Clinical trial NCT04111510
Conditions: Metastatic Triple Negative Breast Cancer
Sponsor: Yale University
Start date: 2019-12-23; Completion date: 2023-05-11
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will investigate the safety and efficacy of TIL therapy in patients with metastatic TNBC who have progressed on at least one and no more than three prior systemic anticancer therapies.

Detailed description:
The primary aims of the study are:

* To evaluate the efficacy of autologous LN-145 as a single therapy in Metastatic Triple Negative Breast Cancer (TNBC) patients by determining the objective response rate (ORR), using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the Investigator.
* To characterize the safety profile of tumor infiltrating lymphocytes (TIL) as a single therapy in Metastatic Triple Negative Breast Cancer patients as measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs).

The secondary aims of the study are:

• To further evaluate the efficacy of autologous LN-145 as a single therapy in Metastatic Triple Negative Breast Cancer patients using complete response duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS), using RECIST 1.1, as assessed by the Investigator, overall survival (OS) and (CR) rate.

Arms: arm 1: LN-145 will be delivered as a single therapy in patients with Metastatic Triple Negative Breast Cancer.
Interventions: intervention 1: Tumor infiltrating lymphocytes (TIL) LN-145
Intervention descriptions: intervention 1: The TIL autologous therapy with LN-145 is comprised of the following steps:

1. Tumor resection to provide the autologous tissue that serves as the source of the TIL cellular product;
2. LN-145 investigational product production at a central Good Manufacturing Practice (GMP) facility;
3. A 7-day nonmyeloablative lymphodepletion (NMA-LD) preconditioning regimen (hospitalization per institution standards);
4. Infusion of the autologous LN-145 product on Day 0 (during inpatient hospitalization);
5. Intravenous (IV) interleukin-2 (IL-2) administrations for up to six doses maximum (during inpatient hospitalization).

Protocol documents:
Prot_SAP_000.pdf: 
ClinicalTrials.gov ID: NCT04111510    
Title: A Phase 2 Study of Autologous Tumor InﬁltraƟng Lymphocytes (LN-145) in PaƟents with Pretreated 
MetastaƟc Triple NegaƟve Breast Cancer 
Document: Protocol w SAP 
Date: 8/10/2023 
 


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CLINICAL PROTOCOL 
A Phase 2 Study of Autologous Tumor Infiltrating Lymphocytes (LN-145) in Patients 
with Pretreated Metastatic Triple Negative Breast Cancer 
 
PROTOCOL NUMBER: 
2000025837 
VERSION: 
8.0 
DATE: 
10 Aug 2023 
SPONSOR 
INVESTIGATOR: 
Michael Hurwitz, MD, PhD 
Yale Comprehensive Cancer Center 
333 Cedar Street, Box 208032 
New Haven, CT 06520 
SUPPORTER: 
Iovance Biotherapeutics, Inc. 
825 Industrial Road, Suite 400 San Carlos, CA 
94070 United States 


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SYNOPSIS 
Protocol Title 
A Phase 2 Study of Autologous Tumor Infiltrating Lymphocytes (LN-145) in 
Patients with Pretreated Metastatic Triple Negative Breast Cancer 
Protocol Number 
2000025837 
Study Type 
Phase 2 
Investigational Agent 
Tumor infiltrating lymphocytes (TIL) LN-145 as a single-therapy 
Study Objectives 
Primary: 
• To evaluate the efficacy of autologous LN-145 as a single therapy in 
Metastatic Triple Negative Breast Cancer (TNBC) patients by determining the 
objective response rate (ORR), using the Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1, as assessed by the Sponsor Investigator. 
• To characterize the safety profile of tumor infiltrating lymphocytes (TIL) as a 
single therapy in Metastatic Triple Negative Breast Cancer patients as 
measured by the incidence of Grade ≥ 3 treatment-emergent adverse events 
(TEAEs). 
Secondary: 
• To further evaluate the efficacy of autologous LN-145 as a single therapy in 
Metastatic Triple Negative Breast Cancer patients using complete response 
duration of response (DOR), disease control rate (DCR), and progression-free 
survival (PFS), using RECIST 1.1, as assessed by the Sponsor Investigator, 
overall survival (OS) and (CR) rate. 
Exploratory: 
• To explore the persistence of LN-145 cells as a single therapy and its resultant 
immune correlates, which may affect response, outcome, and toxicity 
variables. 
• To explore efficacy parameters (excluding OS) using the immune-related 
Response Evaluation Criteria in Solid Tumors (irRECIST), as assessed by the 
Sponsor Investigator. 
• To explore the feasibility of generating TIL (LN-145) from patient-derived 
TNBC core biopsy tumor specimens using Iovance manufacturing process. 


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Study Design 
A prospective, open-label, non-randomized, Phase 2 study to evaluate adoptive cell 
therapy (ACT) with LN-145 as a single therapy in patients with Metastatic Triple 
Negative Breast Cancer. 
• Patients must have had at least one and no more than three prior systemic 
anticancer therapies for metastatic disease. 
• All patients will receive autologous LN-145 therapy. 
The TIL autologous therapy with LN-145 is comprised of the following steps: 
1. Tumor resection to provide the autologous tissue that serves as the source of 
the TIL cellular product; 
2. LN-145 investigational product production at a central Good Manufacturing 
Practice (GMP) facility; 
 
3. A 7-day nonmyeloablative lymphodepletion (NMA-LD) preconditioning 
regimen (hospitalization per institution standards); 
4. Infusion of the autologous LN-145 product on Day 0 (during inpatient 
hospitalization); 
5. Intravenous (IV) interleukin-2 (IL-2) administrations for up to six doses 
maximum (during inpatient hospitalization). 
The following general study periods will take place unless specified otherwise: 
• 
Screening and Tumor Resection: Up to 4 weeks (28 days) from signing the 
informed consent form (ICF); 
• 
Enrollment: Upon tumor resection for TIL generation; 
• 
Manufacturing of the LN-145 Product: approximately 22 days from tumor 
resection; 
•  Treatment Period: NMA-LD preconditioning regimen (up to 7 days), LN-145 
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-145 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 3 years from 
Day 0 (LN-145 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 3 years from LN-145 
infusion or until discontinuation from the study; with telephone contact every 
3 months to obtain survival status and subsequent anticancer therapy 
information (Figure 1). Patients who had tumor resection but did not receive 
LN-145 for any reason will perform an EOA visit and transition directly into 
the OS Follow-up Period. 


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Doses and Treatment 
Schedule 
TIL LN-145 Therapy: 
The cell transfer therapy used in this study involves patients receiving an NMA-LD 
preconditioning regimen, consisting of daily IV cyclophosphamide (60 mg/kg; IV × 2 
doses) followed by daily fludarabine (25 mg/m2; IV × 5 doses). Infusion of LN-145 is 
given on Day 0 and is followed by administration of IL-2 at 600,000 international 
units (IU)/kg BID for up to a maximum of six doses, starting approximately 3–24 
hours after completion of LN-145 infusion. 
Treatment Administration 
Study Day 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
Cyclophosphamide 60 mg/kg 
X 
X 
Mesna 60 mg/kg 
X 
X 
Fludarabine 25 mg/m2/day 
X 
X 
X 
X 
X 
TIL LN-145 infusion 
X 
IL-2 600,000 IU/kg 
X 
X 
X 
X 
 
Duration of 
Participation 
Overall, the study participation time will be up to 3 years: Screening (28 days), TIL 
manufacturing time (~22 days), preconditioning time prior to Day 0 TIL treatment 
(7 or 8 days), and 3 years (Month 36) follow-up from LN-145 infusion on Day 0. 
Number of Study Sites 
1 
Number of Planned 
Patients 
Ten (10) patients are planned to be evaluable for efficacy in this study. If an enrolled 
patient is unable to receive therapy for any reason, she will be replaced by a new 
patient until 10 patients will be evaluable for efficacy (infused and has received at 
least one dose of IL-2). All patients who complete the TIL LN-145 infusion on Day 0 
will be evaluable for safety. Patients who progressed or expired prior to reaching the 
first radiological assessment will also be included in efficacy analysis and 
categorized as progression. 


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Inclusion Criteria 
1. Ability to understand the requirements of the study. Specifically, the patient has 
to provide written informed consent (as evidenced by signature on an IRB 
approved ICF. 
2. All patients must have a triple negative metastatic breast cancer (TNBC) 
(Estrogen Receptor negative, Progesterone Receptor negative, human 
epidermal growth factor receptor 2 (HER2) negative) as defined by the 2018 
ASCO CAP guidelines. Patients with low ER and/or low PR (defined as <10% 
expression by immunohistochemistry (IHC)) may be deemed eligible and 
considered as TNBC (following the ASCO CAP guidelines 2020 and 
ESO/ESMO 2020) 
3. Patients must have a confirmed diagnosis of metastatic triple negative breast 
cancer (Stage IV) histologically confirmed as per American Joint Committee on 
Cancer [AJCC] staging system). 
4. Patients must have had at least one and no more than three prior lines of 
systemic anticancer therapies for metastatic disease. 
5. Patients must have disease progression from the last line of therapy. 
6. Patients must have at least one resectable lesion of a minimum 1.5 cm in 
diameter (or aggregate of 1.5 cm if multiple lesions are sampled) post-resection 
for TIL investigational product production. It is encouraged that tumor tissue be 
obtained from multiple and diverse metastatic lesions, as long as the surgical 
resection does not pose additional risks to the patient. 
• 
If the lesion considered for resection for TIL generation is within a 
previously irradiated field, the lesion must have demonstrated 
radiographic progression post-radiotherapy (XRT) and prior to resection. 
• 
Patients must have an adequate histopathology specimen for protocol 
required testing. 
7. Patients must have remaining measurable disease as defined by RECIST 1.1 
following tumor resection for TIL manufacturing: 
• 
Lesions in previously irradiated areas should not be selected as target 
lesions unless there has been demonstrated progression in those 
lesions. 
• 
Lesions partially resected for TIL production may be chosen as non-target 
lesions but cannot be used as target lesions for RECIST assessment. 
8. Patients must be ≥ 18 years of age at the time of consent. 
9. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1, and an estimated life expectancy of ≥ 3 months in 
the opinion of the Sponsor Investigator. 
10. Patients of childbearing potential (or female partners of male participants) must 
be willing to use effective contraception during treatment and for 12 months 
after their last dose of IL-2. 


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11. Patients must have the following hematologic parameters: 
• 
Absolute neutrophil count (ANC) ≥ 1000/mm3; 
• 
Hemoglobin ≥ 9.0 g/dL; 
• 
Platelet count ≥ 100,000/mm3 
12. Patients must have adequate organ function: 
• 
Serum alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 times the upper limit of normal (ULN), patients with liver 
metastasis ≤ 5 times ULN; 
• 
An estimated creatinine clearance ≥ 40 mL/min using the Cockcroft Gault 
formula; 
• 
Total bilirubin ≤ 2 mg/dL: 
• 
Patients with Gilbert’s Syndrome must have a total bilirubin ≤ 3 mg/dL 
13. Patients must be seronegative for the human immunodeficiency virus (HIV1 
and HIV2). Patients with positive serology for hepatitis B virus surface antigen 
(HBsAg), hepatitis B core antibody (anti-HBc), or hepatitis C virus (anti-HCV) 
indicating acute or chronic infection may be enrolled if the viral load by 
polymerase chain reaction (PCR) is undetectable with/without active 
treatment. 
14. Patients must have a washout period of 21 days from last anticancer therapy 
prior to the first study treatment (ie, start of NMA LD) 
15. Palliative radiation therapy: prior external beam radiation is allowed 
provided all radiation-related toxicities are resolved to Grade 1 or baseline; 
• 
The tumor lesion(s) being assessed as target for response via RECIST 1.1 
must be outside of the radiation portal (however, if within the portal, they 
must have demonstrated progression); 
• 
Surgery/pre-planned procedure: previous surgical procedure(s) is 
permitted provided that wound healing has occurred, all complications 
have resolved, and at least 14 days have elapsed (for major operative 
procedures) prior to the tumor resection. 
16. Patients must have recovered from all prior anticancer treatment-related adverse 
events (TRAEs) to Grade ≤ 1 (per Common Terminology Criteria for Adverse 
Events [CTCAE], version 5.0). Exceptions may be made, at the Sponsor 
Investigator’s discretion, for persistent adverse events (AEs) that are corrected 
or do not pose a clinical risk, such as hypothyroidism, adrenal insufficiency, 
alopecia, and vitiligo: 
• 
Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case 
basis; 
• 
Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment may be included at the Sponsor Investigator’s 
discretion; 
• 
Patients with Grade ≥ 2 toxicity from prior anticancer therapy may be 
considered on a case-by-case basis after consultation with the Sponsor 
Investigator. 
17. Patients must have provided written authorization for use and disclosure of 
protected health information. 


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18. Must be able and willing to comply with the study visit schedule and 
protocol requirements including long-term follow-up (LTFU). 
Exclusion Criteria 
1. Patients who have received an organ allograft or prior cell transfer therapy 
within the past 20 years that included a nonmyeloablative or myeloablative 
chemotherapy regimen. 
2. Patients with symptomatic and/or untreated brain metastases: 
• 
Patients with definitively-treated brain metastases will be considered for 
enrollment if, prior to tumor resection for TIL, the patient is clinically 
stable for ≥ 2 weeks, there are no new brain lesions via magnetic 
resonance imaging (MRI) post-treatment, and the patient does not require 
ongoing corticosteroid treatment. 
3. Patients who are on systemic steroid therapy except for those requiring steroid 
for management of adrenal insufficiency. Patients receiving steroids for 
management of adrenal insufficiency may receive no more than 10 mg 
prednisone or its equivalent daily. 
4. Patients who are pregnant or breastfeeding. 
5. Patients who have active medical illness(es) that would pose increased risk for 
study participation, including: active systemic infections requiring systemic 
antibiotics (ABX), coagulation disorders, or other active major medical 
illnesses of the cardiovascular, respiratory, or immune systems. 
6. Patients who have received a live or attenuated vaccination within 28 days 
prior to the start of NMA-LD. 
7. Patients who have any form of primary immunodeficiency (such as severe 
combined immunodeficiency disease [SCID] and acquired immune deficiency 
syndrome [AIDS]). 
8. Patients with a history of hypersensitivity to any component of the study drugs. 
LN-145 should not be administered to patients with a known hypersensitivity to 
any component of TIL product formulation and TIL treatment regimen 
including, but not limited to: 
• 
NMA-LD (cyclophosphamide, mesna, and fludarabine); 
• 
Proleukin®, aldesleukin, IL-2; 
• 
ABX of the aminoglycoside group (ie, streptomycin, gentamicin); 
• 
Any component of the TIL product formulation including dimethyl 
sulfoxide [DMSO], human serum albumin [HSA], IL-2, and dextran-40. 
9. Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are 
New York Heart Association (NYHA) Class II or higher. A cardiac stress test 
demonstrating any irreversible wall movement abnormality in any patients ≥ 60 
years of age or in patients who have a history of ischemic heart disease, chest 
pain, or clinically significant atrial and/or ventricular arrhythmias. 
10. Patients who have obstructive or restrictive pulmonary disease and have a 
documented FEV1 (forced expiratory volume in 1 second) ≤ 60% of predicted 
normal: 
• 
If a patient is not able to perform reliable spirometry due to abnormal 
upper airway anatomy (ie, tracheostomy), a 6-minute walk test may be 
used to assess pulmonary function. Patients who are unable to walk a 
distance of at least 80% predicted for age and sex or demonstrates 


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evidence of hypoxia at any point during the test (SpO2 < 90%) are 
excluded. 
11. Patients who have had another primary malignancy within the previous 3 years 
(except for curatively treated localized malignancy that has not required 
treatment for greater than 1 year, and in the judgment of the Sponsor 
Investigator, does not pose a significant risk of recurrence including, but not 
limited to, nonmelanoma skin cancer or bladder cancer or cancers that do not 
require treatment in the judgement of the Sponsor Investigator). 
12. Participation in another clinical study with an investigational product within 21 
days of the initiation of NMA-LD treatment. 
Early 
Discontinuation 
from Treatment 
From TIL Therapy: 
• 
Withdrawal of consent to treatment: 
• 
Every effort should be made to continue OS Follow-up, when 
applicable 
• 
Grade 3 or greater immune TRAEs involving vital organs (heart, kidneys, 
brain, liver, colon, adrenal gland, lungs) with symptoms emerging following 
LN-145 infusion 
• 
Grade 3 or greater allergic reactions including bronchospasm or generalized 
urticaria that does not resolve after medical management in the opinion of 
the Sponsor Investigator 
• 
Meeting criteria for permanent discontinuation of IL-2 treatment. (must have 
received at least one dose of IL-2) 
• 
Administration of prohibited concomitant medication/start of new anti- 
cancer therapy 
• 
Determination by the Sponsor Investigator that continued treatment is not 
in the best interest of the patient 
• 
Death 
End-of-Study Criteria 
A patient may reach end-of-study (EOS) status for any of the following reasons: 
• Death 
• Lost to follow-up after 3 documented attempts to contact the 
patient/family/primary care physician 
• Withdrawal of consent 
• Study termination by Sponsor 
• 3 years (Month 36) of study participation after TIL infusion (Day 0) 
Efficacy Assessment 
The following efficacy parameters for LN-145 as a single-therapy for Metastatic 
Triple Negative Breast Cancer will be investigated: ORR, DOR, DCR, PFS, OS and 
CR Rate. 


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Safety Assessment 
AEs will be collected and reported according to the following temporal intervals: 
• Signed ICF to tumor resection (serious adverse events [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/adverse events of 
special interest [AESI]); 
• Day 30 through 6 months post-LN-145 infusion, or the start of new anticancer 
therapy, whichever occurs first (Grade 3 and Grade 4 AEs; SAEs, AESIs if at 
least related to any study drug); 
• Post-Month 6, only SAEs/AESIs related to LN-145 will be collected and 
reported 
The LTFU period begins after the assessment period ends and continues until the 
EOS, where EOS = death, lost to follow-up, withdrawal of consent, study 
termination by sponsor Investigator, or 3 years (Month 36) of follow up after LN145 
infusion, whichever occurs first. During the LTFU period, AEs will not be collected, 
and no visits are required; phone calls will determine survival status (dead or alive) 
and determine all currently-taken anti-cancer medications. 
Statistical 
Considerations 
Descriptive statistics will be used to summarize safety and efficacy parameters. 
The primary efficacy endpoint will be the ORR as assessed by Sponsor 
Investigator, and patients meeting RECIST 1.1 for a complete response (CR) or 
partial response (PR) will be classified as responders. The ORR, the incidence of 
Grade ≥ 3 TEAEs, CR rates, and the DCRs will be summarized using point- 
estimates and two-sided 90% confidence limits. 
Kaplan-Meier methods will be used to summarize time-to-event efficacy endpoints, 
such as DOR, PFS, and OS. DOR analyses will be performed for patients who 
achieve objective responses. 
For safety, the commonly observed TEAEs will be summarized descriptively in 
comparison to historical data of TIL LN-145. Other safety parameters will include 
TEAEs by grade, SAEs, AEs leading to discontinuations of study treatments, vital 
signs, physical examinations, and toxicity data from clinical laboratory results. 
Sample Size 
Determination 
Ten (10) patients are planned for this study. We assume that the ORR for any 
standard of care second line or greater line of chemotherapy is no more than 14%. 
The alternative hypothesis is that treatment with TIL will result in ORR > 35%. If ≥ 
3 of 10 patients achieve response the efficacy null hypothesis is rejected. This 
design will give a 78% power to detect a difference using a one-sided alpha of 
20%. 
Data Safety Monitoring 
Committee (DSMC) 
The Yale Cancer Center Data Safety Monitoring Committee (DSMC) will review 
cumulative safety data on the first five patients enrolled upon completion of 6 weeks 
(Day 42) of assessment post LN-145 infusion. 
Enrollment will continue while study data is under DSMC review. DSMC data 
review will follow Yale DSMC procedures. 


