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.



Iovance Biotherapeutics Inc. 
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Protocol C-144-01 
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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 
EudraCT Number 
2017-000760-15 
Sponsor: 
Iovance Biotherapeutics Inc. 
Version / Date of 
Protocol: 
Version 9.0  
22 Oct 2019 
 
I agree to conduct the study as detailed in the protocol and in compliance with 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice 
(GCP). 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 receive 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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RATIONALE FOR PROTOCOL AMENDMENT 
The purpose of this amendment of Protocol C-144-01 from Version 8.0 to 9.0 is to 
incorporate nonsubstantial changes communicated via Version 8.0, Addendum 1 and 
other changes as specified below. In addition, the amendment incorporates administrative 
changes, including correction of inconsistent language and typographical errors. 
Main changes include: 
• Incorporation of the product release specification for total viable cells and 
clarification that patients will receive the full dose of product manufactured and 
released (Protocol Version 8.0, Addendum 1) 
• Addition of the Independent Data Monitoring Committee (IDMC) (Protocol 
Version 8.0, Addendum 1) 
• Clarification of the Data Safety Monitoring Board (DSMB) responsibility for 
Cohort 3 (Protocol Version 8.0, Addendum 1) 
• Clarification on the interim analysis (Protocol Version 8.0, Addendum 1) 
• Changes/clarification of study procedures, including hospitalization requirement, 
acceptable laboratory tests for viral infection and coagulation, and dosing 
calculation of chemotherapy using body weight  
• Change of baseline brain MRI window from 3 weeks to 4 weeks prior to Day 0, to 
minimize unnecessary scan if not clinically indicated 
 
See below for a comprehensive list of all changes with rationale. 
Changes 
Rationale 
Change in the primary Medical Monitor 
Administrative change 
Section 2.1 (and others) Description of the Study  
Change Blinded Independent Review Committee (BIRC) 
to Independent Review Committee (IRC) 
Administrative change to the 
committee name to reflect the 
open-label nature of the study; the 
composition and the 
responsibilities of the committee 
are unchanged. 
Section 4.1 Inclusion Criteria 
k. Patients with immunotherapy-related endocrinopathies 
stable for at least 6 weeks (eg, hypothyroidism, adrenal 
insufficiency, and hypophysitis stable on hormonal 
substitution), and controlled with hormonal replacement 
(non-corticosteroids), are allowed 
To maintain consistency with 
exclusion criteria ‘f’ and Section 
6.2.1. Prohibited Treatment (and 
others). No systemic 
corticosteroids are allowed even 
for hormonal replacement at 
physiological dose levels from 21 
days prior to lymphodepletion to 
60 days post-TIL infusion. 
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Changes 
Rationale 
Section 4.2 (and others) Exclusion Criteria 
Addition of anti-HBc antibody as part of the serology test 
to exclude HBV infection. 
Add anti-HBc to the serology 
panel as part of the US and EU 
regulatory requirements for 
autologous donor sample 
handling 
Section 4.2 (and others) Exclusion Criteria 
Exclude acute infection per protocol for CMV, EBV, and 
HSV  
Clarify that IgM tests required for determining 
presence/absence of active infection and PCR is an 
acceptable method if IgM is tested positive or when IgM 
tests are not available at the site 
To specify that IgM will be 
required serology test to exclude 
acute viral infection and to allow 
PCR assay as part of evaluation 
for any acute/active viral 
infections, per institutional 
standards 
Section 5.1 (and others) Screening  
Evaluation and measurement of skin and palpable lesions 
may be performed (if applicable). but will not be sent for 
central review  
Administrative change to 
maintain consistency across 
protocol 
Section 5.1 (and others) Screening 
Remove reticulocyte count from the test panel. 
This test does not provide 
information that adds to results 
from the tests already included in 
the CBC panel. 
Section 5.1 Screening and Appendix 3 Assessments 
Coagulation tests clarified that either aPTT + INR or PT + 
INR 
Clarification of the requirement 
of a coagulation panel 
Section 5.1 Screening and Appendix 3 
Creatinine Creatine kinase 
Correct spelling 
Section 5.1 (and others) Screening 
Magnetic resonance imaging (MRI) or positron emission 
tomography (PET) scans will be allowed in lieu of CT 
scans for patients who have an intolerability to contrast 
media; the same imaging modality must be used 
throughout the duration of the study. High-resolution CT 
with PO/IV contrast or contrast-enhanced MRI is the 
preferred imaging modality for assessing radiographic 
tumor response. If a patient has a known allergy to CT 
contrast material, please use the alternate modality. In 
cases where contrast is strictly contraindicated, a non-
contrast scan is acceptable. The same imaging modality 
must be used throughout the duration of the study. 
PET is not an allowable modality 
for RECIST assessment. PET 
alone is not sufficient for tumor 
assessment. 
Section 5.2.1 Tumor Harvest and Processing Procedures 
Tumor specimens must undergo intraoperative frozen 
section (or FNA) or touch prep cytology examination by 
a pathologist to ensure that viable tumor is present. 
To add additional text to verify 
presence of tumor during harvest.  
Adding additional text to ensure 
that tumor should still be shipped 
for manufacturing despite a 
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Changes 
Rationale 
Intraoperative frozen section (or FNA) or touch prep 
cytology examination is not a gold standard.  If any of 
the above-mentioned methods is found to contain no 
viable tumor, the expert opinion of the pathologist and 
surgeon at the time of surgery will supersede, and if 
they believe there is viable tumor, the resected sample 
should still be sent for manufacturing.    
negative finding of viable tumor 
cells. 
Section 5.3 (and others) Baseline (Day -21 to Day  
-10) Procedures 
If a brain MRI was performed within 3 4 weeks prior to 
Day 0 and considered normal or stable, and the patient is 
not showing any clinical symptoms of progression in the 
brain, then a brain MRI does not need to be repeated. 
Expand the window for the 
baseline brain MRI listed in 
protocol Version 8 to reduce the 
unnecessary scan if not clinically 
indicated 
Section 5.4 Patients Who Do Not Receive an LN-144 
Infusion Procedure 
Added language: Patients who meet inclusion and 
exclusion criteria and do not receive LN-144 (eg, due to a 
manufacturing failure) may be rescreened after 
consultation with the Medical Monitor. 
To allow for rescreening the case 
of a manufacturing failure 
Section 5.5.1 (and others) Day -7 Procedures 
Cyclophosphamide and mesna dosing clarified to be 
consistent with prior protocol versions.  
To provide additional details and 
clarifications of mesna dosing 
Section 5.5.1 (and others) Day -7 Procedures 
Allow the use of body weight within 7 days of the start of 
chemotherapy to calculate the doses, per institutional 
standards. 
To allow sites to follow 
institutional standards for body 
weight measurement 
Section 5.5.3 Day -5 to Day -1 Procedures 
Fludarabine (25 mg/m2) to be given IV over 
approximately 30 minutes, once daily. each day. and may 
be stopped after two doses if absolute lymphocyte count 
(ALC) < 100/mm3  
This is to clarify that the full 
course  of fludarabine (5 doses) 
should be given to ensure a 
thorough lymphodepletion. Dose 
hold or discontinuation will only 
be allowed in the case of toxicity 
described in the package insert or 
per institutional guidance 
Section 5.5.4.2 (and others) LN-144 Infusion 
Add the product release specification of total number of 
viable cells between 1 x 109 and 150 x 109 per lot of LN-
144 product and clarify that patients will receive the full 
dose of product manufactured and released. 
Incorporate the changes listed in 
protocol Version 8.0, Addendum 
1 to this protocol amendment 
Section 5.5.4.2.1 (and others) IL-2 Dosing and Dose 
Adjustments 
Allow the use of body weight within 7 days of the start of 
IL-2 to calculate the dose, per institutional standards  
To allow sites to follow 
institutional standards for body 
weight measurement 
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Changes 
Rationale 
Section 5.5.5 Day 1, Day 2, Day 3, and Day 4 Procedures 
Filgrastim (5 µg/kg/day) or biosimilar will be 
administered beginning on Day 1 by subcutaneous 
injection and continue each day until the ANC reaches > 
1000/mm3 for three consecutive days, discontinue if ANC 
rises to > 10,000/mm3, or follow institutional standards. 
To provide additional 
clarification on stopping rule per 
package insert and institutional 
standard. 
Section 5.8 (and others) Hospitalization 
Protocol-mandated hospitalization was clarified. 
Iovance does not require 
hospitalization during NMA-LD 
and defers to institutional 
guidelines.  
Section 7.4.3 Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg PO or IV daily on 
Day 1 and continue until the ALC ANC is > 1000/mm3, or 
as per institutional standards. If ALC ANC count remains 
< 1000/mm3 at 6 months post-chemotherapy, prophylaxis 
will continue until the CD4 count is > 200/mm3 for at least 
6 months, or as per institutional standards. 
To correct a typographical error 
Section 10.1 Tumor Response Assessments 
Added language: Photographic documentation and caliper 
measurement will be performed for superficial dermal and 
subcutaneous lesions that cannot be assessed by 
radiographic scan. 
To clarify documentation and 
measurement of tumors. 
Section 10.1 Tumor Response Assessments 
High-resolution CT with PO/IV contrast or contrast-
enhanced MRI is the preferred imaging modality for 
assessing radiographic tumor response. If a patient has a 
known allergy to CT contrast material, please use the 
alternate modality. In cases where contrast is strictly 
contraindicated, a non-contrast scan will suffice. 
To update the preferred imaging 
modality to comply with RECIST 
and to consider contraindication 
contrast scans. 
Section 11.3.1 Primary Endpoint 
Patients without any baseline or post-baseline tumor 
measurements are considered non-evaluable. 
To clarify the analysis population  
Section 11.3.2 Secondary Endpoints 
For patients who received new anticancer therapies, the 
DOR will be censored at the date of last tumor response 
assessment prior to the start of new anticancer therapies. 
For clinical information and 
clarification on DOR calculation. 
Section 11.5 Interim Final Analysis 
All references to an interim analysis of data for Cohort 4 
were deleted. 
Incorporate the changes listed in 
protocol Version 8.0, Addendum 
1 to this protocol amendment 
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Changes 
Rationale 
Section 12.3 Data Safety Monitoring Board 
Clarify DSMB responsibility to only review data for 
Cohort 3 (Re-treatment Cohort) when 3 patients have been 
enrolled into Cohort 3, have received their second LN-144 
infusion, and 28 days have elapsed (end-of-treatment visit 
and safety assessments). 
Incorporate the changes listed in 
protocol Version 8.0, Addendum 
1 to this protocol amendment 
Section 13 Independent Data Monitoring Committee 
Add the IDMC to the protocol to ensure highest quality, 
scientific, and ethical standards, and consistency of study 
conduct as well as data collection and analysis across 
international study sites.  
Incorporate the changes listed in 
protocol Version 8.0, Addendum 
1 to this protocol amendment 
Section 14.1 Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) 
The Sponsor’s Statement of Investigator Commitments 
was added to the forms that could be signed to assure that 
all aspects of institutional review will be conducted in 
accordance with applicable regulations. 
Form 1572 (FDA Statement of 
Investigator) is not completed by 
all sites but an equivalent form is 
completed. 
Section 15.7 Publications 
The Sponsor will be responsible for determining when the 
study results should be published after discussion with 
the Steering Committee. 
The Sponsor will discuss with the 
Steering Committee to determine 
when study results will be 
published. 
Appendix 1 Schedule of Assessments (SOA) 
Changes made throughout the protocol were carried 
through to the SOA. 
To align the body of the protocol 
with the SOA 
Appendix 3 Assessments 
Allow the sites to calculate BSA and BMI using formulas 
per site standard practice. 
To allow sites to follow 
institutional standards for body 
weight measurement 
 
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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: 
Patients with unresectable or metastatic melanoma who have previously 
been treated with at least one systemic therapy including a PD-1 blocking 
antibody and if BRAF V600 mutation positive, a BRAF inhibitor or BRAF 
inhibitor with MEK inhibitor. 
Investigational Agent: 
LN-144: Autologous tumor infiltrating lymphocytes (TIL) derived from 
the patient’s tumor. 
Study Objectives: 
Primary Objective 
• 
Evaluate the efficacy of LN-144 in patients with unresectable or 
metastatic melanoma using the objective response rate (ORR), as 
assessed by the Independent Review Committee (IRC) per Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Secondary Objectives 
• 
Evaluate the efficacy endpoints of duration of response (DOR), 
disease control rate (DCR), and progression-free survival (PFS), as 
assessed by the IRC per RECIST v1.1  
• 
Further evaluate efficacy of LN-144 in patients with unresectable or 
metastatic melanoma by assessing ORR, DOR, DCR, and PFS, as 
assessed by the Investigator per RECIST v1.1 
• 
Evaluate overall survival (OS) 
• 
Characterize the safety profile of LN-144 in patients with unresectable 
or metastatic melanoma 
Exploratory Objectives 
• 
Explore the persistence of LN-144 and potential immune correlates of 
response, outcome, and toxicity of the treatment 
• 
Explore efficacy based on immune-related RECIST (irRECIST) 
criteria, as assessed by the Investigator 
• 
Assess health-related quality of life (HRQoL) 
Study Design: 
Prospective, interventional multicenter study evaluating adoptive cell 
therapy (ACT) via infusion of LN-144 (autologous TIL) followed by 
interleukin-2 (IL-2) after a nonmyeloablative lymphodepletion (NMA-LD) 
preconditioning regimen.  
Dose and Treatment 
Schedule: 
The cell transfer therapy used in this study involves patients receiving an 
NMA-LD preconditioning regimen, consisting of daily intravenous (IV) 
cyclophosphamide (60 mg/kg; IV × 2 doses) followed by daily fludarabine 
(25 mg/m2; IV × 5 doses). Infusion of LN-144 is given on Day 0 and is 
followed by administration of IL-2 at 600,000 international units (IU)/kg 
approximately every 8–12 hours for up to a maximum of six doses, starting 
approximately 3–24 hours after completion of LN-144 infusion.  
Duration of Study 
Participation and Study 
Periods: 
Overall duration of the study will be approximately 5 years comprising the 
following periods: 
Screening: Up to 28 days from signing of the informed consent form 
(ICF). 
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Enrollment: Upon tumor resection for TIL generation. 
Treatment Period: NMA-LD preconditioning regimen (up to 7 days), 
LN-144 infusion (1 day), IL-2 administration (up to 4 days), continuing to 
Day 28. Patients will need to return for safety assessment visits on Day 14 
and Day 28 (Day 28 corresponds with the End of Treatment [EOT] visit). 
Assessment Period: Following the EOT visit, efficacy (eg, tumor 
response) assessments will be performed at Week 6 (Day 42) post-LN-144 
infusion and then occur every 6 weeks until Month 6 (Week 24). Patients 
will continue to be evaluated for response every 3 months (12 weeks) for 
up to 5 years from Day 0 (LN-144 infusion) or until: 
• 
Disease progression  
• 
Start of a new anticancer therapy 
At that time, the End of Assessment (EOA) visit will be completed. 
Overall Survival Follow-up Period: Begins after completion of the last 
study assessment (eg, EOA) and will continue for up to 5 years from 
Enrollment (tumor resection) or until discontinuation from the study; with 
telephone contact every 3 months to obtain survival status and subsequent 
anticancer therapy information. Patients who had tumor resection but did 
not receive LN-144 for any reason will perform an EOA visit and 
transition directly into the OS Follow-up Period. 
Number of Study 
Centers: 
Approximately 60 enrolling clinical sites in North America and Europe. 
Number of Planned 
Patients: 
The total number of planned patients to be infused in this study will be 
approximately 164. 
Cohort 1: Infused 23 patients and is now closed. 
Cohort 2: Will infuse approximately 66 patients and is now closed to 
Screening. 
Cohort 3: Will include approximately 10 patients who have been 
previously treated in Cohort 1, Cohort 2 or Cohort 4 of this study, for a 
second administration of the cryopreserved TIL product. 
Cohort 4: Approximately 75 patients are planned to be infused. 
Study Population: 
Diagnosis and Main 
Criteria for Inclusion: 
Patients must meet all of the following inclusion criteria to be eligible for 
participation in the study:  
a. 
Patients with unresectable or metastatic melanoma (Stage IIIc or 
Stage IV)  
b. Patients must have progressed following ≥ 1 prior systemic therapy 
including a programmed cell death protein-1 (PD-1) blocking 
antibody; and if proto-oncogene B-Raf (BRAF) V600 mutation-
positive, a BRAF inhibitor or BRAF inhibitor in combination with 
mitogen-activated extracellular signal-regulated kinase (MEK) 
inhibitor 
c. 
Prior to study Enrollment, documentation of radiological disease 
progression after the most recent therapy  
d. At least one measurable target lesion, as defined by RECIST v1.1  
• 
Lesions in previously irradiated areas (or other local therapy) 
should not be selected as target lesions, unless treatment was 
≥ 3 months prior to Screening, and there has been demonstrated 
disease progression in that particular lesion  
• 
If a lesion is partially resected to generate TIL, and remains 
visible on the Baseline scan after surgery, then the partially 
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resected lesion can be used for RECIST v1.1 response 
assessment, but only as a non-target lesion  
e. 
At least one resectable lesion (or aggregate of lesions resected) of a 
minimum 1.5 cm in diameter post-resection to generate TIL; surgical 
removal with minimal morbidity (defined as any procedure for which 
expected hospitalization is ≤ 3 days) 
f. 
Patients must be ≥ 18 years of age at the time of consent. Enrollment 
of patients > 70 years of age may be allowed after consultation with 
the Medical Monitor  
g. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 and an estimated life expectancy of 
≥ 3 months  
h. In the opinion of the Investigator, patients must be able to complete all 
study-required procedures 
i. 
Patients must have the following hematologic parameters: 
• 
Absolute neutrophil count (ANC) ≥ 1000/mm3  
• 
Hemoglobin (Hb) ≥ 9.0 g/dL 
• 
Platelet ≥ 100,000/mm3 
Note: Transfusions or growth factors are not allowed 28 days prior to 
signing the ICF and continuing through the Screening Period  
j. 
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 
• 
Estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the 
Cockcroft-Gault formula  
• 
Total bilirubin ≤ 2 mg/dL 
o 
Patients with Gilbert’s syndrome must have a total bilirubin 
≤ 3 mg/dL 
k. 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)  
• 
Patients with documented ≥ Grade 2 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 tumor resection  
• 
Patients with immunotherapy-related endocrinopathies stable for 
at least 6 weeks (eg, hypothyroidism), and controlled with 
hormonal replacement (non-corticosteroids), are allowed  
l. 
Patients must have a washout period ≥ 28 days from prior anticancer 
therapy(ies) to the start of the planned NMA-LD preconditioning 
regimen:  
• 
Targeted therapy: MEK/BRAF or other targeted agent 
• 
Chemotherapy  
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• 
Immunotherapy: anti-cytotoxic T lymphocyte-associated antigen 
4 (CTLA-4)/anti-PD-1, other monoclonal antibody (mAb), or 
vaccine  
• 
Palliative radiation therapy is permitted so long as it does not 
involve lesions being selected for TIL, or as target or non-target 
lesions. Washout is not required if all related toxicities have 
resolved to ≤ Grade 1 as per CTCAE v4.03 
m. Patients of childbearing potential or their partners of childbearing 
potential must be willing to take the appropriate precaution to avoid 
pregnancy or fathering a child for the duration of the study and 
practice an approved, highly effective method of birth control during 
treatment and for 12 months after receiving the last protocol-related 
therapy 
• 
Approved methods of birth control are as follows: 
o 
Combined (estrogen and progesterone containing) hormonal 
birth control associated with inhibition of ovulation: oral, 
intravaginal, transdermal 
o 
Progesterone-only hormonal birth control associated with 
inhibition of ovulation: oral, injectable, implantable 
o 
Intrauterine device (IUD) 
o 
Intrauterine hormone-releasing system (IUS) 
o 
Bilateral tubal occlusion 
o 
Vasectomized partner 
o 
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 
n. Patients (or legally authorized representative) must have the ability to 
understand the requirements of the study, have provided written 
informed consent as evidenced by signature on an 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, including the OS Follow-up Period 
o. Patients have provided written authorization for use and disclosure of 
protected health information 
Main Criteria for 
Exclusion: 
Patients who meet any of the following criteria are not eligible for 
participation in this study:  
a. 
Patients who have been shown to be BRAF mutation positive (V600), 
but have not received prior systemic therapy with a BRAF inhibitor 
alone or a BRAF inhibitor in combination with a MEK inhibitor 
b. Patients who have received an organ allograft or prior cell transfer 
therapy  
c. 
Patients with melanoma of uveal/ocular origin 
d. Patients who have a history of hypersensitivity to any component or 
excipient of LN-144 or other study drugs:  
• 
NMA-LD preconditioning regimen (cyclophosphamide, mesna, 
and fludarabine) 
• 
Antibiotics (ABX) of the aminoglycoside group (ie, streptomycin, 
gentamicin); except those who are skin-test negative for 
gentamicin hypersensitivity 
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• 
Any component of the LN-144 infusion product formulation 
including dimethyl sulfoxide (DMSO), human serum albumin 
(HSA), IL-2, and dextran-40  
e. 
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, and must be stable for ≥ 14 days prior 
to beginning the NMA-LD preconditioning regimen 
f. 
Patients who are on chronic systemic steroid therapy for any reason  
g. Patients who have active medical illness(es) that would pose 
increased risk for study participation, including: active systemic 
infections requiring systemic ABX, coagulation disorders, or other 
active major medical illnesses of the cardiovascular, respiratory, or 
immune system  
h. Patients who have ≥ Grade 2 hemorrhage within 14 days prior to 
Enrollment (tumor resection) 
i. 
Patients who are seropositive for any of the following:  
• 
Human immunodeficiency virus (HIV)-1 or HIV-2 antibodies 
• 
Hepatitis B antigen (HBsAg), hepatitis B core antibody (anti-
HBc), or hepatitis C antibody (HCV Ab). Patients with acute or 
chronic hepatitis infections may be enrolled if the viral load by 
polymerase chain reaction (PCR) is undetectable with/without 
active treatment.  
• 
Syphilis (Rapid Plasma Reagin [RPR] test or venereal disease 
research laboratory [VDRL] test) 
• 
Cytomegalovirus (CMV) IgM antibody titer or PCR assay; and 
Epstein-Barr virus (EBV) IgM or PCR assay indicating active 
infection 
• 
Positive herpes simplex virus (HSV)-1 and HSV-2 IgM serology 
or PCR assay 
o 
Patients who are HSV immunoglobulin M (IgM) or PCR 
assay positive will need to receive appropriate treatment and 
become IgM or PCR assay negative prior to starting the 
NMA-LD preconditioning regimen 
j. 
Patients who have any form of primary immunodeficiency (such as 
severe combined immunodeficiency disease [SCID] and acquired 
immunodeficiency syndrome [AIDS]) 
k. Patients who have a left ventricular ejection fraction (LVEF) < 45% 
or New York Heart Association (NYHA) functional classification > 
Class 1  
• 
Patients ≥ 60 years of age and who have a history of ischemic 
heart disease, chest pain, or clinically significant atrial and/or 
ventricular arrhythmias must have a cardiac stress test. Patients 
with any irreversible wall movement abnormalities are excluded 
l. 
Patients who have a documented forced expiratory volume in 1 
second (FEV1) of ≤ 60% 
m. 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)  
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n. Patients who have received a live or attenuated vaccine within 28 
days of beginning the NMA-LD preconditioning regimen 
o. Patients who are pregnant or breastfeeding 
p. Patients whose cancer requires immediate attention or who would 
otherwise suffer a disadvantage by participating in this trial 
q. 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 infusion is preceded by an NMA-LD preconditioning regimen of 
cyclophosphamide, and fludarabine, and followed by IL-2, as an open-
label treatment 
Cohort 1: Patients received LN-144, non-cryopreserved TIL product 
• 
Note: Cohort 1 is closed to Enrollment  
Cohort 2: Patients to receive LN-144, cryopreserved TIL product 
• 
Note: Cohort 2 is closed to Screening  
Cohort 3: Patients from Cohort 1, Cohort 2, or Cohort 4, after having 
participated in the study and received LN-144, may rescreen for a second 
administration of LN-144, cryopreserved TIL product 
• 
Note: Patients in Cohort 3 must meet the inclusion and exclusion 
criteria (except exclusion criterion “b”). These patients may have 
a second tumor resection, if needed; especially when new lesions 
are available and feasible for resection. The decision for 
Enrollment into Cohort 3 will be based on discussion between the 
Investigator and the Medical Monitor  
Cohort 4: Patients to receive LN-144, cryopreserved TIL product 
• 
Note: Cohort 4 is open to enroll new patients 
Criteria for 
Discontinuation from 
Treatment: 
• 
Withdrawal of consent to treatment  
o 
Every effort should be made to continue OS Follow-up, when 
applicable 
• 
Grade ≥ 3 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 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 
(must have received at least one dose of IL-2; Appendix 5)  
• 
Determination by the Investigator that continued treatment is not in 
the best interest of the patient 
• 
Administration of prohibited concomitant medications/start of new 
anti-cancer therapy 
• 
Death 
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Criteria for 
Discontinuation from the 
Study: 
• 
Withdrawal of consent  
• 
Lost to follow-up  
• 
Death 
• 
Study terminated by the Sponsor 
Efficacy Assessment: 
Calculated from Day 0 (LN-144 infusion). The statistical analysis of the 
ORR, DOR, DCR, and PFS per cohort will be provided to determine the 
potential efficacy of LN-144, as assessed by the IRC per RECIST v1.1. 
Estimation of OS will depend on the date of death or the last known alive 
status.  
Safety Assessment: 
 
