Phase I Trial of Lymphodepletion Followed by Adoptive Cell Transfer of Autologous Tumor Infiltrating Lymphocytes and High-Dose Interleukin 2 in Select Solid Tumors
Phase: PHASE1
Conditions: Metastatic Melanoma, Locally Advanced Refractory/Recurrent Melanoma, Metastatic Head and Neck Cancer, Locally Advanced Refractory/Recurrent Head and Neck Cancer
Sponsor: Gregory Daniels

Phase I Trial of Lymphodepletion followed by Adoptive Cell 
Transfer of Autologous Tumor Infiltrating Lymphocytes 
and High-Dose Interleukin 2 in Select Solid Tumors 
NCT03991741
Document Date: 9/7/2022

UC San Diego Moores Cancer Center 
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Phase I Trial of Lymphodepletion followed by Adoptive Cell Transfer 
of Autologous Tumor Infiltrating Lymphocytes and High-Dose 
Interleukin 2 in Select Solid Tumors 
PRINCIPAL INVESTIGATOR 
Gregory A Daniels, M.D., Ph.D. 
Clinical Professor of Medicine 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: 858-534-3804 
Fax: 858-822-6190 
E-mail: gdaniels@ucsd.edu
Protocol Number: 
160710 
IND Number:  
18932 
Study Agent: Autologous tumor-infiltrating 
lymphocytes 
IND Holder Name: 
Gregory A Daniels, MD, PhD 
Commercial Sources: 
Aldesleukin 
Cyclophosphamide 
Mesna 
Fludarabine 
Protocol 
Date 
Original (v 1.0) 
November 18, 2018 
Amendment (v 1.1) 
April 9, 2019 
Amendment (v 1.2) 
May 15, 2019 
Amendment (v1.3) 
January 15, 2020 
Amendment (v2) 
November 10, 2020 
Amendment (v2.1) 
November 18, 2020 
Amendment (v3) 
September 7, 2022 

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LIST OF INVESTIGATORS 
 
PRINCIPAL INVESTIGATOR 
Gregory A Daniels, M.D., Ph.D. 
Clinical Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: 858-534-3804 
Fax: 858-822-6190 
E-mail: gdaniels@ucsd.edu 
 
CO-INVESTIGATORS 
Jack Bui, M.D., Ph.D. 
Associate Professor of Pathology 
University of California, San Diego 
9500 Gilman Drive # 0612 
La Jolla, CA 92093-0612 
Email: jbui@ucsd.edu 
 
Sandip Patel, M.D. 
Associate Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0820 
Email: sandippatel@ucsd.edu 
 
Ezra Cohen, M.D. 
Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: ecohen@ucsd.edu 
 
Assuntina Sacco, M.D. 
Associate Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: agsacco@ucsd.edu 
 
Joel Baumgartner, M.D. 
Assistant Professor of Surgery 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: j1baumgartner@ucsd.edu  
 
Joseph Califano, III, M.D. 
Professor of Surgery 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: jcalifano@ucsd.edu 
 
Kevin Brumund, M.D. 
Professor of Surgery 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: kbrumund@ucsd.edu 
 
Brian Sutton, MMS, PA-C 
Physician Assistant 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive #0987  
La Jolla, CA  92093-0987 
Email: bsutton@ucsd.edu 

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Charles Coffey, M.D. 
Associate Professor of Surgery 
University of California, San Diego 
200 W. Arbor Drive #8895  
San Diego, CA  92103-8895  
Email: cscoffey@ucsd.edu 
 
Dan S. Kaufman, MD, PhD 
Professor 
Division of Regenerative Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: dskaufman@ucsd.edu 
 
Stephen Schoenberger, Ph.D. 
Professor 
Division of Developmental Immunology 
La Jolla Institute for Allergy and Immunology  
9420 Athena Circle 
La Jolla, CA 92037 
Email: sps@liai.org 
 
Aaron Miller, M.D. 
Assistant Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: amiller@ucsd.edu 
 