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TABLE OF CONTENTS 
 
SYNOPSIS ............................................................................................................................................. 2 
TABLE OF CONTENTS ..................................................................................................................... 10 
LIST OF TABLES ............................................................................................................................... 14 
LIST OF FIGURES ............................................................................................................................. 15 
LIST OF ABBREVIATIONS .............................................................................................................. 16 
1. INTRODUCTION ........................................................................................................................... 21 
1.1. Triple Negative Breast Cancer ....................................................................................... 21 
1.2. Adoptive Cell Transfer of Tumor-Infiltrating Lymphocytes as Cancer Immunotherapy 22 
1.3. Rationale for Tumor-Infiltrating Lymphocytes for Selected Indication ......................... 23 
1.4. Safety of the TIL LN-144/LN-145 Cellular Therapy ..................................................... 24 
2. STUDY DESIGN ............................................................................................................................ 25 
2.1. Overview ........................................................................................................................ 25 
Figure 1: Study Flowchart ..................................................................................................... 26 
3. STUDY OBJECTIVES AND ENDPOINTS .................................................................................. 27 
3.1. Objectives Primary: ........................................................................................................ 27 
Secondary: ................................................................................................................................ 27 
Exploratory:.............................................................................................................................. 27 
3.2. Endpoints Primary: ......................................................................................................... 27 
Exploratory:.............................................................................................................................. 27 
4. SELECTION OF PATIENT POPULATION ................................................................................. 28 
4.1. Inclusion Criteria ............................................................................................................ 28 
4.2. Exclusion Criteria ........................................................................................................... 30 
5. TREATMENT ................................................................................................................................. 31 
5.1. Investigational Products ................................................................................................. 31 
Table 1: List of Investigational Products ............................................................................... 31 
5.2. Treatment Overview ....................................................................................................... 32 
5.3. Nonmyeloablative Lymphodepletion Regimen .............................................................. 32 
5.3.1. Cyclophosphamide Preparation ...................................................................................... 33 
5.3.2. Mesna Preparation .......................................................................................................... 33 
5.3.3. Infusion of Cyclophosphamide and Mesna .................................................................... 33 
5.3.4. Infusion of Fludarabine .................................................................................................. 33 
5.4. 
LN-145 ........................................................................................................................... 34 
5.4.1. LN-145 Description ........................................................................................................ 34 


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Figure 2: LN-145 Manufacturing Process ............................................................................. 34 
5.4.2. LN-145 Composition ...................................................................................................... 34 
5.4.3. LN-145 Transport ........................................................................................................... 35 
5.4.4. LN-145 Receipt .............................................................................................................. 35 
5.4.5. Administration of LN-145 .............................................................................................. 35 
5.5. Interleukin-2 ................................................................................................................... 36 
5.6. Permitted and Prohibited Medications ........................................................................... 37 
5.6.1. Permitted Medications .................................................................................................... 37 
5.6.2. Prohibited Medications and Prior Treatment Washout .................................................. 37 
5.6.2.1. 
Prohibited Medications ............................................................................................ 37 
5.6.2.2. 
Prior Treatment Washout ......................................................................................... 37 
5.7. Pregnancy ....................................................................................................................... 38 
6. STUDY ASSESSMENTS/PROCEDURES .................................................................................... 39 
6.1. Informed Consent ........................................................................................................... 39 
6.2. Inclusion/Exclusion Criteria ........................................................................................... 39 
6.3. Demographic Data .......................................................................................................... 39 
6.4. Medical History .............................................................................................................. 39 
6.5. Confirmation of Diagnosis ............................................................................................. 39 
6.6. Physical Examinations ................................................................................................... 39 
6.7. Vital Signs ...................................................................................................................... 39 
6.8. Concomitant Medications ............................................................................................... 40 
6.9. Eastern Cooperative Oncology Group Performance Status ........................................... 40 
6.10. Blood and Urine Tests .................................................................................................... 40 
6.11. Human Leukocyte Antigen Typing ................................................................................ 40 
6.12. Estimated Creatinine Clearance ..................................................................................... 40 
6.13. ß-HCG Serum Pregnancy Test ....................................................................................... 41 
If pregnancy is discovered at any point in time during the study, it should be reported 
immediately to the Sponsor Investigator. ...................................................................... 41 
6.14. Infection Testing ............................................................................................................. 41 
6.15. PD-L1 Status .................................................................................................................. 41 
6.16. Cardiac Evaluations ........................................................................................................ 41 
6.16.1. 
Electrocardiograms .................................................................................................. 42 
6.16.2. 
Echocardiograms or Multigated Acquisition Scans................................................. 42 
6.17. Pulmonary Function Tests .............................................................................................. 42 
6.18. Radiographic Assessments ............................................................................................. 42 
6.19. Tumor Resection / Harvest ............................................................................................. 43 
6.20. Optional Sub Study − TIL Growth from Core Biopsies ................................................ 43 


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6.21. Additional Resected Tumor Tissue for Molecular Analyses .......................................... 43 
6.22. Optional Post-TIL Treatment Biopsy ............................................................................. 44 
6.23. Biological and Immune Monitoring ............................................................................... 45 
6.24. Adverse Events ............................................................................................................... 45 
6.25. End of Assessment Visit ................................................................................................ 45 
6.26. Long-term Safety Follow-up Period............................................................................... 45 
7. WITHDRAWAL OF PATIENTS ................................................................................................... 46 
7.1. Treatment Completion .................................................................................................... 46 
7.2. Study Completion ........................................................................................................... 46 
7.3. Criteria for Discontinuation Prior to or During Study Treatment................................... 46 
7.4. Overall Survival Follow-up ............................................................................................ 47 
7.5. Early Termination of Study ............................................................................................ 47 
8. EXPECTED TOXICITIES AND MANAGEMENT GUIDELINES ............................................. 47 
8.1. Nonmyeloablative Lymphodepletion Regimen Toxicity Management.......................... 47 
8.2. Infection Prophylaxis ...................................................................................................... 48 
8.2.1. Pneumocystis Jiroveci Pneumonia ................................................................................. 48 
8.2.2. Herpes Virus Prophylaxis ............................................................................................... 48 
8.2.3. Fungal Prophylaxis (Fluconazole) .................................................................................. 48 
8.3. Hemorrhagic Cystitis Prophylaxis .................................................................................. 49 
8.4. Febrile Neutropenia ........................................................................................................ 49 
8.5. Filgrastim ....................................................................................................................... 49 
8.6. Blood Product Support ................................................................................................... 49 
8.7. LN-145 Toxicity Management ....................................................................................... 49 
8.7.2 Uveitis and Vitiligo ........................................................................................................ 51 
8.8. Interleukin-2 Toxicity Management ............................................................................... 52 
8.8.1. Rigors ............................................................................................................................. 52 
8.8.2. Diarrhea .......................................................................................................................... 52 
8.8.3. Neurologic Toxicity........................................................................................................ 52 
8.8.4. Renal Toxicity ................................................................................................................ 52 
8.8.5. Capillary Leak Syndrome and Weight Gain ................................................................... 52 
8.8.6. Cardiac Arrhythmias and Myocarditis ............................................................................ 53 
8.8.7. Pulmonary ...................................................................................................................... 53 
8.8.8. Sepsis/Febrile Neutropenia During IL-2 ........................................................................ 53 
8.8.9. Heparin-Induced Thrombocytopenia .............................................................................. 53 
8.9. Other Concomitant Medications to Control Side Effects ............................................... 53 
8.9.1. Nausea/Vomiting ............................................................................................................ 53 
8.9.2. Fever ............................................................................................................................... 53 


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9. TUMOR RESPONSE ASSESSMENTS ......................................................................................... 54 
9.1. Response Criteria ........................................................................................................... 54 
9.2. Baseline Documentation of “Target” and “Nontarget” Lesions .................................... 54 
9.3. Evaluation of Target Lesions ......................................................................................... 54 
Table 3: Definition of Objective Tumor Response ................................................................ 54 
9.4. Evaluation of Nontarget Lesions .................................................................................... 55 
Table 4: Definition of Nontarget Lesions Response ............................................................. 55 
9.5. Evaluation of New Lesions ............................................................................................ 55 
9.6. Evaluation of Overall Response ..................................................................................... 56 
Table 5: Response at Each Assessment Timepoint for Patients ............................................ 56 
9.7. Confirmation of Tumor Assessments ............................................................................. 57 
9.7.1. Confirmation of Response (PR or CR) ........................................................................... 57 
9.7.2. Confirmation of Progressive Disease ............................................................................. 57 
10. 
ADVERSE EVENTS ..................................................................................................... 57 
10.1. Adverse Event ................................................................................................................ 57 
10.2. Serious Adverse Event ................................................................................................... 58 
10.3. Relationship to the Investigational Product .................................................................... 59 
10.4. Severity........................................................................................................................... 59 
10.5. Reporting Procedures for Adverse Events ..................................................................... 59 
10.6. Reporting Procedures for Serious Adverse Events......................................................... 60 
10.7. Investigator Communications with Iovance Biotherapeutics.......................................... 61 
10.8. Special Situations Reporting .......................................................................................... 61 
10.8.1. 
Definitions of Special Situations.............................................................................. 61 
10.8.2. 
Procedures for Special Situations ............................................................................ 62 
10.8.2.1. Pregnancy Reporting .............................................................................................. 62 
10.9. Study Halting Rules ....................................................................................................... 63 
10.10. 
Regulatory Reporting Requirements ........................................................................ 63 
10.11. 
Safety Review and Data Safety Monitoring Committee (DSMC) ........................... 64 
10.12 Data and Safety Monitoring Committee......................................................................... 64 
11. 
STATISTICAL CONSIDERATIONS ........................................................................... 65 
11.1. Introduction .................................................................................................................... 65 
11.2. Study Analysis Sets ........................................................................................................ 65 
11.2.1. 
Safety Analysis Set .................................................................................................. 65 
11.2.2. 
Efficacy Analysis Set ............................................................................................... 65 
11.3. Sample Size Justification ................................................................................................ 65 
11.4. Baseline Demographic and Clinical Characteristics ....................................................... 66 
11.5. Study Endpoints and Planned Analyses ......................................................................... 66 


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11.5.1. 
Primary Endpoints ................................................................................................... 66 
11.5.2. 
Secondary Endpoints ............................................................................................... 66 
11.5.3. 
Exploratory Endpoints ............................................................................................. 67 
12. 
ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT ..................... 67 
12.1. Good Clinical Practice .................................................................................................... 67 
12.2. Institutional Review Board (IRB) Approval .................................................................. 67 
12.3. Protocol Modifications ................................................................................................... 68 
12.4. Record Retention ............................................................................................................ 68 
12.5. Data Quality Assurance .................................................................................................. 68 
12.6. Data Processing and Recordkeeping .............................................................................. 68 
12.6.1. 
Electronic Data ........................................................................................................ 68 
12.6.2. 
Electronic Case Report Form Completion ............................................................... 69 
12.7. Study Monitoring ........................................................................................................... 69 
12.8. Institutional Review Board/Independent Ethics Committee (HIC) ................................ 69 
12.9. Informed Consent ........................................................................................................... 70 
12.10. 
Patient Data Protection ............................................................................................ 70 
12.11. 
Adverse Event Reporting ......................................................................................... 71 
12.12. 
Investigator .............................................................................................................. 71 
12.13. 
Confidentiality ......................................................................................................... 71 
12.14. 
Publications .............................................................................................................. 72 
12.15. 
Data Sharing ............................................................................................................ 72 
12.16. 
Use of Stored Specimens ......................................................................................... 72 
13. 
REFERENCES ............................................................................................................... 72 
14. 
APPENDICES ................................................................................................................ 79 
14.1. Schedule of Assessments ................................................................................................ 79 
14.2. ECOG Performance Status Scale ................................................................................... 96 
14.3. Calculation of BMI, BSA, Practical Weight, and Ideal Body Weight ........................... 97 
14.4. Expected Aldesleukin Toxicities and Their Management .............................................. 98 
 
 
LIST OF TABLES 
Table 1: 
List of Investigational Products .................................................................................. 30 
Table 2: 
Highly Effective Methods of Contraception (< 1% Failure Rate) .............................. 36 
Table 3: 
Definition of Objective Tumor Response ................................................................... 53 
Table 4: 
Definition of Nontarget Lesions Response ................................................................. 54 
Table 5: 
Response at Each Assessment Timepoint for Patients ................................................ 55 
Table 6: 
Examples of Best Overall Response for Each Patient Across All 


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Assessments ................................................................................................................ 55 
LIST OF FIGURES 
Figure 1: 
Study Flowchart ........................................................................................................... 23 
Figure 2: 
LN-145 Manufacturing Process .................................................................................. 32 


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LIST OF ABBREVIATIONS 
Term 
Definition 
ABX 
antibiotics 
ACT 
adoptive cell therapy 
ADP 
adenosine diphosphate 
AE 
adverse event 
AESI 
adverse events of special interest 
AIDS 
acquired immune deficiency syndrome 
AJCC 
American Joint Committee on Cancer 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
anti-HCV 
hepatitis C virus antibody 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ß-HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BRAF 
human proto-oncogene that encodes the B-Raf protein 
BSA 
body surface area 
CBC 
complete blood count 
CD3+ 
T-cells positive for cluster of differentiation 3 surface molecule 
CD4+ 
T-cells positive for cluster of differentiation 4 surface molecule 
CD8+ 
T-cells positive for cluster of differentiation 8 surface molecule 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMO 
contract manufacturing organization 
CMV 
cytomegalovirus 
CR 
complete response 
CRO 
contract research organization 


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CT 
computed tomography 
 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events, version 4.03 
CTLA-4 
cytotoxic T lymphocyte-associated antigen-4 
Cy 
cyclophosphamide 
D5W 
dextrose 5% in water 
DCR 
disease control rate 
DFS 
disease-free survival 
DMSO 
dimethyl sulfoxide 
DNA 
deoxyribonucleic acid 
 
Term 
Definition 
DOR 
duration of response 
DS 
double strength 
DSMC 
Data Safety Monitoring Committee 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOA 
end-of-assessment 
EOS 
end-of-study 
EOT 
end-of-treatment 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FFPE 
formalin-fixed, paraffin-embedded 


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Flu 
fludarabine 
FPI 
full prescribing information 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
HBc 
hepatitis B core antigen 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIC 
Human Investigation Committee 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papilloma virus 
HRCT 
high-resolution computed tomography 
HSA 
human serum albumin 
HSV 
herpes simplex virus 
IB 
Investigator’s Brochure 
 
Term 
Definition 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 (aldesleukin, Proleukin®) 
IND 
investigational new drug 


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IRB 
Institutional Review Board 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IU 
international units 
IV 
intravenous 
LN-145 
autologous tumor infiltrating lymphocytes derived from the patient’s tumor 
LTFU 
long-term follow-up 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MEK 
mitogen-activated protein kinase 
MRI 
magnetic resonance imaging 
MUGA 
multi-gated acquisition 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
NEJM 
New England Journal of Medicine 
NIH 
National Institutes of Health 
NMA-LD 
nonmyeloablative lymphodepletion 
ORR 
objective response rate 
OS 
overall survival 
PARPi 
poly adenosine diphosphate ribose polymerase inhibitors 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed cell death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PI 
prescribing information / package insert 
PJP 
pneumocystis jirovecii pneumonia 


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PR 
partial response 
Term 
Definition 
Q3W 
every 3 weeks 
QLQ 
quality-of-life questionnaire 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
REP 
rapid expansion protocol 
RNA 
ribonucleic acid 
RPR 
rapid plasma reagin 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID 
Severe Combined Immune Deficiency 
SD 
stable disease 
SEER 
National Cancer Institute’s Surveillance, Epidemiology, and End Results Program 
SGOT 
serum glutamic-oxaloacetic aminotransferase 
SGPT 
serum glutamic-pyruvic aminotransferase 
SmPC 
summary of product characteristics 
SMX 
sulfamethoxazole 
SMX-TMP DS 
sulfamethoxazole-trimethoprim double strength 
SpO2 
saturation of peripheral oxygen 
SUSAR 
suspected unexpected serious adverse reaction 
TCR 
T-cell receptor 
TEAE 
treatment-emergent adverse event 
TH 
tumor harvested 
TIL 
tumor infiltrating lymphocytes 
TMP 
trimethoprim 
TNBC 
triple negative breast cancer 
TRAE 
treatment-related adverse event 
Treg 
regulatory T cell 
TSH 
thyroid-stimulating hormone 


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ULN 
upper limit of normal 
US 
United States 
VDRL 
venereal disease research laboratory 
XRT 
radiation therapy or radiotherapy 
YCC 
Yale Cancer Center 
 
 
1. 
INTRODUCTION 
 
1.1. 
Triple Negative Breast Cancer 
In the United States (US), breast cancer is the most common cancer in women with an estimated 
234,190 new diagnoses and 40,920 breast cancer related deaths in 2018 [1]. Breast cancers are 
characterized by whether they express three receptors: The Estrogen Receptor (ER), 
Progesterone Receptor (PR), and human epidermal growth factor receptor 2 (HER2). Expression 
of these receptors confers prognostic significance with important therapeutic implications. 
Tumors that do not express any of these receptors are called triple negative breast cancer 
(TNBC) and account for 10–15% of diagnosed breast cancer [2]. TNBC is associated with a 
shorter time to first recurrence of 25 months vs 67 months in ER+/PR+/HER2- [3]. In addition, 
TNBC recurs more frequently in visceral organs including brain, lung and liver compared with 
hormone receptor positive breast cancer [4]. In a review of the SEER database between 2010 and 
2012 median overall survival (OS) for metastatic TNBC was 12 months vs 35 months in 
nonTNBC with a hazard ratio of 2.51 [5]. 
The management of TNBC with curative intent consists of a multidisciplinary approach 
including medical oncology, radiation oncology and surgery. The role of surgery alone is limited 
to T1aN0M0 TNBC, whereas disease > T1a or node positive disease requires multimodality 
therapy including chemotherapy. In general, chemotherapy can be used either in the neoadjuvant 
or adjuvant setting. Upfront surgery followed by adjuvant chemotherapy allows for correct 
pathologic staging. Whereas neoadjuvant chemotherapy provides an opportunity to assess for 
response to treatment at the time of surgery. Multiple studies have demonstrated that patients 
with TNBC that do not attain pathologic complete response (CR) following neoadjuvant 
chemotherapy have worse survival compared with patients with hormone receptor (HR) positive 
disease and that only a small population of these patients are disease-free at 5 years [4, 6]. 
Preferred regimens in the adjuvant or neoadjuvant setting include dose dense 
doxorubicin/cyclophosphamide (ddAC) followed by paclitaxel every 2 weeks, ddAC followed by 
weekly paclitaxel, and docetaxel and cyclophosphamide [7−9]. Despite this, many patients will 
develop recurrent or metastatic disease. 
In patients with residual disease after neoadjuvant chemotherapy, or with recurrent or metastatic 
disease effective treatment options become limited. A study by Masuda et al. randomized 
HER2(-) residual invasive breast cancer following neoadjuvant chemotherapy to receive standard 
post-surgical treatment vs capecitabine with improvement of the 5-year overall survival to 89.2% 


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compared with 83.6% [10]. In the metastatic setting, single agent taxanes or anthracyclines are 
recommended in the first line setting. Chemotherapy combinations can be used in select 
circumstances with rapidly progressing disease, high tumor burden or visceral crisis [11]. 
Despite this, outcomes remain poor with OS of 14.5 months as demonstrated in a multicenter 
French observational cohort including 2317 patients with TNBC [12]. Recent data published in 
the New England Journal of Medicine (NEJM) by Schmid et al. investigated the use of 
atezolizumab plus nab-paclitaxel in the phase III setting compared with nab-paclitaxel and 
placebo. Median OS in the atezolizumab plus nab-paclitaxel was 21.3 vs 17.6 months. Among 
patients with programmed cell death-ligand 1 (PD-L1) positive tumors (defined at ≥ 1% of tumor 
infiltrating immune cells) median OS was 25.0 vs 15.5 months [13]. Based on this study, 
atezolizumab plus nab-paclitaxel has become a Food and Drug Administration (FDA) approved 
therapy for patients with metastatic disease or recurrent disease after treatment with curative 
intent. In patients with germline BRCA1/2 mutations, poly adenosine diphosphate (ADP) ribose 
polymerase inhibitors (PARPi) including olaparib and talazoparib are approved [14, 15]. Despite 
the improvement in OS, many patients will still succumb to this disease and novel therapies are 
needed. 
1.2. 
Adoptive Cell Transfer of Tumor-Infiltrating Lymphocytes as Cancer 
Immunotherapy 
Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) represents a potentially effective 
treatment for patients with a variety of solid tumors. The method involves the recovery and ex 
vivo expansion of autologous antitumor lymphocytes that have infiltrated a patient’s tumor. The 
basic concept of using lymphoid cells for the immunotherapy of cancer arose from animal 
experiments that demonstrated, by histologic analysis, the presence of T-lymphocytes within the 
microenvironment of most solid tumors and their metastases [16−18]. 
Recent findings have clearly shown a predictive relationship between the frequency and 
phenotype of TIL in solid tumors (especially CD8+ T cells) and an increased OS and 
progression-free survival (PFS) in patients with melanoma [19−22], lung cancer [23−26], 
ovarian cancer [27−29], squamous cell carcinomas [56 , 30 ], triple negative breast cancer, 
HER2-positive breast cancer [31], basal-like breast cancer [32−39], and colorectal cancer 
[40−43]. One study found that an increased Foxp3+ regulatory T cell (Treg)/CD8+ ratio and the 
presence of intra-tumoral high Foxp3+ Treg predicted worse outcomes [44]. In addition, gene 
expression studies using deoxyribonucleic acid (DNA) microarrays have indirectly correlated 
“immune signature” genes and T-cell associated gene expression (eg, CD3, CD8, CD4, inducible 
costimulator, granzyme B, dendritic cell-lysosome-associated membrane glycoprotein, and 
chemokine and chemokine receptors) with improved OS and PFS in both primary and metastatic 
tumor settings [22, 40, 41, 45−47]. These findings support the development of therapies based 
on the isolation and expansion of autologous TIL cells as a therapeutic agent against solid 
tumors. 
Adoptive cell therapy (ACT) with TIL has several theoretical and practical advantages over other 
immunotherapeutic approaches. First, the isolation of T cells directly from the tumor tissue 
ensures the recovery of tumor-specific TIL without prior knowledge of their antigens. Second, 


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the ex vivo culture steps involved in TIL manufacturing favor both the expansion of T cells over 
other cell types and the reinvigoration of these T cells through the elimination of immune 
suppressive factors (eg, Treg which are present in the tumor microenvironment) and the exposure 
to activating factors [48−50]. The result is a polyclonal TIL product mostly comprised of 
effector T cells that recognize a potentially wide array of tumor antigens [51−54]. Finally, 
preparation of the patient with lymphodepletion immediately prior to TIL infusion eliminates in 
vivo suppressive influences (eg, Treg and cytokine sinks) to provide an optimal milieu for the 
activity of the transferred T cells [70]. 
The feasibility of TIL preparation was demonstrated in early preclinical studies. Metastatic 
melanoma (MM) tumors were excised and placed in tissue culture conditions under which tumor 
cells do not survive, but under which TIL contained within the excised tumor tissue can survive 
and proliferate to very large numbers (≥ 1 × 108 cells) [16, 18, 53, 54]. Expanded TIL were 
shown to be effective at killing tumor cells in vitro and promoting durable antitumor effects in 
vivo when infused back into the original donor [16, 18, 53, 54]. Further preclinical studies 
established that the efficacy of TIL infusions is enhanced by pretreatment with 
cyclophosphamide (ie, to induce a transient drop in endogenous lymphocytes in the host) and by 
post-dose interleukin-2 (IL-2) administration [16].These findings set the stage for the National 
Cancer Institute (NCI) initiating clinical trials using TIL to treat MM patients; whereby, a 
nonmyeloablative preconditioning regimen consisting of fludarabine and cyclophosphamide was 
combined with post-doses of IL-2. These studies have consistently demonstrated high objective 
response rates (ORRs), from 49% to 72%, with long-term, durable, and potentially curative CR 
rates of ≤ 25% [55, 71]. As a result, Iovance uses this core TIL regimen in its current clinical 
studies, while working in collaboration with the NCI to continually refine original treatment 
protocol. 
Iovance Biotherapeutics has been able to successfully culture TILs from a variety of tumors 
including Triple Negative Breast Cancer (TNBC) [72]. The average yield of TILs from pre-REP 
of 13 TNBC tumors was 429 x 106. Phenotypic characterization of TILs from TNBC were >80% 
CD4+ T-cells. Further characterization of CD4+ and CD8+ TILs demonstrated effector memory 
phenotypic cells that were also CD27+ and CD28+. The success in growth of TIL from TNBC 
allows for the application of Iovance’s Gen 2 manufacturing process for an autologous cellular 
infusion product to treat TNBC patients. 
1.3. 
Rationale for Tumor-Infiltrating Lymphocytes for Selected Indication 
Immunotherapy is an area of active investigation in the treatment of patients with breast cancer. 
Of breast subtypes, TNBC tumors are found to have the greatest immune infiltrate in the range of 
40–60%, followed by HER2+ with 16% and ER+ subtypes with the least immune infiltrates [56]. 
High numbers of tumor infiltrating lymphocytes (TILs) correlate with pCR to neoadjuvant 
chemotherapy in patients with TNBC [57−60]. Studies have shown that the presence of TIL in 
treatment-naïve TNBC is an independent prognostic factor for disease-free survival (DFS) and 
OS [61, 62]. Specifically, TIL counts correlate with DFS, and for every 10% increase in TIL 
there is an 18% reduction in distant metastases [63, 64]. 


