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.

CONFIDENTIAL & PROPRIETARY 
Page 1 of 140 
Dated 23 March 2018 
             
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: 
Iovance Biotherapeutics, Inc. 
999 Skyway Rd, Suite 150 
San Carlos, CA 94070  
United States 
PROTOCOL VERSION: 
Final Version 7.0  
(Incorporating Amendments 1 through 6) 
PROTOCOL DATE: 
23 March 2018 
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 Iovance Biotherapeutics 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 Iovance Biotherapeutics, 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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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: 
Iovance Biotherapeutics, Inc. 
Version / Date of 
Protocol: 
Final Version 7.0 
(Incorporating Amendments 1 through 6),  
23 March 2018 
 
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 tumor 
Study Objectives: 
Primary Objective 
• 
To evaluate the efficacy of LN-144 in patients with metastatic 
melanoma using the objective response rate (ORR) as assessed by the 
Investigator per Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1. 
Secondary Objectives 
• 
To evaluate the efficacy endpoints of duration of response (DOR), 
disease control rate (DCR), and progression-free survival (PFS) as 
assessed by the Investigator per RECIST 1.1  
• 
To further evaluate efficacy of LN-144 therapy in patients with 
metastatic melanoma by assessing ORR, DOR, DCR, and PFS as 
assessed by the Independent Review Committee (IRC) per 
RECIST 1.1 
• 
To evaluate overall survival (OS) 
• 
To characterize the safety profile of LN-144 therapy 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 immune-related RECIST (irRECIST) 
criteria, as assessed by the IRC 
• 
To assess health-related quality of life (HRQoL) 
Study Design: 
Prospective, interventional multicenter study evaluating adoptive cell 
therapy (ACT) with autologous TIL infusion (LN-144) followed by 
interleukin-2 (IL-2) after a nonmyeloablative lymphodepletion (NMA-LD) 
preparative regimen.  
Dose and Treatment 
Schedule: 
The cell transfer therapy used in this study involves patients receiving a 
NMA-LD preparative regimen, consisting of cyclophosphamide 
intravenous (IV) (60 mg/kg × 2 doses) with mesna 15 mg/kg and 
fludarabine IV (25 mg/m2 × 5 doses), followed by infusion of tumor-
derived autologous TIL (LN-144) and administration of IL-2 at 
600,000 international units [IU]/kg approximately every 8 to 12 hours for 
up to a maximum of 6 doses, starting approximately 3 to 24 hours after 
completion of LN-144 infusion.  
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Patients will receive 1 course of LN-144 treatment in Cohort 1 
(noncryopreserved product or Gen 1) and Cohort 2 (cryopreserved product 
or Gen 2). Patients may enter Cohort 3 (retreatment cohort) if in the 
opinion of the Investigator they may benefit from the second treatment 
with TIL regimen and they meet protocol-specified criteria to receive 
retreatment. 
As of December 2017, the Sponsor has selected Gen 2 manufacturing as 
the method of choice and enrollment in Cohort 1 is closed, with all patients 
moving forward to be enrolled for initial LN-144 therapy in Cohort 2 only.  
Duration of Study 
Participation: 
Screening: Up to 4 weeks (28 days) from signing of the informed consent 
form (ICF) 
Enrollment: Upon tumor resection for TIL generation (1 day) 
Treatment Period: Up to 12 days, including NMA-LD (7 days) and 
LN-144 infusion followed by IL-2 (up to 4 days) 
Response Assessment Period:  
Patients will be evaluated for response at Week 6 (Day 42 ± 3 days) 
following the LN-144 infusion and every 6 weeks thereafter, for up to 
6 months (Week 26) post-LN-144 infusion. After this 6-month period, 
patients will be evaluated for response assessment every 3 months 
(12 weeks) until the following criteria are met: 
• 
Disease progression 
• 
Start of a new anticancer therapy 
• 
Withdrawal of consent 
• 
Lost to Follow-Up 
• 
Death 
Overall Survival Follow-Up Period: 
Overall survival (OS) follow-up will start after completion of the Response 
Assessment Period and will continue with telephone contact every 
3 months to obtain survival status and subsequent anticancer therapy 
information for up to 5 years for each patient from the last study treatment.  
Number of Study 
Centers: 
Approximately 60 clinical sites in the United States (US) and Europe 
Number of Planned 
Patients: 
The total number of patients to be enrolled across all cohorts will be 
approximately 85. A minimum of 60 patients who receive Gen 2 
cryopreserved LN-144 infusion product manufactured at Good 
Manufacturing Practices (GMP) facilities in the US and Europe and who 
complete treatment. Treatment completion is defined as having received 
LN-144 infusion followed by at least 1 dose of IL-2. Patients who 
participate in initial TIL therapy in Cohort 1 or Cohort 2 may enter a third 
treatment cohort (Cohort 3) in which approximately 10 patients will be 
retreated with a second manufacturing/administration of LN-144 
(TIL therapy).  
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Study Population: 
Diagnosis and Main 
Criteria for Inclusion: 
a. 
Patients with unresectable or metastatic melanoma (Stage IIIc or 
Stage IV) who progressed following ≥ 1 lines of prior systemic 
therapy, including immune checkpoint inhibitor (eg, anti-PD-1), and 
if BRAF mutation-positive, after BRAF inhibitor systemic therapy. 
Patients must have no other therapy options that are expected to have 
significant benefit in the opinion of the Investigator and must have:  
• At least 1 measurable target lesion, as defined by RECIST 1.1. 
Lesions in previously irradiated areas should not be selected as 
target lesion, unless treatment was ≥ 3 months prior, and there 
has been demonstrated disease progression in the lesion 
• At least 1 resectable target lesion to generate TIL of a minimum 
1.5 cm in diameter post-resection; surgical removal with minimal 
morbidity (defined as any procedure for which expected 
hospitalization is ≤ 3 days)  
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 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 12 months after receiving last 
protocol-related therapy 
Approved methods of birth control are as follows: 
• Combined (estrogen and progestogen containing) hormonal birth 
control associated with inhibition of ovulation: oral; intravaginal; 
transdermal 
• Progestogen-only hormonal birth control associated with 
inhibition of ovulation: oral; injectable; implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• True sexual abstinence when this is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence (eg, calendar 
ovulation, symptothermal, post-ovulation methods) is not 
acceptable. 
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: 
• Serum alanine transaminase (ALT)/ serum glutamic-pyruvic 
transaminase (SGPT) and aspartate transaminase (AST)/serum 
glutamic oxaloacetic transaminase (SGOT) ≤ 3 times the upper 
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limit of normal [ULN]), patients with liver metastasis ≤ 5 times 
ULN 
• An estimated creatinine clearance (eClCr) ≥ 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 human immunodeficiency virus 
(HIV) antibody, hepatitis B antigens, and hepatitis C antibody or 
antigen 
i. 
Patients must have recovered from all prior therapy-related adverse 
events (AEs) to ≤ Grade 1 (per Common Terminology Criteria for 
Adverse Events [CTCAE] v4.03), except for alopecia or vitiligo, 
prior to enrollment (tumor resection), with a washout period from 
prior anticancer therapy(ies) to the start of planned NMA-LD of a 
minimum duration detailed as follows:  
• Targeted therapy: prior targeted therapy with a MEK/BRAF or 
other-directed agent, is allowed provided the washout period is a 
≥ 21 days or 5 half-lives, whichever is longer prior to the start of 
NMA-LD 
• Chemotherapy: adjuvant, neoadjuvant or definitive 
chemotherapy/ chemoradiation is allowed provided the washout 
period is ≥ 21 days or 5 half-lives, whichever is longer prior to 
the start of NMA-LD 
• Immunotherapy: prior checkpoint-targeted therapy with an anti-
CTLA-4/anti-PD-1, other monoclonal antibody (mAb), or 
vaccine is allowed if disease progression is confirmed prior to or 
within the washout period of ≥ 21 days before the start of 
NMA-LD 
• Palliative radiation therapy is permitted between biopsy and 
NMA-LD if it does not involve lesions being selected as target or 
nontarget  
• Patients may undergo preplanned procedures if within 2 to 
3 weeks prior to the start of NMD-LD 
j. 
Patients with documented Grade 2 or higher 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 planned tumor resection 
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 
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Main Criteria for 
Exclusion: 
a. 
Patients with melanoma of uveal/ocular origin 
b. 
Patients who have received an organ allograft or 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 may be 
considered for enrollment after discussion with the Medical 
Monitor, and must be stable for ≥ 2 weeks prior to the start of 
NMA-LD 
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 
symptoms 
f. 
Patients who have active medical illness(es) that in the opinion of the 
Investigator would pose increased risk for study participation that 
may include active systemic infections, such as syphilis, or any other 
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 [SCID] or acquired 
immunodeficiency syndrome [AIDS]) 
h. 
Patients who have a history of hypersensitivity to any component or 
excipient of the TIL therapy and other study drugs:  
• 
NMA-LD (cyclophosphamide, mesna, and fludarabine) 
• 
IL-2 
• 
Antibiotics of the aminoglycoside group (ie, streptomycin, 
gentamicin) 
• 
Any component of the TIL infusion product formulation 
including dimethyl sulfoxide [DMSO], human serum albumin 
[HSA], IL-2, and dextran-40  
i. 
Patients who have a left ventricular ejection fraction (LVEF) < 45% 
or New York Heart Association (NYHA) functional classification 
> Class 1 at Screening. All patients must have echocardiogram 
(ECHO) or multiple gated acquisition scan (MUGA) at Screening. 
For patients ≥ 60 years or patients who have a history of ischemic 
heart disease, chest pain, or clinically significant atrial and/or 
ventricular arrhythmias, a cardiac stress tests must be performed 
showing LVEF ≥45%, and if any wall movement abnormalities, 
they must be reversible. 
j. 
Patients who have obstructive or restrictive pulmonary disease and 
have a documented FEV1 (forced expiratory volume in 1 second) of 
≤ 60% 
 
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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 nonmelanoma 
skin cancer that has been adequately treated) 
l. 
Patients who have been shown to be BRAF mutation positive (V600), 
but have not received prior systemic therapy with a BRAF-directed 
kinase inhibitor 
m. 
Patients who have received a live or attenuated vaccine within 
28 days of the start of NMA-LD 
n. 
Patients whose cancer requires immediate attention or who would 
otherwise suffer a disadvantage by participating in this trial 
o. 
Patients protected by the following constraints: 
• 
Hospitalized persons without consent or persons deprived of 
liberty because of a judiciary or administrative decision 
• 
Adult persons with a legal protection measure or persons who 
cannot express their consent 
• 
Patients in emergency situations who cannot consent to 
participate in the trial 
Treatment Cohorts: 
LN-144 (autologous TIL) infusion is preceded by a NMA-LD preparative 
regimen of cyclophosphamide and fludarabine, and followed by IL-2, as 
an open-label treatment 
Cohort 1: LN-144 process without cryopreservation of the final TIL 
product (Gen 1 infusion product) 
Cohort 2: LN-144 process with cryopreservation of the final TIL product 
(Gen 2 infusion product) 
Cohort 3: Retreatment cohort: patients from Cohort 1 or Cohort 2 may 
rescreen for a second TIL regimen therapy if they meet all Inclusion and 
Exclusion Criteria (except exclusion criterion b). These patients may have 
a second tumor resection, especially when new lesions are available and 
feasible for resection. The decision for enrollment in Cohort 3 will be 
based on discussion between Principal Investigator and a Medical Monitor. 
As of December 2017, all patients receiving retreatment in Cohort 3 will 
receive the Gen 2 LN-144 infusion product.  
Discontinuation from 
Treatment: 
Criteria for discontinuation from treatment: 
• 
Grade 3 or greater drug-related immune AEs that involve vital organs 
(heart, kidneys, brain, eye, liver, colon, adrenal gland, lungs) with 
symptoms emerging following 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  
• 
Meeting criteria for permanent discontinuation of IL-2 treatment  
• 
Determination by the Investigator that continued treatment is not in 
the best interest of the patient 
• 
Administration of prohibited concomitant medication 
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Discontinuation from the 
Study 
Criteria for discontinuation from the study at any time:  
• 
Full withdrawal of consent by patient  
o 
Every effort should be made to continue overall survival 
follow-up 
• 
Administration of any other anticancer therapy(ies)  
o 
Every effort should be made to continue overall survival 
follow-up 
• 
Lost to follow-up after 3 documented attempts to contact the patient 
• 
Death 
• 
Study terminated by the Sponsor 
Efficacy Assessment: 
The descriptive summary of the ORR, DOR, DCR, and PFS per cohort 
will be used to determine the potential efficacy of LN-144, as assessed by 
the Investigator per RECIST 1.1. Estimation of OS will depend on the date 
of death or the last known alive status.  
Safety Assessment: 
Adverse events (AEs) of any attribution will be collected from the time the 
patient signs the ICF up until completion of the response assessment 
period and/or the start of a new anticancer therapy. All AEs attributed to 
treatment will be collected from signing of the ICF from the start of a new 
anticancer therapy, lost to follow-up, or withdrawal of consent, whichever 
occurs first. Treatment-emergent adverse events (TEAEs), defined from 
the LN-144 infusion to 30 days thereafter, and clinical laboratory data will 
be evaluated to assess the safety of this treatment. 
Overview of Statistical 
Plan 
The primary statistical plan of analysis is based on estimation of efficacy 
and safety parameters will be performed by cohort. There is no planned 
statistical comparison among cohorts.  
Patients meeting RECIST 1.1 criteria for a confirmed complete (CR) or 
partial (PR) response and will be classified as responders in the analysis of 
the ORR. The best overall response result will be summarized using a 
point estimate and its 2-sided 95% confidence limits. 
All time-to-event efficacy endpoints will use the Kaplan-Meier method to 
summarize the data. The time origin for all such analyses (except for 
response duration) will be the date on which patients began treatment with 
LD.  
The assessment of safety data will be descriptive and based on the 
summarization of TEAEs, AEs, and serious AEs (SAEs), leading to 
discontinuation from treatment and the study, vital signs, physical 
examinations, and clinical laboratory tests. 
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 reason, will be included in the original cohort for efficacy 
and safety analyses. There will be no formal comparisons among cohorts. 
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Sample Size 
Consideration: 
The planned number of patients is approximately 85 including 60 patients 
in the Efficacy Analysis set who received either US or European 
manufactured Gen 2 LN-144 infusion product in Cohort 2. The lower 95% 
confidence limit for ORR is estimated per the Wilson Score method. 
The maximum half width of the 2-sided confidence limit is less than 
12.3% when ORR is expected to range from 20% to 50%.  
The primary analysis will occur when more than 60 patients have been 
followed for a minimum of 6 months. This allows sufficient time for 
disease-controlled patients (SD or better) to demonstrate emergence and 
durability of response.  
DSMB Safety 
Assessments: 
An independent 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. As of November 2017, the DSMB 
had reviewed the data from Cohort 1 and Cohort 2 and recommended to 
continue enrollment without any changes to the clinical study protocol. 
Additional evaluations of safety data may be specified in the DSMB 
charter. 
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Figure 1 
Study Flowchart (All Cohorts) 
 
 
Abbreviations: NMA-LD = nonmyeloablative lymphodepletion; TIL = tumor infiltrating lymphocytes; IL-2 = interleukin-2; OS = overall survival; FU = follow up;  
Gen 1 = generation 1; Gen 2 = generation 2 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
  
  
 
 
   
 
    
 
 
  
   
 
 
   
 
 
 
 
 
 
 
 
  
  
   
  
  
  
 
 
 
  
 
 
  
 
  
 
 
 
   
