A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN-145/LN-145-S1) for the Treatment of Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: Iovance Biotherapeutics, Inc.

LN-145 
 
Protocol: C-145-03 
 
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CLINICAL PROTOCOL 
A Phase 2 Study to Evaluate the Safety, Tolerability and Efficacy of 
Cell Transfer Therapy Using Autologous Tumor Infiltrating 
Lymphocytes (LN-145) followed by IL-2 in Patients with Recurrent 
and/or Metastatic Squamous Cell Carcinoma of the Head and Neck 
 
PROTOCOL NUMBER:   
C-145-03 
SPONSOR: 
Lion Biotechnologies, Inc. 
112 West 34th Street, 17th Floor 
New York, NY 10120 
ORIGINAL PROTOCOL 
VERSION / DATE: 
Version 1.0; 16 August 2016 
IND NUMBER: 
 
EudraCT NUMBER 
2016-003446-86 
 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of The Sponsor 
or their representative and any unauthorized use or disclosure of such information without 
the prior written authorization of The Sponsor or their representative is expressly prohibited. 
 
 
 

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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Name: 
 
Title: 
Chief Medical Officer 
Address: 
 
Phone: 
 
E-mail: 
 
 
 
 
 

LN-145 
Protocol: C-145-03 
SPONSOR SIGNATURE PAGE 
Protocol Title 
Protocol Number: 
Sponsor: 
Protocol Version and Date: 
Signature 
Lion Biotechnologies. Inc. 
A Phase 2 Study to Evaluate the Safety, Tolerability and Efficacy of 
Cell Transfer Therapy Using Autologous Tumor Infiltrating 
Lymphocytes (LN-145) followed by IL-2 in Patients with Recurrent 
and/or Metastatic Squamous Cell Carcinoma of the Head and Neck 
C-145-03 
Lion Biotechnologies, Inc. 
Version 1.0; 16 August 2016 
 
By my signature, I indicate I have reviewed this protocol and find its content to be acceptable. 
Confidential and Proprietary 
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Version 1.0, Dated 16 August 2016 

LN-145 
 
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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  
A Phase 2 Study to Evaluate the Safety, Tolerability and Efficacy 
of Cell Transfer Therapy Using Autologous Tumor Infiltrating 
Lymphocytes (LN-145) followed by IL-2 in Patients with 
Recurrent and/or Metastatic Squamous Cell Carcinoma of the 
Head and Neck 
Protocol Number:  
 
C-145-03 
Sponsor: 
Lion Biotechnologies, Inc. 
Version / Date of Protocol: 
Version 1.0; 16 August 2016 
 
I agree to conduct the study as detailed in the protocol and in compliance with ICH Guidelines for Good 
Clinical Practice. 
I acknowledge that I am responsible for overall study conduct, and I agree to personally conduct or 
supervise the described clinical study. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study are 
informed about their obligations.  Mechanisms are in place to ensure that site staff receives the 
appropriate information throughout the study. 
 
 
 
Principal Investigator Signature 
 
Date 
 
Principal Investigator Printed Name 
 
Institution 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Study to Evaluate the Safety, Tolerability and Efficacy of Cell Transfer 
Therapy Using Autologous Tumor Infiltrating Lymphocytes (LN-145) followed by 
IL-2 in Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of 
the Head and Neck 
Protocol Number 
C-145-03 
Study Type 
Phase 2  
Indication 
Treatment of recurrent and/or Metastatic Squamous Cell Carcinoma of the Head 
and Neck (HNSCC) 
Investigational 
Agents 
• 
Non-Myeloablative (NMA) lymphodepletion (Cyclophosphamide and 
Fludarabine) 
• 
LN-145:  autologous tumor infiltrating lymphocytes (TILs) derived from 
the patient’s own tumor  
• 
Interleukin-2 
Study Objectives 
Primary Objectives 
• 
To evaluate the safety and tolerability of lymphodepletion, LN-145, and 
IL-2 in patients with recurrent and/or metastatic HNSCC. 
• 
To evaluate the efficacy of therapy using the overall response rate (ORR) 
in patients with recurrent and/or metastatic HNSCC.  
Secondary Objectives 
• 
To evaluate other efficacy parameters such as complete response (CR) 
rate, the duration of response (DOR), progression-free survival (PFS), and 
overall survival (OS) in patients with recurrent and/or metastatic HNSCC.  
Exploratory Objectives 
• 
To explore persistence of TILs and immune correlates of response, 
survival, toxicity of the treatment. 
Number of Study 
Sites 
 Approximately 20 clinical study sites globally. 
Number of 
Planned Patients 
Forty-seven (47) patients completing treatment. Complete treatment is defined 
as successful infusion with non-myeloablative lymphodepletion, followed by LN-
145, then at least one dose of IL-2. 
Duration of 
Participation 
The study will consist of 3 phases: 
• 
Pre-Treatment Phase (approximately 50 days) 
o 
Screening Visit (~28 days) 
o 
Tumor Resection Visit (1 day) 

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o 
LN-145 Pre-Manufacturing period (~21 days) 
• 
Treatment Phase (approximately 92 days) 
o 
NMA lymphodepletion regimen (7 days) 
o 
LN-145 Infusion (1 day) 
o 
IL-2 Infusion (~4 days) and other required concomitant therapies (~80 
days) 
• 
Long Term Follow Up Phase (approximately 588 days) 
o 
Safety and Efficacy evaluations up to Year 2 
Study Design 
This is a Phase 2, multicenter prospective, open label, interventional study 
evaluating adoptive cell therapy (ACT) with autologous TIL infusion (LN-145) 
followed by IL-2 after a non-myeloablative (NMA) lymphodepletion preparative 
regimen.  
Doses and 
Treatment 
Schedule  
NMA Lymphodepletion Regimen – Visits 4 through 10 (Days -7 through -1) 
Cyclophosphamide 60 mg/kg IV with Mesna 15 mg/kg (see Section 5.27.1 for 
drug preparation instructions) infused over 2 hours at Visit 4 (Day -7) and 
Visit 5 (Day -6).  A Mesna infusion will continue at a rate of 3 mg/kg/hour 
over 22 hours after each cyclophosphamide dose.  
• 
Fludarabine 25 mg/ m2 to be given IV over approximately 30 minutes 
once daily for 5 days on Visits 6 through 10 (Days -5 through -1).  
o 
Note:   If the patient’s BMI > 30.0 kg/m2, dosages for 
cyclophosphamide and fludarabine will be calculated using practical 
weight (see Section 16.3 for determination of practical weight). 
• 
Further supportive treatment to prevent infection during neutropenia 
Autologous TILs (LN-145) – Visit 11 (Day 0) 
• 
LN-145 up to 
  
High-dose IL-2– Visits 12 through 15 (Days 1 through 4) 
• 
IL-2 600,000 IU/kg starting approximately 12 to 24 hours after TIL infusion 
and repeated every 8 to 12 hours (as tolerated) for up to 6 doses during 
Visits 12 through 15 (Days 1 through 4) only.  
Inclusion Criteria 
 
To be eligible for the study, Patients must meet ALL of the following criteria prior 
to enrollment in the study: 
1. 
Must be greater than 18 and less than 65 years of age at the time of 
consent. 
• 
Patients greater than or equal to 65 years of age may be allowed in 
the study after discussion between the Principal Investigator and 
Medical Monitor regarding the patient’s ability to tolerate the study 
treatment regimen. 
2. 
Must understand and voluntarily sign an informed consent document 
prior to any study related assessments/procedures being conducted. 

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3. 
Able to adhere to the study visit schedule and other protocol 
requirements. 
4. 
Must have persistent, recurrent or metastatic squamous cell carcinoma, 
histologic documentation of the primary tumor is required via the 
pathology report. Requirements regarding the lesion are as follows: 
• 
CT scans of the head, neck and chest (scans of additional anatomical 
locations with suspected disease may be done as determined by the 
PI) is required and may have been done within 28 days prior to 
screening. 
• 
Patients must have one lesion that is resectable for TIL 
manufacturing. The ideal resected lesion should be least 1.5 cm in 
diameter and no greater than 4.0 cm in diameter after prosection. 
The resection must entail minimal morbidity (as determined by the 
study PI and surgical team). 
5. 
Must have a remaining measurable target lesion as defined by RECIST 
version 1.1 following the surgical resection. 
• 
 Measurable lesions must not have been in a previously irradiated 
field. 
6. 
Must have had at least 1 prior systemic chemotherapeutic regimen for 
management of persistent, recurrent or metastatic carcinoma of the head 
or neck. Patients must not have any curative therapy options, or be 
intolerant of, or decline standard of care therapy for persistent, recurrent 
or metastatic disease. 
7. 
Any prior therapy directed at the malignant tumor, including radiation 
therapy, chemotherapy, biologic/targeted agents and immunologic 
agents must be discontinued at least 21 days prior to tumor resection for 
preparing TIL therapy. 
8. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 or 1. 
9. 
Must meet the following laboratory criteria:  
• 
Absolute neutrophil count (ANC) > 1000/mm3 
• 
Hemoglobin > 8.0 g/dL 
• 
Platelet count > 80,000/mm3 
• 
ALT/SGPT and AST/SGOT < 3.0 x the upper limit of normal (ULN) 
o Patients with liver metastases may have LFT ≤ 3.0 x ULN) 
• 
Calculated creatinine clearance ≥ 50.0 mL/min 
• 
Total bilirubin ≤ 2.0 mg/dL  
o Patients with Gilbert’s Syndrome must have a total bilirubin 
< 3.0 mg/dL.    
10. 
Patients must be seronegative for the HIV antibody, hepatitis B antigen, 

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and hepatitis C antibody or antigen. 
• 
Note: Patients with a positive test for hepatitis B virus surface antigen 
(HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating 
acute or chronic infection may be enrolled if the viral load by PCR is 
undetectable with/without active treatment. 
11. 
Patients must be EBV viral capsid antigen (VCA) IgG positive and/or 
Epstein Barr nuclear antigen (EBNA) IgG positive, and have no clinical 
evidence of active EBV infection. 
12. 
Patients of childbearing potential must be willing to practice an approved 
method of birth control starting at the time of informed consent and for 1 
year after the completion of the lymphodepletion regimen. Patients who 
are of child bearing potential must agree to practice an approved method 
of birth control from the start of the study until one year after the 
completion of all study treatment regimens. 
Approved methods of birth control are as follows: 
• 
Total abstinence 
• 
Hormonal contraception (i.e. birth control pills, injection, implant, 
transdermal patch, vaginal ring) 
• 
Intrauterine device (IUD) 
• 
Tubal Ligation  
• 
Male partner’s vasectomy 
• 
Implantable or injectable contraceptives 
• 
Use of a male or female condom 
• 
Cervical Cap or contraceptive sponge with spermicide 
Exclusion Criteria 
 
Patients who meet ANY of the following criteria will be excluded from the study: 
1. 
Patients who are on a systemic steroid therapy (greater than 10 mg of 
prednisone or equivalent) within 28 days prior to Visit 2.  
2. 
Patients who currently have prior therapy-related toxicities greater than 
Grade 1 according to Common Toxicity Criteria for Adverse Events 
(CTCAE) v4.03; (see Appendix Section 16.4), except for alopecia or vitiligo 
prior to enrollment. 
• 
Note: Patients may have undergone minor surgical procedures not 
involving general anesthesia within three weeks prior to Visit 2 as 
long as all toxicities have recovered to Grade 1 or less or as specified 
in the eligibility criteria.  
3. 
Patients who have had immunotherapy-attributable AE: 
• 
Which led to discontinuation, or   
• 
Have had an ophthalmologic or neurologic AE of any grade, or 
• 
Actively receiving any immunosuppressive agents for the treatment 

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of toxicity related to prior immunotherapy.  
4. 
Patients with documented Grade 2 or greater diarrhea or colitis as a 
result of previous immunotherapy within six months from screening. 
• 
Note: Patients that have a colonoscopy that demonstrates the visual 
appearance of the absence of inflammation are not excluded. 
5. 
History of severe immediate hypersensitivity reaction to 
cyclophosphamide, fludarabine, or IL-2.  
6. 
Patients with active systemic infections, coagulation disorders or other 
active major medical illnesses of the cardiovascular, respiratory or 
immune system. 
7. 
Have any form of primary immunodeficiency, such as severe combined 
immunodeficiency disease or acquired immune deficiency syndrome 
(AIDS).   
8. 
Diagnosis of end-stage renal disorder requiring hemodialysis.  
9. 
Patients who have a left ventricular ejection fraction (LVEF) < 45%.  
10. 
Patients who have a FEV1 (forced expiratory volume in one second) of 
less than or equal to 60 % of normal. 
11. 
Patients with unresolved uveitits. 
12. 
Have had another primary malignancy within the previous 3 years (with 
the exception of a history of 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)  
13. 
Patients who are pregnant or breastfeeding.  
Efficacy 
Assessment 
Response will be determined according to RECIST criteria version 1.1. A 
descriptive summary of the overall response rate (ORR), time to response, and 
progression-free survival (PFS) will be used to determine the potential efficacy of 
LN-145.   
Safety 
Assessment 
Treatment-emergent adverse events (TEAEs), clinical laboratory data assessment, 
and serious adverse events (SAEs) will be evaluated for the duration of the study. 

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Overview of 
Statistical Plan 
The sample size is based on number of patients who receive NMA 
lymphodepletion, LN-145 therapy and at least 1 dose of IL-2.  The Simon’s two-
stage optimal design with one-sided alpha level=0.025 and 80% power is adopted 
for comparing an ORR of 5% versus 20%.  In this study, 15 patients would be 
treated at the first stage and if 1 or fewer patients respond, the study will 
terminate.  Otherwise the study will expand to a total of 47 patients in Stage 2.  
The study would demonstrate that lymphodepletion + LN-145 + IL2 is clinically 
meaningful if 6 or more patients respond in Stages 1 and 2. 
The assessment of safety data will be based on the summarization of treatment-
emergent adverse events (AEs) including, serious AE, AEs leading to 
discontinuation from the study, and clinical laboratory tests. 
The primary efficacy endpoint (ORR) and the secondary endpoint of CR as a best 
overall response (%) will be reported including a 95% confidence interval.  The 
secondary efficacy endpoints (DOR, PFS, and OS) will be summarized by Kaplan-
Meier analyses with estimated means, medians and ranges reported in months.  
DSMB Safety 
Assessments  
The DSMB will evaluate safety data when 3 patients have completed the 
Treatment Phase. Enrollment shall not be halted and will continue while under 
review. Additional evaluations will be specified in the charter. 
Discontinuation 
of Treatment 
The Investigator will document on the appropriate eCRF page the 
reasons/circumstances for discontinuation.  A patient may be removed from 
further study drug administration for the following medical or administrative 
reasons:  
• 
Withdrawal of consent. 
• 
Grade 3 or greater autoimmunity that involves vital organs (heart, 
kidneys, brain, eye, liver, colon, adrenal gland, lungs) with symptoms 
emerging prior to first IL-2 administration.  
• 
Grade 3 or greater allergic reaction including bronchospasm or 
generalized urticaria that does not resolve after medical management in 
the opinion of the investigator.  
• 
Grade 3 or greater toxicity due to IL-2 that does not decrease to Grade 2 
or less within 96 hours of management.   
• 
Pregnancy 
• 
Lost to Follow-up 
 
 
 

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TABLE OF CONTENTS 
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION ............................................................................... 2 
SPONSOR SIGNATURE PAGE .................................................................................................................................. 3 
INVESTIGATOR PROTOCOL SIGNATURE PAGE ........................................................................................................ 4 
PROTOCOL SYNOPSIS ............................................................................................................................................. 5 
TABLE OF CONTENTS ............................................................................................................................................ 11 
LIST OF FIGURES AND TABLES .............................................................................................................................. 15 
LIST OF ABBREVIATIONS ...................................................................................................................................... 16 
1. 
INTRODUCTION ....................................................................................................................................... 18 
1.1. 
HEAD AND NECK CANCER ................................................................................................................................. 18 
1.2. 
ADOPTIVE CELL TRANSFER OF TUMOR-INFILTRATING LYMPHOCYTES AS CANCER IMMUNOTHERAPY ................................ 19 
1.3. 
TILS FOR HEAD AND NECK CANCER .................................................................................................................... 20 
2. 
STUDY DESIGN ........................................................................................................................................ 22 
2.1. 
OVERVIEW ..................................................................................................................................................... 22 
2.2. 
PRODUCTION AND EXPANSION OF TUMOR INFILTRATING LYMPHOCYTES .................................................................... 23 
2.3. 
NON-MYELOABLATIVE (NMA) LYPMPHODEPLETION, TIL AND IL-2 THERAPY.............................................................. 24 
3. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................................................... 25 
3.1. 
STUDY OBJECTIVES .......................................................................................................................................... 25 
3.1.1. 
Primary Objective .............................................................................................................................. 25 
3.1.2. 
Secondary Objective .......................................................................................................................... 25 
3.1.3. 
Exploratory Objectives ...................................................................................................................... 25 
3.2. 
STUDY ENDPOINTS .......................................................................................................................................... 25 
3.2.1. 
Primary Endpoints ............................................................................................................................. 25 
3.2.2. 
Secondary Endpoints ......................................................................................................................... 25 
3.2.3. 
Exploratory Endpoints ....................................................................................................................... 26 
4. 
SELECTION OF PATIENT POPULATION...................................................................................................... 26 
4.1. 
INCLUSION CRITERIA ........................................................................................................................................ 26 
4.2. 
EXCLUSION CRITERIA ........................................................................................................................................ 28 
4.3. 
PATIENT ENROLLMENT AND RE-SCREENING .......................................................................................................... 29 
4.4. 
PATIENT DISCONTINUATION .............................................................................................................................. 29 
5. 
STUDY ASSESMENTS, PROCEDURES AND TREATMENTS .......................................................................... 29 
5.1. 
INFORMED CONSENT ....................................................................................................................................... 29 
5.2. 
INCLUSION/EXCLUSION CRITERIA........................................................................................................................ 29 
5.3. 
DEMOGRAPHIC DATA ....................................................................................................................................... 29 
5.4. 
MEDICAL HISTORY........................................................................................................................................... 29 
5.5. 
DOCUMENTATION OF CONFIRMATION OF DIAGNOSIS ............................................................................................. 29 
5.6. 
DOCUMENTATION OF HPV STATUS ..................................................................................................................... 29 
5.7. 
PHYSICAL EXAMINATION ................................................................................................................................... 30 