At each scheduled visit to the clinical site, AEs/serious adverse events 
(SAEs) will be collected and graded as per CTCAE v4.03, starting from 
signing the ICF until the end of the study. Analyses will include all study 
periods.  
Overview of Statistical 
Plan 
The statistical analysis is based on the estimation of efficacy and safety 
parameters and will be performed by cohort. There is no planned statistical 
comparison among cohorts. Patients who are retreated with LN-144 
(Cohort 3) will have their safety and efficacy data tabulated separately. 
Patients meeting RECIST v1.1 criteria for a confirmed complete response 
(CR) or partial response (PR) as assessed by the IRC will be classified as 
responders in the analysis of the primary endpoint ORR. The ORR will be 
analyzed using a point estimate and its two-sided confidence limits based 
on the Clopper-Pearson exact method at an overall alpha level of 0.05. All 
other binary endpoints will be analyzed similarly as the primary endpoint. 
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 received LN-144 
infusion.  
The assessment of safety data will be descriptive and based on: 1) the 
summarization of treatment-emergent adverse events (TEAEs), SAEs, AEs 
leading to discontinuation from treatment; and 2) the study vital signs and 
clinical laboratory tests.  
Sample Size 
Consideration: 
Cohort 1 (closed to Enrollment): Infused 23 patients using the non-
cryopreserved autologous TIL product manufacturing process. 
Cohort 2 (closed to Screening): The planned number of patients to be 
infused with cryopreserved LN-144 is approximately 66. Sixty patients 
will allow estimation of ORR using the maximum half width of the two-
sided 95% confidence limit of less than 13.2% (Clopper-Pearson) when 
ORR is expected to range from 20–50%. 
Cohort 4: Approximately 75 patients are planned to be infused based on 
the null hypothesis of 10% ORR, which is based on historical control. This 
sample size will result in over 90% power to demonstrate superiority to 
this historical ORR using a conservative assumption for TIL therapy of 
25% and two-sided overall significance level of 0.05. 
Data Safety Monitoring 
Board Safety 
Assessments: 
An independent Data Safety Monitoring Board (DSMB) has evaluated 
cumulative safety data as specified in the DSMB charter for Cohort 1 and 
Cohort 2.  
A DSMB meeting will also take place after 3 patients have been treated in 
Cohort 3 and 28 days have elapsed.   
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Independent Data 
Monitoring Committee: 
An Independent Data Monitoring Committee (IDMC) will be responsible 
for oversight of the C-144-01 study to ensure the study is being conducted 
with the highest quality, scientific, and ethical standard and to ensure 
quality and consistency of study conduct as well as data collection and 
analysis across international study sites.  
The IDMC will review the study data when a total of 30 patients have 
completed 28 days of assessments post-LN-144 infusion for Cohort 4. 
Enrollment will continue while data is under review. The IDMC will also 
review the study data after up to a total of 75 patients for Cohort 4 have 
completed 28 days of assessments post-LN-144 infusion.  
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TABLE OF CONTENTS 
SPONSOR PROTOCOL SIGNATURE PAGE ..................................................................2 
INVESTIGATOR PROTOCOL SIGNATURE PAGE .......................................................3 
SPONSOR MEDICAL MONITOR/EMERGENCY CONTACT INFORMATION ..........4 
RATIONALE FOR PROTOCOL AMENDMENT .............................................................5 
PROTOCOL SYNOPSIS...................................................................................................10 
TABLE OF CONTENTS ...................................................................................................18 
LIST OF TABLES .............................................................................................................21 
LIST OF FIGURES ...........................................................................................................21 
LIST OF ABBREVIATIONS ............................................................................................22 
1. 
INTRODUCTION .................................................................................................26 
1.1. 
Disease Background ...................................................................................................... 26 
1.1.1. 
Main Features of the Disease ......................................................................................... 26 
1.1.2. 
Current Standard Therapy .............................................................................................. 27 
1.2. 
Clinical Experience with Autologous Tumor Infiltrating Lymphocyte Therapy of 
Melanoma ..................................................................................................................... 28 
1.2.1. 
LN-144 TIL Therapy Regimen ...................................................................................... 29 
1.2.2. 
Brief Description of the Product .................................................................................... 30 
1.2.3. 
Production and Expansion of TIL .................................................................................. 30 
1.3. 
Benefit-Risk Assessment of LN-144 ............................................................................ 31 
2. 
STUDY DESIGN...................................................................................................34 
2.1. 
Description of the Study ............................................................................................... 34 
2.2. 
Re-treatment Cohort (Cohort 3) .................................................................................... 35 
3. 
STUDY OBJECTIVES AND ENDPOINTS .........................................................36 
3.1. 
Study Objectives ........................................................................................................... 36 
3.1.1. 
Primary Objective .......................................................................................................... 36 
3.1.2. 
Secondary Objectives ..................................................................................................... 36 
3.1.3. 
Exploratory Objectives ................................................................................................... 36 
3.2. 
Study Endpoints ............................................................................................................ 36 
3.2.1. 
Primary Endpoints .......................................................................................................... 36 
3.2.2. 
Secondary Endpoints ...................................................................................................... 36 
3.2.3. 
Exploratory Endpoints ................................................................................................... 37 
4. 
SELECTION OF PATIENT POPULATION ........................................................38 
4.1. 
Inclusion Criteria .......................................................................................................... 38 
4.2. 
Exclusion Criteria ......................................................................................................... 41 
4.3. 
Definition of Screening and Patient Enrollment ........................................................... 43 
4.3.1. 
Screen Failure ................................................................................................................ 44 
5. 
STUDY PROCEDURES .......................................................................................45 
5.1. 
Screening (up to 28 days from signing the ICF) ........................................................... 45 
5.2. 
Enrollment and Tumor Resection ................................................................................. 48 
5.2.1. 
Tumor Harvest and Processing Procedure ..................................................................... 49 
5.3. 
Baseline (Day -21 to Day -10) Procedures ................................................................... 50 
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5.4. 
Patients Who Do Not Receive an LN-144 Infusion Procedure ..................................... 51 
5.5. 
Treatment Period ........................................................................................................... 51 
5.5.1. 
Day -7 Procedures .......................................................................................................... 51 
5.5.2. 
Day -6 Procedures .......................................................................................................... 53 
5.5.3. 
Day -5 to Day -1 Procedures .......................................................................................... 53 
5.5.4. 
Day 0 (Infusion Day) Procedures ................................................................................... 54 
5.5.4.1. 
Pre-LN-144 Infusion ..................................................................................................... 54 
5.5.4.2. 
LN-144 Infusion ............................................................................................................ 55 
5.5.5. 
Day 1, Day 2, Day 3, and Day 4 Procedures .................................................................. 57 
5.5.6. 
Procedures on Day 14 (± 3 Days) and Day 28 (EOT Visit; ± 3 Days) .......................... 58 
5.6. 
Assessment Period ........................................................................................................ 59 
5.6.1. 
Procedures Every 6 Weeks (Week 6 [Day 42 {+ 7 Days}]; Week 12 [Day 84 
{± 3 Days}], and Week 18 [Day 126 {± 3 Days}]) ....................................................... 59 
5.6.2. 
Procedures Every 3 Months (± 1 Week) Starting at Month 6 Until the End of 
Assessment (EOA) ......................................................................................................... 60 
5.6.3. 
End of Assessment (EOA) Visit Procedures .................................................................. 61 
5.7. 
Overall Survival Follow-up Period ............................................................................... 62 
5.8. 
Hospitalization .............................................................................................................. 62 
6. 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ...............63 
6.1. 
Concomitant Medications ............................................................................................. 63 
6.2. 
Prohibited and Permitted Medications During Study Treatment .................................. 63 
6.2.1. 
Prohibited Treatment ...................................................................................................... 63 
6.2.2. 
Permitted Medications ................................................................................................... 63 
7. 
EXPECTED TOXICITIES AND TREATMENT GUIDELINES ........................64 
7.1. 
Cyclophosphamide and Fludarabine Toxicities ............................................................ 64 
7.1.1. 
Hemorrhagic Cystitis Prophylaxis ................................................................................. 64 
7.1.2. 
Fludarabine Hypersensitivity ......................................................................................... 64 
7.1.3. 
Blood Product Support ................................................................................................... 65 
7.2. 
LN-144 Toxicity ........................................................................................................... 65 
7.2.1. 
Expected Toxicities with LN-144 .................................................................................. 65 
7.2.2. 
LN-144 Toxicity Prevention and Management .............................................................. 66 
7.3. 
IL-2 Toxicity ................................................................................................................. 66 
7.3.1. 
Expected Toxicities with IL-2 ........................................................................................ 67 
7.3.1.1. 
Decreased Mental Status with IL-2 ............................................................................... 67 
7.3.1.2. 
Pulmonary Risk ............................................................................................................. 67 
7.3.1.3. 
Cardiac Arrhythmias and Myocarditis .......................................................................... 67 
7.3.1.4. 
Capillary Leak Syndrome ............................................................................................. 67 
7.3.1.5. 
Heparin-Induced Thrombocytopenia ............................................................................ 68 
7.3.2. 
Renal Toxicity ................................................................................................................ 68 
7.4. 
Infection Prophylaxis .................................................................................................... 68 
7.4.1. 
Pneumocystis jiroveci Pneumonia .................................................................................. 68 
7.4.2. 
Herpes Virus Prophylaxis .............................................................................................. 69 
7.4.3. 
Fungal Prophylaxis (Fluconazole) ................................................................................. 69 
7.4.4. 
Empiric Antibiotics ........................................................................................................ 70 
7.4.5. 
Sepsis ............................................................................................................................. 70 
8. 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF 
PATIENTS .............................................................................................................71 
8.1. 
Treatment Completion .................................................................................................. 71 
8.2. 
Criteria for Early Discontinuation from Treatment ...................................................... 71 
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8.3. 
Assessment Completion / End of Assessment (EOA) .................................................. 71 
8.4. 
Discontinuation from the Study .................................................................................... 72 
8.5. 
Study Completion ......................................................................................................... 72 
9. 
STUDY DRUG INFORMATION .........................................................................73 
9.1. 
Investigational Product Overview ................................................................................. 73 
9.2. 
Qualitative Composition of LN-144 ............................................................................. 73 
9.3. 
Manufacturing Process .................................................................................................. 73 
9.4. 
Final Investigational Product Container ....................................................................... 74 
9.5. 
Shipping/Transport of Investigational Product ............................................................. 74 
9.6. 
Receipt of Investigational Product at Clinical Site ....................................................... 74 
10. 
RESPONSE ASSESSMENTS ...............................................................................75 
10.1. 
Tumor Response Assessments ...................................................................................... 75 
10.1.1. 
Response Criteria ........................................................................................................... 75 
10.1.1.1. Definition of Target and Non-Target Lesions ............................................................... 76 
10.1.1.2. Evaluation of Best Overall Response ............................................................................ 76 
10.2. 
Biomarkers .................................................................................................................... 77 
11. 
STATISTICAL AND ANALYTICAL PLANS ....................................................78 
11.1. 
Introduction ................................................................................................................... 78 
11.2. 
Study Analysis Sets ....................................................................................................... 78 
11.2.1. 
Tumor Harvested Set (also termed Enrolled Set) ........................................................... 78 
11.2.2. 
Full Analysis Set ............................................................................................................ 78 
11.3. 
Endpoints ...................................................................................................................... 78 
11.3.1. 
Primary Endpoint ........................................................................................................... 78 
11.3.2. 
Secondary Endpoints ...................................................................................................... 78 
11.3.3. 
Exploratory Endpoints ................................................................................................... 79 
11.4. 
Sample Size Consideration ........................................................................................... 80 
11.5. 
Final Analysis ............................................................................................................... 82 
11.6. 
Statistical Analyses ....................................................................................................... 82 
11.6.1. 
Patient Disposition ......................................................................................................... 82 
11.6.2. 
Baseline Demographics and Clinical Characteristics ..................................................... 82 
11.6.3. 
Analysis of the Primary Efficacy Endpoint .................................................................... 82 
11.6.4. 
Analysis of the Secondary Efficacy Endpoints .............................................................. 83 
11.6.5. 
Safety Analysis .............................................................................................................. 83 
11.6.6. 
Other Planned Analyses ................................................................................................. 83 
12. 
SAFETY MONITORING AND REPORTING .....................................................84 
12.1. 
Adverse Events ............................................................................................................. 84 
12.1.1. 
Definitions ...................................................................................................................... 84 
12.1.1.1. Adverse Event ............................................................................................................... 84 
12.1.1.2. Serious Adverse Event .................................................................................................. 85 
12.1.1.3. Relationship to Study Drug ........................................................................................... 86 
12.1.1.4. Severity ......................................................................................................................... 86 
12.2. 
Reporting Procedures for Adverse Events .................................................................... 87 
12.2.1. 
All Adverse Events ........................................................................................................ 87 
12.2.1.1. Investigator Reporting to Sponsor ................................................................................ 88 
12.2.1.2. Special Situation Reporting ........................................................................................... 89 
12.2.1.3. Pregnancy Reporting ..................................................................................................... 90 
12.2.1.4. Regulatory Reporting Requirements ............................................................................. 91 
12.2.1.5. Product Complaints ....................................................................................................... 92 
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12.3. 
Data Safety Monitoring Board ...................................................................................... 92 
13. 
INDEPENDENT DATA MONITORING COMMITTEE ....................................93 
14. 
ADMINISTRATIVE REQUIREMENTS .............................................................94 
14.1. 
Good Clinical Practice .................................................................................................. 94 
14.2. 
Adherence to the Protocol ............................................................................................. 94 
14.3. 
Record Retention .......................................................................................................... 94 
14.4. 
Data Quality Assurance ................................................................................................ 95 
14.5. 
Data Handling and Recordkeeping ............................................................................... 96 
14.5.1. 
Regulatory Approval and Documentation ...................................................................... 96 
14.5.2. 
Electronic Data ............................................................................................................... 97 
14.5.3. 
Data Handling and Recordkeeping ................................................................................ 97 
14.5.3.1. Electronic Case Report Form (eCRF) Completion ....................................................... 97 
14.6. 
Study Completion/Termination ..................................................................................... 98 
14.7. 
Monitoring .................................................................................................................... 98 
15. 
INVESTIGATOR REGULATORY OBLIGATIONS ..........................................99 
15.1. 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ....................... 99 
15.2. 
Informed Consent .......................................................................................................... 99 
15.3. 
Patient Data Protection ............................................................................................... 100 
15.4. 
Adverse Event Reporting ............................................................................................ 101 
15.5. 
Investigator ................................................................................................................. 101 
15.6. 
Confidentiality ............................................................................................................ 101 
15.7. 
Publications ................................................................................................................. 102 
16. 
REFERENCES ....................................................................................................103 
APPENDICES .................................................................................................................106 
 
LIST OF TABLES 
Table 1 
Time Point Response: Patients with Target (± Non-target) Disease ........ 77 
Table 2 
Historical Studies with DTIC Monotherapy in Advanced or 
Metastatic Melanoma ................................................................................ 81 
 
LIST OF FIGURES 
Figure 1 
LN-144 GMP Manufacturing Process for Cryopreserved Product 
Supplied to Cohorts 2 and 4 ...................................................................... 31 
  
 
 