 
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TABLE OF CONTENTS 
SPONSOR PROTOCOL SIGNATURE PAGE ..................................................................2 
INVESTIGATOR PROTOCOL SIGNATURE PAGE .......................................................3 
SPONSOR MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION ........4 
PROTOCOL SYNOPSIS ....................................................................................................5 
TABLE OF CONTENTS ...................................................................................................14 
LIST OF TABLES .............................................................................................................17 
LIST OF FIGURES ...........................................................................................................17 
LIST OF ABBREVIATIONS ............................................................................................18 
1 
INTRODUCTION .................................................................................................21 
1.1 
Background ................................................................................................................... 21 
1.2 
Overview of Adoptive Cell Transfer for Metastatic Melanoma ................................... 25 
1.3 
LN-144 TIL Therapy .................................................................................................... 28 
1.4 
Production and Expansion of Tumor Infiltrating Lymphocytes ................................... 28 
2 
STUDY DESIGN...................................................................................................31 
2.1 
Description of the Study ............................................................................................... 31 
2.2 
Description of the Study Centers .................................................................................. 32 
3 
STUDY OBJECTIVES AND ENDPOINTS .........................................................32 
3.1 
Study Objectives ........................................................................................................... 32 
3.1.1 
Primary Objective .......................................................................................................... 32 
3.1.2 
Secondary Objectives ..................................................................................................... 32 
3.1.3 
Exploratory Objectives................................................................................................... 32 
3.2 
Study Endpoints ............................................................................................................ 33 
3.2.1 
Primary Endpoints .......................................................................................................... 33 
3.2.2 
Secondary Endpoints ...................................................................................................... 33 
3.2.3 
Exploratory Endpoints ................................................................................................... 33 
4 
SELECTION OF PATIENT POPULATION ........................................................34 
4.1 
Inclusion Criteria .......................................................................................................... 34 
4.2 
Exclusion Criteria ......................................................................................................... 37 
4.3 
Number of Patients ....................................................................................................... 39 
4.3.1 
Rescreening Patients ...................................................................................................... 40 
4.3.2 
Patient Cohorts ............................................................................................................... 40 
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND 
NONDRUG THERAPIES .....................................................................................41 
5.1 
Prior Treatment and Concomitant Medications ............................................................ 41 
5.2 
Prohibited and Permitted Medications During Study Treatment .................................. 41 
5.2.1 
Prohibited Treatment ...................................................................................................... 41 
5.2.1.1 
Permitted Medications – Use with Caution ................................................................... 42 
6 
STUDY PROCEDURES .......................................................................................42 
6.1 
Screening (up to 28 days from signing the ICF) ........................................................... 42 
6.2 
Enrollment and Tumor Resection ................................................................................. 45 
6.2.1 
Tumor Harvest and Processing Procedure ..................................................................... 45 
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6.2.1.1 
Additional Tumor Tissue from Resected Tumor .......................................................... 47 
6.2.2 
Immune Monitoring and Phenotyping (Sequencing of Tumor and 
PBMC/Cell-Free DNA) ................................................................................................. 47 
6.3 
Baseline (Day -21 to Day -14) ...................................................................................... 47 
6.4 
Patients Who Do Not Receive a LN-144 Infusion ........................................................ 49 
6.5 
Day -7............................................................................................................................ 49 
6.6 
Day -6............................................................................................................................ 52 
6.7 
Day -5 to Day -1 ........................................................................................................... 53 
6.8 
Day 0 (Infusion Day) .................................................................................................... 54 
6.8.1 
Investigational Product................................................................................................... 56 
6.8.1.1 
LN-144 Infusion ............................................................................................................ 57 
6.9 
Treatment Period ........................................................................................................... 58 
6.9.1 
Day 1, Day 2, Day 3, and Day 4 .................................................................................... 58 
6.10 
Visits Prior to Start of Response Assessment Period .................................................... 60 
6.10.1 
Day 14 and Day 28 (Both Visits ± 3 Days [(Calculated from Day 0, TIL Infusion) ..... 60 
6.11 
Response Assessment Period ........................................................................................ 61 
6.11.1 
Every 6 Weeks (Week 6 [Day 42]; Week 12 [Day 84]Week 18 [Day 126], and 
Month 6 [Week 24, Day 168] [All Visits ± 3 Days Calculated from Day 0, TIL 
Infusion]) ........................................................................................................................ 62 
6.11.2 
Every 3 Months After Month 6 Until End of Study Visit (All Visits ± 1 Week, 
Calculated from Day 0, TIL Infusion) or End of Study (EOS) Visit ............................. 64 
6.12 
Overall Survival Follow-Up Period .............................................................................. 66 
6.13 
Treatment Discontinuation (Following LN-144 Infusion) ............................................ 66 
6.14 
Expected Toxicities and Treatment Guidelines ............................................................ 66 
6.14.1 
LN-144 ........................................................................................................................... 66 
6.14.2 
IL-2 Administration ....................................................................................................... 67 
6.15 
Treatment Guidelines for Toxicity Management .......................................................... 68 
6.15.1 
Expected Toxicities with LN-144 .................................................................................. 68 
6.15.2 
Expected Toxicities with Cyclophosphamide and Fludarabine ..................................... 69 
6.15.2.1 Hemorrhagic Cystitis Prophylaxis ................................................................................ 70 
6.15.3 
Nonmyeloablative Lymphodepletion Regimen Toxicity Management ......................... 70 
6.15.4 
Expected Toxicities with IL-2 ........................................................................................ 70 
6.15.4.1 Decreased Mental Status with IL-2 ............................................................................... 70 
6.15.4.2 Pulmonary Risk ............................................................................................................. 70 
6.15.4.3 Cardiac Arrhythmias and Myocarditis .......................................................................... 71 
6.15.4.4 Capillary Leak Syndrome ............................................................................................. 71 
6.15.5 
Blood Product Support ................................................................................................... 71 
6.15.5.1 Heparin-Induced Thrombocytopenia ............................................................................ 71 
6.15.6 
Renal Toxicity ................................................................................................................ 71 
6.16 
Infection Prophylaxis .................................................................................................... 72 
6.16.1 
Pneumocystis jiroveci Pneumonia ................................................................................. 72 
6.16.2 
Herpes Virus Prophylaxis .............................................................................................. 72 
6.16.3 
Fungal Prophylaxis (Fluconazole) ................................................................................. 73 
6.16.4 
Empiric Antibiotics ........................................................................................................ 73 
6.16.5 
Sepsis ............................................................................................................................. 73 
7 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF 
PATIENTS .............................................................................................................74 
7.1 
Treatment Completion .................................................................................................. 74 
7.2 
Criteria for Early Discontinuation from Treatment ...................................................... 74 
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8 
STUDY DRUG INFORMATION .........................................................................75 
8.1 
Investigational Product ................................................................................................. 75 
8.2 
Qualitative Composition of LN-144 ............................................................................. 75 
8.3 
Manufacturing Process .................................................................................................. 75 
8.4 
Final Investigational Product Container ....................................................................... 76 
8.5 
Transport ....................................................................................................................... 76 
8.6 
Receipt at Clinical Site and Administration .................................................................. 76 
8.7 
Retreatment with LN-144 ............................................................................................. 79 
9 
STUDY ASSESSMENTS .....................................................................................79 
9.1 
Tumor Assessments ...................................................................................................... 79 
9.1.1 
Response Criteria ........................................................................................................... 81 
9.1.1.1 
Evaluation of Target Lesions ........................................................................................ 81 
9.1.1.2 
Evaluation of Nontarget Lesions ................................................................................... 82 
9.1.1.3 
Evaluation of Best Overall Response ............................................................................ 82 
9.1.1.4 
Confirmatory Measurement/Duration of Response ...................................................... 83 
9.2 
Biomarkers .................................................................................................................... 83 
9.3 
Data Safety Monitoring Board ...................................................................................... 83 
10 
STATISTICAL AND ANALYTICAL PLANS ....................................................84 
10.1 
Introduction ................................................................................................................... 84 
10.2 
Study Analysis Sets ....................................................................................................... 84 
10.2.1 
Safety Analysis Set ........................................................................................................ 84 
10.2.2 
Efficacy Analysis Set ..................................................................................................... 84 
10.2.3 
Cohort 3 .......................................................................................................................... 85 
10.3 
Endpoints ...................................................................................................................... 85 
10.3.1 
Primary Endpoint ........................................................................................................... 85 
10.3.2 
Secondary Endpoints ...................................................................................................... 85 
10.3.3 
Exploratory Endpoints ................................................................................................... 86 
10.4 
Sample Size Consideration ........................................................................................... 86 
10.5 
Analysis Methods .......................................................................................................... 87 
10.5.1 
Baseline Demographics and Clinical Characteristics ..................................................... 87 
10.5.2 
Primary Endpoint ........................................................................................................... 87 
10.5.3 
Secondary Endpoints ...................................................................................................... 87 
10.5.4 
Safety Analysis .............................................................................................................. 87 
10.5.5 
Other Planned Analyses ................................................................................................. 88 
11 
CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS........................88 
11.1 
Medications Administered during the Study................................................................. 88 
11.2 
LN-144 Treatment ........................................................................................................ 88 
12 
ADVERSE EVENTS .............................................................................................89 
12.1 
Definitions ..................................................................................................................... 89 
12.1.1 
Adverse Event ................................................................................................................ 89 
12.1.2 
Serious Adverse Event ................................................................................................... 90 
12.1.3 
Relationship to Study Drug ............................................................................................ 91 
12.1.4 
Severity .......................................................................................................................... 92 
12.2 
Reporting Procedures for Adverse Events .................................................................... 92 
12.2.1 
All Adverse Events ........................................................................................................ 92 
12.2.1.1 Serious Adverse Events................................................................................................. 93 
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13 
ADMINISTRATIVE REQUIREMENTS .............................................................97 
13.1 
Adherence to the Protocol ............................................................................................. 97 
13.2 
Record Retention .......................................................................................................... 97 
13.3 
Data Quality Assurance ................................................................................................ 98 
13.4 
Data Handling and Recordkeeping ............................................................................... 99 
13.4.1 
Regulatory Approval and Documentation...................................................................... 99 
13.4.2 
Electronic Data ............................................................................................................. 100 
13.4.3 
Data Handling and Recordkeeping .............................................................................. 100 
13.4.3.1 Electronic Case Report Form (eCRF) Completion ..................................................... 100 
13.5 
Study Completion/Termination ................................................................................... 101 
13.5.1 
Study Completion ........................................................................................................ 101 
13.5.2 
Study Termination ........................................................................................................ 101 
13.6 
Monitoring .................................................................................................................. 101 
14 
INVESTIGATOR REGULATORY OBLIGATIONS ........................................101 
14.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ..................... 101 
14.2 
Informed Consent ........................................................................................................ 102 
14.3 
Patient Data Protection................................................................................................ 103 
14.4 
Adverse Event Reporting ............................................................................................ 104 
14.5 
Investigator ................................................................................................................. 104 
14.6 
Confidentiality ............................................................................................................ 104 
14.7 
Publications ................................................................................................................. 105 
15 
REFERENCES ....................................................................................................106 
APPENDICES .................................................................................................................111 
 
LIST OF TABLES  
Table 1 
Time Point Response: Patients with Target (± Nontarget) Disease .......... 82 
Table 2 
Time Point Response: Patients with Nontarget Disease Only .................. 83 
 
LIST OF FIGURES  
Figure 1 
Study Flowchart (All Cohorts).................................................................. 13 
Figure 2 
LN-144 Manufacturing Process ................................................................ 31 
 
 
 