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5.8. 
VITAL SIGNS ................................................................................................................................................... 30 
5.9. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ............................................................. 30 
5.10. 
SAFETY BLOOD AND URINE TESTS ....................................................................................................................... 30 
5.11. 
ß-HCG SERUM PREGNANCY TEST ...................................................................................................................... 30 
5.12. 
VIRUS TESTING ............................................................................................................................................... 30 
5.13. 
HUMAN LEUKOCYTE ANTIGEN (HLA) TYPING ....................................................................................................... 31 
5.14. 
HPV SUBTYPE SEROTYPE .................................................................................................................................. 31 
5.15. 
CMV ANTIGEN ASSAY ..................................................................................................................................... 31 
5.16. 
ESTIMATED CREATININE CLEARANCE ................................................................................................................... 31 
5.17. 
EYE EXAM ...................................................................................................................................................... 31 
5.18. 
CARDIAC EVALUATIONS .................................................................................................................................... 31 
5.18.1. 
Stress Thallium .................................................................................................................................. 31 
5.18.2. 
Echocardiogram (ECHO) or Multigated Acquisition Scan (MUGA) .................................................... 31 
5.18.3. 
Electrocardiogram ............................................................................................................................. 31 
5.19. 
PULMONARY FUNCTION TESTS ........................................................................................................................... 32 
5.20. 
COLONOSCOPY ............................................................................................................................................... 32 
5.21. 
TUMOR ASSESSMENTS ..................................................................................................................................... 32 
5.22. 
RESPONSE ASSESSMENTS .................................................................................................................................. 32 
5.23. 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................................................... 32 
5.24. 
ADVERSE EVENTS ............................................................................................................................................ 32 
5.25. 
TUMOR HARVEST FOR TILS ............................................................................................................................... 33 
5.26. 
SIX PARAFFIN EMBEDDED SLIDES FROM RESECTED TUMOR ....................................................................................... 33 
5.27. 
PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FOR GENETIC SEQUENCING ......................................................... 33 
5.28. 
NON-MYELOABLATIVE (NMA) LYMPHODEPLETION REGIMEN .................................................................................. 33 
5.28.1. 
Preparation of Cyclophosphamide .................................................................................................... 33 
5.28.2. 
Preparation of Mesna ........................................................................................................................ 34 
5.28.3. 
Infusion of Cyclophosphamide and Mesna ....................................................................................... 34 
5.28.4. 
Fludarabine ........................................................................................................................................ 34 
5.29. 
LN-145 INFUSION .......................................................................................................................................... 34 
5.29.1. 
Description ........................................................................................................................................ 34 
5.29.2. 
Composition ...................................................................................................................................... 35 
5.29.3. 
Transport ........................................................................................................................................... 35 
5.29.4. 
Receipt at Clinical Site and Administration ....................................................................................... 35 
5.30. 
INTERLEUKIN-2 ............................................................................................................................................... 36 
5.31. 
REQUIRED CONCOMITANT MEDICATIONS ............................................................................................................ 36 
5.31.1. 
TMP/SMX DS ..................................................................................................................................... 36 
5.31.2. 
Filgrastim ........................................................................................................................................... 36 
5.31.3. 
Fluconazole ........................................................................................................................................ 36 
5.31.4. 
Anti-Viral ............................................................................................................................................ 37 

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5.32. 
IMMUNE MONITORING .................................................................................................................................... 37 
6. 
PERMITTED AND PROHIBITED CONCOMITANT MEDICATIONS ................................................................ 37 
6.1. 
PERMITTED MEDICATIONS ................................................................................................................................ 37 
6.2. 
PROHIBITED MEDICATIONS AND PRIOR TREATMENT WASHOUT ............................................................................... 37 
6.2.1. 
Prohibited Medications ..................................................................................................................... 37 
6.2.2. 
Prior Treatment Washout ................................................................................................................. 37 
7. 
EXPECTED TOXICITIES AND THEIR MANAGEMENT ................................................................................... 37 
7.1. 
GENERAL TOXICITY MANAGEMENT ..................................................................................................................... 38 
7.1.1. 
Empiric Antibiotics ............................................................................................................................. 38 
7.1.2. 
Blood Product Support ...................................................................................................................... 38 
7.1.3. 
Renal Toxicity .................................................................................................................................... 38 
7.1.4. 
Infection Prophylaxis ......................................................................................................................... 38 
7.1.5. 
Pneumocystis Jiroveci Pneumonia .................................................................................................... 38 
7.1.6. 
Herpes Virus Prophylaxis ................................................................................................................... 39 
7.1.7. 
Fungal Prophylaxis (Fluconazole) ...................................................................................................... 39 
8. 
COMPLETION/DISCONTINUATION AND WITHDRAWAL OF PATIENTS...................................................... 39 
8.1. 
TREATMENT COMPLETION ................................................................................................................................ 39 
8.2. 
STUDY COMPLETION ........................................................................................................................................ 39 
8.3. 
CRITERIA FOR EARLY TERMINATION FROM STUDY (REMOVAL FROM TREATMENT) ........................................................ 39 
8.4. 
CRITERIA FOR REMOVAL FROM THE LONG TERM FOLLOW-UP PHASE ........................................................................ 40 
8.5. 
STUDY DISCONTINUATION (STUDY OR SITE TERMINATION) ...................................................................................... 40 
9. 
SAFETY ASSESMENTS............................................................................................................................... 41 
9.1. 
DATA SAFETY MONITORING BOARD .................................................................................................................... 41 
9.2. 
CONSIDERATIONS ............................................................................................................................................ 41 
10. 
ADVERSE EVENTS .................................................................................................................................... 42 
10.1. 
DEFINITIONS .................................................................................................................................................. 42 
10.1.1. 
Adverse Event .................................................................................................................................... 42 
10.1.2. 
Serious Adverse Event ....................................................................................................................... 42 
10.2. 
REPORTING PROCEDURES FOR ADVERSE EVENTS ................................................................................................... 43 
10.2.1. 
All Adverse Events ............................................................................................................................. 43 
10.2.2. 
Relationship to Study Drug ................................................................................................................ 44 
10.2.3. 
Severity .............................................................................................................................................. 44 
10.3. 
REPORTING PROCEDURES FOR SERIOUS ADVERSE EVENTS ....................................................................................... 45 
10.3.1. 
Investigator Reporting to Sponsor .................................................................................................... 45 
11. 
EFFICACY ASSESSMENTS .......................................................................................................................... 45 
11.1. 
TUMOR RESPONSE CRITERIA ............................................................................................................................. 45 
11.1.1. 
Evaluation of Target Lesions .............................................................................................................. 46 
11.1.2. 
Evaluation of Non-Target Lesions ...................................................................................................... 46 
11.1.3. 
Determination of Best Response for Each Patient ............................................................................ 46 

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11.2. 
OVERALL RESPONSE RATE (ORR) ....................................................................................................................... 47 
11.3. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE ..................................................................................... 47 
11.3.1. 
Confirmation ..................................................................................................................................... 47 
11.3.2. 
Duration of Overall Response ............................................................................................................ 47 
12. 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 48 
12.1. 
INTRODUCTION ............................................................................................................................................... 48 
12.2. 
ANALYSIS POPULATIONS ................................................................................................................................... 48 
12.3. 
SAMPLE SIZE JUSTIFICATION .............................................................................................................................. 48 
12.4. 
BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS ...................................................................................... 48 
12.5. 
SAFETY AND EFFICACY ANALYSIS......................................................................................................................... 48 
12.5.1. 
Primary Endpoint ............................................................................................................................... 48 
12.5.2. 
Secondary Endpoints ......................................................................................................................... 49 
12.5.3. 
Exploratory Analyses ......................................................................................................................... 49 
13. 
ADMINISTRATIVE REQUIREMENTS .......................................................................................................... 50 
13.1. 
GOOD CLINICAL PRACTICE................................................................................................................................. 50 
13.2. 
PROTOCOL MODIFICATIONS .............................................................................................................................. 50 
13.3. 
REGULATORY DOCUMENTATION ........................................................................................................................ 50 
13.4. 
RECORD RETENTION ........................................................................................................................................ 51 
13.5. 
DATA QUALITY ASSURANCE............................................................................................................................... 51 
13.6. 
DATA HANDLING AND RECORDKEEPING ............................................................................................................... 52 
13.6.1. 
Electronic Data .................................................................................................................................. 52 
13.6.2. 
Electronic Case Report Form (eCRF) Completion .............................................................................. 52 
13.7. 
STUDY COMPLETION/TERMINATION ................................................................................................................... 52 
13.7.1. 
Study Completion .............................................................................................................................. 52 
13.8. 
MONITORING ................................................................................................................................................. 52 
14. 
INVESTIGATOR REGULATORY OBLIGATIONS ........................................................................................... 53 
14.1. 
INSTITUTIONAL REVIEW BOARDS ........................................................................................................................ 53 
14.2. 
INFORMED CONSENT ....................................................................................................................................... 53 
14.3. 
PATIENT DATA PROTECTION .............................................................................................................................. 54 
14.4. 
ADVERSE EVENT REPORTING ............................................................................................................................. 54 
14.5. 
INVESTIGATOR ................................................................................................................................................ 54 
14.6. 
CONFIDENTIALITY ............................................................................................................................................ 54 
14.7. 
PUBLICATIONS ................................................................................................................................................ 55 
15. 
REFERENCES ............................................................................................................................................ 56 
16. 
APPENDICIES ........................................................................................................................................... 64 
16.1. 
SCHEDULE OF ASSESSMENTS .............................................................................................................................. 64 
16.2. 
ECOG PERFORMANCE STATUS SCALE ................................................................................................................. 68 
16.3. 
CALCULATION OF BMI, BSA AND PRACTICAL WEIGHT ........................................................................................... 68 
16.3.1. 
BMI .................................................................................................................................................... 68 

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16.3.2. 
BSA .................................................................................................................................................... 68 
16.3.3. 
Practical Weight ................................................................................................................................ 68 
16.4. 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................................................................................... 69 
16.5. 
EXPECTED TOXICITIES ....................................................................................................................................... 69 
16.5.1. 
LN-145 ............................................................................................................................................... 69 
16.5.2. 
NMA Lymphodepletion ..................................................................................................................... 69 
16.5.3. 
IL-2 ..................................................................................................................................................... 80 
 
LIST OF FIGURES AND TABLES 
FIGURE 1. 
STUDY FLOW CHART............................................................................................................................. 23 
FIGURE 2. 
LN-145 MANUFACTURING PROCESS ....................................................................................................... 24 
TABLE 1.  
COMPOSITION OF LN-145 ..................................................................................................................... 35 
TABLE 1. 
RESPONSE AT EACH ASSESSMENT TIME POINT FOR PATIENTS WITH TARGET (± NON-TARGET) ............................... 47 
TABLE 2. 
EXAMPLES OF BEST OVERALL RESPONSE FOR EACH PATIENT ACROSS ALL ASSESSMENTS....................................... 47 
TABLE 5. 
ADVERSE EVENTS REPORTED IN >10% OF PATIENTS IN TWO CLINICAL TRIALS OF IL-2 ......................................... 81 
TABLE 6. 
LIFE-THREATENING (GRADE 4) ADVERSE EVENTS REPORTED IN PATIENTS IN TWO CLINICAL TRIALS OF IL-2 .............. 82 
TABLE 7. 
MANAGEMENT OF IL-2 TOXICITIES ........................................................................................................... 83 
 

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LIST OF ABBREVIATIONS 
Term 
Definition 
ACT 
Adoptive Cell Therapy 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AST 
Aspartate transaminase 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events Version 4.03 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCrCl 
Estimated creatinine clearance 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in the first second 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HNSCC 
Squamous Cell Carcinoma of the Head and Neck 
ICH 
International Conference on Harmonization 
IL-2 
Interleukin-2 (aldesleukin) 
IRB 
Institutional Review Board 
IV 
Intravenous 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition scan 
NCI 
National Cancer Institute 
NMA 
Non-myeloablative 
NE 
Not evaluable  
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PO 
Per Os (by mouth) 
PR 
Partial response 

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Term 
Definition 
Pre-REP 
Expansion of TILs from tumor fragments prior to REP 
QD 
(Taken) once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REP 
Rapid Expansion Protocol 
SAE 
Serious adverse event 
SD 
Stable disease 
TIL 
Tumor Infiltrating Lymphocyte 
Treg 
Regulatory T cells 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit normal 
 
 
 
 

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1. INTRODUCTION 
1.1. 
Head and Neck Cancer 
Squamous cell cancers of the head and neck cancer (HNSCC) comprise malignancies of the 
nasal cavity, paranasal sinuses, nasopharnyx, oral cavity, oropharynx, hyopopharynx, larynx, 
salivary glands, and head and neck paraganglial tissues (1).  The majority of these tumors occur 
in older individuals who have a history or smoking or high alcohol use (more than 4 drinks per 
day), and are more frequent in men than in women (2, 3).  The HNSCC subset of oropharyngeal 
cancer (OPC) appears to be a distinct disease, with different risk associations than other HNSCC 
(4).  OPC prevalence among HNSCC has increased worldwide over the last two decades; in the 
US, the rate increased from 18% of all HNSCC in 1973 to 31% in 2004 (5).  HPV-positivity also 
has increased over the same period, reaching an estimated 72% prevalence in OPC between 
2005 and 2009 (6-8).  By contrast, fewer than 20% of other HNSCC are positive for HPV (8, 9).  
The increase in incidence of OPC is 4-fold greater in males than females and among men, is 
associated with age less than 60 years and white race (3, 10).  Of the many strains of HPV, type 
16 (HPV16) has been found in more than 90% of HPV-positive OPC (10).  Notably, genetic 
mutations in HPV-negative HNSCC appear to more frequent and distinct from those in HPV-
positive tumors (2).  For example, mutations of p53, a key tumor suppressor gene, were almost 
always associated with an HPV-negative tumor (11, 12), consistent with the known association 
between smoking and p53 mutations in subjects with HNSCC (13).  By contrast, activating 
mutations and amplifications of phosphatidylinositol 3-kinase, catalytic subunit alpha (PIK3CA) 
were more common in HPV-positive tumors (14).  As most HPV oral infections are sexually 
acquired, the increase in HPV-positive OPC is thought to be associated with changes in sexual 
behavior over time (3).  While HPV vaccines approved for marketing over the last decade can 
prevent the development of precancerous cervical lesions (15), the effect of HPV vaccine on 
oral lesions or OPC is unknown and the HPV vaccines now is use were not available for the 
majority of current subjects with OPC.  
The current standard treatment for HNSCC typically involves combinations of surgery, 
radiation, and chemotherapy, typically with cisplatin (16).  Surgery can be minimally invasive in 
order to preserve organ function.  Radiation with hyperfractionation and accelerated 
fractionation has been found to improve survival (17), but has been associated with swallowing 
dysfunction (18).  Five-year survival has significantly increased for all sites over the past 20 
years from 54.7% in 1992 to 1996, to 65.9% in 2002 to 2006 (19).  By site, estimated 5-year 
survival rates remain ≤ 63% for all sites other than the tongue or lip (20).  Notably, outcome for 
subjects with HPV-positive tumors is better than outcome for HPV-negative HNSCC [(6, 21, 22), 
with reported 2- and 3-year survival rates of approximately 95% and 80%, respectively (6, 21).  
The improved outcome of subjects harboring HPV-positive tumors may be a result of enhanced 
activity of TILs at the tumor site (17).   
The rates of occurrence of a second primary tumor or recurrence of tumors is high in HNSCC, 
particularly among smokers, likely due to the “field cancerization” effect of tobacco-induced 
malignancy, whereby genetic alterations may be induced throughout the upper aerodigestive 

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mucosa (3).  Argiris et al (23) estimated a recurrence rate of 50% for subjects in remission 
following treatment of a locally advanced HNSCC, and Chuang et al estimated that 36% of 
subjects would develop a second primary tumor within 20 years (24) Recurrence is higher in 
HPV-negative than in HPV-positive OPC (3-year recurrence rates of 65.1% vs. 13.6%; P<.001).  
Additionally, the 3-year rates of second primary malignancy were 14.6% vs. 5.9% (P =.02) in 
these groups (6).   
Outcome for recurrent HNSCC is poor across a variety of therapeutic modalities (25-27), 
although Strnad et al (28) reported long-term high rates of local control of recurrent disease 
using interstitial pulsed-dose-rate brachytherapy combined with chemotherapy in a selected 
subject population.  HPV-positive recurrent OPC disease has a higher OS rate than HPV-
negative recurrent OPC:  2-year OS rates were 54.6% for subjects with HPV-positive tumors and 
27.6% for those with HPV-negative tumors (P<.001) (29). 
The findings of survival rates of 63% or less among most subjects with HPV-negative HNSCC or 
recurrent HPV-positive HNSCC, and even lower survival rates among subjects with recurrent 
HPV-negative tumors, indicates a need for improved therapeutic options.   
1.2. 
Adoptive Cell Transfer of Tumor-Infiltrating Lymphocytes as Cancer Immunotherapy  
Adoptive cell transfer of tumor infiltrating lymphocytes 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 (12-14).  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 overall survival (OS) and progression-free 
survival (PFS) in patients with melanoma (15-18), lung cancer (19-22), ovarian cancer (23-25), 
squamous cell cancers (26, 27), triple-negative breast cancer and basal-like breast cancer (28-
35), and colorectal cancer (36-39).  Notably, one study found that an increased Foxp3+ 
Treg/CD8+ ratio and the presence of intra-tumoral high Foxp3+ Tregs predicted worse overall 
survival (40).  In addition, gene expression studies using DNA microarrays have indirectly 
correlated so-called “immune signature” genes and T-cell associated gene expression (e.g., 
CD3, CD8, CD4, inducible costimulator (ICOS), granzyme B (GRZB), DC-LAMP and chemokine 
and chemokine receptors) with improved OS and PFS in both primary and metastatic tumor 
settings (18, 36, 37, 41-43).  These findings support the development of therapies based on the 
isolation and expansion of autologous TIL cells as a therapeutic agent against solid tumors. 
 
ACT has several theoretical and practical advantages over active immunization and nonspecific 
immune stimulation.  First, the ex vivo environment allows expansion to proceed to very high 
cell numbers in the absence of suppressive factors, such as Treg, that are present in the tumor 
microenvironment (44-46); allowing re-infusion of much higher numbers of tumor-reactive T-
cells than is possible with other approaches.  Second, the TIL product potentially recognizes a 

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wider array of tumor antigens, such as mutated tumor neoantigens (47-50).  Preparation of the 
host patient with lymphodepletion immediately prior to the transfer of the antitumor cells also 
eliminates potentially suppressive influences (such as regulatory T cells and cytokine sinks) to 
provide an optimal milieu for the transferred TIL to proliferate and become activated in vivo.   
 