Kathyrn Gold, M.D. 
Associate Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Email: kagold@ucsd.edu 
 
Ryan Orosco, M.D. 
Assistant Professor of Surgery 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: rorosco@ucsd.edu 
 
Soo Park, M.D. 
Assistant Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: sjp047@ucsd.edu 
 
Audrey Zeh, NP 
Nurse Practioner  
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA  92093-0987 
Email: azeh@health.ucsd.edu 
 
 
 
BIOSTATISTICIANS 
Karen Messer, Ph.D. 
Professor of Family Medicine & Public Health 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive #0901 
La Jolla CA, 92093-0901 
Phone: 858-822-6823 
E-mail: kmesser@ucsd.edu 
 
Jing Zhang MS 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive #0901 
La Jolla CA, 92093-0901 
 
 
 
 

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Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:   Gregory Daniels, MD, PhD 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
STUDY SUMMARY .............................................................................................................................................. 8 
1.0 
BACKGROUND AND RATIONALE ............................................................................................................ 10 
2.0 
CANCER IMMUNE THERAPY .................................................................................................................. 10 
2.1 
Tumors Targeted by this Protocol .............................................................................................................. 11 
2.2 
Immune Therapy at UCSD .......................................................................................................................... 11 
2.3 
High Dose IL-2 at UCSD .............................................................................................................................. 11 
2.4 
Fluorine labeling and imaging at UCSD ...................................................................................................... 12 
3.0 
ADOPTIVE CELL THERAPY ...................................................................................................................... 12 
3.1 
Summary of NCI TILS .................................................................................................................................. 12 
3.2 
Predictive Outcomes ................................................................................................................................... 13 
3.3 
Autologous Cell Isolation ............................................................................................................................ 13 
4.0 
RATIONALE FOR DEVELOPING TIL DELIVERY PROTOCOL ........................................................................ 13 
5.0 
STUDY OBJECTIVES ............................................................................................................................... 13 
5.1 
Primary Objectives ..................................................................................................................................... 13 
5.2 
Secondary Objectives ................................................................................................................................. 13 
5.3 
Endpoints .................................................................................................................................................... 14 
6.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................................................ 14 
6.1 
Eligibility Criteria ........................................................................................................................................ 14 
6.1.1 
Inclusion Criteria .................................................................................................................................... 14 
6.1.2 
Exclusion Criteria ................................................................................................................................... 16 
6.2 
Eligibility Evaluation ................................................................................................................................... 17 
7.0 
STUDY IMPLEMENTATION ..................................................................................................................... 19 
7.1 
Overall Schema ........................................................................................................................................... 19 
7.2 
Drug Administration ................................................................................................................................... 19 
7.2.1 
Preparative Regimen ............................................................................................................................. 19 
7.2.2 
Cell Infusion and IL-2 Administration ..................................................................................................... 20 
7.3 
Infection Prophylaxis .................................................................................................................................. 21 
7.3.1 
Pneumocystis Jirovecii Pneumonia ........................................................................................................ 21 
7.3.2 
Herpes Virus Prophylaxis ....................................................................................................................... 22 
7.3.3 
Fungal Prophylaxis (Fluconazole) ........................................................................................................... 22 
7.3.4 
Empiric Antibiotics ................................................................................................................................. 22 
7.4 
Blood Product Support ............................................................................................................................... 22 
7.5 
IL-2: Intravenous Administration ................................................................................................................ 22 
7.6 
On study Evaluation ................................................................................................................................... 25 
7.6.1 
Prior to starting the Preparative Regimen (before Day -8) .................................................................... 25 
7.6.2 
During the Preparative Regimen (daily)................................................................................................. 25 
7.6.3 
During and After Cell Infusion ................................................................................................................ 25 
7.6.4 
During and after IL-2 administration until hospital discharge (daily) .................................................... 25 
7.7 
Post Treatment Evaluation ......................................................................................................................... 26 
7.7.1 
Off Treatment Criteria ........................................................................................................................... 27 
7.7.2 
Off Study Criteria ................................................................................................................................... 27 