 
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LIST OF ABBREVIATIONS 
ABX 
antibiotics 
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 
BMI 
body mass index 
BRAF 
proto-ongcogene B-Raf 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CD4+/CD8+ 
cluster of differentiation 4/8 
CFR 
Code of Federal Regulations 
CK 
creatinine clearance 
ClCr 
clearance creatinine 
CLS 
capillary leak syndrome 
CMO 
Contract Manufacturing Organization  
CMV 
cytomegalovirus 
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response 
CT 
computed tomography 
CTL 
cytotoxic T lymphocyte 
CTLA 
cytotoxic T lymphocyte-associated antigen 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events Version 4.03 
CY 
cyclophosphamide 
DC 
dendritic cell 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein-Barr virus 
ECHO 
echocardiogram 
eClCr 
estimated creatinine clearance using Cockroft-Gault formula 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EKG 
electrocardiogram 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire - Core 30 instrument 
EOS 
end of study 
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ETV 
early termination visit 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG-PET 
flurodeoxyglucose positron emission tomography 
FEV1 
forced expiratory volume in 1 second 
FFPE 
formalin-fixed, paraffin-embedded  
FU 
follow up 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
Gen 
generation 
GMP 
Good Manufacturing Practices 
Gp100 
glycoprotein 100 
HBcAg 
hepatitis B core antibody (IgM) 
HBsAg 
hepatitis B surface antigen 
β-HCG 
β human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIT 
heparin-induced thrombocytopenia 
HIV 
human immunodeficiency virus 
HRQoL 
health related quality of life 
HSA 
human serum albumin 
HSV-1 
herpes simplex virus-1 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL-2 
interleukin-2 (also known as “aldesleukin”) 
IND 
Investigational New Drug (Application) 
IP 
investigational product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IU 
international unit 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
LD 
lymphodepletion 
LDH 
lactate dehydrogenase 
LN-144 
autologous tumor infiltrating lymphocytes 
LPLD 
last patient last dose 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MART-1 
myristylated Akt 
MAGE 
melanoma antigen gene 
MEK 
mitogen-activated extracellular signal-regulated kinase 
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MNC 
mononucleated cells 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA (ribonucleic acid) 
MUGA 
multiple gated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NMA 
nonmyeloablative 
NY-ESO-01 
immunogenic cancer testis antigen 
OKT 
muromonab CD3 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PO 
per Os (by mouth) 
PR 
partial response 
PRBC 
packed red blood cells 
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 
SCID 
severe combined immunodeficiency disease  
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results Program 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
TCR 
T-cell antigen receptor  
TEAE 
treatment-emergent adverse event 
TH 
tumor harvested patient population 
TIL 
tumor infiltrating lymphocyte 
TME 
tumor microenvironment 
TMP-SMX DS 
trimethoprim-sulfamethoxazole double strength 
TRP-1 
tyrosine-related protein-1 
TSH 
thyroid-stimulating hormone 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
VCA 
viral capsid antigen 
VDRL 
venereal disease research laboratory 
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1 
INTRODUCTION 
1.1 
Background 
An estimated 232,000 newly diagnosed cases of melanoma skin cancers occur globally 
each year, making it the fifth most common malignancy in men and sixth most common 
malignancy in women. [1] Unlike other malignancies, the incidence of melanoma is 
increasing by more than 3.2% and 2.4% per year in males and females, respectively. [2] 
Globally, the incidence rate varies with 20 to 30 new melanoma cases per 100,000 people 
in the United States (US), compared to ≤10 to 25 new melanoma cases per 100,000 people 
in the European Union (EU), and with the highest incidence of 50 to 60 per 
100,000 inhabitants in Australia. [3] One estimate predicts 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 United Kingdom 
(UK). [4, 5] Of interest, individuals under the age of 45 years account for 25% of all new 
melanoma cases. [1] 
The National Cancer Institute’s Surveillance, Epidemiology, and End Results uptake 
(SEER) Program estimates that 9,730 deaths due to melanoma have occurred in 2017 in 
the US, despite the approvals of ipilimumab in 2011, pembrolizumab and nivolumab 
in 2014, and the rapid uptake of these immunotherapeutic agents. [2] The 5-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. [4] 
Current melanoma treatment guidelines are similar in Europe, the US, Canada, Australia, 
and New Zealand. [6] Approved first-line treatments for metastatic melanoma include 
immunotherapeutic strategies blocking PD-1 (pembrolizumab, nivolumab), or combining 
nivolumab- with the CTLA-4 blocker ipilimumab, or chemotherapy with agents targeting 
specific activating mutations in the BRAF pathway (eg, vemurafenib, dabrafenib, 
trametinib). Following disease progression, patients can receive additional treatment with 
anti-PD1 monotherapy; ipilimumab combination therapy; ipilimumab monotherapy; 
BRAF and/or MEK inhibitors, if BRAF mutant; high-dose aldesleukin (interleukin-2; 
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IL-2); chemotherapy [eg, dacarbazine, temozolomide, paclitaxel, cisplatin, carboplatin, 
vinblastine; or imatinib for KIT-mutant melanoma] (NCCN Guidelines 
Version 2.2016). [7] 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. [8]  
Until recently, high-dose aldesleukin was the only Food and Drug Administration 
(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 responses (CRs) observed in up to 6% of treated patients. [9] 
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. [10, 11] 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 are administered in 
combination, although the CR rate remains low at 8.9%. [Opdivo® (nivolumab) Label, 
FDA, October 2016] Retreatment of patients who progressed post anti-PD-1 therapy with 
additional checkpoint inhibitors is often selected as a treatment option; however, overall 
response rates of 16% and 21% are the best reported for the ipilimumab or ipilimumab 
plus nivolumab, respectively. [12] 
Use of the immune checkpoint inhibitors is associated with a spectrum of immune-related 
adverse events (AEs), including pneumonitis, colitis, hepatitis, nephritis, and renal 
dysfunction. [13, 14] 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. [10, 14] 
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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 
100,000 in 2011 and remained at this level in 2015. [15] 
Cell transfer therapy with autologous tumor-infiltrating lymphocyte (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. [16-18] present, however, only a limited number of 
clinical centers in the US with access to suitable Good Manufacturing Practice (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 other institutions. Iovance Biotherapeutics, Inc. is utilizing the TIL manufacturing 
method developed by Dr. Steven A. Rosenberg’s team at the National Cancer Institute 
(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 
anticancer therapeutic is based on observations that 1) the immune system is adept at 
producing antigen-specific anti-tumor cytotoxic T-cell responses that have demonstrated 
antitumor reactivity both in vitro and in vivo, the latter having also demonstrated 
therapeutic efficacy; 2) such autologous cellular therapies represent the terminal 
engagement of antigen-specific effector mechanisms mediated by the pro-inflammatory 
immunologic cascade, which are subject to significantly fewer adverse autoimmune 
sequalae than more broad-spectrum, nonspecific, 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; [1, 2][19, 20] 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; [21-23] 
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and 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. [17]  
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. [24-26] 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. [27] The latter are now 
thought to be the key type of antigen recognized by TIL mediating enhanced tumor 
eradication during TIL therapy. [28] 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. [29-33]  
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 2 stages. Iovance 
Biotherapeutics, Inc. 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 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). 
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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, 2-agent NMA-LD preparative 
regimen, post-infusion IL-2 (up to a maximum of 6 doses), and the use of minimally 
cultured (“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 Response 
Evaluation Criteria in Solid Tumors (RECIST) 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. 
[14, 34]  
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. [35] 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. [36-38] 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. [39, 40] 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 myristylated Akt 
(MART-1), glycoprotein 100 (gp100), melanoma associated antigen (MAGE-1), 
tyrosinase, tyrosine-related protein (TRP-1), TRP-2 and immunogenic cancer testis 
antigen (NY-ESO-1). [39, 41] The presence of these antigens on melanoma tumor cells 
has led to immunotherapy regimens that focused on the ability of effector T cells to 
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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 cell population in vitro has led to the 
development of adoptive cell transfer (ACT) regimens for the 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. [42, 43] 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 re-infuse these expanded cells as a 
potential therapeutic back into the patient. Some of the first clinical trials performed in 
individual centers in the US and Europe, such as the 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. [44-47] 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. [47] 
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% to 60%. [48-50] This prior CY preconditioning 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 
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persistence and anti-tumor activity of transferred TIL expanded from implanted murine 
tumors was found when host mice were treated with CY or non-lethally irradiated to 
deplete endogenous lymphocytes. [19, 50] Furthermore, this prior LD preconditioning 
regimen with CY was also later found to remove suppressive CD4+ regulatory cells 
(CD4-Foxp3 of cancer patients have also been 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. [51-54] Alternatively, prior 
depletion of lymphocytes may create ‘space’ for the adoptively transferred cells within 
the lymphocyte compartment. [55] 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, IL-7, IL-15, 
and IL-21. [56] The success of prior LD in animal models and the use of single agent CY 
preconditioning in initial TIL therapy trials, led to testing of more intensive 
preconditioning 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. [57, 58] 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 LD 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. [57, 58]  
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 the NCI, immunotherapy of patients with advanced melanoma with 
autologous TIL therapy has induced durable ORRs by Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.0 criteria in 54 of 101 (54%) patients, including heavily 
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pretreated patients 24 of whom (24%) achieved a CR. Nineteen of the 24 CRs were 
ongoing beyond 3 years of follow-up. [10, 11]  
1.3 
LN-144 TIL Therapy 
LN-144 is an autologous, ready-to-infuse TIL, therapy that is comparable to that 
developed by Dr. Steven A. Rosenberg and colleagues at the NCI.  
Several preconditioning 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 NMA-LD regimen 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 [IP]) followed 
by IL-2. Details for the tumor resection and LN-144 administration are provided in the 
Tumor Procurement & Shipping Manual and Pharmacy & Administration Manual. 
The final IP will be available for administration in one of several volumes for infusion, as 
described in the Pharmacy & Administration Manual.  
1.4 
Production and Expansion of Tumor Infiltrating Lymphocytes 
The LN-144 active biologic is composed of viable TIL 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 °C to 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-REP 
with human recombinant IL-2 (Proleukin®) to generate a suitable number of viable cells 
to move into the REP phase. In the Gen 1 process, pre-REP cells are cryopreserved 
allowing for flexibility in the subsequent scheduling of TIL therapy administration into 
the patient from which they were originally derived. In the shorter Gen 2 process, 
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pre-REP cells are taken directly into the REP. The REP further expands the cells in the 
presence of IL-2 and OKT3 (muromonab-CD3, murine monoclonal antibody to human 
CD3) with irradiated allogenic mononuclear cells as feeder cells. The REP-expanded 
cells (TIL) are then harvested, washed, and formulated in a blood transport/infusion bag 
for shipment by courier to the clinical site. The dosage form of the IP is a live cell 
suspension of either noncryopreserved (Gen 1, Cohort 1) or cryopreserved (Gen 2, 
Cohort 2) autologous TIL for intravenous infusion into the patient from which they were 
derived.  
During the TIL manufacturing process at a timepoint that coincides with protocol study 
Day -8, the number of TIL successfully expanded will be determined. If the number of 
TIL is sufficient for administration (≥ 250 x 106 cells), approval by the Sponsor will be 
granted to begin the NMA-LD regimen (2 days of cyclophosphamide at Day -7 and 
Day 6) followed by 5 days of fludarabine at Day -5 through Day -1. Beyond the point for 
NMA-LD approval, the cell number continues to increase for the duration of culture of 
the TIL product. Clinical experience to date with LN-144 indicates that as few as 
1 x 109 cells can induce an antitumor response.  
The lower limit of 250 x 106 for the TIL manufacturing process has been selected based 
the following research data. While the lower dose limit of efficacious TIL has not been 
defined, the normal response to infection by the body is the generation of approximately 
30 x 106 to 200 x 106 antigen-specific CD8+ cytotoxic T-cells. [59] Based on this 
information, a total cell dose of 250 x 106 would include an approximate number of 
tumor antigen-specific CD8+ T-cells within this physiologic range. To date in patients 
treated on Iovance-sponsored clinical studies, a clinically meaningful response has been 
observed with a total cell count on this order (ie, 1.2 x 109). Therefore, following LD, the 
risk/benefit ratio favors the administration of at least 250 x 106 TIL. 
While an upper limit for viable cells administered for TIL infusion has not been 
established, 150 x 109 viable cells has been chosen as a conservative amount based on the 
number of cells administered in several studies. [60]  
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Cohort 1 (LN-144 manufacturing process without final cryopreservation) 
This final cellular IP 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 
≤75×109 
or 
2) 500 mL (in a 600-mL capacity infusion bag) when the total TIL harvested are 
≤150 × 109 
Cohort 2 (LN-144 manufacturing process with final cryopreservation).  
This final cellular IP is formulated in 50% 10® in Plasma-Lyte A™.  
1) Up to 4 infusion bags containing up to approximately 100 to 150 mL of 
thawed cells. The number of infusion bags is dependent on the total cell count. 
As of December 2017, all patients receiving retreatment in Cohort 3 will receive the 
Gen 2 cryopreserved LN-144 infusion product. 
A diagram of the production process for the LN-144 IP is provided in Figure 2.  
Upon completion of the manufacturing process, the IP, LN-144, will be labeled with a 
patient specific label. The IP will then be shipped from the manufacturing facility to the 
respective clinical site for infusion, as described in the Pharmacy & Administration 
Manual. 
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Figure 2 
LN-144 Manufacturing Process  
 
 
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 IL-2 at 600,000 IU/kg approximately 
every 8 to 12 hours starting approximately 3 hours to 24 hours after the LN-144 infusion 
and continuing for up to 6 doses. All visit dates following the LN-144 infusion (Day 0) 
are calculated from this date forward. Patients will be evaluated for objective response 
6 weeks following the LN-144 infusion for the first 6 months and every 3 months 
thereafter (see Appendix 1 and Appendix 2). Formal response evaluations by an 
Independent Review Committee (IRC) will follow RECIST 1.1 criteria. [61]  
Overall Survival (OS) Follow-Up will continue for up to 5 years for each patient after the 
last study treatment. Patients who do not receive LN-144 will enter into OS Follow-Up to 
collect survival status and subsequent anticancer therapy.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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-LD pretreatment regimen and then also just 
prior to the LN-144 infusion through IL-2 administration. All dates of hospitalization(s) 
must be recorded in the electronic case report form (eCRF).  
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 ORR as assessed by the Investigator per RECIST 1.1 
3.1.2 
Secondary Objectives 
• To evaluate the efficacy endpoints of duration of response (DOR), disease control 
rate (DCR), and progression free survival (PFS) as assessed by the Investigator 
per RECIST 1.1 
• To further evaluate efficacy of LN-144 therapy in patients with metastatic 
melanoma by assessing ORR, DOR, DCR, and PFS as assessed by the 
Independent Review Committee (IRC) per RECIST 1.1 
• To evaluate overall survival (OS) 
• To characterize the safety profile of LN-144 therapy 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 immune-related Response Evaluation Criteria in 
Solid Tumors (irRECIST) criteria, [62] as assessed by the IRC 
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• To assess health-related quality of life (HRQoL) 
3.2 
Study Endpoints  
3.2.1 
Primary Endpoints 
• Objective response rate (ORR) as assessed by the Investigator per RECIST 1.1 
criteria 
3.2.2 
Secondary Endpoints  
• The DOR, DCR, and PFS per RECIST 1.1 criteria [61] as assessed by the 
Investigator  
• The ORR, DOR, DCR, PFS, per RECIST 1.1 criteria [61] as assessed by the IRC 
• Overall survival (OS) 
• Incidence, severity, seriousness, relationship to study treatment, and 
characteristics of treatment-emergent adverse events (TEAEs), including AEs 
leading to early discontinuation from treatment or withdrawal from the Response 
Assessment Period study follow-up, 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 will be determined by 
immunological and molecular assays  
• The ORR, DCR, and PFS using irRECIST [62] as assessed by the IRC 
• Patient-reported outcomes based on the European Organization for Research and 
Treatment of Cancer Quality-of-Life Questionnaire – Core 30 Instrument 
(EORTC QLQ-C30 HRQoL)  
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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 (eg, anti-PD-1), and if BRAF mutation-positive, after BRAF 
inhibitor systemic therapy. Patients must have no other therapy options that are 
expected to have significant benefit in the opinion of the Investigator and must 
have:   
• At least 1 measurable target lesion by RECIST 1.1. [61] Lesions in previously 
irradiated areas should not be selected as target lesion, unless treatment was 
≥ 3 months prior, and there has been demonstrated disease progression in the 
lesion  
• At least 1 resectable target lesion to generate TIL of a minimum 1.5 cm in 
diameter post-resection; surgical removal with minimal morbidity (defined as 
any procedure for which expected hospitalization is ≤ 3 days)  
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 (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 12 months after receiving all protocol-related therapy 
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Approved methods of birth control are as follows: 
• Combined (estrogen and progestogen containing) hormonal birth control 
associated with inhibition of ovulation: oral; intravaginal; transdermal 
• Progestogen-only hormonal birth control associated with inhibition of 
ovulation: oral; injectable; implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• True sexual abstinence when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (eg, calendar ovulation, 
symptothermal, post-ovulation methods) is not acceptable. 
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: 
• Serum alanine transaminase (ALT)/serum glutamic-pyruvic transaminase 
(SGPT) and aspartate transaminase (AST)/serum glutamic-oxaloacetic 
transaminase (SGOT) ≤ 3 times the upper limit of normal (ULN); patients 
with liver metastasis ≤ 5 times ULN 
• An estimated creatinine clearance (eClCr) ≥ 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  
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h. Patients must be seronegative for the human immunodeficiency virus (HIV) 
antibody, hepatitis B antigens, and hepatitis C antibody or antigen 
i. Patients must have recovered from all prior therapy-related AEs to Grade 1 or less 
(per Common Terminology Criteria for Adverse Events [CTCAE] v4.03), except 
for alopecia or vitiligo prior to enrollment (tumor resection) with a washout 
period from prior anticancer therapy(ies) to the start of planned NMA-LD of a 
minimum duration detailed as follows:  
• 
Targeted therapy: prior targeted therapy with a MEK/BRAF or other-directed 
agent, is allowed provided the washout period is a ≥ 21 days or 5 half-lives, 
whichever is longer prior to the start of NMA-LD 
• 
Chemotherapy: adjuvant, neoadjuvant or definitive chemotherapy/ 
chemoradiation is allowed provided the washout period is ≥ 21 days or 5 half-
lives, whichever is longer prior to the start of NMA-LD 
• 
Immunotherapy: prior checkpoint-targeted therapy with an anti-CTLA-4/anti-
PD-1, other monoclonal antibody (mAb), or vaccine is allowed if disease 
progression is confirmed prior to or within the washout period of ≥ 21 days 
before the start of NMA-LD 
• 
Palliative radiation therapy is permitted between biopsy and NMA-LD if it 
does not involve lesions being selected as target or nontarget 
• Patients may undergo preplanned procedures if within 2 to 3 weeks prior to 
the start of NMD-LD 
j. Patients with documented Grade 2 or higher 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 the start of 
NMA-LD 
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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 an organ allograft or 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 may be considered for 
enrollment after discussion with the Medical Monitor, and must be stable for 
≥ 2 weeks prior to the start of treatment NMA-LD 
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 symptoms  
f. Patients who have active medical illness(es) that in the opinion of the Investigator 
would pose increased risk for study participation that may include active systemic 
infections, such as syphilis or any other infection(s) requiring antibiotics, 
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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 [SCID] and acquired immune deficiency 
disease [AIDS]) 
h. Patients who have a history of hypersensitivity to any component or excipient of 
the TIL regimen therapy and other study drugs:  
• NMA-LD (cyclophosphamide, mesna, and fludarabine) 
• IL-2 
• Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin) 
• Any component of the TIL infusion product formulation including dimethyl 
sulfoxide (DMSO), human serum albumin (HSA), IL-2, and dextran-40 
i. Patients who have a left ventricular ejection fraction (LVEF) < 45% or New York 
Heart Association (NYHA) functional classification > Class 1 at Screening. All 
patients must have echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA) at Screening. For patients ≥ 60 years or patients who have a history of 
ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias, a cardiac stress tests must be performed showing LVEF ≥45%, and if 
any wall movement abnormalities, they must be reversible. 
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 who have been shown to be BRAF mutation positive (V600), but have 
not received prior systemic therapy with a BRAF-directed kinase inhibitor 
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m. Patients who have received a live or attenuated vaccine within 28 days of the start 
of NMA-LD 
n. Patients whose cancer requires immediate attention or who would otherwise 
suffer a disadvantage by participating in this trial 
o. Patients protected by the following constraints: 
• Hospitalized persons without consent or persons deprived of liberty because 
of a judiciary or administrative decision 
• Adult persons with a legal protection measure or persons who cannot express 
their consent  
• Patients in emergency situations who cannot consent to participate in the trial 
4.3 
Number of Patients 
Patients who meet all inclusion criteria and do not meet any exclusion criteria will be 
enrolled in the study.  
Patients will be enrolled until approximately 60 patients in the Efficacy Analysis set 
received either US or EU GMP manufactured Gen 2 cryopreserved LN-144 infusion 
product and complete treatment. Treatment completion is defined as having received 
LN-144 infusion followed by at least 1 dose of IL-2. Approximately 10 patients may 
enter the third cohort (Cohort 3) in which they will be retreated with a second 
administration of TIL therapy.  
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.  
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As of December 2017, enrollment in Cohort 1 had been terminated with patients being 
enrolled in Cohort 2 only.  
Patients from Cohort 1 and Cohort 2 may screen for retreatment in Cohort 3 as long as 
this study is open. Prior to enrollment in Cohort 3, patients must undergo abbreviated 
screening evaluation and procedures (see Appendix 2). 
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 re-sign the ICF and be reassessed 
for eligibility following a discussion between the Investigator and Medical Monitor to 
agree on which screening procedures need to be redone.  
4.3.2 
Patient Cohorts 
Patients are no longer being enrolled into Cohort 1. Patients will be assigned Cohort 2 
based on IRB/IEC approval of appropriate protocol/ICF. If Cohort 2 approaches or passes 
the desired 60-patient enrollment, assignment will be adjusted to minimize over-
enrollment. 
The primary efficacy and safety analyses will take place after the last patient in Cohort 2 
has an opportunity to be followed at least for 6 months tumor assessment, and the final 
analysis will take place at the end of the 2-year (24-month) Treatment Response Period. 
Cohort 3 will consist of patients who had received initial TIL regimen as part of Cohort 1 
or Cohort 2 treatment. These patients may have a second tumor resection, especially 
when new lesions are available and feasible for resection. Patients who in the opinion of 
the Principal Investigator will benefit from a second TIL regimen treatment will need to 
be rescreened and meet eligibility criteria as described in the Sections 4.1 and 4.2. 
The decision for enrollment in Cohort 3 will be based on discussion between the 
Principal Investigator and the Medical Monitor. The Medical Monitor will have authority 
to adjudicate enrollment into Cohort 3 (second TIL therapy). Patients who are enrolled in 
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Cohort 3 will receive treatment with Gen 2 cryopreserved LN-144 infusion product. 
Patients in Cohorts 1 and 2 who did not receive an LN-144 infusion will remain in the 
assigned cohort and, based on the Medical Monitor’s discretion, be readmitted to the 
tumor resection and TIL generation and infusion procedure.  
5 
PRIOR TREATMENTS, CONCOMITANT MEDICATIONS AND 
NONDRUG 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 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 Response Assessment Period follow-up phase, including 
those that are part of the tumor resection procedure. The OS follow-up period will start 
after completion of the Response Assessment Period following the LN-144 infusion, and 
will continue for up to 5 years for each patient from the last study treatment.  
Verification of all ongoing concomitant medications will be conducted as part of data 
monitoring.  
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 should not receive live or attenuated vaccine within 4 weeks (28 days) 
prior to the start of NMA-LD, and should not receive a live or attenuated vaccine 
within 3 months after the last dose of IL-2 (Day 84) and until ANC is ≥ 1000/mm3  
• Use of investigational drugs (other than the LN-144 investigational therapy), is 
not permitted 
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• Palliative radiation therapy is permitted between biopsy and NMA-LD as long as 
it does not involve selected target or nontarget lesions  
• Patients may undergo preplanned procedures if ≥ 2 weeks prior to the start of 
NMA-LD 
5.2.1.1 
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 antitumor 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 the ICF) 
The following procedures should be performed in all patients in Cohorts 1, 2, and 3 
(exceptions for Cohort 3 are noted) after signing the ICF: 
• Review of inclusion and exclusion criteria 
• Medical history (repeat medical history not needed for Cohort 3 patients) 
• Melanoma medical history, including prior therapies, response to prior 
therapies, and BRAF mutational status 
• Concurrent medications within 30 days prior to signing the 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 examination. Previous evaluation within 30 days prior to signing 
the ICF is allowed 
• Electrocardiogram (EKG). Prior evaluation within 60 days prior to signing the 
ICF is allowed 
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• Cardiac evaluation for all patients should consist of echocardiogram (ECHO) or 
multiple gated acquisition scan (MUGA) at Screening. For patients ≥ 60 years 
or patients who have a history of ischemic heart disease, chest pain, or clinically 
significant atrial and/or ventricular arrhythmias, a cardiac stress tests must be 
performed showing normal LVEF, NYHA functional classification < class 1 
and if any wall movement abnormalities, they must be reversible  
• Pulmonary function tests (PFTs).  
• 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 
o Previous CT/MRI scans performed within 30 days of ICF signing can be 
used for Screening visit 
• Blood and Urine Tests 
o Hematology – complete blood count (CBC) with differential 
o Chemistry - Sodium, potassium, chloride, total carbon dioxide (CO2) or 
bicarbonate, creatinine, glucose, blood urea nitrogen (BUN), albumin, 
calcium, magnesium, phosphorus, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), 
total protein, total creatinine (CK), uric acid, and thyroid panel (to include 
thyroid-stimulating hormone (TSH) and free T4) 
o Serum pregnancy test (β-human chorionic gonadotropin [β-HCF]) for 
women of childbearing potential 
o Cytomegalovirus (CMV) serology (IgG and IgM, as per local standard) 
o Urinalysis (complete urine culture if indicated) 
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• Syphilis screening (as per local standard; eg, Rapid Plasma Reagin [RPR] 
venereal disease research laboratory [VDRL] or other) at Screening, and 
thereafter as clinically indicated 
• HIV antibody titer, hepatitis B surface antigen (HBsAg) and hepatitis B core 
antigen (HBcAg) determinations, HCV Ab, herpes simplex virus (HSV) serology 
([HSV-1] IgG and [HSV-2] IgG), and EBV serology (viral capsid antigen 
[VCA]-IgM, VCA-IgG, EA-D IgG, EBNA, IgG). Serology for infection must be 
repeated for Cohort 3 patients if there is > 30 days from the last tests results.  
• HLA typing (to be shipped to the central laboratory); repeat HLA typing not 
needed for Cohort 3 patients. Refer to the Laboratory Manual for details. 
• Calculate estimated creatinine clearance (eClCr) using Cockcroft-Gault formula 
Males:  
• 
Creatinine Clearance = 
Weight (kg) x (140 – Age) 
• 
(mL/min) 
 