The feasibility of TIL preparation was demonstrated by early studies showed that metastatic 
melanoma tumor can be excised and placed in tissue culture under conditions in which tumor 
cells do not survive, but any TIL contained within the excised tumor tissue can survive and 
proliferate when small cut tumor fragments are placed in culture.  TIL can be cultured in the 
presence of IL-2 and can be grown to very large numbers using standardized protocols (≥ 1 x 
108 cells) (12, 14, 53, 54).  These TIL were then shown to have the capacity to kill tumor cells in 
vitro and promote durable antitumor effects in vivo when infused back into the original tumor 
donor (12, 14, 53, 54).  Further studies established that the efficacy of infusions of large 
numbers of TIL was enhanced by treating the tumor-bearing animal with cyclophosphamide to 
induce a non-toxic transient drop in endogenous lymphocytes in the host and IL-2.  With this 
combination, mice could be cured of advanced hepatic metastases (12).  These findings set the 
stage for NCI clinical trials of TIL in patients with metastatic melanoma using a non-
myeloablative (NMA) consisting of fludarabine and cyclophosphamide preconditioning regimen 
before TIL infusion, combined with high-dose IL-2 following TIL Infusion.  Such studies have 
consistently demonstrated high objective response rates (ORR), from 49% to 72%, with long-
term durable and potentially curative CR rates of up to 25%.  
1.3. 
TILs for Head and Neck Cancer 
The rationale for investigating the use of TIL for treatment of HNSCC is based on the high rate 
of recurrence and overall low survival rates for subjects with recurrent disease following 
standard combinations of surgery and adjuvant chemotherapy, radiation therapy.  Further, as 
was described above for other solid tumors, a positive correlation between the presence of TIL 
in HNSCC tumor specimens and subject outcome has been reported by a number of 
investigators.  For example, Balermpas et al reported that among patients with HNSCC, those 
with high immunohistochemical CD3 and CD8 expression had significantly increased OS, PFS, 
and distant metastasis-free survival (DMFS), but not local failure-free survival (LFFS) in 
multivariate analysis (45).  Similarly, low CD8+ T-cell infiltration in the tumors of patients with 
laryngeal SCC was correlated with decreased survival (84).  TIL has shown prognostic value in 
both human papilloma virus (HPV)-positive and HPV-negative HNSCC tumor specimens. For 
example, Kong et al reported a survival benefit for higher CD3+ TIL in tumor specimens only for 
HNSCC with weak or no expression of HPV (85), whereas, Wansom et al (86) and Ward et al. 
(87) found that higher numbers of CD8+ cells in tumors were positively correlated survival in 
patients with HPV-positive HNSCC  or HPV-positive oropharyngeal cancer (OPC).  An additional 
report by Wansom et al found that among patients with advanced OPC, CD8+ cells, as well as 
Treg cells (FoxP3) and total T-cell number all were positively correlated with OS and DFS, 

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independently of the tumor’s HPV status (88).  These data strongly suggest a beneficial role for 
TIL in the body’s response to HNSCC.   
The feasibility of generating TIL from HNSCC has been demonstrated by several investigators.  
Junker et al (89) demonstrated the successful expansion of TIL bulk cultures were expanded in 
12/15 (80%) evaluable subjects; tumor specificity of the TIL were shown in 60%.  Up to 3500-
fold expansion was achieved within 17 days.  TIL from 60% of the subjects were able to kill HLA-
A-matched tumor cell lines.  Additional characterization showed that the TIL expanded from an 
HNSCC were phenotypically similar to those from melanomas, ie. CD3+/CD8+ and were similar 
before and after rapid expansion (90).  Moudgil et al (91) reported a success rate of 50% for 
generation of TIL (33 of 63 cultures initiated).  Of 22 tested TIL, 20 secreted IFN-gamma in 
response to co-culture with the autologous tumor cell target.  These findings are consistent 
with those of a retrospective study that showed that that TIL were successfully generated in 
677 (86%) of the 787 specimens from 402 subjects with melanoma (92). 
To date, a single report has described use of TIL for treatment of a subject with HNSCC.  In this 
report, Leidner et al (93) infused autologous TIL in conjunction with DC-targeted microvessicle 
DPV-001 intradermal vaccine (Dribbles) to a heavily pretreated 22-year-old subject with 
recalcitrant HNSCC of the lateral tongue.  Prior to TIL therapy, the subject had under gone 
partial glossectomy followed within 12 weeks by adjuvant intensity modulated radiation 
therapy at 60 Gy in the ipsilateral neck and 54 Gy in the contralateral neck.  Bilateral recurrence 
in the neck was observed at month 6.  During months 7 to 10, the subject received two multi-
drug regimens (cisplatin/cetuximab/5FU, carboplatin/ docetaxel), but progressed locally in the 
neck. The subject was then enrolled on a Phase Ib trial of combination anti-PD-1/anti-KIR (BMS 
CA223-001, Nivolumab/Lirilumab) during months 11 to 14, but again progressed locally in the 
neck.  At month 15, under an individual subject compassionate treatment protocol, the subject 
underwent a reduced-intensity lymphodepletion regimen followed by adoptive transfer of 
expanded autologous TIL in conjunction with Dribbles and imiquimod adjuvant, with high-dose 
IL-2 support.  The expanded TIL had demonstrated tumor-induced IFNγ production in culture.  
Analysis of peripheral blood showed evidence of lymphocyte recovery, in particular, increases 
in T-gamma-delta cells, suggesting that TIL had engrafted.  Further, immunohistochemical 
analysis of tumor biopsy specimens showed a decrease in expression of PD-L1 in the tumor 
microenvironment.   Despite evidence of TIL engraftment and some in vivo effects, the subject 
died at month 18.  
In summary, current methods for the expansion of autologous TIL from excised tumors are 
well-established and are robust enough to ensure a high degree of success in consistently 
generating sufficient numbers of high-quality therapeutic cells, as described above.  Further, 
clinical studies in melanoma have demonstrated that the effects of the TIL persist in patients 
for weeks to months and even years after infusion, thereby mediating highly durable complete 
remissions more than other current immunotherapies or standard therapies, as noted above. 
The large body of data from these studies justifies the development of adoptive TIL therapy as 
an approved therapeutic in other solid tumors, such as HNSCC. 

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2. STUDY DESIGN 
2.1. 
Overview 
This is a prospective single-arm interventional study evaluating patients with HNSCC receive 
adoptive cell therapy (ACT) with LN-145 (autologous TIL).  The TIL therapy to be used in this 
study is almost identical to that developed for melanoma-derived TIL by Dr. Steven Rosenberg 
and colleagues at the National Cancer Institute (NCI).  Melanoma-derived TIL have 
demonstrated efficacy in the treatment of Stage IV melanoma, and Phase 2 clinical trials 
evaluating this product have shown an objective response rate of 49% or more (55-58), 
exceeding rates reported by other immunotherapies in metastatic melanoma.   
Protocols for the tumor harvest and LN-145 administration for the current study are provided 
in separate operating manuals.  TIL therapy comprises multiple interdependent phases:  tumor 
resection for TIL harvest; ex vivo expansion of TIL; NMA lymphodepletion, infusion of TIL, and 
infusion of high-dose IL-2.  A study flow chart is shown in Figure 1. 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. 
Study Flow Chart 
Patient Visits
Visit 1
Screening Period 
(approx. 28 Days)
Visit 2
Tumor Resection 
TIL Preparation
PRE- RAPID EXPANSION 
PROTOCOL
(Pre-REP)
~ 3 Weeks
Manufacturing Process
Visit 3
DAY  -14 
TIL Preparation
RAPID EXPANSION 
PROTOCOL
(REP) 
~ 2 Weeks
Visit 4
DAY  -7
Start of NMA 
lymphodepletion 
TIL Preparation 
Complete
Release of LN-145
Visit 11
DAY 0
LN-145 Infusion 
Visit 12
DAY 1
Start of High Dose IL-2 
Patient Status 
Confirmation:
Site to confirm that 
status of the patient is 
stable and REP 
portion of the 
manufacturing can 
begin
Confirmation by 
Manufacturing      
Day 7 of REP ~ Visit 4:
NMA 
lymphodepletion can 
begin 
Visit 5 – Visit 10
DAY  -6 – DAY -1 
Visit 13 – Visit 16
DAY 2 – Day 14
Visit 17
DAY 28 (Month 1)
Visit 18
DAY 56 (Month 2)
Visit 19
DAY 84 (Month 3)
Long Term Follow Up 
Visits 
Visit 20 – Visit 25
(Month 4  - Month 24)
 
2.2. 
Production and Expansion of Tumor Infiltrating Lymphocytes 
Generating LN-145 involves resecting a tumor deposit 
 
 and culturing tumor fragments in media containing IL-2 to expand them in 
vitro Figure 2. 

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Appropriately expanded TIL cultures should reach several million cells (combined) in 2 to 3 
weeks.  In this trial, TIL cultures will be selected on the basis of better growth and a higher 
proportion of 
TIL.  TIL initially expanded from the tumor fragments then undergo a rapid 
expansion protocol (REP) using the 
resulting in 
billions of cells for re-infusion into the patient.   
Figure 2. 
LN-145 Manufacturing Process 
 
TIL production requires approximately 6 weeks following excision of tumor specimens.  The TIL 
product is manufactured ex vivo using autologous tumor as starting material.  The key 
manufacturing steps include: 
• 
Surgical removal of autologous metastatic tumor and shipment to the sponsor-
designated manufacturing facility 
• 
Initial TIL Culture (Pre-REP) of up to 3 weeks  
• 
REP culture for 14 days 
On Day 7 of the 2-week REP protocol, the number of TILs successfully expanded in the initial 
culture phase, will be determined.  If the number of TILs is sufficient for administration, 
approval by the sponsor will be granted to start the cyclophosphamide/fludarabine 
lymphodepletion regimen at Visit 4 (Day -7). 
2.3. 
Non-myeloablative (NMA) Lypmphodepletion, TIL and IL-2 Therapy 
The lymphodepletion protocol used in the current study (2 days of cyclophosphamide plus 
mesna, followed by 5 days of fludarabine) is based on the method developed and tested by the 
NCI (55, 56, 58, 64, 65, 77) and is also the most often used.  Patients then will receive up to
 
 LN-145. The upper limit of the range for infusion 
 viable cells) is based on the 

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known published upper limit safely infused where a clinical response has been attained (64). 
TIL infusion will be followed by the administration of a regimen of high-dose IL-2 (600,000 
IU/kg) every 8 hours starting approximately 12 to 24 hours after the completion of the LN-145 
infusion and continuing for up to 6 doses.  Patients will be evaluated for response using RECIST 
version 1.1 at Visits 17, 18 and 19 (Days 28, 56 and 84).  Patients who experience stable disease 
(SD), a partial response (PR), or a complete response (CR), as defined by RECIST version 1.1 at 
Visit 19 (Day 84) will continue to be evaluated for response and survival will continue to the 
Long Term Follow Up Phase. Survival status follow-up will continue to the Long Term Follow Up 
Phase for all treated patients.  Radiologic assessment of disease may also be performed at 
additional time points at the discretion of the investigator. 
 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. Primary Objectives 
• 
To evaluate the safety and tolerability of lymphodepletion, LN-145, and IL2 in patients 
with recurrent and/or metastatic HNSCC. 
• 
To evaluate the efficacy of therapy using the overall response rate (ORR) in patients 
with recurrent and/or metastatic HNSCC.  
3.1.2. Secondary Objective 
• 
To evaluate efficacy parameters such as complete response (CR) rate, the duration of 
response (DOR), progression-free survival (PFS), and overall survival (OS) in patients 
with recurrent and/or metastatic HNSCC. 
3.1.3. Exploratory Objectives 
• 
To explore potential immune correlates of response, survival, toxicity of the treatment. 
3.2. 
Study Endpoints 
3.2.1. Primary Endpoints 
• 
Incidence of treatment-emergent AEs (TEAEs), including SAEs, therapy-related AEs, AEs 
leading to early discontinuation of treatment or withdrawal from the study or death.   
• 
Overall Response Rate (ORR) 
3.2.2. Secondary Endpoints 
• 
Complete Response (CR) rate 
• 
Duration of Response (DOR) 
• 
Progression-Free Survival (PFS) 
• 
Overall Survival (OS) 
 

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3.2.3. Exploratory Endpoints 
• 
Evaluation of immune correlates with respect to response, survival, toxicity of the 
treatment, and HPV status of the tumor. 
4. SELECTION OF PATIENT POPULATION 
Patients greater than 18 years of age, with a diagnosis of metastatic or recurrent HNSCC who have 
undergone at least one prior immunotherapy or chemotherapy regimen will be selected for this 
study. 
Details concerning specific benefits and risks for patients participating in this clinical trial may be 
found in the accompanying Investigator’s Brochure and Informed Consent documents. 
4.1. 
Inclusion Criteria 
To be eligible for the study, Patients must meet ALL of the following criteria prior to 
enrollment in the study: 
1. 
Must be greater than 18 and less than 65 years of age at the time of consent. 
• 
Patients greater than or equal to 65 years of age may be allowed in the study after 
discussion between the Principal Investigator and Medical Monitor regarding the 
patient’s ability to tolerate the study treatment regimen. 
2. 
Must understand and voluntarily sign an informed consent document prior to any study 
related assessments/procedures being conducted. 
3. 
Able to adhere to the study visit schedule and other protocol requirements. 
4. 
Must have persistent, recurrent or metastatic HNSCC; histologic documentation of the 
primary tumor is required via the pathology report. Requirements regarding the lesion 
are as follows: 
• 
CT scans of the head, neck and chest (scans of additional anatomical locations with 
suspected disease may be done as determined by the PI) is required and may have 
been done within 28 days prior to screening. 
• 
Patients must have one lesion that is resectable for TIL manufacturing. The ideal 
resected lesion should be least 1.5 cm in diameter and no greater than 4.0 cm in 
diameter after prosection. The resection must entail minimal morbidity (as 
determined by the study PI and surgical team). 
5. 
Must have a remaining measurable target lesion outside the irradiated field as defined 
by RECIST version 1.1 following the surgical resection. 
• 
Measurable lesions must not have been in a previously irradiated field. 
6. 
Must have had at least 1 prior systemic chemotherapeutic regimen for management of 
persistent, recurrent or metastatic HNSCC. Patients must not have any curative therapy 
options, or be intolerant of, or decline standard of care therapy for persistent, recurrent 

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or metastatic disease. 
7. 
Any prior therapy directed at the malignant tumor, including radiation therapy, 
chemotherapy, biologic/targeted agents and immunologic agents must be discontinued 
at least 21 days prior to tumor resection for preparing TIL therapy. 
8. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
9. 
Must meet the following laboratory criteria:  
• 
Absolute neutrophil count (ANC) > 1000/mm3 
• 
Hemoglobin > 8.0 g/dL 
• 
Platelet count > 80,000/mm3 
• 
ALT/SGPT and AST/SGOT < 3.0 x the upper limit of normal (ULN) 
o Patients with liver metastases may have LFT ≤ 3.0 x ULN) 
• 
Calculated creatinine clearance ≥ 50.0 mL/min 
• 
Total bilirubin ≤ 2.0 mg/dL  
o Patients with Gilbert’s Syndrome must have a total bilirubin < 3.0 mg/dL.    
10. 
Patients must be seronegative for the HIV antibody, hepatitis B antigen, and hepatitis C 
antibody or antigen. 
• 
Note: Patients with a positive test for hepatitis B virus surface antigen (HBsAg) or 
hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection 
may be enrolled if the viral load by PCR is undetectable with/without active 
treatment. 
11. 
Patients must be EBV viral capsid antigen (VCA) IgG positive and/or Epstein Barr nuclear 
antigen (EBNA) IgG positive, and have no clinical evidence of active EBV infection. 
12. 
Female patients of childbearing potential must be willing to practice birth control 
starting at the time of informed consent and for 1 year after the completion of the 
lymphodepletion regimen.  
Approved methods of birth control are as follows: 
• 
Total abstinence 
• 
Hormonal contraception (i.e. birth control pills, injection, implant, transdermal 
patch, vaginal ring) 
• 
Intrauterine device (IUD) 
• 
Tubal Ligation  
• 
Male partner’s vasectomy 
• 
Implantable or injectable contraceptives 
• 
Use of a male or female condom 
• 
Cervical Cap or contraceptive sponge with spermicide 
 

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4.2. 
Exclusion Criteria 
Patients who meet ANY of the following criteria will be excluded from the study: 
1. Patients who are on a systemic steroid therapy (greater than 10 mg of prednisone or 
equivalent) within 28 days prior to Visit 2.  
2. Patients who currently have prior therapy-related toxicities greater than Grade 1 
according to Common Toxicity Criteria for Adverse Events (CTCAE) v4.03; (see 
Appendix Section 16.4), except for alopecia or vitiligo prior to enrollment. 
• 
Note: Patients may have undergone minor surgical procedures not involving general 
anesthesia within three weeks prior to Visit 2 as long as all toxicities have recovered 
to Grade 1 or less or as specified in the eligibility criteria.  
3. Patients who have had immunotherapy-attributable AE: 
• 
Which led to discontinuation, or   
• 
Have had an ophthalmologic or neurologic AE of any grade, or 
• 
Actively receiving any immunosuppressive agents for the treatment of toxicity 
related to prior immunotherapy.  
4. Patients with documented Grade 2 or greater diarrhea or colitis as a result of previous 
immunotherapy within six months from screening. 
• 
Note: Patients that have a colonoscopy that demonstrates the visual appearance of 
the absence of inflammation are not excluded. 
5. History of severe immediate hypersensitivity reaction to cyclophosphamide, 
fludarabine, or IL-2.  
6. Patients with active systemic infections, coagulation disorders or other active major 
medical illnesses of the cardiovascular, respiratory or immune system. 
7. Have any form of primary immunodeficiency, such as severe combined 
immunodeficiency disease or acquired immune deficiency syndrome (AIDS).   
8. Diagnosis of end-stage renal disorder requiring hemodialysis.  
9. Patients who have a left ventricular ejection fraction (LVEF) < 45%.  
10. Patients who have a FEV1 (forced expiratory volume in one second) of less than or equal 
to 60 % of normal. 
11. Patients with unresolved uveitis. 
12. Have had another primary malignancy within the previous 3 years (with the exception of 
a history of 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)  

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13. Patients who are pregnant or breastfeeding. 
4.3. 
Patient Enrollment and Re-Screening 
The study is primarily planned to assess efficacy and safety for 47 patients who receive 
treatment with LN-145 followed by at least one dose of IL-2.  
Patients who meet all of the inclusion criteria and do not meet any of the exclusion criteria 
will be enrolled in the study.  Patients who sign an ICF and fail to meet the inclusion and/or 
exclusion criteria are defined as screen failures.  
Patients who fail the initial screening process may be re-screened for eligibility.  The Principal 
Investigator and Medical Monitor will discuss the patient prior to any rescreening procedures. 
4.4. 
Patient Discontinuation 
Patients who discontinue for any reason will be required to complete the early termination 
visit. 
 
5. STUDY ASSESMENTS, PROCEDURES AND TREATMENTS 
5.1. 
Informed Consent  
An Informed Consent Document must be signed before any study related assessments are 
performed. 
5.2. 
Inclusion/Exclusion Criteria 
Patients must meet all inclusion criteria (Section 4.1) and must not have any of the conditions 
specified in the exclusion criteria (Section 4.2).  The patient’s source documents must support 
her qualifications for the study.  
5.3. 
Demographic Data 
The demographic data will include (but not be limited to) the patient’s initials (as allowed per 
local regulations), date of birth (as allowed per local regulations), age, gender, and race/ethnic 
origin. 
5.4. 
Medical History 
Relevant medical history shall be recorded, including previous relevant surgeries at the Visit 1 
(Screening). 
5.5. 
Documentation of Confirmation of Diagnosis 
Patients must have documented diagnosis of metastatic or recurrent HNSCC. 
5.6. 
Documentation of HPV status 
Patients must have documented HPV status prior to Visit 2. If documentation is not available, 
testing for HPV status may be determined at the time of tumor resection at Visit 2, if a 
sufficient sample is available. 

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5.7. 
Physical Examination 
Physical examination will be conducted for all visits except for Visit 2 and shall include 
gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and 
throat, respiratory system, skin, psychiatric (mental status), general nutrition. PE conducted 
during follow-up will be symptom directed.  Adverse changes in the PE shall be recorded as 
adverse events. 
5.8. 
Vital Signs 
Vital signs shall include height, weight, pulse, respirations, blood pressure and temperature. 
Height will be measured at Visit 1, Screening only. All other vital signs will be measured at every 
visit.   
BSA and BMI shall be calculated at Visit 4 (Day -7) only. 
On Visit 11, Day 0 (LN-145 infusion), vital signs will be monitored every 30 minutes during 
infusion then hourly (+/-15 minutes) for four hours and then routinely (every four to six hours), 
unless otherwise clinically indicated, for up to approximately 24 hours post LN-145 infusion. 
5.9. 
Eastern Cooperative Oncology Group (ECOG) performance status 
An ECOG performance status will be assessed at Visits 1 through 4, 11, and 17 through 25. 
5.10. 
Safety Blood and Urine Tests 
The following safety blood and urine tests will be collected at every visit.  
• 
Chemistry - sodium, potassium, chloride, total CO2, or bicarbonate, creatinine, glucose, 
BUN, albumin, calcium, magnesium, phosphorus, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, total bilirubin, direct bilirubin, LDH, total protein, total CK, uric acid 
• 
Hematology - CBC with differential 
• 
Thyroid panel inclusive of TSH and free T4 shall be done only at Visit 1 (Screening) and Visit 
19 (Day 84, Month 3) or as clinically indicated. 
• 
Urinalysis dipstick will be completed at every visit. Abnormal, clinically significant findings 
shall be recorded as an adverse event. A complete urine culture shall be done if clinically 
indicated. 
5.11. 
ß-HCG Serum Pregnancy Test 
Serum pregnancy test for all women of child-bearing potential at Visit 1 (Screening) and Visit 3 
(Day -14). 
5.12. 
Virus Testing 
Blood samples will be collected for the following Virus testing at Visit 1 (Screening) only.  
• 
HIV antibody titer; 
• 
Hepatitis - HBsAG determination (HSV-1 IgG and HSV-2 IgG) and anti HCV; 
• 
HSV serology 
• 
Anti-CMV (IgG) antibody titer 

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• 
EBV VCA-IgG, and/or EBNA IgG (tests conducted to confirm absence of acute or active EBV 
infection; may have been done within 3 months prior to Visit 2 (Tumor Resection Visit). 
5.13. 
Human Leukocyte Antigen (HLA) Typing 
Sample collection for HLA typing shall be conducted during Visit 1 (Screening) and analyzed by 
the central laboratory. Refer to the Laboratory Manual for details. 
5.14. 
HPV Subtype Serotype 
Sample collection for HPV subtype serotyping will be collected at Visit 2 (Tumor Resection Visit) 
and sent to the central laboratory. Refer to the Laboratory Manual for details. 
5.15. 
CMV Antigen Assay 
CMV antigen assay shall be completed at Visit 1 (Screening) and at every visit starting at Visit 4 
(Day -7) through Visit 25 (Month 24) only if clinically indicated. 
5.16. 
Estimated Creatinine Clearance 
The creatinine clearance shall be calculated using the Cockcroft-Gault formula at every visit. 
 