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8.0 
SUPPORTIVE CARE ................................................................................................................................ 28 
9.0 
MEASUREMENT OF EFFECT ................................................................................................................... 28 
9.1 
Toxicity Criteria .......................................................................................................................................... 28 
9.2 
Response Criteria ........................................................................................................................................ 29 
10.0 
STATISTICAL SECTION............................................................................................................................ 29 
10.1 
Study Design ............................................................................................................................................... 29 
10.2 
Endpoints .................................................................................................................................................... 30 
10.3 
Sample size ................................................................................................................................................. 30 
10.4 
Safety stopping rule and safety reporting .................................................................................................. 30 
10.5 
Futility stopping rule .................................................................................................................................. 30 
10.6 
Evaluable populations ................................................................................................................................ 31 
10.7 
Analysis plan .............................................................................................................................................. 31 
11.0 
ADVERSE EVENTS .................................................................................................................................. 31 
11.1 
Adverse Event Monitoring .......................................................................................................................... 33 
11.2 
Severity ....................................................................................................................................................... 33 
11.3 
Seriousness ................................................................................................................................................. 34 
11.4 
Relationship ................................................................................................................................................ 34 
11.5 
Prior experience .......................................................................................................................................... 34 
11.6 
Reporting Requirements for Adverse Events .............................................................................................. 35 
11.6.1 
Expedited Reporting .......................................................................................................................... 35 
11.6.2 
Routine Reporting Requirements ...................................................................................................... 35 
12.0 
PHARMACEUTICAL INFORMATION ........................................................................................................ 36 
12.1 
IL-2 (Aldesleukin, Interleukin-2, Proleukin, Recombinant Human Interleukin 2) ........................................ 36 
12.2 
Fludarabine ................................................................................................................................................ 36 
12.3 
Cyclophosphamide ..................................................................................................................................... 37 
12.4 
Mesna (Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex,) ............................................................ 38 
12.5 
Filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF, Neupogen, Zarxio) ........................................ 38 
12.6 
Trimethoprim and Sulfamethoxazole Double Strength (TMP/SMX DS) ..................................................... 39 
12.6.1 
Aerosolized Pentamidine or Oral Atovaquone in Place of TMP/SMX DS .......................................... 39 
12.7 
Herpes Virus Prohpylaxis ............................................................................................................................ 39 
12.7.1 
Valacyclovir (Valtrex) ......................................................................................................................... 39 
12.7.2 
Acyclovir ............................................................................................................................................ 39 
12.8 
Fluconazole ................................................................................................................................................. 40 
12.9 
Cell Preparation .......................................................................................................................................... 40 
12.10 Support Medication .................................................................................................................................... 40 
13.0 
STUDY MANAGEMENT .......................................................................................................................... 40 
13.1 
Conflict of Interest ...................................................................................................................................... 40 
13.2 
Institutional Review Board (IRB) Approval and Consent ............................................................................ 40 
13.3 
Subject Data Protection ............................................................................................................................. 41 
13.4 
Data and Safety Monitoring/Auditing ........................................................................................................ 41 
13.5 
Record Retention ........................................................................................................................................ 41 
13.6 
Obligations of Investigators ....................................................................................................................... 42 
14.0 
APPENDICES ......................................................................................................................................... 43 
Appendix 1. CS-1000 labeling of TIL ........................................................................................................................ 43 

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Appendix 2. Adverse Events Occurring in ≥ 10% of Patients Treated with IL-2 ....................................................... 45 
Appendix 3. Expected IL-2 Toxicities and their Suggested Management ................................................................ 46 
Appendix 4. Response Evaluation Criteria in Solid Tumors (RECIST) ....................................................................... 48 
Appendix 5 Communication Plan ............................................................................................................................ 54 
15.0 
REFERENCES ......................................................................................................................................... 56 
 
 
 

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STUDY SUMMARY 
Title 
Phase I Trial of Lymphodepletion Followed by Adoptive Cell 
Transfer of Autologous Tumor Infiltrating Lymphocytes and High-
Dose Interleukin 2 in Select Solid Tumors 
 