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ACT with TIL has been successful in treating a proportion of patients with metastatic melanoma 
and cervical cancer. It is currently being investigated in other tumor types including breast, 
ovarian, endometrial, urothelial, and digestive tract in a phase II study at the National Institutes 
of Health (NIH) (NCT01174121). Recently, Lee et al. have demonstrated consistency in the 
ability to expand TIL from primary breast tumors with a success rate of 70%. These TIL were 
able to recognize autologous tumor cells and to induce tumor regression in a xenograft tumor 
mouse model [65]. Zacharakis et al. reported the successful treatment of a patient with hormone 
receptor positive metastatic breast cancer that was treated with TIL reactive against mutant 
versions of four proteins, SLC3A2, KIAA0368, CADPS2, and CTSB in NCT01174121 [66]. 
The 40-year-old female patient was treated with a lymphodepleting chemotherapy regimen of 
cyclophosphamide 60 mg/kg and fludarabine 25 mg/m2 followed by a single infusion of 82 x 109 
TIL containing tumor antigen-reactive T cells and pembrolizumab 2 mg/kg every 3 weeks for 7 
doses. At 6 weeks the target tumor burden had decreased by 51%, and at > 22 months all 
lesions had radiographically resolved. Although the patient was treated with pembrolizumab, 
there are no data to support the efficacy of pembrolizumab in hormone receptor positive breast 
cancer and thus this response was attributed to ACT with TIL. The difference in the prior study 
and our proposed study is that we are using manufactured TIL LN-145 in patients with TNBC 
rather than using TIL selected for tumor antigen reactivity in a patient with hormone receptor 
positive breast cancer. Hormone receptor positive disease (which this patient had) is typically 
associated with less immunogenicity than TNBC. Additionally, TIL selection does not insure 
antitumor activity of the final product as demonstrated in several studies, including the one 
mentioned above. In this study, as well as another TIL trial conducted in cervical cancer, at 
least a fraction of the TIL involved in the antitumor response were not specific for the selected 
antigens [66, 67]. Earlier work also showed that selecting TIL for tumor reactivity did not 
provide any benefit in terms of clinical response relative to non-selected TIL [68]. Thus, we 
might expect that patients with TNBC treated with LN-145 could be responsive as well. 
This study will investigate the safety and efficacy of TIL therapy in female patients with 
metastatic TNBC who have progressed on at least one and no more than three prior systemic 
anticancer therapies. 
1.4. 
Safety of the TIL LN-144/LN-145 Cellular Therapy 
LN-144 and LN-145 are TIL expansion products that are differentiated only by their indication: 
LN-144 is the product for melanoma and LN-145 is used in all other solid tumor indications. As 
both products share the same manufacturing process and infusion regimen (nonmyeloablative 
lymphodepletion [NMA-LD] preconditioning and then IL-2 post TIL infusion), safety data is 
pooled. Overall, toxicities and adverse events (AEs) observed during the TIL LN-144/LN-145 
cellular therapy have been associated primarily with either the lymphodepletion preconditioning 
regimen or the IL-2 administration given after TIL infusion. Few infusion-related AEs have been 
documented following the TIL infusion itself, with Grade ≥ 3 events rarely observed [34]. 
The TIL LN-144/LN-145 product contains: TIL; medium, human serum albumin (HSA); human 
recombinant IL-2; and small amounts of gentamicin and streptomycin, aminoglycoside ABX. 
The cryopreserved TIL cellular product contains the cryopreservation medium CryoStor® CS10, 


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which consists of the cryoprotectants dimethyl sulfoxide (DMSO) and dextran-40, among other 
substances. 
Hypersensitivity events, including severe allergic reactions or anaphylaxis, have occurred during 
infusion with LN-144 (melanoma-specific TIL) and LN-145; this may be anticipated because 
hypersensitivity reactions have been associated with at least one of the aforementioned 
formulation components. Patients who have a known history of hypersensitivity to any 
component or excipient of the TIL treatment regimen and the other study drugs will be excluded 
from this study. Pre-medication and supportive therapy instructions can be found in Section 8.2. 
Details concerning specific risks for patients participating in this clinical study may be found in 
the accompanying TIL LN-144/LN-145 Investigator’s Brochure (IB), informed consent 
documents, and each of the following prescribing information/package insert (PI) documents for 
these components: cyclophosphamide, mesna, fludarabine, and IL-2 (Proleukin®). 
2. 
STUDY DESIGN 
 
2.1. 
Overview 
This is a prospective, open-label, non-randomized, Phase 2 study evaluating ACT with LN-145 
as a single therapy. 
The following indication will be investigated: 
• 
LN-145 monotherapy in patients with Metastatic Triple Negative Breast Cancer who 
must have had at least one and no more than three prior lines of systemic anticancer 
therapies for metastatic breast cancer. 
• 
All patients will receive autologous cryopreserved TIL LN-145 therapy, preceded by 
NMA-LD preconditioning regimen consisting of cyclophosphamide and fludarabine. 
Following LN-145 infusion, up to six IV IL-2 doses will be administered. 
The following general study periods will take place, unless specified otherwise: 
• 
Screening and Tumor Resection: Up to 4 weeks (28 days) from signing the informed 
consent form (ICF); 
• 
Enrollment: Upon tumor resection for TIL generation; 
• 
Manufacturing of the TIL LN-145 Product: approximately 22 days from tumor resection; 
• 
Treatment Period: NMA-LD preconditioning regimen (up to 7 days), LN-145 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); At the discretion of the Investigator, and if deemed in the 
patient’s best interest, the D28 visit can be conducted as a telehealth visit. Results of 
tests performed outside investigator’s office within the positive window period of 
assessment may accept to enter in the eCRF as appreciate. 
• 
Assessment Period: Following the EOT visit, efficacy (eg, tumor response) assessments 
will be performed at Week 6 (Day 42) post-LN-145 infusion and then occur every 6 
weeks until Month 6 (Week 24). Patients will continue to be evaluated for response every 


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3 months (12 weeks) for up to 3 years from Day 0 (LN-145 infusion) or until: 
• 
Disease progression 
• 
Start of a new anticancer therapy 
• 
At that time, the End of Assessment (EOA) visit will be completed. At the discretion of the 
Investigator, and if deemed in the patient’s best interest, a visit can be conducted as a 
telehealth visit if patient is unable to return to the study site. Results of tests performed 
outside investigator’s office within the positive window period of assessment timepoints 
may accept to enter in the eCRF as appreciate. 
• 
Overall Survival Follow-up Period: Begins after completion of the last study assessment 
(eg, EOA) and will continue for up to 3 years from LN-145 infusion or until 
discontinuation from the study; with telephone contact every 3 months to obtain survival 
status and subsequent anticancer therapy information (Figure 1). Patients who had tumor 
resection but did not receive LN-145 for any reason will perform an EOA visit and 
transition directly into the OS Follow-up. 
The TIL autologous therapy with LN-145 is comprised of the following steps: 
1. Tumor resection to provide the autologous tissue that serves as the source of the TIL 
cellular product; 
2. LN-145 investigational product production at a central Good Manufacturing Practice 
(GMP) facility; 
3. A 7-day NMA-LD preconditioning regimen (hospitalization will be per institution 
standards); 
4. Infusion of the autologous TIL LN-145 product on Day 0 (during inpatient 
hospitalization); 
5. IV IL-2 administrations for up to six doses maximum (during inpatient hospitalization) 
 
Figure 1: 
Study Flowchart 
 
 
Abbreviations: CMO=contract manufacturing organization; ICF=informed consent form; IL-2=interleukin-2; 
NMALD=nonmyeloablative lymphodepletion; OS=overall survival. 
 
 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
 
3.1. 
Objectives 
Primary: 
• 
To evaluate the efficacy of autologous TIL LN-145 as a single therapy in Metastatic 
Triple Negative Breast Cancer patients by determining the ORR, by Response Evaluation 
 
Criteria in Solid Tumors (RECIST) 1.1, as assessed by the Sponsor Investigator. 
 
 
• 
To characterize the safety profile of TIL LN-145 as a single-therapy in Metastatic Triple 
Negative Breast Cancer patients as measured by the incidence of Grade ≥ 3 treatment- 
emergent adverse events (TEAEs). 
Secondary: 
• 
To further evaluate the efficacy of autologous TIL LN-145 as a single therapy in 
Metastatic Triple Negative Breast Cancer patients using duration of response (DOR), 
disease control rate (DCR), PFS, using RECIST 1.1, as assessed by the Sponsor 
Investigator, OS and CR Rate. 
Exploratory: 
• 
To explore the persistence of TIL LN-145 cells as a single therapy and its resultant 
immune correlates which may affect response, outcome, and toxicity variables. 
• 
To explore efficacy parameters (excluding OS) using the immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST), as assessed by the Sponsor 
Investigator. 
• 
To explore the feasibility of generating TIL (LN-145) from patient derived TNBC core 
biopsy tumor specimens using Iovance manufacturing process. 
3.2. 
Endpoints 
Primary: 
• 
ORR 
• 
Incidence of Grade ≥ 3 
• 
TEAEs Secondary: 
• 
DOR 
• 
DCR 
• 
PFS 
• 
OS 
• 
CR Rate 
Exploratory: 
• 
Immune correlations with respect to response, percent reduction in target lesion sum of 


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diameters, toxicity of the LN-145 therapy as a single-therapy 
• 
ORR, DOR, DCR, and PFS as assessed by Sponsor Investigators per irRECIST 
 
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: 
1. Ability to understand the requirements of the study. Specifically, the patient has to 
provide written informed consent (as evidenced by signature on an ICF approved by the 
IRB of Record). 
2. All patients must have a triple negative metastatic breast cancer (Estrogen Receptor 
negative, Progesterone Receptor negative, HER2 negative) as defined by 2018 ASCO 
CAP guidelines. Patients with low ER and/or low PR (defined as <10% expression 
by IHC) may be deemed eligible and considered as TNBC (following the ASCO 
CAP guidelines 2020 and ESO/ESMO 2020) 
3. Patients must have a confirmed diagnosis of metastatic triple negative breast cancer 
(Stage IV) histologically confirmed as per American Joint Committee on Cancer [AJCC] 
staging system). 
4. Patients must have had at least one and no more than three prior lines of systemic 
anticancer therapies for metastatic disease. 
5. Patients must have disease progression from the last line of therapy. 
6. Patients must have at least one resectable lesion of a minimum 1.5 cm in diameter (or 
aggregate of 1.5 cm if multiple lesions are sampled) post-resection for TIL 
investigational product production. It is encouraged that tumor tissue be obtained from 
multiple and diverse metastatic lesions, as long as the surgical resection it does not pose 
additional risks to the patient. 
• 
If the lesion considered for resection for TIL generation is within a previously 
irradiated field, the lesion must have demonstrated radiographic progression 
postradiotherapy (XRT) and prior to resection. 
• 
Patients must have an adequate histopathology specimen for protocol-required 
testing. 
7. Patients must have a remaining measurable disease as defined by RECIST 1.1 following 
tumor resection for TIL manufacturing: 
• 
Lesions in previously irradiated areas should not be selected as target lesions unless 
there has been demonstrated progression in those lesions. 
• 
Lesions partially resected for TIL production may be chosen as non-target lesions but 
cannot be used as target lesions for RECIST assessment. 
8. Patients must be ≥ 18 years of age at the time of consent. 
9. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 


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of 0 or 1, and an estimated life expectancy of ≥ 3 months in the opinion of the 
Investigator. 
 
10. Female patients of childbearing potential or female partners of childbearing potential of 
male participants, must be willing to practice an approved method of birth control during 
treatment and for 12 months after receiving all protocol-related therapy. 
Approved methods of birth control are as follows: 
• 
Combined (estrogen and progestogen containing) hormonal birth control associated 
with inhibition of ovulation: oral; intravaginal; transdermal 
• 
Progestogen-only hormonal birth control associated with inhibition of ovulation: oral; 
injectable; implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (female participant)/ Vasectomized male participant 
• 
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. 
11. Patients must have the following hematologic parameters: 
• 
Absolute neutrophil count (ANC) ≥ 1000/mm3; 
• 
Hemoglobin ≥ 9.0 g/dL; 
• 
Platelet count ≥ 100,000/mm3 
12. Patients must have adequate organ function: 
• 
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 
times the upper limit of normal (ULN), patients with liver metastasis ≤ 5 times ULN; 
• 
An estimated creatinine clearance ≥ 40 mL/min using the Cockcroft Gault formula at 
Screening; 
• 
Total bilirubin ≤ 2 mg/dL: o Patients with Gilbert’s Syndrome must have a total 
bilirubin ≤ 3 mg/dL 
13. Patients must be seronegative for the human immunodeficiency virus (HIV1 and HIV2). 
Patients with positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis 
B core antibody (anti-HBc), or hepatitis C virus (anti-HCV) indicating acute or chronic 
infection may be enrolled if the viral load by polymerase chain reaction (PCR) is 
undetectable with/without active treatment. 
14. Patients must have a washout period of 21 days from prior anti-cancer therapy prior to the 
first study treatment (i.e start of NMA LD) 
15. Palliative radiation therapy: prior external beam radiation is allowed provided all 
radiation- related toxicities are resolved to Grade 1 or baseline; 


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• 
The tumor lesion(s) being assessed as target for response via RECIST 1.1 must be 
outside of the radiation portal (however, if within the portal, they must have 
demonstrated progression); 
• 
Surgery/pre-planned procedure: previous surgical procedure(s) is permitted provided 
that wound healing has occurred, all complications have resolved, and at least 14 days 
have elapsed (for major operative procedures) prior to the tumor resection. 
16. Patients must have recovered from all prior anticancer treatment-related adverse events 
(TRAEs) to Grade ≤ 1 (per Common Terminology Criteria for Adverse Events 
[CTCAE], version 5.0). Exceptions may be made, at the Investigator’s discretion, for 
persistent AEs that are corrected or do not pose a clinical risk, such as hypothyroidism, 
adrenal insufficiency, alopecia, and vitiligo: 
• 
Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis; 
• 
Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment may be included at the Investigator’s discretion; 
• 
Patients with Grade ≥ 2 toxicity from prior anticancer therapy may be considered on a 
case-by-case basis after consultation with the Investigator. 
17. Patients must have provided written authorization for use and disclosure of protected 
health information. 
18. Must be able and willing to comply with the study visit schedule and protocol 
requirements including long-term follow-up (LTFU). 
4.2. 
Exclusion Criteria 
1. Patients who have received an organ allograft or prior cell transfer therapy within the past 
20 years that included a nonmyeloablative or myeloablative chemotherapy regimen. 
2. Patients with symptomatic and/or untreated brain metastases: 
• Patients with definitively-treated brain metastases will be considered for enrollment if, 
prior to tumor resection for TIL, the patient is clinically stable for ≥ 2 weeks, there 
are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and 
the patient does not require corticosteroid treatment. 
3. Patients who are on systemic steroid therapy except for those requiring steroid for 
management of adrenal insufficiency. Patients receiving steroids for management of 
adrenal insufficiency may receive no more than 10 mg prednisone or its equivalent daily. 
4. Patients who are pregnant or breastfeeding. 
5. Patients who have active medical illness(es)that would pose increased risk for study 
participation, including: active systemic infections requiring systemic antibiotics (ABX), 
coagulation disorders, or other active major medical illnesses of the cardiovascular, 
respiratory, or immune systems. 
6. Patients who have received a live or attenuated vaccination within 28 days prior to the 
start of NMA-LD. 


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7. Patients who have any form of primary immunodeficiency (such as severe combined 
immunodeficiency disease [SCID] and acquired immune deficiency syndrome [AIDS]). 
8. Patients with a history of hypersensitivity to any component of the study drugs. LN-145 
should not be administered to patients with a known hypersensitivity to any component 
of TIL product formulation including, but not limited to: 
• 
NMA-LD (cyclophosphamide, mesna, and fludarabine); 
• 
Proleukin®, aldesleukin, IL-2; 
• 
ABX of the aminoglycoside group (ie, streptomycin, gentamicin); 
• 
Any component of the TIL product formulation including dimethyl sulfoxide 
[DMSO], HSA, IL-2, and dextran-40. 
9. Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New 
York Heart Association (NYHA) Class II or higher. A cardiac stress test demonstrating 
any irreversible wall movement abnormality in any patients ≥ 60 years of age or in 
patients who have a history of ischemic heart disease, chest pain, or clinically significant 
atrial and/or ventricular arrhythmias. 
10. Patients who have obstructive or restrictive pulmonary disease and have a documented 
FEV1 (forced expiratory volume in 1 second) ≤ 60% of predicted normal: 
• If a patient is not able to perform reliable spirometry due to abnormal upper airway 
anatomy (ie, tracheostomy), a 6-minute walk test may be used to assess pulmonary 
function. Patients who are unable to walk a distance of at least 80% predicted for age 
and sex or demonstrates evidence of hypoxia at any point during the test (SpO2 < 
90%) are excluded. 
11. Patients who have had another primary malignancy within the previous 3 years (except 
for curatively treated localized malignancy that has not required treatment for greater 
than 1 year, and in the judgment of the Investigator, does not pose a significant risk of 
recurrence including, but not limited to, non-melanoma skin cancer or bladder cancer or 
cancers that do not require treatment in the judgement of the Investigator). 
12. Participation in another clinical study with an investigational product within 21 days of 
the initiation of NMA-LD treatment. 
5. 
TREATMENT 
 
Comprehensive treatment plan can be found in the Schedule of Assessments (Appendix 14.1). 
5.1. 
Investigational Products 
The investigational products used in this study are listed in Table 1. 
Table 1: 
List of Investigational Products 
Therapy Type 
Investigational Product 
Dosage Form and Strength 
Cyclophosphamide 
Section 5.3.1 


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LN-145 regimen consisting 
of NMA-LD, LN-145, and 
IL-2 
Mesna 
Section 5.3.2 
Fludarabine 
Section 5.3.4 
LN-145 
1.0 × 109 to 150 × 109 total viable lymphocytes 
IL-2 
Section 5.5 
 
5.2. 
Treatment Overview 
The cell transfer therapy used in this study involves patients receiving an NMA-LD preparative 
chemotherapy regimen, consisting of cyclophosphamide IV (60 mg/kg x 2 doses) with mesna (60 
mg/kg x 2 doses with cyclophosphamide) and fludarabine IV (25 mg/m2 x 5 doses). Patients will 
receive on Day 0 infusion of tumor-derived LN-145 (1–150 x 109 cells) and administration of 
multiple doses of adjuvant IL-2 at 600,000 international units (IU)/kg. 
5.3. 
Nonmyeloablative Lymphodepletion Regimen 
The NMA-LD regimen is scheduled to start on Day -7 for patients, after notification from 
Iovance that TIL production is expected to be successful for the patient. Patients may receive 
lymphodepletion chemotherapy as inpatient or outpatient at the discretion of the Investigator or 
per institutional standards. Modification of the lymphodepletion regimen is allowed as clinically 
indicated and should be guided by daily hematological parameters as described below for 
fludarabine in heavily pre-treated patients or patients with a history of prolonged myeloid 
recovery. Patients may remain hospitalized until the completion of the lymphodepletion regimen 
for close monitoring of toxicity and hematologic parameters. If indicated by daily hematological 
parameters, any modification of the lymphodepletion regimen is at the discretion of the 
Investigator. 
The NMA-LD regimen is comprised of single daily doses of cyclophosphamide on Day -7 and 
Day -6 for a total of two doses followed by single daily doses of fludarabine on Day -5 through 
Day -1 for a total of five doses (until the absolute lymphocyte count [ALC] is < 100 cells/mm3) 
and should be administered as per institutional protocol/standards for nonmyeloablative 
chemotherapy. Guidelines for preparation and administration are described below. For 
consistency in dosing, all patients should be dosed using actual body weight, as described in 
Appendix 14.2. 
Drugs required for lymphodepletion including cyclophosphamide and fludarabine will be 
procured and supplied by Iovance. Antimicrobials will be obtained through the participating 
site’s clinical pharmacy. For formulation and packaging of the lymphodepletion regimen please 
refer to respective package inserts for cyclophosphamide, fludarabine, and mesna. Variations 
from the lymphodepletion (eg, infusion times, schedule of treatments, etc.) prior to Day -1 will 
be documented in the medical record but will not be considered protocol violations/deviations. 
Lymphodepletion, LN-145 infusion, and IL-2 administration will all be performed per the 
Pharmacy & Investigational Product Administration Manual by faculty and staff who are 
experienced in these therapies. 


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5.3.1. 
Cyclophosphamide Preparation 
The dose of cyclophosphamide is 60 mg/kg. Cyclophosphamide is to be reconstituted and given 
per institutional standards. 
 
5.3.2. 
Mesna Preparation 
Mesna is administered to prevent the occurrence of hemorrhagic cystitis related to 
cyclophosphamide. Mesna will be prepared and administered per institutional standards. 
 
5.3.3. 
Infusion of Cyclophosphamide and Mesna 
Cyclophosphamide (60 mg/kg) plus mesna are to be infused together on Day -7 and Day 
-6. Hydration with intravenous fluids will be given as per the guideline below or per 
investigator discretion. Hydration is to begin 4 hours prior to the first Cyclophosphamide 
dose. This infusion will continue until 6 hours after the last Cyclophosphamide dose. If 
the urine output is less then 150 ml/hr, increase hydration rate to 200 ml/h. Hold fluid 
infusion during the Cyclophosphamide infusion. 
• Mesna 60 mg/kg IV is given once on Day -7 to infuse over 24 hours. The infusion is 
to begin 15 minutes prior to Cyclophosphamide infusion and continue 24 hours after 
the first dose of Cyclophosphamide. Modifications can occur at the Investigator 
discretion as per Clinical Practice Guidelines. 
• Mesna 60 mg/kg IV is given once on Day -6 to infuse over 9 hours. The infusion is to 
begin 15 minutes prior to Cyclophosphamide infusion and continue 6 hours after the 
second dose of Cyclophosphamide. Modifications can occur at the Investigator 
discretion as per Clinical Practice Guidelines. 
• Refer to the current PI/summary of product characteristics (SmPC) for 
cyclophosphamide, as applicable. 
 