 
 
 
 
5.17. 
Eye Exam 
Slit lamp eye exam will be completed at Visit 1 (Screening).  
5.18. 
Cardiac Evaluations 
All cardiac evaluations will be performed during Visit 1 (Screening). 
5.18.1. Stress Thallium 
A stress thallium test will be done for all patients >= 60 years of age who have a history 
of ischemic heart disease, chest pain or clinically significant atrial and/or ventricular 
arrhythmias. 
5.18.2. Echocardiogram (ECHO) or Multigated Acquisition Scan (MUGA) 
An ECHO or MUGA shall be performed. Patients resulting in a LVEF <45% are excluded 
from the study. 
5.18.3. Electrocardiogram 
A 12-lead ECG will be performed after the patient has been supine for at least 3 
minutes.  Sites are to use their own, local ECG machines for the study and the ECG 
readings will be interpreted by the Investigator by clinically correlating with the 
patient’s condition.  

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The Investigator’s interpretation will be recorded in the ECG eCRF as: normal; abnormal, 
not clinically significant; or abnormal, clinically significant.  
5.19. 
Pulmonary Function Tests 
Pulmonary evaluation will be completed at Visit 1 (Screening). 
5.20. 
Colonoscopy 
Colonoscopy is only required for patients who have had a documented Grade 2 or greater 
diarrhea or colitis as a result of previous immunotherapy within six months of screening.  
5.21. 
Tumor Assessments 
Tumor assessment by conventional or spiral CT scans of the head, neck and chest will be 
conducted at Visit 1 (Screening), Visit 3 (Day -14) and Visits 17 through 25 (Days 28 through 
672, Months 1 through 24). 
CT scans of additional anatomical locations will be conducted at the above referenced visits if 
prior or suspected disease is clinically indicated. Assessments should be made and recorded by 
the Investigator or an individual authorized by the Investigator. 
MRI or PET scans will be allowed for patients who have an intolerability to contrast media. The 
imaging modality used must be uniform for the duration of the study. 
5.22. 
Response Assessments 
Tumor response will be evaluated starting Visit 17 (Day 28) and at every visit thereafter. 
Response and progression will be evaluated using the RECIST version 1.1 criteria (95).  
CT scans will be forwarded to a central imaging facility for review. Data generated by central 
laboratories and evaluations done by the central reviewers will prevail over locally generated 
information in the evaluation of the patient’s efficacy results. An independent central response 
adjudication committee will perform an assessment of tumor responses. These data will be 
used in the final study analysis and the assessment will be included in the Clinical Study Report 
(CSR). 
5.23. 
Prior and Concomitant Medications 
All medications and therapies (prescription, and non-prescription, including herbal 
supplements) taken by the patient up to 28 days prior to Visit 1 should be recorded, 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. 
5.24. 
Adverse Events 
All patients will have AE assessment by NCI CTCAE Version 4.03 performed during all visits once 
the ICF is signed. 

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5.25. 
Tumor Harvest for TILs 
At Visit 2 (Tumor Resection Visit), following confirmation of patient eligibility, the medical 
monitor, or designee, will provide approval patient for enrollment into the clinical trial.   
If enrolled, tumor resection is expected to occur approximately 44 days prior to the LN-145 
infusion at Visit 11 (Day 0) and is dependent on the rate of cell growth at the central TIL 
manufacturing facility.   
A detailed Tumor Procurement Manual will be provided to each clinical site and training will be 
performed on the procedures for harvest, prosection, transport, and shipping of the tumor to 
the sponsor-designated central TIL Manufacturing Facility. 
5.26. 
Six paraffin embedded slides from resected tumor 
Six paraffin-embedded tumor section slides will be prepared for biomarker analysis Visit 2 
(Tumor Resection). Whole exome sequencing may be performed with consent. 
5.27. 
Peripheral Blood Mononuclear Cells (PBMC) for genetic sequencing 
Whole exome sequencing of normal cells may be performed with consent to enable 
identification of mutations in the tumor specimen at Visit 2 (Tumor Resection). 
5.28. 
Non-myeloablative (NMA) lymphodepletion Regimen 
The NMA lymphodepletion regimen is scheduled to start on Visit 4 (Day -7) which is in 
conjunction with Day 7 of the 2-week REP protocol. Approval from the sponsor is required to 
start the NMA lymphodepletion regimen in order to ensure that the number of TILs cultured is 
adequate. The regimen comprises 2 days of cyclophosphamide followed by 5 days of 
fludarabine, as follows: 
5.28.1. Preparation of Cyclophosphamide 
The dose is 60 mg/kg.  Reconstitute cyclophosphamide per institutional standard to 
deliver calculated dose in a final concentration of 20 mg/mL. Add dextrose 5% in water 
(D5W) to the required volume of cyclophosphamide to reach a total infusion volume of 
250 mL.  If the volume of reconstituted cyclophosphamide is > 250 mL, do not add D5W, 
and the total volume will be infused. 
LN-145 is an autologous product which is procured and delivered by means which 
have more in common with autologous blood product delivery than those of 
traditional drug production.  It is imperative that only the patient’s own (autologous) 
study treatment (LN-145) be administered to the same individual patient. For these 
reasons, the patient specimen must be procured and handled according to a strict 
protocol to ensure optimal quality of the specimen and minimum transport time to 
and from the processing facility, as well as to ensure the unique identification of the 
specimen at all times including injection back into the patient. 

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Note:  if the Patient is obese (BMI > 30.0 kg/m2), the dose of cyclophosphamide will be 
calculated using practical weight as described in Appendix Section 16.3. Infuse with 
Mesna as described below. 
5.28.2. Preparation of Mesna 
The dose is 15 mg/kg.  Actual weight should be used to calculate the Mesna dose, even 
if the Patient’s BMI > 30.0 kg/m2.  Dilute the volume of Mesna injection per institutional 
standard, or in any of the following fluids (per Mesna prescribing information, dated 
9/2015) to obtain a final concentration of 20 mg/mL: 
• 
5% Dextrose Injection, USP 
• 
5% Dextrose and 0.2% Sodium Chloride Injection, USP 
• 
5% Dextrose and 0.33% Sodium Chloride Injection, USP 
• 
5% Dextrose and 0.45% Sodium Chloride Injection, US 
• 
0.9% Sodium Chloride Injection, USP 
• 
Lactated Ringer’s Injection, USP 
5.28.3. Infusion of Cyclophosphamide and Mesna 
Cyclophosphamide (60 mg/kg) in a total volume of 250 mL (or greater if required), plus 
mesna (15 mg/kg) are to be infused together over 2 hours on Visits 4 and 5 (Days -7 and 
-6). Mesna infusion will continue at a rate of 3 mg/kg/hour over 22 hours after each 
cyclophosphamide dose during Visits 4 and 5 (Days -7 and -6).   
5.28.4. Fludarabine  
The fludarabine dose is 25 mg/ m2 administered by IV over approximately 30 minutes 
once daily for 5 days during Visits 6 through 10 (Days -5 through -1)   
Note: If the Patient is obese (BMI > 30.0 kg/m2) fludarabine dosage will be calculated 
using practical weight as described in Appendix 163.3. 
5.29. 
LN-145 Infusion 
Upon completion of the manufacturing process the product will be labeled with a patient 
specific label and shipped overnight by courier to the clinical site pharmacy. The product will be 
shipped under quarantine and received by the appropriate clinical pharmacy for the particular 
patient.   Additional details for handling and administration of the investigational product can 
be found in the Pharmacy and Administration Manual. 
If not already hospitalized, the patient will be admitted 1-2 days prior to planned LN-145 
administration and prepared for study drug administration. Patients will remain hospitalized 
until the completion of the IL-2 therapy, as per institutional standards. 
5.29.1. Description 
LN-145 is a cell product comprising a live cell suspension of autologous tumor-
infiltrating lymphocytes derived from the patient's own tumor.  The overall process of 

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tumor shipping, TIL manufacturing, and TIL product shipping, and infusion was described 
above in Section 5.25 and summarized in Figure 2. 
Each dose contains up to 
 total viable lymphocytes. The total volume to be 
infused will be dependent on cell concentrations. 
The lower limit of viable cells is used to define the minimum number of cells needed on 
day 7 of the 14-day REP in order to make a decision to lymphodeplete the patient using 
NMA lymphodepletion regimen. At the time of the day 14 harvest, all available cells will 
be provided in the final product.  Once lymphodepletion has begun based on this 
minimal attained cell number on day 7, the treatment of the patient is based on the 
number TILs generated at the conclusion of the 14-day REP. The upper limit of the range 
for infusion
viable cells) is based on the known published upper limit safely 
infused where a clinical response has been attained (64).  There is no evidence that 
moving beyond this upper limit will have more clinical benefit. 
5.29.2. Composition  
The active product is autologous, viable, tumor infiltrating lymphocytes. The 
quantitative composition is shown in Table 1. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
5.29.3. Transport 
Each dose of the live suspension LN-145 will be shipped/sent by courier to the clinical 
site from the TIL Manufacturing Facility the day before administration using a method 
that is intended to support 24-hour delivery.  Additional details will be specified in the 
Pharmacy and Administration Manual. 
5.29.4. Receipt at Clinical Site and Administration 
The dose of LN-145 will be received at the clinical site in the pharmacy on the day of 
administration. LN-145 will be shipped to clinical sites under quarantine while awaiting 
results of release tests. Receipt is defined as the moment the LN-145 package is signed 
for by site personnel and released from courier’s custody.  After receiving, verification, 

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and labelling with the clinical sites’ specific labels at the pharmacy, the investigational 
product, LN-145, will be transferred to the patient bedside.  Clinical investigators will be 
instructed to administer autologous LN-145 as soon as feasible.  Administration is 
recommended within 36 hours from the time of manufacture but no later than 48 
hours.  The product is infused by gravity within 45 minutes. If interruption of infusion is 
required for medical reasons, the product infusion should complete within 3 hours of 
beginning infusion.  Refer to the Pharmacy and Administration Manual for additional 
details. 
5.30. 
Interleukin-2 
Please see Section 16.5.3.1.1 for aldesleukin prescribing information. 
The high-dose IL-2 infusion will begin approximately 12 to 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 intravenous infusion at a frequency not greater than every 8 hours 
as per institutional standard of care and continued for up to a maximum of six doses.  IL-2 
doses will be skipped if patient experiences a Grade 3 or 4 toxicity due to IL-2 with the 
exception of reversible Grade 3 toxicities common to IL-2 such as diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes.  Management of IL-2 toxicity is detailed in Table 7.  If these toxicities can 
be easily reversed within 24 hours by supportive measures, then additional doses may be 
given.  If greater than 2 doses of IL-2 are skipped, IL-2 administration will be stopped.  In 
addition, dosing may be held or stopped at the discretion of the treating investigator.  
5.31. 
Required Concomitant Medications 
5.31.1. TMP/SMX DS 
Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg PO should be given per 
standard of care starting from Visit 11 (Day 0) through Visit 19 (Day 84/Month 3).  
5.31.2. Filgrastim 
Filgrastim is administered as per standard of care, or institutional protocol.  Doses 
ranging from 5 μg/kg/day to > 300 μg/kg/day are administered by subcutaneous 
injection.  Filgrastim is administered each day until the absolute neutrophil count 
reaches >1000/mm3 for three consecutive days.    
5.31.3. Fluconazole 
Fluconazole 400 mg PO daily. This should be administered each day until the absolute 
neutrophil count reaches >1000/mm3. 
 
 
 
 

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5.31.4. Anti-Viral 
Antiviral treatment for herpes infection will be initiated in patients positive for HSV. 
Valacyclovir PO or acyclovir IV will be administered daily, and continued until CD4 > 200 
cells/mm3. 
5.32. 
Immune Monitoring 
Blood for biomarker analysis will be drawn on Visits 2, 4, and every visit starting visit 12 
through 25. Samples drawn on Visit 4 (Day -7) will be considered a baseline value. Refer to the 
study Laboratory Manual for the complete procedure details. 
 
6. PERMITTED AND PROHIBITED CONCOMITANT MEDICATIONS 
6.1. 
Permitted Medications  
Current medications for conditions other than HNSCC are permitted. 
• 
Cetuximab is permitted up until approximately 2 weeks prior to start of NMA 
lymphodepletion regimen. No other anti-tumor therapy is permitted during participation in 
the study.   
• 
Systemic steroid therapy greater than 10 mg/day of prednisone or equivalent is 
discouraged unless absolutely medically indicated. 
Any changes in concomitant medications also will be recorded in the site’s source 
documentation and the patient’s eCRF. 
6.2. 
Prohibited Medications and Prior Treatment Washout 
6.2.1. Prohibited Medications 
The following treatments are prohibited during the study: 
• 
Systemic therapies and radiation intended to treat HNSCC are not permitted while 
the patient is on study. 
• 
Other investigational drugs 
6.2.2. Prior Treatment Washout 
Patients will enter a washout period prior to enrollment and must stop prior therapy as 
follows: 
• 
Cetuximab:  approximately 2 weeks before initiation of NMA lymphodepletion 
regimen. 
• 
All other chemotherapy or radiation therapy must have been discontinued 21 days 
prior to Visit 2 (Tumor Resection Visit). 
 
7. EXPECTED TOXICITIES AND THEIR MANAGEMENT 
Expected toxicities with use of the NMA lymphodepletion regimen, the LN-145 infusion, and high 
dose IL-2; and treatment guidelines for such toxicities, are described in Section 16.5.  General 

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toxicity management for cyclophosphamide, fludarabine, and IL-2 are provided in Section 7.1. Full 
prescribing information for cyclophosphamide, fludarabine and IL-2 are provided in Appendix 
Sections 16.5. 
7.1. 
General Toxicity Management 
7.1.1. Empiric Antibiotics  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation 
cephalosporin or a quinolone for fever – defined as 38.3°C once, or two temperature 
recordings of 38.0°C or above at least one hour apart, AND an ANC <500/mm3. 
Infectious disease consultation will be obtained for all patients with unexplained fever 
or any infectious complications. 
7.1.2. Blood Product Support  
Using daily CBCs as a guide, the patient will receive platelets and packed red blood cells 
(PRBCs) as needed.  Attempts will be made to keep hemoglobin >7.5 g/dL, and platelets 
>10,000/mm3.  All blood products will be irradiated.  Leukocyte filters will be utilized for 
all blood and platelet transfusions to decrease sensitization to transfused WBCs and 
decrease the risk of CMV infection. 
7.1.3. Renal Toxicity 
Renal toxicity defined by rapid rise in creatinine levels or clinical symptoms is a risk. If 
patients exhibit signs or symptoms of renal toxicity, manage as per institutional 
standard of care. 
7.1.4. Infection Prophylaxis 
Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be given as clinically 
indicated, per standard of care. 
Note: Other anti-infective agents may be substituted at the discretion of the treating 
Investigator.    
7.1.5. Pneumocystis Jiroveci Pneumonia 
All patients will receive the fixed combination of trimethoprim (TMP) and 
sulfamethoxazole [SMX] as double strength (DS) tab (DS tabs = TMP 160 mg/tab, and 
SMX 800 mg/tab) (PO) daily three times a week on non-consecutive days, beginning on 
the first Monday, Wednesday, or Friday on or after the first dose of chemotherapy.  
Pentamidine will be substituted for TMP/SMX DS in patients with sulfa allergies. It will 
be administered aerosolized at 300 mg per nebulizer within one week prior to receiving 
study treatment and continued monthly until CD4 count is above 200/mm3 and for at 
least six months post chemotherapy, or as Investigator deems appropriate. 
 

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Pneumonia prophylaxis will continue for six months post chemotherapy.  If the CD4 
count is less than 200/mm3 at six months post chemotherapy, or as Investigator deems 
appropriate, prophylaxis will continue until the CD4 count is greater than 200/mm3. 
 
7.1.6. Herpes Virus Prophylaxis 
Patients with positive HSV serology will be given valacyclovir orally at a dose of 500 mg 
daily the day after chemotherapy ends, or acyclovir, 250 mg/m2 IV every 12 hours if the 
patient is not able to take medication by mouth.  Reversible renal insufficiency has been 
reported with IV but not oral acyclovir.  Neurologic toxicity including delirium, tremors, 
coma, acute psychiatric disturbances, and abnormal EEGs has been reported with higher 
doses of acyclovir.  Should this occur, a dosage adjustment will be made or the drug will 
be discontinued.  Acyclovir will not be used concomitantly with other nucleoside analogs 
which interfere with DNA synthesis, e.g. ganciclovir.  In renal disease, the dose is 
adjusted as per product labeling. 
Herpes prophylaxis will continue for six months post-chemotherapy, or as long as 
Investigator deems necessary.  If the CD4 count is less than 200/mm3 at six months post 
chemotherapy, prophylaxis will continue until the CD4 count is greater than 200/mm3. 
7.1.7. Fungal Prophylaxis (Fluconazole) 
Patients will start fluconazole 400 mg (PO) the day after chemotherapy concludes and 
continue until the absolute neutrophil count is greater than 1000/mm3.  The drug may 
be given IV at a dose of 400 mg in 0.9% sodium chloride USP daily in patients unable to 
take it orally. 
 