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LIST OF ABBREVIATIONS 
Term 
Definition 
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 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
BMI 
body mass index 
BRAF 
proto-oncogene B-Raf 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CD4 
cluster of differentiation 4 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CLS 
capillary leak syndrome 
CMO 
contract manufacturing organization  
CMV 
cytomegalovirus 
CO2 
carbon dioxide 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated antigen-4 
D5W 
5% dextrose in water 
DCR 
disease control rate 
DMSO 
dimethyl sulfoxide 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
DTIC 
dacarbazine 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
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Term 
Definition 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCrCl 
estimated creatinine clearance  
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EMA 
European Medicines Agency 
EOA 
End of Assessment  
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire - Core 30 instrument 
EOT 
End of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FEV1 
forced expiratory volume in 1 second 
FNA 
fine-needle aspiration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practices 
Hb 
hemoglobin 
HBc 
hepatitis B core 
HBsAg 
hepatitis B surface antigen 
β-HCG 
β-human chorionic gonadotropin 
Hct 
hematocrit 
HCV Ab 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIT 
heparin-induced thrombocytopenia 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HRQoL 
health-related quality of life 
HSA 
human serum albumin 
HSV 
herpes simplex virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
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Term 
Definition 
IgM 
immunoglobulin M 
IL-2 
interleukin-2 (also known as “aldesleukin”) 
INR 
International Normalized Ratio 
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  
LDH 
lactate dehydrogenase 
LN-144 
autologous tumor infiltrating lymphocytes 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MEK 
mitogen-activated extracellular signal-regulated kinase 
MRI 
magnetic resonance imaging 
MUGA 
multiple gated acquisition scan 
NaCl 
sodium chloride 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NMA-LD 
nonmyeloablative lymphodepletion 
NYHA 
New York Heart Association 
OKT3 
muromonab CD3, murine monoclonal antibody to human CD3 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PHI 
personal health information 
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Term 
Definition 
PO 
per os (by mouth) 
PR 
partial response 
PRBC 
packed red blood cells 
PT 
prothrombin time 
RBC 
red blood cells 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
REP 
rapid expansion protocol 
RNA 
ribonucleic acid 
RPR 
Rapid Plasma Reagin  
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCID 
severe combined immunodeficiency disease  
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SoD 
sum of diameters 
SOP 
Standard Operating Procedure 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TH 
tumor harvested 
TIL 
tumor infiltrating lymphocyte 
TMP-SMX DS 
trimethoprim-sulfamethoxazole double strength 
TSH 
thyroid-stimulating hormone 
TVEC 
talimogene laherparepvec 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States package insert 
UV 
ultraviolet 
VDRL 
venereal disease research laboratory 
WBC 
white blood cells 
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1. 
INTRODUCTION 
1.1. 
Disease Background 
Melanoma is a potentially lethal cancer that is characterized by the uncontrolled growth 
of melanocytes, which are cells that protect against ultraviolet (UV) radiation through the 
production of the dark pigment melanin [Garbe 2016]. The incidence of melanoma, 
historically a rare cancer, has steadily increased in the last decade and is projected to 
continue increasing [Matthews 2017; Rutkowski 2017; Whiteman 2016]. The main 
known and modifiable risk factor for melanoma is cumulative UV radiation exposure, but 
despite local education campaigns regarding this risk, an estimated 91,270 Americans 
[Noone 2018] and more than 144,000 Europeans [Ferlay 2018] are diagnosed each year 
with melanoma; with about 10,000 and 20,000 dying each year, respectively. Melanoma 
is expected to be the fifth most frequently diagnosed cancer in the United States (US) in 
2018, contributing 5.3% of all new cancers in 2018 [Noone 2018]. 
1.1.1. 
Main Features of the Disease 
Approximately 90% of melanomas are diagnosed as primary tumors without any 
evidence of metastasis, and the 10-year survival rate for patients with such tumors is 75–
85% [Garbe 2016]. While in situ and locally invasive melanomas are curable by surgery, 
metastatic disease is difficult to treat and remains a significant public health concern, as 
the cancer has already metastasized in approximately 4% of newly diagnosed cases of 
melanoma [Noone 2018]. Despite recent approvals of new medicines, the five-year 
survival rate for patients who cannot be cured with surgery remains unacceptably low. 
The five-year relative survival rate in the US for patients with metastatic melanoma is 
estimated to be 22.5% [Noone 2018]. A systematic literature review that included studies 
from several countries found that the reported five-year overall survival (OS) rate for 
metastatic (Stage IV) melanoma ranged from 9–28% [Svedman 2016]. Although immune 
checkpoint blockade and targeted therapies have become the standard of care for 
metastatic melanoma, 60–70% of patients either do not respond to, or relapse after, 
single-agent therapy, making this an unmet medical need. Furthermore, dual checkpoint 
inhibition with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-
programmed cell death protein-1 (PD-1) may be associated with prohibitive toxicity. 
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Ipilimumab was first approved in the US and European Union (EU) for the treatment of 
metastatic melanoma in 2011, and pembrolizumab and nivolumab were approved for the 
same indication in the US in 2014 and in the EU in 2015. Although there has been a 
broad and rapid uptake of these immunotherapeutic agents, metastatic melanoma remains 
a serious, life-threatening disease that is still inadequately addressed by available 
therapies, as indicated in the current five-year survival projections for patients with a 
diagnosis of metastatic melanoma. 
1.1.2. 
Current Standard Therapy 
Treatment planning for all unresectable, metastatic disease should be individualized to 
maximize therapeutic benefit while limiting toxicities [Kaufman 2018].  
First-line therapy for metastatic disease includes anti-PD-1 monotherapy (nivolumab or 
pembrolizumab) or the combination of nivolumab (anti-PD-1) and ipilimumab (anti-
CTLA-4), as well as therapies targeting driver mutations in the proto-oncogene B-Raf 
(BRAF) pathway for tumors with these mutations [Coit 2018; Dummer 2015]. In 
treatment-naïve melanoma (first-line use), the reported objective response rate (ORR) for 
single-agent pembrolizumab or nivolumab is about 34% with a complete response (CR) 
rate of 4–5%. Combination therapy with nivolumab and ipilimumab is associated with an 
ORR of 50% and CR rate of 8.9%. Thus, most melanoma patients either do not respond 
to, or progress while on the available first-line therapies.  
Options for second-line therapy of metastatic melanoma, for the most part, duplicate the 
first-line therapies, along with the addition of cytotoxic chemotherapies and high-dose 
interleukin-2 (IL-2). However, response rates to pembrolizumab and nivolumab appear to 
be substantially reduced in patients whose disease has progressed following treatment 
with a PD-1 blocking antibody or BRAF inhibitor relative to responses achieved in 
treatment-naïve patients [Cowey 2018; Johnson 2017; Zimmer 2017]. In addition, use of 
checkpoint inhibitors is associated with a range of immune-related adverse events (AEs), 
including pneumonitis, colitis, hepatitis, nephritis, and renal dysfunction [Hofmann 2016]. 
In addition, treatment-related AEs leading to discontinuation of therapy occurred in 
36.4%, 7.7%, and 14.8% of patients receiving ipilimumab/nivolumab combination 
therapy, nivolumab alone, or ipilimumab alone, respectively [Johnson 2016; Larkin 2015]. 
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Moreover, agents used in second-line therapy should not be in the same class as those 
given in first-line therapy [Coit 2018]. Consequently, patients with disease progression 
after receiving an anti-PD-1 antibody and a targeted therapy, if indicated, have limited 
treatment options. These patients could receive high-dose IL-2 or cytotoxic agents as 
subsequent therapy, however the efficacy of these agents in such a late-line patient 
population is limited. 
In summary, immune checkpoint blockade and targeted therapies constitute the standard 
of care for metastatic melanoma. However, following single-agent therapy, a majority of 
patients either do not respond to, or relapse with limited treatment options; highlighting 
these patients’ unmet medical need. Furthermore, dual checkpoint inhibition with anti-
PD-1 and anti-CTLA-4 can result in prohibitive toxicity, and no agents are approved for 
third line or greater use [Coit 2018; Dummer 2015]. Therefore, it is of major public 
health interest to develop additional therapeutic agents for patients with metastatic 
melanoma. 
1.2. 
Clinical Experience with Autologous Tumor Infiltrating Lymphocyte 
Therapy of Melanoma 
A substantial body of literature on tumor infiltrating lymphocytes (TIL) provides 
information that is relevant to the expected safety and efficacy profile of LN-144 in 
patients with metastatic melanoma. In particular, Professor Steven Rosenberg’s research 
team at the US National Cancer Institute (NCI) National Institutes of Health has 
published extensively on preclinical and clinical research supporting the development of 
TIL-based therapies for cancer. Across clinical studies conducted by the NCI, 
immunotherapy with autologous TIL infusion in patients with advanced melanoma has 
induced objective responses (ORs) by Response Evaluation Criteria in Solid Tumors 
(RECIST) in 54% (54/101) of patients, including heavily pre-treated patients, with 24% 
(24/101) of patients achieving a CR. With a median follow-up of 40.9 months, only one 
of the 24 patients who achieved a CR had disease recurrence [Goff 2016; Rosenberg 2011].  
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Patients with metastatic melanoma have also been treated with autologous TIL therapy at 
the MD Anderson Cancer Center in Texas, US [Forget 2018; Radvanyi 2012]; the Moffitt 
Cancer Center in Florida, US [Pilon-Thomas 2012]; the Chaim Sheba Medical Center in 
Israel [Besser 2013]; and Herlev Hospital, in Copenhagen, Denmark [Andersen 2016]. 
Most protocols used a two-stage manufacturing process like that used in LN-144 
production, and most trials also used a nonmyeloablative lymphodepletion (NMA-LD) 
preconditioning regimen prior to infusion of the ex vivo expanded TIL. Like the NCI, 
these institutions report objective tumor response rates averaging 40–50% in multiple 
phase 2 studies of TIL therapy in patients with treatment-refractory metastatic melanoma.  
Recently, Forget et al. reported the results of a study investigating the impact of prior 
therapy with immune checkpoint inhibitors on the response to TIL therapy in patients 
with metastatic melanoma [Forget 2018]. The best ORR for the entire cohort was 42%; 
47% in 43 checkpoint-blocker-naïve patients; 38% when patients were exposed to anti-
CTLA-4 alone (21 patients); and 33% if also previously exposed to anti-PD-1 (nine 
patients) prior to TIL therapy. There were eight CRs in the study, three of which were in 
the 21 patients who received prior anti-CTLA-4 therapy, for an overall CR rate of 11% 
(8/74). Median OS was 17.3 months in this study [Forget 2018]. 
1.2.1. 
LN-144 TIL Therapy Regimen 
The LN-144 treatment regimen involves a course of NMA-LD using cyclophosphamide 
and fludarabine for one week prior to TIL infusion, and a limited course of IL-2 
administration (up to six doses) following the TIL infusion. The NMA-LD and IL-2 are 
included in the regimen to support the engraftment, expansion, and activation of the 
transferred TIL. 
Several preconditioning regimens have been used in conjunction with TIL therapies. 
NMA-LD regimens have included cyclophosphamide/fludarabine, total body irradiation, 
or the combination of the two. The NMA-LD preconditioning regimen used in the current 
study is based on the method developed and tested by the NCI, which involves 2 days of 
cyclophosphamide followed by 5 days of fludarabine. Each patient will undergo an 
NMA-LD preconditioning regimen prior to infusion of LN-144.  
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1.2.2. 
Brief Description of the Product 
LN-144 is a ready-to-infuse, autologous TIL therapy based on that developed by Dr. 
Rosenberg and colleagues at the NCI and further optimized by Iovance. 
LN-144 is composed of autologous TIL, which are obtained from an individual patient’s 
tumor and expanded ex vivo through cell culture in the presence of the cytokine IL-2 and 
muromonab CD3, a monoclonal antibody (mAb) to human CD3 (OKT3).  
The final drug product is a cryopreserved live-cell suspension that is formulated for 
intravenous (IV) infusion. The ex vivo expanded autologous TIL are formulated in 
CryoStor® CS10 cryopreservation medium/Plasma Lyte (final dimethyl sulfoxide 
[DMSO] concentration: 5%), with 0.5% human serum albumin (HSA) and 300 
international units (IU)/mL (12 ng/mL) of IL-2. The formulated product is frozen at a 
controlled rate to < -150°C in vapor phase liquid nitrogen, shipped in a cryoshipper to the 
appropriate clinical site, and thawed before use for infusion into the patient. 
1.2.3. 
Production and Expansion of TIL 
The manufacturing process begins at the clinical site with the surgical resection of a 
tumor lesion containing viable tumor material of ≥ 1.5 cm. An aggregate of multiple 
separate lesion biopsies may also be resected from the patient and is encouraged if patient 
safety allows. The tumor specimen is placed in transport media and shipped express at 2–
8°C to the Good Manufacturing Practices (GMP) manufacturing facility. Upon arrival at 
the GMP manufacturing facility, the tumor specimen is dissected into fragments, which 
are then cultured in a pre-rapid expansion protocol (REP) stage with human recombinant 
IL-2 to generate the minimum number of viable cells required for the REP stage. The 
REP stage further expands the cells in the presence of IL-2, OKT3, and irradiated 
allogeneic peripheral blood mononuclear cell (PBMC). The REP-expanded cells are then 
harvested, washed, and formulated in a blood transport/infusion bag for shipment by 
courier to the clinical site. 
A diagram of the manufacturing process for LN-144 is provided in Figure 1. 
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Figure 1 
LN-144 GMP Manufacturing Process for Cryopreserved Product 
Supplied to Cohorts 2 and 4 
Abbreviations: CMO=contract manufacturing organization; IL-2=interleukin-2; NMA-LD=nonmyeloablative 
lymphodepletion; REP=rapid expansion protocol; TIL=tumor infiltrating lymphocytes 
Each cryopreservation bag of the LN-144 final product is labeled with a patient-specific 
label. LN-144 is shipped from the manufacturing facility to clinical sites for 
administration to patients as described in the Pharmacy & Administration Manual.  
1.3. 
Benefit-Risk Assessment of LN-144 
This protocol is enrolling patients with unresectable or metastatic melanoma who have 
previously been treated with at least one systemic therapy including a PD-1 blocking 
antibody and if BRAF V600 mutation positive, a BRAF inhibitor or BRAF inhibitor in 
combination with mitogen-activated extracellular signal-regulated kinase (MEK) 
inhibitor.  
As discussed above, immune checkpoint blockade and targeted therapies constitute the 
current standard of care for metastatic melanoma; however, many patients either do not 
respond to, or relapse after available single-agent therapy, and the combination of two 
checkpoint inhibitors often have unacceptable toxicity. Once a patient progresses after 
receiving a checkpoint inhibitor, they have limited treatment options. These patients 
could receive high-dose IL-2 or cytotoxic agents as subsequent therapy, but the efficacy 
of these agents in such a late-line patient population has not been reported. A response 
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rate of 4–10% has been observed for Investigator’s choice of chemotherapy (dacarbazine 
[DTIC], carboplatin plus paclitaxel, paclitaxel alone, or temozolomide) administered as 
second-line therapy in patients who had progressed after ipilimumab in phase 3 trials of 
nivolumab [Weber 2015] and pembrolizumab [Hamid 2017]. Similarly, a retrospective 
study of the response to chemotherapy in melanoma patients previously treated with anti-
PD-1 therapy found an ORR of 11% to chemotherapy and a median progression-free 
survival (PFS) of only 2.5 months (2.1, 2.8) in these patients [Goldinger 2018]. 
The feasibility of cell therapy with autologous TIL has been demonstrated by durable 
tumor responses, including CRs, in patients with metastatic melanoma, irrespective of 
prior systemic treatment with immune checkpoint inhibitors (anti-PD-1 and/or anti-
CTLA-4), BRAF-mutation targeted therapies, chemotherapies, IL-2, or interferon-alpha. 
Dramatic and durable reductions in tumor burden have been attained in even heavily 
pretreated metastatic melanoma patients [Forget 2018; Goff 2016; Rosenberg 2011; Tran 
2016].  
In addition, the mechanism of action of LN-144 affords at least three important 
advantages in the treatment of solid tumors over other forms of immunotherapy: 1) the 
substantial clinical experience with TIL therapy of metastatic melanoma shows an 
encouraging safety profile for TIL therapy; 2) TIL recognizes a diverse array of tumor 
antigens, especially mutated neoantigens in melanoma, many of which are undefined but 
are effective targets for TIL in achieving anti-tumor effects; 3) clinical studies have 
demonstrated that the effects of TIL therapy persist in patients for weeks to months, and 
even years, after infusion, thereby mediating highly durable tumor responses after only a 
single treatment regimen in even highly pre-treated patients.  
The risks associated with TIL therapy include: a delay in treatment due to the need to 
harvest and grow the cells; a surgical procedure (possibly major) to obtain tumor for the 
cell product; the possibility that a cell product cannot be generated; and the toxicities 
known to be associated with the NMA-LD regimen and IL-2 administration. However, 
current methods for the expansion of autologous TIL from excised tumors are shorter 
than previously used for TIL at 22 days for manufacturing. These methods are well 
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established with over 90% success rates for manufacturing and are sufficiently robust to 
ensure a high degree of success in consistently generating adequate numbers of high-
quality therapeutic cells from resected melanoma lesions. As such, the risk-benefit 
balance for Study C-144-01 should be viewed as favorable considering the following: 
• Substantial clinical experience with TIL in the treatment of advanced melanoma 
and other solid tumors has demonstrated the capacity to induce clinically 
meaningful responses in patients with progressive disease (PD) following PD-1 
blocking antibodies who had also received targeted therapy, if indicated  
• Safety monitoring and risk mitigation strategies are incorporated into this 
C-144-01 study protocol 
In summary, adoptive cell therapy (ACT) with TIL represents a one-time treatment, with 
the possibility of offering a durable treatment option for patients with cancer, especially 
those with advanced metastatic disease who have limited to no treatment options after the 
failure of available conventional therapies (eg, immune checkpoint inhibitors or targeted 
therapies). 
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2. 
STUDY DESIGN 
2.1. 
Description of the Study 
This is a prospective, interventional multicenter study evaluating patients who receive 
ACT via infusion of LN-144 (composed of autologous TIL). Patients will receive an 
NMA-LD preconditioning regimen, then a single infusion of LN-144, followed by the 
administration of a regimen of IL-2.  
This clinical trial consists of four cohorts, which enrolled similar patient populations with 
unresectable or metastatic melanoma: 
• Cohort 1 infused 23 patients with non-cryopreserved autologous TIL and is closed 
to Enrollment. 
• Cohort 2 will infuse approximately 66 patients with the cryopreserved autologous 
TIL product and is closed to Screening. 
• Cohort 3 is limited to infused patients from Cohort 1, Cohort 2, or Cohort 4, who 
may rescreen after having participated in the study for a second administration of 
LN-144, cryopreserved product, and will include approximately 10 patients. 
• Cohort 4 will include approximately 75 patients who are planned to be infused 
with the cryopreserved autologous TIL product. Cohort 4 is open to enroll new 