5.3.4. 
Infusion of Fludarabine 
The fludarabine dose of 25 mg/m2 is administered IV over approximately 30 minutes once daily 
for five consecutive days from Day -5 through Day -1. 
• NS 1000ml IV is to be infused over 2 hours prior to the Day -5 Fludarabine dose or per 
investigator discretion The final dose of fludarabine should be administered on Day -1 (at 
least 24 hours prior to the LN-145 infusion). 
Hematological parameters (complete blood count [CBC] and differential) are to be reviewed 
daily during lymphodepletion. If after three or four doses of fludarabine, the ALC falls below 
100 cells/mm3, the remaining dose(s) of fludarabine may be omitted at the discretion of the 
Investigator. 
The fludarabine dose will be adjusted according to measured/estimated creatinine clearance 
(CrCl) as follows: 
• 
CrCl 50-79 mL/min: Reduce dose to 20 mg/m2 
• 
CrCl 40-49 mL/min: Reduce dose to 15 mg/m2 


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Note: 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 Sponsor 
Investigator is recommended. 
5.4. 
LN-145 
 
5.4.1. 
LN-145 Description 
LN-145 is a cellular investigational product comprising a live cell suspension of autologous TIL 
derived from the patient’s own tumor that is shipped as cryopreserved product. A summary of 
the LN-145 manufacturing process is described in Figure 2. For details about tumor handling, see 
Section 6.20 as well as the Tumor Procurement and Shipping Manual. 
Each dose of LN-145 contains from 1.0 × 109 to 150 × 109 total viable lymphocytes. The total 
volume to be infused will be dependent on total cell dose. 
At the time of completion of TIL manufacturing, the appropriate number of cells will be 
harvested and provided in the final investigational product. 
Figure 2: 
LN-145 Manufacturing Process 
 
 
 
5.4.2. 
LN-145 Composition 
Cryopreserved formulations of LN-145 have been developed for use in clinical studies. The 
cryopreserved investigational TIL product is a sterile product formulated in CryoStor® CS10 
cryopreservation media (a cryopreservation medium containing DMSO and other cryoprotectants 
diluted with Plasma-Lyte A, containing 0.5% HSA and 300 IU/mL (12 ng/mL) of IL-2. The 
cryopreserved product is provided in one or more 750-mL cryopreservation bags, each 
containing approximately 100 mL of cells suspended at 100 to 300 x 106 cells/mL. 


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5.4.3. 
LN-145 Transport 
Each dose of the live suspension LN-145 product will be shipped/sent by courier from the 
contract manufacturing organization (CMO) to the clinical site at least the day before planned 
administration using a method that is intended to support 24-hour delivery and expected to 
arrive on the morning of scheduled infusion (Day 0) or can be held for a later infusion, per the 
flexibility the cryopreserved LN-145 product allows. 
Additional details are specified in the Pharmacy & Investigational Product Administration 
Manual. 
 
5.4.4. 
LN-145 Receipt 
LN-145 will be received at the clinical site prior to administration (Day 0). Receipt is defined as 
the moment the LN-145 shipper is signed for by site personnel and released from the courier’s 
custody. 
After receiving, inspecting, verifying, and re-labeling with the clinical site’s specific labels, the 
investigational product, LN-145, will be transferred to the patient’s bedside, preferably in its 
original shipping container (vapor phase liquid nitrogen container for the cryopreserved product) 
for administration. The clinical site is instructed to administer the LN-145 investigational product 
immediately after thawing each cryopreserved infusion bag, sequentially. 
Additional details are specified in the Pharmacy & Investigational Product Administration 
Manual. 
 
5.4.5. 
Administration of LN-145 
At least 24 hours must have elapsed from the last dose of fludarabine and the administration of 
LN-145. If fludarabine is discontinued due to a low ALC, then LN-145 may be administered 
24 hours after the last dose of fludarabine given. If fludarabine is discontinued due to an AE, LN- 
145 may be given after resolution of that AE or with approval of the Investigator. Approval of 
the Investigator is required prior to administration of LN-145 if more than 4 days has elapsed 
from the last dose of fludarabine. 
Within 24 hours prior to administering LN-145, the patient must be hospitalized and prepared 
with IV hydration, as needed, to ensure good hydration status. Patients must be premedicated 
with acetaminophen/paracetamol 650 mg PO and diphenhydramine 25 to 50 mg IV (or other 
histamine H1 antagonist) between 30 and 60 minutes prior to administration of LN-145. In 
addition, emergency anaphylaxis medications must be available at bedside (epinephrine, and 
diphenhydramine, and corticosteroids). Prophylactic use of systemic corticosteroids should be 
avoided, as it may interfere with the activity of LN-145. Corticosteroids should only be given in 
a life-threatening situation. Patients will remain hospitalized until the completion of IL-2 
administration or until deemed necessary per treating iInvestigator, as per institutional 
standards. Prolongation of admission post IL-2 will not be considered an SAE. 
Additional supportive medications may include the following: 


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• 
Acetaminophen (650 mg q4h) 
• 
Indomethacin (50 to 75 mg q6h) 
• 
Ranitidine (150 mg q12h) 
• 
Meperidine (25 to 50 mg) IV or other medications per institutional standards may be 
given for severe rigors/chills 
The LN-145 is to be infused by gravity beginning at a rate of 1 mL/min for the first 5 minutes. If 
no adverse reaction is observed, the rate can then increase to between 5 and 10 mL/min for the 
completion of the infusion. Multiple cryopreserved bags are thawed individually and 
administered sequentially. If interruption of infusion is required for medical reasons, the LN-145 
infusion bags not yet thawed should be kept in the cryoshipper and any thawed LN-145 product 
should be infused within 3 hours of being thawed. The Pharmacy & Investigational Product 
Administration Manual should be consulted. 
Continuous supervision of the patient by site medical staff is required until completion of 
infusion of the first bag of LN-145 to monitor for potential signs and symptoms (eg, of a 
severe hypersensitivity reaction, such as anaphylaxis) that may require immediate medical 
attention and treatment. For details on LN-145 toxicities, see Section 8.7. 
5.5. 
Interleukin-2 
The IL-2 infusion will begin no sooner than 3 and no later than 24 hours after completion of the 
LN-145 infusion. IL-2 will be administered at a dose of 600,000 IU/kg (based on total body 
weight) and will be administered by IV infusion BID.As per institutional standard of care, and 
continued for up to a maximum of six doses. Pulse oximetry is to be conducted during IL-2 
administration. 
Days 0-4 
• Zofran is to be given 16 mg PO q12h 
IL-2 doses will be skipped if patient experiences a Grade 3 or 4 toxicity due to IL-2, except for 
reversible Grade 3 toxicities common to IL-2 (such as diarrhea, nausea, vomiting, hypotension, 
skin changes, anorexia, mucositis, dysphagia, constitutional symptoms, or laboratory changes). 
Management of IL-2 toxicity is detailed in Appendix 14.4. If these toxicities can be easily 
reversed within 24 hours by supportive measures, then additional doses may be given. If greater 
than two doses of IL-2 are skipped, IL-2 administration will be stopped. In addition, dosing may 
be held or stopped at the discretion of the treating Investigator. 
When a patient experiences any AE Grade ≥ 3 after infusion of LN-145, which in opinion of 
the Sponsor Investigator could be exacerbated by the IL-2 infusion or cause delay of IL-2 
infusion for ≥ 48 hours, IL-2 infusion can be skipped. 
All patients will remain hospitalized until the completion of IL-2 administration, as per 
institutional standards. 
For details on IL-2 toxicities, please refer to Appendix 14.4. 


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Refer to the IL-2/aldesleukin (Proleukin®) (80) current PI/SmPC for additional information. 
5.6. 
Permitted and Prohibited Medications 
 
5.6.1. 
Permitted Medications 
The following treatments are permitted during the study: 
• Palliative radiation therapy is permitted between tumor resection and lymphodepletion if it 
does not affect target and nontarget lesions. 
Any changes in concomitant medications also will be recorded in the source documentation and 
the patient’s electronic case report form (eCRF) throughout the study. 
 
5.6.2. 
Prohibited Medications and Prior Treatment Washout 
 
5.6.2.1. 
Prohibited Medications 
The following treatments are prohibited during the study: 
• 
Systemic therapies and radiation intended to treat TNBC are not permitted while the 
patient is on study. Palliative radiation may be allowed if it is not directed at any target or 
nontarget lesions. 
• 
Systemic use of corticosteroids is not allowed starting 21 days prior to beginning the 
NMA-LD preconditioning regimen, through treatment, and up to 60 days post-LN-145 
infusion. Such medications should only be used to treat immediate life-threatening 
conditions. Prophylactic use of steroids is absolutely contraindicated. The one exception is 
for those requiring steroid for management of adrenal insufficiency. Patients receiving steroids 
for management of adrenal insufficiency may receive no more than 10 mg prednisone or its 
equivalent daily. 
• 
Other investigational drugs 
• 
Live attenuated vaccines (should not be given during the study and through 30 days after 
the last dose of study treatment) 
• 
Monoclonal Abs against CTLA-4, PD-1, or PD-L1 
5.6.2.2. 
Prior Treatment Washout 
A washout period from prior anticancer therapy(ies) of a minimum duration as detailed below is 
required prior to start of NMA-LD: 
• 
Cellular therapy: patients may not have received prior cell therapy 
• 
A washout period of 21 days from last anticancer therapy to the start of NMA LD 


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• 
Surgery: previous surgical procedure(s) is permitted provided that wound healing has 
occurred and at least 28 days have elapsed (for major operative procedures) prior to start 
of treatment 
5.7. 
Pregnancy 
Patients of childbearing potential must be willing to take the appropriate precaution to avoid 
pregnancy for the duration of the study and practice an approved, highly effective method of 
birth control during treatment and for 12 months after LN-145 therapy from the last dose of IL-2. 
• 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 (female participant), vasectomized (male participant) 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 
Highly effective methods of contraception, defined as one that results in a low failure rate 
(< 1% per year), when used consistently and correctly, are described in Table 2. Table 2: 
Highly Effective Methods of Contraception (< 1% Failure Rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
Copper T intrauterine device 
Levonorgestrel-releasing 
intrauterine 
system (eg, Mirena®)* 
Implants: 
Etonogestrel-releasing implants: eg, 
Implanon® or Norplant® 
Intravaginal: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: eg, NuvaRing® 
Injection: 
Medroxyprogesterone injection: eg, 
Depo-Provera® 
Combined Pill: Normal and low dose combined oral 
contraceptive pill 
Patch: 
Norelgestromin/ethinylestradiol-releasing 
transdermal system: eg, Ortho Evra® 
Minipill: 
Progesterone based oral contraceptive pill 
using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based 
* This is also considered a hormonal method. 


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6. 
STUDY ASSESSMENTS/PROCEDURES 
 
The study assessments and procedures described below will be performed at the time points 
specified in Appendix 14.1. 
6.1. 
Informed Consent 
An ICF must be signed before any study-related assessments are performed. 
6.2. 
Inclusion/Exclusion Criteria 
Patients must meet all inclusion criteria (Section 4.1) and must not meet any of the exclusion 
criteria (Section 4.2). Patients must continue to meet eligibility criteria at Baseline (Day -21 to 
Day -9). 
6.3. 
Demographic Data 
The demographic data will include date of birth, age, sex, and race/ethnic origin. 
6.4. 
Medical History 
Relevant and significant medical/surgical history and concurrent illnesses will be collected for all 
patients at Screening. 
6.5. 
Confirmation of Diagnosis 
Patients must have a confirmed diagnosis of metastatic triple negative breast cancer and have 
received at least one prior systemic anticancer therapy. Histologic confirmation is required for all 
patients via pathology report. 
6.6. 
Physical Examinations 
Physical examinations will be conducted at the time points specified in Appendix 14.1. Physical 
examinations will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, 
eyes, ears, nose, and throat, respiratory system, skin, and psychiatric (mental status). 
Height will be measured at Screening only. Body surface area (BSA) and body mass index 
(BMI) will be calculated at Day -7 only. 
Physical examinations conducted after Day 14 will be symptom-directed only. Clinically 
significant changes should be recorded as AEs. 
6.7. 
Vital Signs 
Vital signs will include: weight, pulse rate, respiratory rate, blood pressure, and temperature. 
Vital signs will be measured at the time points specified in Appendix 14.1. On Day 0 (LN-145 
infusion), vital signs will be taken pre-infusion, every 15 minutes during infusion and then every 
30 minutes for 2 hours post infusion or until stable. 


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6.8. 
Concomitant Medications 
All medications and therapies (prescription, and nonprescription, including herbal supplements) 
taken by the patient up to 28 days prior to screening will be collected and recorded in the 
database (including the stop dates for medications prohibited in the study) at the time of consent. 
All medications and therapies being taken by the patients, or changes thereof, at any time during 
the study, must also be recorded. Concomitant medications, therapies, or interventions will be 
collected at each visit until completion of the assessment period. The assessment period begins 
after LN-145 infusion on Day 0 and ends at disease progression, the start of a new anticancer 
therapy, or 3 years (Month 36), whichever occurs first. 
6.9. 
Eastern Cooperative Oncology Group Performance Status 
The patient’s ECOG performance status will be assessed at the time points specified in Appendix 
14.1. 
6.10. 
Blood and Urine Tests 
The following safety blood and urine tests will be collected at the time points specified in 
Appendix 14.1: 
• 
Serum chemistry: sodium, potassium, chloride, total CO2 (bicarbonate), serum creatinine, 
glucose, blood urea nitrogen, albumin, calcium, magnesium, phosphorus, alkaline 
phosphatase, lactate dehydrogenase, total protein, total creatine kinase, uric acid, 
amylase, and lipase; 
• 
Liver function tests: ALT, AST, total bilirubin, direct bilirubin; 
• 
Thyroid panel: thyroid-stimulating hormone (TSH) and free T4; 
• 
Hematology: CBC with differential; 
• 
Coagulation panel: prothrombin time, activated partial thromboplastin time (aPTT), and 
international normalized ratio; 
• 
Urinalysis dipstick (a complete urine culture will be performed if clinically indicated). 
6.11. 
Human Leukocyte Antigen Typing 
High resolution human leukocyte antigen (HLA) Class I typing samples will be collected and 
analyzed locally at the Screening Visit. 
6.12. 
Estimated Creatinine Clearance 
Creatinine clearance will be calculated by the site using the Cockcroft-Gault formula at 
Screening and Day 84 (Week 12). 


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6.13. 
ß-HCG Serum Pregnancy Test 
Serum ß-HCG pregnancy tests will be performed for all women of childbearing potential at the 
timepoints indicated in the schedule of assessments (Appendix 14.1) and as clinically indicated. 
If pregnancy is discovered at any point in time during the study, it should be reported 
immediately to the Sponsor Investigator. 
6.14. 
Infection Testing 
Blood samples will be collected and tested for the following viral infections at Screening and 
thereafter as clinically indicated (as per local standard): 
• 
Cytomegalovirus (CMV) serology (CMV immunoglobulin G [IgG] and CMV 
immunoglobulin M [IgM]); 
• 
Syphilis assay (as per local standard; eg, rapid plasma reagin [RPR], venereal disease 
research laboratory [VDRL], or other); 
• 
HIV1 and HIV2 antibody titer; 
• 
HBsAg and anti-HBc; 
• 
Anti-HCV; 
• 
Herpes simplex virus (HSV) serology determination (HSV-1 IgG and HSV-2 IgG); 
• 
Epstein-Barr virus (EBV) Panel (VCA-IgG, and/or Epstein-Barr nuclear antigen IgG [or 
tests conducted as per local standard to confirm absence of acute or active EBV infection] 
(may have been done within 3 months prior to tumor resection). 
Infection testing must be repeated if > 28 days occurs from the last tests results. 
6.15. 
PD-L1 Status 
A sample of tumor resected for TIL generation will be analyzed locally for PD-L1 status by 
immunohistochemistry (IHC). See Section 6.22. 
6.16. 
Cardiac Evaluations 
All cardiac evaluations (NYHA, echocardiogram [ECHO], electrocardiogram [ECG], cardiac 
stress test) will be performed during screening, and ECG will be performed at screening and 
baseline. Cardiac stress test will only be performed if clinically indicated. If an ECG was 
performed within 2 weeks prior to screening, then it does not need to be repeated. Other 
evaluations completed within 3 months prior to screening will be accepted. 


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6.16.1. 
Electrocardiograms 
At Screening and Baseline, a 12-lead ECG will be performed after the patient has been supine for 
at least 3 minutes. If an ECG has been performed within 2 weeks prior to Screening, an ECG 
does not need to be repeated. 
 
6.16.2. 
Echocardiograms or Multigated Acquisition Scans 
During screening, an ECHO or multigated acquisition scan (MUGA) will be performed to assess 
ventricular function for all patients. 
6.17. 
Pulmonary Function Tests 
Prior evaluations completed within 6 months prior to Screening will be accepted, apart from 
patients with known pulmonary metastases or clinically significant pulmonary disease. 
Pulmonary function tests using spirometry will be completed during screening, as clinically 
indicated. Patients who are unable to conduct reliable pulmonary function test measurements due 
to abnormal anatomy may undergo a 6-minute walk test to evaluate pulmonary function [69]. 
These patients must walk a distance of at least 80% predicted for age and sex as well as maintain 
oxygen saturation > 90% throughout. 
6.18. 
Radiographic Assessments 
Computed tomography (CT) scans which have been performed within 4 weeks prior to 
enrollment can be utilized for Screening. Radiographic assessments by CT scans with contrast of 
the chest, abdomen, and pelvis are required for all patients for tumor assessments. CT scans are 
performed throughout the study as outlined in the Schedule of Assessment (Appendix 14.1) until 
disease progression as measured by RECIST 1.1 is noted (or if the patient withdraws full 
consent). Radiographic assessments of additional anatomical locations will be conducted at the 
referenced visits (see Appendix 14.1 for specific timepoints) if clinically indicated per disease 
history and clinical symptoms. Magnetic resonance imaging (MRI) or positron emission 
tomography (PET) scans of the chest, abdomen, and pelvis in lieu of CT scans may be allowed 
for patients are intolerant to contrast media. The same method of assessment (CT or MRI) and 
the same technique for acquisition of data should be used consistently throughout the study to 
characterize each identified and reported lesion at Baseline (Day -21 to Day -9). At the 
Investigator’s discretion, the baseline brain MRI and CT scans may be performed as early as Day 
-21. The baseline Brain MRI may not be repeated if negative at screening. 
Patients will be evaluated for response at Weeks 6, 12, 18, 24; and then every 3 months 
thereafter until disease progression, initiation of a new anticancer therapy, or patient withdrawal 
from the study. Tumor assessments are to be performed within the positive window period only, 
for the timepoints mentioned above. The same imaging parameters should be utilized for all 
scans throughout the study. Response assessments should be evaluated and documented by a 
qualified Investigator participating in the study. 


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6.19. 
Tumor Resection / Harvest 
Preferably, the targeted tumor will not have been previously irradiated. Prior irradiation of the 
resected tumor is allowed if at least 3 months have elapsed between irradiation and resection and 
the tumor has demonstrated growth during that interim. Whenever possible, resection from 
multiple tumors for TIL generation should be obtained if it would not significantly increase the 
potential morbidity of the surgical procedure. If there is only one lesion, then it may be used for 
both TIL generation and as a target lesion, provided the appropriate criteria are met. Tumor 
resection is expected to occur approximately 23 days prior to the LN-145 infusion on Day 0 and 
is dependent on the rate of TIL cell growth at the CMO. 
It is imperative that only the patient’s own (autologous) study treatment (LN-145) be 
administered to the same individual patient. For these reasons, the patient specimen must be 
procured and handled per institutional practice to ensure optimal quality of the specimen and 
minimum transport time to the CMO, as well as to ensure the appropriate identification of the 
study product at all times including infusion back into the patient. 
Refer to the Tumor Procurement and Shipping Manual for details. 
 