Short Title 
Safety of Adoptive Cell Transfer of Autologous Tumor Infiltrating 
Lymphocytes and High-Dose Interleukin 2 in Select Solid Tumors 
Phase 
Phase I 
Methodology 
Single arm. 
Study Duration 
2-3 years 
Study Center(s) 
University of California, San Diego 
Objectives 
1. To establish a low rate of Dose Limiting Toxicity for this treatment 
regimen in metastatic or locally advanced refractory/recurrent 
head and neck cancer or melanoma.  
2. To obtain preliminary evidence of efficacy 
3. To assess the safety and tolerability of this treatment regimen 
4. To study immunologic correlates associated with TIL therapy.  
5. To determine if autologous TIL infused in conjunction with high 
dose aldesleukin following a non-myeloablative lymphodepleting 
preparative regimen can mediate tumor regression in patients 
with cancer. 
Study Endpoints 
The primary safety endpoint is the rate of Dose Limiting Toxicity, defined 
as 
• 
Any treatment related death 
• 
Neutropenia (grade 4 ANC) 4 weeks following treatment. 
• 
Thrombocytopenia (grade 3 or 4 platelets) 4 weeks following 
treatment. 
• 
Grade 4 infection. 
• 
Grade 3 creatinine level at 4 weeks post treatment. 
• 
Grade 4 acute respiratory distress syndrome. 
• 
Any grade 3 or higher AE, except as described above, at least 
possibly related to study treatment that does not resolve within 
48 hours 
 
The primary efficacy endpoint is objective response rate using RECIST 
criteria 
 
Number of Subjects 
12 subjects with metastatic or locally advanced refractory/recurrent head 
and neck cancer  
 
12 subjects with metastatic or locally advanced refractory/recurrent 
melanoma  
 
Diagnosis and Main 
Inclusion Criteria 
Patients greater than or equal to 18 years of age with a pathologically 
confirmed diagnosis of metastatic or locally advanced refractory/recurrent 
head and neck cancer or melanoma refractory to standard therapy.  

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Study Product(s), Dose, 
Route, Regimen 
• 
Patients will undergo biopsy or resection to obtain tumor for 
generation of autologous TIL cultures and autologous cancer cell 
lines per HRPP 190787. 
• 
All patients will receive a non-myeloablative lymphocyte depleting 
preparative regimen of cyclophosphamide (60 mg/kg/day IV) on 
days -8 and -7 and fludarabine (25 mg/m2/day IV) on days -6 
through -2.  
• 
On day 0 patients will receive between 1x109 to 3x1011 TIL and 
then begin high dose aldesleukin (720,000 IU/kg IV every 8 hours 
for up to 15 doses).  
• 
Clinical and immunologic response will be evaluated about 5 
weeks after TIL infusion. A second confirmatory scan will be 
performed at 10 weeks post infusion. 
 
Duration of administration 
Hospital course of approximately 10 to 21 days 
Reference therapy 
Patients who have progressed following at least one prior systemic 
therapy and are not candidates for known curative therapy. 
Statistical Methodology 
This is a Phase I study with no dose escalation. There is a safety 
stopping rule based on cohorts of size 3, within each indication.  In 
addition, there is a futility stopping rule after the first 6 patients, within 
each indication.  
 
• 
There will be up to 4 cohorts of size 3 in each indication 
(melanoma and HNSCC).  Safety will be assessed at 4 weeks 
post treatment in each cohort prior to enrolling the next cohort.  
The trial will stop if one or more DLT’s are observed in any 
cohort. 
 
• 
Within each indication, after the first 6 patients have been treated 
if one or fewer patients have achieved an objective response by 
RECIST criteria, the trial will stop for that indication.  For this 
stopping rule, efficacy will be assessed at 8 weeks following 
infusion of TILs. 
 
