Clinical trial NCT03610490
Conditions: Malignant Solid Neoplasm Metastatic Colorectal Adenocarcinoma Metastatic Ovarian Carcinoma Metastatic Pancreatic Ductal Adenocarcinoma Platinum-Resistant Ovarian Carcinoma Recurrent High Grade Ovarian Serous Adenocarcinoma Recurrent Ovarian Carcinosarcoma Refractory Colorectal Carcinoma Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-10-16; Completion date: 2024-08-21
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well autologous tumor infiltrating lymphocytes MDA-TIL works in treating patients with ovarian cancer, colorectal cancer, or pancreatic ductal adenocarcinoma that has come back (recurrent) or does not respond to treatment (refractory). Autologous tumor infiltrating lymphocytes MDA-TIL, made by collecting and growing specialized white blood cells (called T-cells) from a patient's tumor, may help to stimulate the immune system in different ways to stop tumor cells from growing.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate efficacy using objective response rate (ORR) using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in subjects with ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), and colorectal cancers.

SECONDARY OBJECTIVES:

I. Determine the disease control rate (DCR) within and across cohorts. II. Determine the duration of response (DOR). III. Determine progression-free survival (PFS) and overall survival (OS). IV. Further characterize the safety profile of adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) across multiple tumor types.

EXPLORATORY OBJECTIVES:

I. Establish duration of TIL persistence. II. Compare the molecular and immunological features of tumors before and after TIL therapy.

III. Prospectively evaluate the existing immunotherapy response criteria (immune-related Response Evaluation Criteria in Solid Tumors \[irRECIST\]) as the best response assessment tool for TIL therapy among a diverse group of solid tumors.

IV. Investigate TIL attributes (CD8 %, CD27 and CD28 expression) and correlation with response to therapy.

V. Assess tumor marker (CA19-9; CA-125) response in patients who produce this tumor marker.

VI. Assess Health-Related Quality of Life (HRQOL).

OUTLINE:

LYMPHODEPLETION REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -7 and -6, and fludarabine IV over 15-30 minutes on days -5 to -1 in the absence of disease progression or unacceptable toxicity.

T-CELL INFUSION: Patients receive autologous tumor infiltrating lymphocytes MDA-TIL IV over 45 minutes on day 0. Patients then receive IL-2 IV over 30 minutes on days 1-4 for up to 6 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at week 18, at 6, 9, 12, 18, and 24 months, and then every 3 months for up to 3 years.

Arms: arm 1: LYMPHODEPLETION REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days -7 and -6, and fludarabine IV over 15-30 minutes on days -5 to -1 in the absence of disease progression or unacceptable toxicity.

T-CELL INFUSION: Patients receive autologous tumor infiltrating lymphocytes MDA-TIL IV over 45 minutes on day 0. Patients then receive IL-2 IV over 30 minutes on days 1-4 for up to 6 doses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Autologous Tumor Infiltrating Lymphocytes MDA-TIL intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: Interleukin-2 intervention 5: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2017-0671 
Protocol Title 
Clinical Study to Assess Efficacy and Safety of MDA-TIL (Autologous 
Expanded Tumor Infiltrating Lymphocytes) across Multiple Tumor 
Types 
Protocol Phase 
2 
Protocol Version 
2.1 / Institutional Version 13 (MOD001) 
Version Date 
12/2/2019 
 
Protocol PI 
Amir Jazaeri, MD 
Department 
Gynecologic Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
18172 
 
 
 


Clinical Study to Assess Efficacy and Safety of MDA-TIL 
(Autologous Expanded Tumor Infiltrating Lymphocytes) 
across Multiple Tumor Types 
 
MD Anderson Study Number: 2017-0671 
Bristol-Meyers Squibb Study Number: CA186-124 
Version: 2.1 
Version Date: 02 December 2019 
 
Principal Investigator: Amir Jazaeri, MD 
Co-Principal Investigators: Rodabe Amaria, MD, Chantale Bernatchez, PhD 
 
Disease Site Co-Principal Investigators: 
Scott Kopetz, MD, PhD, Michael J Overman, MD, and Milind Javle, MD (GI 
Medical Oncology) 
 
Co-Investigators: 
Marie-Andrée Forget, PhD 
Cara Haymaker, PhD 
Anirban Maitra, MBBS 
Ching-Wei Tzeng, MD(Surgical Oncology) 
Christina Roland, MD (Surgical Oncology) 
Matthew Tillman, MD (Surgical Oncology) 
Valerae Lewis, MD (Orthopedic Oncology) 
Karen Lu, MD 
 
Statistician: Ying Yuan, PhD 
IND/IDE Sponsor: MD Anderson IND Office 
Funded by: Iovance Biotherapeutics 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................... 7 
1.1 
BACKGROUND INFORMATION ......................................................................................................... 7 
1.2 
SCIENTIFIC RATIONALE .................................................................................................................. 8 
1.2.1 
INCLUSION OF COLORECTAL CARCINOMAS ...................................................................................................... 8 
1.2.2 
INCLUSION OF CHEMORESISTANT EPITHELIAL OVARIAN CANCER............................................................... 9 
1.2.3 
INCLUSION OF SUBJECTS WITH PANCREATIC CANCER ................................................................................. 10 
1.3 
POTENTIAL RISKS AND BENEFITS ................................................................................................. 12 
1.3.1 
KNOWN POTENTIAL RISKS AND THEIR MITIGATION ....................................................................................... 12 
1.3.2 
KNOWN POTENTIAL BENEFITS ............................................................................................................................ 13 
2. 
OBJECTIVES .................................................................................................................................... 14 
2.1 
PRIMARY ....................................................................................................................................... 14 
2.2 
SECONDARY .................................................................................................................................. 14 
2.3 
EXPLORATORY .............................................................................................................................. 14 
3. 
STUDY DESIGN AND ENDPOINTS ............................................................................................. 14 
3.1 
PRIMARY ENDPOINT ..................................................................................................................... 14 
3.2 
SECONDARY ENDPOINTS .............................................................................................................. 14 
3.3 
EXPLORATORY ENDPOINTS .......................................................................................................... 15 
4. 
ELIGIBILITY CRITERIA ............................................................................................................... 15 
4.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................................. 15 
4.1.1 
GENERAL INCLUSION CRITERIA ......................................................................................................................... 15 
4.1.2 
COHORT-SPECIFIC INCLUSION CRITERIA ........................................................................................................ 16 
4.2 
PARTICIPANT EXCLUSION CRITERIA ............................................................................................ 17 
4.2.1 
GENERAL STUDY EXCLUSION CRITERIA ........................................................................................................... 17 
4.3 
TREATMENT ELIGIBILITY CRITERIA ............................................................................................. 18 
4.3.1 
TREATMENT INCLUSION CRITERION ................................................................................................................. 18 
4.3.2 
TREATMENT EXCLUSION CRITERIA.................................................................................................................... 18 
4.4 
COMPLETION OR DISCONTINUATION OF TREATMENT ................................................................... 18 
4.4.1 
TREATMENT COMPLETION .................................................................................................................................. 18 
4.4.2 
CRITERIA FOR EARLY DISCONTINUATION FROM TREATMENT ..................................................................... 18 
4.4.3 
CRITERIA FOR EARLY DISCONTINUATION FROM STUDY ............................................................................... 19 
4.4.4 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION .................................................................. 19 
5. 
STUDY AGENTS .............................................................................................................................. 19 
5.1 
STUDY AGENTS AND THEIR ACQUISITION ................................................................................... 19 
5.1.1 
LYMPHODEPLETION REGIMEN ........................................................................................................................... 19 
5.1.2 
MDA-TIL (AUTOLOGOUS EXPANDED TIL PRODUCT) ...................................................................................... 21 
5.1.3 
INTERLEUKIN 2 ...................................................................................................................................................... 21 
6. 
STUDY PROCEDURES AND SCHEDULE ................................................................................... 22 
6.1 
STUDY SPECIFIC PROCEDURES ...................................................................................................... 22 
6.1.1 
INFORMED CONSENT............................................................................................................................................ 22 
6.1.2 
ELIGIBILITY CRITERIA .......................................................................................................................................... 22 
6.1.3 
DEMOGRAPHIC DATA ........................................................................................................................................... 22 
6.1.4 
MEDICAL HISTORY ................................................................................................................................................ 22 


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6.1.5 
CONFIRMATION OF DIAGNOSIS .......................................................................................................................... 22 
6.1.6 
CONCOMITANT MEDICATIONS ........................................................................................................................... 23 
6.1.7 
BASELINE TOXICITY ASSESSMENT ...................................................................................................................... 23 
6.1.8 
VITAL SIGNS ............................................................................................................................................................ 23 
6.1.9 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ........................................ 23 
6.1.10 
PHYSICAL EXAMINATION ................................................................................................................................. 23 
6.1.11 
SAFETY BLOOD AND URINE TESTS ................................................................................................................. 23 
6.1.12 
HUMAN LEUKOCYTE ANTIGEN (HLA) TYPING ............................................................................................. 23 
6.1.13 
INFECTIOUS DISEASE SEROLOGY .................................................................................................................. 24 
6.1.14 
ESTIMATED CREATININE CLEARANCE .......................................................................................................... 24 
6.1.15 
CARDIAC EVALUATION .................................................................................................................................... 24 
6.1.16 
PULMONARY FUNCTION TESTS ...................................................................................................................... 24 
6.1.17 
COLONOSCOPY.................................................................................................................................................. 24 
6.1.18 
HRQOL QUESTIONNAIRE – EORTC QLQ-C30 ................................................................................................ 24 
6.1.19 
RADIOGRAPHIC ASSESSMENTS ....................................................................................................................... 24 
6.1.20 
TUMOR RESECTION / EXCISIONAL BIOPSY ................................................................................................... 25 
6.1.21 
ADDITIONAL RESEARCH BIOPSY .................................................................................................................... 25 
6.1.22 
BIOLOGICAL AND IMMUNE MONITORING .................................................................................................... 26 
6.2 
SCHEDULES OF EVENTS ................................................................................................................ 27 
6.3 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .............................................. 32 
6.3.1 
PERMITTED MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................................... 32 
6.3.2 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................................. 32 
6.3.3 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................................ 32 
6.3.4 
SUPPORTIVE MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................................. 33 
7. 
ASSESSMENT OF SAFETY ............................................................................................................ 34 
7.1 
SPECIFICATION OF SAFETY PARAMETERS .................................................................................... 34 
7.1.1 
DEFINITION OF ADVERSE EVENTS ..................................................................................................................... 34 
7.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) .......................................................................................... 35 
7.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) ......................................................................................... 36 
7.2 
INVESTIGATOR COMMUNICATIONS WITH IOVANCE BIOTHERAPEUTICS...................................... 36 
7.3 
ASSESSMENT OF SAFETY PARAMETERS ......................................................................................... 36 
7.3.1 
ASSESSMENT OF SEVERITY .................................................................................................................................. 36 
7.3.2 
ASSESSMENT OF RELATIONSHIP......................................................................................................................... 37 
7.4 
RECORDING AND REPORTING OF AES AND SAES ........................................................................... 37 
7.4.1 
STUDY RECORDING PERIOD AND FOLLOW-UP FOR AES AND SAES ............................................................ 37 
7.4.2 
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS........................................................................................... 38 
7.4.3 
SAFETY DATA EXCHANGE .................................................................................................................................... 38 
7.4.4 
UNANTICIPATED PROBLEM REPORTING .......................................................................................................... 38 
7.4.5 
SPECIAL SITUATION REPORTS ............................................................................................................................ 38 
7.4.6 
REPORTING OF PREGNANCY ............................................................................................................................... 39 
7.5 
STUDY HALTING RULES ............................................................................................................... 39 
7.6 
SAFETY OVERSIGHT ..................................................................................................................... 40 
8. 
STATISTICAL CONSIDERATIONS ............................................................................................. 40 
8.1 
STATISTICAL AND ANALYTICAL PLANS ....................................................................................... 40 
8.2 
ANALYSIS DATASETS ................................................................................................................... 40 
8.2.1 
EFFICACY PRIMARY .............................................................................................................................................. 40 
8.2.2 
EFFICACY SECONDARY ........................................................................................................................................ 40 
8.2.3 
SAFETY PRIMARY ................................................................................................................................................... 40 
8.2.4 
SAFETY SECONDARY ............................................................................................................................................. 40 


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8.3 
DESCRIPTION OF STATISTICAL METHODS .................................................................................... 41 
8.3.1 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT ......................................................................................... 41 
8.3.2 
ANALYSES OF THE SECONDARY EFFICACY ENDPOINTS ................................................................................ 41 
8.3.3 
ANALYSES OF THE EXPLORATORY ENDPOINTS ............................................................................................... 41 
8.3.4 
SAFETY ANALYSES ................................................................................................................................................. 41 
8.3.5 
ADHERENCE AND RETENTION ANALYSES ......................................................................................................... 42 
8.3.6 
BASELINE DESCRIPTIVE STATISTICS .................................................................................................................. 42 
8.3.7 
PLANNED INTERIM ANALYSES ............................................................................................................................. 42 
8.3.8 
SAFETY REVIEW ..................................................................................................................................................... 42 
8.3.9 
EFFICACY REVIEW ................................................................................................................................................ 42 
8.3.10 
MULTIPLE COMPARISON/MULTIPLICITY ...................................................................................................... 43 
8.3.11 
TABULATION OF INDIVIDUAL RESPONSE DATA .......................................................................................... 43 
8.3.12 
EXPLORATORY ANALYSES ................................................................................................................................ 43 
8.4 
SAMPLE SIZE ................................................................................................................................. 43 
8.5 
EFFICACY/TOXICITY SUMMARY REPORTS ....................................................................... 43 
9. 
STUDY DATA MANAGEMENT .................................................................................................... 43 
9.1 
CLINICAL STUDY DATA ................................................................................................................ 43 
9.2 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA ...................... 44 
9.3 
FUTURE USE OF STORED SPECIMENS ........................................................................................... 44 
9.4 
PUBLICATION AND DATA SHARING POLICY .................................................................................. 44 
10. LITERATURE REFERENCES ....................................................................................................... 44 
 