6.20. 
Optional Sub Study − TIL Growth from Core Biopsies 
If available and if patient consent to the substudy is provided, additional core biopsies from 
primary and/or metastatic tumor will be collected during tumor harvest. Core biopsies should be 
from an area of the tumor lesion that will be different from that prepared for TIL manufacturing. 
Ideally, 10 or more cores (14G) of 20 mm will be collected and sent to Iovance per the Tumor 
Procurement and Shipping Manual (for Research Specimens to Iovance Tampa). The core 
biopsies will be used to determine the feasibility of generating TIL using the Iovance LN-145 
manufacturing process, from patient derived TNBC specimens that are much smaller than the 
current specimens and obtainable through non-invasive procedures. 
If exploratory TIL growth from core biopsy tissue collected during this sub study is found to be 
successful, the protocol may be amended in the future to allow tissue collected via core biopsy to 
be used for LN-145 generation. 
6.21. 
Additional Resected Tumor Tissue for Molecular Analyses 
If there is an excess of tumor tissue available after resection for TIL manufacturing, it will be 
utilized for exploratory biomarker analysis. 
If no excess tumor tissue is available, a single 2 mm punch biopsy from the center of the resected 
tumor can be collected. If excess viable tumor tissue and punch biopsy are not available, excess 
viable tumor tissue can be resected from additional (non-target) lesion (if feasible). Depending 
on the size of excess viable tumor tissue collected, tissue will be divided into approximately 
three 0.5 cm diameter portions in the following order of priority: 
(1) 0.5 cm tissue prepared as formalin-fixed, paraffin-embedded (FFPE) block (sent to local 
laboratory) 


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(2) 0.5 cm tissue can be placed in hypothermosol (send to Iovance Tampa) 
(3) 0.5 cm tissue placed in ribonucleic acid (RNA) later (send to local laboratory) 
(4) Any remaining tissue will be sent fresh to Dr Tristen Park, Yale Cancer Center laboratory 
Any additional available tissue can be further prepared in the following order: 
FFPE -> Hypothermosol -> RNA later -> fresh applications 
Tumor tissue sent to the Yale Cancer Center laboratory and Iovance laboratory may be used as 
follows: 
 
(1) For IHC to identify different immune cell populations and PD-L1 status; and for isolation of 
DNA, which will be used for sequencing of common oncogenic mutations, tumor-associated 
gene and/or T cell receptors and for whole exome sequencing and tumor mutation analyses 
(subject to patient consent) 
(2) For tumor-reactivity assays 
(3) For gene expression analyses; and 
(4) For the production of Research TIL, the generation of patient-derived xenografts into 
immunocompromised mice, and the establishment of primary breast tumor lines 
Provision of adequate amount of tumor tissue for TIL manufacturing sent to the CMO is priority 
over the collection of additional tumor tissue that is sent for exploratory purposes. Every effort 
should be made to obtain adequate tumor tissue for both TIL manufacturing and additional 
analysis. 
Refer to the Tumor Procurement and Shipping Manual for Research Specimens for sending fresh 
tissue to Iovance Tampa. 
6.22. 
Optional Post-TIL Treatment Biopsy 
If available and if patient consent is provided, on-study post-treatment (post LN-145 infusion) 
biopsy will be collected at Week 6 (Day 42) following the first post-baseline tumor response 
assessment scans; Core biopsies (1-6 cores) from lesions not being assessed by RECIST will be 
collected. FFPE blocks need to be prepared from first core and second core and can be placed in 
RNA later solution. If more than two core biopsies are available, they should be utilized in the 
following order: 
 
FFPE -> RNA later -> FFPE -> RNA later 
The Week 6 (Day 42) core biopsies may be used to ascertain molecular and immunological 
changes in the tumor following treatment as described below: 
• 
FFPE block sent to Yale Cancer Center laboratory may be used for IHC including PD-L1 
staining and DNA sequencing; and 


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• 
Sample in RNA later (sent to Yale Cancer Center) may be used for gene expression 
analyses 
 
6.23. 
Biological and Immune Monitoring 
In addition to tumor tissue samples, samples of the TIL product as well as blood samples 
collected at different time points before and after TIL infusion will be studied to identify 
biomarkers of TIL antitumor activity. 
TIL from the infusion product will be stored for research. The samples used in these research 
studies will be used to gain further information about the disease and the characteristics of the 
TIL before and after infusion (TIL phenotype, TIL function, TIL reactivity, and TIL diversity). 
Lab experiments will include flow cytometry analyses, cell-based assays, gene expression 
analyses, and T-cell receptor (TCR) sequencing. 
Mandatory peripheral blood will be collected at the timepoints of surgery/tumor resection and 
day 1 for immune monitoring by testing for an array of cellular and soluble factors that may 
include: 
• 
The detection of circulating immune molecules, such as cytokines; 
• 
The monitoring of immune cell numbers; 
• 
The identification, characterization, and functional assessment of circulating TIL; and 
• 
The identification of circulating tumor DNA 
Blood for immune monitoring will be collected at the following timepoints: Week 6 (Day 
42), Week 12 (Day 84), Month 6, and Month 12 if patient is able to return to the study site . 
See Appendix 14.1. 
Refer to Blood Immuno-Monitoring Shipping Manual for more details. 
6.24. 
Adverse Events 
All AEs for all patients will be assessed as per NCI CTCAE Version 5.0 during all visits after the 
ICF is signed. Additional safety reporting requirements are described in Section 10.5. 
6.25. 
End of Assessment Visit 
Once a patient has reached disease progression or started a new anticancer therapy, an EOA visit 
should take place according the schedule of assessments in Appendix 14.1. If the patient has 
performed the required assessments during a visit within the previous 6 weeks, and results are 
either normal, or abnormal but expected, the assessments do not need to be repeated for the EOA 
visit. 
6.26. 
Long-term Safety Follow-up Period 
Long-term follow-up for OS will commence when a patient completes the EOA visit and will 
consist of telephone contact (or other means of communication) made every 3 months with the 
patient (or designee) to collect subsequent anticancer therapy and survival status. Patients are to 
be followed for OS for at least 3 years from the end of LN-145 infusion (Day 0). 


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During the LTFU for OS period, AEs will not be collected, and no visits are required, with only 
phone calls determining the survival status and any current anticancer therapy the patient is 
taking. 
 
7. 
WITHDRAWAL OF PATIENTS 
 
7.1. 
Treatment Completion 
Patients will be considered to have completed treatment if they have tumor harvest, receive the 
NMA-LD regimen, the LN-145 infusion and at least one dose of IL-2. 
7.2. 
Study Completion 
The study is expected to be completed: at approximately 3 years after LN-145 infusion; at the 
time point when all patients have exited the study for any reason; or at the Sponsor PI’s/ 
Regulatory Agency/Iovance’s discretion, whichever occurs first. The intent is that all patients 
will be followed post-treatment (LN-145) for a minimum of 3 years. 
7.3. 
Criteria for Discontinuation Prior to or During Study Treatment 
Patients who have tumor harvested, but do not receive any of the study treatment (NMA-LD, 
LN-145, and/or IL-2) will perform an EOA visit and transition directly into the LTFU for OS 
period, if study if consent remains in place. Patients who discontinue from the study for any 
reasons are to complete the EOA visit. An EOA visit is not required if the same procedures are 
done within 2 weeks from the previous visit (see Appendix 14.1). End-of-study (EOS) occurs 
when the patient has completed study participation (eg, death or lost to follow-up). Appropriate 
reasons for the discontinuation must be documented in the patient’s source documentation and 
eCRF page. 
Criteria for discontinuation from the study are as follows: 
• 
Withdrawal of consent from further participation in the study 
• 
Sponsor Investigators’ decision 
• 
Death 
• 
Lost to follow-up after 3 documented attempts to contact the patient 
• 
Study terminated by Sponsor Investigator 
Criteria for treatment discontinuation from NMA-LD, LN-145, and/or IL-2 administration are as 
follows: 
• 
Grade 3 or greater immune TRAEs that involves vital organs (heart, kidneys, brain, liver, 
colon, adrenal gland, lungs) with symptoms emerging following LN-145 infusion 
• 
Grade 3 or greater allergic reaction including bronchospasm or generalized urticaria that 
does not resolve after medical management in the opinion of the Sponsor Investigator 
• 
Grade 3 or greater toxicity due to NMA-LD that does not decrease to Grade 2 or less 
within 96 hours of management 
• 
Determination by the Sponsor Investigator that continued treatment is not in the best 


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interest of the patient 
 
• 
Withdrawal of consent from further study treatment. The patient is, at any time, free to 
discontinue treatment, without prejudice to further treatment. A patient who discontinues 
treatment is normally expected to continue to participate in the study unless they 
specifically withdraw their consent to further participation in any study procedures and 
assessments 
• 
Pregnancy 
• 
Patient becomes ineligible for study after tumor harvest and prior to LN-145 or IL-2 
administration 
• 
Administration of prohibited concomitant medication 
• 
Patient meets any of the criteria for early discontinuation from study 
In the event of a patient’s full withdrawal of consent from post-treatment follow-up, the 
Sponsor Investigator will make every effort to complete the EOA visit as appropriate. All 
AEs attributable to the investigational product may be followed until resolution or 
permanent sequelae. The final outcome of unrelated AEs ongoing at the time of the EOA 
visit will be captured as “Not Recovered/Not Resolved.” 
7.4. 
Overall Survival Follow-up 
Approximately every 3 months following the EOA visit, patients will be contacted (eg, via 
telephone contact, or other means) to assess survival status, receipt, and ongoing status of 
subsequent anticancer therapies. Quarterly follow-up will continue until death, full withdrawal of 
consent by patient, lost to follow-up, or study terminated by Sponsor PI’s/ Regulatory 
Agency/Iovance. Patients are to be followed for 3 years from the end of LN-145 infusion (Day 
0). 
Every effort must be made to locate any patient who is lost to follow-up. Patients can only be 
considered as lost to follow-up after 3 documented attempts to contact the patient, with no 
response. 
7.5. 
Early Termination of Study 
The study may be terminated at any time by Sponsor PI’s/ Regulatory Agency/Iovance. 
8. 
EXPECTED TOXICITIES AND MANAGEMENT GUIDELINES 
 
Expected toxicities due to the chemotherapy preparative regimen, cytokines or support 
medication administration (as listed in the protocol or in the package inserts for commercial 
agents) will not result in discontinuing therapy (please refer to Sections 8.1 and 8.3). 
8.1. 
Nonmyeloablative Lymphodepletion Regimen Toxicity Management 
The use of the NMA-LD regimen (cyclophosphamide and fludarabine) prior to cell 
administration is expected to lead to myelosuppression in all patients. Therefore, a high index of 
suspicion for occult bacteremia should be maintained until marrow recovery. 
Refer to cyclophosphamide and fludarabine current PI/SmPC for additional information. 


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Expected toxicities with cyclophosphamide and fludarabine administration are listed in the 
PI/SmPC. Also included in the package inserts is information on supportive care and 
management of toxicities. Treatment will be given as per Investigator discretion and per 
institutional standard of care. 
8.2. 
Infection Prophylaxis 
 
8.2.1. 
Pneumocystis Jiroveci Pneumonia 
All patients should receive appropriate Pneumocystis jiroveci pneumonia (PJP) prophylaxis per 
institutional standards for patients undergoing chemotherapy-induced immunosuppression. This 
may include any of the following and should begin on or after their first dose of chemotherapy 
(Day -7), or as the Investigator deems appropriate, and continue until the ALC is > 1000 
cells/mm3 (typically for at least 6 months) or as per institutional standard of care. 
 
• 
Trimethoprim (TMP) and sulfamethoxazole (SMX) as double strength (DS) tab (DS 
tabs = TMP 160 mg/tab, and SMX 800 mg/tab) by mouth two times daily, three times a 
week on nonconsecutive days, beginning on the first Monday, Wednesday, or Friday 
on or after the first dose of chemotherapy. 
• 
Pentamidine or alternative as per standard of care at the treating institution may be 
substituted for TMP/SMX DS in patients with sulfa allergies and may be administered 
either IV or aerosolized monthly using standard doses indicated for PJP prophylaxis. 
Note: Other appropriate PJP prophylactic agents may be substituted at the discretion of the 
treating Investigator. 
 
8.2.2. 
Herpes Virus Prophylaxis 
Patients with positive HSV serology should receive appropriate re-activation prophylaxis with 
either valacyclovir or acyclovir. 
Herpes prophylaxis should begin on Day7 or as theInvestigator deems appropriate and continue 
until the absolute lymphocyte count is > 1000/mm3 (typically for at least 6 months) or as per 
standard institutional guidelines. 
Note: Other appropriate viral prophylactic agents may be substituted at the discretion of the 
treating Investigator. 
 
8.2.3. 
Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg (by mouth) from Day 1, or when patient becomes 
neutropenic and continue until ANC > 1000/mm3, or another suitable fungal prophylaxis 
regimen as per standard of care at the treating institution. 


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8.3. 
Hemorrhagic Cystitis Prophylaxis 
Patients will receive mesna to reduce the risk of cyclophosphamide-associated hemorrhagic 
cystitis in addition to IV fluids. Please refer to treatment guidelines for recommended mesna 
dosing. Alternative dosing regimens of mesna are allowed per institutional standards and 
Investigator discretion. 
8.4. 
Febrile Neutropenia 
Patients are expected to become neutropenic following the lymphodepletion regimen. 
Furthermore, IL-2 causes neutrophil migration dysfunction putting patients at risk for 
pseudomonas infection as well as severe occult bacteremia. Therefore, for first fever > 38.3°C 
(or 38.0°C or above at least 1 hour apart) at any point following lymphodepletion (from Day 0 
onward), patients will be started on empiric broad-spectrum ABX with adequate Pseudomonas 
coverage (as per local institutional antibiogram) regardless of neutrophil count. 
Empiric ABX should continue until the neutrophil count is > 500 cells/mm3, even if no 
bloodstream infectious agent is identified. If a bloodstream agent is identified, broad-spectrum 
ABX may be tailored to treat the infection as per institutional standard of care. Infectious disease 
consultation will be obtained for all patients with unexplained fever, any infectious 
complications, or as per standard of care at the treating institution. 
8.5. 
Filgrastim 
Patients will receive filgrastim 5 µg/kg/day (recommended maximum dose of 300 µg/day or 
higher as per institutional standard) subcutaneously starting from Day 1 until ANC is > 
1000/mm3 for 3 consecutive days, or as per standard of care at the treating institution. 
 
8.6. 
Blood Product Support 
Using daily CBCs as a guide, the patient will receive platelets and packed red blood cells as 
clinically indicated. As a general guideline, patients may be transfused to maintain: 
• 
Hemoglobin ≥ 7.5 g/dL 
• 
Platelets ≥ 10,000/mm3 
Note: Patients may be transfused for different parameters as clinically indicated, eg, increased 
risk for bleeding such as undergoing an invasive procedure or presence of metastatic lesion likely 
to bleed (such as in the brain), high-grade fever, or sepsis. 
All blood products will be irradiated. Leukocyte filters will be utilized for all blood and platelet 
transfusions to decrease sensitization to transfused white blood cells and decrease the risk of 
CMV infection. 
 
8.7. 
LN-145 Toxicity Management 
 
8.7.1. 
Hypersensitivity Reactions, Including Severe Allergic Reactions and 
Anaphylaxis 


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The TIL product formulations contain 0.5% HSA, 300 IU/mL of IL-2, and potentially low 
residual amounts of gentamycin and streptomycin, which belong to the aminoglycoside group of 
ABX. The cryopreserved TIL product formulation includes the cryopreservation medium 
CryoStor® CS10, which contains the cryoprotectants DMSO and dextran-40. 
Hypersensitivity reactions, including severe allergic reactions and life-threatening anaphylaxis, 
have occurred during infusion with the LN-145 investigational product. Within 24 hours prior to 
administering LN-145, the patient must be hospitalized and prepared with IV hydration, as 
needed, to ensure good hydration status. The following must be administered as premedication 
prior to the LN-145 infusion: 
• 
Within 30 to 60 minutes prior to the LN-145 infusion, premedicate the patient with 
acetaminophen (650 mg) and diphenhydramine (25 to 50 mg IV), or another H1 
histamine antagonist. 
o Avoid prophylactic use of systemic corticosteroids, as it may interfere with the activity 
of LN-145. Corticosteroids should only be used to treat life-threatening conditions. 
In addition, emergency anaphylaxis medications must be available at bedside (epinephrine and 
diphenhydramine; corticosteroids should only be given in a life-threatening situation). 
Additional supportive medications may include the following: 
• 
Indomethacin (50 to 75 mg q6h); 
• 
Ranitidine (150 mg q12h); 
• 
Meperidine (25 to 50 mg), or other medication per institutional standards may be given 
IV if severe chills/rigors develop. 
The initial infusion rate should not exceed 1 mL/min for the first 5 minutes. The rate of infusion 
may be increased thereafter to 5–10 mL/min as tolerated. Continuous supervision of the patient 
by site medical staff is required until completion of infusion of the first bag of TIL, to monitor 
for potential signs and symptoms (eg, of a severe hypersensitivity reaction such as anaphylaxis) 
that may require immediate medical attention and treatment. For additional information, please 
refer to the study-specific Pharmacy & Investigational Product Administration Manual. 
Hypersensitivity events 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. More severe 
reactions, including anaphylaxis, have occurred and require immediate treatment with emergency 
medications. During infusion of the LN-145 product, appropriate emergency medications (eg, 
epinephrine, diphenhydramine, and corticosteroids) should be available at bedside during 
administration and institutional guidelines should be followed for the treatment of anaphylaxis. 
Corticosteroids should only be used in life-threatening conditions. 


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Infusion of LN-145 must occur before the expiration time (usually within 24 hours of 
manufacture). Please refer to the Pharmacy & Investigational Product Administration Manual for 
specific LN-145 infusion instructions. Historically, toxicities or AEs during TIL infusion have 
almost entirely been associated with either the NMA-LD regimen or the IL-2 therapy given after 
TIL infusion [61]. The following AEs have been observed in published studies that treated 
patients with TIL products prepared by a process like that being used to prepare LN-145: 
• 
Short-term, transient/reversible effects of TIL infusion include fever, chills, shortness of 
breath, increased heart rate, hypotension (prolonged hypotension necessitating pressor 
treatment has been reported) [61] following TIL infusion 
• 
Lung congestion, which could be mild (shortness of breath) to severe (difficulty 
breathing – possibly needing a breathing tube and breathing machine for a few days) 
• 
Autoimmune reaction such as loss of skin pigment (known as vitiligo) or inflammation of 
the eye (uveitis, refer to 8.7.2), which may require the use of steroid eye drops 
 
8.7.2 Uveitis and Vitiligo 
Uveitis and vitiligo have been observed in studies of patients with melanoma who received treatment 
with a TIL product. Melanocytes, melanin, and pigment in the human uvea tissues share many surface 
proteins with skin melanocytes. Hence, it is possible that a therapy targeting melanocytes involved in 
melanoma may trigger autoantibodies against normal melanocytes in uveal tissue or skin melanocytes, 
leading to uveitis or vitiligo. 
• 
Uveitis may present with mild to moderate in intensity, associated with symptoms such as 
blurred vision, dull, aching, eye pain, nyctalopia, photopsia, retinal hemorrhage, and/or vitreous 
floaters, and often improved with corticosteroid therapy. Uveitis may be caused by a number of 
different etiologies; therefore, diagnosis and treatment of the underlying disease are imperative 
not only to treat the disease but also to preserve vision and potentially uncover underlying 
systemic diseases. If untreated or not appropriately treated, acute inflammation can develop into 
chronic, sight-threatening inflammation. Thus, when a patient presents with clinical signs and 
symptoms that may be associated with uveitis, the Investigator should complete a thorough 
examination to determine an appropriate etiology for the diagnosis. The examination should 
include an evaluation of location (anterior vs intermediate vs posterior), duration (acute vs 
chronic), pathology (granulomatous vs non-granulomatous), and laterality (unilateral vs 
bilateral). Once an etiology has been established, appropriate treatment should be commenced 
and customized to each participant as suboptimal treatment may lead to complications and loss 
of vision. 
• 
Vitiligo may present in these patients with mild to moderate in intensity. For patients who 
develop vitiligo, a thorough history should be taken including the site and type of vitiligo 
(segmental, nonsegmental), disease extent (affected body surface area), disease stability, and 
speed of onset. Topical corticosteroids (medium or high potency) are recommended for 
localized vitiligo (<10% of body surface area) and may be used at Investigator discretion. 
Specialized dermatology consultation is recommended for appropriate management in all cases 
unless vitiligo is self-limited, localized, and non-progressive. 
Patients may experience severe allergic reaction (anaphylaxis) due to DMSO contained in LN- 
145. Thus, appropriate emergency medications (eg, epinephrine and diphenhydramine) should be 


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available at bedside during time of administration and institutional guidelines should be followed 
for administering supportive care for anaphylaxis. 
Details concerning specific risks for patients participating in this clinical study may be found in 
the accompanying LN-145 IB. 
 
 
8.8. 
Interleukin-2 Toxicity Management 
IL-2 (Proleukin, aldesleukin) can affect nearly every organ system, but essentially every 
abnormality will most often normalize following discontinuation of IL-2 dosing. Below is a list 
of the commonly seen toxicities. Appendix 14.4 has further details for suggested management as 
well as decision for holding (skipping a dose) and discontinuing IL-2 therapy. 
 
8.8.1. 
Rigors 
IL-2 associated rigors can routinely be treated with meperidine/pethidine. An initial dose of 25 
mg can be initiated and followed with an additional 25 mg 15 minutes later if rigors persist or as 
per local standard institutional guidelines. Prophylactic use of meperidine is discouraged. 
 
8.8.2. 
Diarrhea 
IL-2 associated diarrhea may be observed. Anti-motility agents, such as loperamide and Lomotil, 
may be used as per local standard institutional guidelines (after testing for infectious etiologies 
such as Clostridium difficile, if present). 
8.8.3. 
Neurologic Toxicity 
Decreased mental status may occur and can range from somnolence to obtundation. IL-2 should 
be discontinued for any significant mental status changes or hallucinations. Agitation may be 
observed due to mild hallucinations. Appropriate psychiatry consultation would be warranted for 
guidance in management. 
 
8.8.4. 
Renal Toxicity 
Renal toxicity defined by rapid rise in serum/plasma creatinine levels or clinical symptoms is a 
risk that is commonly observed (creatinine 1.5 to 2.0 x ULN for mild elevation, or greater than 
3.0 x ULN for marked elevation). If patients exhibit signs or symptoms of renal toxicity, manage 
as per institutional standard of care (and may include low-dose dopamine to improve perfusion 
or continuous veno-venous hemofiltration). Hemodialysis should be reserved for life-threatening 
renal failure such as prolonged anuria, hyperkalemia, and profound uremia. 
 
8.8.5. 
Capillary Leak Syndrome and Weight Gain 
Capillary leak syndrome is expected to occur with IL-2 dosing. Resultant intravascular volume 
depletion should be managed with IV fluids. Diuresis should be initiated as tolerated following 
completion of IL-2 dosing. Hypotension not responsive to IV fluids should raise suspicion for 
occult bacteremia and associated sepsis. 
 


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8.8.6. 
Cardiac Arrhythmias and Myocarditis 
All new cardiac arrhythmias should be promptly evaluated and continuously monitored with 
intensive management. 
 
8.8.7. 
Pulmonary 
LN-145 can remain in the pulmonary circulation for 24 to 48 hours following infusion and may 
cause transient shortness of breath. In addition, pulmonary edema is commonly observed with 
IL-2 dosing. Supplemental oxygen may be administered as needed. Subsequent IL-2 dosing 
should be delayed until supplemental oxygen has been weaned or is minimal (< 2 L/min per 
nasal cannula). If hypoxia persists or is significant, IL-2 should be discontinued. 
 
8.8.8. 
Sepsis/Febrile Neutropenia During IL-2 
Sepsis can mimic IL-2 side effects. Fever symptoms may be masked during IL-2 dosing due to 
scheduled indomethacin and acetaminophen. In neutropenic patients exhibiting hypotension or 
oliguria unresponsive to IV fluids, a high degree of suspicion for infection should be entertained 
and broad-spectrum ABX should be initiated. 
 
8.8.9. 
Heparin-Induced Thrombocytopenia 
Heparin-induced thrombocytopenia has been observed with IL-2 administration. To minimize 
this risk, heparin flushes should be avoided or minimized, if possible during IL-2 dosing. 
Refer to interleukin-2/aldesleukin (Proleukin®) current package insert for additional information. 
 