8. COMPLETION/DISCONTINUATION AND WITHDRAWAL OF PATIENTS 
8.1. 
Treatment Completion 
Patients will be considered to have completed treatment if they complete the tumor harvest, 
receive the NMA-lymphodepletion regimen, the LN-145 infusion, at least one dose of IL-2, and 
have at least one post-treatment efficacy evaluation. 
8.2. 
Study Completion 
Study completion for an individual patient is defined as reaching Visit 25 (Day 672/Month 24). 
8.3. 
Criteria for Early Termination from Study (Removal from Treatment)  
The Investigator will document on the appropriate eCRF page the reasons/circumstances for 
discontinuation and complete an Early Termination Visit.  A patient may be removed from 
further study drug administration for the following medical or administrative reasons:  
• 
Withdrawal of consent  
o Patients may voluntarily withdraw at any time during the course of the study 
o The patient may withdraw consent to treatment but continue consent for follow-up 
evaluations and/or survival status 

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• 
Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, brain, eye, liver, 
colon, adrenal gland, lungs) with symptoms emerging prior to first IL-2 administration.  
• 
Grade 3 or greater allergic reaction including bronchospasm or generalized urticaria that 
does not resolve after medical management in the opinion of the investigator.  
• 
Grade 3 or greater toxicity due to IL-2 that does not decrease to Grade 2 or less within 96 
hours of management.   
• 
Determination by the PI that continued treatment is not in the best interest of the patient. 
• 
Death 
• 
Study Terminated by sponsor 
• 
Pregnancy 
• 
Lost to Follow-up 
Efforts will be made to follow all patients who are lost to follow up.  Patients can only be 
considered lost to follow-up after 3 documented attempts to contact the patient.  
8.4. 
Criteria for Removal from the Long Term Follow-Up Phase 
Patients will be removed from the Long Term Follow Up phase of the study in the following 
situations: 
• 
The patient voluntarily withdraws (the reason patient withdraws consent will be collected).   
• 
There is significant noncompliance with protocol required activities. 
• 
General or specific changes in the patient’s condition render continued participation the 
patient unacceptable for further participation in the judgment of the Investigator. 
• 
Death 
• 
Lost to Follow-Up 
• 
Study Terminated by Sponsor 
8.5. 
Study Discontinuation (Study or Site Termination) 
Conditions may arise during the study that could prompt the study to be stopped or a study 
site to be closed.  Conditions that may prompt such considerations include, but are not limited 
to the following: 
• 
The discovery of unexpected, serious, or unacceptable risk to patients enrolled in the 
study; 
• 
A decision on the part of the Sponsor to suspend, discontinue, or shorten the study; 
• 
Study conduct at a study site may warrant termination under conditions that include the 
following:  
o Failure of the Investigator(s) to enroll eligible patients into the study 
o Failure of the Investigator(s) to comply with FDA or country-specific regulations  
o Submission of false information from the research facility to the Sponsor, the 
Clinical Monitor, or a regulatory authority 
o Insufficient adherence to protocol requirements 
o A conflict of interest on the part of the Investigator, his/her institution, or site 
personnel that would negatively impact the integrity of the clinical trial 

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o Institution or IRB under investigation for cause by a federal agency 
 
9. SAFETY ASSESMENTS 
9.1. 
Data Safety Monitoring Board 
The DSMB will perform a safety evaluation of data analyzed when the first 3 patients have 
completed the Treatment Phase. Enrollment shall not be halted and will continue while under 
review. Additional evaluations may be specified in the charter. 
9.2. 
Considerations 
Adverse events are detailed in Section 10.  Other measures of safety include the following:  
physical exam including weight (calculate BSA using Dubois formula and BMI), ECOG 
performance status, vital signs (pulse, respirations, blood pressure and temperature), blood 
and urine tests (prior to cyclophosphamide administration), hematology (CBC with differential), 
serum chemistry (see below), urinalysis (complete urine culture if indicated), and ongoing 
assessment of CMV antigen status, as clinically indicated.  
In particular, attention will be made to the expected toxicities of the NMA lymphodepletion 
regime and the high-dose IL-2 regimens (see Appendix Section 16.5.2).  
• 
Serum chemistry parameters include the following: 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Total CO2, or bicarbonate 
• 
Creatinine 
• 
Glucose 
• 
Bun 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Alkaline phosphatase 
• 
ALT/SGPT 
• 
AST/SGOT 
• 
Bilirubin (total and direct) 
• 
LDH 
• 
Total protein 
• 
Total CK 
• 
Uric acid 
• 
Thyroid panel (including TSH and free T4) 
 

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10. ADVERSE EVENTS 
Toxicities will be recorded as AEs and SAEs in the patient’s source documents and on the Adverse 
Events eCRF and must be graded using the NCI’s CTCAE v4.03 dated June 14, 2010 (see Appendix 
Section 16.4).  
10.1. 
Definitions 
10.1.1. Adverse Event 
An AE is defined as any untoward medical occurrence that occurs during a clinical 
investigation regardless of causal relationship with the investigational product.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease assessed in eligible Patients after enrollment in 
the study. 
Events meeting the definition of an AE include: 
• 
Adverse event temporally associated with the use of any of the study drugs or 
TIL treatment whether or not considered related to the use of any of the study 
drugs or TIL treatment. 
• 
Any abnormal laboratory test results (e.g. hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., EKGs, radiological scans, vital signs 
measurements), that worsen from baseline, and are felt to be clinically 
significant in the medical and scientific judgment of the Investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after investigational product 
administration. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction with 
investigational product. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication. 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the Patient’s condition.  
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.1.2. Serious Adverse Event 

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An AE is considered serious if, in the view of either the Investigator or the Sponsor, it 
results in any of the following outcomes:  
• 
Death 
• 
Is Life Threatening 
• 
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 that may not directly result in death, be life-threatening, or 
require hospitalization may be considered serious when, based on Investigator decision, 
they may jeopardize the Patient and may require intervention to prevent one of the 
above outcomes as listed in this definition. 
Hospitalization including admission to a telemetry unit or intensive care unit specifically 
for administration of study treatment is not considered a serious adverse event.  
Any pregnancy that occurs while on the study must be reported to the Sponsor or their 
representative.  The pregnancy must be followed up until discharge following delivery or 
premature termination to determine outcome and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.  Any SAE 
occurring in association with a pregnancy, brought to the Investigator’s attention after 
the Patient has completed the study and considered by the Investigator as possibly 
related to the investigational product, must be promptly reported to the Sponsor or 
their representative.  In addition, the Investigator must attempt to collect pregnancy 
information on any female partners of male study Patients who become pregnant while 
the Patient is enrolled in the study. Pregnancy information must be reported to the 
Sponsor or their representative. 
10.2. 
Reporting Procedures for Adverse Events 
10.2.1. All Adverse Events 
All AEs occurring after enrollment in the study and either observed by the Investigator 
or reported by the patient (whether or not attributed to the use of IL-2 or LN-145), will 
be reported on the eCRF.  Monitoring and reporting AEs will be conducted through the 
last on-study visit.   
Medically significant AEs considered related to the study treatment by the Investigator 
or the Sponsor will be followed until resolved or resolved with sequelae.  The 
Investigator shall categorize the cause of the AE as chemotherapy, LN-145, IL-2 or other 
and must assign the following attributes:  description; dates of onset and resolution; 
severity; assessment of relatedness to investigational product, and action taken.  The 
Investigator may be asked to provide follow-up information. 
If any patient should die while on the study, the Investigator will inform the Sponsor as 

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soon as possible.  (Note: Death due to disease progression should not be reported as a 
SAE unless it is deemed to be related to the use of study treatment.)  The cause of death 
should be recorded in detail on the SAE Report Form. 
Each site will be responsible for reporting SAEs occurring at the site to the applicable IRB 
per the IRB’s reporting guidelines.   
It will be left to the Investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the patient’s removal from the study treatment.  A patient may also 
voluntarily discontinue treatment due to what he or she perceives as an intolerable AE. 
This should be captured in the eCRF. If either of these occurs, the patient must undergo 
an early termination visit and be given appropriate care under medical supervision until 
symptoms cease or the condition becomes stable and returns for a safety Follow-up 
visit.  If the patient was permanently removed from the study or investigational product 
due to an SAE, this information must be included in either the initial or follow-up SAE 
Report Form and in the eCRF. 
10.2.2. Relationship to Study Drug 
The following categories and definitions of causal relationship to study treatment should 
be considered: 
• 
Definite: There is a known causal relationship between the study drug and the 
AE/SAE.  The event responds to withdrawal of study drug (de-challenge), and 
recurs with re-challenge when clinically feasible. (>95% certainty of 
relatedness). 
• 
Probable: There is reasonable causal relationship between the study drug and 
the AE/SAE.  The event responds to de-challenge. Re-challenge is not required. 
(65%-95% probability of relatedness). 
• 
Possible: There is reasonable causal relationship between the study drug and 
the AE/ SAE.  De-challenge information is lacking or unclear. (35%-65% 
probability of relatedness). 
• 
Not likely: There is temporal relationship to study drug administration, but 
there is not a reasonable causal relationship between the study drug and the 
AE/SAE. (5-35% probability of relatedness). 
• 
Not related: There is not a temporal relationship to study drug administration 
(too early, or late, or study drug not taken), or there is known causal 
relationship between the AE/SAE and another drug, concurrent disease, or 
other circumstance. (<5% chance of relatedness). 
10.2.3. Severity 
The severity of an event describes the degree of impact and/or the need for medical 
care necessary to treat an event.   
AE grading will be defined by the CTCAE v 4.03 (see Section 16.4).  In the event the 
CTCAE v 4.03 does not apply, the severity descriptions below will be used. 

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• 
Mild:  Asymptomatic; clinical or diagnostic observations only; intervention not 
indicated 
• 
Moderate:   Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate activities of daily life 
• 
Severe:   Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization may be required; disabling; 
limiting activities of daily life 
• 
Life-threatening:  Urgent intervention is required 
10.3. 
Reporting Procedures for Serious Adverse Events 
10.3.1. Investigator Reporting to Sponsor 
All SAEs, regardless of relationship to study treatment, must be collected while on the 
study.  In addition, the Investigator must notify the Sponsor of any SAE that may occur 
after this time period which (s)he believes to be certainly, probably, or possibly related 
study treatment.   
SAE terminology and severity grading will be based on the NCI’s CTCAE v4.03 guidelines. 
All SAEs that occur during the course of the investigation must be reported by the 
Investigator to the Sponsor or designee within 24 hours of learning of the event.  The 
initial notification should be as complete as is possible with the information available 
and include the Investigator’s assessment of whether there is a reasonable possibility 
that the study drug caused the event.  SAE reports will be reported to Chiltern 
International, Inc. via EDC system, MERGE eCOS. Paper SAE forms can be used as back 
up and send via GlobalSAEinbox@chiltern.com or fax (1-888-726-8416). Reporting to 
Regulatory Agencies and Institutional Review Boards (IRBs). 
In the event of a serious adverse event, the Sponsor, or their designee, will notify the 
appropriate regulatory authorities and all appropriate parties as per the regulations.  
The Investigator is responsible for reporting serious adverse events to their IRBs 
In addition, the Sponsor must submit expedited reports of an increased rate of 
occurrence of serious adverse events over that listed in the protocol or Investigational 
Brochure. Sponsor will notify participating sites of any serious adverse events which 
occur during trial. 
 
11. Efficacy ASSESSMENTS 
11.1. 
Tumor Response Criteria 
Clinical response will be determined using RECIST version 1.1. 

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11.1.1. Evaluation of Target Lesions1 
• 
Complete Response (CR):  Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have a reduction in short axis to 
<10 mm). 
• 
Partial Response (PR):  At least a 30% decrease in the sum of the diameter of target 
lesions taking as reference the baseline sum diameters. 
• 
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. 
11.1.2. Evaluation of Non-Target Lesions2  
• 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
• 
Non-Complete Response:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above normal limits. 
• 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression) 
11.1.3. Determination of Best Response for Each Patient 
The best response for each patient is determined once all the data for the patient is known.  The 
best overall response is the best response recorded from the start of treatment until disease 
progression/recurrence, the initiation of new anti-cancer therapy, death or 24 months 
whichever comes first.  The patient's best response assignment will depend on the achievement 
                                                          
1 All measurable lesions up to a maximum of two lesions per organ and five lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured during screening. A sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. The baseline sum diameters will be used as reference by which to 
characterize any objective tumor regression in the measurable dimension of the disease. If lymph nodes are to 
be included in the sum, only the short axis will contribute. 
2 All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at 
baseline.   

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of both measurement and confirmation criteria.  The assignment of response for an individual 
patient, based on both target and non-target lesions, at each assessment time point is shown in 
Table 1.  The best overall response for each patient is determined as shown in Table 2. 
Table 1.           Response at each Assessment Time Point for Patients with Target (± Non-target) Disease 
Target Lesions at the 
indicated Time point 
Non-Target Lesions at the 
indicated Time point 
New Lesions at the 
indicated Time point 
Overall Response at the 
indicated Time point 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 2.          Examples of Best Overall Response for each Patient Across All Assessments 
Overall Response at 
Time point 1 
Overall Response at Time 
point 2 
Overall Response at 
Time point 3 
Best Overall Response 
Across Assessment 
Time points 
CR 
CR 
CR 
CR 
PR 
PR 
CR 
CR 
SD 
SD 
PR 
PR 
SD 
PR 
SD 
PR 
SD 
SD 
PD 
SD 
11.2. 
Overall Response Rate (ORR) 
The ORR will be based on the best overall response for each patient.  The ORR rate is the 
percentage of patients who achieved a best response of CR or PR among those successfully 
undergone NMA lymphodepletion and infused with LN-145 and at least one dose of IL-2.  
11.3. 
Confirmatory Measurement/Duration of Response 
11.3.1. Confirmation 
To be assigned a status of PR or CR changes in tumor measurements must be confirmed 
by repeat studies that should be performed at least 4 weeks after the criteria for 
response are first met.   
11.3.2. Duration of Overall Response 
The duration of overall complete response is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
 

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12. STATISTICAL ANALYSIS PLAN 
12.1. 
Introduction 
The primary statistical plan of analysis is based on use of descriptive methods unless 
mentioned otherwise. Continuous data will be summarized as the number of patients with 
non-missing data (N), mean, standard deviation, median, minimum, and maximum values. 
Categorical data will be summarized as counts and their related percentages, where applicable. 
Estimation of confidence limits will use two-sided, 95%. Missing data will not be imputed unless 
mentioned otherwise.  
A more detailed description of the analyses and reporting plan of the data will be provided in 
the Statistical Analysis Plan (SAP).  
12.2. 
Analysis Populations 
Three analysis populations will be defined to summarize the data. The resected population will 
consist of all patients with resection of tumor for TIL harvest. The treated population consists 
of the resected patients who have been successfully infused with lymphodepletion, LN-145 
followed by at least 1 dose of IL-2. Separately, the untreated population also represents the 
other subset of the resected population who did not receive the study treatment. 
 The efficacy analysis is performed among patients in the treated population. The responder 
population comprises those patients achieving a CR or PR as a best overall response.  The 
responder population will be used to summarize the duration of response.   
12.3. 
Sample Size Justification 
The planned sample size for this single arm study is 47 patients.  A Simon’s optimal two-stage 
design will be used to test the null hypothesis that ORR will be ≤5% (not considered clinically 
meaningful).  Fifteen patients will be included in the first stage, and if there are 1 or fewer 
patients responding to therapy, the study will terminate.  Expansion into Stage 2 to a total of 
47 patients will occur concurrently with the interim analysis of Stage 1.  If at least 6 patients 
respond to therapy, the study therapy would be considered to have met its statistical goal. This 
two-stage design has 80% power to detect a difference of an ORR of 5% versus 20% using a 
one-sided 0.025 alpha level test.   
12.4. 
Baseline Demographic and Clinical Characteristics 
 
 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. 
12.5. 
Safety and Efficacy Analysis 
12.5.1. Primary Endpoint 
The assessment of safety data will be descriptive and based on the summarization of 
treatment-emergent adverse events including serious adverse events, adverse events 

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leading to discontinuation from the study, and clinical laboratory tests.  Adverse event 
summaries will be based on patient incidence counts and their related percentages; the 
number of events will be displayed as appropriate. In additional to an overall summary 
of adverse events, separate displays will be made by intensity (grades by CTCAE) and 
relationship. These toxicity grade summaries will also be provided separately for 
applicable laboratory parameters. 
A separate safety summary will be provided for patients in the resected treated 
population until the lymphodepletion therapy and resected untreated population.  
The primary efficacy endpoint is the overall response rate (CR+PR) as assessed by a 
central imaging reader.  The ORR is defined as the proportion of patients who achieve 
either a PR or CR as best response as assessed by investigators according to the RECIST 
version 1.1 Criteria.  Objective response will be evaluated per each disease assessment 
and the ORR will be calculated for the Safety population.  The corresponding 95% two-
sided confidence interval will be derived.   
12.5.2. Secondary Endpoints 
12.5.2.1. 
Additional Measures of Efficacy  
• 
The CR rate is based on responders (patients with ORR) who achieved CR as 
a best overall response, as assessed by investigators. 
• 
PFS is defined as the time (in months) 
o 
PD, or death due to any cause, whichever event is earlier. Patients not 
experiencing PD or having expired 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 
 
 due to any cause. Patients not having expired 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. 
• 
Duration of overall response is measured from the first time response 
criteria are met until the first date that recurrent or progressive disease 
occurs. Patients not experiencing PD or death 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. 
• 
PFS, OS, durations of any response will be subjected to right censoring. 
Kaplan-Meier methods will apply. 
12.5.3. Exploratory Analyses 
Correlations of immune factors with response, survival, and toxicity will be explored. 
  

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13. ADMINISTRATIVE REQUIREMENTS 
13.1. 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor., its authorized 
representative, and Investigator abide by Good Clinical Practice (GCP), as described in 
International Conference on Harmonization (ICH) Guideline E6 and in accordance with the 
general ethical principles outlined in the Declaration of Helsinki. The study will receive approval 
from an IRB/EC prior to commencement. The Investigator will conduct all aspects of this study 
in accordance with applicable national, state, and local laws of the pertinent regulatory 
authorities. 
13.2. 
Protocol Modifications 
The Investigator will not modify this protocol without obtaining the concurrence of the 
sponsor.  All protocol amendments must be issued by the Sponsor, signed and dated by the 
Investigator, and should not be implemented without prior IRB approval, except where 
necessary to eliminate immediate hazards to the patients or when the change(s) involves only 
logistical or administrative aspects of the trial (e.g., change in monitor[s], change of telephone 
number[s]).  Responsibilities for reporting protocol amendments to any Regulatory Authority (if 
applicable) and/or IRB are further described in the Ethical Aspects section of the protocol. 
In situations requiring a departure from the protocol, the Investigator or other physician in 
attendance will contact the Sponsor or its representative for approval prior to any intended 
departure from the protocol.   
13.3. 
Regulatory Documentation 
Documents that must be provided to the Sponsor prior to study drug shipment are as follows: 
• 
Up-to-date curriculum vitae for each Investigator.  
• 
Signed and dated Investigator Agreement.  
• 
Applicable local regulatory documentation (e.g., FDA 1572 Form). 
• 
A copy of the formal written notification to the Investigator regarding approval of the 
protocol by an IEC/IRB that is in compliance with regulatory guidelines. The written 
notification is to be signed by the chairman or authorized designee and must identify the 
specific protocol.  In cases where an IEC/IRB member has a known conflict of interest, 
abstention of that individual from voting should be documented; an Investigator may be a 
member of the IEC/IRB, but may not vote on any research in which he or she is involved. 
• 
Name and address of the IRB with a statement that it is organized and operates according 
to GCP and the applicable laws and regulations, and a current list of the IRB members. If 
accompanied by a letter of explanation from the IRB, a general statement may be 
substituted for this list. 