 
Study will be suspended pending on further investigation and discussion 
with FDA if excessive rate of severe toxicities are observed in the 
enrolled subjects, e.g., grade 3 or greater toxicities related to study 
products are observed in enrolled subjects. 
 
  
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
The aim of this study is to establish the safety of autologous cell therapy developed for 
melanoma and other solid tumor patients at the Surgery Branch of the National Cancer Institute 
here at the University of California, San Diego (UCSD)1-3. UCSD is both a high-dose interleukin 
2 treatment center with >100 patients treated and a bone marrow transplant center. Tumor 
infiltrating lymphocytes (TILs) demonstrate activity in melanoma and other select solid tumors 
including metastatic HPV related head and neck mucosal squamous cell cancer. We seek to 
establish a protocol to deliver TILs in a safe and effective manner utilizing the Surgery Branch 
protocol as a model. We will examine as separate cohorts patients with melanoma and head 
and neck cancers. Subsequent projects will look to better optimize and expand this technique to 
a variety of tumor types. 
 
2.0 
CANCER IMMUNE THERAPY 
Cancer immune therapy has transformed oncology practice with multiple agents from vaccines, 
cytokines, checkpoint inhibitors and cell products. Tumors responsive to immune modulation 
include but not limited to melanoma, renal cell cancer, lung cancer, cervical cancer, colorectal 
cancer and head and neck cancers. 
 
The first successful solid tumor immune therapy was high-dose interleukin 2 (IL2)4-7. IL2 was 
clinically developed at the NCI as part of efforts of the surgery branch to develop cell therapy. 
Following completion of a series of phase 2 studies, high-dose IL2 was approved in the 1990s 
for the treatment of metastatic renal cell cancer and melanoma. The enthusiasm for IL2 was 
based upon the induction of complete and durable clinical responses in select patients. 
However, use was tempered due to the toxicity associated with therapy and the relatively low 
response rate. 
 
The application of immune therapy has exploded with the development of additional immune 
modulators that includes targeting the CTLA48,9 and PD110-12 (see below melanoma) receptors. 
Ipilimumab (anti-CTLA4) was approved in 2011 for patients with metastatic melanoma. Similar 
to IL2, Ipilimumab delivers durable remission in a small number of patients but is administered 
as an outpatient. The immune dysregulation accompanying CTLA4 blockade also places the 
patient at risk for immune-related adverse events (irAEs) including colitis, hepatitis, dermatitis 
and other autoimmune reactions. Blocking either PD1 or PDL1 receptors demonstrates better 
response rates and improved toxicity profiles for some patients with not only melanoma but also 
other malignancies having an inflamed context. To date, combinations of immune modulators 
have increased both the response rate and toxicity for patients. In melanoma, the response 
rates are more than 80% when combining ipilimumab and Nivolumab for therapy13-15. However, 
the majority of patients experience grade 3 or 4 dose limiting toxicity and can not proceed with 
further therapy. Thus, there continues to be a need for additional treatment options and 
combination immune therapy trials are ongoing. 
 
The tumor microenvironment (TME) offers a window to predict patient outcomes as well as a 
source of effector cells. Tumors rich in lymphocytic infiltration have a better prognosis. In fact, 
patients can be risk stratified based upon an “immunoscore” that out performs TNM staging in 
colorectal cancer patients16. This observation has been extended to a number of other solid 
tumors17. The cells in the TME are not only prognostic and predictive of outcomes and therapy 
response but can be utilized as a therapeutic tool. Ex vivo manipulation of TILs allows for the 
generation and activation of a high number of tumor specific cells. Durable responses have 
been observed in a variety of solid tumor patients including but not limited to melanoma, cervical 

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and head and neck cancer patients. The application of TILs may expand as we understand 
better the regulatory control and nature of the effector response. 
 