patients. 
Patients must be hospitalized prior to the planned LN-144 infusion for overnight 
hydration. Patients will remain hospitalized until completion of the IL-2 administration, 
or as per institutional standards. 
All visits following LN-144 infusion, except OS Follow-up, are calculated from LN-144 
infusion (Day 0). Patients will need to return for safety assessment visits on Day 14 and 
Day 28 (Day 28 corresponds with the End of Treatment [EOT] visit).  
Patients will be evaluated for efficacy (eg, tumor response) following the EOT visit, and 
at Week 6 (Day 42), then every 6 weeks until Month 6 (Week 24). Response assessments 
will be conducted by the Investigator following both RECIST v1.1 and immune-related 
RECIST (irRECIST), and by the Independent Review Committee (IRC) following 
RECIST v1.1 (primary endpoint).  
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Patients will continue to be evaluated for response every 3 months (12 weeks) for up to 
5 years from Day 0 or until: disease progression; or the start of a new anticancer therapy 
(Appendix 1).  
OS Follow-up is calculated from Enrollment (tumor resection), will begin after 
completion of the End of Assessment (EOA) visit (eg, last study assessment), and will 
continue for up to 5 years or until discontinuation from the study.  
Patients who had tumor resection but did not receive LN-144 for any reason will perform 
an EOA visit and transition directly into the OS Follow-up Period.  
2.2. 
Re-treatment Cohort (Cohort 3) 
Patients who initially received LN-144 in Cohort 1, Cohort 2, or Cohort 4 may receive a 
second administration of LN-144. Patients, who in the opinion of the Investigator and the 
Medical Monitor will benefit from a second LN-144 treatment regimen, will need to be 
rescreened and meet the inclusion and exclusion criteria (except exclusion criterion “b”) 
as described in Sections 4.1 and 4.2.  
Patients may have a second tumor resection, if needed, especially when new lesions are 
available and feasible for resection.  
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
• Evaluate the efficacy of LN-144 in patients with unresectable or metastatic 
melanoma using the ORR, as assessed by the IRC per RECIST v1.1 
3.1.2. 
Secondary Objectives 
• Evaluate the efficacy endpoints of duration of response (DOR), disease control 
rate (DCR), and PFS, as assessed by the IRC per RECIST v1.1 
• Further evaluate efficacy of LN-144 in patients with unresectable or metastatic 
melanoma by assessing ORR, DOR, DCR, and PFS, as assessed by the 
Investigator per RECIST v1.1 
• Evaluate OS 
• Characterize the safety profile of LN-144 in patients with unresectable or 
metastatic melanoma  
3.1.3. 
Exploratory Objectives 
• Explore the persistence of LN-144 and potential immune correlates of response, 
outcome, and toxicity of the treatment 
• Explore efficacy based on irRECIST criteria [Bohnsack 2014], as assessed by the 
Investigator 
• Assess health-related quality of life (HRQoL; Appendix 14)  
3.2. 
Study Endpoints  
3.2.1. 
Primary Endpoints 
• ORR, as assessed by the IRC per RECIST v1.1  
3.2.2. 
Secondary Endpoints  
• DOR, DCR, and PFS per RECIST v1.1, as assessed by the IRC  
• ORR, DOR, DCR, and PFS per RECIST v1.1, as assessed by the Investigator 
• OS 
• Incidence, severity, seriousness, relationship to study treatment, and 
characteristics of treatment-emergent adverse events (TEAEs), including AEs 
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leading to early discontinuation from treatment or withdrawal from the 
Assessment Period, 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  
• ORR, DOR, DCR, and PFS using irRECIST, as assessed by the Investigator 
• Patient-reported outcomes for HRQoL based on the European Organisation for 
Research and Treatment of Cancer Quality-of-Life Questionnaire – Core 30 
Instrument (EORTC QLQ-C30; Appendix 14)  
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4. 
SELECTION OF PATIENT POPULATION 
4.1. 
Inclusion Criteria  
Patients must meet all of the following inclusion criteria to be eligible for participation in 
the study:  
a. Patients with unresectable or metastatic melanoma (Stage IIIc or Stage IV) 
b. Patients must have progressed following ≥ 1 prior systemic therapy including a 
PD-1 blocking antibody; and if BRAF V600 mutation-positive, a BRAF inhibitor 
or BRAF inhibitor in combination with MEK inhibitor  
c. Prior to study Enrollment, documentation of radiological disease progression after 
the most recent therapy 
d. At least one measurable target lesion, as defined by RECIST v1.1 
• Lesions in previously irradiated areas (or other local therapy) should not be 
selected as target lesions, unless treatment was ≥ 3 months prior to Screening, 
and there has been demonstrated disease progression in that particular lesion  
• If a lesion is partially resected to generate TIL, and remains visible on the 
Baseline scan after surgery, then the partially resected lesion can be used for 
RECIST v1.1 response assessment, but only as a non-target lesion 
e. At least one resectable lesion (or aggregate of lesions resected) of a minimum 
1.5 cm in diameter post-resection to generate TIL; surgical removal with minimal 
morbidity (defined as any procedure for which expected hospitalization is ≤ 3 days)  
f. Patients must be ≥ 18 years of age at the time of consent. Enrollment of patients 
> 70 years of age may be allowed after consultation with the Medical Monitor 
g. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 (Appendix 2) and an estimated life expectancy of 
≥ 3 months 
h. In the opinion of the Investigator, patients must be able to complete all study-
required procedures 
i. Patients must have the following hematologic parameters: 
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• Absolute neutrophil count (ANC) ≥ 1000/mm3 
• Hemoglobin (Hb) ≥ 9.0 g/dL 
• Platelet ≥ 100,000/mm3 
Note: Transfusions or growth factors are not allowed 28 days prior to signing the 
informed consent form (ICF) and continuing through the Screening Period 
j. 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 
• Estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the Cockcroft-
Gault formula  
• Total bilirubin ≤ 2 mg/dL  
o Patients with Gilbert’s syndrome must have a total bilirubin ≤ 3 mg/dL  
k. Patients must have recovered from all prior therapy-related AEs to ≤ Grade 1 (per 
Common Terminology Criteria for Adverse Events [CTCAE] v4.03), except for 
alopecia or vitiligo, prior to Enrollment (tumor resection) 
• Patients with documented ≥ Grade 2 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 tumor resection  
• Patients with immunotherapy-related endocrinopathies stable for at least 
6 weeks (eg, hypothyroidism), and controlled with hormonal replacement 
(non-corticosteroids), are allowed  
l. Patients must have a washout period of ≥ 28 days from prior anticancer 
therapy(ies) to the start of the planned NMA-LD preconditioning regimen:  
• Targeted therapy: MEK/BRAF or other targeted agents 
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• Chemotherapy  
• Immunotherapy: anti-CTLA-4/anti-PD-1, other mAb, or vaccine  
• Palliative radiation therapy is permitted so long as it does not involve lesions 
being selected for TIL, or as target or non-target lesions. Washout is not 
required if all related toxicities have resolved to ≤ Grade 1 as per CTCAE 
v4.03 
m. Patients of childbearing potential or their partners of childbearing potential must 
be willing to take the appropriate precaution to avoid pregnancy or fathering a 
child for the duration of the study and practice an approved, highly effective 
method of birth control during treatment and for 12 months after receiving the last 
protocol-related therapy 
• Approved methods of birth control are as follows: 
o Combined (estrogen and progesterone containing) hormonal birth 
control associated with inhibition of ovulation: oral, intravaginal, 
transdermal 
o Progesterone-only hormonal birth control associated with inhibition of 
ovulation: oral, injectable, implantable 
o Intrauterine device (IUD) 
o Intrauterine hormone-releasing system (IUS) 
o Bilateral tubal occlusion 
o Vasectomized partner 
o 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  
n. Patients (or legally authorized representative) must have the ability to understand 
the requirements of the study, have provided written informed consent as 
evidenced by signature on an ICF approved by an Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), and agree to abide by the study 
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restrictions and return to the site for the required assessments, including the OS 
Follow-up Period  
o. Patients have provided written authorization for use and disclosure of protected 
health information 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for participation in this 
study:  
a. Patients who have been shown to be BRAF mutation positive (V600), but have 
not received prior systemic therapy with a BRAF inhibitor alone or a BRAF 
inhibitor in combination with a MEK inhibitor 
b. Patients who have received an organ allograft or prior cell transfer therapy  
c. Patients with melanoma of uveal/ocular origin  
d. Patients who have a history of hypersensitivity to any component or excipient of 
LN-144 or other study drugs:  
• NMA-LD preconditioning regimen (cyclophosphamide, mesna, and 
fludarabine) 
• Antibiotics (ABX) of the aminoglycoside group (ie, streptomycin, 
gentamicin); except those who are skin-test negative for gentamicin 
hypersensitivity 
• Any component of the LN-144 infusion product formulation including 
DMSO, HSA, IL-2, and dextran-40 
e. 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, and must be stable for ≥ 14 days prior to beginning the NMA-LD 
preconditioning regimen 
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f. Patients who are on chronic systemic steroid therapy for any reason 
g. Patients who have active medical illness(es) that would pose increased risk for 
study participation, including: active systemic infections requiring systemic ABX, 
coagulation disorders, or other active major medical illnesses of the 
cardiovascular, respiratory, or immune system 
h. Patients who have ≥ Grade 2 hemorrhage within 14 days prior to Enrollment 
(tumor resection) 
i. Patients who are seropositive for any of the following:  
• Human immunodeficiency virus (HIV)-1 or HIV-2 antibodies 
• Hepatitis B antigen (HBsAg), hepatitis B core antibody (anti-HBc), or 
hepatitis C antibody (HCV Ab); patients with acute or chronic hepatitis 
infections may be enrolled if the viral load by polymerase chain reaction 
(PCR) is undetectable with/without active treatment.  
• Syphilis (rapid plasma reagin [RPR] test or venereal disease research 
laboratory [VDRL] test) 
• Cytomegalovirus (CMV) IgM antibody titer or PCR assay and Epstein-Barr 
virus (EBV) IgM or PCR assay indicating active infection 
• Positive herpes simplex virus (HSV)-1 and HSV-2 IgM serology or PCR 
assay 
o Patients who are HSV immunoglobulin M (IgM) or PCR assay 
positive will need to receive appropriate treatment and become IgM or 
PCR assay negative prior to starting the NMA-LD preconditioning 
regimen 
j. Patients who have any form of primary immunodeficiency (such as severe 
combined immunodeficiency disease [SCID] and acquired immunodeficiency 
syndrome [AIDS]) 
k. Patients who have a left ventricular ejection fraction (LVEF) < 45% or New York 
Heart Association (NYHA) functional classification  Class > 1  
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• Patients ≥ 60 years of age and who have a history of ischemic heart disease, 
chest pain, or clinically significant atrial and/or ventricular arrhythmias must 
have a cardiac stress test. Patients with any irreversible wall movement 
abnormalities are excluded 
l. Patients who have a documented forced expiratory volume in 1 second (FEV1) of 
≤ 60%  
m. 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) 
n. Patients who have received a live or attenuated vaccine within 28 days of 
beginning the NMA-LD preconditioning regimen 
o. Patients who are pregnant or breastfeeding 
p. Patients whose cancer requires immediate attention or who would otherwise 
suffer a disadvantage by participating in this trial 
q. 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. 
Definition of Screening and Patient Enrollment 
Patients have 28 days from signing the ICF to complete the study assessments required to 
meet all inclusion and no exclusion criteria. Patients will then be approved to proceed to 
Enrollment in the study.  
• If a patient does not meet the inclusion and exclusion criteria, then they will be 
defined as a screen failure 
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• The case for a patient who meets the inclusion and exclusion criteria, but does not 
have tumor resection within 28 days of signing the ICF, must be discussed with 
the Medical Monitor 
• Assessments that become ‘out of window’ (eg, more than 28 days from 
Enrollment [tumor resection]) will need to be repeated  
• Patients who meet inclusion and exclusion criteria and do not receive LN-144 
(eg, due to a manufacturing failure) may be re-screened after consultation with the 
Medical Monitor 
Enrollment will occur upon tumor resection.  
4.3.1. 
Screen Failure 
Patients who do not meet eligibility criteria will need to have the reason for the screen 
failure documented. Any serious adverse events (SAEs) occurring in such patients after 
signing the ICF until study discontinuation (the day of screen failure) will also be 
documented/reported in the Electronic Data Capture (EDC) system.  
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5. 
STUDY PROCEDURES  
5.1. 
Screening (up to 28 days from signing the ICF) 
After signing the ICF, the following procedures should be performed in all patients 
(exceptions for Cohort 3 are noted; Appendix 1): 
• Review of inclusion and exclusion criteria 
• Demographic data (date of birth, age, sex, and race/ethnic origin) 
• Medical history (does not need to be repeated for Cohort 3 patients) 
• Melanoma medical history, including BRAF mutational status as well as 
programmed death-ligand 1 (PD-L1) expression when available (does not need to 
be repeated for Cohort 3 patients) 
o All cancer-related therapies including surgeries, radiotherapy, neoadjuvant 
or adjuvant systemic therapies, other local therapies and all palliative 
therapies should be recorded. Best response to each therapy should be 
recorded 
o Documentation of most recent prior therapy: documentation of best 
response to such therapy and radiological disease progression  
• ECOG performance status evaluation 
• Physical examination will be performed as clinically indicated, unless otherwise 
specified, and findings will be source documented: (Appendix 3) 
o Clinically relevant changes will be recorded on the electronic case report 
form (eCRF) AE page 
o The examination will be symptom-driven, including, as applicable: 
weight, gastrointestinal (abdomen, liver), cardiovascular, extremities, 
head, eyes, ears, nose, throat, respiratory system, dermatological, 
musculoskeletal, neurological, and psychiatric (mental status) 
 Body weight will include calculated body surface area (BSA), and 
body mass index (BMI) as described in Appendix 3; all patients 
must be dosed using actual body weight 
 Height to be measured at Screening only; does not need to be 
repeated for Cohort 3 patients  
• Vital signs (Appendix 3) 
o Pulse rate, respiratory rate, blood pressure, and temperature  
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• All AEs/SAEs occurring after the patient has signed the ICF will be collected 
• List all concomitant medications taken within 28 days prior to signing the ICF  
• Blood and urine tests 
o Hematology: (Appendix 3) 
 Complete blood count (CBC) with differentials, when available; 
transfusions or growth factors are not allowed 28 days prior to 
signing ICF and continuing through the Screening Period  
 White blood cell (WBC) count with differentials (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), red blood 
cell (RBC) count, Hb, hematocrit (Hct), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), platelet count 
o Coagulation: (Appendix 3) 
 International Normalized Ratio (INR) and prothrombin time (PT) 
or INR and activated partial thromboplastin time (aPTT)  
o Chemistry: (Appendix 3) 
 Sodium, potassium, chloride, total carbon dioxide (CO2) or 
bicarbonate, creatinine, glucose, blood urea nitrogen (BUN), 
albumin, calcium total, magnesium total, phosphorus, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, total bilirubin, direct 
bilirubin, lactate dehydrogenase (LDH), total protein, total creatine 
kinase (CK), uric acid  
o Thyroid panel to include thyroid stimulating hormone (TSH) and free T4 
o Serology testing: HIV-1 and HIV-2 antibody titer, HBsAg, anti-HBc, 
HCV Ab, syphilis (eg, RPR test or VDRL test), HSV-1 serology, HSV-2 
serology, anti-CMV titer, EBV panel (Appendix 3) 
 In patients who are seropositive for HSV IgM or PCR assay: 
valacyclovir (500 mg per os [by mouth; PO] daily), or acyclovir 
(250 mg/m2 IV every 12 hours) if the patient is unable to take 
medication by mouth, or as per institutional standards. Treatment 
should be administered as soon as infection is diagnosed and must 
be completed prior to the start of NMA-LD preconditioning 
regimen to ensure patient is seronegative for HSV (IgM) or PCR 
assay 
o Serum pregnancy test (β-human chorionic gonadotropin [β-HCG]) for 
women of childbearing potential 
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o Dipstick urinalysis (with complete urinalysis and culture, if applicable; 
Appendix 3) 
o Human leukocyte antigen (HLA) typing (to be shipped to the Central 
Laboratory); does not need to be repeated for Cohort 3 patients  
• Evaluation and measurement of all skin and palpable lesions (if applicable) 
o Evaluation and measurement of skin and palpable lesions may be 
performed (if applicable)  
• Skin test for gentamicin hypersensitivity, as needed 
• Slit-lamp eye examination in patients with history of uveitis. Previous evaluation 
within 28 days prior to signing the ICF is allowed 
• Electrocardiogram (ECG); if an ECG was performed within 60 days prior to 
signing the ICF, and considered normal, it does not have to be repeated  
• Echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) for all 
patients  
o Patients ≥ 60 years of age and who have a history of ischemic heart 
disease, chest pain, or clinically significant atrial and/or ventricular 
arrhythmias must have a cardiac stress test  
• Pulmonary function tests (PFTs)  
• Colonoscopy on patients with documented ≥ Grade 2 diarrhea or colitis as a result 
of previous treatment with immune checkpoint inhibitor(s) who have not been 
asymptomatic for at least 6 months  
• Imaging assessments (Appendix 3) 
o Computed tomography (CT) of chest, abdomen, pelvis, and additional 
anatomic regions (eg, extremities, neck) per disease history and clinical 
symptoms 
 High-resolution CT with PO/IV contrast or contrast-enhanced MRI 
is the preferred imaging modality for assessing radiographic tumor 
response. If a patient has a known allergy to CT contrast material, 
please use the alternate modality. In cases where contrast is strictly 
contraindicated, a non-contrast scan is acceptable. The same 
imaging modality must be used throughout the duration of the 
study. 
 Previous CT/MRI/PET scans performed within 28 days prior to 
signing the ICF can be used for Screening 
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o MRI of the brain 
 MRI scans performed within 28 days prior to signing the ICF with 
normal results do not have to be repeated  
o All imaging assessments, including scheduled and unscheduled scans, 
should be recorded in the eCRF and will be assessed by the IRC 
• Tumor assessment (per RECIST v1.1)  
5.2. 
Enrollment and Tumor Resection  
The patient is enrolled into the study upon tumor resection.  
Use of systemic corticosteroids is not allowed starting 21 days prior to beginning the 
NMA-LD preconditioning regimen, through treatment, and up to 60 days post-LN-144 
infusion. Prophylactic use of systemic corticosteroids is not allowed under any 
circumstances. Such medications should only be used to treat immediate life-threatening 
conditions. 
The following procedures should be completed during this visit: (Appendix 1) 
• Physical examination (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
o Concomitant medications include those that are administered as part of the 
tumor resection procedure 
• Repeat serology testing only for tumor samples acquired in the EU (HIV-1, HIV-
2, HBsAg, anti-HBc, HCV Ab, and syphilis). These are to be done on the day of 
the tumor resection or within 7 days after the resection (Appendix 3) 
• Blood for immune monitoring (± 3-day window); refer to Laboratory Manual 
• Tumor resection  
• Intraoperative frozen section (or fine-needle aspiration [FNA]) or touch prep 
cytology 
• The following medications should be administered as follows or as per 
institutional standards: 
o Herpetic treatment as per Screening (Section 5.1) 
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5.2.1. 
Tumor Harvest and Processing Procedure 
 
