Response 
The best overall response is determined once all the data for the patient is known. The best 
overall response is the best response recorded from Day -21 to Day -14 (Baseline) 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.   
                                            
2 All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.   
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Table 1. 
Time Point Response: Patients with Target (± Non-target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
 
 
 
 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 2. 
Time Point Response: Patients with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
9.1.1.4 
Confirmatory Measurement/Duration of Response 
9.1.1.4.1 Confirmation 
A response of PR or CR must be confirmed by a subsequent assessment of response, which 
should be performed at least 4 weeks after the criteria for response are first met.  
9.2 
Biomarkers 
Peripheral blood mononuclear cells (PBMC), serum, plasma and tumor specimens will be 
collected to test for cellular and soluble factors, via immunological assays and molecular assays 
related to exome sequencing, TCR sequencing, mRNA analysis and immunohistochemistry 
staining. 
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9.3 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will evaluate cumulative safety data on the first 
3 patients completing 12 weeks of assessment in Cohort 1 and Cohort 2, respectively. 
Enrollment will continue while under DSMB review. 
Additional evaluations of safety data may be conducted as specified in the DSMB charter. 
10 STATISTICAL AND ANALYTICAL PLANS  
10.1 Introduction  
The primary statistical plan of analysis is based on use of descriptive methods unless 
mentioned otherwise. Continuous data will be summarized as the number of patients with non-
missing data (N), mean, standard deviation, median, minimum, and maximum values. 
Categorical data will be summarized as counts and their related percentages, where applicable. 
Point estimates of treatment effect will be derived from maximum likelihood methods. 
Estimation of confidence limits will use 2-sided, 90% criteria and implement the Wilson score 
method. 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 Study and Analysis Populations 
The 2 study cohorts (Cohort 1 and Cohort 2) comprise the Tumor Harvested (TH) population 
defined as all resected patients. The TH population is further divided into the following 
analysis populations: 
10.2.1 
Efficacy Population 
Primary:  
the All-Treated population that consists of patients in the safety population 
who have been successfully treated with nonmyeloablative chemotherapy, 
LN-144 followed by IL-2 (at least 1 dose), based on Investigators’ assessment 
 