2.1 
Tumors Targeted by this Protocol 
Melanoma 
Melanoma incidence continues to rise accounting for approximately 10,000 deaths per year in 
the US. Interleukin 2 therapy was approved for treatment of select patients with advanced 
melanoma in 1998 due to long-term disease control in a subset of patients. It was not until 2011 
that outcomes began to significantly change for the majority of patients with the approval of both 
targeted agents (BRAF inhibitors) and immune modulation (CLTA4). Additional targeted agents 
(cKit and MEK) along with immune checkpoint modulators (PD1/PDL1) has led to dramatic 
changes in overall survival in advanced disease. Unfortunately, there continues to remain a 
need for additional therapeutic options due to significant toxicities (immune related adverse 
events) and progression despite these new agents. We will examine patients who have 
undergone TIL harvest and have no standard therapy options. 
 
Head and neck squamous cell cancers 
Despite a decline in tobacco and alcohol related oropharyngeal cancers, the total rate of 
oropharyngeal cancers has increased due to HPV infections. HPV-associated cancers, 
including cervix, vagina, anus and oropharynx, represent a large and increasing health burden 
accounting for approximately 11,000 deaths per year. Viral-related cancers would appear to be 
an ideal target for immune-based therapy due to potentially unique tumor-associated viral 
antigens, a possible pre-existing natural immune response and dependency upon viral driven 
pathways for oncogenesis. However, response to immune modulation (anti-PD1 therapy) 
appeared similar between HPV-positive and HPV-negative oropharyngeal cancer patients. 
Preliminary response data from the NCI suggests responses to unselected TIL therapy in 
patients with metastatic HPV-related head and neck cancers. We propose to include both HPV-
positive and HPV-negative patients. 
 
2.2 
Immune Therapy at UCSD 
The expansion of immune therapy beyond a few select tumors (melanoma and renal cell 
cancer) in oncology has been reflected with the changing treatment patterns at UCSD. Immune 
therapeutics (cytokine therapy, cell therapy and immune checkpoints) are commonly utilized in 
standard cancer care. In addition, novel agent development and immune response monitoring 
continue to be an active area of research at UCSD. 
 
2.3 
High Dose IL-2 at UCSD 
IL2 (Aldesleukin) therapy was FDA approved in the 1990s for metastatic renal cell and then 
metastatic melanoma patients following a series of phase 2 clinical trials demonstrating durable 
remission in a modest percentage of highly selected patients. Modeled after the therapy 
developed at the NCI, UCSD initiated a HD IL2 protocol in 2007. In 2010, a medication 
utilization evaluation was conducted on the first 32 patients. The evaluation focused on safety, 
benefit and cost. No treatment related deaths were found in a heavily pretreated population of 
melanoma (n=27) and renal cell (n=5) patients. The length of hospital stay was less than other 
University of California programs while the number of doses of IL2 delivered was higher. The 
overall response rate of 15% was similar to other published reports. Thus, the conclusion in 

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2010 was that the developed standard protocol for IL2 was safe and effective. An update to this 
analysis is ongoing and will include the first one hundred consecutive patients. 
 
2.4 
Fluorine labeling and imaging at UCSD 
Cell Sense (CS-1000) is perfluorocarbon emulsion designed to enable cellular uptake and the 
monitoring of cellular distribution by MRI after administration. CS-1000 is the subject of a Drug 
Master File (BB-MF14062) that was submitted to the U.S. Food and Drug Administration in 
2009. CS-1000 is biologically and chemically inert. When CS-1000 is added to a cellular product 
in vitro, it is rapidly absorbed. In 2018 UCSD initiated cellular labeling experiments to examine 
cellular uptake and verify that the TIL cellular properties (viability, phenotype, and IFN-gamma 
production) were maintained (cellular labeling data included in Appendix 1).  Cellular labeling is 
achieved by coincubation of CS-1000 with the cellular product for at least 24h before the 
completion of culture. Imaging optimization has also been performed using UCSD MRI facilities 
to accommodate the examination of TIL pharmacokinetics and trafficking patterns. 
 