 


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LIST OF ABBREVIATIONS 
 
ACT 
Adoptive Cell Therapy 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Transaminase 
ASMR 
Age-standardized Mortality Rate 
aPTT 
Activated Partial Thromboplastin Time 
BID 
Twice Per Day 
BSA 
Body Surface Area 
CBC 
Complete Blood Count 
CD4+T 
CD4+ T Cells 
CD8+T 
CD8+ T Cells 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLS 
Capillary Leak Syndrome 
CMO 
Contract Manufacturing Organization  
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CT 
Computed Tomography 
CTCAE v4.03 
Common Terminology Criteria for Adverse Events Version 4.03 
D5W 
Dextrose 5% by weight 
DCR 
Disease control rate 
DOR 
Duration of Response 
EBV 
Epstein-Barr Virus 
ECHO 
Echocardiogram 
EKG 
Electrocardiogram 
EOC 
Epithelial Ovarian Cancer 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire - Core 30 instrument 
EWV 
Early Withdrawal Visit 
FDA 
Food and Drug Administration 
FEV 
Forced Expiratory Volume 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HRQoL 
Health-related Quality-of-life 
ICH 
International Conference on Harmonization 
IL 
Interleukin 
IND 
Investigational New Drug (Application) 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IV 
Intravenous 
IVPB 
Intravenous Piggyback 
LVEF 
Left Ventricular Ejection Fraction 


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M1 
HLA-DR+CD68+ M1 Macrophages 
M2 
CD163+ or CD204+ M2 Macrophages 
MDA-TIL 
Autologous Tumor Infiltrating Lymphocytes 
MDACC 
MD Anderson Cancer Center 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multiple Gated Acquisition Scan 
NCI 
National Cancer Institute 
Neu 
CD66b+ Neutrophils 
NMA 
Nonmyeloablative 
NS 
Normal Saline 
OC 
Ovarian Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PDAC 
Pancreatic Ductal Adenocarcinoma 
PE 
Physical Exam 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PJP 
Pneumonitis Jiroveci Pneumonia 
PO 
Per Os (by mouth) 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin Time 
QTcF 
Fridericia’s Corrected QT Interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REP 
Rapid Expansion Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SGOT 
Serum Glutamic-oxaloacetic Transaminase 
SGPT 
Serum Glutamic-pyruvic Transaminase 
SMX 
Sulfamethoxazole  
TCR 
T-cell Receptor 
TIL 
Tumor-infiltrating lymphocyte 
TMA 
Tissue Microarray 
TMP 
Trimethoprim 
Treg 
FOXP3+ Regulatory T Cells 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46). The Principal Investigator will assure that no deviation 
from, or changes to the protocol will take place without prior written agreement as specified in the 
Strategic Alliance Agreement and/or the Study Order pertinent to this study, and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection Training. 
SCHEMATIC OF STUDY DESIGN 
 
1. 
INTRODUCTION  
1.1 
BACKGROUND INFORMATION  
Adoptive cell immunotherapy (ACT) using tumor-infiltrating lymphocytes (TIL) consists of isolation of 
TIL from fresh tumor biopsy, interleukin (IL)-2 mediated selection of activated cells expressing IL-2 
receptors, and expansion to large numbers ex-vivo with subsequent administration of the expanded TIL 
product to the patient.  TIL infusion is preceded by lymphodepletion chemotherapy to reduce the number 
of regulatory T cells, creating a hostile tumor microenvironment, and followed by adjuvant IL-2 to assist 
with in vivo engraftment. As with other immunotherapy approaches, TIL therapy has been most 
extensively utilized in melanoma where response rates of approximately 50% have been reported (Dudley 
et al., 2002; Dudley et al., 2005; Dudley et al., 2008; Radvanyi et al., 2012).  
Previous trials investigating TIL therapy in other solid tumors have shown limited success, however most 
of these studies predated the recognition of the crucial importance of lymphodepleting chemotherapy 
prior to TIL infusion (Aoki et al., 1991; Freedman et al., 1994; Fujita et al., 1995; Ikarashi et al., 1994). 


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However, when ovarian cancer TIL therapy was administered after surgical extirpation and primary 
adjuvant chemotherapy (a situation analogous to the use of lymphodepleting chemotherapy), the results, 
in small numbers of patients, showed 100% three-year survival in patients who received TIL versus 
67.5% in those who did not (Fujita et al., 1995). More recently, clinical activity for TIL therapy has been 
reported for other solid tumors (Stevanovic et al., 2015; Tran et al., 2014) and clinical testing for other 
epithelial malignancies including ovarian cancer (OC), renal cell carcinoma, colorectal cancer, pancreatic 
cancer, hepatocellular carcinoma, cholangiocarcinoma and gastric cancer is ongoing at NCI 
(ClinicalTrials.gov identifier NCT02482090, NCT02926053, NCT01883297, NCT01174121). 
1.2 
SCIENTIFIC RATIONALE  
1.2.1 INCLUSION OF COLORECTAL CARCINOMAS 
Non-resectable metastatic CRC is incurable with life expectancy of approximately 2 years.  Frontline 
therapy is highly active with response rates over 50%, however subsequent therapy, 2nd line and greater 
have response rates <15% with short time to progression and novel therapeutic approaches in the 2nd line 
or greater and urgently needed.  There is substantial evidence that tumor-infiltrating lymphocytes possess 
important predictive and prognostic significance in colorectal cancer (Cavalleri et al., 2019; Kong et al., 
2019; Reissfelder et al., 2015; Zhou et al., 2019). In addition, T cells recognizing shared antigens have 
been isolated from TIL and peripheral T cell populations from patients with colorectal cancers (Cafri et 
al., 2019; Lo et al., 2019).  
Direct evidence for TIL recognition of colorectal tumor specific antigens has been reported by 
Rosenberg’s Group at NCI (Tran et al., 2016; Turcotte et al., 2014).  Germane to this trial, they identified 
a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes 
obtained from a patient with metastatic colorectal cancer. TIL therapy resulted in objective regression of 
all metastases.  Interestingly, progression of one the lesions 9 months after therapy was associated with 
the loss of chromosome 6 encoding the relevant class I major histocompatibility complex (MHC) 
molecule resulting in tumor immune evasion (Tran et al., 2016).  In addition, Rosenberg’s group has 
successfully identified TP53 specific TCRs from the TIL analysis pipeline in 12 patients, of which 9 are 
colorectal cancer, again demonstrating the potential of endogenous TIL therapy in CRC (NCI Workshop 
on Cell-based Immunotherapy for Solid Tumors held December 10-11, 2018 in Bethesda, Maryland). 
Our group has had an active interest in evaluating TIL expansion from CRC patients undergoing resection 
of liver metastasis and have collected over 40 cases with successful TIL expansion rate utilizing 41BB 
stimulation of 83%. 


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Figure 1: TIL expansion from colorectal carcinoma patient tumor sample. High yield of TIL can be 
expanded with the use of anti-4-1BB (BMS, Urelumab), anti-CD3 (clone OKT3) and IL-2 and the 
resulting product is enriched in CD3+CD8+ T cells.  
1.2.2 INCLUSION OF CHEMORESISTANT EPITHELIAL OVARIAN CANCER 
Despite high rates of complete response to the combination of tumor reductive surgery and adjuvant 
platinum-taxane based chemotherapy, the vast majority of patients with stage III/IV epithelial ovarian 
cancer (EOC) recur with a median progression free survival of approximately 18 months (Jayson, Kohn, 
Kitchener, & Ledermann, 2014). With rare exceptions, relapsed ovarian cancer is considered incurable, 
and patients who progress on, or recur less than 6 months from the completion of platinum-based 
chemotherapy, are deemed “platinum resistant,” and constitute a very poor prognostic group. Despite 
decades of clinical investigations, most therapies are associated with only modest response rates and a 
typical median progression free survival of 3-4 months across a wide variety of cytotoxic and biological 
agents (Naumann & Coleman, 2011). Thus, development of new strategies that will ultimately improve 
the overall survival of patients with EOC represents a crucial unmet need. 
Immunogenicity of EOC has been well documented, and there is extensive literature demonstrating the 
presence of clonally activated CD3+CD8+ TCRαβ+ T-cells in ovarian tumors and their prognostic 
significance (Hayashi et al., 1999; Ioannides, Freedman, Platsoucas, Rashed, & Kim, 1991; Peoples, 
Schoof, Andrews, Goedegebuure, & Eberlein, 1993; Preston et al., 2013; Sato et al., 2005; Webb, Milne, 
Watson, Deleeuw, & Nelson, 2014; Zhang et al., 2003). TIL derived from EOC patients demonstrate 
tumor specificity and killing of autologous EOC tumor cells (Ioannides et al., 1991).  A meta-analysis of 
studies investigating the prognostic significance of TIL in ovarian cancer revealed an independent 
positive effect on survival associated with the presence of TIL (Hwang, Adams, Tahirovic, Hagemann, & 
Coukos, 2012).  Emerging data on single agent, anti-PD1 / antiPDL-1 therapies in ovarian cancer point to 
response rates of only 10-15%.  These low response rates could be improved by using adoptive cell 


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therapy (ACT) strategies and as noted in Section 1.1 clinical trials aimed at testing the efficacy of TIL 
therapy in ovarian cancer are ongoing. 
Our group has characterized the immune component of OC, explored the ability to grow and expand TIL 
from tumor fragments, and tested their functionality (Sakellariou-Thompson et al., SITC 2015).   
Extensive flow cytometry analysis detected a robust, activated T-cell infiltrate that can be grown from OC 
samples obtained pre- and post-chemotherapy.  The addition of an agonistic anti-41BB antibody to the 
cultures preferentially increased CD8+ TIL outgrowth as well as favored the expansion of Natural Killer 
cells.  Importantly, success rate of TIL growth was increased from 40% to 90% for cultures grown 
without and with anti-41BB respectively.  Next, it was established that the CD3+ TIL initially grown with 
anti-41BB could be rapidly expanded at least 1000-fold over two weeks.  Finally, the rapidly expanded T 
cells exhibited anti-tumor capabilities in the context of re-directed killing assays (Sakellariou-Thompson 
et al., SITC 2015). 
1.2.3 INCLUSION OF SUBJECTS WITH PANCREATIC CANCER 
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease and has been identified as a 
“recalcitrant cancer” by the National Cancer Institute (NCI). Despite being the 12th most common cancer 
in 2017, with 53,670 new cases, it is the 3rd deadliest in the U.S. with 43,090 deaths, having surpassed 
breast cancer deaths last year. The 5-year survival rate for patients with stage IV, or metastatic, disease is 
a dismal 1%.  While the age-standardized mortality rate (ASMR) for breast cancer and colorectal cancers 
have decreased by over 50% during the past 30 years and are decreasing annually by 2.4% and 2.7% 
respectively, the ASMR for PDAC has only improved marginally (Rahib et al., 2014).  Thus, it is 
estimated that PDAC will be the second leading cause of cancer death in North America within 10 years. 
Late presentation of the disease, no screening methods, lack of effective treatments, and high mortality 
rates highlight the desperate need for development of innovative methods to treat this disease. 
Currently there are only six FDA approved agents for PDAC and at present, front-line therapy for 
metastatic PDAC is combination chemotherapy, most commonly FOLFIRINOX (fluorouracil, irinotecan, 
and oxaliplatin) or gemcitabine and nanoparticle albumin-bound paclitaxel. We have not made a seismic 
shift in the overall survival for this disease over the past few decades. Given our growing understanding 
of the biology and tumor microenvironment and lack of actionable genomic aberrations, it is crucial to 
exploit therapeutic efforts outside of cytotoxics and targeted agents and evaluate benefit of T cell 
therapies in PDAC. 
The tumor microenvironment is composed by multiple cell types, molecular factors, and extracellular 
matrix forming a strong desmoplastic reaction, which is a hallmark of the disease. A complex cross-talk 
between tumor cells and the stroma exists with reciprocal influence that dictates tumor progression and 
ultimately the clinical outcome. In this context, tumor infiltrating immune cells through secretion of 
chemokine and cytokines exert an important regulatory role. TILs, mast cells, and macrophages all 
contribute to a Th2-type inflammatory and immunosuppressive microenvironment. Fibrosis is due to 
activation by tumor and immune cells of pancreatic stellate cells, which are responsible for extracellular 
matrix deposition. Importantly, fibrogenesis is differentially regulated by Th1 (i.e., IFN-γ) and Th2 (i.e., 
IL-4, IL-5, and IL-13) cytokines, which exert opposing roles by promoting collagen degradation and 
synthesis, respectively (Wynn, 2004).  Th1 or Th2 polarized immune cells may thus differentially 
contribute to fibrosis in PDAC and possibly influence tumor progression. 