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10.2.2 
Safety Population 
Primary:  
all patients in the TH population who received at least one component of the 
study treatment; cyclophosphamide, fludarabine, LN-144 or IL-2.   
Secondary:  
all patients in the TH population.  Non-treated patients who are not a part of 
the primary safety population will be summarized separately  
Patients who are retreated with LN-144 therapy (Cohort 3) will have their safety and efficacy 
data tabulated separately. Patients who received LN-144 for the first time in Cohort 3 due to a 
previous manufacturing failure or other reasons, will be included in the original cohort for 
efficacy and safety analyses. There will be no formal comparisons among cohorts. 
10.3 Endpoints 
10.3.1 
Primary 
The primary endpoint is the ORR using RECIST 1.1 criteria2.  The ORR is derived as the sum 
of the number of patients with a CR or partial response (PR) divided by the number of patients 
in the All-Treated population x 100%.  
10.3.2 
Secondary 
CR rate is derived as the sum of the number of patients with a confirmed CR divided by the 
number of patients in the All-Treated population x 100%.  
PFS is defined as the time (in months) from the start date of lymphodepletion to PD or death 
due to any cause, whichever event is earlier. Patients not experiencing PD or death at the time 
of data cut or end of study (i.e., database lock) will have their event times censored on the last 
adequate tumor assessment date.  
DOR is measured from the first time measurement criteria are met for a CR or PR, whichever 
response is observed first, until the first date that progressive disease (PD) or death occurs. 
Patients not experiencing PD or death prior to the time of data cut or end of study will have 
their event times censored on the last adequate tumor assessment date.  
DCR is derived as the sum of the number of patients who achieved PR/CR or SD per the 
RECIST v1.1 divided by the number of patients in the All-Treated population x 100%. 
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OS is defined as the time (in months) from the start date of the lymphodepletion to death due 
to any cause. Patients not having expired at the time of data cut or end of study will have their 
event times censored on the last date of their known survival status. 
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. 
10.3.3 
Exploratory 
The exploratory endpoints include measures of LN-144 persistence in the peripheral blood as 
well as immune response with the objective to evaluate their correlation with response, 
outcome, and toxicity of the treatment. Tumor responses via ir-RECIST1 will also be assessed. 
HRQoL will be assessed using the EORTC QLQ-C30 instrument (see Appendix 10) and 
scored/evaluated as described in the Statistical Analysis Plan. 
10.4 Sample Size Consideration 
The planned number of all-treated patients per Cohort 1 and Cohort 2 is approximately 30 
(total 60, inclusive of Cohort 3 retreated patients).  The hypotheses test of primary endpoint 
analysis per cohort in this study assumes an underlying ORR of 15% over best monotherapy 
available, as the historical control, for the treatment of patients with metastatic melanoma after 
progression on anti-PD-1 therapy.3  Assuming a true response rate of 30% for the LN-144 
therapy, a sample size of 30 all-treated patients provides approximately 70% power to reject 
the null hypothesis H0 ≤ 15% at 1-sided 5% significance level. 
10.4.1 
Baseline Demographics and Clinical Characteristics 
Baseline demographic and clinical (disease) characterized will be summarized descriptively 
for the Safety and the All-Treated patient populations if they are not identical. Age will be 
derived as a function of the date of informed consent. 
10.4.2 
Primary Endpoint 
ORR is expressed as binomial proportions and will be summarized using both a point estimate 
and its 2-sided 90% confidence limits based on the Wilson’s score method. 
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10.4.3 
Secondary Endpoints 
CR rate and DCR are also expressed as binomial proportions and will be summarized using 
both a point estimate and its 2-sided 90% confidence limits based on the Wilson’s score 
method.  
PFS, OS, durations of overall are time-to-event variables subjected to right censoring. Kaplan-
Meier probabilities and related summary statistics will be provided for the entire time-to-event 
curve as well as for the following landmark event-free rates: 6 months, 12 months, 18, months, 
and 24 months. The landmark analyses will be applied to the PFS and OS data.  
The primary safety variable is a binomial proportion of a safety event and will be summarized 
using both a point estimate and its 2-sided 90% confidence limits. 
10.4.4 
Safety Analysis 
The assessment of safety data will be descriptive and based on the summarization of 
treatment-emergent adverse events, serious adverse events, adverse events leading to 
discontinuation from the study, vital signs, physical examinations, and clinical laboratory tests. 
Treatment emergent is considered to start the time of lymphodepletion for the Safety and 
All-Treated populations. Adverse event summaries will be based on patient incidence counts 
and their related percentages; the number of events will be displayed as appropriate. In 
addition to an overall summary of adverse events, separate displays will be made by severity 
and relationship. Certain safety data will be amenable to summary by use of toxicity grades, 
and all such analyses will evaluate the worst grade observed per patient during the treatment-
emergent period. These toxicity grade summaries will be derived separately based on the 
current version of CTCAE for each measure under consideration (e.g., ANCs for neutropenia; 
platelets for thrombocytopenia). 
10.4.5 
Other Planned Analyses 
Should exploratory analyses other than those described in this study protocol, but described in 
the SAP or the DSMB charter be performed, their details will be described in the Clinical 
Study Report. 
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11 CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS 
11.1 Medications Administered during the Study 
Please refer to the Information for Use package insert provided with all drugs used in this 
study to understand the contraindications, precautions and warning relative to a specific drug. 
11.2 LN-144 Treatment  
Early toxicities related specifically to the infusion of the cells (those seen immediately 
following cell infusion and prior to IL-2 administration) are generally mild and include fevers, 
chills, headache, and malaise. Toxicities that occur following administration of IL-2 but 
thought to be related to the cells include immune mediated events such as vitiligo, transient 
uveitis, hearing loss and vestibular dysfunction. (IL-2 specific toxicity is discussed in 
Section 6.17.2). The use of the nonmyeloablative regimen prior to cell administration increases 
the toxicity of this treatment as profound myelosuppression occurs in all patients.   
11.3 IL-2 Administration 