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• 
A copy of the IRB approved informed consent and other adjunctive materials (e.g., 
advertising) to be used in the study, including written documentation of IEC approval of 
these items. 
• 
Name and address of any local laboratory conducting tests for the study, a dated copy of 
the laboratory reference values for tests to be performed during the study and a copy of 
the certification or other documentation establishing adequacy of the facility. 
• 
Required financial agreement. 
• 
In addition to the documents required prior to the study, other documentation may be 
required during the course of the study. 
13.4. 
Record Retention 
In compliance with the ICH/GCP guidelines the Investigator/institution will be responsible for 
all information in the eCRF and will maintain the source documents that support the data 
collected from each patient, and all trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial and as specified by the applicable regulatory requirement(s). The 
Investigator/Institution will take measures to prevent accidental or premature destruction of 
these documents.  Essential documents must be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
will be retained for a longer period if required by the applicable regulatory requirements or by 
an agreement with the Sponsor.  It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. If the 
responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility.  The Sponsor must be notified in writing of the name and address of 
the new custodian. 
13.5. 
Data Quality Assurance  
Steps to be taken to assure the accuracy and reliability of data include; the selection of 
qualified Investigators and appropriate study centers, review of protocol procedures with the 
Investigator and associated personnel prior to the study, periodic monitoring visits by the 
Sponsor and direct transmission of clinical laboratory data from a central laboratory into the 
database.  Electronic CRFs will be reviewed for accuracy and completeness by Clinical Research 
Monitors during on- site monitoring visits and after their return from the site, and any 
discrepancies will be resolved with the Investigator or designees, as appropriate. The data will 
be verified for accuracy. 
Agreements made by the Sponsor with the Investigator/Institution and any other parties 
involved in the clinical trial will be in writing as a separate agreement. On-Site Audits 
Representatives of the Sponsor’s Clinical Quality Assurance department 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 

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and comparison with the eCRFs.  Patient privacy must, however, be respected.  Sufficient prior 
notice will be provided to allow the Investigator to prepare properly for the audit. 
Similar auditing procedures may also be conducted by agents of any regulatory body reviewing 
the results of this study in support of a Licensing Application. The Investigator should 
immediately notify the Sponsor if they have been contacted by a regulatory agency concerning 
an upcoming inspection. 
13.6. 
Data Handling and Recordkeeping 
13.6.1. Electronic Data 
When using electronic data handling, the Sponsor or their designee will ensure that 
systems comply with 21CFR Part 11 requirements.  Documentation regarding the 
electronic data systems used in this protocol is located in the study-specific plans or 
SOPS for that particular task. 
13.6.2. Electronic Case Report Form (eCRF) Completion 
Electronic data capture (EDC) will be used for this study.  The site will be suitably trained 
on the use of the eCRF and appropriate site personnel will be provided electronic 
signatures.  Data must be entered into the eCRF screens in English. The eCRFs are to be 
completed at the time of the patient's visit, with the exception of results of tests 
performed outside the Investigator's office, so that they always reflect the latest 
observations on the patients participating in the trial. 
Data must be recorded first on a source document that can be verified before it is 
entered in the EDC system.  Completed eCRFs are to be signed off by the Investigator as 
per the data completion guidelines written for this trial.  
All eCRF corrections are to be made by the Investigator or other authorized study site 
personnel. The Investigator must authorize changes to the recorded safety and efficacy 
data. 
Completed eCRFs will be submitted according to the Sponsor's instructions, and 
reviewed by the Sponsor to determine their acceptability.  If necessary, Data Correction 
Requests will be generated for resolution by the study site. 
13.7. 
Study Completion/Termination 
13.7.1. Study Completion 
The Investigator will complete the study and submit all eCRFs in satisfactory compliance 
with the protocol after study completion. 
13.8. 
Monitoring 
On-site monitoring visits will be performed by the Sponsor as frequently as necessary. Visits are 
usually made at intervals of at least four to twelve weeks.  The dates of the visits will be 
recorded by the monitor in a trial center visit log to be kept at the site. The first post-initiation 
visit will usually be made as soon as possible after enrollment has begun.  At these visits the 

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monitor will compare the data entered into the eCRFs with the hospital or clinic records 
(source documents). At a minimum, source documentation must be available to substantiate 
proper informed consent procedures, adherence to protocol procedures, adequate reporting 
and follow-up of adverse events, administration of concomitant medication, drug 
receipt/dispensing/return records, and study drug administration information.  Specific items 
required as source documents will be reviewed with the Investigator prior to the study.  
Findings from this review of eCRFs and source documents will be discussed with the 
Investigator. The Sponsor expects that, during monitoring visits, the Investigator (and as 
appropriate the Study Coordinator) will be available, the source documentation will be 
available, and a suitable environment will be provided for review of study-related documents. 
 
14. INVESTIGATOR REGULATORY OBLIGATIONS 
14.1. 
Institutional Review Boards 
This trial will be undertaken only after full approval of the protocol and addenda has been 
obtained from an IRB and a copy of this approval has been received by the Sponsor.  The IRB 
must be informed of all subsequent protocol amendments issued by the Sponsor.  Reports on, 
and reviews of, the trial and its progress will be submitted to the IRB by the Investigator at 
intervals stipulated in their guidelines. 
The IRB must meet all regulatory requirements governing IRBs (CFR, Title 21, Part 56). 
14.2. 
Informed Consent 
Each patient (or a legally authorized representative) must give written consent (and sign other 
locally required documents) according to local requirements after the nature of the study has 
been fully explained. The consent form must be signed prior to performance of any study-
related activity.  The consent form that is used must be approved both by the Sponsor and by 
the reviewing IRB.  The informed consent should be in accordance with the current revision of 
the Declaration of Helsinki, current International Conference on Harmonization (ICH) and Good 
Clinical Practice (GCP) guidelines, and the Sponsor’s policies. 
The Investigator must explain to potential patients or their legal representatives the aims, 
methods, reasonably anticipated benefits and potential hazards of the trial, and any discomfort 
it may entail.  Patients will be informed that they are free not to participate in the trial and that 
they may withdraw consent to participate at any time.  They will be told which alternative 
treatments are available if they refuse to take part and that such refusal will not prejudice 
future treatment. Finally, they will be told that their records may be examined by competent 
authorities and authorized persons but that personal information will be treated as strictly 
confidential and will not be publicly available. Patients must be given the opportunity to ask 
questions. After this explanation and before entry into the trial, consent should be 
appropriately recorded by means of the patient's or his/her legal representative's dated 
signature.  If a patient and his/her legal representative are unable to read, an impartial witness 
must be present during the entire informed consent discussion. The signature of the impartial 

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witness will certify the patient's consent. The patient should receive a signed and dated copy of 
the informed consent. The informed consent process should be documented in the patient’s 
medical record. 
In accordance with HIPAA, the written Informed Consent Form must include a patient 
authorization to release medical information to the Sponsor or their representative and/or 
allow the Sponsor or their representative, a regulatory authority, or IRB access to patient’s 
medical information that includes all hospital records relevant to the study, including a 
patient’s medical history. 
14.3. 
Patient Data Protection 
The Principal Investigator at each site and designees, employees, and agents involved with this 
study will comply with relevant state and federal laws relating to the confidentiality, privacy, 
and security of patient’s personal health information (PHI). They will only create, maintain, use, 
or disclose any data that is generated by this study or other information disclosed to the 
Principal Investigator or their employees or agents during the course of the study to the 
Sponsor, IRB, FDA, or other authorized recipients as appropriate for the execution, analysis, 
review, and reporting of this study. Such information shall not be used for any other purposes 
and will remain confidential. Patient records are only to be identified by initials and patient ID 
numbers. 
14.4. 
Adverse Event Reporting 
The Investigator agrees to report all AEs to the Sponsor as described in the Adverse Events 
section.  Furthermore, the Investigator is responsible for ensuring that any co-Investigator or 
sub-Investigator promptly bring AEs to the attention of the Investigator.  If applicable, the 
Investigator also is responsible for informing the participating IRB/IEC of any SAEs. 
14.5. 
Investigator 
The Investigator will permit study-related monitoring, audits, IEC/IRB review, and regulatory 
inspections by providing direct access to source data and documents. The Investigator must 
notify the Sponsor when contacted by a regulatory authority regarding inspection of her/his 
study site. 
All required data will be recorded in the eCRFs in a timely manner.  All eCRF data must be 
submitted to the Sponsor throughout and at the end of the study. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify the Sponsor to agree upon an acceptable storage solution. Regulatory 
authorities will be notified with the appropriate documentation detailing the person to whom 
the responsibility has been transferred. 
14.6. 
Confidentiality 
Unless otherwise specified in the clinical study agreement, the following process shall occur: 
The Investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  In the eCRFs or other documents 

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submitted to the Sponsor, patients should not be identified by their names, but by an 
identification code. The Investigator should keep a site enrollment log showing codes, names, 
and addresses.  Documents not for submission to the Sponsor (e.g., patients’ written consent 
forms) should be maintained by the Investigator in strict confidence, in accordance with all 
applicable local and national regulations.  All information provided to the Investigator prior to 
the study, as well as all data developed during the study, is confidential and remains the 
property of the Sponsor.  The Investigator agrees that no information based on the conduct of 
this study (including the protocol, the data resulting from this study, or the fact that this study 
is/was conducted) will be released without prior written consent of the Sponsor unless this 
requirement is superseded by local or national regulations. 
14.7. 
Publications 
The Sponsor will be responsible for determining when the study results should be published. 
The Sponsor will work jointly with the Investigators to publish information. The Investigator 
shall not submit a publication to journals or professional societies without the prior written 
approval of the Sponsor. 

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65. Robbins, P.F., Lu, Y.C., El-Gamil, M., Li, Y.F., Gross, C., Gartner, J., Lin, J.C., Teer, J.K., Cliften, P., 
Tycksen, E., et al. 2013. Mining exomic sequencing data to identify mutated antigens recognized 
by adoptively transferred tumor-reactive T cells. Nat Med 19:747-752. 

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66. Tran, E., Turcotte, S., Gros, A., Robbins, P.F., Lu, Y.C., Dudley, M.E., Wunderlich, J.R., Somerville, 
R.P., Hogan, K., Hinrichs, C.S., et al. 2014. Cancer immunotherapy based on mutation-specific 
CD4+ T cells in a patient with epithelial cancer. Science 344:641-645. 
67. Kvistborg, P., van Buuren, M.M., and Schumacher, T.N. 2013. Human cancer regression antigens. 
Curr Opin Immunol 25:284-290. 
68. van Rooij, N., van Buuren, M.M., Philips, D., Velds, A., Toebes, M., Heemskerk, B., van Dijk, L.J., 
Behjati, S., Hilkmann, H., El Atmioui, D., et al. 2013. Tumor exome analysis reveals neoantigen-
specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31:e439-442. 
69. Sim, G.C., Chacon, J., Haymaker, C., Ritthipichai, K., Singh, M., Hwu, P., and Radvanyi, L. 2014. 
Tumor-infiltrating lymphocyte therapy for melanoma: rationale and issues for further clinical 
development. BioDrugs 28:421-437. 
70. Wu, R., Forget, M.A., Chacon, J., Bernatchez, C., Haymaker, C., Chen, J.Q., Hwu, P., and Radvanyi, 
L.G. 2012. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for 
metastatic melanoma: current status and future outlook. Cancer J 18:160-175. 
71. Besser, M.J., Treves, A.J., Itzhaki, O., Hardan, I., Nagler, A., Papa, M.Z., Catane, R., Winkler, E., 
Shalmon-Zifroni, B., and Schachter, J. 2006. Adoptive cell therapy for metastatic melanoma 
patients: pre-clinical development at the Sheba Medical Center. Isr Med Assoc J 8:164-168. 
72. Spiess, P.J., Yang, J.C., and Rosenberg, S.A. 1987. In vivo antitumor activity of tumor-infiltrating 
lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst 79:1067-1075. 
73. Dudley, M.E., Wunderlich, J.R., Yang, J.C., Sherry, R.M., Topalian, S.L., Restifo, N.P., Royal, R.E., 
Kammula, U., White, D.E., Mavroukakis, S.A., et al. 2005. Adoptive cell transfer therapy following 
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol 23:2346-2357. 
74. Dudley, M.E., Yang, J.C., Sherry, R., Hughes, M.S., Royal, R., Kammula, U., Robbins, P.F., Huang, 
J., Citrin, D.E., Leitman, S.F., et al. 2008. Adoptive cell therapy for patients with metastatic 
melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin 
Oncol 26:5233-5239. 
75. Dudley, M.E., Gross, C.A., Langhan, M.M., Garcia, M.R., Sherry, R.M., Yang, J.C., Phan, G.Q., 
Kammula, U.S., Hughes, M.S., Citrin, D.E., et al. 2010. CD8+ enriched "young" tumor infiltrating 
lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res 16:6122-6131. 
76. Rosenberg, S.A., Yang, J.C., Sherry, R.M., Kammula, U.S., Hughes, M.S., Phan, G.Q., Citrin, D.E., 
Restifo, N.P., Robbins, P.F., Wunderlich, J.R., et al. 2011. Durable complete responses in heavily 
pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer 
Res 17:4550-4557. 
77. Besser, M.J., Shapira-Frommer, R., Treves, A.J., Zippel, D., Itzhaki, O., Schallmach, E., Kubi, A., 
Shalmon, B., Hardan, I., Catane, R., et al. 2009. Minimally cultured or selected autologous 
tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic 
melanoma patients. J Immunother 32:415-423. 
78. Besser, M.J., Shapira-Frommer, R., Treves, A.J., Zippel, D., Itzhaki, O., Hershkovitz, L., Levy, D., 
Kubi, A., Hovav, E., Chermoshniuk, N., et al. 2010. Clinical responses in a phase II study using 

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adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma 
patients. Clin Cancer Res 16:2646-2655. 
79. Ellebaek, E., Iversen, T.Z., Junker, N., Donia, M., Engell-Noerregaard, L., Met, O., Holmich, L.R., 
Andersen, R.S., Hadrup, S.R., Andersen, M.H., et al. 2012. Adoptive cell therapy with autologous 
tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J 
Transl Med 10:169. 
80. Besser, M.J., Shapira-Frommer, R., Itzhaki, O., Treves, A.J., Zippel, D.B., Levy, D., Kubi, A., 
Shoshani, N., Zikich, D., Ohayon, Y., et al. 2013. Adoptive transfer of tumor-infiltrating 
lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after 
failure to prior immunotherapies. Clin Cancer Res 19:4792-4800. 
81. Anderson, A., Donia, M., Holz-Borch, T., Ellebaek-Steensgaard, E., Zeeeberg-Iversen, T., 
Kongsted, P., Anderson, M.H., Straten, P.T., and Svane, I.M. 2014. Adoptive cell therapy with 
tumor infiltrating lymphocytes and intermediate dose IL-2 for metastatic melanoma. 29th 
Annual Meeting of the Society for the Immunotherapy of Cancer (SITC). 
82. Radvanyi, L.G., Bernatchez, C., Zhang, M., Fox, P.S., Miller, P., Chacon, J., Wu, R., Lizee, G., 
Mahoney, S., Alvarado, G., et al. 2012. Specific lymphocyte subsets predict response to adoptive 
cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma 
patients. Clin Cancer Res 18:6758-6770. 
83. Pilon-Thomas, S., Kuhn, L., Ellwanger, S., Janssen, W., Royster, E., Marzban, S., Kudchadkar, R., 
Zager, J., Gibney, G., Sondak, V.K., et al. 2012. Efficacy of adoptive cell transfer of tumor-
infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother 
35:615-620. 
84. Ogino, T., Shigyo, H., Ishii, H., Katayama, A., Miyokawa, N., Harabuchi, Y., and Ferrone, S. 2006. 
HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a 
poor prognostic marker. Cancer Res 66:9281-9289. 
85. Kong, C.S., Narasimhan, B., Cao, H., Kwok, S., Erickson, J.P., Koong, A., Pourmand, N., and Le, 
Q.T. 2009. The relationship between human papillomavirus status and other molecular 
prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 
74:553-561. 
86. Wansom, D., Light, E., Worden, F., Prince, M., Urba, S., Chepeha, D.B., Cordell, K., Eisbruch, A., 
Taylor, J., D'Silva, N., et al. 2010. Correlation of cellular immunity with human papillomavirus 16 
status and outcome in patients with advanced oropharyngeal cancer. Arch Otolaryngol Head 
Neck Surg 136:1267-1273. 
87. Ward, M.J., Thirdborough, S.M., Mellows, T., Riley, C., Harris, S., Suchak, K., Webb, A., Hampton, 
C., Patel, N.N., Randall, C.J., et al. 2014. Tumour-infiltrating lymphocytes predict for outcome in 
HPV-positive oropharyngeal cancer. Br J Cancer 110:489-500. 
88. Wansom, D., Light, E., Thomas, D., Worden, F., Prince, M., Urba, S., Chepeha, D., Kumar, B., 
Cordell, K., Eisbruch, A., et al. 2012. Infiltrating lymphocytes and human papillomavirus-16--
associated oropharyngeal cancer. Laryngoscope 122:121-127. 
89. Junker, N., Andersen, M.H., Wenandy, L., Dombernowsky, S.L., Kiss, K., Sorensen, C.H., 
Therkildsen, M.H., Von Buchwald, C., Andersen, E., Straten, P.T., et al. 2011. Bimodal ex vivo 

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expansion of T cells from patients with head and neck squamous cell carcinoma: a prerequisite 
for adoptive cell transfer. Cytotherapy 13:822-834. 
90. Junker, N., Kvistborg, P., Kollgaard, T., Straten, P., Andersen, M.H., and Svane, I.M. 2012. Tumor 
associated antigen specific T-cell populations identified in ex vivo expanded TIL cultures. Cell 
Immunol 273:1-9. 
91. Mougdil, T., Paustian, C., Feng, Z., Leidne, r.R., Dubay, C., Curti, B., Hu, H.-M., Bifulco, C., Fox, B., 
and Bell, B. 2015. An Evaluation of autologous tumor-reactive TIL generation from head and 
neck squamous cell cancers. J ImmunoTherapy of Cancer  3 37. 
92. Goff, S.L., Smith, F.O., Klapper, J.A., Sherry, R., Wunderlich, J.R., Steinberg, S.M., White, D., 
Rosenberg, S.A., Dudley, M.E., and Yang, J.C. 2010. Tumor infiltrating lymphocyte therapy for 
metastatic melanoma: analysis of tumors resected for TIL. J Immunother 33:840-847. 
93. Leidner, R., BD, C., Payne, R., Urba, W., Bahjat, K., Koguchi, Y., Nelson, K., Moore, J., Crittenden, 
M., Ying, Y., et al. 2015. Adoptive TIL in HPV-negative Oral SCCA. J ImmunoTherapy of Cancer 
3:26. 
94. Dudley, M.E., Wunderlich, J.R., Robbins, P.F., Yang, J.C., Hwu, P., Schwartzentruber, D.J., 
Topalian, S.L., Sherry, R., Restifo, N.P., Hubicki, A.M., et al. 2002. Cancer regression and 
autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 
298:850-854. 
95. Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 

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16. APPENDICIES 
16.1. 
Schedule of Assessments 
 
 
Pre Treatment Phase 
Treatment Phase 
  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visits 6, 7, 8, 9, 10 
Visit 11 
Visit Name 
Screening 
Visit 
Tumor 
Resection 
Visit 
Day -14 
Day -7 
Day -6 
Days -5, -4, -3, -2, -
1 
Day 0 (LN-145 
Infusion Visit) 
Visit Window 
up to 4 weeks 
(28 days) 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Informed Consent 
X 
  
  
  
  
  
  
Inclusion/Exclusion 
X 
  
  
  
  
  
  
Demographic Data 
X 
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
Documentation of diagnosis 
X 
  
  
  
  
  
  
Documentation of HPV status 
X 
  
  
  
  
  
  
Physical Exam [1] 
X 
  
X 
X 
X 
X 
X 
Vital Signs [2] 
X 
X 
X 
X 
X 
X 
X [3] 
ECOG performance status 
X 
X 
X 
X 
  
  
X 
Safety blood and urine tests [4] 
X 
X 
X 
X 
X 
X 
X 
ß-HCG Serum Pregnancy Test 
X 
  
X 
  
  
  
  
Virus testing [5] 
X 
  
  
  
  
  
  
HLA typing [6] 
X 
  
  
  
  
  
  
HPV Serotype 
 
 X 
  
  
  
  
  
CMV Antigen Assay [7] 
X 
  
  
X 
X 
X 
X 
Estimated Creatinine Clearance [8] 
X 
X 
X 
X 
X 
X 
X 
Eye Exam 
X 
  
  
  
  
  
  
Cardiac Evaluations [9] 
X 
  
  
  
  
  
  
Pulmonary function tests [10] 
X 
  
  
  
  
  
  
Colonoscopy [11] 
X 
  
  
  
  
  
  
Tumor Assessments [12]  
X 
  
X 
  
  
  
  
Response Assessments (RECIST v. 1.1) 
  
  
  
  
  
  
  
Concomitant Meds 
X 
     X [13] 
X 
X 
X 
X 
X 
Adverse events 
 X 
X 
X 
X 
X 
X 
X 
Tumor Harvest for TIL [14] 
  