72 x serum creatinine (mg/dL) 
Females:  
• 
Creatinine Clearance = 
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 NMA-LD 
• Assessment of AEs / serious AEs (SAEs). All AEs occurring after the patient has 
consented, but before enrollment (prior to tumor resection), 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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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. 
• List all medications including those that are part of the tumor resection procedure 
• Obtain blood for immune monitoring/phenotyping (refer to Laboratory Manual) 
• Serology testing (HIV, HBsAg, HBcAg, HCV Ab, and syphilis) is to be done on 
the day of the tumor resection or within 7 days after the resection (required only 
for tumor samples entering the EU for manufacture of the TIL product in the EU).  
• Tumor resection (see Section 6.2.1) 
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
• Dates of hospitalization of the patient need to be recorded in the eCRF.  
6.2.1 
Tumor Harvest and Processing Procedure 
The detailed Tumor Procurement & Shipping Manual will be provided to each clinical 
site and training will be conducted on the procedures for collecting and shipping of the 
tumor to the LN-144 manufacturing facility. Ideally, the resected tumor specimen for TIL 
manufacturing 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. Biopsy from 
multiple lesions is encouraged.  
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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 × 5 mm × 5 mm is to be placed in a 
formalin-fixed, paraffin-embedded (FFPE) block and sent to the central laboratory 
(refer to the 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 
laboratory. When tumor tissue is limiting, a single 2-mm punch biopsy from the center of 
the resected tumor will be placed into an FFPE block and sent to the central laboratory 
(refer to the 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 laboratory.  
Tumor tissue sent to the central laboratory will be used as follows:  
• For immunohistochemistry (IHC) to identify different immune cell populations, and  
• For isolation of deoxyribonucleic acid (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 (eg, Genetic Research ICF) for 
exome sequencing. 
Tumors will be resected at the investigational sites participating in the trial according to 
their respective institutional protocols for sterile resection for TIL preparation.  
LN-144 is an autologous IP that 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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6.2.1.1 
Additional Tumor Tissue from Resected Tumor 
If there is an excess of tumor tissue after resection for TIL manufacturing, to process this 
additional tumor tissue please follow the procedures outline in Section 6.2.1. 
6.2.2 
Immune Monitoring and Phenotyping (Sequencing of Tumor and 
PBMC/Cell-Free DNA) 
Peripheral blood will be collected from the patient utilizing vacutainer blood collection 
vials for immune monitoring (biomarker analysis) and sequencing (exome and high-
throughput T-cell antigen receptor [TCR] sequencing) of lymphocyte DNA. Refer to the 
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 examination, including weight. Baseline (Day -21 to Day -14) weight 
can be used for calculation of dosing of cyclophosphamide, fludarabine, and 
IL-2. 
• 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 (If the EKG was done within 2 weeks prior to Screening, it does not 
have to be repeated.) 
• 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 Response Assessment Period disease assessments, 
[scheduled and unscheduled]) 
o Chest (include neck there is prior or suspected neck disease) 
o Abdomen 
o Pelvis 
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• MRI of the brain in patients who had brain abnormalities at Screening. 
For those patients who had negative brain scans at Screening, the Baseline 
(Day -21 to Day -14) 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 Response Assessment Period disease assessments 
[scheduled and unscheduled]). 
• Blood and urine tests 
o Hematology: CBC with differential 
o Chemistry: sodium, potassium, chloride, total carbon dioxide (CO2) or 
bicarbonate, creatinine, glucose, blood urea nitrogen (BUN), albumin, 
calcium, magnesium, phosphorus, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), 
total protein, total creatinine (CK), uric acid, and thyroid panel (to include 
thyroid-stimulating hormone [TSH] and free T4, only if clinically 
indicated) 
o Serum pregnancy test for women of childbearing potential 
o Urinalysis (complete urine culture if indicated) 
• ECOG performance status evaluation 
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, 
but before enrollment (prior to tumor resection), will be collected on the 
medical history eCRF unless the event is new and attributed to protocol-
required procedures or assessments 
• EORTC QLQ-C30 HRQoL questionnaire 
• Recheck of abbreviated Inclusion/Exclusion Criteria to ensure that patient 
performance status and main eligibility criteria have not changed from time of 
Screening, a reconfirmation is to be perform and approved by Sponsor or 
designee 
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6.4 
Patients Who Do Not Receive a LN-144 Infusion 
Some patients may undergo tumor resection and LN-144 manufacture but will not receive 
the infusion of IP. Patients who discontinue the study (prior to NMA-LD) are to complete 
the Early Termination Visit (ETV). The ETV is not required if the same procedures are 
performed within 2 weeks from the previous visit. However, a follow-up visit for safety 
should be performed 30 days following tumor resection, or until all surgery-related AEs 
have resolved or are without clinical sequalae. 
In a situation in which due to a medical event (AE), a patient did not complete NMA-LD 
and/or did not receive any LN-144 infusions, a potential for continuing therapy is 
available to the patient after the patient recovers and becomes fit to complete NMA-LD 
and/or LN-144 infusion. The REP cells (for Cohort 2 patients) may remain frozen for a 
period of time, and upon agreement between the Investigator and the Medical Monitor, 
treatment may continue after the patient meets criteria to receive LN-144 infusion. If a 
decision is made that the patient will not receive their TIL, then the patient should remain 
on study, but the data collection will be reduced to survival status and start of any new 
anticancer therapy. 
6.5 
Day -7  
Prior to beginning the LD 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 IL-2. Specifically, the Investigator should consider whether a 
worsening of ECOG status and/or a deterioration of laboratory values is such that the 
patient no longer meets the requirements of the inclusion and exclusion criteria. If this 
deterioration is believed to be reversible, the LN-144 IP 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 IL-2 administration, the patient should not proceed to LD and 
subsequent therapy and be followed as per Section 6.4.  
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Prior to the start of NMA-LD, verification of sufficient TIL (LN-144) cell expansion 
(≥ 250 × 106 cells) will be confirmed by the Sponsor and authorization to initiate LD will 
be sent to the site.  
The following procedures/assessments should be completed during this visit: 
• Physical exam including weight, calculated body surface area (BSA), and body 
mass index (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 carbon dioxide (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 
o Serum pregnancy test for women of childbearing potential 
o Obtain blood for immune monitoring (refer to the Laboratory Manual) 
• Authorization for Lymphodepletion 
Note: The ‘Authorization to Receive 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 to the site prior to the initiation of the 
NMA-LD preconditioning regimen.  
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• Cyclophosphamide, 60 mg/kg IV with mesna 15 mg/kg, are infused over 
approximately 2 hours. Cyclophosphamide may be prepared in 250 or 500 mL 
per institutional standard of practice (D5W or 0.9% NaCl can per used as per 
institutional standard of practice). If the patient is obese (BMI > 35 kg/m2) drug 
dosage will be calculated using practical weight as described in Appendix 4. 
Refer to the current package insert or SmPC for cyclophosphamide for full 
prescribing information (Appendix 8). 
• 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 or per site 
institutional standard. Patient may be discharged following completion of the 
mesna administration. Dates of hospitalization of the patient need to be recorded 
in the eCRF. Higher or continued doses of mesna can be administered as per 
standard of care at the treating institution for prevention of hemorrhagic cystitis. 
Local standards of care for mesna use can be used. Refer to the current package 
insert or SmPC for mesna for full prescribing information (Appendix 9). 
• 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 × 3 days) will be 
given for nausea, or as per standard of care at the treating institution. If the 
patient is obese (BMI > 35 kg/m2), drug dosage will be calculated using 
practical weight as described in Appendix 4. Refer to the current package insert 
or SmPC for ondansetron for full prescribing information (Appendix 10). 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be given as 
clinically indicated, per standard of care. Refer to the current package insert or 
SmPC for the specific antibiotic presribed for full prescribing information. 
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), 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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6.6 
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 
• Cyclophosphamide, 60 mg/kg IV with mesna 15 mg/kg, are infused over 
approximately 2 hours. Cyclophosphamide may be prepared in 250 or 500 mL per 
institutional standard of practice (D5W or 0.9% NaCl can per used as per 
institutional standard of practice). If the patient is obese (BMI > 35 kg/m2) drug 
dosage will be calculated using practical weight as described in Appendix 4. 
Refer to the current package insert or SmPC for cyclophosphamide for full 
prescribing information (Appendix 8). 
• 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 or per site institutional 
standard. Patient may be discharged following completion of the mesna 
administration. Dates of hospitalization of the patient need to be recorded in the 
eCRF. Higher or continued doses of mesna can be administered as per standard of 
care at the treating institution for prevention of hemorrhagic cystitis. Local 
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standards of care for mesna use can be used. Refer to the current package insert or 
SmPC for mesna for full prescribing information (Appendix 9). 
• 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 × 3 days) will be 
given for nausea, or as per standard of care at the treating institution. If the patient 
is obese (BMI > 35 kg/m2), drug dosage will be calculated using practical weight 
as described in Appendix 4. Refer to the current package insert or SmPC for 
ondansetron for full prescribing information (Appendix 10). 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be given as 
clinically indicated, per standard of care. Refer to the current package insert or 
SmPC for the specific antibiotic presribed for full prescribing information. 
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
6.7 
Day -5 to Day -1 
The following procedures should be performed: 
• Physical examination 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 
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o 
CMV serology (IgG and IgM, as per local standard), only if clinically 
indicated. Note: CMV serology (as per local standard) at Screening, within 
3 days of LN-144 infusion and thereafter as 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 Note: Fludarabine dose will be adjusted according to estimated creatinine 
clearance (CrCl) as follows: 
- 
CrCl 50-79 mL/min: reduce dose to 20 mg/m2 
- 
CrCl 40-49 mL/min: reduce dose to 15 mg/m2 
o Note: If the patient is obese (BMI > 35.0 kg/m2), fludarabine dosage will be 
calculated using practical weight as described in Appendix 4. Refer to the 
current package insert or SmPC for fludarabine for full prescribing 
information (Appendix 13). 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be given as 
clinically indicated, per standard of care. Refer to the current package insert or 
SmPC for the specific antibiotic prescribed for full prescribing information. 
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
6.8 
Day 0 (Infusion Day) 
Day 0 is the day of LN-144 infusion.  
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 IL-2 
administration, as per institutional standards. Dates of hospitalization of the patient need 
to be recorded in the eCRF. The following procedures should be performed: 
• Physical examination, including weight  
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• 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 
o 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, 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) 
o Serum pregnancy test for women of childbearing potential 
The following medications will be administered: 
• Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg will be given as 
per standard of care. Refer to the current package insert or SmPC for the specific 
antibiotic prescribed for full prescribing information 
The patient will be admitted prior to planned LN-144 administration and prepared with 
overnight intravenous hydration prior to the IP administration. Patients will remain 
hospitalized until the completion of the IL-2 therapy, as per institutional standards.  
Concomitant medications will be given to the patient starting within 24 hours prior to 
LN-144 infusion. This therapy will include the following:  
• Hydration per institutional standards 
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• Within 30 to 60 minutes prior to infusion of LN-144, premedicate the patient with 
acetaminophen (650 mg) and diphenhydramine (25 to 50 mg IV), or another 
H1-histamine antagonist. Avoid prophylactic use of systemic corticosteroids, 
which may interfere with the activity of LN-144. Corticosteroids should only be 
used to treat life-threatening conditions. 
For details, please, refer to Section 8.6.  
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
6.8.1 
Investigational Product  
Upon completion of the manufacturing process, the IP, LN-144, will be labeled with a 
patient specific label. The IP will then be shipped overnight from the manufacturing 
facility by courier to the clinical site pharmacy in a shipping container validated to 
maintain the appropriate IP temperature. All visit dates following the LN-144 infusion 
(Day 0) are calculated from Day 0 forward. 
The IP will be received by the appropriate clinical pharmacy or designee for subsequent 
administration into the specific patient from whom the TIL were derived. See the LN-144 
Pharmacy & Administration Manual for precise details for handling of LN-144 for 
Cohort 1 (noncryopreserved cells) or Cohort 2 (cryopreserved cells).  
Receipt is defined as the moment the LN-144 package is signed for by site personnel and 
released from courier’s custody. After receiving, verifying, and labelling with the clinical 
site’s specific labels at the pharmacy, the IP, LN-144, will be transferred to the patient’s 
bedside in the shipping container. Release for infusion status will be made available and 
must be confirmed as received at the clinical site prior to LN-144 infusion.  
At the time of release of LN-144 product for infusion, the results of the in-process 
sterility test are available, as are the results for the Gram stain test on the final product. 
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With this supportive information, it is felt that the benefit of administering the product to 
patients who urgently require therapy outweighs the potential risk of administering a 
product prior to the final sterility test results.  
In the case of a positive sterility test for an administered LN-144 product, the site will be 
immediately notified of the results of the test. Appropriate and prompt evaluation of the 
patient will be required and immediate initiation of appropriate anti-infective 
management per local standard of care must be instituted based on the results of the 
sterility tests. 
6.8.1.1 
LN-144 Infusion  
Autologous TIL (LN-144) will be administered intravenously. The fresh LN-144 IP 
(for Cohort 1 patients) will be administered (by gravity) at an infusion rate of 5 to 
10 mL/minute. 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) IP should be refrigerated.  
The frozen LN-144 IP (for Cohort 2 patients) will be thawed in a 37oC water bath and 
each infusion bag will be administered sequentially. The cryopreserved LN-144 IP 
(for Cohort 2 and Cohort 3 patients) will be administered (by gravity) at an infusion rate 
of 5 to 10 mL/minute. During periods of infusion interruption, the remaining cryobags of 
frozen TIL (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. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
Autologous TIL (LN-144) infusion is Day 0 of the Treatment Period (Section 6.9 below).  
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6.9 
Treatment Period  
6.9.1 
Day 1, Day 2, Day 3, and Day 4  
While the patient remains hospitalized (hospitalization days should be recorded in the 
eCRF), the following procedures should be performed: 
• Physical examination including weight  
• List all concomitant medications 
• Vital signs: pulse rate, respiratory rate, blood pressure, and temperature; pulse 
oximetry is to be conducted during IL-2 administration 
• Blood and urine tests (must be drawn prior to the first IL-2 administration of each 
calendar day) 
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) 
o Obtain blood for immune monitoring samples. Sample must be collected 
before first IL-2 dose and on Day 4 only (Refer to Laboratory Manual). 
Note: The first sample for immune monitoring panel should be drawn prior to 
IL-2 dosing.  
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), 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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The following medications will be administered: 
• IL-2: the first IL-2 administration can begin approximately 3 hours to 24 hours 
after the conclusion of the LN-144 infusion. IL-2 will be administered at a dose of 
approximately 600,000 IU/kg (based on total body weight). Note: If the patient is 
obese (BMI > 35.0 kg/m2), the IL-2 dosage will be calculated using practical 
weight as described in Appendix 4. IL-2 is to be administered by intravenous 
infusion at a frequency of every 8 to 12 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 Grade 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 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, IL-2 dosing may be held or stopped at the discretion 
of the treating Investigator. Refer to Appendix 6 for guidance about the 
management of IL-2 toxicities.  
• Filgrastim, 5 µg/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. Refer to the current package insert or 
SmPC for filgrastim for full prescribing information (Appendix 11).  
• 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. 
Refer to the current package insert or SmPC for fluconazole for full prescribing 
information (Appendix 12). 
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• Prophylactic antibiotics, such as TMP/SMX DS 160 mg/800 mg, may be given as 
clinically indicated, per standard of care. Refer to the current package insert or 
SmPC for the specific antibiotic prescribed for full prescribing information. 
• 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 
6.10 
Visits Prior to Start of Response Assessment Period 
6.10.1 
Day 14 and Day 28 (Both Visits ± 3 Days [(Calculated from Day 0, TIL 
Infusion) 
The following procedures will be performed on Days 14 and 28 calculated from Day 0 
(tumor resection): 
• Physical examination including weight  
• List of all concomitant medications 
• 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,  
o 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.  
o Serum pregnancy test for women of childbearing potential (Day 28 only, or 
when clinically indicated) 
o Obtain blood for immune monitoring (Day 14 only) (Refer to the Laboratory 
Manual)  
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• If required, the following medications will continue to be administered 
o Filgrastim, 5 µg/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. Refer to the current 
package insert or SmPC for filgrastim for full prescribing information 
(Appendix 11). 
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. 
Refer to the current package insert or SmPC for fluconazole for full 
prescribing information (Appendix 12). 
o Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be given 
as clinically indicated, per standard of care. Refer to the current package insert 
or SmPC for the specific antibiotic prescribed for full prescribing information. 
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. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
6.11 
Response Assessment Period 
The Response Assessment Period includes all assessments every 6 weeks until 6 months 
after Day 0 and then every 3 months until the end of the study for each patient (End of 
Study: death, lost to follow-up, or withdrawal of consent, or Month 60 from last study 
treatment). 
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6.11.1 
Every 6 Weeks (Week 6 [Day 42]; Week 12 [Day 84]Week 18 [Day 126], 
and Month 6 [Week 24, Day 168] [All Visits ± 3 Days Calculated from 
Day 0, TIL Infusion]) 
The following procedures will be performed during this post treatment evaluation visit: 
• Physical examination including weight 
• List of all concomitant medications 
• ECOG performance status evaluation 
• Evaluation and measurement of all skin and palpable lesions 
• Vital signs - pulse rate, respiratory rate, blood pressure and temperature 
• Assessment of AE/SAEs. All AEs occurring after the patient has consented, but 
before enrollment (prior to tumor resection), will be collected on the medical 
history eCRF unless the event is new and attributed to protocol-required 
procedures or assessments 
• Slit lamp eye exam, if clinically indicated 
• 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 
o Serum pregnancy test for women of childbearing potential  
• Obtain blood for immune monitoring (Refer to the Laboratory Manual)  
• Calculate creatinine clearance using Cockcroft-Gault formula  
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• CT Examination (repeat the same CT series for Response Assessment Period 
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 Response Assessment Period 
tumor assessment [scheduled and unscheduled] as completed at Baseline [Day -21 
to Day -14]) 
• EORTC QLQ-C30 HRQoL questionnaire  
• If required, the following medications will continue to be administered 
o Filgrastim, 5 µg/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. Refer to the current 
package insert or SmPC for filgrastim for full prescribing information 
(Appendix 11).  
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. Refer to the current package insert or SmPC for fluconazole for 
full prescribing information (Appendix 12).  
o Prophylactic antibiotics, such as TMP/SMX DS 160 mg/800 mg, may be 
given as clinically indicated, per standard of care. Refer to the current package 
insert or SmPC for the specific antibiotic prescribed for full prescribing 
information. 
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 