CS-1000 has been used in one US FDA-approved Phase I clinical trial (NCT 01671592). The 
trial was completed in February 2014. To date, no adverse events have been reported by the 
sponsor.  CS-1000 is currently being used in one FDA-authorized Phase I clinical trial (NCT 
02035085). It is contemplated that the trial will involve 6 patients presenting with radiation 
induced fibrosis following treatment for breast cancer. The patients will be treated with CS-1000 
labeled autologous stromal vascular fraction derived from adipose tissues that are administered 
subcutaneously at the site of disease. Neither of these trials are affiliated with UCSD. 
 
3.0 
ADOPTIVE CELL THERAPY 
3.1 
Summary of NCI TILS 
The NCI has pioneered novel T cell based cancer therapies for chemotherapy-refractory 
cancers and forms the basis of our protocol development. The NCI demonstrated in three 
consecutive trials the successful treatment of metastatic melanoma with adoptive transfer of 
tumor infiltrating lymphocytes (TILs) who received autologous product following a 
lymphodepleting regimen plus IL2 administration, with or without total body irradiation2. 
Forty-three patients received a non-myeloablative chemotherapy consisting of 60 mg/kg 
cyclophosphamide daily for two doses followed by 25mg/m2 fludarabine daily for five days 
prior to cell transfer and IL2 administration. Twenty-five patients each also received the 
same chemotherapy agents in conjunction with either 200 or 1200 cGy total body irradiation 
(TBI) prior to cell infusion and IL2 administration. The overall objective response rate using 
RECIST criteria in these 93 patients was 56%. There was one treatment related death in 
these 93 patients which occurred in a patient who had an undetected diverticular abscess 
prior to beginning therapy. Of the 52 responding patients in this trial, 42 had disease that 
was refractory to IL2 therapy and 22 had disease that was refractory to prior IL2 plus 
chemotherapy. Thus, TIL therapy demonstrated immune mediated regression in a 
significant fraction of patients with refractory metastatic melanoma. 
 

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The NCI and others have expanded the use of the same TIL product to other solid tumors 
including HPV-associated malignancies and GI tumors1. Cell product has been successfully 
produced and delivered in an analogous manner to HPV-associated head and neck and 
cervical cancer patients in ongoing protocols. Current protocols are examining the selection 
of cells, optimizing culturing conditions and subsequent treatment strategies. 
 
The surgery branch of the NCI has provided guidance and templates for the development of 
this cell delivery protocol based upon the current ongoing cell delivery trials. 
 
3.2 
Predictive Outcomes 
This protocol will focus on the development of a standard delivery platform for cell therapy. 
Understanding how to select patients who may respond to therapy, the mechanism of response 
and barriers to response will be the focus of a companion protocol. Examining the cell product, 
subsequent immune changes and response to additional therapies will be the focus of other 
protocols.  
 
3.3 
Autologous Cell Isolation 
Tumor infiltrating lymphocytes will be isolated and expanded per a companion protocol (HRPP 
190787). Briefly, after obtaining consent, patients will undergo resection of tumors appropriate 
for TIL generation. Autologous cells cultures will be initiated from tumor fragments in media 
containing IL2. Multiple tumor cultures will be pooled and rapidly expanded. 
 
4.0 
RATIONALE FOR DEVELOPING TIL DELIVERY PROTOCOL 
We hope to establish a safe autologous cell delivery protocol for patients with melanoma and 
head and neck cancers. Once established, we anticipate that this protocol will provide a 
backbone for subsequent clinical trials directed at questions of patient selection, optimal cell 
preparation and therapy sequencing or combination. 
 
5.0 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
To determine the rate of Dose Limiting Toxicity of adoptive cell transfer (ACT) using cultured 
autologous tumor infiltrating lymphocytes (TIL) following non-myeloablative chemotherapy plus 
IL-2 treatment for treating patients with cancer. 
 
5.2 
Secondary Objectives  
1. To provide preliminary evidence of efficacy. 
 
2. To describe treatment related Adverse Events and to assess tolerability. 
 
3. To describe the response rate and progression free survival in head and neck 
cancer and melanoma patients receiving ACT plus IL-2. 
 

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4. To characterize immunologic changes during therapy including distribution of TILs 
after infusion. 
 