X 
  
  
  
  
  
Slides from resected tumor  
  
X 
  
  
  
  
  
PBMC genetic sequencing 
 
X 
 
 
 
 
 
NMA lymphodepletion [15] 
  
  
  
X 
X 
X 
  
LN-145 Infusion [16] 
  
  
  
  
  
  
X 
IL-2 600,000 IU/kg [17] 
  
  
  
  
  
  
  
TMP/SMX DS [18] 
  
  
  
  
  
  
X 
Filgrastim [19] 
  
  
  
  
  
  
  
Fluconazole [20] 
  
  
  
  
  
  
  
Anti-viral [21] 
  
  
  
  
  
  
  
Immune Monitoring [22] 
  
X 
  
X 
  
  
  

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Treatment Phase 
  
Visits 12, 13, 14, 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Visit Name 
Days 1, 2, 3, 4 
Day 14 
Day 28 
(Month 1) 
Day 56 
(Month 2) 
Day 84 
(Month 3) 
Visit Window 
N/A 
(+/- 3 days) 
(+/- 3 days) 
(+/- 3 days) 
(+/- 3 days) 
Informed Consent 
  
  
  
  
  
Inclusion/Exclusion 
  
  
  
  
  
Demographic Data 
  
  
  
  
  
Medical History 
  
  
  
  
  
Documentation of diagnosis 
  
  
  
  
  
Documentation of HPV status 
  
  
  
  
  
Physical Exam [1] 
X 
X 
X 
X 
X 
Vital Signs [2] 
X 
X 
X 
X 
X 
ECOG performance status 
  
  
X 
X 
X 
Safety blood and urine tests [4] 
X 
X 
X 
X 
X 
ß-HCG Serum Pregnancy Test 
  
  
  
  
  
Virus testing [5] 
  
  
  
  
  
HLA typing [6] 
  
  
  
  
  
HPV Serotype 
  
  
  
  
  
CMV Antigen Assay [7] 
X 
X 
X 
X 
X 
Estimated Creatinine Clearance [8] 
X 
X 
X 
X 
X 
Eye Exam 
  
  
  
  
  
Cardiac Evaluations [9] 
  
  
  
  
  
Pulmonary function tests [10] 
  
  
  
  
  
Colonoscopy [11] 
  
  
  
  
  
Tumor Assessments [12]  
  
  
X 
X 
X 
Response Assessments (RECIST v 1.1) 
  
  
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Tumor Harvest for TIL [14] 
  
  
  
  
  
Slides from resected tumor  
  
  
  
  
  
PBMC genetic sequencing 
 
 
 
 
 
NMA lymphodepletion [15] 
  
  
  
  
  
LN-145 Infusion [16] 
  
  
  
  
  
IL-2 600,000 IU/kg [17] 
X 
  
  
  
  
TMP/SMX DS [18] 
X 
X 
X 
X 
X 
Filgrastim [19] 
X 
X 
X 
X 
X 
Fluconazole [20] 
X 
X 
X 
X 
X 
Anti-viral [21] 
X 
X 
X 
X 
X 
Immune Monitoring [22] 
X  
X 
X  
X 
X 
 

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Long Term Follow Up Phase 
  
  
Visit 20  
Visit 21 
Visit 22 
Visit 23 
Visit 24 
Visit 25 
 ETV [23] 
Visit Name 
Day 112     
(Month 4)  
Day 168 
(Month 6) 
Day 252 
(Month 9) 
Day 336 
(Month 12) 
Day 504 
(Month 18) 
Day 672 
(Month 24) 
Early 
Termination Visit 
Visit Window 
(+/- 7 days) 
(+/- 7 days) 
(+/- 7 days) 
(+/- 7 days) 
(+/- 21 days) 
(+/- 21 days) 
(+/- 3 days) 
Informed Consent 
  
  
  
  
  
  
  
Inclusion/Exclusion 
  
  
  
  
  
  
  
Demographic Data 
  
  
  
  
  
  
  
Medical History 
  
  
  
  
  
  
  
Documentation of diagnosis 
  
  
  
  
  
  
  
Documentation of HPV status 
  
  
  
  
  
  
  
Physical Exam [1] 
X 
X 
X 
X 
X 
X 
X 
Vital Signs [2] 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
Safety blood and urine tests [4] 
X 
X 
X 
X 
X 
X 
X 
ß-HCG Serum Pregnancy Test 
  
  
  
  
  
  
  
Virus testing [5] 
  
  
  
  
  
  
  
HLA typing [6] 
  
  
  
  
  
  
  
HPV Serotype 
  
  
  
  
  
  
  
CMV Antigen Assay [7] 
X 
X 
X 
X 
X 
X 
X 
Estimated Creatinine Clearance [8] 
X 
X 
X 
X 
X 
X 
X 
Eye Exam 
  
  
  
  
  
  
  
Cardiac Evaluations [9] 
  
  
  
  
  
  
  
Pulmonary function tests [10] 
  
  
  
  
  
  
  
Colonoscopy [11] 
  
  
  
  
  
  
  
Tumor Assessments [12]  
X 
X 
X 
X 
X 
X 
X 
Response Assessments (RECIST 1.1) 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Tumor Harvest for TIL [14] 
  
  
  
  
  
  
  
Slides from resected tumor  
  
  
  
  
  
  
  
PBMC genetic sequencing 
 
 
 
 
 
 
 
NMA lymphodepletion [15] 
  
  
  
  
  
  
  
LN-145 Infusion [16] 
  
  
  
  
  
  
  
IL-2 600,000 IU/kg [17] 
  
  
  
  
  
  
  
TMP/SMX DS [18] 
  
  
  
  
  
  
  
Filgrastim [19] 
  
  
  
  
  
  
  
Fluconazole [20] 
  
  
  
  
  
  
  
Anti-viral [21] 
  
  
  
  
  
  
  
Immune Monitoring [22] 
X 
X 
X  
 X 
 X 
 X 
X 

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[1]     Physical examination (PE) will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, 
respiratory system, skin, psychiatric (mental status), general nutrition. PE conducted during follow-up will be symptom directed.   
[2]      Vital signs will include height, weight, heart rate, respiratory rate, blood pressure, and temperature.  Height will be measured at Screening 
only. BSA and BMI shall be Calculated at Visit 4 (Day -7) only. 
 
 
 
 
 
 
[3]     On Day 0 (LN-145 infusion), vital signs will be monitored every 30 minutes during infusion then hourly (+/-15 minutes) for four hours and then 
routinely (every four to six hours), unless otherwise clinically indicated, for up to approximately 24 hours post TIL infusion. 
[4]      Chemistry:  sodium, potassium, chloride, total CO2, or bicarbonate, creatinine, glucose, BUN, albumin, calcium, magnesium, phosphorus, 
alkaline phosphatase, ALT/SGPT, AST/SGOT, total bilirubin, direct bilirubin, LDH, total protein, total CK, uric acid.  Thyroid panel (to include 
TSH and Free T4) is to be done at Visits 1 and 19 or as clinically indicated. 
 
 
Hematology:  CBC with differential 
 
 
 
 
 
 
Urinalysis Dipstick:  A complete urine culture shall be conducted if indicated 
 
 
 
 
 
[5]     HIV antibody titer; Hepatitis - HbsAG determination (HSV-1 IgG and HSV-2 IgG) and anti HCV; CMV antigen assay; Anti-CMV antibody titer; HSV 
serology; EBV viral capsid antigen (VCA) IgG and/or Epstein Barr nuclear antigen (EBNA) IgG (may be within previous 3 months to Visit 2). 
[6]     HLA typing by central laboratory.  
 
 
 
. 
 
[7]     CMV assay to be completed at Screening and every other specified visit only if clinically indicated 
[8]     Estimated CrCl based on the Cockcroft-Gault calculation. 
 
 
 
 
 
[9]     Cardiac Evaluations consist of Stress Thallium, ECHO or MUGA and ECG. See section 5.17 for further descriptions.  
[10]   Pulmonary evaluation using spirometry will be completed for all patients. 
[11]   Colonoscopy only required for documented Grades 2 or greater diarrhea or colitis as a result of previously immunotherapy within six months 
from screening. Patients who have had a previous colonoscopy within six months from Visit 2 and demonstrate the visual appearance of the 
absence of inflammation will not need to repeat the colonoscopy. 
[12]   CT Scans of  head, neck and chest, are required at the indicated time points. Additional anatomical locations may be scanned if clinically 
indicated.  Scans will be read centrally. MRI or PET scans will be allowed for patients who have an intolerability to contrast media. The imaging 
modality used must be uniform for the duration of the study. 
[13]   Include only medications that are NOT part of the tumor harvest procedure. 
 
 
[14]   See Section 5.25. 
 
 
 
 
[15]   Cyclophosphamide with mesna for 2 days followed by fludarabine for 5 days. See Section 5.27. 
 
[16]   LN-145 infusion is to be done 1 to 2 days after the last dose of agent in the NMA lymphodepletion regimen.  See Section 5.28 
[17]   Initiate IL-2 at 600,000 IU/kg within approximately 12 to 24 hours after LN-145 infusion and continue every eight hours for up to six doses. See 
Section 5.29.  
 
[18]   Prophylactic antibiotics such as TMP/SMX DS 160 mg/800 mg may be given as clinically indicated, per standard of care.   
[19]   Filgrastim 5 μg/kg/day SC; this will be administered each day until the absolute neutrophil count reaches >1000/mm3 for three consecutive 
days. Filgrastim at doses > 300 μg per day is allowed if this is the institutional standard protocol 
 
[20]   Fluconazole 400 mg PO daily. This should be administered each day until the absolute neutrophil count reaches >1000/mm3.  
[21]   Anti-viral treatment will be initiated in Patients positive for HSV.  Valacyclovir PO or acyclovir IV will be administered daily, and continued until 
CD4 > 200 cells/mm3. 
 
 
[22]   50 mL of blood drawn using vacutainers; refer to the Laboratory Manual.  Site should make best effort should be made to collect follow-up 
samples at Months 4 and 6. 
[23]   The Early Termination Visit is completed if discontinuation from the study occurs for at any time after Visit 2 and before Visit 25. 
 

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16.2. 
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 (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
Adapted from Oken MM, Creech RH, Tormey DC, et al.  Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol.  1982;5:649-655. 
16.3. 
Calculation of BMI, BSA and Practical 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 > 30.0 kg/m2), the practical 
weight will be used. 
16.3.1. BMI 
 
BMI = weight (kg)/[height (m)]2 
16.3.2. BSA  
BSA = 0.007184 x height (m)0.725 x weight (kg)0.425 
16.3.3. 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 > 30.0 kg/m2. 
Note: Practical weight will NOT be used in the calculation of dose for IL-2. 
16.3.3.1.1. 
Ideal Body Weight 
Male = 50 kg + 2.3 x (number of inches over 60 inches) 
Example:  ideal body weight of 5’10’’ male 
50 + 2.3 x 10 = 73 kg 
Female = 45.5 kg + 2.3 (number of inches over 60 inches) 
Example:  ideal body weight of 5’3’’ female 
      
 
 
 
45.5 + 2.3 x (3) = 57 kg 
 

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16.4. 
Common Terminology Criteria for Adverse Events 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
16.5. 
Expected Toxicities 
16.5.1. LN-145 
Overall, toxicities or adverse events during the LN-145 infusion have almost entirely been 
associated with the either the non-myeloablative lymphodepletion regimen or the high-dose 
IL-2 therapy given after TIL infusion.  The following adverse events have been observed in 
published studies that treated patients with TIL products prepared by a process highly similar 
to 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) (8) following TIL infusion.    
• 
Autoimmune melanocyte destruction resulting in conditions such as vitiligo and 
uveitis have been reported.   
In addition, it should be noted that 2 deaths have been reported in conjunction with the 
lymphodepletion/TIL/IL-2 protocol.  One patient died of cardiac failure caused by 
cyclophosphamide before receiving the TIL infusion (10), and the other patient developed an 
EBV lymphoproliferative disease 4 months after treatment and died of this lymphoma 8 
months later (3). 
16.5.2. NMA Lymphodepletion 
The use of the NMA lymphodepletion regimen (cyclophosphamide and fludarabine) prior to 
cell administration increases the toxicity of this treatment as profound myelosuppression 
occurs in all Patients.  A summary of risks expected with use of each of these agents is 
provided below. Full prescribing information for cyclophosphamide and fludarabine are 
provided in Section 16.5.2.1.1 and Section 16.5.2.2.1 , respectively. 
16.5.2.1. 
Cyclophosphamide 
16.5.2.1.1. 
Package Insert for Cyclophosphamide  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,0
12142s112lbl.pdf 
16.5.2.1.2. 
Contraindications 
Hypersensitivity  
Cyclophosphamide is contraindicated in patients who have a history of severe 
hypersensitivity reactions to it, any of its metabolites, or to other components 
of the product. Anaphylactic reactions including death have been reported 
with cyclophosphamide. Possible cross-sensitivity with other alkylating agents 
can occur. 
Urinary Outflow Obstruction  

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Cyclophosphamide is contraindicated in patients with urinary outflow 
obstruction. 
16.5.2.1.3. 
Warning and Precautions 
Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections 
Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, 
thrombocytopenia and anemia), bone marrow failure, and severe 
immunosuppression which may lead to serious and sometimes fatal 
infections, including sepsis and septic shock. Latent infections can be 
reactivated.   
Monitoring of complete blood counts is essential during cyclophosphamide 
treatment so that the dose can be adjusted, if needed. Cyclophosphamide 
should not be administered to patients with neutrophils ≤1,500/mm3 and 
platelets < 50,000/mm3. Cyclophosphamide treatment may not be indicated, 
or should be interrupted, or the dose reduced, in patients who have or who 
develop a serious infection. G-CSF may be administered to reduce the risks of 
neutropenia complications associated with cyclophosphamide use. For 
additional information, see Section 5.1 of Full Prescribing Information. 
Urinary Tract and Renal Toxicity 
Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported 
with cyclophosphamide.  Urotoxicity can occur with short-term or long-term 
use of cyclophosphamide and can be fatal. 
Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. 
Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary 
cancer) may require interruption of cyclophosphamide treatment or 
cystectomy.   
Before starting treatment, exclude or correct any urinary tract obstructions 
[see Contraindications]. Urinary sediment should be checked regularly for the 
presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. 
Cyclophosphamide should be used with caution, if at all, in patients with 
active urinary tract infections. Aggressive hydration with forced diuresis and 
frequent bladder emptying can reduce the frequency and severity of bladder 
toxicity. Mesna has been used to prevent severe bladder toxicity.   
Cardiotoxicity 
Myocarditis, myopericarditis, pericardial effusion including cardiac 
tamponade, and congestive heart failure, which may be fatal, have been 
reported with cyclophosphamide therapy.   
Supraventricular arrhythmias (including atrial fibrillation and flutter) and 
ventricular arrhythmias (including severe QT prolongation associated with 
ventricular tachyarrhythmia) have been reported after treatment with 
regimens that included cyclophosphamide.  

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Monitor patients with risk factors for cardiotoxicity and with pre-existing 
cardiac disease. 
For additional information, see Section 5.3 of Full Prescribing Information. 
Pulmonary Toxicity 
Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other 
forms of pulmonary toxicity leading to respiratory failure have been reported 
during and following treatment with cyclophosphamide. Late onset 
pneumonitis (greater than 6 months after start of cyclophosphamide) appears 
to be associated with increased mortality. Pneumonitis may develop years 
after treatment with cyclophosphamide.   
Monitor patients for signs and symptoms of pulmonary toxicity. 
Secondary Malignancies 
Cyclophosphamide is genotoxic (see 13.1 [Nonclinical Toxicology] of Full 
Prescribing Information).  Secondary malignancies (urinary tract cancer, 
myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) 
have been reported in patients treated with cyclophosphamide-containing 
regimens.   
Veno-occlusive Liver Disease 
Veno-occlusive liver disease (VOD) including fatal outcome has been reported 
in patients receiving cyclophosphamide-containing regimens. A cytoreductive 
regimen in preparation for bone marrow transplantation that consists of 
cyclophosphamide in combination with whole-body irradiation, busulfan, or 
other agents has been identified as a major risk factor.  For additional 
information, see Section 5.6 of Full Prescribing Information. 
Embryo-Fetal Toxicity 
Cyclophosphamide can cause fetal harm when administered to a pregnant 
woman (see Section 8.1 [Use in Specific Populations] of Full Prescribing 
Information).  Exposure to cyclophosphamide during pregnancy may cause 
birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in 
the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in 
mice, rats, rabbits and monkeys.  
Advise female patients of reproductive potential to avoid becoming pregnant 
and to use highly effective contraception during treatment and for up to 1 
year after completion of therapy. 
Infertility 
Male and female reproductive function and fertility may be impaired in 
patients being treated with cyclophosphamide. Cyclophosphamide interferes 
with oogenesis and spermatogenesis. It may cause sterility in both sexes. 
Development of sterility appears to depend on the dose of cyclophosphamide, 

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duration of therapy, and the state of gonadal function at the time of 
treatment. Cyclophosphamide-induced sterility may be irreversible in some 
patients. Advise patients on the potential risks for infertility. 
Wound Healing 
Cyclophosphamide may interfere with normal wound healing.  See Section 5.9 
of Full Prescribing Information. 
Hyponatremia 
Hyponatremia associated with increased total body water, acute water 
intoxication. A syndrome resembling syndrome of inappropriate secretion of 
antidiuretic hormone (SIADH), which may be fatal, has been reported. 
16.5.2.1.4. 
Common Adverse Events 
Hematopoietic system 
Neutropenia occurs in patients treated with cyclophosphamide. The degree of 
neutropenia is particularly important because it correlates with a reduction in 
resistance to infections. Fever without documented infection has been 
reported in neutropenic patients. 
Gastrointestinal system 
Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, 
less frequently, abdominal discomfort or pain and diarrhea may occur. There 
are isolated reports of hemorrhagic colitis, oral mucosal ulceration and 
jaundice occurring during therapy. 
Skin 
Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs 
occasionally in patients receiving the drug. Pigmentation of the skin and 
changes in nails can occur. 
16.5.2.1.5. 
Post-Marketing Experience 
The following adverse reactions have been identified from clinical trials or 
post-marketing surveillance.  Because they are reported from a population 
from unknown size, precise estimates of frequency cannot be made. 
Cardiac 
Cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic 
shock, pericardial effusion (progressing to cardiac tamponade), myocardial 
hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), 
cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, 
supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, 
palpitations, QT prolongation. 
Congenital, Familial and Genetic  
Intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity 
(including myelosuppression, gastroenteritis). 
Ear and Labyrinth  

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Deafness, hearing impaired, tinnitus. 
Endocrine  
Water intoxication. 
Eye 
Visual impairment, conjunctivitis, lacrimation. 
Gastrointestinal  
Gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, 
stomatitis, constipation, parotid gland inflammation. 
General Disorders and Administrative Site Conditions 
Multi-organ failure, general physical deterioration, influenza-like illness, 
injection/infusion site reactions (thrombosis, necrosis, phlebitis, 
inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal 
inflammation, asthenia, pain, chills, fatigue, malaise, headache. 
Hematologic 
Myelosuppression, bone marrow failure, disseminated intravascular 
coagulation and hemolytic uremic syndrome (with thrombotic 
microangiopathy). 
Hepatic  
Veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, 
hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic 
encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic 
function abnormal, hepatic enzymes increased. 
Immune  
Immunosuppression, anaphylactic shock and hypersensitivity reaction. 
Infections  
The following manifestations have been associated with myelosuppression 
and immunosuppression caused by cyclophosphamide: increased risk for and 
severity of pneumonias (including fatal outcomes), other bacterial, fungal, 
viral, protozoal and, parasitic infections; reactivation of latent infections, 
(including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, 
Strongyloides, sepsis and septic shock. 
Investigations 
Blood lactate dehydrogenase increased, C-reactive protein increased. 
Metabolism and Nutrition 
Hyponatremia, fluid retention, blood glucose increased, blood glucose 
decreased. 
Musculoskeletal and Connective Tissue 
Rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia. 
Neoplasms 

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Acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell 
carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid 
cancer. 
Nervous System 
Encephalopathy, convulsion, dizziness, neurotoxicity has been reported and 
manifested as reversible posterior leukoencephalopathy syndrome, 
myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, 
hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia. 
Pregnancy 
Premature labor. 
Psychiatric  
Confusional state. 
Renal and Urinary 
Renal failure, renal tubular disorder, renal impairment, nephropathy toxic, 
hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, 
hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial 
cells. 
Reproductive System 
Infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, 
testicular atrophy, azoospermia, oligospermia. 
Respiratory 
Pulmonary veno-occlusive disease, acute respiratory distress syndrome, 
interstitial lung disease as manifested by respiratory failure (including fatal 
outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, 
pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary 
hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, 
hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, 
rhinorrhea. 
Skin and Subcutaneous Tissue 
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, 
palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic 
skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, 
facial swelling, hyperhidrosis. 
Tumor lysis syndrome  
Similar to other cytotoxic drugs, cyclophosphamide may induce tumor-lysis 
syndrome and hyperuricemia in patients with rapidly growing tumors. 
Vascular 
Pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, 
hypertension, hypotension, flushing, hot flush. 
 