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will be administered daily, and continued until ALC > 1000/mm3, or as per 
standard of care at the treating institution 
6.11.2 
Every 3 Months After Month 6 Until End of Study Visit (All Visits 
± 1 Week, Calculated from Day 0, TIL Infusion) or End of Study (EOS) 
Visit  
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, 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 
o Serum pregnancy test for women of childbearing potential (every 3 months 
until Month 12 or EOS Visit, whichever occurs first) 
o Obtain blood for immune monitoring (Refer to the Laboratory Manual) 
(Months 6, 9, and 12 only) 
• CT Examination (repeat the same CT series for Response Assessment Period 
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) 
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o Abdomen 
o Pelvis 
• MRI of brain if positive for CNS involvement at Screening or Baseline (Day -21 
to Day -14) or as clinically indicated (repeat the same MRI series for Response 
Assessment Period 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 µg/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. Refer to the current 
package insert or SmPC for filgrastim for full prescribing information 
(Appendix 11). 
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. Refer to the current package insert or SmPC for fluconazole for 
full prescribing information (Appendix 12).  
o Prophylactic antibiotics, such as TMP/SMX DS 160 mg/800 mg, may be 
given as clinically indicated, per standard of care. Refer to the current package 
insert or SmPC for the specific antibiotic prescribed for full prescribing 
information. 
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 12.2 for guidance on AE/SAE reporting 
requirements during the follow-up period). All AEs occurring after the patient has 
consented, but before enrollment (prior to tumor resection), will be collected on 
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the medical history eCRF unless the event is new and attributed to protocol-
required procedures or assessments 
• EORTC QLQ-C30 HRQoL questionnaire (Every visit until End of Study Visit) 
6.12 
Overall Survival Follow-Up Period 
Patients are to be followed in Overall Survival (OS) Follow-Up (FU) to collect 
subsequent anticancer therapy and survival status. Overall Survival FU Period will start 
when a patient completes the Response Assessment Period and continues up to 5 years 
from the last study treatment until death, lost to follow-up, or withdrawal of consent.  
Patients who receive no study drug, including LN-144 infusion will be followed for OS 
follow-up for a minimum of 3 years from the tumor resection, in addition, information 
about new anticancer therapy will be collected during this period.  
6.13 
Treatment Discontinuation (Following LN-144 Infusion) 
A patient who is discontinued from treatment or the Response Assessment Period 
follow-up, after receiving LN-144 should remain on the study and continue with all 
scheduled study visit assessments. 
However, if a patient must initiate a new anticancer 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 anticancer therapy 
6.14 
Expected Toxicities and Treatment Guidelines 
6.14.1 
LN-144  
Early toxicities related specifically to the infusion of the cells (those which are seen 
immediately following the cell infusion and prior to IL-2 administration) are generally 
mild and include fevers, chills, headache, and malaise. Toxicities 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 6.14.2). 
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6.14.2 
IL-2 Administration 
Administration of IL-2 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.  
Decreased mental status may occur and can range from somnolence to obtundation. IL-2 
should be discontinued for any significance status changes or hallucinations. Agitation 
may be observed due to mild hallucinations. Treatment with IL-2 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. Administration of IL-2 should be withheld in patients 
developing moderate to severe lethargy or somnolence; continued administration may 
result in coma.  
Tumor infiltrating lymphocytes can remain in the pulmonary circulation for 
24 to 48 hours following infusion and may cause transient shortness of breath. In addition, 
pulmonary edema is commonly observed with IL-2 dosing. Supplemental oxygen may be 
administered as needed. Subsequent IL-2 dosing should be delayed until supplemental 
oxygen has been weaned or is minimal (< 2 L/min per nasal cannula). If hypoxia persists 
or is significant, IL-2 should be discontinued.  
All new cardiac arrhythmias should be promptly evaluated for myocarditis and 
continuously monitored with intensive management.  
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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 most patients have 
experienced no long-term sequelae following this treatment regimen. However, fatal 
complications are possible. Subcutaneous administration of IL-2 is not permitted.  
The full prescribing information for IL-2 is presented in Appendix 14.  
6.15 
Treatment Guidelines for Toxicity Management  
Concomitant medications must be given to the patient starting within 24 hours prior to 
LN-144 infusion. Premedication instructions are provided in Section 8.6.  
Additional supportive therapy may include: 
• Acetaminophen (650 mg q4h), indomethacin (50 to 75 mg q6h), and ranitidine 
(150 mg q12h) 
• Meperidine (25 to 50 mg), or other medication per institutional standards may be 
given IV if severe chills develop 
Other supportive therapy shall be given as required.  
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.  
6.15.1 
Expected Toxicities with LN-144 
The cryopreserved TIL product formulations contain 0.5% human serum albumin (HSA), 
300 IU/mL of interleukin-2 (IL-2), and potentially low residual amounts of gentamycin 
and streptomycin, which belong to the aminoglycoside group of antibiotics. 
Cryopreserved TIL product formulations include the cryopreservation medium 
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CryoStor® CS10, which contains the cryoprotectants dimethyl sulfoxide (DMSO) and 
dextran-40. 
Hypersensitivity events, including severe allergic reactions or anaphylaxis have occurred 
during infusion with LN-144 because hypersensitivity has been associated with at least 
one of the above-mentioned formulation components. Patients who have known allergies 
to antibiotics of the aminoglycoside group are excluded from the studies of LN-144. 
Premedication and supportive therapy instructions are provided in Section 8.6. 
Allergic reaction may present with symptoms such as rash, low blood pressure, shortness 
of breath, swelling of the face or throat, cough, chest tightness, and/or wheezing. These 
symptoms can usually be reversed promptly using an inhaled bronchodilator. During 
infusion of LN-144 product, appropriate emergency medications (eg, epinephrine and 
diphenhydramine) should be available at bedside during administration and institutional 
guidelines should be followed for the treatment of anaphylaxis. A more severe reaction is 
less likely but may occur and may require treatment with an injection of epinephrine, 
steroids, and inhaled bronchodilators.  
Rarely have severe breathing problems, known as anaphylaxis, developed. If these 
symptoms do occur, they will be treated immediately with the medications listed above. 
Details concerning specific risks for patients participating in this clinical study may be 
found in the accompanying LN-144 Investigator’s Brochure. 
6.15.2 
Expected Toxicities with Cyclophosphamide and Fludarabine 
Expected toxicities with cyclophosphamide and fludarabine administration are listed in 
the package inserts (see Appendix 8 and Appendix 13, 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.  
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6.15.2.1 
Hemorrhagic Cystitis Prophylaxis 
To reduce the risk of cyclophosphamide-associated hemorrhagic cystitis, patients will 
receive mesna in addition to intravenous fluids. Please refer to treatment guidelines for 
recommended mesna dosing. Alternative dosing regimens of mesna are allowed if the 
dose is greater than what is suggested in this protocol per institutional standards and 
Investigator discretion. 
6.15.3 
Nonmyeloablative Lymphodepletion Regimen Toxicity Management 
The use of the NMA-LD regimen (cyclophosphamide and fludarabine) prior to cell 
administration is expected to lead to myelosuppression in all patients. Therefore, a high 
index of suspicion for occult bacteremia should be maintained until marrow recovery. 
Refer to cyclophosphamide and fludarabine current package inserts for additional 
information. Expected toxicities with cyclophosphamide and fludarabine administration 
are listed in the package inserts (see Appendix 8 and Appendix 13). 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.  
6.15.4 
Expected Toxicities with IL-2 
6.15.4.1 
Decreased Mental Status with IL-2 
Decreased mental status may occur and can range from somnolence to obtundation. IL-2 
should be discontinued for any significant mental status changes or hallucinations. 
Agitation may be observed due to mild hallucinations. See Appendix 5 and Appendix 6 
for guidelines for IL-2 toxicity management.  
6.15.4.2 
Pulmonary Risk 
Tumor infiltrating lymphocytes can remain in the pulmonary circulation for 24 to 48 hours 
following infusion and may cause transient shortness of breath. In addition, pulmonary 
edema is commonly observed with IL-2 dosing. Supplemental oxygen may be 
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administered as needed. Subsequent IL-2 dosing should be delayed until supplemental 
oxygen has been weaned or is minimal (< 2 L/min per nasal cannula). If hypoxia persists 
or is significant, IL-2 should be discontinued. Pulse oximetry is to be conducted during 
IL-2 administration. Refer to Appendix 5 for IL-2 AEs.  
6.15.4.3 
Cardiac Arrhythmias and Myocarditis 
All new cardiac arrhythmias should be promptly evaluated and continuously monitored 
with intensive management. 
6.15.4.4 
Capillary Leak Syndrome 
Capillary leak syndrome (CLS) is expected to occur with IL-2 dosing. Resultant 
intravascular volume depletion should be managed with intravenous fluids. Diuresis 
should be initiated as tolerated following completion of IL-2 dosing. Hypotension not 
responsive to intravenous fluids should raise suspicion for occult bacteremia and 
associated sepsis.  
6.15.5 
Blood Product Support  
Using daily CBCs as a guide, the patient will receive platelets and packed red blood cells 
(PRBCs) as needed as per standard of care at the treating institution. Attempts will be 
made to keep hemoglobin >7.5 g/dL, and platelets > 10,000/mm3. All blood products will 
be irradiated. Leukocyte filters will be utilized for all blood and platelet transfusions to 
decrease sensitization to transfused WBCs and decrease the risk of CMV infection.  
6.15.5.1 
Heparin-Induced Thrombocytopenia  
Heparin-induced thrombocytopenia (HIT) has been observed with IL-2 administration. 
To minimize this risk, heparin flushes should not be used during IL-2 dosing.  
6.15.6 
Renal Toxicity 
Renal toxicity, defined by rapid rise in creatinine levels or clinical symptoms, is a risk. 
If patients exhibit signs or symptoms of renal toxicity, manage as per institutional 
standard of care. 
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6.16 
Infection Prophylaxis 
Other anti-infective agents may be substituted at the discretion of the Investigator as per 
standard of care at the treating institution.  
6.16.1 
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 or alternative as per standard of care at the treating institution may 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. 
6.16.2 
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. Oral acyclovir is also an acceptable treatment regimen. Reversible renal 
insufficiency has been reported with IV but not oral acyclovir. Neurologic toxicity 
including delirium, tremors, coma, acute psychiatric disturbances, and abnormal 
electroencephalogram (EEG) has been reported with higher doses of acyclovir. Should 
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this occur, a dosage adjustment will be made or the drug will be discontinued. Acyclovir 
will not be used concomitantly with other nucleoside analogs, which interfere with DNA 
synthesis, eg, 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. 
6.16.3 
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. 
6.16.4 
Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a third or fourth 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.  
6.16.5 
Sepsis 
Sepsis can mimic IL-2 side effects. Fever symptoms may be masked during IL-2 dosing 
due to scheduled indomethacin and acetaminophen. In neutropenic patients exhibiting 
hypotension or oliguria unresponsive to intravenous fluids, patients should be tested for 
infection, and broad-spectrum antibiotics should be initiated. 
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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 IL-2.  
7.2 
Criteria for Early Discontinuation from Treatment  
Criteria for early discontinuation from treatment: 
• Grade 3 or greater drug-related immune AEs that involve vital organs 
(heart, kidneys, brain, eye, liver, colon, adrenal gland, lungs) with symptoms 
emerging following 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  
• Meeting criteria for permanent discontinuation of IL-2 treatment  
• Determination by the Investigator that continued treatment is not in the best 
interest of the patient 
• Administration of prohibited concomitant medications 
Criteria for early discontinuation from study: 
• Full withdrawal of consent by patient  
o Every effort should be made to continue overall survival follow-up 
• Administration of any other anticancer therapy(ies)  
o Every effort should be made to continue overall survival follow-up 
• Lost to follow-up after 3 documented attempts to contact the patient 
• Death 
• Study terminated by the Sponsor 
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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 noncryopreserved (Cohort 1) or cryopreserved 
(Cohort 2) 
8.2 
Qualitative Composition of LN-144 
LN-144 is a cellular IP 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 (noncryopreserved 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 a single LN-144 intravenous infusion is given following 
the NMA-LD preconditioning regimen. After the LN-144 infusion is completed, the IL-2 
administration starts as soon as 3 hours, but not later than 24 hours, and continues for up 
to 6 doses of intravenous IL-2. 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 × 109 LN-144 or 500 mL (up to 600-mL transfer bag for Cohort 1) for cell 
concentrations ≤150 × 109 LN-144. Patients on Cohort 2 will have up to 4 bags 
containing up to approximately 100 to 150 mL of thawed cells. 
8.3 
Manufacturing Process 
The overall process of tumor shipping, LN-144 manufacturing, and LN-144 IP shipping, 
and infusion is shown in Figure 2 (Cohorts 1 and 2). The LN-144 IP is manufactured 
ex vivo using autologous tumor as starting material. The key manufacturing steps 
include: 
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• Surgical resection of autologous metastatic tumor and shipment to manufacturing 
facility 
• Culture of small 2-mm to 3-mm (length × width × 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 IP 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 × 109 LN-144 or 600-mL blood transfer pack 
(Baxter) for cell concentrations ≤ 150 × 109 LN-144. Alternatively, in Cohort 2, TIL will 
be received cryopreserved in up to 4 bags containing up to approximately 100 to 125 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 IP 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 2oC to 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 IP will be received at the clinical site on or prior to Day 0.  
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Receipt is defined as the moment the LN-144 package is signed for by site personnel and 
released from courier’s custody. After receiving, verifying, and labeling with the clinical 
sites’ specific labels at the pharmacy, the IP, LN-144, will be transferred to the patient 
bedside in the cryoshipper. The clinical site is instructed to administer the autologous 
LN-144 IP immediately after thawing each cryopreserved infusion bag, sequentially. 
Additional details are specified in the Pharmacy & Administration Manual. 
The LN-144 IP is infused by gravity within approximately 15 minutes for each 
sequentially thawed and infused bag. If interruption of infusion is required for medical 
reasons, the LN-144 infusion bags not yet thawed should be kept in the cryoshipper and 
any thawed LN-144 product should be infused within 3 hours of being thawed. 
The Pharmacy & Administration Manual should be consulted. Continuous supervision of 
the patient by site medical staff is required until completion of infusion of the first bag of 
TIL, to monitor for potential signs and symptoms (eg, of a severe hypersensitivity 
reaction such as anaphylaxis that may require immediate medical attention and 
treatment). 
The cryopreserved TIL product formulations contain 0.5% human serum albumin (HSA), 
300 IU/mL of interleukin-2 (IL-2), and potentially low residual amounts of gentamycin 
and streptomycin, which belong to the aminoglycoside group of antibiotics. 
Cryopreserved TIL product formulations include the cryopreservation medium CryoStor® 
CS10, which contains the cryoprotectants dimethyl sulfoxide (DMSO) and dextran-40. 
Hypersensitivity events, including severe allergic reaction and anaphylaxis, have 
occurred during infusion with LN-144/LN-145 product, as hypersensitivity has been 
associated with at least one of the above-mentioned formulation components. 
If not already hospitalized, the patient will be admitted prior to planned LN-144 
administration and prepared with overnight intravenous hydration prior to the IP 
administration. Patients will remain hospitalized until the completion of the IL-2 therapy, 
as per institutional standards.  
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Concomitant medications must be given to the patient starting within 24 hours prior to 
LN-144 infusion. This therapy will include the following:  
• Hydration per institutional standards 
• Within 30 to 60 minutes prior to infusion of LN-144, premedicate the patient with 
acetaminophen (650 mg) and diphenhydramine (25 to 50 mg IV), or another 
H1-histamine antagonist. Avoid prophylactic use of systemic corticosteroids, as it 
may interfere with the activity of LN-144. Corticosteroids should only be used to 
treat life-threatening conditions. 
Additional supportive therapy may include: 
• 
Acetaminophen (650 mg q4h), indomethacin (50 to 75 mg q6h), and ranitidine 
(150 mg q12h) 
• Meperidine (25 to 50 mg), or other medication per institutional standards may be 
given IV if severe chills develop 
Patients may experience severe allergic reaction including anaphylaxis that can be life 
threatening during infusion of LN-144 product. During infusion of LN-144 product, 
appropriate emergency medications (eg, epinephrine and diphenhydramine) should be 
available at bedside during administration and institutional guidelines should be followed 
for the treatment of anaphylaxis. 
Earlier versions of the protocol required that Cohort 3 patients received their TIL 
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 
noncryopreserved TIL or cryopreserved TIL), alternatively if no prior LN-144 infusion 
was received, treatment in Cohort 3 would be by whichever manufacturing process has 
the first availability. As of December 2017, all patients receiving retreatment in Cohort 3 
will receive the Gen 2 LN-144 infusion product. 
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8.7 
Retreatment with LN-144 
Retreatment with LN-144 will be permitted for patients who received TIL therapy. 
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 
criterion b). These patients may have a second tumor resection, especially when new 
lesions are available and feasible for resection.  
The decision for enrollment in Cohort 3 will be based on discussion between the 
Principal Investigator and the Medical Monitor. The Medical Monitor will have authority 
to adjudicate enrollment into Cohort 3 (second TIL therapy). All procedures and 
assessments assigned to receiving LN-144 therapy are the same as described in 
Sections 6.2, 6.2.2, and 6.8.  
9 
STUDY ASSESSMENTS 
9.1 
Tumor Assessments 
Tumor assessment (scheduled or unscheduled) 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, Baseline (Day -21 to Day -14), and 
(Week 6 [Day 42 ± 3 days]) following the LN-144 infusion and every 
Week 6 (Day 42± 3 days) thereafter, up to 6 months post-LN-144 infusion (Response 
Assessment Period), at which time the tumor assessments (scheduled and unscheduled) 
will occur every 3 months until the following criteria are met: 
• Disease progression 
• Start of a new anticancer therapy 
• Withdrawal of consent 
• Lost to Follow-Up 
• Death 
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Overall survival follow-up will start after completion of the Response Assessment Period 
and will continue for up to 5 years for each patient from the last study 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 Response 
Assessment Period disease assessments, [scheduled and unscheduled]). Assessments 
should be made and recorded by the Investigator or an individual authorized by the 
Investigator.  
Magnetic resonance imaging or positron emission tomography (PET; specifically, 
fluorodeoxyglucose-PET [FDG-PET]) scans may be used in lieu of CT scans for patients 
who have an intolerability to contrast media. The imaging modality used must be uniform 
for the duration of the study.  
Note: The use of the same imaging location/equipment and settings should be kept 
constant for each individual patient during their participation in the study. 
The same method of assessment (CT or MRI) and the same technique for acquisition of 
data should be used to characterize each identified and reported lesion at Baseline 
(Day -21 to Day -14) and at all post-treatment tumor assessments (scheduled and 
unscheduled). At the Investigator’s discretion, the Baseline brain MRI and CT scans may 
be performed as early as Day -21. Patients will be evaluated for response at 6, 12, 18, and 
24 weeks after the last dose of IL-2; then every 3 months until disease progression, 
initiation of a new anticancer therapy, or patient withdrawal from the study. Additional 
radiological assessments may be performed per Investigator’s discretion. 
All patients should have radiographic tumor measurements performed at the participating 
study center or an acceptable alternate imaging facility using an identical imaging 
protocol. The same imaging equipment and parameters should be used for all scans 
throughout the study. 
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9.1.1 
Response Criteria 
Tumor response will be determined using RECIST version 1.1 [61] with a modification 
to require confirmation of PD. Refer to Table 1 and Table 2 for RECIST 1.1 response 
criteria 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 (scheduled or unscheduled) 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 IRC 
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 nontarget) must have a reduction in short axis to 
<10 mm). 
• Partial Response (PR): At least a 30% decrease in the sum of the diameter of 
target lesions taking as reference the Baseline (Day -21 to Day -14) 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 (Day -21 to Day -14) 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). 
                                            