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Studies have shown that tumor-infiltrating CD4+Thigh/CD8+Thigh/%Treglow and %M1high/M2low are 
independent prognosticators useful for evaluating the immune microenvironment of PDAC. In a study by 
Ino and colleagues, using immunohistochemistry, they examined tumor-infiltrating CD68+ pan-
macrophages, HLA-DR+CD68+ M1 macrophages (M1), CD163+ or CD204+ M2 macrophages (M2), 
CD66b+ neutrophils (Neu), CD4+ T cells (CD4+T), CD8+ T cells (CD8+T), and FOXP3+CD4+ regulatory 
T cells (Treg) in 212 cases of PDAC, and conducted correlation and survival analyses using the Kaplan–
Meier method and Cox proportional hazards model (Ino et al., 2013). Higher levels of tumor-infiltrating 
pan-macrophages, M2, Neu, or the ratio of Tregs to CD4+T (%Treg) are  significantly associated with 
shorter survival, whereas higher levels of tumor-infiltrating CD4+T, CD8+T, or the ratio of M1 to pan-
macrophages (%M1) are  significantly associated with longer survival (Ino et al., 2013).  
Several groups have optimized methods for generating pancreatic cancer–specific TILs that can be used 
for adoptive cellular therapy of patients with pancreatic cancer including our team at MDACC.  
1.2.3.1 4-1BB AGONIST TREATMENT FACILITATES TIL EXPANSION FROM 
POORLY IMMUNOGENIC TUMORS; THE CASE OF PANCREATIC CANCER. 
Our group at MDACC piloted pre-clinical development of TIL therapy for pancreatic cancer and 
observed a significantly lower TIL infiltration in fresh PDAC samples compared to melanoma, coupled 
with a predominance of CD4+ T cells (Figure 2). The poor CD8+ T cell infiltrate observed may not be 
sufficient to respond to immunomodulatory drugs administered systemically (i.e.it is a cold tumor). 
Indeed, pancreatic cancer has been resistant to single agent checkpoint blockade (Brahmer et al., 2012; 
Royal et al., 2010); TIL therapy could provide these patients with large numbers of pancreatic-cancer 
specific T cells, potentially turning a “cold tumor” into a “hot tumor.”  
 
 
 
 
 
 
Figure 2. PDAC tumors are poor in CD8+ T cells. 
Freshly dissociated tumor tissue of different tumor types were 
evaluated for the presence of T cells by flow cytometry. The 
percentage of CD4 and CD8 T cells within the CD3+ T cell 
population was evaluated and a ratio of %CD8/%CD4 was 
determined.  


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1.2.3.2 TIL CAN BE EXPANDED FROM PDAC SAMPLES AND THEIR EXPANSION IS 
POTENTIATED WITH ANTI-4-1BB ANTIBODY 
In our hands the success rate of growing TIL from PDAC samples increased from 25% to 50% with the 
addition of 4-1BB antibody to the cultures. Importantly, the amount of tissue used to generate TIL was no 
larger than 2 core biopsies, which is critical given the limited availability of tissue from pancreatic 
cancer patients. The threshold for considering a culture successful was established at 12x106 TIL grown 
from 6 tumor fragments within 5 weeks based on a scale-down from our melanoma clinical protocol. Use 
of anti-4-1BB also dramatically increased the proportion of CD8+ TIL in the product (Figure 3). 
1.3 
POTENTIAL RISKS AND BENEFITS  
1.3.1 KNOWN POTENTIAL RISKS AND THEIR MITIGATION 
Adoptive cell therapy with TIL is comprised of four main components each of which carry potential risks. 
1. Tissue acquisition.  Culture and expansion of TIL requires surgical biopsies of primary or 
metastatic tumor sites (metastatic only for PDAC).  As with any surgical procedure and 
depending on the patients’ other comorbidities, surgical biopsies have well-known risks including 
bleeding, infection, delayed wound healing, and damage to surrounding structures.  In addition, 
there may be risks associated with general anesthesia.  Overall, life-threatening complications are 
quite rare, and risks are minimized at MDACC by use of collaborating expert surgeons who 
specialize in oncologic surgery. 
2. Non-myeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and 
fludarabine.  The regimen of cyclophosphamide (60 mg/kg IV days -7 and -6) and fludarabine 
(25 mg/m2 days -5 to -1) used in this trial is a standard aspect of TIL and some other ACT 
protocols and has been used in hundreds of patients in and outside of clinical trials.  Therefore, 
the major risks of this regimen are well characterized and include: hemorrhagic cystitis from 
cyclophosphamide (mitigated by co-administration of Mesna), neutropenia and lymphopenia and 
their infectious complications (mitigated by the use of antimicrobial, antiviral, and anti-fungal 
therapeutic and prophylactic antibiotics). 
3. TIL infusion.  Early toxicities related specifically to the infusion of the cells (those which are 
seen immediately following the cell infusion and prior to IL-2 administration) are generally mild 
and include fevers, chills, headache, and malaise. Toxicities that occur following administration 
of IL-2 but are thought to be related to the cells include immune-mediated events. In metastatic 
melanoma patients, autoimmune toxicities include vitiligo, transient uveitis, hearing loss, and 
Figure 3. Addition of anti-4-1BB increases the 
total number of TIL and the percentage of CD8+ 
TIL grown from PDAC tumors. 
PDAC tumor fragments were cultured with IL-2 
alone (green circles) or with IL-2 plus anti-4-1BB 
(pink squares). (A) Total number of TIL (B) % 
CD8 in the product. N=16. Statistical analysis was 
done using a Mann-Whitney t test. 


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vestibular dysfunction.  However, these side effects are thought to be related to melanocyte 
specificity and have not been reported in cervical cancer patients treated with TIL therapy 
(Stevanovic et al., 2015). 
4. 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 associated also 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 IL-2 is to continue dosing until grade 3 or 4 events occur 
but this study calls for 1 to 6 doses based on tolerance. The most commonly seen grade 4 events are 
pulmonary and renal impairment and mental status changes. These toxicities may sometimes require 
intubation for protection of the patient’s airway. It is important to note that although these patients require 
significant supportive measures during this period, almost all toxicities are reversible, and the 
overwhelming majority of patients have suffered no long-term sequelae following this treatment regimen. 
However, fatal complications are possible.  
1.3.2 KNOWN POTENTIAL BENEFITS  
Most of the evidence for efficacy of ACT using TIL is in patients with metastatic melanoma where this 
therapy has been most often used.  Response rates of approximately 50% have been reported (Dudley et 
al., 2002; Dudley et al., 2005; Dudley et al., 2008) at NCI and also at MDACC (Radvanyi et al., 2012). 
Approximately 20-24% durable complete response (CR) rates have been observed with TIL therapy (Goff 
JCO 2016).  However, more recently TIL therapy has been reported to result in complete durable 
responses of at least 54 and 46 months or partial responses in patients with non-melanoma cancers 
including cervical cancer (Stevanovic et al., 2015; Stevanovic et al., 2017) and cholangiocarcinoma (Tran 
et al., 2014).  In both cervical cancer and cholangiocarcinoma, responses were observed in subjects for 
whom conventional therapies would have been extremely unlikely to produce a response.  The two 
subjects with cervical cancer who achieved complete remission had already received multiple lines of 
chemotherapy and radiotherapy and would receive the recommendation for best supportive care with 
transition to hospice by most clinicians had they not elected to undergo TIL therapy at NCI. 
Hence, the potential benefit for subjects on this trial is response that is durable in nature.  
 
 
 


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2. 
OBJECTIVES  
2.1 
PRIMARY 
The primary objective of this investigation is to evaluate efficacy using objective response rate (ORR) 
according to RECIST v1.1 in subjects with ovarian cancer, PDAC, and colorectal cancers. 
2.2 
SECONDARY 
The secondary objectives of this investigation are to: 
1. Determine the disease control rate (DCR) within and across cohorts,  
2. Determine the duration of response (DOR), 
3. Determine progression-free survival (PFS) and overall survival (OS), and 
4. Further characterize the safety profile of adoptive cell therapy with TIL across multiple tumor types. 
2.3 
EXPLORATORY 
The exploratory objectives of this investigation are to: 
1. Establish duration of TIL persistence, 
2. Compare the molecular and immunological features of tumors before and after TIL therapy, 
3. Prospectively evaluate the existing immunotherapy response criteria (irRECIST) as the best response 
assessment tool for TIL therapy among a diverse group of solid tumors, 
4. Investigate TIL attributes (CD8 %, CD27 and CD28 expression) and correlation with response to 
therapy, 
5. Assess tumor marker (CA19-9; CA-125) response in patients who produce this tumor marker, and 
6. Assess Health-Related Quality of Life (HRQOL). 
3. 
STUDY DESIGN AND ENDPOINTS  
This is a multi-cohort phase II trial aimed at evaluating the efficacy of MDA-TIL in subjects with: a) 
advanced or relapsed colorectal cancers refractory to conventional therapy, b) platinum-resistant ovarian 
cancer, and c) PDAC who have progressed on, or received maximal benefit from, front-line therapy. Each 
cohort begins with ten subjects in the first stage, and expansion to the second stage is guided by a 
modified Simon’s two stage design as described in the Statistical Considerations section. 
3.1 
PRIMARY ENDPOINT 
The primary endpoint is ORR by RECIST v1.1 for ovarian cancer, colorectal cancer, and PDAC. 
3.2 
SECONDARY ENDPOINTS 
The secondary efficacy endpoints include CRR, DCR, DOR, PFS using RECIST v1.1, and OS. The 
landmark survival rates will also be estimated for 6 and 12 months. DCR includes complete response 
(CR), partial response (PR), and stable disease (SD).  Safety endpoints will include overall assessment of 
AEs including grade 3 or greater non-hematological toxicities, SAEs and treatment-emergent AEs by 
grade and relationship to the study treatment. 
 


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3.3 
EXPLORATORY ENDPOINTS 
Exploratory endpoints will include the following: 
1. Duration of TIL persistence as determined by T cell receptor (TCR) sequencing of infused T cells 
serially isolated following MDA-TIL infusion, or alternatively iRepertoire assessment of mRNA for 
the TCRs.  
2. Response as determined by the immune-related response criteria (Wolchok et al., 2009). 
3. Immunological Phenotype of MDA-TIL at the time of infusion by multichannel flow cytometry 
4. Baseline and post-treatment tumor assessment via IHC, TCR sequencing, and transcriptional analysis. 
5. HRQOL as assessed per EORTC QLQ-C30 questionnaire. 
4. 
ELIGIBILITY CRITERIA 
4.1 
PARTICIPANT INCLUSION CRITERIA 
4.1.1 GENERAL INCLUSION CRITERIA 
1. Age between 18 and 70  
2. Subjects must be willing and able to provide informed consent.  
3. Clinical performance status of ECOG 0 or 1 at enrollment and within 7 days of initiating 
lymphodepleting chemotherapy. 
4. Subjects must have an area of tumor amenable to excisional biopsy (core biopsies may be allowed as 
detailed in section 6.1.20) for the generation of TIL separate from, and in addition to, a target lesion 
to be used for response assessment. 
5. Any prior therapy directed at the malignant tumor, including radiation therapy, chemotherapy, and 
biologic/targeted agents must be discontinued at least 28 days prior to tumor resection for preparing 
TIL therapy. 
6. Within 7 days of enrollment, subjects must meet the following laboratory criteria: 
 
Absolute neutrophil count (ANC) ≥ 1000/mm3 
 
Hemoglobin ≥ 9.0 g/dL (transfusion allowed) 
 
Platelet count ≥ 100,000/mm3 
 
ALT/SGPT and AST/SGOT < 2.5 x the upper limit of normal (ULN) 
o Patients with liver metastases may have LFT ≤ 5.0 x ULN 
 
Calculated creatinine clearance (Cockcroft-Gault) ≥ 50.0 mL/min 
 
Total bilirubin ≤ 1.5 X ULN 
 
Prothrombin Time (PT) & Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN 
(correction with vitamin K allowed) unless subject is receiving anticoagulant therapy (which 
should be managed according to institutional norms prior to and after excisional biopsy) 
 
Negative serum pregnancy test (female subjects of childbearing potential) 
7. Subjects must not have a confirmed human immunodeficiency virus (HIV) infection. 
8. Subjects must have a 12-lead electrocardiogram (EKG) showing no active ischemia and Fridericia’s 
corrected QT interval (QTcF) less than 480 ms. 
9. Subjects must also have a negative dobutamine stress echocardiogram before beginning treatment. 


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10. Subjects of childbearing potential must be willing to practice an approved highly effective method of 
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: 
 
Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal 
ring), 
 
Intrauterine device (IUD), 
 
Tubal Ligation or hysterectomy, 
 
Subject/partner status post vasectomy, 
 
Implantable or injectable contraceptives, and 
 
Condoms plus spermicide 
11. Able to adhere to the study visit schedule and other protocol requirements. 
12. Pulmonary function tests (spirometry) demonstrating forced expiratory value (FEV) 1 greater than 
65% predicted or forced vital capacity (FVC) greater than 65% of predicted. 
4.1.2 COHORT-SPECIFIC INCLUSION CRITERIA 
In addition to meeting the above general inclusion criteria subjects must also meet respective cohort 
specific inclusion criteria listed below. 
Ovarian Cancer 
1. Subjects must have high grade non-mucinous histology (carcinosarcomas are allowed). 
2. Subjects must have failed at least two prior lines of chemotherapy (i.e. frontline adjuvant 
chemotherapy plus one additional line for recurrent/progressive disease), or have platinum resistant 
disease. 
Colorectal Cancer  
1. Subjects with colorectal adenocarcinoma must have metastatic disease that is considered incurable 
with currently available therapies and have derived maximal benefit from or have become refractory 
to frontline conventional therapy (e.g. FOLFOX, FOLFIRI).  
2. Subjects should have low disease burden such that in the treating physician’s opinion the patient 
would not require additional intervening treatment for 7-8 weeks (required for TIL harvest and 
manufacturing). 
Pancreatic Adenocarcinoma  
1. Subjects must have histologically or cytologically documented diagnosis of PDAC with oligo-
metastatic disease.  
2. Subjects must have progressed on, or received maximal benefit from, front-line therapy. 
3. Patients may have received unlimited lines of prior standard of care therapy.  
4. Patients with ascites or carcinomatosis are not eligible for the study. 
5. Patients will need an albumin of ≥ 3.0 mg/dL within 7 days of enrollment. 
 