8.9. 
Other Concomitant Medications to Control Side Effects 
 
8.9.1. 
Nausea/Vomiting 
Nausea and vomiting should be controlled with ondansetron or similar medication. Other second- 
and third-line medications (eg, prochlorperazine, promethazine, lorazepam, scopolamine, and 
aprepitant) can be used per local standard institutional guidelines. Steroids, such as 
dexamethasone may be used as an antiemetic only during cyclophosphamide administration but 
should be avoided and only used with intractable nausea and vomiting. Steroids must be 
discontinued a minimum of 3 days prior to administration of LN145. 
 
8.9.2. 
Fever 
Premedication for fever should be initiated as per standard institutional guidelines and may begin 
the night prior to LN-145 administration (Day -1) and continue throughout IL-2 treatment. 
Medications may include indomethacin 50 mg every 8 hours and/or acetaminophen every 4 to 6 
hours. Indomethacin 75 mg may be used for persistently febrile patients. 


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9. 
TUMOR RESPONSE ASSESSMENTS 
 
9.1. 
Response Criteria 
Response assessment will be evaluated using RECIST 1.1 with a modification to require 
confirmation of progressive disease. Refer to Table 3 and Table 4 for RECIST 1.1 response 
criteria definitions [1]. 
9.2. 
Baseline Documentation of “Target” and “Nontarget” Lesions 
Baseline documentation of all lesions will occur on Day -21 to Day -9. Measurable disease is 
defined as the presence of at least one measurable lesion of ≥ 10 mm in diameter by CT scan. 
When > 1 measurable lesion is present at Baseline, all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ system) should be identified as target lesions and 
will be recorded and measured at Baseline. Target lesions should be selected based on their size 
(lesions with the longest diameter) and should be representative of all involved organs. 
Pathological lymph nodes which are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of 
these nodes will contribute to the baseline sum. All other pathological nodes (those with short 
axis ≥ 10 mm but < 15 mm) should be considered nontarget lesions. Nodes that have a short axis 
< 10 mm are considered nonpathological and should not be recorded or followed. 
A sum of diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the Baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is to be added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at Baseline. Measurements are not required, and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.” 
9.3. 
Evaluation of Target Lesions 
This section provides the definition of the criteria used to determine objective tumor response for 
target lesions. 
Table 3: 
Definition of Objective Tumor Response 
Response 
Criteria 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or nontarget) must have a reduction in short axis to < 10 mm). 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameter of target lesions taking as 
reference the baseline sum diameters. 
Response 
Criteria 


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Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as references the smallest sum diameters while on study. 
 
9.4. 
Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of nontarget lesions. While some nontarget lesions may be measurable, they need not be 
measured and instead should be assessed only qualitatively at the time points of radiographic 
assessments. 
Table 4: 
Definition of Nontarget Lesions Response 
Response 
Criteria 
Complete Response (CR) 
Disappearance of all nontarget lesions. All lymph nodes must be nonpathological 
in size (< 10 mm short axis). 
Non-complete Response / 
Non-Progressive Disease 
Persistence of 1 or more nontarget lesion(s). 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. (Note: the appearance of 
one or more new lesions is also considered progression). 
 
9.5. 
Evaluation of New Lesions 
New measurable lesions may be identified if the new lesions meet criteria as defined for Baseline 
target lesion selection and meet the same minimum RECIST 1.1 size requirements of 10 mm in 
long diameter for non-nodal lesions and a minimum of 15 mm in short axis for nodal lesions. 
New measurable lesions shall be prioritized according to size with the largest lesions selected as 
new measured lesions. 
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only unequivocal progression of new non-measurable 
lesions leads to an overall assessment of PD for the time point. 
The finding of a new lesion should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient’s Baseline lesions show PR or CR. 
For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion, which it is not. 


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If a new lesion is equivocal, for example because of its small size, continued therapy and follow- 
up evaluation will clarify if it represents truly new disease. If repeat scans confirm a definite new 
lesion, then progression should be declared using the date of the initial scan. 
9.6. 
Evaluation of Overall Response 
The best overall response for each patient is the best response recorded from the start of 
treatment until disease progression/recurrence, the initiation of subsequent anticancer therapy, 
death, or 36 months after therapy with LN-145 whichever occurs first (taking reference for PD 
the smallest measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria (see 
Section 9.2). The assignment of response for an individual patient, based on both target and 
nontarget lesions, at each assessment time point is shown in Table 5. The best overall response 
for each patient is determined as shown in Table 6. 
Table 5: 
Response at Each Assessment Timepoint for Patients 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response* 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease *If 
the Investigator’s response assessment is difficult to determine due to presence of confounding factors (ie, tumor flare), 
then overall response should be SD until proven otherwise. 
 
 
Table 6: 
Examples of Best Overall Response for Each Patient Across All Assessments 
Overall Response at 
Timepoint 1 
Overall Response at 
Timepoint 2 
Overall Response at 
Timepoint 3 
Best Overall Response 
Across Assessment 
Timepoints 
CR 
CR 
CR 
CR 
PR 
PR 
CR 
PR 
SD 
SD 
PR 
SD 
SD 
PR 
SD 
SD 


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SD 
SD 
PD 
SD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease 
 
 
9.7. 
Confirmation of Tumor Assessments 
 
9.7.1. 
Confirmation of Response (PR or CR) 
Confirmation of response (either PR or CR) is required. Changes in tumor measurements must be 
confirmed by repeat assessments that should be performed ≥ 4 weeks apart after the criteria for 
response are first met. If the confounding factor/tumor flare is considered at subsequent 
assessment points, as the previous assessment was SD or PR, then the response should be SD or 
PR, until proven otherwise. The response assessment should be updated, if needed, based on the 
consecutive observation. ‘Not Evaluable (NE)’ should only be selected if the response was truly 
not evaluable (eg, scan was not done). 
 
9.7.2. 
Confirmation of Progressive Disease 
If PD is assessed, then this must be confirmed by objective measures or symptomatic 
deterioration that was based on other clinical data suggesting clear evidence of disease 
progression. 
For patients with a minimum increase of over 20% in the sum of diameters of target lesions 
taking as reference the smallest sum on study or for nontarget or new non-measurable lesions, a 
confirmation scan is required at least 4 weeks after the first PD assessment. 
 
10. 
ADVERSE EVENTS 
 
Toxicities will be recorded as AEs, AESIand serious adverse events (SAEs) in the patient’s 
source documents and on the AEs eCRF and must be graded using the CTEP Version 5.0 of 
the NCI Common Terminology Criteria for Adverse Events (CTCAE). 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
10.1. 
Adverse Event 
An AE as defined by International Council for Harmonization (ICH)-Good Clinical Practice 
(GCP) is any untoward medical occurrence in a patient or clinical study patient administered a 
medicinal/investigational product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal product, whether considered related to the medicinal/investigational product or not. 
Events meeting the definition of an AE include: 
• 
AEs temporally associated with the use of any of the investigational products or TIL 
treatment whether or not considered related to the use of any of the investigational 
products or TIL treatment 


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• 
Any abnormal laboratory test results (eg, hematology, clinical chemistry, or urinalysis) or 
other assessments (eg, ECGs, radiological scans, vital signs measurements) that are 
abnormal and are considered clinically significant (eg, led to hospitalization or 
prolongation of hospitalization, required change in study treatment, required initiation of 
concomitant therapy or intervention) 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product administration 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction with investigational 
product 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication 
 
• 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition 
• 
Any laboratory abnormal value that has not clinical significance and does not require 
treatment 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that leads to 
the procedure is an AE. Planned elective procedures are not AEs 
• 
Overdose without clinical sequelae (see Section 10.9) 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
10.2. 
Serious Adverse Event 
An AE is considered serious if, in the view of the Sponsor Investigator or Iovance, it results in 
any of the following outcomes: 
• 
Death 
• 
Is life threatening 
• 
In-patient hospitalization or prolongation of an existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
Important medical events: such events may not directly result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based on Sponsor Investigator 


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decision, they may jeopardize the patient and may require intervention to prevent one of the 
above outcomes as listed in this definition. 
Hospitalization including admission to a telemetry unit or intensive care unit specifically for 
administration of study treatment is not considered an SAE. 
Prolongation of admission post IL-2 is not considered an SAE. 
10.3. 
Relationship to the Investigational Product 
The Sponsor 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 investigational product and 
the AE/SAE. The event responds to withdrawal of study treatment (dechallenge) and 
recurs with rechallenge when clinically feasible. 
• 
Probable: There is reasonable causal relationship between the investigational product 
and the AE/SAE. The event responds to dechallenge. 
• 
Possible: There is reasonable causal relationship between the investigational product and 
the AE/ SAE. Dechallenge information is lacking or unclear. 
• 
Not likely: There is temporal relationship to the investigational product 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 investigational product 
administration (too early, or late, or investigational product not administered), or there is 
known causal relationship between the AE/SAE and another drug, concurrent disease, or 
other circumstance. 
 
10.4. 
Severity 
The severity of an event describes the degree of impact and/or the need for medical care 
necessary to treat an event. 
AE grading will be defined by the CTCAE v 5.0. In the event the CTCAE v 5.0 does not apply, 
the severity descriptions below will be used. 
• 
Mild: Asymptomatic; clinical or diagnostic observations only; intervention not indicated. 
• 
Moderate: Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate activities of daily life. 
• 
Severe: Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization may be required; disabling; limiting activities of daily life. 
• 
Life-threatening: Urgent intervention is required. 
• 
Death: When death is the outcome of the AE. 
10.5. 
Reporting Procedures for 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 v5.0. Disease progression is not considered an AE for the 


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purposes of this study. 
AEs will be collected and reported according to the following temporal intervals: 
• 
Signed ICF to tumor resection (SAEs only) 
• 
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-145 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) 
• 
After this period, only SAEs related to LN-145 will be collected and reported 
Medically significant AEs considered related to LN-145 by either the Investigator will be 
reported and followed until resolved or resolved with sequelae. 
If a patient dies while on the study, the Sponsor Investigator will report to Iovance and the 
Data Safety Monitoring Committee (DSMC) 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” 
The investigator will be responsible for reporting SAEs to the IRB of record. It will be left to 
the Sponsor 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-145 due to an SAE, this 
information must be included in the initial or follow-up SAE Report Form and in the eCRF. 
10.6. 
Reporting Procedures for Serious Adverse Events 
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. 
Only Grade 3 and Grade 4 AEs and SAEs possibly attributed to study treatment should be 
reported from Day 30 through 6 months post-LN-145 infusion, or the start of a new anticancer 


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therapy, whichever occurs first. After 6 months, only SAEs related to LN-145 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 DSMC and Iovance/designee. 
The Sponsor Investigator will report to Iovance and the FDA as applicable, any SAE that occurs 
during the study. The initial notification should be as complete as possible with the information 
available and include the Investigator’s assessment of study drug relationship. 
Iovance shall have the opportunity to review and comment on the Investigator’s determination as 
to causality and Severity for each AE and shall have the opportunity to submit comments for 
consideration by Investigator in accordance with the contractual agreement between Yale Cancer 
Center and Iovance Biotherapeutics. All AEs, regardless of their severity, will be captured in the 
eCRF. 
SAE terminology and severity grading will be based on the NCI’s CTCAE v5.00 guidelines. 
 
10.7. 
Investigator Communications with Iovance Biotherapeutics 
 The Sponsor Investigator, or designee, will report to Iovance in accordance with the contractual 
agreement between Yale Cancer Center and Iovance Biotherapeutics. Reports will be sent to 
Iovance Biotherapeutics’ designated mailboxes: 
 
 
10.8. 
Special Situations Reporting 
 
10.8.1. 
Definitions 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. The special situation reports will be reported as an SAE but not considered an AE/SAE 
unless associated with an AE/SAE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal/investigational product while in the control of the health care provider, patient, or 
consumer. 
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal/investigational product given per administration or cumulatively which is above the 
maximum recommended dose as per protocol or in the product labeling (as it applies to the daily 
dose of the patient in question). 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal/investigational product. 
Occupational exposure is defined as the exposure to a medicinal product as a result of one’s 
professional or nonprofessional occupation. 
Special situation reports must be reported to Iovance Biotherapeutics’ designated mailboxes 
iovancesafety@iovance.com and safetyfax@synteract.com 


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using the SAE Report Form within 24 hours of becoming aware of the situation to: 
 
 
10.8.2. 
Procedures for Special Situations 
 
10.8.2.1. 
Pregnancy Reporting 
Any pregnancy that occurs while on the study through 12 months from the last dose of IL-2 or 
until the first dose of the next anti-cancer therapy, whichever occurs first, must be reported using 
the Pregnancy Report form within 24 hours of becoming aware of the pregnancy. The pregnancy 
itself is not considered an AE nor is an induced abortion to terminate a pregnancy without 
medical reasons. Any premature termination of pregnancy (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 10.7. 
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 to Iovance Biotherapeutics’ designated mailboxes using the Pregnancy Outcome form. Any 
SAE occurring in association with a pregnancy, brought to the Sponsor Investigator’s attention 
after the patient has completed the study treatment and post-treatment follow-up visits, must be 
promptly reported to Iovance or their representative. 
The pregnancy must be followed up until discharge following delivery or premature termination 
to determine outcome and status of mother and child. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must 
be reported as an SAE. Any SAE occurring in association with a pregnancy, brought to the 
Sponsor Investigator’s attention after the patient has completed the study and considered by the 
Sponsor Investigator as possibly related to the investigational product, must be promptly 
reported to Iovance 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 using the Pregnancy and Pregnancy 
Outcome forms within 24 hours. Monitoring of the female partners should continue until the 
conclusion of the pregnancy. 
10.8.2.2 Adverse Events of Uveitis Special Interest Reporting 
AEs of uveitis is considered as AESI, must be recorded in the eCRFs and reported to the 
sponsor or designee within 24 hours of the study personnel’s discovery of the event, even if 
they are considered nonserious according to the usual regulatory criteria. The investigator must 
follow any patient experiencing uveitis until resolution or stabilization of the event, an 
alternative explanation other than study intervention is provided for the event, or the patient is 
lost to follow-up. The Sponsor investigator should submit any further details obtained from 
follow-up to the sponsor within 24 hours of it becoming available. 
 
 
iovancesafety@iovance.com and safetyfax@synteract.com 


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10.9. 
Study Halting Rules 
The study may be stopped following review of the safety data by the Yale Cancer Center DSMC 
according to their normal procedures. 
10.10. 
Regulatory Reporting Requirements 
AEs classified as “serious” and “unexpected” that are possibly, probably, or definitely attributed 
to drug administration (suspected unexpected serious adverse reaction [SUSAR]), or SAEs 
whose frequency exceeds expectations, require expeditious handling and reporting. 
Within 24 hours of awareness of an AE deemed serious, unexpected and related to LN-145, the 
Sponsor Investigator will promptly investigate all safety information related to the adverse event 
and will promptly discuss the event details with Iovance Biotherapeutics for comments. The 
Sponsor Investigator will review Iovance’ s comments and shall provide such comments to the 
IRB of record. Any updated information shall be submitted by the Sponsor Investigator as a 
follow-up SAE report. 
The Sponsor Investigator is the Sponsor of this study and is responsible for expedited reporting 
to regulatory agencies. 
If the results of the Sponsor Investigator’s investigation show an adverse drug experience not 
initially determined to be reportable (based on whether the event is serious, unexpected, and 
associated with drug administration) is so reportable, the Sponsor Investigator will report such 
experience. Follow-up information to a safety report shall be submitted as soon as the relevant 
information is available. 
Final assessment of expectedness for SAEs will be determined by the Sponsor Investigator 
using reference safety information in the IB, comments from Iovance and relevant 
prescribing information, as applicable. 
There are two types of expedited safety reports to the FDA: 
1. 7-Calendar-Day FDA Telephone or Fax Report: The Sponsor Investigator will directly 
notify the FDA, within 7 calendar days after his initial receipt of the information, of any 
adverse event that is ALL of the following: 
Death or immediately life-threatening 
Unexpected 
Associated with the use of study drug 
Notification to the FDA will be made directly to the new drug review division in the 
Center for Drug Evaluation and Research or in the product review division for the Center 
for Biologics Evaluation and Research, whichever was responsible for the review of the 
investigational new drug (IND) application. [21CFR312.32(c)] A written report of the 
event is to follow within 15 calendar days. 


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2. 15-Calendar-Day FDA Written Report: The Sponsor investigator will directly notify the 
FDA within 15 calendar days of any adverse event that is ALL of the following: 
Serious (due to non-fatal and non-life-threatening criteria 
Unexpected 
Associated with the use of study drug 
Note: SAEs which do not meet the criteria for expedited reporting will be reported to the FDA in 
the IND Annual Report. 
In addition, the Sponsor investigator must submit expedited reports of potential serious risks 
from clinical studies or any other source based on relevant local legislation or regulations, 
including the applicable US FDA Code of Federal Regulations and relevant updates. The 
Sponsor investigator should notify the IRB of record of SUSAR reports as soon as is 
practical where required by local regulatory agencies and in accordance with the local 
institutional policy. 
10.11. 
Safety Review and Data Safety Monitoring Committee (DSMC) 
The safety parameters will be reviewed on an on-going basis including Grades 3 and 4 AEs, 
SAEs, deaths, TRAEs, AEs that lead to reduced or missed doses of lymphodepletion or IL-2, 
clinical laboratory tests, vital signs, and physical examinations. The expected toxicities of the 
NMA-LD regimen and IL-2 regimens will be closely monitored. 
Safety data in this study will be reviewed by the Yale University DSMC on an ongoing basis to 
identify any potential new safety risks. The DSMC will have authority to suspend the trial. 
The Sponsor Investigator and the Yale University DSMC will review cumulative safety data on 
the first five patients enrolled upon completion of 6 weeks (Day 42) of assessment post- LN-145 
infusion. 
Enrollment will continue while study data are under DSMC review. 
 
10.12 
Data and Safety Monitoring Committee 
 
The Yale Cancer Center (YCC) Data and Safety Monitoring Committee (DSMC) will provide 
the primary oversight of data and safety monitoring. The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Sponsor Investigator. 
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided to 
the committee includes: a study narrative by the PI, a summary DSMC report produced by 
OnCore (which includes participant accrual, response, trial status history, SAEs, adverse 
events, deviations and survival); audit results, and monitoring reports, as applicable. Other 


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information (e.g., scans, laboratory values, etc.) will be provided upon request. Upon 
completing the review, the DSMC will approve whether the study should continue as planned, 
require modification/ amendment, or be placed on administrative hold with accrual temporarily 
suspended. 
Trials being monitored by the YCC DSMC will remain under the YCC DSMC purview until a 
DSMC review has occurred that includes the research activity of the last subject who 
completed the intervention, or until the DSMC feels there are no patient safety concerns that 
require further monitoring. The DSMC will determine the length of continued DSMC review. 
The DSMC has authority to intervene in the conduct of these studies as necessary to ensure the 
safety of the participants and to maintain the highest quality in the clinical research performed 
at YCC. The DSMC has the authority to require additional monitoring and/ or more frequent 
reporting on study progress and serious adverse events. 
 
11. 
STATISTICAL CONSIDERATIONS 
 
11.1. 
Introduction 
The statistical analysis will be based on the use of descriptive methods unless mentioned 
otherwise. Continuous data will be summarized as the number of patients with non-missing data 
(n), mean, standard deviation, median, minimum, and maximum values. Categorical data will be 
summarized as counts and their related percentages, where applicable. Estimation of confidence 
limits will use two-sided, 90% criteria. Missing data will not be imputed unless mentioned 
otherwise. 
All laboratory results will be summarized using descriptive statistics. SAEs will also be 
summarized. A separate safety summary will be provided for patients in the tumor harvested 
(TH) population starting from the tumor resection for 30 days (TH non-treated population) and 
until date of first dose of the study treatment (safety population). 
11.2. 
Study Analysis Sets 
The TH Set is defined as all tumor-resected patients for production of LN-145. The TH 
population is further divided into the efficacy and safety sets for analyses. 
 
11.2.1. 
Safety Analysis Set 
The Safety Analysis Set consists of patients who received LN-145 infusion. 
 
11.2.2. 
Efficacy Analysis Set 
The Efficacy Analysis Set consists of patients in the Safety Analysis set with Baseline 
assessments (Day -21 or Day -9) and at least one post-Baseline radiological assessments. 
Patients who progressed or expired prior to reaching the first radiological assessment will be 
included and considered as non-responders. 
11.3. 
Sample Size Justification 
The planned sample size consists of 10 patients in the efficacy evaluable set. The null hypothesis 


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for this trial is 14% based on the ORR rates for standard of care second line chemotherapy in 
metastatic triple negative breast. A sample size of 10 patients yields over 78% power to test the 
alternative hypothesis of an ORR rate of 35% at one-tailed alpha level of 20%. The sample size 
is based on the number of patients in the efficacy analysis set, consisting of patients who have 
received LN-145 infusion and had at least one post-Baseline radiological assessment. Patients 
who progressed or died prior to reaching the first radiological assessment will be included and 
considered as non-responders. The planned analysis will be conducted when the 10th patient has 
had the opportunity to be followed for a minimum of 3 months. This will allow sufficient time 
for disease-controlled patients (SD or better) to demonstrate extended durability. If the number 
of responding patients is three or greater (out of 10) the lower bound of an 80% one-sided 
confidence interval will exclude the null ORR rate of 14%. 
 