See Section 6.17.2 for IL-2 toxicity considerations. The standard approach to the 
administration of adjuvant IL-2 in all studies is to continue dosing without putting the patient 
at risk for severe or irreversible toxicities. The most commonly seen Grade 4 events are 
pulmonary and renal impairment, and mental status changes. It is important to note that 
although these patients require significant supportive measures during this period, most 
toxicities are reversible and the overwhelming majority of patients have suffered no long-term 
sequelae following this treatment regimen. However, fatal complications are possible and it is 
therefore only appropriate to carry out this experimental treatment in the context of life 
threatening metastatic cancer. 
12 ADVERSE EVENTS 
Toxicities will be recorded as AEs and SAEs in the patient’s source documents and on the 
Adverse Event eCRF and must be graded using the NCI’s CTCAE v4.03 dated 14 June 2010.  
12.1 Definitions 
12.1.1 
Adverse Event 
An adverse event (AE) as defined by ICH-GCP is any untoward medical occurrence in a 
patient or clinical trial patient administered a medicinal/investigational product and which does 
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not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal/investigational product. 
Events meeting the definition of an AE include: 
• 
Adverse event temporally associated with the use of any of the study drugs or TIL 
treatment whether or not considered related to the use of any of the study drugs or TIL 
treatment 
• 
Any abnormal laboratory test results (e.g., hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., EKGs, radiological scans, vital signs measurements), 
that worsen from baseline, and are felt to be clinically significant in the medical and 
scientific judgment of the Investigator 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product administration 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction with investigational 
product 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication 
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) 
• 
Overdose without clinical sequelae (see 12.2.1.2.2.1) 
• 
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 
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During clinical trials, AEs can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a patient.   
12.1.2 
Serious Adverse Event 
An AE is considered ‘serious” if, in the view of either the Investigator or the Sponsor, it results in 
any of the following outcomes:  
• 
Death 
• 
Is Life Threatening 
• 
Inpatient hospitalization or prolongation of an existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
Important medical events that may not directly result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on Investigator decision, they may 
jeopardize the patient and may require intervention to prevent one of the above outcomes as 
listed in this definition. 
Hospitalization including admission to a telemetry unit or intensive care unit (ICU) 
specifically for administration of study treatment is not considered a serious adverse event.  
12.1.3 
Relationship to Study Drug 
The Investigator is responsible for assessing the relationship to study treatment using clinical 
judgement and the following considerations: 
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.  
Probable:  
There is reasonable causal relationship between the study drug and the 
AE/SAE.  The event responds to de-challenge.  
Possible:  
There is reasonable causal relationship between the study drug and the AE/ 
SAE. De-challenge information is lacking or unclear.  
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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.  
Not related:  
There is not a temporal relationship to study drug administration (too early, or 
late, or study drug not taken), or there is known causal relationship between 
the AE/SAE and another drug, concurrent disease, or other circumstance. 
12.1.4 
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 Reporting Procedures for Adverse Events 
12.2.1 
Relationship to Study Drug 
12.2.1.1 All Adverse Events 
Adverse Events occurring after signature of informed consent and either observed by the 
Investigator or reported by the patient must be entered into the eCRFs. All AEs occurring after 
the patient has consented, but before enrollment (prior to tumor harvested), will be collected 
on the medical history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments.  
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Monitoring and reporting of AEs, regardless of cause or relationship will be collected through 
6 months from the last dose date of IL-2 or until the first dose of anti-cancer therapy, 
whichever occurs first. All AEs attributed to protocol-required procedures or treatment will be 
collected from signing of the informed consent form through Month 24 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.  
If any patient should die while on the study, the Investigator will inform the Sponsor within 
24 hour and report the cause of death as an SAE. The cause of death should be recorded in 
detail on the SAE Report Form. Disease progression itself is not an AE, but the clinical signs 
or symptoms leading to death should be reported as an SAE with an outcome of death. 
Each site will be responsible for reporting SAEs occurring at the site to the applicable 
IRB/IEC per the IRB’s/IEC’s reporting guidelines. Sites that are required to utilize a local IRB 
will be responsible for their own local IRB/IEC 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. 
12.2.1.2 Serious Adverse Events 
12.2.1.2.1 Investigator Reporting to Sponsor 
All SAEs, regardless of relationship to study treatment, must be collected while on the study 
(from patient signing of informed consent through 6 months from the last dose of IL-2 or until 
the first dose of the next anti-cancer therapy, whichever occurs first). All AEs/SAEs attributed 
to protocol-required procedures or treatment will be collected through Month 24 of the study. 
If the Investigator learns of any SAEs that occur after the follow-up period and there is a 
reasonable possibility that the event may have been caused by the study treatment, then the 
SAE should be promptly reported to the Sponsor or designated Safety CRO.   
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 
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complete as is possible with the information available and include the Investigator’s 
assessment of study drug relationship, as defined in Section 12.2.1. All AEs, regardless of their 
severity, will be captured in the eCRF within the timelines outlined in the eCRF completion 
guidelines.  
SAE terminology and severity grading will be based on the NCI’s CTCAE v 4.03 guidelines.   
All SAEs will also be reported on the SAE Report Form, and submitted by email or fax within 
24-hours of knowledge of the event to the attention of the Safety CRO contact below.  
Safety CRO 
Contact Information for Submission of SAE Report 
Form 
SynteractHCR 
E-mail:  
 