 
 


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4.2 
PARTICIPANT EXCLUSION CRITERIA 
4.2.1 GENERAL STUDY EXCLUSION CRITERIA 
1. Active systemic infections requiring intravenous antibiotics, coagulation disorders or other major 
medical illnesses of the cardiovascular, respiratory or immune system. PI or his/her designee shall 
make the final determination regarding appropriateness of enrollment. 
2. Patients with active viral hepatitis. 
3. Patients who have a left ventricular ejection fraction (LVEF) < 45% at Screening. 
4. Patients with a history of prior adoptive cell therapies. 
5. Persistent prior therapy-related toxicities greater than Grade 2 according to Common Toxicity Criteria 
for Adverse Events (CTCAE) v4.03, except for peripheral neuropathy, alopecia, or vitiligo prior to 
enrollment. 
6. Primary immunodeficiency. 
7. History of organ or hematopoietic stem cell transplant. 
8. Chronic steroid therapy, however prednisone or its equivalent is allowed at < 10 mg/day. 
9. Patients who are pregnant or nursing.  
10. Presence of a significant psychiatric disease, which in the opinion of the principal investigator or 
his/her designee, would prevent adequate informed consent.  
11. History of clinically significant autoimmune disease including active, known, or suspected 
autoimmune disease. Subjects with resolved side effects from prior checkpoint inhibitor therapy, 
vitiligo, psoriasis, type 1 diabetes or resolved childhood asthma/atopy would be an exception to this 
rule.  Subjects that require intermittent use of bronchodilators or local steroid injections would not be 
excluded.  Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will 
not be excluded. 
12. History of clinically significant chronic obstructive pulmonary disease (COPD), asthma, or other 
chronic lung disease. 
13. History of a second malignancy (diagnosed in the last 5 years).  Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.   
14. History of known active central nervous system metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and 
any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to initiation of lymphodepletion.   
15. Has received a live vaccine within 30 days prior to the initiation of lymphodepletion. 
16. Patients who have a contraindication to or history of hypersensitivity reaction to any components or 
excipients of the TIL therapy or the other study drugs: NMA-LD (cyclophosphamide, mesna, and 
fludarabine); IL-2; Any component of the TIL infusion product formulation including human serum 
albumin (HSA), IL-2, and dextran-40. 
17. Any other condition that in the investigator’s judgement would significantly increase the risks of 
participation. 
 


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4.3 
TREATMENT ELIGIBILITY CRITERIA 
After tissue acquisition, subjects must also meet treatment eligibility criteria before beginning 
lymphodepletion. 
4.3.1 TREATMENT INCLUSION CRITERION 
Within 24 h of starting lymphodepleting chemotherapy, subjects must meet the following laboratory 
criteria: 
o Absolute neutrophil count (ANC) ≥ 1000/mm3 
o Hemoglobin ≥ 9.0 g/dL (transfusion allowed) 
o Platelet count ≥ 100,000/mm3 
o ALT/SGPT and AST/SGOT ≤ 2.5 x the upper limit of normal (ULN) 
 
Patients with liver metastases may have liver function tests (LFT) ≤ 5.0 x 
ULN 
o Calculated creatinine clearance (Cockcroft-Gault) ≥ 50.0 mL/min 
o Total bilirubin ≤ 1.5 X ULN 
4.3.2 TREATMENT EXCLUSION CRITERIA 
 
Patient has any complication or delayed healing from excisional procedure that in the 
investigator’s opinion would increase the risks of lymphodepletion, adoptive TIL therapy and 
adjuvant IL-2. 
 
Patients has a decline in performance status to ECOG > 1 (at the visit prior to admission for 
lymphodepletion). 
4.4 
COMPLETION OR DISCONTINUATION OF TREATMENT 
4.4.1 TREATMENT COMPLETION 
Completion of treatment is defined as having received any volume of MDA-TIL infusion followed by at 
least 1 dose of adjuvant IL-2. 
4.4.2 CRITERIA FOR EARLY DISCONTINUATION FROM TREATMENT  
This study includes a one-time treatment regimen consisting of lymphodepleting chemotherapy, MDA-
TIL infusion, and adjuvant IL-2 (up to 6 doses). Discontinuation from study treatment should be 
considered if any of the following criteria are met. However, unless the patient also meets criteria for 
discontinuation from study participation, every effort should be made to continue follow-up and 
assessment of all patients, including those that do not complete the full course of therapy, as specified in 
the schedule of events. 
Criteria for early discontinuation from treatment are: 
 
Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, brain, eye, liver, 
colon, adrenal gland, lungs) with symptoms emerging following MDA-TIL infusion, 


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 
Grade 3 or greater allergic reaction including bronchospasm or generalized urticaria that does not 
resolve after medical management in the opinion of the Investigator, 
 
Grade 3 or greater toxicity due to IL-2 that does not decrease to Grade 2 or less within 96 hours 
of management, 
 
Determination by the Investigator that continued treatment is not in the best interest of the patient, 
 
Withdrawal by patient. The patient (or parents/legal guardian for patients < 18 years of age) may 
withdraw consent to treatment but continue consent for follow-up evaluations and/or survival 
status, 
 
Pregnancy, 
 
Patient meets criteria for early discontinuation from study, and 
 
Patient has become ineligible for study after tumor harvest and prior to MDA-TIL or IL-2 
administration 
4.4.3 CRITERIA FOR EARLY DISCONTINUATION FROM STUDY 
 
Withdrawal by patient. The patient (or parents/legal guardian for patients < 18 years of age) may 
withdraw consent. All efforts should be made to continue consent for survival status follow-up. 
 
Patient has become ineligible for study after tumor harvest or did not receive any study treatment. 
 
Death. 
 
Lost to follow-up after 3 documented attempts to contact the patient. 
4.4.4 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Some subjects may undergo tumor harvest and TIL manufacture but will not receive the infusion of 
investigational product.  If MDA-TIL is not administered to the patient for whatever reason, even if after 
lymphodepleting chemotherapy, then the patient should remain on study, but data collection will be 
reduced to survival status and start of any new anticancer therapy for 3 years. Such subjects will be 
considered unevaluable for statistical analysis of efficacy and will be replaced. 
If a patient must initiate anti-cancer therapy or exhibits disease progression after TIL infusion they will 
remain in the study, but the data collection will be reduced to response status, survival status and other 
anti-cancer therapy for 3 years. 
5. 
STUDY AGENTS 
5.1 
STUDY AGENTS AND THEIR ACQUISITION 
5.1.1 LYMPHODEPLETION REGIMEN 
The lymphodepletion regimen is scheduled to start on Day -7, after notification from the MDACC Cell 
Therapy Lab that TIL production is expected to be successful for the patient. Patients may receive 
lymphodepleting chemotherapy as inpatient or outpatient at the discretion of the investigator.  
Modification of the lymphodepletion regimen is allowed as clinically indicated and should be guided by 
daily hematological parameters as described below for fludarabine in heavily pre-treated patients or 
subjects with a history of prolonged myeloid recovery. The regimen comprises 2 daily doses of 
cyclophosphamide (with mesna) followed by 5 daily doses of fludarabine and should be administered as 
per institutional protocol/standards for nonmyeloablative chemotherapy. Guidelines for preparation and 


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administration are described below. Subjects should be dosed using actual body weight but not to exceed 
140% of Ideal Body Weight as defined below: 
 
Ideal Body Weight for Males = 50 kg + 2.3 x (number of inches over 60 inches in height) 
Example:  ideal body weight of a 5’10’’ male subject 
50 + 2.3 x 10 = 73 kg 
 
Ideal Body Weight for Females = 45.5 kg + 2.3 (number of inches over 60 inches in height)  
Example:  ideal body weight of a 5’3’’ female subject 
45.5 + 2.3 x 3 = 52.4 kg 
Drugs required for lymphodepletion including cyclophosphamide, fludarabine, and mesna will be 
obtained from the MD Anderson Investigational Pharmacy. Supportive medications including 
antimicrobials will be obtained through MD Anderson clinical pharmacy. For formulation and packaging 
of the lymphodepletion regimen please refer to respective package inserts for cyclophosphamide, 
fludarabine, and mesna. 
Variations from the lymphodepletion (e.g. infusion times; schedule of treatments, etc.) prior to day 0 will 
be documented in the medical record but will not be considered protocol violations/deviations. 
5.1.1.1 CYCLOPHOSPHAMIDE 
Cyclophosphamide will be administered at 60 mg/kg/day intravenously (IV) in normal saline (NS) over 
approximately 2 hours on Days -7 and -6.  Mesna 60 mg/kg with dextrose 5% by weight (D5W) or NS 
infused intravenously over 24 h on Days -7 and -6. 
As noted above the dose will be based on the patient’s actual body weight, but to prevent undue toxicity, 
it will not exceed the dose based on 140% of the maximum ideal body weight (defined above). For 
patients with a history of multiple lines of prior cytotoxic chemotherapy, history of radiation, or 
prolonged neutropenia with prior chemotherapy, the dose of cyclophosamide may be reduced to 30 mg/kg 
with approval of the PI. 
5.1.1.2 FLUDARABINE 
Fludarabine will then be infused at 25 mg/m2 IV piggyback (PB) daily over approximately 15-30 minutes 
on Days -5 to -1.  To prevent undue toxicity with fludarabine, the dose will be based on body surface area 
(BSA), but will not exceed a dose calculated on surface areas based on body weights greater than 140% 
of the maximum ideal body weight.   
Fludarabine dose will be adjusted according to estimated creatinine clearance (CrCl) as follows: 
CrCl 50-79 mL/min: Reduce dose to 20 mg/m2 
CrCl 40-49 mL/min: Reduce dose to 15 mg/m2  
Hematological parameters (complete blood count [CBC] and differential) are to be reviewed daily during 
lymphodepletion. If the absolute lymphocyte count falls below 100 cells/mm3 at any point during 
lymphodepletion, the remaining dose(s) of fludarabine may be omitted following discussion with the PI. 
If lymphodepletion is terminated early, TIL infusion may be initiated at least 24 hours after the last dose 
of fludarabine if absolute lymphocyte count remains below 100 cells/mm3. 


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5.1.2 MDA-TIL (AUTOLOGOUS EXPANDED TIL PRODUCT) 
The TIL product used in this protocol is a cellular investigational product comprising a live cell 
suspension of autologous TIL derived from the patient's own tumor. Each dose contains up to 150 x 109 
total viable lymphocytes.  The total volume to be infused will be up to 600 mL dependent on total cell 
dose. TIL will be manufactured in a state-of-the-art GMP facility that will allow compliance with all FDA 
regulations regarding investigational cell transfer products. The MD Anderson TIL facility has 
demonstrated the ability to successfully expand TIL on the tumor samples attempted and have 
successfully treated over 100 patients with melanoma and other cancers with TIL therapy. 
Urelumab (anti-41BB) will be provided by BMS for use only in the MDA-TIL production. Urelumab will 
not be administered to patients. This reagent will be supplied at volumes of 1.6 or 3 mL in a 5-mL vial at 
a concentration of 5 mg/mL. The Urelumab will be stored at 2-8 °C and will be protected from light and 
freezing. 
The procedures and reagents for expanding the human TIL cells and the Certificates of Analysis are 
contained in the Chemistry, Manufacturing, and Controls document (CMC) located in the IND office. 
At least 24 hours from the last dose of fludarabine, MDA-TIL is administered via intravenous infusion by 
gravity at a rate of 5-10 mL/min and not over more than 3 hours.   
If not already hospitalized for the lymphodepleting chemotherapy, the patient will be admitted 1-2 days 
prior to planned MDA-TIL administration and prepared with overnight intravenous hydration prior to the 
MDA-TIL administration. Patients will remain hospitalized until the completion of the IL-2 therapy, as 
per institutional standards. 
Patients must be premedicated with acetaminophen/paracetamol 650 mg by mouth (PO) and 
diphenhydramine (or other histamine H1 antagonist) 25 to 50 mg IV or PO between 30 and 60 minutes 
prior to administration of LN-145. Additional supportive therapy may include indomethacin (50 to 75 mg 
q6h), ranitidine (150 mg q12h), and meperidine (25 to 50 mg) IV for severe rigors/chills. 
Severe infusion reactions have been reported during adoptive cell transfer. Thus, appropriate emergency 
medications (e.g., epinephrine and diphenhydramine) will be available at bedside during administration 
and institutional guidelines will be followed for administering supportive care for anaphylaxis and other 
infusion reactions. Patients should not be premedicated with corticosteroids to prophylax against such 
reactions without prior clearance from the PI or Co-PI. Corticosteroids may be used only at the discretion 
of the treating physician for Grade 4 reactions or if the patient is not responsive to other medications. 
For subjects who experience an NCI CTCAE v 4.03 grade 1 or 2 infusion reaction, MDA-TIL infusion 
may be resumed if the event is short-lived and responds to supportive therapies such as acetaminophen 
and histamine blockers. Patients who experience grade 3 or 4 infusion reactions may not resume 
treatment. Although clinical presentations can be overlapping, when possible, efforts should be 
undertaken to differentiate hypersensitivity type infusion reactions (due to excipients in MDA-TIL) from 
cytokine release syndrome based on clinical and laboratory evaluation since the latter can be mitigated 
using tocilizumab and other cytokine directed therapies. 
5.1.3 INTERLEUKIN 2 
The IL-2 infusion will begin 3-24 h after completion of the MDA-TIL infusion. IL-2 will be administered 
at a dose of 600,000 IU/kg (based on total body weight) and will be administered by IV infusion at a 