11.4. 
Baseline Demographic and Clinical Characteristics 
Baseline demographic and clinical (disease) characteristics will be summarized descriptively for 
the treated and untreated populations. Age will be derived as a function of the date of informed 
consent. Patients among the resected, untreated population will be summarized by the primary 
reason of not receiving the treatment together with the safety events. 
11.5. 
Study Endpoints and Planned Analyses 
 
11.5.1. 
Primary Endpoints 
The ORR is defined as the proportion of patients who achieve either a confirmed PR or CR as 
best response as assessed by Investigators per RECIST 1.1 among the Efficacy Analysis Set. 
Objective response will be evaluated per each disease assessment and the ORR will be calculated 
with the corresponding 90% two-sided confidence interval. 
The primary safety analysis will be descriptive and based on the summarization of TEAEs, 
including SAEs, AEs leading to discontinuation from the study treatment and efficacy follow-up. 
The treatment-emergent period is defined from LN-145 infusion until 30 days thereafter. AE 
summaries will be based on patient incidence counts and percentages per the Safety Analysis 
Set. In addition to the overall summary of AEs, breakdown summaries will be made by NCI 
CTCAE grade of severity, and relationship to the study treatment 
 
11.5.2. 
Secondary Endpoints 
Additional Measures of Efficacy: 
The secondary efficacy endpoints are defined as follows: 
• 
DOR is measured from the first-time response (PR/CR) criteria are met until the first date 
that recurrent or progressive disease is objectively documented, or receipt of subsequent 
anticancer therapy or the patient expires (whichever is first recorded). Patients not 
experiencing PD or who have not died prior to the time of data cut or the final database 
lock will have their event times censored on the last date that an adequate assessment of 
tumor status is made 
• 
DCR is derived as the sum of the number of patients who achieved confirmed PR/CR or 


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sustained SD (at least 6 weeks) divided by the number of patients in the All Treated 
population x 100% 
• 
PFS is defined as the time (in months) from the time of lymphodepletion to PD, or death 
due to any cause, whichever event is earlier. Patients not experiencing PD or not having 
died at the time of the data cut or the final database lock will have their event times 
censored on the last date that an adequate assessment of tumor status is made 
• 
OS is defined as the time (in months) from the time of lymphodepletion to death due to 
any cause. Patients not having died by the time of data cut or the final database lock will 
have their event times censored on the last date of their known survival status 
• 
CR rate is based on responders who achieved confirmed CR as assessed by the 
Investigators. The CR rate will be summarized using a point estimate and its two-sided 
90% confidence interval (CI) 
• 
DOR, DCR, PFS, and OS will be subjected to right censoring. Kaplan-Meier methods 
will apply 
 
11.5.3. 
Exploratory Endpoints 
• 
Correlations of immune factors with efficacy and safety will be explored. The results will 
be reported in a separate document 
• 
Details of exploratory tissue biomarkers analyses will be provided in a separate report 
• 
Feasibility of generating TIL (LN-145) from patient derived TNBC core biopsy tumor 
specimens using Iovance manufacturing process. analyses will be provided in a separate 
report 
 
12. 
ADMINISTRATIVE PROCEDURES AND STUDY MANAGEMENT 
 
12.1. 
Good Clinical Practice 
It is the responsibility of the Sponsor Investigator to oversee the safety of the patients in the 
study. The Sponsor Investigator will ensure that this study is conducted in full compliance with 
the principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, and 
South Africa), ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted. The Sponsor Investigator will conduct all aspects of the study in 
accordance with applicable country, national, state and local laws of the pertinent regulatory 
authority. All Investigators will ensure adherence to ICH guidelines for GCP and Clinical 
Safety Data Management. 
By signing the US FDA Form 1572, “Statement of Investigator,” the Investigator commits to 
adhere to applicable sections of the US Code of Federal Regulations (CFR) parts 50 “Protection 
of Human Patients,” 54 “Financial Disclosure by Clinical Investigators,” 56 "Institutional 
Review Boards,” and 312 subpart D “Responsibilities of Sponsors and Investigators.” 
12.2. 
Institutional Review Board (IRB) Approval 
The Investigator shall assure that the IRB of record provides initial and continuing review of the 
study according to local policy. Prior to screening and enrollment of study patients, documented 


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IRB approval of the protocol, ICF and any patient materials, must be obtained. 
12.3. 
Protocol Modifications 
Protocol amendments should not be implemented without prior regulatory submission and IRB 
approval, except where necessary to eliminate immediate hazards to the patients or when the 
change(s) involves only logistical or administrative aspects of the study (eg, change in 
monitor[s], change of telephone number[s]). 
12.4. 
Record Retention 
In compliance with the ICH/GCP guidelines, the Sponsor Investigator will be responsible for 
all information in the eCRF and will maintain the source documents that support the data 
collected from each patient, and all study documents as specified in Essential Documents for 
the Conduct of a Clinical Trial and as specified by the applicable regulatory requirement(s). 
The Sponsor Investigator will take measures to prevent accidental or premature destruction of 
these documents. Essential documents must be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with Iovance. It is the responsibility of Iovance to inform the 
Sponsor Investigator/institution as to when these documents no longer need to be retained. If 
the Sponsor 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. Iovance must be notified in writing 
of the name and address of the new custodian. 
12.5. 
Data Quality Assurance 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 2008) and all revisions thereof, and in accordance with FDA regulations (21 CFR Parts 
11, 50, 54, 56, and 312, Subpart D: Responsibilities of Sponsors and Investigators) and with the 
ICH guidelines on GCP (ICH E6 R2). 
Steps to be taken to assure the accuracy and reliability of data include; the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the Investigator 
and associated personnel prior to the study, periodic monitoring visits by the Sponsor 
Investigator or designee and direct transmission of clinical study data into the database. 
. On-site audit representatives of Iovance 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 eCRF. Patient privacy must, however, be respected. Prior notice will be 
provided to allow the Sponsor Investigator to prepare properly for the audit. 
12.6. 
Data Processing and Recordkeeping 
 
12.6.1. 
Electronic Data 


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When using electronic data processing, the Sponsor Investigator will ensure that systems 
comply with 21 CFR Part 11, CTR EU No. 536/2014 and General Data Protection Regulation 
(GDPR) EU 2016/679 requirements, as applicable. Documentation regarding the electronic data 
systems used in this protocol is described in the relevant study-specific plans or standard 
operating procedures. 
 
12.6.2. 
Electronic Case Report Form Completion 
Electronic data capture 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 in the eCRFs in English. The eCRFs are to be completed at the time of the patient's 
visit. Tests performed outside the Sponsor Investigator's office may be used, provided that the 
tests are done within the window dictated by the protocol. 
All eCRF corrections are to be made by the Sponsor Investigator or other authorized study site 
personnel. The Sponsor Investigator must authorize changes to the recorded safety and efficacy 
data and changes must reflect in source documents. 
 
12.7. 
Study Monitoring 
In accordance with 21 CFR Part 312.56, a clinical monitor will periodically inspect eCRF, study 
documents, research facilities, and clinical laboratory facilities associated with this study at 
mutually convenient times during and after completion of the study. As required by 21 CFR Part 
312, Subpart D: Responsibilities of Sponsors and Investigators, the monitoring visits provide the 
Principal Investigator with the opportunity to evaluate the progress of the study; verify the 
accuracy and completeness of eCRF against source documentation; ensure that all protocol 
requirements, applicable to FDA regulations, and Investigator’s obligations are being fulfilled; 
and resolve any inconsistencies in the study records. This includes inspection of all documents 
and records related to the study that are required to be maintained by the Investigator, including 
but not limited to medical records (office, clinic, or hospital) and investigational pharmacy 
records for the patients participating in this study. The names and identities of all research 
patients will be kept in strict confidence and will not appear on eCRF or other records provided 
to or retained by the Sponsor-Investigator. Regulations also require the Investigator to allow 
authorized representatives of Yale Cancer Center, Iovance, the FDA or Regulatory Authorities to 
inspect and make copies of the same records. The Investigator should immediately notify the 
Principal Investigator and Iovance if they have been contacted by a regulatory agency 
concerning an upcoming inspection. 
12.8. 
Institutional Review Board/Independent Ethics Committee (HIC) 
Before enrollment of patients into the study, as required by Federal regulations (21 CFR 56) and 
international regulations (ie, ICH/GCP Guidelines), the protocol and ICF must be reviewed and 
approved by the IRB of Record. By signing the FDA Statement of Investigator Form 1572, the 
Sponsor Investigator assures that all aspects of the institutional review will be conducted in 
accordance with current federal regulations. A letter documenting IRB approval must be 
received by Iovance before the initiation of the study. Amendments to the protocol will be 
subject to the same requirements as the original protocol. 
 
Reports on, and reviews of, the study and its progress will be submitted to the IRB by the 


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Sponsor Investigator at intervals stipulated in their local policies and guidelines. 
12.9. 
Informed Consent 
Each patient (or a legally authorized representative) preferably gives 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 reviewing IRB of 
Record. 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 Regulation 2016/679 (GDPR), as interpreted by the 
national laws and regulatory bodies. 
At the discretion of the Investigator, and if deemed in the patient’s best interest and approved by 
the IRB of record, the consent form can be sent to the patient by facsimile or email. The consent 
discussions with the study participant or study participant’s legally authorized representative 
may be conducted by telephone or via teleconference systems. After the consent discussion, the 
patient or the study participant's legally authorized representative will sign and date the consent 
form and provide a copy of the document to the study staff by facsimile, scanning the consent 
form and returning a copy through a secure e-mail account, or by mail. An original signed 
consent document must be provided to the study staff at a subsequent study visit or via mail. 
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 that they may withdraw consent to 
participate at any time. They will be told which alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that their records may be examined by competent authorities and authorized persons but 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 or her legally designated representative to consider his or her decision 
to participate in the study. 
In accordance with the Health Insurance Portability and Accountability Act (HIPAA), the written 
ICF must include a patient authorization to release medical information to the Sponsor - 
Investigator or their representative and/or allow the Sponsor -Investigator or their representative, 
Iovance, a regulatory authority, or IRB access to patient’s medical information that includes all 
hospital records relevant to the study, including a patient’s medical history and other data that may 
identify him/her. 
12.10. 
Patient Data Protection 


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The Sponsor Investigator and designees, employees, and agents involved with the study will 
comply with relevant state, federal national and regional regulations relating to the 
confidentiality, privacy, and security of patient’s personal health information. 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 study to Iovance, the IRB 
of Record, FDA, European Medicines Agency (EMA), Regulatory Agencies, or other 
authorized recipients as appropriate for the execution, analysis, review, and reporting of this 
study. Such information shall not be used for any other purposes and will remain confidential. 
Patient will not be individually identified but will be referred to in records by the study-assigned 
number and patient initials (if applicable by local regulations). 
12.11. 
Adverse Event Reporting 
The Sponsor Investigator agrees to report all AEs/AESI//SAEs to Iovance per the Study Order. 
Furthermore, the Investigator is responsible for ensuring that any sub-investigator promptly 
bring AEs/AESI to the attention of the PI. The Sponsor Investigator shall promptly notify 
Iovance of any SAEs or any other information that may affect the safe use of the investigational 
product during the study. The Investigator shall promptly notify the IRB of Record of any 
SAEs, or any other information that may affect the safe use of the investigational product 
during the study as applicable. 
 
12.12. 
Investigator 
The Investigator will permit study-related monitoring, audits, IRB review, and regulatory 
inspections by providing direct access to source data and documents. The Investigator must 
notify Iovance when contacted by a regulatory authority regarding inspection of the study site. 
All required data will be recorded in the eCRF in a timely manner. All eCRF data and periodic 
reports must be submitted to Iovance per the Study Order. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify Iovance to agree upon an acceptable study records storage solution. 
Regulatory authorities will be notified with the appropriate documentation detailing the person to 
whom the responsibility has been transferred. 
12.13. 
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 eCRF or other documents submitted to Iovance, 
patients should not be identified by their names, but by an identification code. The Investigator 
should keep a site enrollment log showing codes, names, and addresses. Documents not for 
submission to Iovance (eg, patients’ written consent forms) should be maintained by the 
Investigator in strict confidence, in accordance with all applicable local and national regulations. 
All information provided to the Investigator prior to the study, as well as all data developed 
during the study, is confidential and remains the property of Iovance. The Investigator agrees 
that no information based on the conduct of this study (including the protocol, the data resulting 
from this study, or the fact that this study is/was conducted) will be released without prior written 
consent of Iovance unless this requirement is superseded by local or national regulations. 


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12.14. 
Publications 
The Sponsor Investigator and Iovance will be responsible for determining when the study results 
should be published. The Investigator shall not submit a publication or abstract to journals or 
professional societies without the prior written approval of Iovance (and vice versa), except as 
permitted by the agreed terms of the Study Order agreement, including after the reporting of the 
results of this study by Iovance. 
12.15. 
Data Sharing 
In accordance with the study order, Iovance, its project monitor(s) and others designated by 
Iovance, at mutually agreeable times during the study or as applicable after completion or early 
termination of the study shall be entitled to (in each case subject to study sites’s generally 
applicable measures for confidentiality, security, and generally applicable premises rules): 
examine and inspect, at regular business hours, study sites facilities being used, or otherwise 
required, for performance of the Study; subject to applicable patient confidentiality 
considerations, inspect, audit, and copy or have copied, all records, data and work product 
relating to the Study conducted under the Study Order; and inspect and make copies of all data 
necessary to confirm that the Study is being or was conducted in conformance with the Study 
Order. 
Yale Cancer Center, through the Sponsor Investigator, shall provide to Iovance interim written 
reports regarding the research, no less than once per calendar quarter, and a draft final written 
study report per the Study Order. Further subsequent development of the final written study 
report will follow the terms specified in Study Order or Strategic Alliance Agreement. 
12.16. 
Use of Stored Specimens 
Research material from patients enrolled on this study will be kept at Yale Cancer Center, 
Iovance or Iovance designated laboratory. De-identified patient material will be shared with 
Iovance for testing during the study. Residual material will be sent to Iovance at the completion 
of the study. 
 
13. 
REFERENCES 
 
1. 
CDC. Available from: https://www.cdc.gov/cancer/breast/statistics/index.htm 
2. 
Dawson, S.J., E. Provenzano, and C. Caldas, Triple negative breast cancers: clinical and 
prognostic implications. Eur J Cancer, 2009. 45 Suppl 1: p. 27-40. 
3. 
Malorni, L., et al., Clinical and biologic features of triple-negative breast cancers in a large 
cohort of patients with long-term follow-up. Breast Cancer Res Treat, 2012. 136(3): p. 795- 
804. 
4. 
Liedtke, C., et al., Response to neoadjuvant therapy and long-term survival in patients with 
triple-negative breast cancer. J Clin Oncol, 2008. 26(8): p. 1275-81. 
5. 
Li, X., et al., Triple-negative breast cancer has worse overall survival and cause-specific 
survival than non-triple-negative breast cancer. Breast Cancer Res Treat, 2017. 161(2): p. 
279-287. 
6. 
Cortazar, P., et al., Pathological complete response and long-term clinical benefit in breast 


Yale Cancer Center Protocol v8.0 
 
Confidential and Proprietary                                                Page 73 of 89 
 
cancer: the CTNeoBC pooled analysis. Lancet, 2014. 384(9938): p. 164-72. 
7. 
Citron, M.L., et al., Randomized trial of dose-dense versus conventionally scheduled and 
sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment 
of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and 
Leukemia Group B Trial 9741. J Clin Oncol, 2003. 21(8): p. 1431-9. 
8. 
Jones, S., et al., Docetaxel With Cyclophosphamide Is Associated With an Overall Survival 
Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US 
Oncology Research Trial 9735. J Clin Oncol, 2009. 27(8): p. 1177-83. 
9. 
Sparano, J.A., et al., Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J 
Med, 2008. 358(16): p. 1663-71. 
10. Masuda, N., et al., Adjuvant Capecitabine for Breast Cancer after Preoperative 
Chemotherapy. N Engl J Med, 2017. 376(22): p. 2147-2159. 
11. Breast Cancer 3.2018. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. 
12. Gobbini, E., et al., Time trends of overall survival among metastatic breast cancer patients 
in the real-life ESME cohort. Eur J Cancer, 2018. 96: p. 17-24. 
13. Schmid, P., et al., Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast 
Cancer. N Engl J Med, 2018. 379(22): p. 2108-2121. 
14. Robson, M., et al., Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA 
Mutation. N Engl J Med, 2017. 377(6): p. 523-533. 
15. Litton, J.K., et al., Talazoparib in Patients with Advanced Breast Cancer and a Germline 
BRCA Mutation. N Engl J Med, 2018. 379(8): p. 753-763. 
16. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of 
cancer with tumor- infiltrating lymphocytes. Science. 1986;233(4770):1318-21. 
 
17. Vose BM, Moore M. Human tumor-infiltrating lymphocytes: a marker of host response. 
Semin Hematol. 1985;22(1):27-40. 
18. Yron I, Wood TA, Jr., Spiess PJ, Rosenberg SA. In vitro growth of murine T cells. V. The 
isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol. 
1980;125(1):238-45. 
19. Haanen JB, Baars A, Gomez R, Weder P, Smits M, de Gruijl TD, et al. Melanoma-specific 
tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict 
survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother. 
2006;55(4):451-8. 
20. Ladanyi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, et al. Density of DC-LAMP(+) 
mature dendritic cells in combination with activated T lymphocytes infiltrating primary 
cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol 
Immunother. 2007;56(9):1459-69. 
21. Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, et al. 
Tumorinfiltrating lymphocyte grade is an independent predictor of sentinel lymph node 
status and survival in patients with cutaneous melanoma. J Clin Oncol. 2012;30(21):2678- 


Yale Cancer Center Protocol v8.0 
 
Confidential and Proprietary                                                Page 74 of 89 
 
83. 
22. Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, et al. Immunotype 
and immunohistologic characteristics of tumor-infiltrating immune cells are associated with 
clinical outcome in metastatic melanoma. Cancer Res. 2012;72(5):1070-80. 
23. Horne ZD, Jack R, Gray ZT, Siegfried JM, Wilson DO, Yousem SA, et al. Increased levels 
of tumor- infiltrating lymphocytes are associated with improved recurrence-free survival in 
stage 1A non-small-cell lung cancer. J Surg Res. 2011;171(1):1-5. 
24. Kilic A, Landreneau RJ, Luketich JD, Pennathur A, Schuchert MJ. Density of 
tumorinfiltrating lymphocytes correlates with disease recurrence and survival in patients 
with large non-small-cell lung cancer tumors. J Surg Res. 2011;167(2):207-10. 
25. Liu H, Zhang T, Ye J, Li H, Huang J, Li X, et al. Tumor-infiltrating lymphocytes predict 
response to chemotherapy in patients with advance non-small cell lung cancer. Cancer 
Immunol Immunother. 2012;61(10):1849-56. 
26. Ruffini E, Asioli S, Filosso PL, Lyberis P, Bruna MC, Macri L, et al. Clinical significance 
of tumor- infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg. 2009;87(2):365-71; 
discussion 71-2. 
27. Hagemann AR, Hagemann IS, Cadungog M, Hwang WT, Patel P, Lal P, et al. Tissue-based 
immune monitoring II: multiple tumor sites reveal immunologic homogeneity in serous 
ovarian carcinoma. Cancer Biol Ther. 2011;12(4):367-77. 
28. Milne K, Alexander C, Webb JR, Sun W, Dillon K, Kalloger SE, et al. Absolute lymphocyte 
count is associated with survival in ovarian cancer independent of tumor-infiltrating 
lymphocytes. J Transl Med. 2012;10:33. 


Yale Cancer Center Protocol v8.0 
 
Confidential and Proprietary                                                Page 75 of 89 
 
 
29. Webb JR, Milne K, Watson P, Deleeuw RJ, Nelson BH. Tumor-infiltrating lymphocytes 
expressing the tissue resident memory marker CD103 are associated with increased survival 
in high-grade serous ovarian cancer. Clin Cancer Res. 2014;20(2):434-44. 
30. Wang J, Jia Y, Wang N, Zhang X, Tan B, Zhang G, et al. The clinical significance of 
tumorinfiltrating neutrophils and neutrophil-to-CD8+ lymphocyte ratio in patients with 
resectable esophageal squamous cell carcinoma. J Transl Med. 2014;12:7. 
31. Luen SJ, Salgado R, Fox S, Savas P, Eng-Wong J, Clark E, et al. Tumour-infiltrating 
lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo 
in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA 
study. Lancet Oncol. 2017;18(1):52-62. 
32. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, et al. Association between 
CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 
2014;25(8):1536-43. 
33. Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, Kazkaz GA. The prognostic value of 
tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. Breast 
Cancer Res Treat. 2014;148(3):467-76. 
34. Cormier JN, Hijazi YM, Abati A, Fetsch P, Bettinotti M, Steinberg SM, et al. 
Heterogeneous expression of melanoma-associated antigens and HLA-A2 in metastatic 
melanoma in vivo. Int J Cancer. 1998;75(4):517-24. 
35. Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO. CD8+ lymphocyte 
infiltration is an independent favorable prognostic indicator in basal-like breast cancer. 
Breast Cancer Res. 2012;14(2):R48. 
36. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. 
Tumorinfiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin 
Oncol. 2011;29(15):1949-55. 
37. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. The prognostic 
significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat. 
2012;132(2):545-53. 
38. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. Tumour-infiltrating 
macrophages and clinical outcome in breast cancer. J Clin Pathol. 2012;65(2):159-63. 
39. West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, et al. Tumour-infiltrating 
FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical 
outcome in oestrogen receptor-negative breast cancer. Br J Cancer. 2013;108(1):155-62. 
40. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict clinical 
outcome. Science. 2006;313(5795):1960-4. 
41. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. Towards the 
introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol. 
2014;232(2):199-209. 


Yale Cancer Center Protocol v8.0 
 
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42. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector 
memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 
2005;353(25):2654-66. 
43. Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ 
cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. 
J Clin Oncol. 2009;27(35):5944-51. 
44. Shen Z, Zhou S, Wang Y, Li RL, Zhong C, Liang C, et al. Higher intratumoral infiltrated 
Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in 
resectable gastric cancer. J Cancer Res Clin Oncol. 2010;136(10):1585-95. 
45. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. 
Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in 
human cancer. Immunity. 2013;39(4):782-95. 
46. Mlecnik B, Bindea G, Angell HK, Sasso MS, Obenauf AC, Fredriksen T, et al. Functional 
network pipeline reveals genetic determinants associated with in situ lymphocyte 
proliferation and survival of cancer patients. Sci Transl Med. 2014;6(228):228ra37. 
47. Stoll G, Enot D, Mlecnik B, Galon J, Zitvogel L, Kroemer G. Immune-related gene 
signatures predict the outcome of neoadjuvant chemotherapy. Oncoimmunology. 
2014;3(1):e27884. 
48. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique 
subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth 
factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res. 
2007;13(15 Pt 1):4345-54. 
49. Martin-Orozco N, Li Y, Wang Y, Liu S, Hwu P, Liu YJ, et al. Melanoma cells express 
ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res. 
2010;70(23):9581-90. 
50. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B 
and perforin are important for regulatory T cell-mediated suppression of tumor clearance. 
Immunity. 2007;27(4):635-46. 
51. Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, et al. Mining exomic 
sequencing data to identify mutated antigens recognized by adoptively transferred 
tumorreactive T cells. Nat Med. 2013;19(6):747-52. 
52. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy 
based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 
2014;344(6184):641-5. 
53. Kvistborg P, van Buuren MM, Schumacher TN. Human cancer regression antigens. Curr 
Opin Immunol. 2013;25(2):284-90. 
54. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, et al. Tumor 
exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive 
melanoma. J Clin Oncol. 2013;31(32):e439-42. 