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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• 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 Nontarget Lesions2 
• Complete Response (CR): Disappearance of all nontarget 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 nontarget lesion(s) and/or 
maintenance of tumor marker level above normal limits. 
• Progressive Disease (PD): Unequivocal progression of existing nontarget 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 until disease progression/recurrence, 
the initiation of new anticancer therapy, death or 24 months whichever comes first. 
The patient's best response assignment will depend on target lesion SoD, nontarget lesion 
status, absence of a new lesion, and the confirmation criteria.  
Table 1 
Time Point Response: Patients with Target (± Nontarget) Disease 
Target Lesions 
Nontarget Lesions 
New Lesions 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
                                            
2 All other lesions (or sites of disease) should be identified as nontarget lesions and should also be 
recorded at Baseline.  
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Table 2 
Time Point Response: Patients with Nontarget Disease Only 
Nontarget Lesions 
New Lesions 
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 
Biomarkers, or immune monitoring, include peripheral blood mononuclear cells 
(PBMCs), serum, plasma and tumor specimens that 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. 
9.3 
Data Safety Monitoring Board 
An independent 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. As of November 2017, the DSMB had reviewed the data from Cohort 1 and 
Cohort 2 and recommended to continue enrollment without any changes to the clinical 
study protocol. Additional evaluations of safety data may be conducted as specified in the 
DSMB charter. 
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10 
STATISTICAL AND ANALYTICAL PLANS  
10.1 
Introduction  
The primary statistical plan of analysis is based on use of descriptive methods unless 
mentioned otherwise. Continuous data will be summarized as the number of patients with 
non-missing data (N), mean, standard deviation, median, minimum, and maximum 
values. Categorical data will be summarized as counts and their related percentages, 
where applicable. Point estimates of treatment effect will be derived from maximum 
likelihood methods. Estimation of confidence limits will use 2-sided, 95% criteria and 
implement the Wilson score method. Missing data will not be imputed unless defined in 
the statistical analysis plan (SAP). If inferential statistics are calculated (eg, p-values), 
they will be used in a descriptive manner). 
A more detailed description of the analyses and reporting plan of the study data will be 
provided in the SAP.  
10.2 
Study Analysis Sets 
The Tumor Harvested (TH) set is defined as all tumor-resected patients for production of 
LN-144. The TH set is further divided into the efficacy and safety sets for analyses. 
There is no planned statistical or descriptive comparison among cohorts.  
10.2.1 
Safety Analysis Set 
The Safety Analysis set consists of patients who have received TIL LN-144 infusion. 
10.2.2 
Efficacy Analysis Set 
The Efficacy Analysis set consists of subjects in the Safety Analysis set with a Baseline 
(Day -21 to Day -14) and at least one post-Baseline radiological assessments. Patients 
who progressed or expired prior to reaching the first radiological assessment will be 
included. 
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10.2.3 
Cohort 3 
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 
Efficacy and Safety Analysis sets of the original cohort. There will be no formal 
comparisons among cohorts. 
10.3 
Endpoints 
10.3.1 
Primary Endpoint 
The primary endpoint is the ORR using RECIST 1.1 criteria [61] as assessed by the 
Investigator. The ORR is derived as the sum of the number of patients with a best 
response of complete response (CR) or partial response (PR) divided by the number of 
patients in the Efficacy Analysis set × 100%.  
10.3.2 
Secondary Endpoints 
The secondary endpoint will include DOR, DCR, and PFS per RECIST 1.1 criteria as 
assessed by the Investigator. In addition, the secondary endpoints will include the ORR, 
DOR, DCR, and PFS per RECIST 1.1 criteria as assessed by the IRC. Overall survival 
will be assessed as a secondary endpoint.  
The DOR is measured from the time point at which the initial 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 
complete tumor assessment date.  
The 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 Efficacy Analysis set 
multiplied by 100%. 
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The 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 (ie, database lock) will have their event times 
censored on the last complete tumor assessment date.  
The OS is defined as the time (in months) from the start date of the LD 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 Endpoints 
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-RECIST [61] 
will also be assessed. -HRQoL will be assessed using the EORTC QLQC30 instrument 
(see Appendix 15) and scored/evaluated as described in the Statistical Analysis Plan. 
10.4 
Sample Size Consideration 
The planned number of patients is approximately 60 in the Efficacy Analysis set who 
received either US or European manufactured LN-144 infusion product in Cohort 2. 
The total number of patients to be enrolled across all cohorts will be approximately 85.  
The lower 95% confidence limit for ORR is estimated per the Wilson Score method. 
The maximum half width of the 2-sided confidence limit is less than 12.3% when ORR is 
expected to range from 20% to 50%.  
The primary analysis will occur when more than 60 patients have been followed for a 
minimum of 6 months. This allows sufficient time for disease-controlled patients (SD or 
better) to demonstrate emergence and durability of response.  
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10.5 
Analysis Methods 
10.5.1 
Baseline Demographics and Clinical Characteristics 
Baseline (-21 to Day -14) demographic and clinical (disease) characterized will be 
summarized descriptively for the Safety and Efficacy Analysis sets if they are not 
identical. Age will be derived as a function of the date of informed consent. 
10.5.2 
Primary Endpoint 
The ORR is expressed as binomial proportions and will be summarized for the best 
overall response using a point estimate and its 2-sided 95% confidence limits based on 
the Wilson’s score method. 
10.5.3 
Secondary Endpoints 
The DCR is also expressed as binomial proportions and will be summarized using both a 
point estimate and its 2-sided 95% confidence limits based on the Wilson’s score method.  
The PFS, OS, and DOR 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 depending on the maturity of the study data at the time of 
analysis.  
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 95% confidence limits. 
10.5.4 
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 at the time of the LN-144 infusion for the 
Safety Analysis set. Adverse event summaries will be based on patient incidence counts 
and their related percentages. In addition to an overall summary of adverse events, 
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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 (eg, ANCs for neutropenia; platelets for 
thrombocytopenia). 
10.5.5 
Other Planned Analyses 
Should additional 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. 
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 6.14.2). The use of the nonmyeloablative regimen prior to cell 
administration increases the toxicity of this treatment as profound myelosuppression 
occurs in all patients.  
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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-Good Clinical Practice (GCP) is any untoward 
medical occurrence in a patient or clinical trial patient administered a medicinal/IP and 
which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal/IP. 
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 
• Abnormal laboratory test results (eg, hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, EKGs, radiological scans, vital signs 
measurements), will be reported as AEs only if they are clinically significant; led 
to hospitalization or prolongation of hospitalization, required change in dosing or 
treatment of study therapies, required initiation of concomitant therapy for 
laboratory abnormalities. 
• 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 IP administration 
• Signs, symptoms, or the clinical sequelae of a suspected interaction with IP 
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• Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP 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 (eg, 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 Section 12.2.1) 
• 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 
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 
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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 1 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.  
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. 
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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 that 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 
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 resection), will be 
collected on the medical history eCRF unless the event is new and attributed to protocol-
required procedures or assessments.  
Monitoring and reporting of AEs, regardless of cause or relationship will be collected 
until completion of response assessment period. All AEs attributed to treatment will be 
collected from signing of the informed consent form until lost to follow-up, withdrawal 
of consent or the start of a new anti-cancer therapy, whichever occurs first. 
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Medically significant AEs considered related to the IP 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 hours 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 IP due to an SAE, this information must be included in either the initial or 
follow-up SAE Report Form and in the eCRF. 
12.2.1.1 
Serious Adverse Events 
12.2.1.1.1 
Investigator Reporting to Sponsor 
All SAEs of any attribution will be collected from the time the patient signs the ICF up 
until completion of the Response Assessment Period and/or from the start of a new 
anticancer therapy.  
All AEs/SAEs attributed to treatment will be collected from signing of the ICF until the 
end of the Response Assessment Period, lost to follow-up, withdrawal of consent, or the 
start of a new anti-cancer therapy, whichever occurs first. 
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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 
complete as is possible with the information available and include the Investigator’s 
assessment of study drug relationship, as defined in Section 12.1.3. 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 
Synteract 
 
 
 