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frequency of every 8-12 hours as per institutional standard of care and continued for up to a maximum of 
six doses or as tolerated. IL-2 doses will be skipped if patient experiences a Grade 3 or 4 toxicity due to 
IL-2 except for reversible Grade 3 toxicities common to IL-2 such as diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and laboratory 
changes. Management of IL-2 toxicity is detailed in Appendix A. 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. 
Refer to the current IL-2/aldesleukin (Proleukin®) package insert for additional information. IL-2 will be 
obtained through the MD Anderson Investigational Pharmacy. 
6. 
STUDY PROCEDURES AND SCHEDULE 
6.1 
STUDY SPECIFIC PROCEDURES  
Potentially eligible patients will be approached by their clinical teams at MDACC. Study procedures are 
summarized in the Schedule of Events (Section 6.2). 
6.1.1  INFORMED CONSENT  
Potential subjects will be informed about the study by the investigator.  The risks, benefits, and 
alternatives will be discussed and the Informed Consent Document will be signed before any study related 
assessments are performed. 
6.1.2  ELIGIBILITY CRITERIA  
Subjects must meet all inclusion criteria and must not have any of the conditions specified in the 
exclusion criteria (as described in Section 4). Confirmation of general, cohort, specific, and treatment 
inclusion/exclusion criteria must be documented within seven days of starting lymphodepletion 
chemotherapy. 
6.1.3  DEMOGRAPHIC DATA  
The demographic data will include date of birth (as allowed per local regulations), age, gender, and 
race/ethnic origin. 
6.1.4  MEDICAL HISTORY  
Relevant and significant medical/surgical history and concurrent illnesses will be collected for all patients 
at Screening (Visit 1) and updated as applicable. Any worsening from pre-existing conditions should be 
reported as AEs. Patient’s prior anti-cancer treatment will also be collected. 
6.1.5  CONFIRMATION OF DIAGNOSIS 
Documentation of cohort-specific diagnosis of cancer must be made and confirmed histologically. 
 
 


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6.1.6  CONCOMITANT MEDICATIONS 
All medications and therapies (prescription, and non-prescription, including herbal supplements) taken by 
the patient up to 28 days prior to Screening (Visit 1) will be collected in the medical record, 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, will be recorded in the 
medical record (see Section 6.3). 
6.1.7  BASELINE TOXICITY ASSESSMENT 
All baseline grade 2 and higher toxicities will be assessed as per CTCAE v4.03.  Any events occurred 
after screening, but prior to enrollment/tumor resection, will be recorded as Medical History in the 
database, unless the events are related to protocol mandated procedures. Any events occurring after 
enrollment/tumor resection will be captured as AEs in the database until the 6 Month visit, subject is 
taken off the study, or starts other cancer therapy.   
6.1.8  VITAL SIGNS 
Vital signs shall include height, weight, pulse, respirations, blood pressure and temperature. Height will 
be measured at Screening (Visit 1) only. All other vital signs will be measured at applicable time points. 
On Day 0 (Visit 11/MDA-TIL infusion), vital signs will be monitored per MD Anderson melanoma TIL 
infusion unit protocol unless otherwise clinically indicated, for up to approximately 24 hours post MDA-
TIL infusion. 
6.1.9  EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS 
An ECOG performance status will be assessed at Screening (Visit 1) and other time points indicated on 
the schedule of events. 
6.1.10 PHYSICAL EXAMINATION 
Physical examination will be conducted for all visits except for Tumor Resection and shall include vital 
signs and weight, head and neck, cardiovascular, pulmonary, extremities, and other relevant evaluation. 
Exams during conducted during follow-up will be symptom directed. Clinically significant changes in the 
exam findings will be recorded as adverse events as indicated. 
6.1.11 SAFETY BLOOD AND URINE TESTS 
Safety blood and urine tests will be collected and analyzed locally at every visit as indicated in the 
Schedule of Events (Section 6.2). 
6.1.12 HUMAN LEUKOCYTE ANTIGEN (HLA) TYPING 
Sample collection for high resolution HLA Class I typing will be conducted according to the Schedule of 
Events (Table 1).  
 
 


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6.1.13 INFECTIOUS DISEASE SEROLOGY 
Serology for the following diseases will be completed at Screening (Visit 1) to be analyzed locally per 
institutional standard: HIV, Hepatitis B Virus, Hepatitis C Virus, Cytomegalovirus (CMV), Herpes 
Simplex Virus; Epstein-Barr virus (EBV) (may be within previous 3 months to Tumor Resection/Visit 2), 
Chagas Disease, Human T cell Lymphotropic Virus, and West Nile Virus. Sickle Cell Disease will also 
be screened. Additional testing is to be done as clinically indicated. 
6.1.14 ESTIMATED CREATININE CLEARANCE 
The creatinine clearance will be calculated by site using the Cockcroft-Gault formula at Screening only. 
6.1.15 CARDIAC EVALUATION 
All subjects must have a baseline 12-lead EKG and assessment of ventricular function by echocardiogram 
or MUGA.  In addition, subjects must have a negative dobutamine stress echocardiogram at Screening.  
6.1.16 PULMONARY FUNCTION TESTS 
Pulmonary evaluation will be completed within 28 days from Screening (Visit 1). Prior evaluations 
completed within 6 months prior to Screening (Visit 1) will be accepted. An FEV1 greater than 65% of 
predicted or FVC greater than 65% of predicted is required. 
Patients who are unable to conduct reliable PFT spirometry measurements due to abnormal upper airway 
anatomy (e.g. tracheostomy) may undergo a 6-minute walk test to be evaluate pulmonary function.  These 
patients must walk a distance of at least 80% predicted for age and sex as well as maintain oxygen 
saturation greater than 90% throughout. 
6.1.17 COLONOSCOPY 
Colonoscopy is only required for patients who have had a documented Grade 2 or greater diarrhea or 
colitis due to previous immunotherapy within six months of Screening. Patients that have been 
asymptomatic for at least 6 months from Screening or had a normal colonoscopy post anti-PD-1/anti-PD-
L1 treatment, with uninflamed mucosa by visual assessment will not need to repeat the colonoscopy. 
6.1.18 HRQOL QUESTIONNAIRE – EORTC QLQ-C30 
Health related quality of life (HRQOL) questionnaire will be conducted in person at baseline Day -21 
(Visit 3) and be performed as the first procedure on the subsequent visits. See the Schedules of Events 
(Section 6.2) for specific time points. Only patients who are fluent in English will participate in the 
questionnaires. Failure to complete any questionnaires will not be considered a deviation requiring 
reporting. 
6.1.19 RADIOGRAPHIC ASSESSMENTS 
Radiographic assessments by computed tomography (CT) scans with contrast of the chest, abdomen and 
pelvis are required for all patients for tumor assessments. CT scans are performed as indicated in the 
Schedule of Events until progressive disease by modified RECIST v1.1 is noted (or if the patient 
withdraws full consent). Response assessments should be evaluated and documented by a qualified 
radiologist participating in the trial. 


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Magnetic Resonance Imaging (MRI) or positron emission tomography (PET) scans of the chest, abdomen 
and pelvis in lieu of CT scans may be allowed for patients who have an intolerability to contrast media.  
The same method of assessment (CT or MRI) and the same technique for acquisition of data should be 
used consistently throughout the study to characterize each identified and reported lesion.  
Radiographic assessments will occur at screening, baseline, and then at 6, 12, 18, and 24 weeks post 
MDA-TIL infusion. Thereafter, patients will be evaluated for response approximately every 12 weeks 
through month 24 or until their participation on the study ends. Additional radiological assessments may 
be performed as clinically indicated. 
6.1.20 TUMOR RESECTION / EXCISIONAL BIOPSY 
Prior to surgical biopsy, subject eligibility will be confirmed, and the PI or designee will provide approval 
for patient enrollment into the clinical trial and subsequent tumor resection. Subjects will undergo a pre-
procedural consultation and a separate informed consent by the team performing the surgical biopsy per 
institutional standards. The tumor resection should be done as a research procedure. However, if a routine 
procedure is already medically required, the tumor resection may be done as part of that procedure. 
Ideally, the targeted tumor should have not been previously irradiated. If the tumor has been previously 
irradiated a minimum period of 3 months must have elapsed between irradiation and resection, during 
which time additional target-tumor growth must have been demonstrated. If enrolled, tumor resection is 
expected to occur approximately 6 weeks prior to the anticipated MDA-TIL infusion (Day 0). 
The PI, in consultation with treating physician(s) and Interventional Radiology faculty, will have the 
discretion to determine that it would be in the subject’s best interest to undergo multiple core biopsies for 
tumor harvest rather than open surgery. This judgment will be based on patient safety and surgical risk 
considerations, as well as, the feasibility of obtaining sufficient tissue from Interventional Radiology-
performed multiple core biopsies for tumor harvest. This decision will be communicated to, and approved 
by, the TIL manufacturing team. 
MDA-TIL is an autologous investigational product which is procured and delivered by means that have 
more in common with autologous blood product delivery than those of traditional drug production. It is 
imperative that only the patient’s own (autologous) study treatment (MDA-TIL) be administered to the 
same individual patient. For these reasons, the patient specimen must be procured and handled per a strict 
protocol to ensure optimal quality of the specimen and minimum transport time to and from the 
processing MDACC Cell Therapy Lab facility, as well as to ensure the appropriate identification of the 
study product at all times including infusion back into the patient. 
Refer to the CMC for details. 
6.1.21 ADDITIONAL RESEARCH BIOPSY 
In cases where additional or excess tumor tissue can be safely procured at the time of the initial excisional 
biopsy for TIL harvest, excess tumor tissue for research will be sent to Dr. Chantale Bernatchez’s 
laboratory according to established institutional procedures. Provision of adequate amount of tumor tissue 
for TIL manufacturing is priority over the collection of additional tumor tissue that is sent for research. 
Every effort should be made to obtain adequate tumor tissue for both TIL manufacturing and additional 
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In addition, a mandatory on-study biopsy will be used to ascertain molecular and immunological changes 
following treatment and as well as to document presence of infused T cells in the tumor. The tumor tissue 
analysis will include: 1) immunohistochemical studies to identify individual immune cell populations and 
immune marker expression including tissue mass cytometry (if sufficient tissue available) and 2) DNA 
and RNA analysis, including possible exploratory genomic and transcriptomic evaluation and TCR 
sequencing to evaluate infused TIL homing to tumor (in the post-treatment biopsy). 
Provision of adequate amount of tumor tissue for TIL manufacturing is priority over the collection of 
additional tumor tissue for research. Every effort should be made to obtain adequate tumor tissue for both 
TIL manufacturing and additional analysis. 
Additionally, if a diagnostic biopsy is required while a patient is on study, including during the follow-up 
period to confirm disease progression, additional tissue may be taken for research as an optional 
procedure.  
6.1.22 BIOLOGICAL AND IMMUNE MONITORING 
Up to 500 x 106 TIL from the infusion product (and genetic material extracted from these samples) will be 
stored for research. Flow cytometry analysis of the infused TIL will be done in Dr. Bernatchez’s 
laboratory, and DNA from the infusion product will be sent for TCR sequencing. The samples in these 
research studies will be used to gain further information about the disease and the characteristics of the 
TIL before and after infusion. 
Peripheral blood will be collected from the patients and processed into 3 fractions: whole blood, serum, 
and plasma. These fractions will be used for biological monitoring, immune monitoring, and T cell 
tracking using TCR sequencing. Blood samples will be drawn at the time points listed in the Schedules of 
Events (Tables 2 and 3). 