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16.5.2.2. 
Fludarabine (FLUDARA for INJECTION) 
16.5.2.2.1. 
Package Insert for Fludarabine 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020038s032lb
l.pdf 
16.5.2.2.2. 
Warning 
BOXED WARNING 
WARNING: FLUDARA FOR INJECTION should be administered under the 
supervision of a qualified physician experienced in the use of antineoplastic 
therapy. FLUDARA FOR INJECTION can severely suppress bone marrow 
function. When used at high doses in dose-ranging studies in patients with 
acute leukemia, FLUDARA FOR INJECTION was associated with severe 
neurologic effects, including blindness, coma, and death. This severe central 
nervous system toxicity occurred in 36% of patients treated with doses 
approximately four times greater (96 mg/m2/day for 5-7 days) than the 
recommended dose. Similar severe central nervous system toxicity has been 
rarely (≤0.2%) reported in patients treated at doses in the range of the dose 
recommended for chronic lymphocytic leukemia.  Instances of life-
threatening and sometimes fatal autoimmune hemolytic anemia have been 
reported to occur after one or more cycles of treatment with FLUDARA FOR 
INJECTION. Patients undergoing treatment with FLUDARA FOR INJECTION 
should be evaluated and closely monitored for hemolysis.  In a clinical 
investigation using FLUDARA FOR INJECTION in combination with 
pentostatin (deoxycoformycin) for the treatment of refractory chronic 
lymphocytic leukemia (CLL), there was an unacceptably high incidence of 
fatal pulmonary toxicity.  Therefore, the use of FLUDARA FOR INJECTION in 
combination with pentostatin is not recommended. 
16.5.2.2.3. 
Precautions 
General: FLUDARA FOR INJECTION is a potent antineoplastic agent with 
potentially significant toxic side effects. Patients undergoing therapy should 
be closely observed for signs of hematologic and non-hematologic toxicity. 
Periodic assessment of peripheral blood counts is recommended to detect the 
development of anemia, neutropenia and thrombocytopenia. 
Tumor lysis syndrome associated with FLUDARA FOR INJECTION treatment has 
been reported in CLL patients with large tumor burdens. Since FLUDARA FOR 
INJECTION can induce a response as early as the first week of treatment, 
precautions should be taken in those patients at risk of developing this 
complication. 
There are inadequate data on dosing of patients with renal insufficiency. 
FLUDARA FOR INJECTION must be administered cautiously in patients with 
renal insufficiency. The total body clearance of 2-fluoro-ara-A has been shown 

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to be directly correlated with creatinine clearance. Patients with moderate 
impairment of renal function (creatinine clearance 30-70 mL/min/1.73 m2) 
should have their Fludara dose reduced by 20% and be monitored closely. 
Fludara is not recommended for patients with severely impaired renal 
function (creatinine clearance less than 30 mL/min/1.73 m2).  For additional 
precautions in special populations, refer to the Full Prescribing Information in 
Section 16.9. 
16.5.2.2.4. 
Adverse Events 
The most common adverse events include myelosuppression (neutropenia, 
thrombocytopenia and anemia), fever and chills, infection, and nausea and 
vomiting. Other commonly reported events include malaise, fatigue, anorexia, 
and weakness. Serious opportunistic infections have occurred in CLL patients 
treated with FLUDARA FOR INJECTION.  Non-hematoglic AEs observed in two 
clinical trials of fludarabine in patients with chronic lymphocytic leukemia are 
shown in Table 4. 
Table 4. 
Percent of Patients with Refractory CLL Reporting Non-
Hematologic Adverse Events 
Adverse Events  
MDAH (N=101) 
% 
SWOG (N=32) 
% 
Any Adverse Event 
88 
91 
Body as a Whole 
72 
84 
Fever 
60 
69 
Chills 
11 
19 
Fatigue 
10 
38 
Infection 
33 
44 
Pain 
20 
22 
Malaise 
8 
6 
Diaphoresis 
1 
13 
Alopecia 
0 
3 
Anaphylaxis 
1 
0 
Hemorrhage 
1 
0 
Hyperglycemia 
1 
6 
Dehydration 
1 
0 
Neurological 
21 
69 
Weakness 
9 
65 
Paresthesia 
4 
12 
Headache 
3 
0 
Visual Disturbance 
3 
15 
Hearing Loss 
2 
6 

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Adverse Events  
MDAH (N=101) 
% 
SWOG (N=32) 
% 
Sleep Disorder 
1 
3 
Depression 
1 
0 
Cerebellar Syndrome 
1 
0 
Impaired Mentation 
1 
0 
Pulmonary 
35 
69 
Cough 
10 
44 
Pneumonia 
16 
22 
Dyspnea 
9 
22 
Sinusitis 
5 
0 
Pharyngitis 
0 
9 
Upper Respiratory Infection 
2 
16 
Allergic Pneumonitis 
0 
6 
Epistaxis 
1 
0 
Hemoptysis 
1 
6 
Bronchitis 
1 
0 
Hypoxia 
1 
0 
Gastrointestinal 
46 
63 
Nausea/Vomiting 
36 
31 
Diarrhea 
15 
13 
Anorexia 
7 
34 
Stomatitis 
9 
0 
GI Bleeding 
3 
13 
Esophagitis 
3 
0 
Mucositis 
2 
0 
Liver Failure 
1 
0 
Abnormal Liver Function Test 
1 
3 
Cholelithiasis 
0 
3 
Constipation 
1 
3 
Dysphagia 
1 
0 
Cutaneous 
17 
18 
Rash 
15 
15 
Pruritus 
1 
3 
Seborrhea 
1 
0 
Genitourinary 
12 
22 
Dysuria 
4 
3 
Urinary Infection 
2 
15 
Hematuria 
2 
3 

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Adverse Events  
MDAH (N=101) 
% 
SWOG (N=32) 
% 
Renal Failure 
1 
0 
Abnormal Renal Function Test 
1 
0 
Proteinuria 
1 
0 
Hesitancy 
0 
3 
Cardiovascular 12 38 
12 
38 
Edema 
8 
19 
Angina 
0 
6 
Congestive Heart Failure 
0 
3 
Arrhythmia 
0 
3 
Supraventricular Tachycardia 
0 
3 
Myocardial Infarction 
0 
3 
Deep Venous Thrombosis 
1 
3 
Phlebitis 
1 
3 
Transient Ischemic Attack 
1 
0 
Aneurysm 
1 
0 
Cerebrovascular Accident 
0 
3 
Musculoskeletal 
7 
16 
Myalgia 
4 
16 
Osteoporosis 
2 
0 
Arthralgia 
1 
0 
Tumor Lysis Syndrome 
1 
0 
Source: FLUDARA INJECTION Full Prescribing Information, October 2014. 
 
The most frequently reported adverse events and those reactions which are 
more clearly related to the drug are arranged below according to body 
system. 
Hematopoietic Systems 
Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were 
reported in the majority of CLL patients treated with FLUDARA FOR 
INJECTION. During FLUDARA FOR INJECTION treatment of 133 patients with 
CLL, the absolute neutrophil count decreased to less than 500/mm3 in 59% of 
patients, hemoglobin decreased from pretreatment values by at least 2 grams 
percent in 60%, and platelet count decreased from pretreatment values by at 
least 50% in 55%. Myelosuppression may be severe, cumulative, and may 
affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient 
treated with FLUDARA FOR INJECTION. 
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in 
ancytopenia, sometimes resulting in death, have been reported in 

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postmarketing surveillance. The duration of clinically significant cytopenia in 
the reported cases has ranged from approximately 2 months to approximately 
1 year. These episodes have occurred both in previously treated or untreated 
patients. 
Life-threatening and sometimes fatal autoimmune hemolytic anemia have 
been reported to occur in patients receiving FLUDARA FOR INJECTION (see 
WARNINGS section). The majority of patients rechallenged with FLUDARA FOR 
INJECTION developed a recurrence in the hemolytic process. 
Metabolic 
Tumor lysis syndrome has been reported in CLL patients treated with 
FLUDARA FOR INJECTION. This complication may include hyperuricemia, 
hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, 
hematuria, urate crystalluria, and renal failure. The onset of this syndrome 
may be heralded by flank pain and hematuria.  
Nervous System 
(See WARNINGS section) Objective weakness, agitation, confusion, visual 
disturbances, and coma have occurred in CLL patients treated with FLUDARA 
FOR INJECTION at the recommended dose. Peripheral neuropathy has been 
observed in patients treated with FLUDARA FOR INJECTION and one case of 
wrist-drop was reported. 
Pulmonary System 
Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 
16%, and 22% of those treated with FLUDARA FOR INJECTION in the MDAH 
and SWOG studies, respectively. Pulmonary hypersensitivity reactions to 
FLUDARA FOR INJECTION characterized by dyspnea, cough and interstitial 
pulmonary infiltrate have been observed.  In post-marketing experience, cases 
of severe pulmonary toxicity have been observed with Fludara use which 
resulted inARDS, respiratory distress, pulmonary hemorrhage, pulmonary 
fibrosis, and respiratory failure. After an infectious origin has been excluded, 
some patients experienced symptom improvement with corticosteroids. 
Gastrointestinal System 
Gastrointestinal disturbances such as nausea and vomiting, anorexia, 
diarrhea, stomatitis, and gastrointestinal bleeding have been reported in 
patients treated with FLUDARA FOR INJECTION. 
Cardiovascular 
Edema has been frequently reported. One patient developed a pericardial 
effusion possibly related to treatment with FLUDARA FOR INJECTION. No 
other severe cardiovascular events were considered to be drug related. 
Genitourinary System 
Rare cases of hemorrhagic cystitis have been reported in patients treated with 

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FLUDARA FOR INJECTION. 
Skin 
Skin toxicity, consisting primarily of skin rashes, has been reported in patients 
treated with FLUDARA FOR INJECTION. 
16.5.3. IL-2 
IL-2 administration has been associated with capillary leak syndrome (CLS) which is 
characterized by a loss of vascular tone and extravasation of plasma proteins and fluid 
into the extravascular space. CLS results in hypotension and reduced organ perfusion 
which may be severe and can result in death. CLS may be associated with cardiac 
arrhythmias (supraventricular and ventricular), angina, myocardial infarction, 
respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, 
renal insufficiency, edema, and mental status changes.  
IL-2 treatment is also associated with impaired neutrophil function (reduced 
chemotaxis) and with an increased risk of disseminated infection, including sepsis and 
bacterial endocarditis. Consequently, preexisting bacterial infections should be 
adequately treated prior to initiation of IL-2 therapy. Patients with indwelling central 
lines are particularly at risk for infection with gram positive microorganisms. Antibiotic 
prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin has been associated 
with a reduced incidence of staphylococcal infections. IL-2 administration should be 
withheld in Patients developing moderate to severe lethargy or somnolence; 
continued administration may result in coma. 
The standard approach to the administration of high-dose IL-2 in all studies is to 
continue dosing until grade 3 or 4 events occur. The most commonly seen grade 4 
events are pulmonary and renal impairment, and mental status changes.  These 
toxicities may sometimes require intubation for protection of the Patient’s airway.  It 
is important to note that although these Patients require significant supportive 
measures during this period, all toxicities are reversible and the overwhelming 
majority of Patients have suffered no long term sequelae following this treatment 
regimen.  However, fatal complications are possible and it is therefore only 
appropriate to carry out this experimental treatment in the context of life threatening 
metastatic cancer. 
16.5.3.1.1. 
Package Insert for IL-2 (aldesleukin) 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130l
bl.pdf 
 
16.5.3.1.2. 
Adverse Events 
Adverse events reported in > 10% of participants in a clinical trial of IL-2 in 255 
patients with metastatic renal cell cancer and 270 patients with metastatic 
melanoma were reported in the Proleukin® as listed in Table 5. Life-

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threatening (Grade 4) AEs reported in the same patient populations are listed 
in Table 6.  
 
Table 5. 
Adverse Events Reported in >10% of Patients in Two Clinical Trials of IL-2 
Body System/Events 
% Patients    
(N = 525) 
Body as a whole 
 
Chills 
52 
Fever 
29 
Malaise 
27 
Asthenia 
23 
Infection 
13 
Pain 
12 
Abdominal pain 
11 
Enlarged Abdomen 
10 
Cardiovascular System 
 
Hypotension 
71 
Tachycardia 
23 
Vasodilation 
13 
Supraventricular Tachycardia 
12 
Cardiovascular disordera 
11 
Arrhythmia 
10 
Digestive System 
 
Diarrhea 
67 
Vomiting 
50 
Nausea 
35 
Stomatitis 
22 
Anorexia 
20 
Nausea and Vomiting 
19 
Hematologic and Lymphatic 
 
Thrombocytopenia 
37 
Anemia 
29 
Leukopenia 
16 
Metabolic and Nutritional Disorders 
 
Bilirubinemia 
40 
Creatinine Increase 
33 
Peripheral Edema 
28 
SGOT increase 
23 
Weight gain 
16 

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Body System/Events 
% Patients    
(N = 525) 
Edema 
15 
Acidosis 
12 
Hypomagnesemia 
12 
Hypocalcemia 
11 
Alkaline Phosphatase Increase 
10 
Nervous System 
 
Confusion 
34 
Somnolence 
22 
Anxiety 
12 
Dizziness 
11 
Respiratory System 
 
Dyspnea 
43 
Lung Disorderb 
24 
Respiratory Disorderc 
11 
Cough increase 
11 
Rhinitis 
10 
Skin and Appendages 
 
Rash 
42 
Pruritus 
24 
Exfoliative dermatitis 
18 
Urogenital System 
 
Oliguria 
63 
a      Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b      Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c      Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
Source: Proleukin® Prescribing Information, January 2015. 
 
Table 6. 
Life-Threatening (Grade 4) Adverse Events Reported in Patients in Two Clinical Trials of IL-2 
Body System/Events 
% Patients 
(N = 525) 
 
N (%) 
Body as a whole 
 
Fever 
5 (1) 
Infection 
7 (1) 
Sepsis 
6 (1) 
Cardiovascular System 
 
Hypotension 
15 (3) 

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Body System/Events 
% Patients 
(N = 525) 
Supraventricular Tachycardia 
3 (1) 
Cardiovascular disordera 
7 (1) 
Myocardial infarct 
7 (1) 
Ventricular Tachycardia 
5 (1) 
Cardiac arrest 
4 (1) 
Digestive System 
 
Diarrhea 
10 (2) 
Vomiting 
7 (1) 
Hematologic and Lymphatic 
 
Thrombocytopenia 
5 (1) 
Coagulation disorderb 
4 (1) 
Metabolic and Nutritional Disorders 
 
Bilirubinemia 
13 (2) 
Creatinine Increase 
5 (1) 
SGOT increase 
3 (1) 
Acidosis 
4 (1) 
Nervous System 
 
Confusion 
5 (1) 
Stupor 
3 (1) 
Coma 
8 (2) 
Psychosis 
7 (1) 
Respiratory System 
 
Dyspnea 
5 (1) 
Respiratory Disorderc 
14 (3)  
Apnea 
5 (1) 
Urogenital System 
 
Oliguria 
33 (6) 
Anuria 
25 (5) 
Acute kidney failure 
3 (1) 
a      Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b      Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c      Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
Source: Proleukin® Prescribing Information, January 2015. 
 
 
Table 7. 
Management of IL-2 Toxicities 
Expected toxicity 
Expected 
Grade 
Supportive Measures 
suggested 
Stop Cycle* 
 
Stop 
Treatment ** 
Chills 
3 
IV Meperidine 25-50 mg, IV q1h, prn, 
No 
No 
Fever 
3 
Acetaminophen 650 mg, po, q4h; 
Indomethacin 50-75 mg, po, q8h 
No 
No 

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Expected toxicity 
Expected 
Grade 
Supportive Measures 
suggested 
Stop Cycle* 
 
Stop 
Treatment ** 
Pruritus 
3 
Hydroxyzine HCl 10-20 mg po q6h, prn; 
Diphenhydramine HCl 25-50 mg, po, q4h, 
prn 
No 
No 
Nausea/ Vomiting/ 
Anorexia 
3 
Ondansetron 10 mg, IV, q8h, prn; 
Granisetron 0.01 mg/kg IV daily prn; 
Droperidol 1 mg, IV q4-6h, prn; 
Prochlorperazine 25 mg q4h p.r., prn or 
10 mg IV q6h prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg, po, q3h, prn; 
Diphenoxylate HCl 2.5 mg and atropine 
sulfate 25 µg, po, q3h, prn; codeine 
sulfate 30-60 mg, po, q4h, prn 
If uncontrolled 
after 24 hours 
despite all 
supportive 
measures 
No 
Malaise 
3 or 4 
Bedrest interspersed with activity 
If other 
toxicities occur 
simultaneously 
No 
Hyperbilirubinemia 
3 or 4 
Observation 
If other 
toxicities occur 
simultaneously 
No 
Anemia  
3 or 4 
Transfusion with PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytopenia 
3 or 4 
Transfusion with platelets 
If uncontrolled 
despite all 
supportive 
measures 
No 
Edema/Weight 
gain 
3 
Diuretics prn 
No 
No 
Hypotension 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled 
despite all 
supportive 
measures 
No 
Dyspnea 
3 or 4 
Oxygen or ventilatory support 
If requires 
ventilatory 
support 
No 
Oliguria 
3 or 4 
Fluid boluses or dopamine at renal doses 
If uncontrolled 
despite all 
supportive 
measures 
No 
Increased 
creatinine 
3 or 4 
Observation 
Yes (Grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 

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Expected toxicity 
Expected 
Grade 
Supportive Measures 
suggested 
Stop Cycle* 
 
Stop 
Treatment ** 
Pleural effusion  
3 
Thoracentesis 
If uncontrolled 
despite all 
supportive 
measures 
No 
Bowel perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid and electrolyte 
imbalances; chemical conversion or 
electrical conversion therapy 
If uncontrolled 
despite all 
supportive 
measures 
No 
Elevated Troponin 
levels 
3 or 4 
Observation 
Yes 
If changes in 
LV function 
have not 
improved to 
baseline by 
next dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
Elevated 
transaminases 
3 or 4 
Observation 
For Grade 4 
without liver 
metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Electrolyte 
imbalances 
3 or 4 
Electrolyte replacement 
If uncontrolled 
despite all 
supportive 
measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to Grade 2 or less by next re-treatment.