If the patient has only one identified target lesion at Screening, then another lesion needs 
to be identified and used for TIL generation.  
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. The resected tumor specimen for LN-144 
manufacturing should be viable solid tumor tissue (or aggregate of lesions resected) that 
is ≥ 1.5 cm, but no more than 4.0 cm in diameter. Viable solid tumor tissue is tissue that 
has all portions of necrotic, hemorrhagic, and fatty tissue removed. Biopsy from multiple 
different lesions is encouraged.  
Tumor specimens must undergo intraoperative frozen section (or FNA) or touch prep 
cytology examination by a pathologist to ensure that viable tumor is present. In addition, 
at the time of tumor resection, the surgeon and/or pathologist must use their best 
judgement to evaluate the results of the frozen section (or FNA) or touch prep cytology, 
incorporating visual inspection of the specimen. This is done to ensure that viable tumor 
specimens are being shipped for TIL generation. The pathologist and surgeon must 
perform these assessments in parallel prior to shipping the tumor specimen for TIL 
generation to the contract manufacturing organization (CMO).  
Intraoperative frozen section (or FNA) or touch prep cytology examination is not a gold 
standard. If any of the above-mentioned methods is found to contain no viable tumor, the 
expert opinion of the pathologist and surgeon at the time of surgery will supersede, and if 
they believe there is viable tumor, the resected sample should still be sent for 
manufacturing.    
If a portion of the viable tumor tissue is still available after completion of preparation of 
tumor tissue for LN-144 manufacturing, then the excess tumor tissue will be utilized for 
exploratory biomarker analysis. If no excess tumor tissue is available, then a single 2-mm 
punch biopsy from the center of the resected tumor can be collected. Ensure that this 
biopsy does not bring final tumor tissue for TIL generation to < 1.5 cm. If excess viable 
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tumor tissue and punch biopsy are not available, then excess viable tumor tissue can be 
resected from an additional lesion (if available). Note that this excess tumor tissue cannot 
originate from a target lesion. Please refer to the Laboratory Manual for details on 
utilization, processing, and shipping of excess viable tumor tissue/punch biopsy.  
5.3. 
Baseline (Day -21 to Day -10) Procedures 
To ensure the patient still meets the inclusion and exclusion criteria, the following 
procedures should be completed during this visit. If the Day 0 visit is re-scheduled to a 
later date and assessments, which have already been performed, become out of window, 
then they will need to be repeated within 4 weeks prior to the new Day 0. 
• Review of inclusion and exclusion criteria  
o Reconfirmation of eligibility requires review and approval by the Medical 
Monitor or designee  
• ECOG performance status evaluation 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood and urine tests  
o Hematology (Appendix 3)  
o Chemistry (Appendix 3) 
o Serum pregnancy test for women of childbearing potential 
o Dipstick urinalysis (Appendix 3) 
• Evaluation and measurement of all skin and palpable lesions (if applicable) 
• ECG  
• Complete imaging assessments (Appendix 3) 
o MRI of the brain: 
 If a brain MRI was performed within 4 weeks prior to Day 0 and 
considered normal or stable, and the patient is not showing any 
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clinical symptoms of progression in the brain, then a brain MRI 
does not need to be repeated  
• Tumor assessment (per RECIST v1.1)  
o Baseline target lesions should also have been measured at Screening 
(Section 10.1.1.1) 
• HRQoL questionnaire EORTC QLQ-C30 (Appendix 14) 
• The following medications should be administered as follows or as per 
institutional standards: 
o Herpetic treatment as per Screening (Section 5.1)  
5.4. 
Patients Who Do Not Receive an LN-144 Infusion Procedure 
Some patients may undergo tumor resection but will not receive infusion of LN-144 
(eg, discontinue treatment; Section 8.2). Such patients who do not begin the NMA-LD 
preconditioning regimen and/or do not receive LN-144 infusion for any reason, will 
perform an EOA visit and transition directly into the OS Follow-up Period (Section 5.7).  
Patients who meet inclusion and exclusion criteria and do not receive LN-144 (eg, due to 
a manufacturing failure) may be rescreened after consultation with the Medical Monitor. 
5.5. 
Treatment Period  
The Treatment Period will begin on Day -7 (start of NMA-LD preconditioning regimen) 
and continue to Day 28 (EOT visit; Appendix 1).  
Use of systemic corticosteroids is not allowed starting 21 days prior to beginning the 
NMA-LD preconditioning regimen, through treatment, and up to 60 days post-LN-144 
infusion. Prophylactic use of systemic corticosteroids is not allowed under any 
circumstances. Such medications should only be used to treat immediate life-threatening 
conditions. 
5.5.1. 
Day -7 Procedures 
Verification of sufficient LN-144 viable cell expansion will be confirmed by the Sponsor 
and site will receive the authorization to begin the NMA-LD preconditioning regimen.  
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Furthermore, prior to beginning the NMA-LD preconditioning regimen, patients must be 
seronegative for HSV IgM or PCR assay. 
The following procedures/assessments should be completed during this visit: 
• ECOG performance status evaluation 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood and urine tests (to be drawn prior to cyclophosphamide administration) 
o Hematology (Appendix 3) 
o Chemistry (Appendix 3) 
o Serum pregnancy test for women of childbearing potential 
o Dipstick urinalysis (Appendix 3) 
o Blood for immune monitoring (prior to starting NMA-LD) 
• Authorization for lymphodepletion 
o Authorization to Receive Lymphodepletion must be received by the site 
from the Sponsor or designee prior to beginning the NMA-LD 
preconditioning regimen (with a planned start on Day -7)  
• The following medications must be dosed using actual body weight (as recorded 
at Day -7 or within 7 days of the start of the chemotherapy per institutional 
standards) and administered as follows or as per institutional standards: 
o Cyclophosphamide (60 mg/kg) with mesna (15 mg/kg) will be infused 
over approximately 2 hours. Cyclophosphamide may be prepared in 
250 mL or 500 mL (eg, 5% dextrose in water [D5W] or 0.9% sodium 
chloride [NaCl]). Refer to the current package insert or Summary of 
Product Characteristics (SmPC) for cyclophosphamide full prescribing 
information (Appendix 7) 
o Mesna will continue to be infused at a rate of 3 mg/kg/hour in a suitable 
diluent over 22 hours after each cyclophosphamide dose. Higher or 
continued doses of mesna can be administered for prevention of 
hemorrhagic cystitis. Refer to the current package insert or SmPC for 
mesna full prescribing information (Appendix 8) 
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o Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose 
between 8 mg and 16 mg] IV every 8 hours × 3 days), or as per 
institutional standards, will be given for nausea. Refer to the current 
package insert or SmPC for ondansetron full prescribing information 
(Appendix 9) 
o Broad-spectrum ABX will be initiated if fever (defined as 38.3°C, one or 
two temperatures of 38.0°C or above at least 1 hour apart), AND an ANC 
≤ 500/mm3 (Section 7.4.4), or per institutional standard 
5.5.2. 
Day -6 Procedures 
The following procedures should be performed: 
• Physical examination (Appendix 3) 
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood tests (to be drawn prior to cyclophosphamide administration) 
o Hematology (Appendix 3) 
o Chemistry (Appendix 3)  
• The following medications should be administered as follows or as per 
institutional standards: 
o Cyclophosphamide as per Day -7 (Section 5.5.1)  
o Mesna as per Day -7 (Section 5.5.1)  
o Ondansetron as per Day -7 (Section 5.5.1)  
o Broad Spectrum ABX as per Day -7 (Section 5.5.1) 
5.5.3. 
Day -5 to Day -1 Procedures 
The following procedures should be performed: 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood and urine tests (to be drawn prior to fludarabine administration) 
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o Hematology (Appendix 3) 
o Chemistry (Appendix 3)  
o Dipstick urinalysis (Appendix 3) 
 Day -4 and Day -1 only 
• The following medication must be dosed using actual body weight (as recorded at 
Day -7 or within 7 days of the start of the chemotherapy per institutional 
standards) and administered as follows or as per institutional standards: 
o Fludarabine (25 mg/m2) to be given IV over approximately 30 minutes, 
once daily  
 Fludarabine dose will be adjusted according to eCrCl as follows: 
eCrCl 50–79 mL/min: reduce dose to 20 mg/m2 
eCrCl 40–49 mL/min: reduce dose to 15 mg/m2 
 Dose hold or discontinuation of fludarabine will only be allowed in 
the case of toxicity described in the package insert. Refer to the 
current package insert or SmPC for fludarabine full prescribing 
information (Appendix 12) or per institutional standard. 
o Broad Spectrum ABX as per Day -7 (Section 5.5.1) 
5.5.4. 
Day 0 (Infusion Day) Procedures 
Patients must be hospitalized prior to the planned LN-144 infusion for overnight 
hydration and will remain hospitalized until completion of the IL-2 administration, or as 
per institutional standards.  
Day 0 is the day of LN-144 infusion.  
5.5.4.1. 
Pre-LN-144 Infusion  
On Day 0, just prior to LN-144 infusion, the following procedures should be performed: 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
o Vital signs will be monitored every 30 minutes during infusion then 
hourly (± 15 minutes) for 4 hours, and then routinely (every 4–6 hours), 
unless otherwise clinically indicated, for up to approximately 24 hours 
post-LN-144 infusion  
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• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood and urine tests 
o Hematology (Appendix 3) 
o Chemistry (Appendix 3)  
o Serum pregnancy test for women of childbearing potential 
o Dipstick urinalysis (Appendix 3) 
o Blood for immune monitoring must be collected: 
 Day 0 OR Day 1 (after LN-144 AND prior to first IL-2 dose) 
• The following medications will be administered to the patient prior to LN-144 
infusion as follows or as per institutional standards:  
o Within 24 hours, hydration  
o Within 30–60 minutes, premedicate the patient with acetaminophen 
(650 mg) or equivalent and diphenhydramine (25–50 mg IV), or another 
H1-histamine antagonist  
 Prophylactic use of systemic corticosteroids is not allowed; such 
medications should only be used to treat immediate life-threatening 
conditions 
• During infusion of LN-144, appropriate emergency medications (eg, epinephrine 
and diphenhydramine) should be available at bedside, and institutional emergency 
guidelines should be followed as needed. Additional supportive therapy may 
include: 
o Continued acetaminophen (650 mg q4h) or equivalent 
o Indomethacin (50–75 mg q6h) 
o Ranitidine (150 mg q12h) 
o Meperidine (25–50 mg)  
o Other medications as per institutional standards  
5.5.4.2. 
LN-144 Infusion  
Each lot of LN-144 product contains between 1 x 109 and 150 x 109 viable cells per the 
product specification. Patients will receive the full dose of product that is manufactured 
and released.   
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LN-144 should be infused as soon as practically possible, after approximately 24 hours 
following the last dose of fludarabine. If ≥ 4 days have elapsed between the last 
fludarabine dose and LN-144 infusion, the ALC should be measured and there should be 
a discussion with the Medical Monitor. 
Each cryobag of LN-144 will be thawed at 37oC using a water bath or other thawing 
device, one at a time, for sequential infusion. 
LN-144 will be administered IV and infused by gravity beginning at a rate of 1 mL/min 
for the first 5 minutes. If no adverse reaction is observed, the infusion rate can then 
increase to between 5 and 10 mL/minute for the completion of the infusion. During 
periods of infusion interruption, any remaining cryobags of LN-144 should be kept in the 
cryoshipper. Any thawed LN-144 should be infused within 3 hours of being thawed. 
Refer to the LN-144 Pharmacy and Administration Manual for details on the thawing and 
administration procedure.  
Blood for immune monitoring must be collected after LN-144 infusion and prior to the 
first dose of IL-2 (Day 0 or Day 1).  
All visits following LN-144 infusion are calculated from Day 0 forward. 
5.5.4.2.1. IL-2 Dosing and Dose Adjustments 
The following medications will be administered as follows or as per institutional 
standards: 
• IL-2: the first IL-2 administration will begin approximately 3–24 hours after the 
completion of LN-144 infusion at a dose of approximately 600,000 IU/kg (based 
on actual body weight recorded at Day 0 [Section 5.5.4.1] or within 7 days of the 
start of IL-2, per institutional standards). IL-2 is administered by IV at a 
frequency of approximately every 8–12 hours. Continue for up to a maximum of 
six doses  
o 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 1–6 doses based on 
tolerance 
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o IL-2 dosing is allowed for up to 4 days post-LN-144 infusion to allow for 
proper management of any IL-2 toxicities  
o If 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 six doses) may be given  
o IL-2 dosing may be held or stopped at the discretion of the Investigator  
o Skipping IL-2 doses is allowed if patient experiences a Grade 3 or Grade 4 
toxicity (Appendix 4 and Appendix 5). If > 2 doses of IL-2 are skipped, 
then IL-2 administration will be discontinued  
o IL-2 AEs are described in Appendix 4 and toxicities/management are 
described in Section 7.3 and Appendix 5 
• Broad Spectrum ABX as per Day -7 (Section 5.5.1) 
5.5.5. 
Day 1, Day 2, Day 3, and Day 4 Procedures 
While the patient remains hospitalized, the following procedures should be performed: 
• Physical examination (Appendix 3)  
• Vital signs, including pulse oximetry (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood and urine tests (must be drawn each day prior to the first IL-2 
administration) 
o Hematology (Appendix 3) 
o Chemistry (Appendix 3)  
o Dipstick urinalysis on days that IL-2 is administered, and subsequently, if 
clinically indicated (Appendix 3) 
o Blood for immune monitoring must be collected: 
 Day 0 OR Day 1 (after LN-144 AND prior to first IL-2 dose) 
 After last dose of IL-2, but no earlier than Day 3  
• IL-2 treatment per Day 0 (Section 5.5.4.2.1) 
• Filgrastim (5 µg/kg/day) or biosimilar will be administered beginning on Day 1 
by subcutaneous injection and continue each day until the ANC reaches > 
1000/mm3 for three consecutive days, discontinue if ANC rises to > 10,000/mm3, 
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or follow institutional standards. Refer to the current package insert or SmPC for 
filgrastim full prescribing information (Appendix 10)  
• Fluconazole (400 mg PO or IV daily) will be administered beginning on Day 1 
and continue daily until the ANC reaches > 1000/mm3. Refer to the current 
package insert or SmPC for fluconazole full prescribing information 
(Appendix 11) 
• Broad Spectrum ABX as per Day -7 (Section 5.5.1) 
5.5.6. 
Procedures on Day 14 (± 3 Days) and Day 28 (EOT Visit; ± 3 Days)  
The following procedures will be performed: 
• ECOG performance status evaluation (Day 14 only) 
• Physical examination (Appendix 3)  
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood tests: 
o Hematology (Appendix 3) 
o Chemistry  
o Thyroid panel to include TSH and free T4 on Day 14 only (Appendix 3) 
o Serum pregnancy test for women of childbearing potential (Day 28 [EOT 
visit] only) 
o Blood for immune monitoring (Day 14 only) 
• If required, the following medications will be administered as follows or per 
institutional standards: 
o Filgrastim or biosimilar is administered as per Day 1 (Section 5.5.5)  
o Fluconazole is administered as per Day 1 (Section 5.5.5) 
o Trimethoprim-sulfamethoxazole double strength (TMP-SMX DS; 
160mg/800 mg) to be administered daily beginning on Day 14 and 
continue until ALC reaches > 1000/mm3 for three consecutive days; if at 
6 months, ALC < 1000/mm3, continue treatment until CD4 count is 
> 200/mm3 for at least 6 months. Refer to the current package insert or 
SmPC for TMP-SMX full prescribing information 
o Viral prophylaxis: valacyclovir (500 mg PO daily), or acyclovir 
(250 mg/m2 IV every 12 hours) if the patient is unable to take medication 
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by mouth. Valacyclovir PO or acyclovir IV should begin on Day 14, or as 
the Investigator deems appropriate, and continue until ALC > 1000/mm3; 
if at 6 months, ALC < 1000/mm3, continue until CD4 > 200/mm3 for at 
least 6 months 
o Broad Spectrum ABX as per Day -7 (Section 5.5.1) 
5.6. 
Assessment Period  
Following the EOT visit, efficacy/imaging (eg, tumor response) assessments will be 
performed at Week 6 (Day 42) with a + 7-day window. Subsequent assessments will 
occur every 6 weeks (± 3-days) until Month 6 (Week 24), and then every 3 months 
(12 weeks) with a ± 7-day window for up to 5 years from Day 0; or until disease 
progression or start of new anticancer therapy. Subsequently, patients will perform the 
EOA visit and begin the OS Follow-up Period (Section 5.7). 
5.6.1. 
Procedures Every 6 Weeks (Week 6 [Day 42 {+ 7 Days}]; Week 12 
[Day 84 {± 3 Days}], and Week 18 [Day 126 {± 3 Days}])  
The following procedures will be performed: 
• ECOG performance status evaluation 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood tests 
o Hematology (Appendix 3) 
o Chemistry (Appendix 3)  
o Serum pregnancy test for women of childbearing potential  
o Blood for immune monitoring (Day 42 and Day 84 only)  
• Evaluation and measurement of all skin and palpable lesions (if applicable) 
• Slit-lamp eye examination in patients with history of uveitis, if clinically indicated 
(Day 84 only) 
• Imaging assessments (Appendix 3) 
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o Brain MRI following the Baseline visit should only be performed if 
clinically indicated or if positive at Baseline 
• Tumor response assessment (per RECIST v1.1 and irRECIST)  
• HRQoL questionnaire EORTC QLQ-C30 (Day 84 only; Appendix 14) 
• If required, the following medications will continue to be administered as follows, 
or as per institutional standards: 
o Filgrastim or biosimilar is administered as per Day 1 (Section 5.5.5)  
o Fluconazole is administered as per Day 1 (Section 5.5.5)  
o TMP-SMX DS as per Day 14 (Section 5.5.6) 
o Herpetic treatment as per Day 14 (Section 5.5.6) 
• On-study, post-treatment (post-LN-144 infusion) core biopsy at Week 6 (Day 42) 
following the first post-Baseline tumor response assessment scans  
o Mandatory when available and if patient consent is provided, two to six 
post-treatment core biopsies should be collected from a lesion distinct 
from those used as target or non-target for tumor response assessment 
o Refer to the Laboratory Manual for details on collection, processing, and 
shipment to the Central Laboratory 
5.6.2. 
Procedures Every 3 Months (± 1 Week) Starting at Month 6 Until the 
End of Assessment (EOA)  
The following procedures will be performed during these visits: 
• ECOG performance status evaluation 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood tests: 
o Hematology (Appendix 3) 
o Chemistry (Appendix 3) 
o Serum pregnancy test for women of childbearing potential (every 3 
months until Month 12 or the EOA visit, whichever occurs first) 
o Blood for immune monitoring (Month 6, Month 9, and Month 12 only)  
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• Evaluation and measurement of all skin and palpable lesions (if applicable) 
• Imaging assessments (Appendix 3) 
• Tumor response assessment (per RECIST v1.1 and irRECIST)  
• If required, the following medications will continue to be administered as follows 
or as per institutional standards: 
o Filgrastim (5 µg/kg/day) or biosimilar is administered by as per Day 1 
(Section 5.5.5) 
o Fluconazole is administered as per Day 1 (Section 5.5.5) 
o TMP-SMX DS as per Day 14 (Section 5.5.6)  
o Herpetic treatment as per Day 14 (Section 5.5.6) 
• HRQoL questionnaire EORTC QLQ-C30 (Month 6, Month 12, and Month 24; 
Appendix 14) 
5.6.3. 
End of Assessment (EOA) Visit Procedures 
The EOA visit will be completed at any time, post-Enrollment if: a patient withdraws 
from treatment, at the time of disease progression, or the start of a new anticancer 
therapy. Assessments performed within 14 days prior to the EOA visit do not need to be 
repeated. 
The following procedures should be performed:  
• Documentation of the cause leading to EOA 
• ECOG performance status evaluation 
• Physical examination (Appendix 3)  
• Vital signs (Appendix 3) 
• Assessment of AEs/SAEs (Section 12.2.1) 
• List all concomitant medications 
• Blood tests: 
o Hematology (Appendix 3) 
o Chemistry  
o Thyroid panel (Appendix 3) 
o Serum pregnancy test for women of childbearing potential  
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• Evaluation and measurement of all skin and palpable lesions (if applicable) 
• Imaging assessments (Appendix 3) 
• Tumor response assessment (per RECIST v1.1 and irRECIST) 
• HRQoL questionnaire EORTC QLQ-C30 (Appendix 14) 
Imaging assessment will be performed at least 28 days from the last date of progression 
to confirm disease progression per irRECIST, as applicable, as assessed by the 
Investigator. 
5.7. 
Overall Survival Follow-up Period 
The OS Follow-up Period will begin when a patient completes the EOA visit (last 
efficacy assessment) and will continue for up to 5 years from Enrollment or until 
discontinuation from the study (eg, withdrawal of consent to the study, lost to follow up, 
death, or study terminated by the Sponsor).  
Patients who had tumor resection but did not receive LN-144 for any reason will perform 
an EOA visit and transition directly into OS Follow-up Period. 
OS Follow-up will consist of telephone calls (or other means of contact) with the patient 
or designee every 3 months for survival and subsequent anticancer therapy.  
5.8. 
Hospitalization  
Patients will require hospitalization as per protocol preconditioning regimen, and for 
hydration prior to the LN-144 infusion through completion of IL-2 administration or per 
institutional standards. 
Patients may also require hospitalization as per institutional guidelines (for tumor 
resection; fludarabine preconditioning regimen; and treatment recovery). However, if the 
institutional guidelines mandate a required hospitalization longer than the protocol, this 
pre-planned hospitalization event will not be considered as an AE.  
All dates of hospitalization, regardless if required per protocol, including intensive care 
unit (ICU) stays, must be recorded in the Hospitalization eCRF. 
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6. 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 
6.1. 
 Concomitant Medications 
Use of all medications taken by the patient 28 days prior to signing the ICF will be 
recorded in the eCRF. All medications taken by the patient, or any changes in 
medications will also be recorded throughout the duration of the study, including those 
taken as part of the tumor-resection procedure.  
6.2. 
Prohibited and Permitted Medications During Study Treatment 
6.2.1. 
Prohibited Treatment 
• Systemic therapies intended to treat melanoma or any medications that may have 
an antitumor effect 
• Use of systemic corticosteroids are not allowed starting 21 days prior to beginning 
the NMA-LD preconditioning regimen, through treatment, and up to 60 days 
post-LN-144 infusion. Prophylactic use of systemic corticosteroids is not allowed 
under any circumstances. Such medications should only be used to treat 
immediate life-threatening conditions.  
• Palliative radiation therapy that involves lesions selected as target or non-target  
• Investigational drugs (other than LN-144) 
• Live or attenuated vaccine within 28 days prior to beginning the NMA-LD 
preconditioning regimen or within 3 months after the last dose of IL-2 (Day 84) 
until ANC is ≥ 1000/mm3  
6.2.2. 
Permitted Medications 
Concurrent medications for conditions other than patients’ unresectable or metastatic 
melanoma are permitted.  
Refer to the Information for Use package insert provided with all drugs used in this study 
to understand the contraindications, precautions, and warnings relative to a specific drug. 
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7. 
EXPECTED TOXICITIES AND TREATMENT GUIDELINES 
The following sections present information for common adverse effects. For more details 
on side effects, refer to the Investigator’s Brochure and relevant prescribing information. 
An overdose is not applicable for LN-144. In the event of cyclophosphamide, 
fludarabine, or IL-2 overdose, refer to the package insert for details on management 
(Section 12.1.1.1). 
7.1. 
Cyclophosphamide and Fludarabine Toxicities  
Expected toxicities with cyclophosphamide and fludarabine administration, as well as 
supportive care and management of toxicities are listed in the package inserts 
(Appendix 7 and Appendix 12, respectively). Treatment will be given as per institutional 
standards.  
In general, the use of the NMA-LD preconditioning regimen (cyclophosphamide and 
fludarabine) prior to LN-144 administration can to lead to myelosuppression. Therefore, 
a high index of suspicion for occult bacteremia should be maintained until marrow 
recovery. 
Additional guidelines for toxicity management are outlined below.  
7.1.1. 
Hemorrhagic Cystitis Prophylaxis 
To reduce the risk of cyclophosphamide-associated hemorrhagic cystitis, patients will 
receive continuous infusion of mesna in addition to IV fluids. Higher doses of mesna are 
allowed if the institutional standards recommend. Refer to treatment guidelines for 
recommended mesna dosing (Appendix 8). 
7.1.2. 
Fludarabine Hypersensitivity 
Fludarabine has been reported to cause skin toxicity consisting primarily of skin rashes. If 
this or other fludarabine-related toxicity events occur, consultation with the Medical 
Monitor is recommended prior to administration of LN-144. 
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7.1.3. 
Blood Product Support  
Using daily CBCs as a guide, the patient may receive platelets and packed red blood cells 
(PRBCs) as needed or as per institutional standards. Attempts will be made to keep Hb > 
7.5 g/dL, and platelets > 10,000/mm3. All blood products must be irradiated. Leukocyte 
filters will be utilized for all blood and platelet transfusions to decrease sensitization to 
transfused WBCs and decrease the risk of CMV infection.  
7.2. 
LN-144 Toxicity  
Toxicities related to the infusion of LN-144 (those which may be seen immediately 
following LN-144 infusion and prior to IL-2 administration), are generally mild and 
include fevers, chills, headache, and malaise. Dysgeusia may occur and should be limited 
to the duration of infusion. It also is possible that patients may experience severe allergic 
reaction including anaphylaxis that can be life threatening during infusion of LN-144 
product.  
7.2.1. 
Expected Toxicities with LN-144 
Allergic reactions to components of the cryopreserved LN-144 product (Section 9.2) 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. 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. Rarely have severe allergic reactions, such as anaphylaxis, 
developed. If anaphylaxis does occur, it will be treated immediately with an injection of 
epinephrine, steroids, and inhaled bronchodilators. 
Patients who have known allergies to ABX of the aminoglycoside group are excluded 
from studies of LN-144 (except those who are skin-test negative for gentamicin). 
Premedication and supportive therapy instructions are provided in Section 7.2.2. 
Details on the specific toxicities and risks may be found in the Investigator’s Brochure. 
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7.2.2. 
LN-144 Toxicity Prevention and Management  
During infusion of LN-144, appropriate emergency medications (eg, epinephrine and 
diphenhydramine) should be available at bedside, and institutional emergency guidelines 
should be followed as needed. 
The following medications will be administered to the patient prior to LN-144 infusion as 
follows or as per institutional standards:  
• Within 24 hours, hydration 
• Within 30–60 minutes, premedicate the patient with acetaminophen (650 mg) or 
equivalent, and diphenhydramine (25–50 mg IV), or another H1-histamine 
antagonist  
o Prophylactic use of systemic corticosteroids is not allowed under any 
circumstances; such medications should only be used to treat immediate 
life-threatening conditions  
Additional supportive therapy may include: 
• Continued acetaminophen (650 mg q4h) or equivalent 
• Indomethacin (50–75 mg q6h) 
• Ranitidine (150 mg q12h) 
• Meperidine (25–50 mg) 
• Other medications as per institutional standards  
7.3. 
IL-2 Toxicity  
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 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.  
Refer to the prescribing information for IL-2 in Appendix 13.  
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7.3.1. 
Expected Toxicities with IL-2 
7.3.1.1. 
Decreased Mental Status with IL-2 
IL-2 can result in decreased mental status, which can range from somnolence to 
obtundation; continued administration may result in coma. Agitation may also be 