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6.2 
SCHEDULES OF EVENTS 
Table 1. Schedule of Events: Pre-treatment and Treatment Phases 
 
Pre-treatment Phase 
Treatment Phase 
Visit Number 
1 
2 
3 
4 
5 
6, 7, 8, 
9, 10 
11 
12, 13, 
14, 15 
16 
17 
18 
19 
Visit Name 
Screeninga 
Biopsy 
Baseline 
(Day -14 
to -21) 
Day 
-7 
Day 
-6 
Days -5, 
-4, -3, 
-2, -1 
Day 0 
(MDA-TIL 
Infusion) 
Days 1, 
2, 3, 4 
Day 
14 
Day 
28 
Day 42 
(Week 6) 
Day 84 
(Week 12) 
Visit Window (in days) 
≤28 
-7b 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
± 7 
± 7 
± 7 
± 7 
Written Informed Consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation of diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exame 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
CBC and Chemistry Panelh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation testsi 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Thyroid testsj 
X 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysisk 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ß-HCG Serum Pregnancy Testl 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Infection testingm 
X 
 
 
 
 
 
 
 
 
 
 
 
HLA typingn 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Evaluationso 
X 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function testsp 
X 
 
 
 
 
 
 
 
 
 
 
 
Colonoscopyq 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor Assessments (CT/MRI)r 
X 
 
Xs 
 
 
 
 
 
 
 
X 
X 
Tumor Markerst 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Response Assessments 
 
 
 
 
 
 
 
 
 
 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor Excision 
 
Xv,w 
 
 
 
 
 
 
 
 
Xw 
 
NMA lymphodepletionx 
 
 
 
X 
X 
X 
 
 
 
 
 
 
MDA-TIL Infusiony 
 
 
 
 
 
 
X 
 
 
 
 
 
IL-2z 
 
 
 
 
 
 
 
X 
 
 
 
 
Immune Monitoringaa 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
HRQOL Questionnairebb 
 
 
X 
 
 
 
 
 
 
 
 
X 
Prophylactic Medicationscc 
Infection Preventiondd 
 
 
 
Administered daily until ANC ≥500/mm3 
PJPee 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Filgrastimff 
 
 
 
 
 
 
 
X 
 
 
 
 
Fungal Prophylaxisgg 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 


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Herpes Virus Prophylaxishh 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
a All screening criteria must be assessed within 28 days of the biopsy (Visit 2) 
b Assessment of ECOG, Concomitant Meds, and Adverse Events, as well as blood draws (for CBC, Chemistry Panel, Coagulation tests, and Immune 
Monitoring) may be done up to 5 days before the tumor excision if the patient has a pre-operative consultation during that time. 
c Also includes assignment of subject identification number 
d Including Demographics and history of tobacco and alcohol use. (History of tobacco and alcohol use can be collected at any time.) 
e Physical examination (PE) will include gastrointestinal (abdomen, liver), cardiovascular, extremities, head, eyes, ears, nose, and throat, respiratory 
system, skin, psychiatric (mental status), general nutrition. See Section 6.1.10. 
f Vital signs will include height, weight, heart rate, respiratory rate, blood pressure, and temperature.  Height will be measured at Screening only. BSA 
and BMI will be calculated at Day -7 (Visit 4) only. See Section 6.1.8. 
g On Day 0 (MDA-TIL 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. 
h 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, and uric acid.  Hematology: CBC with differential. 
i PT, PTT, and INR on the marked Visits and as clinically indicated. 
j Thyroid panel (to include TSH and Free T3 and T4) on the marked Visits and as clinically indicated. 
k Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific gravity, Color and Appearance. 
l Only in women of childbearing potential 
m See Section 6.1.13. 
n See Section 6.1.12. Blood for HLA typing can be drawn any time before Day 0. 
o See Section 6.1.15. 
p Pulmonary evaluation using spirometry will be completed for all patients. See Section 6.1.16. 
q Colonoscopy is only required for documented Grade 2 or greater diarrhea or colitis as a result of previous immunotherapy within six months from 
Screening. Patients that have been asymptomatic for at least 6 months from Screening or had a normal colonoscopy post anti-PD-1/anti-PD-L1 
treatment, with uninflamed mucosa by visual assessment will not need to repeat the colonoscopy. See Section 6.1.17. 
r CT Scans of the chest, abdomen, and pelvis are required at the indicated time points. Additional radiological assessments may be performed per 
Investigator’s discretion. MRI may be used if patients are intolerable to contrast media. See Section 6.1.19.  
s Baseline scans must occur prior to lymphodepletion. 
t CA19-9 for patients with PDAC and CA-125 for patients with ovarian cancer. 
u Any AEs occurred after Screening but prior to enrollment/tumor resection will be recorded as Medical History in the database. Any AEs occurred after 
enrollment/tumor resection will be captured as AEs through Day 168 (Visit 21/Month 6) and as clinically indicated, or until the first dose of the 
subsequent anti-cancer therapy, whichever occurs first. All AEs attributed to protocol-required procedures or treatment will be collected through Day 
672 (Visit 25/Month 24). See Section 7. 
 
 


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v For tumor harvest for TIL manufacturing and FFPE tumor slides for exploratory analyses, see Section 6.1.20. The disease will also be reassessed 
after the tumor excision. 
w For research. See Section 6.1.21.  
x Cyclophosphamide with mesna for 2 days at Day -7 and Day -6 (Visits 4 thru 5) followed by 5 days of fludarabine at Day -5 thru Day -1 (Visits 
6 thru 10). See Section 5. 
y MDA-TIL infusion is to be done 1 to 2 days after the last dose of agent in the NMA lymphodepletion regimen. See Section 5. 
z Initiate IL-2 at 600,000 IU/kg within approximately 3 to 24 hours after MDA-TIL infusion and continue every 8-12 hours for up to six doses. See 
Section 5. 
aa Blood draw for Immune Monitoring is to be collected at Tumor Resection (Visit 2), Day -7 (Visit 4), Day 14 (Visit 16) through Day 84 (Visit 
19/Week 12), and Day 168 (Visit 21/Month 6) through Day 336 (Visit 23/Month 12) and ETV. See Section 6.1.22. 
bb HRQOL Questionnaire(s) to include EORTC QLQ-C30 version 3.0 is to be performed as the first procedure at baseline Day -21 (Visit 3) and be 
performed as the first procedure on Day 84 (Visit 19/Week 12), Day 168 (Visit 21/Month 6), Day 336 (Visit 23/Month 12), and Day 672 (Visit 
25/Month 24). 
cc See Section 6.3.3 for details regarding prophylactic medications. 
dd See Section 6.3.3.1 for details regarding infection prevention. 
ee Pneumocystis Jiroveci Pneumonia (PJP) prophylaxis should be given as described in Section 6.3.3.2. 
ff Filgrastim should be administered daily as described in Section 6.3.4.1. 
gg Fungal prophylaxis should be administered each day described in Section 6.3.3.4. 
hh Herpes prophylaxis should be administered as described in Section 6.3.3.3. 


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Table 2. Schedule of Events: Post-treatment and Long-term Follow-up 
 
Post-treatment Follow-up 
Long-term 
Follow-up 
Visit Number 
20 
21 
22 
23 
24 
25 
EWV 
 
Visit Name 
Day 126 
(Month 4.5/ 
Week 18)  
Day 168 
(Month 6) 
Day 252 
(Month 9) 
Day 336 
(Month 12) 
Day 504 
(Month 18) 
Day 672 
(Month 24) 
Early 
Withdrawal 
Visit 
Quarterly 
Contact 
Visit Window (in days) 
± 14 
± 14 
± 14 
± 14 
± 21 
± 21 
 
± 21 
Physical Exama 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsb 
X 
X 
X 
X 
 
 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
CBC and Chemistry Panelc 
X 
X 
 
 
 
 
X 
 
Coagulation testsd 
As Clinically Indicated 
Thyroid testse 
As Clinically Indicated 
Urinalysisf 
X 
X 
X 
X 
X 
X 
X 
 
Tumor Assessments (CT/MRI)g 
X 
X 
X 
X 
X 
X 
X 
 
Tumor Markersh 
X 
X 
X 
X 
X 
X 
X 
 
Response Assessments 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Meds 
X 
X 
X 
X 
 
 
X 
 
Adverse eventsi 
X 
X 
 
 
 
 
X 
 
Immune Monitoringj 
 
X 
X  
X 
 
 
X 
 
HRQOL Questionnairek 
 
X 
 
X 
 
X 
 
 
Survival Follow-upl 
 
 
 
 
 
 
 
X 
Prophylactic Medicationsm 
Infection Preventionn 
Administered daily until ANC ≥500/mm3 
 
 
PJPo 
X 
X 
 
 
 
 
 
 
Fungal Prophylaxisp 
X 
X 
 
 
 
 
 
 
Herpes Virus Prophylaxisq 
X 
X 
 
 
 
 
 
 
 
 
 


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a 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. See Section 6.1.10. 
b Vital signs will include weight, heart rate, respiratory rate, blood pressure, and temperature. 
c 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, and uric acid.  Hematology: CBC 
with differential. 
d PT, PTT, and INR as clinically indicated. 
e Thyroid panel (to include TSH and Free T3 and T4) as clinically indicated. 
f Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific gravity, Color and Appearance. 
g CT Scans of the chest, abdomen and pelvis, are required at the indicated time points. Additional radiological assessments may be performed per 
Investigator’s discretion. MRI may be used if patients are intolerable to contrast media. See Section 6.1.19. 
h CA19-9 for patients with PDAC and CA-125 for patients with ovarian cancer. 
i Any AEs occurred after Screening, but prior to enrollment/tumor resection, will be recorded as Medical History in the database. Any AEs 
occurred after enrollment/tumor resection will be captured as AEs through Day 168 (Visit 21/Month 6) and as clinically indicated, or until the first 
dose of the subsequent anti-cancer therapy, whichever occurs first. All AEs attributed to protocol-required procedures or treatment will be 
collected through Day 672 (Visit 25/Month 24). See Section 7. 
j Blood draw for Immune Monitoring is to be collected at visits between Day 168 (Visit 21/Month 6) through Day 336 (Visit 23/Month 12) and 
ETV. See Section 6.1.22. 
k HRQOL Questionnaire(s) to include EORTC QLQ-C30 version 3.0 is to be performed as the first procedure at baseline Day -21 (Visit 3) and be 
performed as the first procedure on Day 84 (Visit 19/Week 12), Day 168 (Visit 21/Month 6), Day 336 (Visit 23/Month 12), and Day 672 (Visit 
25/Month 24). 
l Patients are to be contacted quarterly (~every 3 months) once discontinue/complete the Post-Treatment Follow-up to assess disease status and 
subsequent anticancer therapy.  
m See Section 6.3.3 for details regarding prophylactic medications. 
n See Section 6.3.3.1 for details regarding infection prevention. 
o PJP prophylaxis should be given as described in Section 6.3.3.2. 
p Fungal prophylaxis should be administered each day described in Section 6.3.3.4. 
q See Section 6.3.3.3. 
 


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6.3 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
Concomitant medications and any changes in them will be recorded in the medical record. 
6.3.1 PERMITTED MEDICATIONS, TREATMENTS, AND PROCEDURES 
Medications for medical problems other than antineoplastic agents are permitted.  Those with conditions 
requiring anti-inflammatory drugs for chronic conditions potentially affecting TIL administration may be 
considered only with approval of the PI.  
Palliative radiation therapy is permitted between tumor resection and lymphodepletion as long as it does not 
affect target and non-target lesions. 
Use of systemic steroid therapy ≤ 10 mg/day of prednisone or equivalent is permitted.  Use of > 10 mg/day of 
prednisone or equivalent is permitted in cases of exacerbation of known disease or for treatment of new 
symptoms on study per Investigator’s discretion. 
Any changes in concomitant medications will be recorded only in the patient’s medical record throughout the 
trial. 
For subject who have CT IV contrast allergy, radiologic evaluation using MRI or PET-CT (without intravenous 
contrast is the preferred management.  Every attempt should be made to maintain consistency in imaging 
modality for each patient. 
6.3.2 PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
All other anti-neoplastic drugs and radiation (except for that described in Section 6.3.1) are prohibited. Subjects 
are also discouraged from using over-the-counter supplements and homeopathic products, especially those with 
purported anti-inflammatory properties, such as boswelia. 
6.3.3 PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
Patients treated with lymphodepletion are subject to opportunistic infections and appropriate infectious agent 
prophylaxis is required. The prophylaxis regimens and duration listed below may be modified as clinically 
indicated in consultation with an Infectious Diseases specialist. 
6.3.3.1 INFECTION PREVENTION 
Patients will receive levofloxacin starting on Day 1 at 500 mg daily (or an equivalent antibiotic) until ANC 
recovers to greater than 500/mm3 for two days. 
6.3.3.2 PNEUMOCYSTIS JIROVECI PNEUMONIA (PJP) PROPHYLAXIS 
Patients will receive the fixed combination of trimethoprim (TMP) and sulfamethoxazole (SMX) as double 
strength (DS) tablet [DS tabs = TMP 160 mg/tab and SMX 800 mg/tab] PO BID on two days per week.  
TMP/SMX-DS will be taken by patients beginning on Day -7 and continuing for a minimum of 6 months after 
lymphodepletion.  For patients with sulfa allergies, Pentamidine will be given (once discharged from the 
hospital) 300 mg IV every 21 days for 6 months after lymphodepletion. If IV Pentamidine is not feasible after 
discharge, PCP prophylaxis can be substituted with oral antimicrobials such as Atovaquone as per standard of 


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care for 6 months after lymphodepletion. Patients will be given prophylactic antibiotics intravenously during 
high dose IL-2 therapy. 
6.3.3.3 HERPES VIRUS PROPHYLAXIS 
Starting on the day of TIL infusion (Day 0) subjects will be administered valacylcovir 500 mg PO daily if 
patient is able to take oral medications or acyclovir 5 mg/kg IVPB every 8 hours if patient needs intravenous 
medications, which is continued for 6 months (or at the discretion of the treating physician).  Reversible renal 
insufficiency has been reported with IV administered acyclovir but not with oral acyclovir.  Neurologic toxicity 
including delirium, tremors, coma, acute psychiatric disturbances, and abnormal electroencephalograms has 
been reported with higher doses of acyclovir.  If symptoms occur, a dosage adjustment will be made or the drug 
be discontinued.  Acyclovir will not be used concomitantly with other nucleoside analogs (e.g. ganciclovir), 
which interfere with DNA synthesis. In patients with renal disease, the dose is adjusted as per product labeling. 
6.3.3.4 FUNGAL PROPHYLAXIS  
Patients will begin Fluconazole 200 mg PO daily with the T cell infusion (Day 0) and continue for 6 months (or 
at the discretion of the treating physician). 
6.3.4 SUPPORTIVE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Other supportive medications will include the following. 
6.3.4.1 FILGRASTIM (G-CSF) 
To reduce the duration of neutropenia following NMA lymphodepletion chemotherapy, filgrastim (G-CSF) will 
be given at 5 μg/kg/day daily subcutaneously until ANC > 500/mm3 for at least 2 consecutive days.  
Approximate dosing to correspond to the 300 mcg or 480 mcg dosage forms is allowed.  
6.3.4.2 ONDANSETRON HYDROCHLORIDE (ZOFRAN) 
Ondansetron will be used to control nausea and vomiting during the chemotherapy preparative regimen.  It can 
cause headache, dizziness, myalgias, drowsiness, malaise, and weakness.  Less common side effects include 
chest pain, hypotension, pruritus, constipation and urinary retention.  Consult the package insert for a complete 
list of side effects and specific dose instructions. 
6.3.4.3 FUROSEMIDE (LASIX) 
Furosemide will be used to enhance urine output during the chemotherapy preparative regimen with 
cyclophosphamide. Adverse effects include dizziness, vertigo, paresthesias, weakness, orthostatic hypotension, 
photosensitivity, rash and pruritus.  Consult the package insert for a complete list of side effects and specific 
dose instructions. 
6.3.4.4 EMPIRIC ANTIBIOTICS  
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation cephalosporin with adequate 
pseudomonas coverage as per local antibiogram or a quinolone for temperature ≥ 38.5oC with an ANC less than 
500/mm3.  Aminoglycosides should be avoided if possible. Infectious disease consultation will be obtained from 
all patients with unexplained fever or any infectious complications. 