Fax:  
 
12.2.1.2.2 Special Situation Reporting 
12.2.1.2.2.1 Definition of Special Situations 
Special situation reports include reports of medication error, overdose, adverse events 
associated with product complaints, occupational exposure, and pregnancy reports regardless 
of an associated AE.   
Medication error is any unintentional error in the prescribing, dispensing, or administration of 
a medicinal/investigational product while in the control of the health care provider, patient, or 
consumer.  
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal/investigational product given per administration or cumulatively which is above the 
maximum recommended dose as per protocol or in the product labelling (as it applies to the 
daily dose of the patient in question).  
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal/investigational product.   
Occupational exposure is defined as the exposure to a medicinal/investigational product as a 
result of one’s professional or non-professional occupation. 
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12.2.1.2.3 Pregnancy Reporting 
Any pregnancy that occurs while on the study through 12 months from the last dose of IL-2 or 
until the first dose of the next anti-cancer therapy, whichever occurs first, must be reported 
using the Pregnancy Report form within 24 hours of becoming aware of the pregnancy.  The 
pregnancy itself is not considered an AE nor is an induced abortion to terminate a pregnancy 
without medical reasons. Any premature termination of pregnancy (e.g., a spontaneous 
abortion, an induced therapeutic abortion due to complications or other medical reasons) must 
be reported within 24 hours as an AE or SAE. The underlying medical reason for this 
procedure should be recorded as the AE or SAE term. A spontaneous abortion is always 
considered to be an SAE and will be reported as described in Section 12.2.1.2.4.  
The patient should receive appropriate monitoring and care until the conclusion of the 
pregnancy to determine the outcome and status of the patient and child.  The outcome should 
be reported to the safety CRO using the Pregnancy Outcome form. Any SAE occurring in 
association with a pregnancy, brought to the Investigator’s attention after the patient has 
completed the study treatment and post-treatment follow-up visits, must be promptly 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.  
Pregnancies of female partners of male study participants exposed to study treatment must also 
be reported and relevant information should be submitted to the safety CRO using the 
Pregnancy and Pregnancy Outcome forms within 24 hours. Monitoring of the female partners 
should continue until the conclusion of the pregnancy. 
12.2.1.2.4 Other Special Situations Reporting 
All other special situation reports involving the study treatment must be reported on to the 
Safety CRO using the SAE Report Form within 24 hours of becoming aware of the situation. 
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Special situations involving concomitant medications do not need to be reported; however, 
any AE resulting from a special situation should be reported on the AE eCRF page. 
12.2.1.2.5 Regulatory Reporting Requirements 
In the event of a suspected unexpected serious adverse reaction (SUSAR), the Sponsor, or 
their designee, will notify the appropriate regulatory authorities and all appropriate parties as 
per the regulations.  
Assessment of expectedness for SAEs will be determined by Lion using reference safety 
information in the Investigator’s Brochure and relevant prescribing information, as applicable. 
In addition, the Sponsor must submit expedited reports of potential serious risks from clinical 
trials or any other source based on relevant local legislation or regulations, including the 
applicable US FDA Code of Federal Regulations and the EU Clinical Trial Directive 
(2001/20/EC) and relevant updates. The Sponsor will notify participating sites of relevant 
SUSAR reports and other applicable serious safety findings, which occur during the trial 
including the post study treatment follow-up phase.  
13 ADMINISTRATIVE REQUIREMENTS 
13.1 Adherence to the Protocol  
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in the protocol. The Investigator will not deviate from 
this protocol without obtaining the concurrence of the Sponsor, specifically without discussion 
with the Medical Monitor. All protocol amendments must be issued by the Sponsor, signed 
and dated by the Investigator, and should not be implemented without prior IRB/IEC 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/IEC are further described per Sponsor or 
designee operating procedures and delegation of regulatory obligations. 
13.2 Regulatory Approval and Documentation 
Lion Biotechnologies, Inc. (Sponsor) will determine the appropriate local, national and or 
regional regulatory approvals that need to be obtained in order to conduct the study. 
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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 IRB/IEC 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 IRB/IEC member has a known conflict of 
interest, abstention of that individual from voting should be documented; an 
Investigator may be a member of the IRB/IEC, but may not vote on any research in 
which he or she is involved. 
• 
Name and address of the IRB/IEC 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/IEC members. If accompanied by a letter of explanation from the IRB/IEC, a 
general statement may be substituted for this list. 
• 
A copy of the IRB/IEC approved informed consent and other adjunctive materials 
(e.g., advertising) to be used in the study, including written documentation of 
IRB/IEC approval of these items 
• 
Name and address of any local laboratory conducting tests for the study, a dated copy 
of the laboratory reference values for tests to be performed during the study and a 
copy of the certification or other documentation establishing adequacy of the facility 
• 
Required financial agreement 
In addition to the documents required prior to the study, other documentation may be required 
during the course of the study. 
13.3 Record Retention 
In compliance with the ICH/GCP guidelines the Investigator/Institution will be responsible for 
all information in the eCRF and will maintain the source documents that support the data 
collected from each patient, and all trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial and as specified by the applicable regulatory requirement(s). 
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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  
This trial shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 2008) and all revisions thereof, and in accordance with FDA regulations (21 CFR 
Parts 11, 50, 54, 56, and 312, Subpart D - Responsibilities of Sponsors and Investigators) and 
with the ICH guidelines on GCP (ICH E6 R2). 
Steps to be taken to assure the accuracy and reliability of data include; the selection of 
qualified Investigators and appropriate study centers, review of protocol procedures with the 
Investigator and associated personnel prior to the study, periodic monitoring visits by the 
Sponsor/designee. Electronic CRFs will be reviewed for accuracy and completeness by 
Clinical Research Monitors during on- site monitoring visits and after their return from the 
site, and any discrepancies will be resolved with the Investigator or designees, as appropriate. 
The data will be verified for accuracy. 
Agreements made by the Sponsor with the Investigator/Institution and any other parties 
involved in the clinical trial will be in writing as a separate agreement.  
Representatives of the Sponsor’s Clinical Quality Assurance department/designee may visit 
the site to carry out an audit of the study in compliance with regulatory guidelines and 
company policy. Such audits will require access to all study records, including source 
documents, for inspection and comparison with the eCRFs. Patient privacy must, however, be 
respected. Sufficient prior notice will be provided to allow the Investigator to prepare properly 
for the audit. 
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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 processing, the Sponsor or their designee will ensure that systems 
comply with 21 CFR Part 11, CTR EU No. 536/2014 and General Data Protection 
Regulation (GDPR), EU 2016/679 requirements, as applicable. 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 
Data Handling and Recordkeeping 
13.5.2.1 Electronic Case Report Form (eCRF) Completion 
Electronic data capture (EDC) will be used for the 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 the 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 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 
Upon completion of the study, the Investigator will ensure that the complete set of source data 
has been entered into the eCRFs and sign-off on the final eCRF.  Continuation of the 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 patients enrolled in the 
study 
• 
A decision on the part of the Sponsor to suspend, discontinue, or shorten the study 
13.7 Monitoring 
On-site monitoring visits will be performed by the Sponsor as frequently as necessary. At 
these visits the monitor will compare the data entered into the eCRFs with the hospital or 
clinic records (source documents). At a minimum, source documentation must be available to 
substantiate proper informed consent procedures, adherence to protocol procedures, adequate 
reporting and follow-up of adverse events, administration of concomitant medication, drug 
receipt/dispensing/return records, and study drug administration information. Specific items 
required as source documents will be reviewed with the Investigator prior to the study. 
Findings from this review of eCRFs and source documents will be discussed with the 
Investigator. The source documentation will be available, and a suitable environment will be 
provided for review of study-related documents. 
14 INVESTIGATOR REGULATORY OBLIGATIONS 
14.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Before enrollment of patients into the study, as required by Federal regulations (21 CFR 56) and 
international regulations (ICH GCP Guidelines), the protocol and informed consent form(s) must 
be reviewed and approved by an appropriate IRB/IEC.  By signing the FDA Statement of 
Investigator Form 1572, the Investigator assures that all aspects of the institutional review will be 
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conducted in accordance with current federal regulations. A letter documenting the IRB/IEC 
approval with the names and titles of the IRB/IEC members must be received by the Sponsor 
before the initiation of the trial. Amendments to the protocol will be subject to the same 
requirements as the original protocol. 
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/IEC. 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, Directive 2001/20/EC (and when in force 
EU Regulation 536/2014), and Regulation 2016/679 (GDPR), as interpreted by the national 
laws and regulatory bodies, and the Sponsor’s policies. 
The Investigator must explain to potential patients or their legal representatives the purpose, 
methods, reasonably anticipated benefits and potential hazards of the study, it’s duration and 
any discomfort it may entail. Patients will be informed in their native language, 
comprehensive, concise, clear, relevant and understandable to a layperson, that their 
participation is voluntary and that they that they are free not to participate in the study 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 their personal data 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 study, 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 and their legally designated 
representative must receive a signed and dated copy of the informed consent. The informed 
consent process should be documented in the patient’s medical record. Adequate time shall be 
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given for the subject or his or her legally designated representative to consider his or her 
decision to participate in the study. 
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/IEC access to patient’s 
medical information that includes all hospital records relevant to the study, including a 
patient’s medical history and other data that may identify him/her, including of the purpose of 
this access and data processing connected with it. 
14.3 Patient Data Protection 
The Principal Investigator at each site and designees, employees, and agents involved with the 
study will comply with relevant state, federal national and regional 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 the 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/IEC, FDA, EMA, national 
regulatory authorities or other authorized recipients as appropriate for the execution, analysis, 
review, and reporting of the study. Such information shall not be used for any other purposes 
and will remain confidential. Patient will not be individually identified but will be referred to 
in records by the study-assigned number and patient initials (if allowed by law). 
14.4 Adverse Event Reporting 
The Investigator agrees to report all AEs/SAEs to the Sponsor as described in Section 12, 
Adverse Events. Furthermore, the Investigator is responsible for ensuring that any 
co-Investigator or sub-Investigator promptly bring AEs to the attention of the Investigator. The 
PI shall promptly notify the IRB/IEC of any SAEs, or any other information that may affect 
the safe use of the investigational product during the course of the trial as applicable per the 
local IRB/IEC requirements. 
14.5 Investigator 
The Investigator will permit study-related monitoring, audits, IRB/IEC 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 
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study site, and document all access to personal data and their transfers covered by this 
protocol. 
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. 
14.6 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 the study, or the fact that the study is/was conducted) will be 
released without prior written consent of the Sponsor unless this requirement is superseded by 
local or national regulations. 
14.7 Publications 
The Sponsor will be responsible for determining when the study results should be published. 
The Sponsor will work jointly with the Investigators to publish information. The Investigator 
shall not submit a publication or abstract to journals or professional societies without the prior 
written approval of the Sponsor, except as permitted by the agreed terms of the clinical trial 
agreement, including after the reporting of the results of this multi-center study by the Sponsor 
and other institutions.  
 