12.2.1.1.2 
Special Situation Reporting 
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/IP while in the control of the health care provider, patient, 
or consumer.  
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An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal/IP 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/IP.  
Occupational exposure is defined as the exposure to a medicinal/IP as a result of one’s 
professional or non-professional occupation. 
12.2.1.1.3 
Pregnancy Reporting 
Any pregnancy that occurs while on the study through 12 months from the last study 
treatment or until the first dose of the next anticancer 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 
(eg, 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 12.2.1.1.4.  
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 Response Assessment Period follow-up 
visits, must be promptly reported to the Sponsor or their representative. 
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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 IP, 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. 
12.2.1.1.4 
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. 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. 
12.2.1.1.5 
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 Iovance Biotherapeutics, 
Inc. 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 
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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 (eg, 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 
Record Retention 
In compliance with the ICH/GCP guidelines the Investigator/Institution will be 
responsible for all information in the eCRF and will maintain the source documents that 
support the data collected from each patient, and all trial documents as specified in 
Essential Documents for the Conduct of a Clinical Trial and as specified by the 
applicable regulatory requirement(s). The Investigator/Institution will take measures to 
prevent accidental or premature destruction of these documents. Essential documents 
must be retained until at least 2 years after the last approval of a marketing application in 
an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the IP. 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, 
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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. 
13.3 
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. 
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. 
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13.4 
Data Handling and Recordkeeping 
13.4.1 
Regulatory Approval and Documentation 
Iovance Biotherapeutics, Inc. (Sponsor) will determine the appropriate local, national and 
or regional regulatory approvals that need to be obtained to conduct the study. 
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 (eg, 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 
(eg, 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 
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• Required financial agreement 
• In addition to the documents required prior to the study, other documentation may 
be required during the course of the study. 
13.4.2 
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. 
13.4.3 
Data Handling and Recordkeeping 
13.4.3.1 
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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13.5 
Study Completion/Termination 
13.5.1 
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.  
13.5.2 
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 
13.6 
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 
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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 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. In other countries, the protocol and any amendments must be approved by the 
concerned Ethics Committees as per the applicable laws and requirements on the national 
and EU level. 
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, 
its 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 
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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 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 the Health Insurance Portability and Accountability Act (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). 
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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 
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 IP 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 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 (eg, patients’ written 
consent forms) should be maintained by the Investigator in strict confidence, in 
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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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38. Royal RE, Steinberg SM, Krouse RS, Heywood G, White DE, Hwu P, et al. Correlates of 
response to IL-2 therapy in patients treated for metastatic renal cancer and melanoma. 
Cancer J Sci Am. 1996;2(2):91-98. 
39. Le AX, Bernhard EJ, Holterman MJ, Strub S, Parham P, Lacy E, 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(4):1366-1371. 
40. 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(7):4247-4250. 
41. Kirkin AF, Dzhandzhugazyan K, Zeuthen J. Melanoma-associated antigens recognized by 
cytotoxic T lymphocytes. APMIS. 1998;106(7):665-679. 
42. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, 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(1):347-352. 
43. Seiter S, Monsurro V, Nielsen MB, Wang E, Provenzano M, Wunderlich JR, 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(3):252-263. 
44. Goedegebuure PS, Douville LM, Li H, Richmond GC, Schoof DD, Scavone M, et al. 
Adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 in patients 
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1995;13(8):1939-1949. 
45. Kradin RL, Kurnick JT, Lazarus DS, Preffer FI, Dubinett SM, Pinto CE, et al. Tumour-
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1989;1(8638):577-580. 
46. Ravaud A, Legrand E, Delaunay MM, Bussieres E, Coulon V, Cany L, et al. A phase I trial 
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47. Tessier MH, Pandolfino MC, Jotereau F, Boudart D, Litoux P, Dreno B. Home therapy with 
autologous tumour-infiltrating lymphocytes and subcutaneous interleukin-2 in metastatic 
melanoma. Eur J Cancer. 1996;32A(4):735-736. 
48. Aebersold P, Hyatt C, Johnson S, Hines K, Korcak L, Sanders M, et al. Lysis of autologous 
melanoma cells by tumor-infiltrating lymphocytes: association with clinical response. J Natl 
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49. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, 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(25):1676-1680. 
50. Topalian SL, Solomon D, Avis FP, Chang AE, Freerksen DL, Linehan WM, et al. 
Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and 
recombinant interleukin-2: a pilot study. J Clin Oncol. 1988;6(5):839-853. 
51. Ahmadzadeh M, Felipe-Silva A, Heemskerk B, Powell DJ, Jr., Wunderlich JR, Merino MJ, 
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that selectively accumulate in metastatic melanoma lesions. Blood. 2008;112(13):4953-
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52. Poehlein CH, Haley DP, Walker EB, Fox BA. 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(11):3121-3133. 
53. Song S, Zhang K, You H, Wang J, Wang Z, Yan C, 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(1):75-83. 
54. Wang W, Lau R, Yu D, Zhu W, Korman A, Weber J. PD1 blockade reverses the suppression 
of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol. 
2009;21(9):1065-1077. 
55. Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with 
metastatic melanoma. Curr Opin Immunol. 2009;21(2):233-240. 
56. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, 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(7):907-912. 
57. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. 
Cancer regression and autoimmunity in patients after clonal repopulation with antitumor 
lymphocytes. Science. 2002;298(5594):850-854. 
58. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, 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(10):2346-2357. 
59. Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O'Callaghan CA, et al. Direct 
visualization of antigen-specific CD8+ T cells during the primary immune response to 
Epstein-Barr virus In vivo. J Exp Med. 1998;187(9):1395-1402. 
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60. Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, 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(24):6758-6770. 
61. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247. 
62. Bohnsack O, Ludajic K, Hoos A. Adaptation of the Immune-related Response Criteria: 
irRECIST.  ESMO2014. 
63. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-655. 
 
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Appendix 1 
SCHEDULE OF EVENTS – FOR COHORT 1 AND COHORT 2 PATIENTS 
Assessmentsb 
Screening & 
Enrollment Period 
Treatment Perioda 
(All visits following LN-144 infusion [Day 0]  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response Assessment 
Perioda 
(All visits following 
LN-144 infusion 
[Day 0] calculated 
from Day 0 forward.) 
End of Study 
(EOS) or Early 
Termination 
Visita 
Overall 
Survival 
Follow-Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks  
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months  
(±1 Week) 
(Starting at Month 6) 
End of Study (EOS) or 
Early Termination 
Visit 
(Month 24 or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 weeks) 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationd 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Evaluation and 
measurement of skin 
and palpable lesions 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Eye examination 
(slit lamp)e 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
Medical historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationsg 
X 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weighth 
X 
 
X 
Xh 
 
 
 
 
 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
X 
X 
 
 
X 
X 
X 
 
Pulse oximetryj 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
CMV serologyk 
X 
 
 
 
 
 
 
Xk 
Xk 
Xk 
 
 
 
 
 
 
 
 
 
 
 
Syphilis testingl 
X 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac function 
tests with ECHO or 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessmentsb 
Screening & 
Enrollment Period 
Treatment Perioda 
(All visits following LN-144 infusion [Day 0]  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response Assessment 
Perioda 
(All visits following 
LN-144 infusion 
[Day 0] calculated 
from Day 0 forward.) 
End of Study 
(EOS) or Early 
Termination 
Visita 
Overall 
Survival 
Follow-Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks  
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months  
(±1 Week) 
(Starting at Month 6) 
End of Study (EOS) or 
Early Termination 
Visit 
(Month 24 or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 weeks) 
MUGA. cardiac 
stress testm 
CT chest, abdomen, 
pelvisn 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
MRI – brainn 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Serum chemistryo 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid panelp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Hematologyq 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisr 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Calculated creatinine 
clearances 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ß-HCG pregnancy 
testt 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
HIV titeru 
X 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBcAgv 
X 
Xv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAgv 
X 
Xv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Abw 
X 
Xw 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typingx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV serology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EBV serology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessmentsb 
Screening & 
Enrollment Period 
Treatment Perioda 
(All visits following LN-144 infusion [Day 0]  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response Assessment 
Perioda 
(All visits following 
LN-144 infusion 
[Day 0] calculated 
from Day 0 forward.) 
End of Study 
(EOS) or Early 
Termination 
Visita 
Overall 
Survival 
Follow-Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks  
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months  
(±1 Week) 
(Starting at Month 6) 
End of Study (EOS) or 
Early Termination 
Visit 
(Month 24 or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 weeks) 
Pulmonary function 
testingy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Colonoscopyz 
Xz 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor resectionaa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ondansetron 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Authorization to 
Receive 
Lymphodepletionbb 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
60 mg/kg 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 
25 mg/m2/day 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
LN-144 infusioncc 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IL-2 600,000 IU/kgdd 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Filgrastimee 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TMP/SMX DS, or 
appropriate Abxff 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Fluconazolegg 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Valacyclovir/ 
acyclovirhh 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immune monitoringii 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
 
 
Tumor assessment 
(local)jj 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
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Assessmentsb 
Screening & 
Enrollment Period 
Treatment Perioda 
(All visits following LN-144 infusion [Day 0]  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response Assessment 
Perioda 
(All visits following 
LN-144 infusion 
[Day 0] calculated 
from Day 0 forward.) 
End of Study 
(EOS) or Early 
Termination 
Visita 
Overall 
Survival 
Follow-Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks  
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months  
(±1 Week) 
(Starting at Month 6) 
End of Study (EOS) or 
Early Termination 
Visit 
(Month 24 or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 weeks) 
Assessment of 
AEs/SAEskk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hospitalization(s)ll 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EORTC QLQ-C30 
HRQoLmm 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Overall survival (OS) 
follow-up telephone 
contacnn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: Ab=antibody; ABX=antibiotics; AE=adverse events; Ag=antigen; ALC=absolute lymphocyte count; ALT=alanine transaminase; ANC=absolute neutrophil count; 
AST=aspartate transaminase; BUN=blood urea nitrogen; CK=creatine kinase; CMV=cytomegalovirus; CT=computed tomography; EBV=Epstein-Barr virus; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EKG=electrocardiogram; EORTC=European Organization for Research and Treatment of Cancer; 
EOS=end of study; HBcAg=hepatitis B virus core antigen; HBsAg=hepatitis B virus surface antigen; βHCG=beta human chorionic gonadotropin; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; HLA=human leukocyte antigen; HRQoL=health-related quality of life; HSV=herpes simplex virus; IL-2 interleukin-2; 
LD=lymphodepletion; LDH=lactate dehydrogenase; LPLD=last patient last dose; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA=multiple 
gated acquisition; NMA-LD=nonmyeloablative-lymphodepletion; OS=overall survival; PE=physical examination; PET=positron emission tomography; PFT=pulmonary function 
test; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; RPR=rapid plasma reagin; SAE=serious adverse event; SGOT=serum glutamic-oxaloacetic 
transaminase; SGPT=serum glutamic pyruvic transaminase; TIL=tumor-infiltrating lymphocytes; TMP-SMX DS=trimethoprim-sulfamethoxazole double strength; TSH=thyroid-
stimulating hormone; VDRL=venereal disease research laboratory. 
a. 
All visits preceding LN-144 infusion (Day 0) are calculated going backwards (eg, Day -1, Day -2, Day -3, …Day -7, etc.), and all visits following LN 144 infusion (Day 0) 
are calculated going forward from Day 0 (eg, Day 1, Day 2, Day 3…Day 28, etc). 
b. 
Unscheduled visit(s) for any assessment may be conducted per the medical judgement of Investigator.  
c. 
Re-check of Inclusion/Exclusion Criteria at Baseline (Day -21 to Day -7) to ensure that patient performance status and eligibility has not changed from time of Screening; this 
re-confirmation of eligibility is to be reviewed and approved by Sponsor or designee. 
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d. 
Physical examination (PE) to include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory system, skin, psychiatric 
(mental status), and general nutrition.  
e. 
Eye examination (slit lamp) required at Screening and Week 12 (Day 84 ± 3 days) visits, and when clinically indicated. 
f. 
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. 
g. 
List all medications, including those that are administered as part of the tumor resection procedure.  
h. 
Weight at Day -7 to be used for dose calculations for cyclophosphamide and fludarabine; whereas weight at Day 0 to be used for dose calculation for IL-2.  
i. 
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. 
j. 
Pulse oximetry to be conducted during IL-2 administration  
k. 
CMV serology (as per local standard) at Screening, within 3 days of LN-144 infusion, and thereafter as clinically indicated.  
l. 
Syphilis testing (as per local standard; eg, Rapid Plasma Reagin [RPR] venereal disease research laboratory [VDRL], or other) at Screening, at Enrollment (within 7 days of 
tumor resection [required only for tumor samples entering the EU for manufacture of the TIL product in the EU]), and thereafter as clinically indicated.  
m. Cardiac evaluation (stress test) for all patients (per current package insert for IL-2). All patients must have echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA) at Screening. For patients ≥ 60 years or patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias, a cardiac stress tests must be performed showing LVEF ≥45%, and if any wall movement abnormalities, they must be reversible. 
n. 
Required radiographic imaging at Screening, and at Baseline (Day -21 to 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 -21 to 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.  
o. 
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 Day -7 through 
Day -1 and Day +1 through Day +4. 
p. 
Thyroid panel must include TSH and Free T4. Obtain only at Screening, Day 14, and End of Study (EOS) Visit, also at any visit as clinically indicated. 
q. 
Hematology panel must include complete blood count with differential 
r. 
Dipstick urinalysis with culture, if indicated 
s. 
Calculate creatinine clearance using Cockcroft-Gault calculation 
t. 
Serum pregnancy test for women of childbearing potential only. Serum pregnancy testing to continue to Week 52 (Month 12) or EOS visit, whichever occurs first. 
u. 
At Screening, at Enrollment (on the day of tumor resection or within 7 days of tumor resection [required only for tumor samples entering the EU for manufacture of the TIL 
product in the EU]), and when clinically indicated 
v. 
At Screening, at Enrollment (on the day of tumor resection or within 7 days of tumor resection [required only for tumor samples entering the EU for manufacture of the TIL 
product in the EU]), and when clinically indicated 
w. At Screening, at Enrollment (on the day of tumor resection or within 7 days of tumor resection [required only for tumor samples entering the EU for manufacture of the TIL 
product in the EU]), and when clinically indicated 
x. 
Sample for HLA tissue typing to be sent to the central laboratory 
y. 
Pulmonary function testing (PFT) required for all patients at Screening  
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z. 
Colonoscopy only for patients with documented Grade 2 or greater diarrhea or colitis as a result of previous treatment with immune checkpoint inhibitors who have not been 
asymptomatic for at least 6 months. To meet eligibility, patients 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 NMA-LD. 
aa. For detailed instructions on processing and shipment of resected tumor tissue to the manufacturing facility and central laboratory refer to protocol Section 6.2.1: Tumor 
Harvest and Processing Procedures, and the separate Tumor Procurement & Shipping Manual. 
NOTE: All serology testing is to be done on the day of the tumor resection or within 7 days after the resection (required only for tumor samples entering the EU for 
manufacture of the TIL product in the EU).  
bb. The ‘Authorization to Receive Lymphodepletion’ form is to be completed by the Investigator prior to Day -7 (eg, between Day -10 to Day -8) and sent to the Sponsor or 
designee, if acceptable, will be signed and returned to the site prior to the initiation of the NMA-LD preconditioning regimen start on planned Day -7. 
cc. 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. 
dd. The first IL-2 dose should be administered within 3 hours to 24 hours after completion of the LN-144 infusion, and continue every 8 hours for up to protocol-defined 
maximum of 6 doses of 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 (see Section 6.14.2 
and Appendix 6). 
ee. Continue filgrastim until ANC >1000/mm3 × 3 consecutive days or per standard of care at the institution.  
ff. 
The TMP/SMX DS schedule should be adjusted to once-daily (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 
gg. Continue fluconazole until ANC >1000/mm3 or per standard of care at the institution  
hh. In patients positive for HSV, continue until ALC >1000/mm3 or per standard of care at the institution 
ii. 
Blood for immune monitoring to be drawn at Enrollment (tumor resection), Day -7, Day 1, Day 4, Day 14, Day 42, Day 84, Month 6, Month 9 and Month 12. Refer to the 
Laboratory Manual, for vacutainer tubes for peripheral blood draws to be sent to the central laboratory. There is a ± 2-day 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. On Day 1 immune monitoring samples should be drawn prior to IL-2 dosing.  
jj. 
Local tumor assessment (per RECIST 1.1) (scheduled or unscheduled) should be used for clinical treatment decisions, and may include photographic/caliper measurement of 
superficial dermal and subcutaneous lesion. For Independent Review Committee (IRC) tumor assessment, adhere to the IRC Manual for submission of radiographic images.  
kk. All adverse events (AEs) occurring after the patient has signed the informed consent form (ICF), but prior to enrollment (prior to tumor resection), will be collected on the 
medical history eCRF, unless the event is new and attributed to protocol-required procedures or assessments.  
ll. 
Dates of any hospitalization from signing of ICF through the LN-144 Therapy Treatment Period are to be collected in the eCRFs. 
mm. The health-related quality of life (HRQoL) questionnaire EORTC QLQ-C30 is to be completed at Baseline (Day -21 to Day -7), Day 84, and Month 6, Month 12 and 
Month 24 (or EOS/ET) visits.  
nn. Overall Survival (OS) Follow-Up Period will commence when each patient has their last response assessment visit, and will consist of telephone contact made quarterly with 
the patient or designee up until 5 years after the last study treatment. Collect information about subsequent anticancer therapy. 
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Appendix 2 
SCHEDULE OF EVENTS – FOR COHORT 3 PATIENTS 
Assessmentsb 
Screening & 
Enrollment 
Procedures 
Treatment Perioda 
(All visit dates following LN-144 infusion (Day 0)  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response 
Assessment Perioda 
(All visit dates 
following LN-144 
infusion (Day 0) 
calculated from Day 
0 forward) 
End of Study 
(EOS) or 
Early 
Termination 
Visita 
Overall 
Survival 
Follow-
Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks 
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months 
(± 1 Week) 
(Starting at Month 6) 
Early Termination 
Visit 
(Mont 24 [Week 104 ± 
3 Weeks] or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 Weeks) 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationd 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Evaluation and 
measurement of 
skin and palpable 
lesions 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Eye examination 
(slit lamp) 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
Concomitant 
medicationsf 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weightg 
X 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Pulse oximetryi 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
CMV serologj 
X 
 