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6.3.4.5 BLOOD PRODUCT SUPPORT  
Using daily CBC values as a guide, the patient will also receive platelets and packed red blood cells as needed.  
Attempts will be made to keep Hgb > 8.0 g/dL, and platelets > 20,000/mL guided by the clinical scenario.    
Leukocyte filters will be utilized for all blood and platelet transfusions to decrease sensitization to transfused 
WBC’s and decrease the risk of CMV infection.  Irradiated blood and blood products should be used. 
7. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar with the 
content of this section. 
7.1 
SPECIFICATION OF SAFETY PARAMETERS 
7.1.1 DEFINITION OF ADVERSE EVENTS 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6 (R1) 
defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s preexisting condition. An 
abnormal laboratory finding (including EKG finding) that requires an action or intervention by the investigator, 
or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation, 
should be reported as an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational product) or 
nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or other untoward 
medical event that begins after written informed consent has been obtained but before the subject has received 
investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the subject being 
enrolled into the study) for a documented pre-existing condition, that did not worsen from baseline, is not 
considered an AE (serious or nonserious). An untoward medical event occurring during the prescheduled 
elective procedure or routinely scheduled treatment should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
The Principal Investigator or designee shall be responsible for reporting and tracking of all AEs in compliance 
with all Laws, verifying and providing source documentation, and assigning the attribution for all AEs, included 
any expedited safety reports. 
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 database. If the patient was permanently 


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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 database. 
7.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator 
or the sponsor, it results in any of the following outcomes: 
 
Death 
 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the view 
of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that, had it occurred in a more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of 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 result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
1. Important medical events as defined above, may also be considered serious adverse events. Any important 
medical event can and should be reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office. 
2. All events occurring during the conduct of a protocol and meeting the definition of a SAE must be reported 
to the IRB in accordance with the timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting Serious 
Unanticipated Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, regardless of attribution (within 24 hours of 
knowledge of the event). 
3. All life-threatening or fatal events that are unexpected and related to the study drug must have a written 
report submitted within 24 hours (next working day) of knowledge of the event to the Safety Project 
Manager in the IND Office.  
4. Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the 
IND Office and MDACC IRB.  
5. Serious adverse events will be captured from the time of informed consent until 6 months after the last dose 
of IL-2 or until the first dose of anti-cancer therapy, whichever occurs first, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable resolution of 
the event. 
6. Additionally, any serious adverse events that occur after the 30-day time period that are related to the study 
treatment must be reported to the IND Office. This may include the development of a secondary 
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If any patient should die while on the study, the Investigator will inform within 24 hours and report the cause of 
death as an SAE.  The cause of death should be recorded in detail on the SAE Report Form.  Disease 
progression itself is not an AE, but the clinical signs or symptoms leading to death should be reported as an SAE 
with an outcome of death. 
Reporting to FDA: 
Serious adverse events will be forwarded to the FDA by the IND Sponsor (Safety Project Manager IND Office) 
according to 21 CFR 312.32, including Grade 3-5 infusion reactions and all unexpected SAEs that require 
expedited reporting. 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported according to 
the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy. 
7.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
Unanticipated problems are defined as per 21 CFR 312.32(a): An adverse event or suspected adverse reaction is 
considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application, as amended. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers 
to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
7.2 
INVESTIGATOR COMMUNICATIONS WITH IOVANCE BIOTHERAPEUTICS 
Reports for SAEs and other events requiring reporting will be sent to Iovance at the same time they are sent to 
the FDA, in accordance with the Strategic Alliance between MD Anderson and Iovance Biotherapeutics. 
Additionally, reports will also be sent to Synteract, an Iovance associated clinical research organization (CRO). 
Reports will be sent to Iovance Biotherapeutics’ designated mailbox: iovancesafety@iovance.com and 
safetyfax@synteract.com. 
7.3 
ASSESSMENT OF SAFETY PARAMETERS 
7.3.1 ASSESSMENT OF SEVERITY 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs and SAEs. 
Severity will be graded according to the CTCAE v4.03. The determination of severity for all other events not 
listed in the CTCAE should be made by the investigator based upon medical judgment and the severity 
categories of Grade 1 to 5 as defined below. 
 
Grade 1 (mild): An event that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 


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 
Grade 2 (moderate): An event that is usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject. 
 
Grade 3 (severe): An event that requires intensive therapeutic intervention. The event interrupts usual 
activities of daily living, or significantly affects the clinical status of the subject. 
 
Grade 4 (life threatening): An event, and/or its immediate sequelae, that is associated with an imminent 
risk of death or with physical or mental disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, etc.). 
 
Grade 5 (fatal): Death (loss of life) as a result of an event. 
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 7.1.2. A Grade 3 AE need not necessarily be considered 
an SAE. For example, a Grade 3 headache that persists for several hours may not meet the regulatory definition 
of an SAE and would be considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital 
admission would be considered an SAE. 
7.3.2 ASSESSMENT OF RELATIONSHIP 
Attribution is the relationship between an adverse event or serious adverse event and the study treatment. 
Attribution will be assigned as follows: 
1. Definite – The AE is clearly related to the study treatment 
2. Probable – The AE is likely related to the study treatment 
3. Possible – The AE may be related to the study treatment 
4. Unlikely – The AE is doubtfully related to the study treatment 
5. Unrelated – The AE is clearly NOT related to the study treatment 
7.4 
RECORDING AND REPORTING OF AES AND SAES 
All non-hematologic AEs and SAEs will be recorded. Only clinically significant laboratory abnormalities will 
be reported as an AE or SAE. A laboratory abnormality is considered clinically significant if it: resulted in 
initiation of concomitant therapy for laboratory abnormality; resulted in change of study treatment due to 
laboratory abnormality; or resulted in hospitalization or prolongation of hospitalization due to a laboratory 
abnormality. All laboratory abnormalities otherwise are reported in the database as laboratory assessment done 
per protocol defined schedule of assessment. 
7.4.1 STUDY RECORDING PERIOD AND FOLLOW-UP FOR AES AND SAES  
AEs and SAEs will be recorded and reported from time of informed consent throughout the treatment phase. 
SAEs will  recorded and reported during the follow-up period (6 months after the last dose of IL-2) or until the 
first dose of anti-cancer therapy, whichever comes first. Treatment of procedure-related (possible, probable, 
definitive) AEs/SAEs must be reported at any time while a subject is being followed for tumor assessments.  
During the course of the study all AEs and SAEs should be proactively followed up for each subject. Every 
effort should be made to obtain a resolution for all events, even if the events continue after discontinuation/study 
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The investigator is responsible for following all AEs and SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, even if this 
extends beyond study participation. 
7.4.2 FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS 
Any AEs that are unresolved at the subject’s last visit in the treatment phase are followed up by the investigator 
for as long as medically indicated, but without further recording in the database. After 30 days, only subjects 
with ongoing investigational product-related AEs/SAEs will continue to be followed for safety. Iovance 
Biotherapeutics and the IND office retain the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.4.3 SAFETY DATA EXCHANGE   
MD Anderson and Iovance Biotherapeutics will share information with each other of any findings that may 
impact the safety of a Study Drug as Study Drug safety may adversely affect the health and safety of any Study 
subject, influence the conduct of a Study, alter an IRB’s approval to continue a Study, or affect the willingness 
of a Study subject to continue participation in the Study.  
SAE terminology and severity grading will be based on the NCI CTCAE v 4.03 guidelines. 
7.4.3.1 IOVANCE BIOTHERAPEUTICS 
MD Anderson and Iovance Biotherapeutics will share information as described in the MD Anderson/Iovance 
Strategic Alliance Agreement.  
7.4.3.2 BRISTOL-MYERS SQUIBB 
MD Anderson, Iovance Biotherapeutics and BMS will share information as described in the Investigator-
Initiated Research Agreement between MD Anderson, Iovance Biotherapeutics and BMS. BMS will receive a 
quarterly AE report from MD Anderson using MD Anderson’s SAE Report Forms. 
Reports for Bristol-Myers Squibb (BMS) will be sent to their designated mailbox:  
MG-RD-GPVE-PHARMACOVIGILANCE@bms.com.      
7.4.4 UNANTICIPATED PROBLEM REPORTING  
Unexpected events must be reported to Iovance Biotherapeutics safety department by electronic mail to 
iovancesafety@iovance.com and safetyfax@synteract.com within 24 hours of knowledge of the event using the 
eSAE form. 
7.4.5 SPECIAL SITUATION REPORTS 
Special situation reports include reports of medication error, overdose, adverse events associated with product 
complaints, occupational exposure, and pregnancy reports regardless of an associated AE.   
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal/investigational 
product given per administration or cumulatively which is above the maximum recommended dose as per 
protocol or in the product labelling (as it applies to the daily dose of the patient in question).  
Product complaint is defined as complaints arising from potential deviations in the manufacture, packaging, or 
distribution of the medicinal/investigational product.   
Occupational exposure is defined as the exposure to a medicinal/investigational product as a result of one’s 
professional or non-professional occupation. 
All other special situation reports involving the study treatment must be reported to Iovance Biotherapeutics 
safety department and Synteract by electronic mail to: iovancesafety@iovance.com and 
safetyfax@synteract.com within 24 hours of becoming aware of the situation. Special situations involving 
concomitant medications do not need to be reported; however, any AE resulting from a special situation should 
be reported in the database. 
7.4.6  
REPORTING OF PREGNANCY  
Any pregnancy that occurs while on the study through 12 months from the last dose of IL-2 or until the first 
dose of the next anti-cancer therapy, whichever occurs first, must be reported using the Pregnancy Report form 
within 24 hours of becoming aware of the pregnancy.  The pregnancy itself is not considered an AE nor is an 
induced abortion to terminate a pregnancy without medical reasons. Any premature termination of pregnancy 
(e.g., a spontaneous abortion, an induced therapeutic abortion due to complications or other medical reasons) 
must be reported within 24 hours as an AE or SAE. The underlying medical reason for this procedure should be 
recorded as the AE or SAE term. A spontaneous abortion is always considered to be an SAE and will be 
reported as described in Section.  
The patient should receive appropriate monitoring and care until the conclusion of the pregnancy to determine 
the outcome and status of the patient and child.  The outcome should be reported to Iovance Therapeutics using 
the Pregnancy Outcome form. Any SAE occurring in association with a pregnancy, brought to the Investigator’s 
attention after the patient has completed the study treatment and post-treatment follow-up visits, must be 
promptly reported to the Sponsor or their representative. 
The pregnancy must be followed up until discharge following delivery or premature termination to determine 
outcome and status of mother and child. Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. Any SAE occurring in 
association with a pregnancy, brought to the Investigator’s attention after the patient has completed the study 
and considered by the Investigator as possibly related to the investigational product, must be promptly reported 
to the Sponsor or their representative.  
Pregnancies of female partners of male study participants exposed to study treatment must also be reported and 
relevant information should be submitted to the safety CRO using the Pregnancy and Pregnancy Outcome forms 
within 24 hours. Monitoring of the female partners should continue until the conclusion of the pregnancy. 
7.5 
STUDY HALTING RULES  
The study may be stopped following review of the safety data by MDACC IND Office according to their normal 
procedures. 
 