Yale Cancer Center Protocol v8.0 
 
Confidential and Proprietary                                                Page 77 of 89 
 
 
55. Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, Danforth DN, et al. 
Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before 
Adoptive Transfer of Tumor- Infiltrating Lymphocytes for Patients With Metastatic 
Melanoma. J Clin Oncol. 2016;34(20):2389-97. 
56. Stanton, S.E. and M.L. Disis, Clinical significance of tumor-infiltrating lymphocytes in 
breast cancer. J Immunother Cancer, 2016. 4: p. 59. 
57. Ono, M., et al., Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant 
chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat, 2012. 132(3): p. 
793-805. 
58. Denkert, C., et al., Tumor-associated lymphocytes as an independent predictor of response 
to neoadjuvant chemotherapy in breast cancer. J Clin Oncol, 2010. 28(1): p. 105-13. 
59. Denkert, C., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant 
chemotherapy with or without carboplatin in human epidermal growth factor receptor 
2positive and triple-negative primary breast cancers. J Clin Oncol, 2015. 33(9): p. 983-91. 
60. Wimberly, H., et al., PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes 
and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunol Res, 2015. 
3(4): p. 326-32. 
61. Rody, A., et al., A clinically relevant gene signature in triple negative and basal-like breast 
cancer. Breast Cancer Res, 2011. 13(5): p. R97. 
62. Iwamoto, T., et al., Gene pathways associated with prognosis and chemotherapy sensitivity 
in molecular subtypes of breast cancer. J Natl Cancer Inst, 2011. 103(3): p. 264-72. 
63. Loi, S., et al., Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase 
III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the 
addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J 
Clin Oncol, 2013. 31(7): p. 860-7. 
64. Adams, S., et al., Prognostic value of tumor-infiltrating lymphocytes in triple-negative 
breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and 
ECOG 1199. J Clin Oncol, 2014. 32(27): p. 2959-66. 
65. Lee, H.J., et al., Expansion of tumor-infiltrating lymphocytes and their potential for 
application as adoptive cell transfer therapy in human breast cancer. Oncotarget, 2017. 
8(69): p. 113345-113359. 
66. Zacharakis, N., et al., Immune recognition of somatic mutations leading to complete durable 
regression in metastatic breast cancer. Nat Med, 2018. 24(6): p. 724-730. 
67. Stevanovic S, Pasetto A, Helman SR, et al. Landscape of immunogenic tumor antigens in 
successful immunotherapy of virally induced epithelial cancer. Science 2017;356:200-5. 
68. Besser MJ, Shapira-Frommer R, Treves AJ, et al. Minimally cultured or selected autologous 
tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in 
metastatic melanoma patients. J Immunother 2009;32:415-23. 


Yale Cancer Center Protocol v8.0 
 
Confidential and Proprietary                                                Page 78 of 89 
 
 
69. Zarogoulidis P, Kerenidi T, Huang H, Kontakiotis T, Tremma O, Porpodis K, Kalianos A, 
Rapti A, Foroulis C, Zissimopoulos A, Courcoutsakis N, Zarogoulidis K. Six minute 
walking test and carbon monoxide diffusing capacity for non-small cell lung cancer: easy 
performed tests in every day practice. J Thorac Dis. 2012;4(6):569-76. doi: 
10.3978/j.issn.20721439.2012.08.18. PubMed PMID: 23205280; PMCID: PMC3506801. 
70. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and 
antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. 
Trends in immunology. 2005 Feb;26(2):111-7. PubMed PMID: 15668127. Pubmed Central 
PMCID: 1388277. 
71. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable 
complete responses in heavily pretreated patients with metastatic melanoma using T-cell 
transfer immunotherapy. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2011 Jul 01;17(13):4550-7. PubMed PMID: 21498393. 
Pubmed Central PMCID: PMC3131487. 
72. Jyothi Sethuraman, Joy Prewitt, Alexis Hutchinson, Laurelis Santiago, Jie Qing Chen, 
Zhimin Dai, Ian Frank, Seth Wardell, James Bender, Michael T Lotze. Successful 
Expansion and Characterization of Tumor Infiltrating Lymphocytes (TILs) from 
Nonmelanoma Tumors. Poster presented at: Society for Immunotherapy of Cancer; 
November 9-13, 2016; National Harbor Maryland, USA. 


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Baseline (Day -21 to Day -9)- 
14. 
APPENDICES 
14.1. 
Schedule of Assessments 
Treatment Perioda 
(Day-7 to Last Dose of IL-2 [ie, not specifically to Day 4]) 
Assessment b 
Screeni 
ng & 
Enroll 
ment 
Period a 
Assessment Perioda 
After TIL Infusion on Day 0 to EOA 
EOAa 
LTFUa 
 
 
 
 
 
Month 6/Week 24 (± 1 Week) 
and Every 3 Months 
Thereafter until EOA 
Disease Progression or 
New Therapy 
Informed consent 
X 
Confirmation of diagnosis 
X 
Inclusion/Exclusionb 
X 
X 
Demographics 
X 
Medical history 
X 
Physical examinationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, weighte 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry and LFTsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HLA Typing 
X 
Thyroid panelg 
X 
X 
X 
Hematologyh 
X 
X 
X 
X 
if clinically indicated 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Coagulation panel i 
X 
Urinalysis j 
X 
X 
X 
X
if clinically indicated 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calculated creatinine clearance 
k 
X 
X 
Treatment Period a 
(Day-7 to Last Dose of IL-2 [ie, not specifically to Day 4]) 
Assessment b 
Screening & Enrollment 
Period a 
Assessment Period a 
After TIL Infusion on Day 0 to EOA 
EOAa 
LTFUa 
 
 
Baseline (Day -21 to Day -9)- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6/Week 24 (± 1 Week) 
and Every 3 Months 
Thereafter until EOA 
ß-HCG pregnancy test l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV, EBV, HIV, HBsAg, 
anti- 
HBc, anti-HCV, Syphilis, 
HSVm 
X 
PD-L1 status n 
X 
ECG o 
X 
X 
ECHO or MUGA stress test p 
X 
Pulmonary function tests q 
X 
Radiographic imaging CT – 
chest, abdomen, pelvis; MRI – 
brain r 
X 
X 
X 
X 
X 
X 
X 
Tumor harvest s 
X 


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Biopsy tissue sample 
(biomarkers) t 
X 
 
Optional TIL growth from 
Core 
Biopsy Sub Study 
X 
Optional post-treatment (Post 
TIL 
LN-145) biopsy u 
X 
Authorization for NMA-LDv 
X 
Hospitalization 
X 
X 
X 
X 
Cyclophosphamide 60 mg/kg 
X 
X 
Mesna 60 mg/kg 
X 
X 
Fludarabine 25 mg/m2/day 
X 
X 
X 
X 
X 
LN-145 infusion w 
X 
 
Treatment Period a 
(Day-7 to Last Dose of IL-2 [ie, not specifically to Day 4]) 
Assessment b 
Screening & 
Enrollment 
Period a 
Assessment Period a 
After TIL Infusion on Day 0 to EOA 
EOA a LTFUa 
 
 
Baseline (Day -21 to Day -9)- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6/Week 24 (± 1 Week) 
and Every 3 Months 
Thereafter until EOA 
IL-2 600,000 IU/kg x 
X 
X 
X 
X 


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Pulse Oximetryy 
X 
X 
X 
X 
Filgrastim z 
X 
X 
X 
SMX-TMP DS, or appropriate 
ABX aa 
X 
Fluconazole bb 
X 
Valacyclovir/acyclovir cc 
X 
Immune Monitoring (blood sample 
collection) dd 
X 
X 
X 
X 
X 
Assessment of AE/SAEs ee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Response assessment 
X 
X 
X 
X 
X 
Telephone contact ff 
X 
ABX = antibiotic; AE = adverse event; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; ß-HCG = beta human chorionic gonadotropin; CMV = 
cytomegalovirus; CT = computed tomography; EBV = Epstein-Barr virus; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic case report form;; EOA=End of Assessment; EOS = end of study; FFPE = formalin-fixed paraffin-embedded; HBc = hepatitis B core antigen; HBsAg = 
hepatitis B virus surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus;; HPV = human papilloma virus;; HSV = herpes simplex virus; ICF = informed 
consent form; IHC = immunohistochemistry; IL-2 = interleukin-2; LFTs = liver function tests; LTFU = long-term follow-up; LVEF = left ventricular ejection fraction; MRI = 
magnetic resonance imaging; MUGA = multi- gated acquisition; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events; NMA-LD = 
nonmyeloablative-lymphodepletion; ; OS = overall survival; PD = progressive disease; PD1 = programmed cell death; PET = positron emission tomography; PJP = Pneumocystis 
jiroveci pneumonia; Q3W = every 3 weeks; ; RECIST = Response Evaluation Criteria in Solid Tumors; RPR = rapid plasma reagin; SAE = serious adverse event; SMX-TMP 
DS = sulfamethoxazole and trimethoprim double strength; TIL = tumor infiltrating lymphocytes; TSH = thyroid-stimulating hormone; 
 
a. 
All visits preceding LN-145 infusion (Day 0) are calculated going backwards (eg, Day -1, Day -2, Day -3, …Day -7, etc.), and all visits following LN-145 infusion (Day 
0) are calculated going forward from Day 0 (eg, Day 1, Day 2, Day 3…Day 28, etc.). The treatment period lasts from Day -7 to the last dose of IL-2. D4 assessments may 
not be performed if the last day of IL-2 is on D3The maximum duration for IL-2 is six doses from Days 0 to 4. The assessment period begins after TIL infusion on Day 0 
and ends at disease progression, the start of a new anticancer therapy, or Month 36, whichever occurs first – this is EOT The LTFU period begins after the assessment 
period ends and stops at the EOS, where EOS = death, lost to follow-up, withdrawal of consent, study termination by Sponsor/Investigator, or Month 36, whichever 
occurs first. 
b. 
A re-check of inclusion/exclusion criteria at Baseline (Day -21 to Day -9) must be performed to ensure that patient performance status and eligibility criteria have not 
changed after Screening. 
c. 
Physical examination (PE) to include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory system, skin, and 
psychiatric (mental status). Height will be recorded at Screening only. Body surface area (BSA) and body mass index (BMI) will be calculated at Day -7 only. Physical 
examinations conducted after Day 14 will be symptom-directed. Clinically significant changes should be recorded as AEs. 
d. 
All medications, therapies, or interventions, including those that are part of the tumor resection procedure received by the patient at any time during the study must be 
recorded and entered into the eCRF. 
e. 
Vital signs will include: weight, pulse rate, respiratory rate, blood pressure, and temperature. On Day 0 (LN-145 infusion), vital signs will be taken pre-infusion, every 15 


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minutes during infusion and then every 30 minutes for 2 hours post infusion or until stable. Serum chemistry and liver function tests will be performed for the following 
parameters: sodium, potassium, chloride, total CO2 (bicarbonate), creatinine, glucose, blood urea nitrogen, albumin, calcium, magnesium, phosphorus, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, lactate dehydrogenase, total protein, total creatine kinase, uric acid, 
amylase, and reflex lipase. 


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f. 
Thyroid panel will include TSH and free T4. Obtain only at Screening, Day 14, and EOA visit, also at any visit as clinically indicated. h. 
Complete blood count 
with differential is to be performed. 
i. 
Coagulation panel including prothrombin time, activated partial thromboplastin time, and international normalized ratio is to be performed at Screening, and as clinically 
indicated. 
j. 
Dipstick urinalysis with culture to be performed, if indicated. 
k. 
Calculate estimated creatinine clearance using Cockcroft-Gault calculation. 
l. 
Serum ß-HCG pregnancy tests will be performed for women of childbearing potential at Screening, Day -7, Day 0, Day 28, Day 42, Day 84, Day 126 and then at visits 
every 3 months to Week 52 (Month 12) or EOA visit, whichever occurs first, as well as anytime and as clinically indicated. (NOTE: If pregnancy is discovered at any 
point in time during the study, it should be reported immediately). 
m. Infectious disease testing to be performed at Screening and when clinically indicated. 
n. 
A sample of tumor resected for TIL generation will be analyzed locally for PD-L1 status by IHC 
o. 
At Screening and Baseline, ECG (12-lead) to be performed after patient has been supine for at least 3 minutes. If an ECG has been performed within 2 weeks prior to 
Screening, no need to repeat. 
p. 
All patients must have an ECHO or a MUGA at Screening. For patients ≥ 60 years or patients who have a history of ischemic heart disease, chest pain, or clinically 
significant atrial and/or ventricular arrhythmias, a cardiac stress tests must be performed showing LVEF ≥ 45%; and if any wall movement abnormalities are present, they 
must be reversible. 
q. 
Pulmonary evaluation using spirometry will be completed for all patients. Patients who are unable to conduct reliable pulmonary function test measurements due to 
abnormal anatomy may undergo a 6-minute walk test to evaluate pulmonary function. 
r. 
CT scans are required at Screening and Baseline (Day -21 to Day -9). MRI or PET scans will be allowed in lieu of CT scans for patients who have an intolerability to 
contrast media. If scans have been performed within 4 weeks prior to enrollment, these scans can be utilized for Screening. Anatomic regions included in the CT or MRI 
scans (for patients with intolerance to contrast media) should be per disease history and clinical symptoms (repeat the same CT and MRI series for all post-treatment tumor 
assessments [scheduled and unscheduled] as completed at Baseline [Day -21 to Day -9]). Include a neck scan if there is prior or suspected neck disease. The imaging 
modality and anatomic regions assessed must be kept the same for all assessments while on study. At the Investigator’s discretion, the Baseline MRI and CT scans may be 
performed as early as Day -21. Brain MRI should not be repeated at baseline if negative at screening. 
s. 
At least one resectable target lesion to generate TIL of a minimum 1.5 cm in diameter (or aggregate of 1.5 cm if multiple lesions are sampled) post-resection. 
Biopsies from multiple lesions are recommended. 
t. 
Refer to Section 6.21. 
u. 
An optional “post-LN-145 infusion” biopsy will be collected at Week 6 (Day 42), if feasible and if patient consent is provided. See Section 6.22. 
v. 
‘Authorization to Receive Lymphodepletion’ form is to be completed by the Investigator between Day -10 to Day -7 and submitted to Iovance for approval prior to the 
initiation of the NMA-LD preconditioning regimen 
w. TIL LN-145 infusion will be administered no sooner than 24 hours following the last dose of the preparative NMA-LD preconditioning regimen. All visits following TIL 
infusion (Day 0) are calculated from that date. 
x. 
Initiate IL-2 dosing no sooner than 3 hours, but no later than 24 hours after completion of the LN-145 infusion and continue BID for up to the protocol defined maximum 
of six doses of IL-2. IL-2 dosing is allowed for up to 4 days following LN-145 infusion to allow for proper management of IL-2 toxicity, if necessary. y. Pulse oximetry is 
to be conducted during IL-2 administration. 
z. 
Patients will receive filgrastim 5 µg/kg/day (recommended maximum dose of 300 µg/day) subcutaneously daily starting from Day 1 until the ANC is > 1000/mm3 for 3 
consecutive days, or as per standard of care at the treating institution. 
aa. All patients should receive appropriate PJP prophylaxis per institutional standard of care for patients undergoing chemotherapy-induced immunosuppression. Such 
prophylaxis may include any of the following (below) and should begin on or after their first day of chemotherapy, or as the Investigator deems appropriate, and continue 
until the ALC is > 1000 cells/mm3 (approximately 3–6 months), or as per institutional standard of care. One acceptable regimen includes trimethoprim (TMP) and 
sulfamethoxazole (SMX) as double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) (PO) twice daily three times a week on non-consecutive days, 
beginning on the first Monday, Wednesday, or Friday. Pentamidine may be substituted for TMP/SMX DS in patients with sulfa allergies and may be administered either 


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IV or aerosolized monthly using standard doses indicated for PJP prophylaxis. Other appropriate PJP prophylactic agents may be substituted at the discretion of the 
treating Investigator. 
bb. Patients will start fluconazole 400 mg (PO) from Day 1, or when patients become neutropenic, and continue until the ANC is > 1000/mm3. Another suitable fungal 
prophylaxis regimen as per standard of care at the treating institution may also be used for the duration of Grade 3 neutropenia. In patients, positive for HSV, herpes 
prophylaxis should begin by Day 7, or as the Investigator deems appropriate and continue until the ALC is > 1000/mm3 (typically for at least 6 months). 
cc. Patients with positive HSV serology should begin herpes reactivation prophylaxis (typically valacyclovir or acyclovir) by Day 14, or as the Investigator deems 
appropriate, and continue until the ALC is > 1000/mm3 (approximately 3-6 months), or as per institutional standard of care. Other appropriate viral prophylactic agents 
may be substituted at the discretion of the treating Investigator. 
dd. Mandatory peripheral blood will be collected at timepoints of Surgery/Tumor resection, Day 1 for immune monitoring (biomarker analysis). Collection timepoints: 
Week 6 (Day 42), Week 12 (Day 84), Month 6 and Month 12 if patient is able to return to the study site. See Section 6.23 
ee. All AEs for all patients will be assessed as per NCI-CTCAE Version 5.00 during all visits after the ICF is signed. Any events occurring after Screening, but prior to the 
tumor resection will be recorded as medical history in the eCRF, unless the events are related to protocol-mandated procedures and assessments. Any events occurring 
after the tumor resection should be captured as AEs in the eCRF. 
ff. The LTFU period begins after the assessment period ends and stops at the EOS, where EOS = death, lost to follow-up, withdrawal of consent, study termination by 
Sponsor -Investigator, or Month 36, whichever occurs first. Patients will be called every 3 Months (± 3 weeks) after the assessment period until they reach an EOS 
designation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential and Proprietary 
 
10 Aug 2023 


 
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14.2. 
ECOG Performance Status 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, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 


 
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14.3. 
Calculation of BMI, BSA, Practical Weight, and Ideal Body Weight 
Unless otherwise specified in this protocol, actual body weight is used for dose calculations of 
treatment agents. In patients who are determined to be obese (BMI > 35.0 kg/m2), the practical 
weight will be used. 
BMI 
 
 
 
BSA 
BMI = weight (kg)/[height (m)]2 
 
 
BSA = 0.007184 x height (cm)0.725 x weight (kg)0.425 
 
Practical Weight 
Practical body weight (average of the actual weight and ideal body weight) is to be used when 
dosing cyclophosphamide and fludarabine in patients who have a BMI > 35.0 kg/m2. 
Note: Practical weight will NOT be used in the calculation of dose for IL-2. 
Ideal Body Weight 
Female = 45.5 kg + 2.3 (number of inches over 60 inches) 
Example: ideal body weight of 5’3’’female 45.5 + 2.3 x (3) = 57 kg 


 
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14.4. 
Expected Aldesleukin Toxicities and Their Management 
Expected Toxicity 
Expected 
Grade 
Supportive Measures 
Stop Treatmenta 
Chills 
3 
IV Meperidine 25-50 mg, IV q1h, prn 
No 
Fever 
3 
Acetaminophen 650 mg, po, q4h; 
Indomethacin 50-75 mg, po, q8h 
No 
Pruritus 
3 
Hydroxyzine HCL 10-20 mg po q6h, prn; 
Diphenhydramine HCL25-50 mg, po, q4h, prn 
No 
Nausea/ Vomiting/ 
Anorexia 
3 
Ondansetron 8 mg, IV, q8h, prn 
nausea/vomiting 
If Zofran is ineffective: add prochlorperazine 
10 mg IV q6h prn nausea/vomiting. 
If above is ineffective add Lorazepam 0.5 mg 
PO q6h PRN anticipatory nausea or 
Lorazepam 0.5 mg IV q6h PRN for 
anticipatory nausea and unable to take PO. 
No 
Diarrhea 
3 
Loperamide 2 mg, po, q3h, prn; 
Diphenoxylate HCl 2.5 mg and atropine 
sulfate 25 mcg, po, q3h, prn; codeine sulfate 
30 mg, po, q4h, prn 
If above regimen of Loperamide and 
Diphenoxylate/Atropine is ineffective: 
- 
Add loperamide 2mg PO QID PRN 
- 
Add Diphenoxylate 2.5 mg and 
Atropine 25 mcg QID PRN 
If uncontrolled after 
24 hours despite all 
supportive measures 
Malaise 
3 or 4 
Bedrest interspersed with activity 
If other toxicities occur 
simultaneously 
Hyperbilirubinemia 
3 or 4 
Observation 
If other toxicities occur 
simultaneously 
Anemia 
3 or 4 
Transfusion with PRBCs 
If uncontrolled despite all 
supportive measures 
Thrombocytopenia 
3 or 4 
Transfusion with platelets 
If uncontrolled despite all 
supportive measures 
Neutropenia 
4 
Observation 
No 
Edema/Weight gain 
3 
Diuretics prn 
No 


 
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Hypotension 
3 
Fluid resuscitation; Vasopressor support 
If uncontrolled despite all 
supportive measures 
Dyspnea 
3 or 4 
Oxygen or ventilatory support 
If requires ventilatory 
support 
Oliguria 
3 or 4 
Fluid boluses or dopamine at renal doses 
If uncontrolled despite all 
supportive measures 
Increased creatinine 
3 or 4 
Observation 
Yes (grade 4) 
Renal failure 
3 or 4 
Dialysis 
Yes 
Pleural effusion 
3 
Thoracentesis 
If uncontrolled despite all 
supportive measures 
Bowel perforation 
3 
Surgical intervention 
Yes 
Confusion 
3 
Observation 
Yes 
Somnolence 
3 or 4 
Intubation for airway protection 
Yes 
Arrhythmia 
3 
Correction of fluid and electrolyte imbalances; 
chemical conversion or electrical conversion 
therapy 
If uncontrolled despite all 
supportive measures 
Elevated troponin 
levels 
3 or 4 
Observation 
Yes 
Expected Toxicity 
Expected 
Grade 
Supportive Measures 
Stop Treatmenta 
Myocardial 
Infarction 
3 or 4 
Supportive care 
Yes 
Elevated 
transaminases 
3 or 4 
Observation 
For Grade 4 without liver 
metastases 
Electrolyte 
imbalances 
3 or 4 
Electrolyte replacement 
If uncontrolled despite all 
supportive measures