observed due to mild hallucinations. Administration of IL-2 should be withheld or 
permanently discontinued in patients with decreased mental status. See Appendix 4 and 
Appendix 5 for IL-2 AEs and toxicity management guidelines.  
7.3.1.2. 
Pulmonary Risk 
LN-144 can remain in the pulmonary circulation for 24–48 hours following infusion and 
may cause transient shortness of breath. In addition, pulmonary edema is commonly 
observed with IL-2 treatment. Supplemental oxygen should 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, then IL-2 
should be withheld or stopped. Refer to Appendix 4 and Appendix 5 for IL-2 AEs and 
toxicity management guidelines.  
7.3.1.3. 
Cardiac Arrhythmias and Myocarditis 
All new cardiac arrhythmias should be promptly evaluated and continuously monitored 
with intensive management. Upon patient recovery from the cardiac event, continuation 
of IL-2 administration is per the Investigator’s discretion. 
7.3.1.4. 
Capillary Leak Syndrome 
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. 
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Resultant intravascular volume depletion should be managed with IV fluids. Diuresis 
should be initiated as tolerated following completion of IL-2 treatment. Hypotension not 
responsive to IV fluids should raise suspicion for occult bacteremia and associated sepsis.  
7.3.1.5. 
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 treatment.  
7.3.2. 
Renal Toxicity 
Renal toxicity, defined by a rapid rise in creatinine levels or clinical symptoms, is a risk. 
If patients exhibit signs or symptoms of renal toxicity, manage as per institutional 
standards. 
7.4. 
Infection Prophylaxis 
Treatment with IL-2 is associated with impaired neutrophil function (reduced 
chemotaxis) and with an increased risk of disseminated infection, including sepsis and 
bacterial endocarditis. Preexisting bacterial infections should be adequately treated prior 
to start of IL-2 administration. 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.  
Other anti-infective agents may be substituted at the discretion of the Investigator as per 
institutional standards.  
7.4.1. 
Pneumocystis jiroveci Pneumonia 
Pneumonia prophylaxis should begin on Day 14 and continue until ALC is > 1000/mm3 
or for at least 6 months post-chemotherapy at the discretion of the Investigator as per 
institutional standards. All patients will receive the fixed combination of TMP-SMX DS 
(160 mg/800 mg; PO) daily, three times a week on non-consecutive days, or as per 
institutional standards.  
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Pentamidine or alternative as per institutional standards 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 > 1000/mm3. 
If the ALC remains < 1000/mm3 at 6 months post-chemotherapy, prophylaxis will 
continue until the CD4 count is > 200/mm3 for at least 6 months, or as per institutional 
standards.  
7.4.2. 
Herpes Virus Prophylaxis 
Patients with positive HSV IgM or PCR assay will be given valacyclovir orally at a dose 
of 500 mg daily, or acyclovir 250 mg/m2 IV every 12 hours if the patient is not able to 
take medication by mouth. IgM or PCR assay must be tested negative prior to initiation 
of NMA-LD. 
Herpes prophylaxis should begin for all patients on Day 14 and will continue for at least 
6 months, or until ALC count > 1000/mm3. If ALC count remains < 1000/mm3 at 6 months 
post-chemotherapy, prophylaxis will continue until the CD4 count is > 200/mm3, or as 
per institutional standards. 
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. If this occurs, then the acyclovir dose should be adjusted or discontinued. 
Acyclovir cannot be used concomitantly with other nucleoside analogs, which interfere 
with deoxyribonucleic acid (DNA) synthesis (eg, ganciclovir). In renal disease, the dose 
is adjusted as per product labeling.  
7.4.3. 
Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg PO or IV daily on Day 1 and continue until the 
ANC is > 1000/mm3, or as per institutional standards. If ANC count remains < 1000/mm3 
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at 6 months post-chemotherapy, prophylaxis will continue until the CD4 count is > 
200/mm3 for at least 6 months, or as per institutional standards. 
7.4.4. 
Empiric Antibiotics  
Patients will start on broad-spectrum ABX, either a third or fourth generation 
cephalosporin or a quinolone, for: fever (defined as 38.3°C, one or two temperatures of 
38.0°C or above at least 1 hour apart); AND 1) ANC ≤ 500/mm3; or 2) receiving IL-2 
administration, or follow institutional standards. 
Aminoglycosides should be avoided unless there is clear evidence of sepsis.  
Infectious disease consultation will be obtained for all patients with unexplained fever or 
any infectious complications as per institutional standards.  
7.4.5. 
Sepsis 
Sepsis can mimic IL-2 side effects. Fever may be masked during IL-2 administration due 
to scheduled indomethacin and acetaminophen or equivalent. Neutropenic patients 
exhibiting hypotension or oliguria unresponsive to IV fluids should be tested for 
infection, and broad-spectrum ABX should be initiated. 
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8. 
COMPLETION / DISCONTINUATION AND WITHDRAWAL OF 
PATIENTS 
8.1. 
Treatment Completion 
The Treatment Period is from Day -7 (start of NMA-LD preconditioning regimen) to 
Day 28 (EOT visit). 
Treatment completion is defined as having received LN-144 infusion.  
8.2. 
Criteria for Early Discontinuation from Treatment 
Some patients may undergo tumor resection but will not receive infusion of LN-144. 
Such patients will perform an EOA visit and transition directly into the OS Follow-up 
Period of the study. 
Patients may discontinue any component of the study regimen. Criteria for 
discontinuation from treatment: 
• Withdrawal of consent to treatment (every effort should be made to continue OS 
Follow-up, when applicable) 
• Grade ≥ 3 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 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 (must have 
received at least one dose of IL-2; Appendix 5)  
• Determination by the Investigator that continued treatment is not in the best 
interest of the patient 
• Administration of prohibited concomitant medications/start of new anti-cancer 
therapy 
• Death 
8.3. 
Assessment Completion / End of Assessment (EOA) 
All patients will be assessed for up to 5 years from Day 0 or until disease progression or 
the start of new anticancer therapy.  
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8.4. 
Discontinuation from the Study 
Patients will be discontinued from the study after 5 years from Enrollment (tumor 
resection), withdrawal of consent to the study, lost to follow-up, death, or if the study is 
terminated by the Sponsor. 
8.5. 
Study Completion  
The study is expected to be completed approximately 5 years (60 months) from 
Enrollment (tumor resection) of the last patient. This is the time point when all patients 
have exited the study for any reason, or study is terminated by the Sponsor, whichever 
occurs first. 
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9. 
STUDY DRUG INFORMATION 
9.1. 
Investigational Product Overview 
Investigational Product Name 
• LN-144 
Active Investigational Product Components 
• Autologous TIL 
Dosage Form 
• Live cell suspension either noncryopreserved (Cohort 1) or cryopreserved 
(Cohort 2, Cohort 3, and Cohort 4) 
9.2. 
Qualitative Composition of LN-144 
The product is composed of autologous TIL obtained from an individual patient through 
surgical resection of tumor and expanded ex vivo through cell culture in the presence of 
IL-2 and a mAb to CD3. The cryopreserved final drug product is a cell suspension that is 
formulated in CryoStor® CS10 cryopreservation medium/Plasma-Lyte (final DMSO 
concentration: 5%) containing 0.5% HSA, and 300 IU/mL of IL-2. The non-
cryopreserved final drug product, used to treat patients from Cohort 1, is formulated in 
HypoThermosol™ transport medium. 
9.3. 
Manufacturing Process 
An overview of the manufacturing process for cryopreserved product from tumor 
resection through to infusion of LN-144 product is provided in Figure 2. 
LN-144 is manufactured ex vivo using autologous tumor as starting material. The key 
steps to manufacturing drug substance and drug product are: 
Drug Substance 
• Surgical removal of tumor tissue from a single patient and shipment of the 
material to the GMP manufacturing facility 
• Ex vivo expansion of the TIL present in the tumor sample through placement of 
fragments of the tumor into medium containing the cytokine IL-2, and subsequent 
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expansion of the TIL through culture in medium with IL-2 and OKT3 mAb, and 
irradiated PBMC “feeder” cells 
• Harvesting and washing of the cultured TIL 
Drug Product 
• Suspension of the culture-derived TIL in medium suitable for cryopreservation 
and patient infusion 
• The product release specification requires that each LN-144 product lot contain 
between 1 x 109 and 150 x 109 viable cells. Patients will receive the full dose of 
product that is manufactured and released.   
9.4. 
Final Investigational Product Container 
Cryopreserved LN-144 is packaged in up to four cryopreservation bags containing 300–
500 mL of viable cells. Each bag of product is labeled with patient-specific information. 
9.5. 
Shipping/Transport of Investigational Product 
LN-144 is shipped by express courier to the clinical site in a shipping container qualified 
to maintain a temperature of < -150°C for cryopreserved product. 
9.6. 
Receipt of Investigational Product at Clinical Site  
LN-144 will be received by the clinical site’s pharmacy or designee prior to, or on, the 
day of infusion (Day 0). The date and time that possession of the product transfers from 
the courier to the clinical site will be documented on, and determined by, the courier’s 
shipping paperwork. 
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10. 
RESPONSE ASSESSMENTS 
10.1. Tumor Response Assessments 
Tumor response assessments will be performed by clinical examination (skin lesions) and 
by conventional or spiral CT scans of the chest, abdomen, pelvis, and MRI of the brain. 
Photographic documentation and caliper measurement will be performed for superficial 
dermal and subcutaneous lesions that cannot be assessed by radiographic scan. Tumor 
assessments are planned for: Screening and Baseline (Day -21 to Day -10). Tumor 
response assessments are planned for: Week 6 (Day 42), then every 6 weeks until Month 
6 (Week 24), and every 3 months (12 weeks) for up to 5 years from Day 0 or until the 
EOA visit has been completed.  
CT scans of additional anatomical locations will be conducted at the above referenced 
visits if prior or suspected disease is clinically indicated. Additional radiological 
assessments may be performed per Investigator’s discretion. All imaging assessments, 
including scheduled and unscheduled scans, must be recorded in the eCRF by the 
Investigator or designee, and will be assessed by the IRC.  
High-resolution CT with PO/IV contrast or contrast-enhanced MRI is the preferred 
imaging modality for assessing radiographic tumor response. If a patient has a known 
allergy to CT contrast material, please use the alternate modality. In cases where contrast 
is strictly contraindicated, a non-contrast scan will suffice. The same image modality 
must be used throughout the study. 
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 modality should be used for all scans throughout the study. 
10.1.1. 
Response Criteria 
Tumor response will be determined using RECIST v1.1 with a modification to require 
confirmation of PD per irRECIST performed at least 28 days from the last date of 
progression, as applicable, as assessed by the Investigator. Refer to Table 1 for RECIST 
v1.1 definitions. Images (CT scans and/or MRI scan) obtained at Baseline visit (Day -21 
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to Day -10) are to be utilized for RECIST v1.1 response assessments throughout the 
study. 
Tumor response assessments performed at the site should be used for clinical treatment 
decisions and may include photographic and caliper measurement of superficial dermal 
and subcutaneous lesion.  
All locally-obtained images will be forwarded to a central imaging facility for the IRC 
assessment of tumor responses. 
10.1.1.1. 
Definition of Target and Non-Target Lesions 
Patients should have at least one measurable target lesion as defined by RECIST v1.1. 
If the patient has only one identified target lesion at Screening, then another lesion needs 
to be identified and harvested for TIL generation. If a lesion was partially resected to 
generate TIL, and remains visible on the Baseline scan after surgery, then the partially 
resected lesion can be used for RECIST v1.1 response assessment, but only as a non-
target lesion. 
Ideally, Baseline target lesions should have also been measured at Screening so as to 
understand the tumor dynamics and potentially identify hyperprogressors.  
Lesions in previously irradiated areas (or other local therapy [eg, talimogene 
laherparepvec {TVEC}]) should not be selected as target lesions unless treatment was 
≥ 3 months prior to Screening and there has been demonstrated disease progression of the 
lesion.  
The on-study, post-treatment (post-LN-144 infusion) core biopsy at Week 6 is 
mandatory, when available and if patient consent is provided, and should be done in a 
lesion not being followed for response assessment (either as a target or as a non-target 
lesion; Section 5.6.1). 
10.1.1.2. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the first post-Baseline tumor 
assessment at Week 6 (Day 42) until disease progression or the start of a new anticancer 
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therapy. The patient's best response assignment will depend on target lesion sum of 
diameters (SoD), non-target lesion status, absence of a new lesion, and the confirmation 
criteria. The best overall response is determined once all the data for the patient is known. 
Table 1 
Time Point Response: Patients with Target (± Non-target) Disease 
Target Lesions 
Non-target 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 
Not evaluated 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease  
10.2. Biomarkers 
Immune monitoring samples and tumor specimens will be collected to identify 
biomarkers of LN-144. Refer to the Laboratory Manual for additional details. 
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11. 
STATISTICAL AND ANALYTICAL PLANS  
11.1. Introduction  
The statistical analysis will be performed by cohort. Patients who receive a second TIL 
regimen therapy (Cohort 3) will have their safety and efficacy data tabulated separately. 
Rescreened patients, who received LN-144 for the first time due to a previous 
manufacturing failure or other reasons, will be included in the analysis sets of the original 
cohort. There is no planned statistical comparison among cohorts. 
11.2. Study Analysis Sets 
Two analysis sets are defined for the analysis and presentation of the data. The Full 
Analysis Set (FAS) will be the primary set for the analysis of safety and efficacy data. 
Additional analysis for the primary efficacy endpoint, AEs, and SAEs will be conducted 
using the Tumor Harvested (TH) Set.  
11.2.1. 
Tumor Harvested Set (also termed Enrolled Set) 
The TH Set is defined as all tumor-resected patients for production of LN-144, regardless 
of whether they have received treatment or not.  
11.2.2. 
Full Analysis Set 
The FAS is defined as patients who have received LN-144 infusion.  
11.3. Endpoints 
11.3.1. 
Primary Endpoint 
The primary endpoint is the ORR using RECIST v1.1 criteria as assessed by the IRC. 
Patients without any baseline or any post-baseline tumor measurements are considered 
non-evaluable. 
11.3.2. 
Secondary Endpoints 
The secondary endpoints will include DOR, DCR, and PFS per RECIST v1.1 criteria as 
assessed by the IRC. In addition, the secondary endpoints will include the ORR, DOR, 
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DCR, and PFS per RECIST v1.1 criteria as assessed by the Investigator. OS 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 PD or 
death occurs. Patients not experiencing PD or death prior to the time of data cut or 
database lock will have their event times censored on the last complete tumor response 
assessment date. For patients who received new anticancer therapies, the DOR will be 
censored at the date of last tumor response assessment prior to the start of new anticancer 
therapies. DCR is the sum of confirmed CR/PR and stable disease tumor responses 
divided by the number of patients in the analysis set. PFS is defined as the time (in months) 
from the start date of LN-144 infusion to PD or death due to any cause, whichever occurs 
earlier. Patients not experiencing PD or death at the time of data cut or database lock will 
have their event times censored on the last tumor response assessment date. For patients 
who received new anticancer therapies, the PFS is measured from the date of LN-144 
infusion to the date of last tumor response assessment prior to the start of new anticancer 
therapies. 
The OS is defined as the time (in months) from the start date of LN-144 infusion to death 
due to any cause. Patients not having expired at the time of data cut 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 AEs, clinical laboratory tests, and vital signs. 
11.3.3. 
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 (ORR, DOR, DCR, 
and PFS) per irRECIST will be assessed by the Investigator. HRQoL will be assessed 
using the EORTC QLQ-C30 instrument (Appendix 14) and scored/evaluated as described 
in the Statistical Analysis Plan (SAP). 
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11.4. Sample Size Consideration 
Cohort 1: Infused 23 patients using the non-cryopreserved autologous TIL product 
manufacturing process. Enrollment into this cohort was stopped to focus on the 
cryopreserved autologous TIL product manufacturing process. 
Cohort 2: Approximately 66 patients are planned to be infused and receive 
cryopreserved LN-144. Sixty patients will allow estimation of ORR using the maximum 
half width of the two-sided 95% confidence limit of less than 13.2% (Clopper-Pearson) 
when ORR is expected to range from 20–50%. 
Cohort 3: This cohort will infuse approximately 10 patients from Cohort 1, Cohort 2, or 
Cohort 4 who have elected to undergo a second retreatment.  
Cohort 4: Approximately 75 patients are planned to be infused and receive 
cryopreserved LN-144. It will test the prospectively defined hypothesis for the primary 
endpoint of ORR as assessed by the IRC based on the null hypothesis of ORR ≤ 10% and 
alternative hypothesis of ORR > 10%. A sample size of 75 patients in the FAS will 
provide more than 90% power to demonstrate statistical significance at a two-sided 
overall significance level of 0.05 using the exact test. It is assumed the true response rate 
for TIL therapy in this population is 25%. 
Justification of the null hypothesis of ORR ≤ 10% for Cohort 4 based on historical 
control estimate: 
As cited in the National Comprehensive Cancer Network (NCCN) guideline for 
metastatic melanoma and/or frequently observed as prior therapies in Cohorts 1 and 2, 
only DTIC is an approved therapy for the metastatic melanoma patient population. Other 
agents such as carboplatin, paclitaxel, docetaxel, nab-paclitaxel and temozolomide are 
not approved by the US Food and Drug Administration (FDA) and therefore they are not 
appropriate comparators for Cohort 4 of LN-144. 
Table 2 below is a summary of historical studies that included a DTIC monotherapy arm. 
The first half of the table summarizes those trials conducted in the post-checkpoint era, 
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Furthermore, response rates to chemotherapy, including DTIC, in multiple recent phase 3 
melanoma trials ranged from 4–10% (studies comparing DTIC with trametinib or 
vemurafenib in patients with BRAF V600 mutant tumors; or pembrolizumab and 
nivolumab in patients who are refractory to ipilimumab) [Hamid 2017; Weber 2015].  
The historical control ORR of 10% for advanced melanoma was also used for the single 
arm study Keynote-001 [Kang 2017], which enrolled ipilimumab-naïve patients, and for 
the randomized study Checkmate-037 after it discontinued the control arm (ie, 
Investigators’ choice) due to a high dropout rate. 
11.5. Final Analysis 
An interim analysis of patients within Cohort 4 will not be conducted for this study. The 
primary analysis will be conducted after all Cohort 4 patients have been infused. 
The primary statistical analysis will utilize a two-sided significance level of 0.05. The 
lower bound of the two-sided 95% Clopper-Pearson exact CI for ORR would need to be 
> 10% to reject the null hypothesis. The details will be described in the SAP. 
11.6. Statistical Analyses 
11.6.1. 
Patient Disposition 
Patient disposition (analysis population allocation, entered, completed, discontinued, 
along with primary reason for discontinuation) will be summarized using frequency and 
percentage. A summary of patients enrolled by site will be provided.  
11.6.2. 
Baseline Demographics and Clinical Characteristics 
Baseline (Day -21 to Day -10) demographic and clinical (disease) characteristics will be 
summarized descriptively for the FAS. 
11.6.3. 
Analysis of the Primary Efficacy Endpoint 
The ORR as assessed by the IRC is expressed as binomial proportions and will be 
summarized for the best overall response using a point estimate and its two-sided 
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confidence limits based on the Clopper-Pearson exact method, at an overall alpha level of 
0.05. 
11.6.4. 
Analysis of the Secondary Efficacy Endpoints 
The DCR is expressed as binomial proportions and will be summarized using both a point 
estimate and its two-sided 95% confidence limits based on the Clopper-Pearson exact 
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 from the date on which patients received LN-144 infusion 
(Day 0), depending on the maturity of the study data at the time of analysis.  
11.6.5. 
Safety Analysis 
The assessment of safety data will be descriptive and based on the summarization of 
TEAEs, SAEs, and AEs leading to discontinuation from the study, vital signs, and 
clinical laboratory tests. Treatment emergent is considered to start at the time of the 
LN-144 infusion through 30 days post-infusion for the FAS. AE summaries will be based 
on patient incidence counts and their related percentages. In addition to an overall 
summary of AEs, 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 v4.03 for each measure under consideration (eg, ANCs for neutropenia; platelets 
for thrombocytopenia; Appendix 6). 
11.6.6. 
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. 
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12. 
SAFETY MONITORING AND REPORTING 
12.1. Adverse Events 
Safety events will be recorded as AEs and SAEs in the patient’s source documents and on 
the AE eCRF, and must be graded using the NCI’s CTCAE v4.03 dated 14 June 2010 
(Appendix 6).  
12.1.1. 
Definitions 
12.1.1.1. 
Adverse Event 
An AE as defined by the International Conference on Harmonisation (ICH) Guidelines 
for Good Clinical Practice (GCP) as any untoward medical occurrence in a patient or 
clinical trial patient starting from signing the ICF, which does not necessarily have a 
causal relationship with LN-144 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 LN-144. 
Events meeting the definition of an AE include: 
• AE temporally associated with the use of any of the study drugs, including 
LN-144 treatment, whether or not considered related to the use of any of the study 
drugs or LN-144 treatment 
• Abnormal laboratory test values or results (eg, hematology, clinical chemistry, 
urinalysis) or other safety assessments (eg, ECGs, radiological scans, vital sign 
measurements, significant physical examination changes) or events related to 
protocol mandated procedures (eg, incidental patient injury during a procedure), 
will be reported as AEs only if they are deemed by the Investigator as being 
clinically significant, led to hospitalization or prolongation of hospitalization, 
required a change in dosing or treatment of study therapies, or 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 LN-144 administration 
• Signs, symptoms, or the clinical sequelae of a suspected interaction with LN-144  
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• Signs, symptoms, or the clinical sequelae of special situations (eg, suspected 
overdose of either cyclophosphamide, fludarabine, IL-2, or a concomitant 
medication; medication error; product complaint; or occupational/accidental 
exposure) 
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) 
• Special situations, as described above (eg, overdose from a study medication or 
concomitant medication; medication error; product complaint; or 
occupational/accidental exposure) without clinical sequelae (Section 12.2.1) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present (eg, AE grade change from 1 to 2 is an anticipated fluctuation) 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.  
12.1.1.2. 
Serious Adverse Event  
An SAE is considered “serious” if, in the view of either the Investigator or the Sponsor, it 
results in any of the following outcomes:  
• Death 
• A life-threatening situation 
• Requires 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 
• An important medical event or a medically significant event that may not result in 
death, be immediately life-threatening, or require hospitalization but may be 
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considered serious when, based on appropriate medical judgment, the event may 
jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above 
Note: Hospitalization including admission to a telemetry unit or ICU specifically when 
pre-planned for administration of study treatment is not considered an SAE.  
12.1.1.3. 
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, too late, or study drug not taken), or there is known causal 
relationship between the AE/SAE and another drug, concurrent disease, or 
other circumstance 
12.1.1.4. 
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 v4.03 (Appendix 6). If the CTCAE v4.03 does 
not apply, the severity descriptions below will be used: 
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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 
All AEs/SAEs occurring after the patient has signed the ICF will be collected and 
recorded in the eCRFs and graded as per CTCAE v4.03. Disease progression is not 
considered an AE for the purposes of this study. 
AEs will be collected and reported according to the following temporal intervals:  
• Signed ICF to tumor resection (SAEs only, if patient did not have tumor resected) 
• Tumor resection to start of NMA-LD preconditioning regimen (AEs and SAEs) 
• NMA-LD preconditioning regimen to Day 0 (AEs and SAEs) 
• Day 0 to Day 30 (TEAEs and treatment-emergent SAEs) 
• Day 30 through 6 months post-LN-144 infusion, or the start of new anti-cancer 
therapy, whichever occurs first (Grade 3 and Grade 4 AEs; SAEs, if at least 
related to any study drug)  
• Post-Month 6, only SAEs related to LN-144 will be collected and reported 
Medically significant AEs considered related to LN-144 by either the Investigator or the 
Sponsor will be reported and followed until resolved or resolved with sequelae.  
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If a patient dies while on the study, the Investigator will inform the Sponsor within 24 
hours and report the cause of death as an SAE. The clinical event leading to 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. On the SAE Report Form, the cause of death should be recorded as 
follows: 
• If due to an AE, it should be specified from which AE 
o Disease progression is not considered an AE 
• If due to sequelae of disease under study, the specific reason should be identified 
(eg, clinical deterioration, respiratory insufficiency, liver failure, etc.) 
• If due to “other” causes, the specific cause should be identified 
• For patients who expired during OS Follow-up and medical records were 
unavailable, the cause of death should be marked as “unknown” 
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 if 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 
LN-144 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. 
Investigator Reporting to Sponsor  
All SAEs of any attribution will be collected from the time the patient signs the ICF 
through Day 30. In patients who fail the initial Screening process, any SAEs occurring 
after signing ICF until study discontinuation (ie, the day of screen failure) will be 
collected.  
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Only Grade 3 and Grade 4 AEs and SAEs possibly attributed to any study drug should be 
reported from Day 30 through 6 months post-LN-144 infusion, or the start of a new anti-
cancer therapy, whichever occurs first. After 6 months, only SAEs related to LN-144 will 
be collected and reported. 
If the Investigator learns of any SAEs that occur after the OS 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 contract 
research organization (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 possible with the information available and include the Investigator’s 
assessment of study drug relationship, as defined in Section 12.1.1.3. 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 v4.03 
guidelines (Appendix 6).  
All SAEs will also be reported on the Iovance 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 
 