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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. 
44. 
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. 
45. 
Kirkin AF, Dzhandzhugazyan K, Zeuthen J. Melanoma-associated antigens recognized by 
cytotoxic T lymphocytes. APMIS 1998;106:665-679. 
46. 
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. 
47. 
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. 
48. 
Kradin RL, Kurnick JT, Lazarus DS, et al. Tumour-infiltrating lymphocytes and 
interleukin-2 in treatment of advanced cancer. Lancet 1989;1:577-580. 
49. 
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. 
50. 
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. 
51. 
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. 
52. 
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. 
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53. 
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 
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54. 
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. 
55. 
Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of 
cancer with tumor-infiltrating lymphocytes. Science 1986;233:1318-1321. 
56. 
Alexander RB, Rosenberg SA. Long-term survival of adoptively transferred tumor-
infiltrating lymphocytes in mice. J Immunol 1990;145:1615-1620. 
57. 
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. 
58. 
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. 
59. 
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. 
60. 
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. 
61. 
Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with 
metastatic melanoma. Curr Opin Immunol 2009;21:233-240. 
62. 
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. 
63. 
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. 
64. 
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. 
65. 
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. 
66. 
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. 
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67. 
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. 
68. 
Ellebaek E, Iversen TZ, Junker N, et al. Adoptive cell therapy with autologous tumor 
infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J 
Transl Med 2012;10:169. 
 