 
 
 
 
 
Xj 
Xj 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Syphilis testingk 
X 
Xk 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac function 
tests with ECHO or 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessmentsb 
Screening & 
Enrollment 
Procedures 
Treatment Perioda 
(All visit dates following LN-144 infusion (Day 0)  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response 
Assessment Perioda 
(All visit dates 
following LN-144 
infusion (Day 0) 
calculated from Day 
0 forward) 
End of Study 
(EOS) or 
Early 
Termination 
Visita 
Overall 
Survival 
Follow-
Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks 
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months 
(± 1 Week) 
(Starting at Month 6) 
Early Termination 
Visit 
(Mont 24 [Week 104 ± 
3 Weeks] or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 Weeks) 
MUGA. cardiac 
stress testl 
CT chest, abdomen, 
pelvism 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
MRI – brainm 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Serum chemistryn 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid panelo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Hematologyp 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisq 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Calculated 
creatinine clearancer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ß-HCG pregnancy 
tests 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
HIV titret 
X 
Xt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBcAgu 
X 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAgu 
X 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Abv 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV serologyv 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EBV serologyv 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary fuction 
testingw 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessmentsb 
Screening & 
Enrollment 
Procedures 
Treatment Perioda 
(All visit dates following LN-144 infusion (Day 0)  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response 
Assessment Perioda 
(All visit dates 
following LN-144 
infusion (Day 0) 
calculated from Day 
0 forward) 
End of Study 
(EOS) or 
Early 
Termination 
Visita 
Overall 
Survival 
Follow-
Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks 
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months 
(± 1 Week) 
(Starting at Month 6) 
Early Termination 
Visit 
(Mont 24 [Week 104 ± 
3 Weeks] or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 Weeks) 
Colonoscopyx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor resectiony 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ondansetron 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Authorization to 
Receive 
Lymphodepletionz 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
60 mg/kg 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 
25 mg/m2/day 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
LN-144 infusionaa 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IL-2 
600,000 IU/kgbb 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Filgrastimcc 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TMP/SMX DS, or 
appropriate Abxdd 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Fluconazoleee 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Valacyclovir/ 
acyclovirff 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immune 
monitoringgg 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
X 
X 
 
 
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Assessmentsb 
Screening & 
Enrollment 
Procedures 
Treatment Perioda 
(All visit dates following LN-144 infusion (Day 0)  
calculated from Day 0 forward) 
Visits 
Prior to 
Response 
Assessment 
Perioda 
Response 
Assessment Perioda 
(All visit dates 
following LN-144 
infusion (Day 0) 
calculated from Day 
0 forward) 
End of Study 
(EOS) or 
Early 
Termination 
Visita 
Overall 
Survival 
Follow-
Up 
Period 
Screening (up to 
28 days) 
Enrollment/ Tumor 
Resection 
Day -21 to Day -14 
(Baseline) 
Day -7 
Day -6 
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0  
Day 1 
Day 2 
Day 3 
Day 4 
Day 14 (+/- 3 days) 
Day 28 (+/- 3 days) 
Visit Every 6 Weeks 
(±3 days)  
(Weeks 6, 12, and 18) 
Visit Every 3 Months 
(± 1 Week) 
(Starting at Month 6) 
Early Termination 
Visit 
(Mont 24 [Week 104 ± 
3 Weeks] or upon 
Early Termination) 
Visit Every 3 Months / 
Month 27 to Month 60 
(+/- 3 Weeks) 
Tumor assessment 
(local)hh 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Assessment of 
AEs/SAEsii 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hospitalization(s)jj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EORTC QLQ-C30 
HRQoLkk 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Overall survival 
(OS) follow-up 
telephone contactll 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: Ab=antibody; ABX=antibiotics; AE=adverse events; Ag=antigen; ALC=absolute lymphocyte count; ALT=alanine transaminase; ANC=absolute neutrophil count; 
AST=aspartate transaminase; BUN=blood urea nitrogen; CK=creatine kinase; CMV=cytomegalovirus; CT=computed tomography; EBV=Epstein-Barr virus; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EKG=electrocardiogram; EORTC=European Organization for Research and Treatment of Cancer; 
EOS=end of study; HBcAg=hepatitis B virus core antigen; HBsAg=hepatitis B virus surface antigen; β-HCG=β-human chorionic gonadotropin; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; HLA=human leukocyte antigen; HRQoL=health-related quality of life; HSV=herpes simplex virus; IL-2 interleukin-2; 
LD=lymphodepletion; LDH=lactate dehydrogenase; LPLD=last patient last dose; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA=multiple 
gated acquisition; NMA-LD=nonmyeloablative-lymphodepletion; OS=overall survival; PE=physical examination; PET=positron emission tomography; PFT=pulmonary function 
test; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; RPR=rapid plasma reagin; SAE=serious adverse event; SGOT=serum glutamic-oxaloacetic 
transaminase; SGPT=serum glutamic pyruvic transaminase; TIL=tumor-infiltrating lymphocytes; TMP-SMX DS=trimethoprim-sulfamethoxazole double strength; TSH=thyroid-
stimulating hormone; VDRL=venereal disease research laboratory. 
a. 
All visits preceding LN-144 infusion (Day 0) are calculated going backwards (eg, Day -1, Day -2, Day -3, …Day -7, etc), and all visits following LN 144 infusion (Day 0) are 
calculated going forward from Day 0 (eg, Day 1, Day 2, Day 3…Day 28, etc.). 
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b. 
Unscheduled visit(s) for any assessment may be conducted per the medical judgement of Investigator. List all medications even those that are part of the tumor resection 
procedure. 
c. 
Re-check of Inclusion/Exclusion Criteria at Baseline (Day -21 to Day -7) to ensure that patient performance status and eligibility has not changed from time of Screening; this 
re-confirmation of eligibility is to be reviewed and approved by Sponsor or designee. 
d. 
Physical examination (PE) to include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory system, skin, psychiatric 
(mental status), and general nutrition.  
e. 
Eye examination (slit lamp) required at Screening and Week 12 (Day 84 ± 3 days) visits, and when clinically indicated. 
f. 
List all medications, including those that are administered as part of the tumor resection procedure.  
g. 
Weight at Day -7 to be used for dose calculations for cyclophosphamide and fludarabine; whereas weight at Day 0 to be used for dose calculation for IL-2.  
h. 
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. 
i. 
Pulse oximetry to be conducted during IL-2 administration  
j. 
CMV serology (as per local standard) at Screening, within 3 days of LN-144 infusion and thereafter as clinically indicated.  
k. 
Syphilis testing (as per local standard; eg, Rapid Plasma Reagin [RPR] venereal disease research laboratory [VDRL], or other) at Screening, at Enrollment (within 7 days of 
tumor resection [required only for tumor samples entering the EU for manufacture of the TIL product in the EU]), and thereafter as clinically indicated. 
l. 
Cardiac evaluation (stress test) for all patients (per current package insert for IL-2). All patients must have echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA) at Screening. For patients ≥ 60 years or patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias, a cardiac stress tests must be performed showing LVEF ≥45%, and if any wall movement abnormalities, they must be reversible. 
m. Required radiographic imaging at Screening, and at Baseline (Day -21 to 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 -21 to 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.  
n. 
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 Day -7 through 
Day -1 and Day +1 through Day +4. 
o. 
Thyroid panel must include TSH and Free T4. Obtain only at Screening, Day 14, and End of Study (EOS) Visit, also at any visit as clinically indicated. 
p. 
Hematology panel must include complete blood count with differential 
q. 
Dipstick urinalysis with culture, if indicated 
r. 
Calculate creatinine clearance using Cockcroft-Gault calculation 
s. 
Serum pregnancy test for women of childbearing potential only. Serum pregnancy testing to continue to Week 52 (Month 12) or EOS visit, whichever occurs first. 
t. 
At Screening, at Enrollment (on the day of tumor resection or within 7 days of tumor resection [required only for tumor samples entering the EU for manufacture of the TIL 
product in the EU]), and when clinically indicated. Serology for infection must be repeated for Cohort 3 patients if there is >30 days from the last test results.  
u. 
At Screening, at Enrollment (on the day of tumor resection or within 7 days of tumor resection [required only for tumor samples entering the EU for manufacture of the TIL 
product in the EU]), and when clinically indicated. Serology for infection must be repeated for Cohort 3 patients if there is >30 days from the last test results. 
v. 
At Screening, at Enrollment (on the day of tumor resection or within 7 days of tumor resection [required only for tumor samples entering the EU for manufacture of the TIL 
product in the EU]), and when clinically indicated. Serology for infection must be repeated for Cohort 3 patients if there is >30 days from the last test results. 
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w. Pulmonary function testing (PFT) required for all patients at Screening  
x. 
Colonoscopy only for patients with documented Grade 2 or greater diarrhea or colitis as a result of previous treatment with immune checkpoint inhibitors who have not been 
asymptomatic for at least 6 months. To meet eligibility, patients 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 NMA-LD. 
y. 
For detailed instructions on processing and shipment of resected tumor tissue to the manufacturing facility and central laboratory refer to protocol Section 6.2.1: Tumor 
Harvest and Processing Procedures, and the separate Tumor Procurement & Shipping Manual. 
NOTE: All serology testing is to be done on the day of the tumor resection or within 7 days after the resection (required only for tumor samples entering the EU for 
manufacture of the TIL product in the EU).  
z. 
The ‘Authorization to Receive Lymphodepletion’ form is to be completed by the Investigator prior to Day -7 (eg, between Day -10 to Day -8) and sent to the Sponsor or 
designee, if acceptable, will be signed and returned to the site prior to the initiation of the NMA-LD preconditioning regimen start on planned Day -7. 
aa. 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. 
bb. The first IL-2 dose should be administered within 3 hours to 24 hours after completion of the LN-144 infusion, and continue every 8 hours for up to protocol-defined 
maximum of 6 doses of 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 (see Section 6.14.2 
and Appendix 6). 
cc. Continue filgrastim until ANC >1000/mm3 × 3 consecutive days or per standard of care at the institution.  
dd. The TMP/SMX DS schedule should be adjusted to once-daily (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 
ee. Continue fluconazole until ANC >1000/mm3 or per standard of care at the institution  
ff. 
In patients positive for HSV, continue until ALC >1000/mm3 or per standard of care at the institution 
gg. Blood for immune monitoring to be drawn at Enrollment (tumor resection), Day -7, Day 1, Day 4, Day 14, Day 42, Day 84, Month 6, Month 9 and Month 12. Refer to the 
Laboratory Manual, for vacutainer tubes for peripheral blood draws to be sent to the central laboratory. There is a ± 2-day 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. On Day 1 immune monitoring samples should be drawn prior to IL-2 dosing.  
hh. Local tumor assessment (per RECIST 1.1) (scheduled or unscheduled) should be used for clinical treatment decisions, and may include photographic/caliper measurement of 
superficial dermal and subcutaneous lesion. For Independent Review Committee (IRC) tumor assessment, adhere to the IRC Manual for submission of radiographic images.  
ii. 
All adverse events (AEs) occurring after the patient has signed the informed consent form (ICF), prior before enrollment (prior to tumor resection), will be collected on the 
medical history eCRF, unless the event is new and attributed to protocol-required procedures or assessments.  
jj. 
Dates of any hospitalization from signing of ICF through the LN-144 Therapy Treatment Period are to be collected in the eCRFs. 
kk. The health-related quality of life (HRQoL) questionnaire EORTC QLQ-C30 is to be completed at Baseline (Day -21 to Day -7), Day 84, and Month 6, Month 12 and Month 
24 (or EOS/ET) visits.  
ll. 
Overall Survival (OS) Follow-Up Period will commence when each patient has their last response assessment visit, and will consist of telephone contact made quarterly with 
the patient or designee up until 5 years after the last study treatment. Collect information about subsequent anticancer therapy. 
 
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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 (eg, 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 et al, 1982 [63]  
 
 
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Appendix 4 
PRACTICAL WEIGHT 
Modification of Dose Calculations* in Patients whose BMI is > 35 mg/m2 
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 6 
EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT1 
Expected toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
Stop  
Treatment ** 
Chills 
3 
IV Meperidine 25 to 50 mg, 
IV q1h, prn, 
No 
No 
Fever 
3 
Acetaminophen 650 mg, po, 
q4h; Indomethacin 50 to 
75 mg, po, q8h 
No 
No 
Pruritus 
3 
Hydroxyzine HCl 10 to 
20 mg po q6h, prn; 
Diphenhydramine HCl 25 to 
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 to 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 to 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 
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 
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Expected toxicity 
Expected 
grade 
Supportive Measures 
suggested 
Stop Cycle* 
Stop  
Treatment ** 
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 
(Day -21 to 
Day -14) levels 
by next dose 
Myocardial 
Infarction 
3 
Supportive care 
Yes 
Yes 
Elevated 
transaminases 
3 or 4 
Observation 
For Grade 4 
without liver 
metastases 
If changes have 
not improved 
to Baseline 
(Day -21 to 
Day -14) levels 
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.  
Proleukin® Prescribing Information – January 2012 [9] 
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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 
Cyclophospamide, Full Prescribing Information, 2013 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdf 
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CONFIDENTIAL & PROPRIETARY 
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Final, Dated 23 March 2018 
Appendix 9 
MESNA (MEXNEX®) PACKAGE INSERT 
Mesna (Mesnex®), Full Prescribing Information, Sargeant Pharmaceutials, July 2015 
http://www.sagentpharma.com/wp-content/uploads/2016/01/Mesna_PI.pdf 
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Final Version 7.0 
CONFIDENTIAL & PROPRIETARY 
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Appendix 10 
ONDANSETRON PACKAGE INSERT 
Ondansetron hydrochloride (Zofran®), Full Prescribing Information, Novartis, 
October 2017 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zofran.pdf 
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Final Version 7.0 
CONFIDENTIAL & PROPRIETARY 
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Final, Dated 23 March 2018 
Appendix 11 
FILGRASTIM PACKAGE INSERT 
Filgrastim (Neupogen®), Full Prescribing Information, Amgen, 2016. 
https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-
com/neupogen/neupogen_pi_hcp_english.pdf 
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Protocol C-144-01 
Final Version 7.0 
CONFIDENTIAL & PROPRIETARY 
Page 134 of 140 
Final, Dated 23 March 2018 
Appendix 12 
FLUCONAZOLE PACKAGE INSERT 
Fluconazole (Diflucan®), Full Prescribing Information Pfizer, 2016. 
http://labeling.pfizer.com/ShowLabeling.aspx?id=575 
 
 
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Final Version 7.0 
CONFIDENTIAL & PROPRIETARY 
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Appendix 13 
FLUDARABINE PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020038s032lbl.pdf 
 
 
 
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CONFIDENTIAL & PROPRIETARY 
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Final, Dated 23 March 2018 
Appendix 14 
IL-2 (ALDESLEUKIN) PACKAGE INSERT 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf 
 
 
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CONFIDENTIAL & PROPRIETARY 
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Appendix 15 
EORTC QLQ-C30 
 
This page intentionally left blank. 
 
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CONFIDENTIAL & PROPRIETARY 
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Final Version 7.0 
CONFIDENTIAL & PROPRIETARY 
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Appendix 16 
SUMMARY OF CHANGES (MAJOR/MINOR) IN PROTOCOL 
C-144-01 VERSION 7.0 (DATED, 23 March 2018) 
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 
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 6.0 to Version 7.0, and includes rationale for the changes. 
 
 
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