 
12.2.1.2. 
Special Situation Reporting 
Definition of Special Situations 
Special situation reports include: reports of medication error; overdose; AEs associated 
with product complaints; occupational exposure; and pregnancy reports regardless of an 
associated AE. Medication error is considered any unintentional error in the prescribing, 
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dispensing, or administration of investigational product while in the control of the health 
care provider, patient, or consumer. An overdose is defined as an accidental or intentional 
administration of a quantity of a medicinal/investigational product given per 
administration or cumulatively that is above the maximum recommended dose as per 
protocol or in the product label. 
Product complaints are defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal/investigational product.  
Occupational exposure is defined as the exposure to a medicinal product as a result of 
one’s professional or nonprofessional occupation.  
Special situation reports must be reported to the Safety CRO using the SAE Report Form 
within 24 hours of becoming aware of the situation.  
12.2.1.3. 
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 12.2.1.2.  
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 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 LN-144, 
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. 
12.2.1.4. 
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 (RSI) in the Investigator’s Brochure and relevant 
prescribing information for TIL, as well as the RSI for cyclophosphamide, fludarabine 
and IL-2. Assessment of expectedness based on local label (US package insert [USPI]) 
for cyclophosphamide, fludarabine, and IL-2 will apply for reports to the FDA.  
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 (CFR) and the EU 
Clinical Trial Directive (2001/20/EC) and relevant updates. The Sponsor will notify 
participating sites of relevant SUSAR reports and other applicable serious safety findings 
that occur during the trial including the post-study treatment follow-up phase.  
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12.2.1.5. 
Product Complaints 
The Sponsor collects product complaints arising from potential deviations in the 
manufacture, packaging, or distribution of LN-144 in order to ensure the safety of study 
participants, monitor quality, and facilitate process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the 
Sponsor or its designee will be reported to the Sponsor. All product complaints associated 
with other study material will be reported directly to the respective manufacturer. 
The Investigator or his/her designee is responsible for reporting a complete description of 
the product complaint via email or other written communication to the Sponsor contact or 
respective manufacturer as noted in the packaging information. Any AE associated with a 
product complaint should be reported as described in Section 12.2. 
If the Investigator is asked to return the product for investigation, he/she will return a 
copy of the product complaint communication with the product. Any AE associated with 
a product complaint should be reported as described in Section 12.2.1.2. 
12.3. Data Safety Monitoring Board  
A Data Safety Monitoring Board (DSMB) has evaluated cumulative safety data as 
specified in the DSMB charter for Cohort 1 and Cohort 2. A meeting will also take place 
after 3 patients have been treated in Cohort 3 (initially infused patients who have been re-
treated with a second course of LN-144) and 28 days have elapsed (end of treatment visit 
and safety assessments). Enrollment in Cohort 4 will continue while the DSMB reviews 
the patient data. 
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13. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) composed of a group of clinicians 
appointed by Iovance will provide oversight of this clinical trial to ensure the study is 
being conducted with the highest quality, scientific, and ethical standards and to ensure 
quality and consistency of study conduct as well as data collection and analysis across 
international study sites. The IDMC will review the study data when up to a total of 30 
patients have completed 28 days of assessments post-LN-144 infusion for Cohort 4. 
Enrollment will continue while data is under review. IDMC will also review the study 
data after up to a total of 75 patients in Cohort 4 have completed 28 days of assessments 
post-LN-144 infusion.  
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14. 
ADMINISTRATIVE REQUIREMENTS 
14.1. Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by GCP, as described in ICH Guideline (ICH E6) 
and in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. The study will receive approval from an IRB/IEC prior to commencement. The 
Investigator will conduct all aspects of this study in accordance with applicable national, 
state, and local laws of the pertinent regulatory authorities. 
The specific contact details of the Iovance Biotherapeutics Inc. 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. 
14.2. 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 Medical 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. 
14.3. Record Retention 
In compliance with the ICH-GCP guidelines, the Investigator/Institution will be 
responsible for all information in the eCRF and will maintain the source documents that 
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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 LN-144. These documents will be retained for a longer period if required 
by the applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these 
documents no longer need to be retained. If the responsible Investigator retires, relocates, 
or for other reasons withdraws from the responsibility of keeping the study records, 
custody must be transferred to a person who will accept the responsibility. The Sponsor 
must be notified in writing of the name and address of the new custodian. 
14.4. Data Quality Assurance  
This trial shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 2008) and all revisions thereof, and in accordance with FDA 
regulations (21 CFR Parts 11, 50, 54, 56, and 312, Subpart D – Responsibilities of 
Sponsors and Investigators) and with the ICH guidelines on GCP (ICH E6). 
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; and periodic monitoring 
visits by the Sponsor/designee. The eCRFs 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.  
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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. 
14.5. Data Handling and Recordkeeping 
14.5.1. 
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 
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• 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 
• Required financial agreement 
• In addition to the documents required prior to the study, other documentation may 
be required during the study 
14.5.2. 
Electronic Data 
When using electronic data processing, the Sponsor or their designee ensures 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 Standard Operating Procedures (SOPs) for that particular task. 
14.5.3. 
Data Handling and Recordkeeping 
14.5.3.1. 
Electronic Case Report Form (eCRF) Completion 
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. 
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. 
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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. 
14.6. Study Completion/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 
Upon completion of the study, the Investigator will ensure that the complete set of source 
data has been entered into the eCRFs. 
14.7. Monitoring 
On-site monitoring visits will be performed by the Sponsor as frequently as necessary. 
At these visits, the monitor will compare the data entered into the eCRFs with the 
hospital or clinic records (source documents). At a minimum, source documentation must 
be available to substantiate proper informed consent procedures, adherence to protocol 
procedures, adequate reporting and follow-up of AEs, administration of concomitant 
medications, 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. 
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15. 
INVESTIGATOR REGULATORY OBLIGATIONS 
15.1. Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Before Enrollment of patients into the study, as required by federal regulations (21 CFR 
56), international regulations, and ICH-GCP Guidelines, the protocol and ICF(s) must be 
reviewed and approved by an appropriate IRB/IEC. By signing the FDA Statement of 
Investigator Form 1572 or the Sponsor’s Statement of Investigator Commitments, the 
Investigator assures that all aspects of the institutional review will be conducted in 
accordance with current applicable 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 IECs as per the applicable laws and 
requirements on the national and EU level. 
15.2. 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 ICH and GCP guidelines, 
Directive 2001/20/EC (and when in force EU Regulation 536/2014), and General Data 
Protection 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 are free not to participate in the study and 
may withdraw consent to participate at any time. They will be told which alternative 
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treatments are available if they refuse to take part and that such refusal will not prejudice 
future treatment. Finally, they will be told that their records may be examined by 
competent authorities and authorized persons but that their personal data will be treated 
as strictly confidential and will not be publicly available. Patients must be given the 
opportunity to ask questions. After this explanation and before entry into the study, 
consent should be appropriately recorded by means of the patient's or his/her legal 
representative's dated signature. If a patient and his/her legal representative are unable to 
read, an impartial witness must be present during the entire informed consent discussion. 
The signature of the impartial witness will certify the patient's consent. The patient and 
their legally designated representative must receive a signed and dated copy of the 
informed consent. The informed consent process should be documented in the patient’s 
medical record. Adequate time shall be given for the patient or his/her legally designated 
representative to consider his/her decision to participate in the study. 
In accordance with the Health Insurance Portability and Accountability Act (HIPAA), the 
written ICF 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 the purpose of this access and data processing 
connected with it. 
15.3. Patient Data Protection 
The 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 Investigator or their employees or agents during the course 
of the study to the Sponsor, the Sponsor’s collaborators, IRB/IEC, FDA, European 
Medicines Agency (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. 
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Patients will not be individually identified but will be referred to in records by the study-
assigned number and patient initials (if allowed by law). 
15.4. Adverse Event Reporting 
The Investigator agrees to report all AEs/SAEs to the Sponsor as described in Section 12. 
Furthermore, the Investigator is responsible for ensuring that any co-Investigator or sub-
Investigator promptly bring AEs to the attention of the Principal Investigator. The 
Investigator shall promptly notify the IRB/IEC of any SAEs, or any other information 
that may affect the safe use of LN-144 during the course of the trial as applicable per the 
local IRB/IEC requirements. 
15.5. 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. 
15.6. 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, 
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names, and addresses. Documents not for submission to the Sponsor (eg, patients’ written 
ICFs) should be maintained by the Investigator in strict confidence, in accordance with 
all applicable local and national regulations. All information provided to the Investigator 
prior to the study, as well as all data developed during the study, is confidential and 
remains the property of the Sponsor. The Investigator agrees that no information based on 
the conduct of this study (including the protocol, the data resulting from the study, or the 
fact that the study is/was conducted) will be released without prior written consent of the 
Sponsor unless this requirement is superseded by local or national regulations. 
15.7. Publications 
The Sponsor will be responsible for determining when the study results should be 
published after discussion with the Steering Committee. The Sponsor will work jointly 
with the Investigators to publish information on study results. An Investigator shall not 
submit a publication or abstract to journals or scientific meetings 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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16. 
REFERENCES 
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Bohnsack O, Ludajic K, Hoos A. Adaptation of the Immune-related Response Criteria: 
irRECIST. ESMO; 2014. 
Coit DG, Thompson JA, Algazi A, et al. NCCN Clinical Guidelines in Oncology (NCCN 
Guidelines®: Melanoma v2.2018). 2018; 
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Cowey CL, Liu FX, Black-Shinn J, et al. Pembrolizumab Utilization and Outcomes for 
Advanced Melanoma in US Community Oncology Practices. J Immunother. 
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Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis G, Keilholz U. Cutaneous 
melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
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Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in 
Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 
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Forget MA, Haymaker C, Hess KR, et al. Prospective Analysis of Adoptive TIL Therapy 
in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and 
Biomarkers to Predict Clinical Outcome. Clin Cancer Res. 2018;24(18):4416-
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Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European 
consensus-based interdisciplinary guideline - Update 2016. Eur J Cancer. 
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Goff SL, Dudley ME, Citrin DE, et al. Randomized, prospective evaluation comparing 
intensity of lymphodepletion before adoptive transfer of tumor-infiltrating 
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Goldinger SM, Lo S, Hassel JC, et al. The utility of chemotherapy after immunotherapy 
failure in metastatic melanoma: A multicenter case series. Journal of Clinical 
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Hamid O, Puzanov I, Dummer R, et al. Final analysis of a randomised trial comparing 
pembrolizumab versus investigator-choice chemotherapy for ipilimumab-
refractory advanced melanoma. Eur J Cancer. 2017;86:37-45. 
Hersh EM, Del Vecchio M, Brown MP, et al. A randomized, controlled phase III trial of 
nab-Paclitaxel versus dacarbazine in chemotherapy-naive patients with metastatic 
melanoma. Ann Oncol. 2015;26(11):2267-2274. 
Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, 
and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190-209. 
Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination 
immune checkpoint blockade. N Engl J Med. 2016;375(18):1749-1755. 
Johnson DB, Pectasides E, Feld E, et al. Sequencing Treatment in BRAFV600 Mutant 
Melanoma: Anti-PD-1 Before and After BRAF Inhibition. J Immunother. 
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Kang SP, Gergich K, Lubiniecki GM, et al. Pembrolizumab KEYNOTE-001: an adaptive 
study leading to accelerated approval for two indications and a companion 
diagnostic. Ann Oncol. 2017;28(6):1388-1398. 
Kaufman HL, Margolin K, Sullivan R. Management of Metastatic Melanoma in 2018. 
JAMA oncology. 2018;4(6):857-858. 
Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy 
in untreated melanoma. N Engl J Med. 2015;373(13):1270-1271. 
Livingstone E, Zimmer L, Vaubel J, Schadendorf D. Current advances and perspectives 
in the treatment of advanced melanoma. Journal der Deutschen 
Dermatologischen Gesellschaft = Journal of the German Society of Dermatology 
: JDDG. 2012;10(5):319-325. 
Lui P, Cashin R, Machado M, et al. Treatments for metastatic melanoma: synthesis of 
evidence from randomized trials. Cancer treatment reviews. 2007;33(8):665-680. 
Matthews NH, Li W, Qureshi AA, Weinstock MA, Cho E. Epidemiology of Melanoma. 
In: Ward WH, Frama JM, eds. Cutaneous Melanoma: Etiology and Therapy 
[Internet]. Brisbane, Australia: Codon Publications; 2017. 
Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015, 
National Cancer Institute. 2018; https://seer.cancer.gov/csr/1975_2015/. Accessed 
December 7, 2018. 
Novartis. PROLEUKIN® (aldesleukin) for injection, for intravenous infusion - 
prescribing information. 2015; https://www.proleukin.com/health-care-
professional/tools/pi.html. Accessed September 14, 2018. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
Pilon-Thomas S, Kuhn L, Ellwanger S, et al. Efficacy of adoptive cell transfer of tumor-
infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J 
Immunother. 2012;35(8):615-620. 
Radvanyi LG, Bernatchez C, Zhang M, et al. Specific lymphocyte subsets predict 
response to adoptive cell therapy using expanded autologous tumor-infiltrating 
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Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing 
tremelimumab with standard-of-care chemotherapy in patients with advanced 
melanoma. J Clin Oncol. 2013;31(5):616-622. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526. 
Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily 
pretreated patients with metastatic melanoma using T-cell transfer 
immunotherapy. Clin Cancer Res. 2011;17(13):4550-4557. 
Rutkowski P, Kozak K. News from the melanoma sessions of the European Cancer 
Congress 2017. BMC medicine. 2017;15(1):57. 
Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for 
metastatic melanoma: thirty-year experience overview. Journal of experimental & 
clinical cancer research : CR. 2000;19(1):21-34. 
Svedman FC, Pillas D, Taylor A, et al. Stage-specific survival and recurrence in patients 
with cutaneous malignant melanoma in Europe - a systematic review of the 
literature. Clinical epidemiology. 2016;8:109-122. 
Tran E, Robbins PF, Lu YC, et al. T-Cell transfer therapy targeting mutant KRAS in 
cancer. N Engl J Med. 2016;375(23):2255-2262. 
Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with 
advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 
037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 
2015;16(4):375-384. 
Whiteman DC, Green AC, Olsen CM. The growing burden of invasive melanoma: 
projections of incidence rates and numbers of new cases in six susceptible 
populations through 2031. J Invest Dermatol. 2016;136(6):1161-1171. 
Zimmer L, Apuri S, Eroglu Z, et al. Ipilimumab alone or in combination with nivolumab 
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APPENDICES  
Appendix 1 
SCHEDULE OF ASSESSMENTS ......................................................... 107 
Appendix 2 
ECOG SCALE ........................................................................................ 113 
Appendix 3 
ASSESSMENTS ..................................................................................... 114 
Appendix 4 
IL-2 ADVERSE EVENTS ...................................................................... 116 
Appendix 5 
EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT ......... 117 
Appendix 6 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS ................................................................................................. 119 
Appendix 7 
CYCLOPHOSPHAMIDE PACKAGE INSERT .................................... 120 
Appendix 8 
MESNA (MEXNEX®) PACKAGE INSERT ......................................... 121 
Appendix 9 
ONDANSETRON PACKAGE INSERT ................................................ 122 
Appendix 10 FILGRASTIM PACKAGE INSERT ...................................................... 123 
Appendix 11 FLUCONAZOLE PACKAGE INSERT................................................. 124 
Appendix 12 FLUDARABINE PACKAGE INSERT ................................................. 125 
Appendix 13 IL-2 (ALDESLEUKIN) PACKAGE INSERT ....................................... 126 
Appendix 14 EORTC QLQ-C30 QUESTIONNAIRE ................................................. 127 
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Appendix 1 
SCHEDULE OF ASSESSMENTS 
Assessments  
Screening, Enrollment, & 
Baseline Period 
Treatment Period 
(All visit dates are calculated from LN-144 infusion [Day 0]) 
Assessment Period 
(All visit dates are calculated 
from LN-144 infusion [Day 0]) 
Overall Survival 
Follow-up 
Period a 
Screening (≤ 28 days from 
ICF signature) 
Enrollment/Tumor 
Resection 
Baseline (Day -21 to Day -
10) 
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) 
End of Treatment Visit 
Day 28 (± 3 days) 
Every 6 Weeks 
(Week 6 [+ 7 days], Week 
12 [± 3 days], and Week 
18 [± 3 days]) 
Every 3 Months 
(± 1 Week) 
(Starting at Month 6)  
EOA Visit b 
Every 3 Months (± 3 
Weeks)  
SCREENING 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history d  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Melanoma medical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Physical examination e 
X e 
X 
X 
X 
e 
X 
X 
X X X 
X  
X 
e 
X  
X  
X  X  
X  
X  
X  
X  
X  
 