 
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1. 
Re-check of Inclusion/Exclusion Criteria in order to ensure that patient performance status and main eligibility criteria have not changed from time of 
Screening, a re-confirmation is to be perform and approved by Sponsor or designee. 
2. 
Physical examination (PE) will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory system, 
skin, psychiatric (mental status), general nutrition.  
3. 
Medical History including melanoma disease history, prior radiotherapy, prior cancer related surgery and prior systemic therapy (with start/stop dates). 
In addition, date of most recent disease progression, if applicable should be documented. 
4. 
List only medications that are NOT part of the tumor harvest procedure. 
5. 
Vital signs will include pulse rate, respiratory rate, blood pressure, and temperature. On Day 0 (LN-144 infusion), vital signs will be monitored every 
30 minutes during infusion then hourly (+/-15 minutes) for 4 hours and then routinely (every 4 to 6 hours), unless otherwise clinically indicated, for up to 
approximately 24 hours post LN-144 infusion. 
6. 
CMV serology (as per local standard) at Screening, within 3 days of LN-144 infusion and thereafter as clinically indicated.  
7. 
Syphilis screening (as per local standard; e.g., Rapid Plasma Reagin [RPR] venereal disease research laboratory [VDRL] or other) at Screening, and 
thereafter as clinically indicated. 
8. 
Cardiac evaluation (stress thallium) for all patients (per current package insert for IL2). ECHO 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. 
9. 
Required for Screening, and at Baseline (Day -14). Anatomic regions included in CT scans or MRIs per disease history and clinical symptoms, (repeat the 
same CT and MRI series for all post-treatment tumor assessment [scheduled and unscheduled] as completed at Baseline [Day -14]). At Investigator 
discretion, the Baseline brain MRI and CT scans may be done as early as Day -21. Include neck if there is prior or suspected neck disease. MRI or PET scans 
will be allowed in lieu of CT for patients who have an intolerability to contrast media. The imaging modality and anatomic regions assessed used must be 
uniform for the duration of the study.  
10. Chem 20: [Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Phosphorus, Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, Total CK, Uric 
Acid]. Uric acid not collected on Days -7 through Day -1 and Day +1 through Day +4. 
11. Thyroid panel: TSH and Free T4. Obtain only at Screening, Day 14 and Month 24/End of Study (EOS) Visit, also at any visit as clinically indicated. 
12. Complete blood count with differential 
13. Dipstick urinalysis with culture, if indicated 
14. Calculate creatinine clearance using Cockcroft-Gault calculation 
15. Serum pregnancy test for women of childbearing potential   
16. HLA typing to be sent to central laboratory 
17. Pulmonary evaluation for all patients   
18. Patients with documented Grades 2 or greater diarrhea or colitis as a result of previous treatment with immune checkpoint inhibitor antibodies must have 
been asymptomatic for at least 6 months or had a normal colonoscopy post treatment, with uninflamed mucosa by visual assessment, prior to the start of 
nonmyeloablative lymphodepletion.  
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19. For detailed instructions on processing and shipment of tumor tissue to the Manufacturing Facility and Central Lab refer to protocol Section 6.2.1: Tumor 
Harvest and Processing Procedures, and the separate Tumor Procurement & Shipping Manuals. 
20. The ‘Authorization to Initiate Lymphodepletion’ form is to be completed by the Investigator between Day -10 to Day -8 and sent to the Sponsor or designee 
and then will be returned ot the site prior to the initiation of the lymphodepletion preconditioning regimen. 
21. LN-144 infusion to be given 1 to 2 days after the last dose of the preparative NMA-LD preconditioning regimen. All visits following LN-144 infusion (Day 
0) are calculated from that date. 
22. Initiate adjuvant IL-2 dosing no sooner than 3 hours, but no later than 24 hours after completion of the LN-144infusion and continue every 8 hours for up to 
protocol-defined maximum of 6 doses of adjuvant IL-2. IL-2 dosing is allowed for up to 4 days post LN-144 infusion to allow for proper management of 
IL-2 toxicity, if necessary. 
23. Continue until ANC >1000/mm3 X 3 consecutive days or per standard of care at the institution.   
24. The TMP/SMX DS schedule should be adjusted to QD 3 times per week (Monday, Wednesday, Friday) and continue for at least 6 months and until ANC 
>1000/mm3 or per standard of care at the institution 
25. Continue until ANC >1000/mm3 or per standard of care at the institution  
26. In patients positive for HSV continue until ALC >1000/mm3 or per standard of care at the institution    
27. Refer to the Laboratory Manual, for vacutainer tubes for peripheral blood drawnsto be sent to central laboratory. There is a ± 2-days window for the Immune 
Monitoring samples. If the scheduled visit is on a Friday, the Immune Monitoring sample should be collected on the prior Thursday. If the scheduled visit is 
on a Saturday or Sunday, the Immune Monitoring sample should be collected on the following Monday. 
28. Local tumor assessment (per RECIST 1.1)2 should be used for clinical treatment decisions, and may include photographic/caliper measurement of superficial 
dermal and subcutaneous lesion. 
29. Overall Survival (OS) Follow-Up will commence when each patient has their Month 24 or EOS visit and will consist of telephone contact made quarterly 
with the patient or designee up until 3 years following when Last Patient Last Dose (LPLD) of IL-2 is met. 
 