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7.6 
SAFETY OVERSIGHT  
Safety oversight will be performed by the MDACC IND Office. See Section 8.5 for the study specific 
monitoring plan. 
8. 
STATISTICAL CONSIDERATIONS  
8.1 
STATISTICAL AND ANALYTICAL PLANS  
The planned statistical analysis is primarily based on use of descriptive methods unless mentioned otherwise.  
Continuous data will be summarized as number of patients with non-missing data, mean, SD, median, min and 
max values.  Categorical data will be summarized as counts and their related percentages, where applicable.  
Estimation of the primary endpoint, ORR, will use 80% CIs by the Wilson score method.  All other estimations 
will adopt the 2-sided 95% criteria.  PFS and OS will be summarized using Kaplan-Meier estimates. For 
exploratory objectives, paired t-test will be used to examine the molecular and immunological features of tumors 
before and after TIL therapy. Pearson correlation coefficient and linear regression, when appropriate, will be 
used to quantify the relationship between phenotypic attributes (CD8 %, CD27 and CD28 expression, etc.) and 
response to therapy.  Missing data will not be imputed unless defined in the statistical analysis plan.  The 
inferential statistics may be calculated (e.g., p-values) for a descriptive purpose.   
There is no formal statistical comparison among multiple disease cohorts.  The study success criteria are ≥ 3 
responders for each of the cohorts at the end of Stage II.  
8.2 
ANALYSIS DATASETS 
8.2.1 EFFICACY PRIMARY 
The All-Treated analysis set consists of patients who had tumor harvested successfully and treated with 
nonmyeloablative chemotherapy, and MDA-TIL followed by IL-2 (at least 1 dose), based on the Investigators’ 
assessment.  Patients who are clinically/unequivocally progressed or expired prior to reaching the first 
radiological assessment will be included. 
8.2.2 EFFICACY SECONDARY 
The Efficacy-Evaluable analysis set consists of patients in the All-Treated analysis set who had an adequate 
baseline and at least one post-baseline radiological assessments by investigators.  
8.2.3 SAFETY PRIMARY 
The Safety analysis set consists of patients who had tumor harvested successfully and received at least one 
component of the study treatment; cyclophosphamide, fludarabine, MDA-TIL, or IL-2.   
8.2.4 SAFETY SECONDARY 
The Non-Treated analysis set consists of patients who have tumor harvested but did not receive any component 
of the study treatment.  The non-treated analysis set is not a part of the primary Safety analysis set and will be 
listed and summarized separately along with the primary reason of not receiving MDA-TIL.  
 


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8.3 
DESCRIPTION OF STATISTICAL METHODS 
8.3.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
The primary endpoint for each cohort is the ORR as assessed by investigators using RECIST 1.1 criteria.  The 
ORR is derived as the sum of the number of patients with a confirmed CR or partial response (PR) divided by 
the number of patients in the All-Treated analysis set x 100%.  
8.3.2 ANALYSES OF THE SECONDARY EFFICACY ENDPOINTS 
PFS is defined as the time (in months) from the start date of lymphodepletion to PD or death due to any cause, 
whichever event is earlier. Patients not experiencing PD or death at the time of data cut or end of study (i.e., 
database lock) will have their event times censored on the last adequate tumor assessment.  
DOR is measured from the first time measurement criteria are met for a CR or PR, whichever response is 
observed first, until the first date that progressive disease (PD) or death occurs. Patients not experiencing PD or 
death prior to the time of data cut or end of study will have their event times censored on the last adequate tumor 
assessment.  The analysis of DOR is based on responders only as assessed by investigators per RECIST v1.1. 
DCR is derived as the sum of the number of patients who achieved PR/CR or SD per the RECIST v1.1 divided 
by the number of patients in the All-Treated analysis set x 100%. 
OS is defined as the time (in months) from the start date of the lymphodepletion to death due to any cause. 
Patients not having expired at the time of data cut or end of study will have their event times censored on the last 
date of their known survival status. 
The 6- and 12-month landmark survival rates will be calculated based on the Kaplan-Meier method. 
8.3.3 ANALYSES OF THE EXPLORATORY ENDPOINTS 
All exploratory analyses will be descriptive and performed by cohort.  Some analysis results will be reported 
separated from the final clinical study report. 
T-cell repertoire analysis will be used to determine TIL persistence. 
Molecular and immunological features of tumors before and after TIL therapy will be determined using exome 
sequencing and immunohistochemistry/immunofluorescence analyses. 
Sensitivity analyses on ORR, DCR, DOR, and PFS as measured by investigators using the irRECIST criteria 
will be performed. 
Pearson correlation coefficient and linear regression, when appropriate, will be used to quantify the relationship 
between phenotypic attributes (CD8 %, CD27 and CD28 expression, etc.) and tumor response to therapy. 
Baseline CA19-9 of patients with PDAC and baseline CA-125 of patients with ovarian cancer will be assessed 
for potential correlations with the efficacy outcome 
8.3.4 SAFETY ANALYSES 
Grade 3 or higher treatment-emergent AEs and their incidence rates will be compared descriptively to historical 
data of TIL in other cancer disease types.  AE incidence rates will be estimated with 95% CIs per cohort and all 


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cohorts combined.  The treatment-emergent AEs start from the first dose of cyclophosphamide and up to 6 
months from the last dose of IL-2. 
We will monitor the probability of not completing TIL administration across all cohorts aggregately using the 
following Bayesian stopping rule. Let pTIL denote the probability of not completing TIL administration due to 
toxicities. The stopping rule says that if Pr(pTIL >0.3|data)>0.6, i.e., if the data suggest that there is more than 
60% chance that the rate of not completing TIL administration is greater than 0.3, we suspend the accrual and 
inspect the safety data with possible termination of the trial. Assuming a vague beta prior that pTIL ~ Beta(0.3, 
0.7), the Bayesian stopping rule corresponds to the following stopping boundaries: suspend accrual if 
number of patients not completing TIL administration/number of patients treated 
>= 2/3, 3/6, 5/12, 8/24, 12/36, 18/54 
8.3.5 ADHERENCE AND RETENTION ANALYSES 
A study disposition summary will display number and percentages of patients who exit the study early by the 
primary reason in 2 parts:  
1. After the tumor harvest prior to lymphodepletion and 
2. On or after the first dose of cyclophosphamide   
Patients who are treated and being followed for the survival status at the time of study termination (i.e., 
completers) are not a part of this summary.   Patients who did not receive planned full study treatment doses will 
also be summarized by its primary reason. 
8.3.6 BASELINE DESCRIPTIVE STATISTICS 
Baseline demographic and disease characteristics will be summarized descriptively for the Safety and the All-
Treated analysis sets.  Age will be derived as a function of the date of informed consent. 
8.3.7 PLANNED INTERIM ANALYSES  
Each cohort will be analyzed for the stage I criteria within first 10 treated patients. 
8.3.8 SAFETY REVIEW 
The safety parameters will be reviewed on an on-going basis including grades 3 and 4 adverse events (AEs), 
serious AEs, deaths, treatment-related AEs, AEs that lead to reduced or missed doses of lymphodepletion or IL-
2, clinical laboratory tests, vital signs, and physical examinations. 
8.3.9 EFFICACY REVIEW 
The purpose of ongoing efficacy review is to maintain the accuracy of tumor measures for all target lesions in 
the clinical database and ensure the consistent follow-up of all target and non-target lesions identified at 
baseline. 
Sub-groups defined by histology and/or potential biomarkers that are unique to each disease cohort will be used 
to summarize efficacy in addition to all patients per cohort if such analyses are feasible considering the smaller 
sub-group sample size.   
 


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8.3.10 MULTIPLE COMPARISON/MULTIPLICITY 
There is no formal statistical comparison and therefore adjustment for multiplicity does not apply to this study. 
8.3.11 TABULATION OF INDIVIDUAL RESPONSE DATA 
Summary of tumor response data per cohort will be based on the best overall response as assessed by 
investigators per RECIST 1.1.  The summary will display percentages with 80% confidence intervals (CIs) for 
ORR and 95% CIs for DCR by the Wilson score method among patients in the All-Treated analysis set.  The 
median time-to-event and the landmark rates will also be measured with 95% CIs for DOR, PFS, and OS by the 
KM method. 
8.3.12 EXPLORATORY ANALYSES 
All exploratory analyses will be descriptive and performed by cohort.  The analysis will be defined separately 
from the statistical analysis plan for this study and reported independently outside the clinical study report 
(CSR). 
HRQOL will be assessed using the EORTC QLQ-C30 instrument and analyzed per the published evaluation 
manual. 
8.4 
SAMPLE SIZE 
The Simon’s two stage minimax design will be used to monitor the efficacy of each cohort independently. The 
null hypothesis that the historical response rate of 5% to be tested against the estimated experimental cohort 
response rate of 20%. In the first stage, 10 patients will be treated per cohort. If there is no confirmed response 
in these 10 patients, so long as the patient are evaluable, the cohort will be terminated.  Other efficacy estimates 
including maximum % reductions in target lesion sum of diameters and/or time to PD/death may be considered 
for termination. A confirmed response shall be determined by RECIST 1.1 criteria with first assessment at 6 
weeks and second confirmatory scan at 12 weeks.  If the study moves forward to Stage II, an additional 8 
patients will be treated leading to a total of 18 patients for that cohort.  Three or more responders out of 18 
treated patients for the cohort will be considered clinically relevant to justify further investigation. The power of 
this design is >=70% under the 1-sided type I error rate of 10%. 
8.5 
EFFICACY/TOXICITY SUMMARY REPORTS 
The Investigator is responsible for completing efficacy/toxicity summary reports and submitting them to the 
IND office Medical Affairs and Safety Group for review.  These should be submitted as follows:  
Stage I: After the first 10 evaluable patients per cohort complete 12 weeks post-initiation of study treatment and  
Stage II: After additional 8 evaluable patients per cohort complete 12 weeks post-initiation of study treatment. 
9. 
STUDY DATA MANAGEMENT  
9.1 
CLINICAL STUDY DATA 
Clinical study data for this trial will be collected and managed using Prometheus, a 21CFR11- compliant 
electronic data capture system. Prometheus is a secure portal that requires users to login with validated 
credentials, has granular data access controls to ensure that the minimal amount of information required to 
complete a task is presented, handles the de-linking and de-identification of patient information to maintain 


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patient confidentiality. Prometheus provides a multi-institute 21 CFR 11 compliant data capture portal to 
simplify these tasks. Standard data collection, storage procedures, and quality assurance procedures will be 
followed to ensure integrity and auditability of all information entered. 
9.2 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
PBMCs and TIL infusion product will be used for flow cytometry studies. DNA and RNA will also be extracted 
to be used for TCR sequencing. Leftover tumor tissue from TIL harvest as well as from any biopsies performed 
after therapy will be used for translational studies and may include flow cytometry studies, DNA and RNA 
extraction for gene expression studies. 
If sufficient biological samples are available and at the discretion of the PI and Iovance Biotherapeutics, samples 
may be sent to Iovance for additional exploratory studies. 
9.3 
FUTURE USE OF STORED SPECIMENS  
Research material from patients enrolled on this study will be kept at MD Anderson in Dr. Bernatchez’s 
laboratory and Dr. Wistuba’s laboratory for the duration of the study. De-identified patient material may be 
shared with Iovance for testing during the study. 
9.4 
PUBLICATION AND DATA SHARING POLICY 
MD Anderson, through the Principal Investigator, shall provide to Iovance Biotherapeutics interim written 
reports regarding the Research, no less than once per calendar quarter, and a draft final written study report 
within thirty (30) days after completion (or earlier termination) of the study.  Further subsequent development of 
the final written study report will follow the terms specified in Study Order or Strategic Alliance Agreement.  
10. 
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APPENDIX A. EXPECTED ALDESLEUKIN TOXICITIES AND THEIR MANAGEMENT 
 
Expected toxicity  
Expected grade 
Supportive Measures  
Stop Treatment*  
Chills  
3 
IV Meperidine 25-50 
mg, IV q1h, prn  
No  
Fever  
3 
Acetaminophen 650 
mg, po, q4h; 
Indomethicin 50-75 
mg, po, q8h  
No  
Pruritis  
3 
Hydroxyzine HCL 10-20 
mg po q6h, prn; 
Diphenhydramine 
HCL25-50 mg, po, q4h, 
prn  
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  
Diarrhea  
3 
Loperamide 2 mg, po, 
q3h, prn; 
Diphenoxylate HCl 2.5 
mg and atropine 
sulfate 25 mcg, po, 
q3h, prn; codeine 
sulfate 30-60 mg, po, 
q4h, prn  
If uncontrolled after 24 
hours despite all 
supportive measures  
Malaise  
3 or 4 
Bedrest interspersed 
with activity  
If other toxicities occur 
simultaneously  
Hyperbilirubinemia  
3 or 4 
Observation  
If other toxicities occur 
simultaneously  
Anemia  
3 or 4 
Transfusion with PRBCs  If uncontrolled despite 
all supportive 
measures  
Thrombocytopenia  
3 or 4 
Transfusion with 
platelets  
If uncontrolled despite 
all supportive 
measures  
Neutropenia  
4 
Observation  
No  
Edema/Weight gain  
3 
Diuretics prn  
No  
Hypotension  
3 
Fluid resuscitation;  
Vasopressor support  
If uncontrolled despite 
all supportive 
measures 


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Dyspnea  
3 or 4 
Oxygen or ventilatory 
support  
If requires ventilatory 
support  
Oliguria  
3 or 4 
Fluid boluses or 
dopamine at renal 
doses  
If uncontrolled despite 
all supportive 
measures  
Increased creatinine  
3 or 4 
Observation  
Yes (grade 4)  
Renal failure  
3 or 4 
Dialysis  
Yes  
Pleural effusion  
3 
Thoracentesis  
If uncontrolled despite 
all supportive 
measures  
Bowel perforation  
3 
Surgical intervention  
Yes  
Confusion  
3 
Observation  
Yes  
Somnolence  
3 or 4 
Intubation for airway 
protection  
Yes  
Arrhythmia  
3 
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion 
therapy  
If uncontrolled despite 
all supportive 
measures  
Elevated Troponin 
levels  
3 or 4 
Observation  
Yes  
Myocardial Infarction  
4 
Supportive care  
Yes  
Elevated transaminases  
3 or 4 
Observation  
For grade 4 without 
liver metastases  
Electrolyte imbalances  
3 or 4 
Electrolyte 
replacement  
If uncontrolled despite 
all supportive 
measures  
*Unless the toxicity is not reversed within 12 hour