Vital signs 
X 
 
X 
X 
X 
X 
X X X 
X 
X f  X f 
X f X f  X f  
 
 
X 
X 
X 
 
Skin test for 
hypersensitivity g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GENERAL PROCEDURES 
Eye examination (slit 
lamp) h 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECG 
X i 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA (and 
stress test) j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Colonoscopy k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GENERAL ASSESSMENTS 
Assessment of 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X l 
X 
X 
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Assessments  
Screening, Enrollment, & 
Baseline Period 
Treatment Period 
(All visit dates are calculated from LN-144 infusion [Day 0]) 
Assessment Period 
(All visit dates are calculated 
from LN-144 infusion [Day 0]) 
Overall Survival 
Follow-up 
Period a 
Screening (≤ 28 days from 
ICF signature) 
Enrollment/Tumor 
Resection 
Baseline (Day -21 to Day -
10) 
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) 
End of Treatment Visit 
Day 28 (± 3 days) 
Every 6 Weeks 
(Week 6 [+ 7 days], Week 
12 [± 3 days], and Week 
18 [± 3 days]) 
Every 3 Months 
(± 1 Week) 
(Starting at Month 6)  
EOA Visit b 
Every 3 Months (± 3 
Weeks)  
Concomitant 
medications m 
X m 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hospitalization(s) n 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Survival status/anti-
cancer therapy a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IMAGING & TUMOR RESPONSE ASSESSMENT  
Evaluation and 
measurement of skin 
and palpable lesions o 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Tumor assessment p 
X p 
 
X p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
CT – chest, abdomen, 
pelvis q 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X r 
 
MRI – brain s 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X r 
 
LABORATORY EVALUATIONS 
Hematology  
X 
 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
X  
 
X 
X 
X 
X 
X X X 
X 
X  
X 
X 
X 
X 
X  
X 
X 
X 
X  
 
Thyroid panel  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X  
 
ß-HCG pregnancy test t 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X t 
X t 
 
Dipstick urinalysis u 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
X  
X  
X  X  
 
 
 
 
 
 
SEROLOGY TESTING 
HIV Ab  
X 
X v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, anti-HBc 
X 
X v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Ab 
X 
X v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Syphilis testing 
X 
X v 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV  
X w 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Assessments  
Screening, Enrollment, & 
Baseline Period 
Treatment Period 
(All visit dates are calculated from LN-144 infusion [Day 0]) 
Assessment Period 
(All visit dates are calculated 
from LN-144 infusion [Day 0]) 
Overall Survival 
Follow-up 
Period a 
Screening (≤ 28 days from 
ICF signature) 
Enrollment/Tumor 
Resection 
Baseline (Day -21 to Day -
10) 
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) 
End of Treatment Visit 
Day 28 (± 3 days) 
Every 6 Weeks 
(Week 6 [+ 7 days], Week 
12 [± 3 days], and Week 
18 [± 3 days]) 
Every 3 Months 
(± 1 Week) 
(Starting at Month 6)  
EOA Visit b 
Every 3 Months (± 3 
Weeks)  
CMV 
X 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
EBV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TUMOR RESECTION 
Tumor resection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intraoperative frozen 
section (or FNA) or 
touch prep cytology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-treatment (LN-144) 
biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X x 
 
 
 
TREATMENT 
Authorization to 
Receive 
Lymphodepletion y 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
(with mesna) 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine  
 
 
 
 
 
X 
X X X 
X 
 
 
 
 
 
 
 
 
 
 
 
LN-144 infusion z  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IL-2 aa 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PROPHYLACTIC MEDICATIONS 
Ondansetron 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Filgrastim bb 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Fluconazole cc 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TMP-SMX DS, or 
appropriate ABX dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Broad spectrum ABX 
 
 
 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Valacyclovir/acyclovir w 
X w 
X w 
X w 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X  
 
 
EXPLORATORY 
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j. 
ECHO or MUGA at Screening required for all patients. Patients ≥ 60 years of age and who have a history of ischemic heart disease, chest pain, or clinically significant 
atrial and/or ventricular arrhythmias, must have a cardiac stress test.  
k. 
Colonoscopy on patients with documented ≥ Grade 2 diarrhea or colitis as a result of previous treatment with immune checkpoint inhibitors who have not been 
asymptomatic for at least 6 months.  
l. 
Post-Month 6, only SAEs related to LN-144 will be collected and reported. 
m. All concomitant medications taken within 28 days prior to signing the ICF are to be collected, and subsequently throughout the duration of study.  
n. 
Dates of all hospitalizations, including ICU stays, are collected and recorded in the Hospitalization eCRF. Patients may require hospitalization at the Investigator’s 
discretion or as per institutional guidelines (for tumor resection; NMA-LD [cyclophosphamide, fludarabine] preconditioning regimen; and treatment recovery). If the 
institutional guidelines mandate a required hospitalization longer than the protocol required hospitalization, this pre-planned hospitalization event will not be considered 
an AE. 
o. 
Evaluation and measurement of skin and palpable lesions may be performed (if applicable). 
p. 
Screening and Baseline tumor assessments are per RECIST v1.1 only. Tumor response assessment performed per RECIST v1.1 and irRECIST.  
q. 
CT of chest, abdomen, pelvis, and additional anatomic regions (eg, extremities, neck) per disease history and clinical symptoms. The same imaging modality must be 
used throughout the duration of the study. Radiographic imaging performed within 28 days prior to signing the ICF do not have to be repeated (Appendix 3).  
r. 
Patients will have disease progression confirmed at least 28 days from the last date of progression per irRECIST, as applicable, assessed by the Investigator.  
s. 
MRI scans performed within 28 days prior to signing the ICF do not have to be repeated at Screening if normal. If a brain MRI was performed within 4 weeks prior to 
Day 0 and considered normal or stable, and the patient is not showing any clinical symptoms of progression in the brain, then a brain MRI does not need to be repeated at 
Baseline. Brain MRI following the Baseline visit should only be performed if clinically indicated or if positive at Baseline.  
t. 
Serum pregnancy test for women of childbearing potential only. Serum pregnancy testing to continue to Month 12 (Week 52) or EOA, whichever occurs first. 
u. 
On the days of IL-2 administration, dipstick urinalysis (with complete urinalysis and culture, if applicable) will be collected on the same days. Subsequently collections 
are done only if clinically indicated (Appendix 3).  
v. 
Serology for HIV-1, HIV-2, HBsAg, anti-HBc, HCV Ab, and syphilis are required at tumor resection or within 7 days after tumor resection, for tumor samples acquired 
in the EU. (Appendix 3). 
w. In patients who are seropositive for HSV IgM or PCR assay at Screening, herpetic treatment will be initiated and must be completed prior to starting NMA-LD to ensure 
patient is seronegative for HSV (IgM). Patients who are not HSV IgM positive at Screening will begin herpetic prophylaxis on Day 14 (or as the Investigator deems 
appropriate) and continue until ALC > 1000/mm3.  
x. 
The post-treatment core biopsy at Week 6 is mandatory (when available and patient consent is provided) and should be done in a lesion not being followed for response 
assessment (either as a target or non-target lesion). 
y. 
Site must receive Authorization to Receive Lymphodepletion from the Sponsor or designee prior to beginning the NMA-LD preconditioning regimen. 
z. 
Refer to Section 5.5.4.1 for a list of pre-medications to be administered to the patient prior to LN-144 infusion. 
aa. The first IL-2 dose should be administered approximately 3–24 hours after completion of the LN-144 infusion and continue approximately every 8–12 hours for up to 
protocol-defined maximum of six doses. Broad-spectrum ABX will be initiated if fever (defined as 38.3°C, one or two temperatures of 38.0°C or above at least one hour 
apart), AND an ANC ≤ 500/mm3, or per institutional standards. 
bb. Filgrastim or biosimilar may be administered beginning on Day 1 and continued each day until ANC > 1000/mm3 × three consecutive days, discontinue if ANC rises to 
> 10,000/mm3, or follow institutional standards.  
cc. Fluconazole should be administered beginning on Day 1 and continue each day until ANC > 1000/mm3. If ANC count remains < 1000/mm3 at 6 months post-
chemotherapy, prophylaxis will continue until the CD4 count is > 200/mm3 for at least 6 months, or as per institutional standards. 
dd. TMP-SMX DS should be administered once daily, beginning on Day 14 and continue until the ALC reaches > 1000/mm3 for three consecutive days; if at 6 months ALC 
< 1000/mm3, continue until CD4 count is > 200/mm3 for at least 6 months. 
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ee. HLA typing does not need to be repeated for Cohort 3 patients. 
ff. 
Immune monitoring will be collected at the following timepoints: Enrollment/tumor resection (+ 3 days), Day -7 (prior to NMA-LD), Day 0 or Day 1 (after LN-144 
infusion and before first IL-2 dose), Day 4 (after last dose of IL-2, but not earlier than Day 3), Day 42, Day 84, Month 6, Month 9, and Month 12. 
gg. HRQoL is performed at Baseline, Day 84, Month 6, Month 12, Month 24, and the EOA visit.
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Appendix 2 
ECOG SCALE 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (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 [Oken 1982]  
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 Appendix 4 IL-2 ADVERSE EVENTS 
Adverse Events occurrence in > 10% of patients treated with IL-2 (n=525) 
  
Body System/Events 
% patients 
Body System/Events 
% patients 
Body as a whole 
Metabolic and Nutritional Disorders 
Chills 
52 
Bilirubinemia 
40 
Fever 
29 
Creatinine Increase 
33 
Malaise 
27 
Peripheral Edema 
28 
Asthenia 
23 
SGOT increase 
23 
Infection 
13 
Weight gain 
16 
Pain 
12 
Edema 
15 
Abdominal pain 
11 
Acidosis 
12 
Enlarged Abdomen 
10 
Hypomagnesemia 
12 
Cardiovascular System 
Hypocalcemia 
11 
Hypotension 
71 
Alkaline Phosphatase Increase 
10 
Tachycardia 
23 
Nervous System 
Vasodilation 
13 
Confusion 
34 
Supraventricular Tachycardia 
12 
Somnolence 
22 
Cardiovascular disorder a 
11 
Anxiety 
12 
Arrhythmia 
10 
Dizziness 
11 
Digestive System 
Respiratory System 
Diarrhea 
67 
Dyspnea 
43 
Vomiting 
50 
Lung disorder b 
24 
Nausea 
35 
Respiratory disorder c 
11 
Stomatitis 
22 
Cough increase 
11 
Anorexia 
20 
Rhinitis 
10 
Nausea and Vomiting 
19 
Skin and Appendages 
Hematologic and Lymphatic 
Rash 
42 
Thrombocytopenia 
37 
Pruritus 
24 
Anemia 
29 
Exfoliative dermatitis 
18 
Leukopenia 
16 
Urogenital System 
  
  
Oliguria 
63 
a  
Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, congestive heart 
failure (CHF). 
b  
Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c  
Respiratory disorder: Acute respiratory distress syndrome (ARDS), Chest X-Ray (CXR) infiltrates, 
unspecified pulmonary changes. 
Source: Proleukin® Prescribing Information – January 2015 [Novartis 2015] 
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Appendix 5 
EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT 
 
Expected Toxicity 
Expected Grade 
Supportive Measures 
Skip Dose/Stop Treatment* 
Anemia 
3 or 4 
Transfusion with pRBCs 
Yes, if active bleeding or 
hemolysis, despite supportive 
measures 
Arrythmia 
3 
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion therapy 
Yes, if uncontrolled despite all 
supportive measures 
Bowel Perforation 
3 
Surgical intervention 
Yes 
Chills/Rigors 
3 
Meperidine (Pethidine) 25-50 
mg, IV q1h, prn 
No 
Confusion, Delirium 
3 
Look for and treat other 
contributors 
Yes 
Creatinine Increase 
3 or 4 
Medical management of 
hemodynamic needs 
Yes (if Grade 4) 
Diarrhea 
3 
Loperamide 2 mg, po, q3h, 
prn; Diphenoxylate HCl 2.5 
mg and Atropine sulfate 
25 mcg, po, q3h, prn; Codeine 
sulfate 30-60 mg, po, q4h, prn 
Yes, if uncontrolled after 24 
hours despite all supportive 
measures 
Dyspnea 
3 or 4 
Oxygen or ventilatory 
Yes, if requires ventilatory 
support 
Edema/Weight Gain 
3 
Diuretics prn, after initial 
volume resuscitation and 
falling pressor requirement 
No 
Electrolyte Imbalance 
3 or 4 
Electrolyte replacement 
Yes, if uncontrolled despite all 
supportive measures 
Fever 
3 
Acetaminophen 650 mg, po, 
q4h; Indomethacin 50-75 mg, 
po, q8h 
No 
Hyperbilirubinemia 
3 or 4 
Observation - r/o other 
causes 
Yes, if other toxicities occur 
simultaneously 
Hypotension 
3 
Fluid resuscitation; 
Vasopressor support 
Yes, if uncontrolled despite all 
supportive measures. 
NOTE: Hypotension is the most 
common reason for permanent 
discontinuation of IL-2 dosing. 
In most situations there is a 
constellation of life-threatening 
toxicities, including 
hypotension, rather than a single 
DLT that results in permanent 
discontinuation of IL-2 dosing. 
Malaise 
3 or 4 
Bedrest interspersed with 
activity 
Yes, if other toxicities occur 
simultaneously 
Myocardial Infarction 
3 or 4 
Standard management, 
thrombolytic therapy only if 
considered safe 
Yes 
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Expected Toxicity 
Expected Grade 
Supportive Measures 
Skip Dose/Stop Treatment* 
Nausea/Vomiting/Anorexia  3 
Ondansetron 8 mg, IV, q8h, 
prn; Granisetron 0.01 mg/kg 
IV daily prn; Droperidol 1 
mg, IV q4-6h, prn; 
Lorazepam 0.5–1 mg po q8h, 
as needed (w/ attention to 
somnolence, altered mental 
status, etc.); Prochlorperazine 
25 mg q4h or prn or 10 mg 
IV q6h prn (maximum dose: 
40 mg/day) 
No 
Neutropenia 
4 
Observation 
Yes, if contributing to sepsis 
Oliguria 
3 or 4 
Fluid resuscitation and 
maintenance; consider 
dopamine at “renal” doses 
Yes, if uncontrolled despite all 
supportive measures 
Pleural Effusion 
3 
Thoracentesis 
Yes, if uncontrolled despite all 
supportive measures 
Pruritis 
3 
Hydroxyzine HCL 10-20 mg 
po q6h, prn; 
Diphenhydramine HCL 25-
50 mg, po, q4h, prn 
No 
Renal Failure  
3 or 4 
Dialysis 
Yes 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Thrombocytopenia 
3 or 4 
Transfusion with platelets 
Yes, if not recovering despite 
supportive measures 
Transaminase Elevation 
3 or 4 
Observation - r/o other 
causes 
Yes, for Grade 4 (> 20 times 
ULN) either without or without 
liver metastases 
Troponin Elevation 
3 or 4 
Look for causes of ischemia 
and correct; routine 
management of ischemia 
Yes 
*Unless the toxicity is not reversed to ≤ Grade 2 by next retreatment. If two consecutive doses are missed, then 
treatment is permanently discontinued. 
Proleukin® Prescribing Information – January 2012 [Novartis 2015] 
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Appendix 6 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf  
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Appendix 7 
CYCLOPHOSPHAMIDE PACKAGE INSERT 
Cyclophosphamide, Full Prescribing Information, 2013 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.p
df 
Cyclophosphamide, Summary of Product Characteristics, 2017 
https://www.medicines.org.uk/emc/product/3526/smpc 
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Appendix 8 
MESNA (MEXNEX®) PACKAGE INSERT 
Mesna (Mesnex®), Full Prescribing Information, Sargent Pharmaceuticals, July 2015 
http://www.sagentpharma.com/wp-content/uploads/2016/01/Mesna_PI.pdf 
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Appendix 9 
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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Appendix 10 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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Appendix 11 FLUCONAZOLE PACKAGE INSERT 
Fluconazole (Diflucan®), Full Prescribing Information Pfizer, 2016. 
http://labeling.pfizer.com/ShowLabeling.aspx?id=575 
 
 
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Appendix 12 FLUDARABINE PACKAGE INSERT 
Fludarabine, Full Prescribing Information, 2008 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020038s032lbl.pdf 
Fludarabine, Summary of Product Characteristics, 2018 
https://www.medicines.org.uk/emc/product/1274/smpc 
 
  
 
 
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Appendix 13 IL-2 (ALDESLEUKIN) PACKAGE INSERT 
Proleukin (aldesleukin), Full Prescribing Information, 2008 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf  
Proleukin, Summary of Product Characteristics, 2017 
https://www.medicines.org.uk/emc/product/291/smpc 
 
 
 
 
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Appendix 14 EORTC QLQ-C30 QUESTIONNAIRE 
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