 
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1. 
Re-check of Inclusion/Exclusion Criteria in order to ensure that patient performance status and main eligibility criteria have not changed from time of 
Screening, a re-confirmation is to be perform and approved by Sponsor or designee. 
2. 
Physical examination (PE) will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory system, 
skin, psychiatric (mental status), general nutrition.  
3. 
List only medications that are NOT part of the tumor harvest procedure. 
4. 
Vital signs will include pulse rate, respiratory rate, blood pressure, and temperature. On Day 0 (LN-144 infusion), vital signs will be monitored every 30 
minutes during infusion then hourly (+/-15 minutes) for 4 hours and then routinely (every 4 to 6 hours), unless otherwise clinically indicated, for up to 
approximately 24 hours post LN-144 infusion. 
5. 
CMV serology (as per local standard) at Screening, within 3 days of LN-144 infusion and thereafter as clinically indicated.  
6. 
Syphilis screening (as per local standard; e.g., Rapid Plasma Reagin [RPR] venereal disease research laboratory [VDRL] or other) at Screening, and 
thereafter as clinically indicated. 
7. 
If the test was done within 2 weeks prior to screening, there is no need to repeat it. 
8. 
All appropriate scans should be repeted before enrollment in Cohort 3 if the latest scans are done ≥ 4 weeks prior to enrollment. If scans the latest scans were 
done within 4 weeks prior to enrollment they can be utilized for screening purpose. Required for Screening, and at Baseline (Day -14). Anatomic regions 
included in CT scans or MRIs per disease history and clinical symptoms, (repeat the same CT and MRI series for all post-treatment tumor assessment 
[scheduled and unscheduled] as completed at Baseline [Day -14]). At Investigator discretion, the Baseline brain MRI and CT scans may be done as early as 
Day -21. Include neck if there is prior or suspected neck disease. MRI or PET scans will be allowed in lieu of CT for patients who have an intolerability to 
contrast media. The imaging modality and anatomic regions assessed used must be uniform for the duration of the study.  
9. 
Chem 20: [Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Phosphorus, Alkaline Phosphatase, ALT/SGPT, AST/SGOT, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, Total CK, Uric 
Acid]. Uric acid not collected on Days -7 through Day -1 and Day +1 through Day +4 
10. Thyroid panel: TSH and Free T4. Obtain only at Screening, Day 14 and Month 24/End of Study (EOS) Visit, also at any visit as clinically indicated. 
11. Complete blood count with differential 
12. Dipstick urinalysis with culture, if indicated 
13. Calculate creatinine clearance using Cockcroft-Gault calculation 
14. Serum pregnancy test for women of childbearing potential   
15. The ‘Authorization to Initiate Lymphodepletion’ form is to be completed by the Investigator between Day -10 to Day -8 and sent to the Sponsor or designee 
and then will be returned ot the site prior to the initiation of the lymphodepletion preconditioning regimen. 
16. LN-144 infusion to be given 1 to 2 days after the last dose of the preparative NMA-LD preconditioning regimen. All visits following LN-144 infusion 
(Day 0) are calculated from that date. 
17. Initiate adjuvant IL-2 dosing no sooner than 3 hours, but no later than 24 hours after completion of the LN-144infusion and continue every 8 hours for up to 
protocol-defined maximum of 6 doses of adjuvant IL-2. IL-2 dosing is allowed for up to 4 days post LN-144 infusion to allow for proper management of 
IL-2 toxicity, if necessary. 
18. Continue until ANC >1000/mm3 X 3 consecutive days or per standard of care at the institution.   
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19. The TMP/SMX DS schedule should be adjusted to QD 3 times per week (Monday, Wednesday, Friday) and continue for at least 6 months and until ANC 
>1000/mm3 or per standard of care at the institution 
20. Continue until ANC >1000/mm3 or per standard of care at the institution 
21. In patients positive for HSV continue until ALC >1000/mm3 or per standard of care at the institution    
22. Refer to the Laboratory Manual, for vacutainer tubes for peripheral blood drawnsto be sent to central laboratory. There is a ± 2-days window for the Immune 
Monitoring samples. If the scheduled visit is on a Friday, the Immune Monitoring sample should be collected on the prior Thursday. If the scheduled visit is 
on a Saturday or Sunday, the Immune Monitoring sample should be collected on the following Monday. 
23. Local tumor assessment (per RECIST 1.1)2 should be used for clinical treatment decisions, and may include photographic/caliper measurement of superficial 
dermal and subcutaneous lesion. 
24. Overall Survival (OS) Follow-Up will commence when each patient has their Month 24 or EOS visit and will consist of telephone contact made quarterly 
with the patient or designee up until 3 years following when Last Patient Last Dose (LPLD) of IL-2 is met. 
 
 
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APPENDIX 3: 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 4: 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 5:  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 6: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT 
Expected toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
Stop Treatment 
** 
Chills 
3 
IV Meperidine 25-50 mg, 
IV q1h, prn, 
No 
No 
Fever 
3 
Acetaminophen 650 mg, 
po, q4h; Indomethacin 50-
75 mg, po, q8h 
No 
No 
Pruritus 
3 
Hydroxyzine HCl 10-20 
mg po q6h, prn; 
Diphenhydramine HCl 25-
50 mg, po, q4h, prn 
No 
No 
Nausea/ Vomiting/ 
Anorexia 
3 
Ondansetron 10 mg, IV, 
q8h, prn; Granisetron 0.01 
mg/kg IV daily prn; 
Droperidol 1 mg, IV q4-
6h, prn; Prochlorperazine 
25 mg q4h p.r., prn or 10 
mg IV q6h prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg, po, q3h, 
prn; Diphenoxylate HCl 
2.5 mg and atropine sulfate 
25 µg, po, q3h, prn; 
codeine sulfate 30-60 mg, 
po, q4h, prn 
If uncontrolled 
after 24 hours 
despite all 
supportive 
measures 
No 
Malaise 
3 or 4 
Bedrest interspersed with 
activity 
If other toxicities 
occur 
simultaneously 
No 
Hyperbilirubinemia 
3 or 4 
Observation 
If other toxicities 
occur 
simultaneously 
No 
Anemia  
3 or 4 
Transfusion with PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytopenia 
3 or 4 
Transfusion with platelets 
If uncontrolled 
despite all 
supportive 
measures 
No 
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Expected toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
Stop Treatment 
** 
Edema/Weight 
gain 
3  
Diuretics prn 
No 
No 
Hypotension 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled 
despite all 
supportive 
measures 
No 
Dyspnea 
3 or 4 
Oxygen or ventilatory 
support 
If requires 
ventilatory 
support 
No 
Oliguria 
3 or 4 
Fluid boluses or dopamine 
at renal doses 
If uncontrolled 
despite all 
supportive 
measures 
No 
Increased 
creatinine 
3 or 4 
Observation 
Yes (Grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 
Pleural effusion  
3 
Thoracentesis 
If uncontrolled 
despite all 
supportive 
measures 
No 
Bowel perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion 
therapy 
If uncontrolled 
despite all 
supportive 
measures 
No 
Elevated Troponin 
levels 
3 or 4 
Observation 
Yes 
If changes in LV 
function have not 
improved to 
baseline by next 
dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
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Expected toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
Stop Treatment 
** 
Elevated 
transaminases 
3 or 4 
Observation 
For Grade 4 
without liver 
metastases 
If changes have 
not improved to 
baseline by next 
dose 
Electrolyte 
imbalances 
3 or 4 
Electrolyte replacement 
If uncontrolled 
despite all 
supportive 
measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to Grade 2 or less by next re-treatment. 
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APPENDIX 7: 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 8: CYCLOPHOSPHAMIDE PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112l
bl.pdf 
 
 
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APPENDIX 9: FLUDARABINE PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020038s032lbl.pdf 
 
 
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APPENDIX 10: IL-2 (ALDESLEUKIN) PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf 
 
 
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APPENDIX 11: EORTC QLQ-C30 
 
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Lion Biotechnologies, Inc. 
 
LN-144 
Protocol C-144-01 
 
 
 
 
CONFIDENTIAL & PROPRIETARY 
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APPENDIX 12: SUMMARY OF CHANGES (MAJOR/MINOR) IN PROTOCOL C-144-01 
VERSION 6.0 (DATED, 13 MAY 2017) 
The major changes and purposes for revising the C-144-01 protocol are to: 
• 
Update of Primary and Secondary Objectives and Endpoints 
• 
Clarification of Exploratory Objectives and Endpoints 
• 
Adjustment of Eligibility Criteria for definition of Patient Population  
• 
Adjustment of Sample Size and rationale for determination 
• 
Clarification around requirements for Cohort 3 patients  
• 
Clarification around assessment and procedure timing 
• 
Numerous clarifications to Safety and Statistical sections 
• 
Updating of key Sponsor and designee contact information  
The minor changes and purposes for revising the C-144-01 protocol are to: 
• 
Numerous typographical changes were made for clarity and consistency 
• 
Minor administrative changes addressing clarification of operational issues 
A separate Summary of Changes document outlines noteworthy changes from Version 5.0 to 
Version 6.0, and includes rationale for the changes. 
 
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