5.3 
Endpoints 
Primary Endpoint:  
 
Dose Limiting Toxicity defined as any one of the following: 
• 
Any treatment related death 
• 
Neutropenia (grade 4 ANC) 4 weeks following treatment. 
• 
Thrombocytopenia (grade 3 or 4 platelets) 4 weeks following treatment. 
• 
Grade 4 infection. 
• 
Grade 3 creatinine level at 4 weeks post treatment.  
• 
Grade 4 acute respiratory distress syndrome. 
• 
Any grade 3 or higher AE, except as described above, at least possibly related to study 
treatment that does not resolve within 48 hours 
 
The primary efficacy endpoint is objective response rate using RECIST criteria.  
 
Secondary Endpoints: 
• 
Adverse events related to ACT plus IL-2 treatment (description, timing, grade [CTCAE 
v5.0], severity, seriousness, and relatedness). 
• 
Progression free survival, complete response rate and overall survival  
• 
Immunologic subsets in the TIL product and tumor microenvironment if available. 
 
6.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
6.1 
Eligibility Criteria 
6.1.1 Inclusion Criteria 
Patients must meet all of the inclusion criteria to participate in this study. 
 
1. Patient has the ability to understand and the willingness to sign a written informed consent. 
 
2. Patients with a histologically confirmed diagnosis of head and neck squamous cell 
carcinoma OR metastatic cutaneous or mucosal melanoma measurable per RECIST. 
 
3. Progressive squamous cell cancer of the head and neck or metastatic melanoma since prior 
systemic treatment and who are: 
 
a. Not candidates for known curative intent therapy. 
b. Progressed following at least one prior systemic therapy. 
i. Unresectable metastatic melanoma: must have progressed on 
pembrolizumab, Nivolumab, or the combination of Nivolumab and 
ipilimumab prior to enrollment. 

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ii. Unresectable BRAF V600E-mutated metastatic melanoma: must have 
progressed on pembrolizumab, Nivolumab, or the combination of 
Nivolumab and ipilimumab prior to enrollment. In addition, must have 
progressed on (or been intolerant to) prior BRAF-targeting therapy (with 
or without a MEK inhibitor) prior to enrollment. 
iii. Recurrent/metastatic squamous cell cancer of the head and neck: must 
have received prior therapy with a platinum-containing regimen and with 
pembrolizumab or Nivolumab prior to enrollment.  
c. Have advanced disease 
i. Melanoma=unresectable stage III or stage IV 
ii. Head and Neck=recurrent or metastatic disease 
 
4. Patient has undergone resection and a successful generation of an autologous TIL culture 
(per HRPP 190787). 
 
5. Patient with up to three brain lesions may be included if the lesions are < 1cm and 
demonstrate radiographic stability for at least three months following therapy.  . 
 
6. Patient is ≥ 18 years of age. 
 
7. Patient has a life expectancy of greater than 3 months. 
 
8. Patient has an ECOG Performance Status of 0 or 1. 
ECOG Performance Status 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
 
9. Patient has adequate organ and marrow function as defined below: 
Absolute Neutrophil Count 
≥ 1.0 x 109/L 
Platelet count 
≥ 100 x 109/L 
Hemoglobin 
≥ 9.0 g/dL 
AST/SGOT and ALT/SPGT 
≤ 2.5 X institutional upper limit of normal 
Calculated creatinine clearance (Cockcroft gault) 
> 50 ml/min  
Total bilirubin 
≤ 1.5 mg/dl (or ≤ 3 mg/dl in patients with  
 
Gilbert’s Syndrome) 
 
10. Patient is seronegative for HIV antibody. 

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Note: The experimental treatment being evaluated depends on an intact immune system. 
Patients who are HIV seropositive can have decreased immune competence and thus are 
less responsive to the experimental treatment and more susceptible to its toxicities. 
 
11. Patient is seronegative for Hepatitis B antigen, or Hepatitis C antibody or antigen. 
 
12. Patient agrees to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) for the duration of study treatment, and for 4 months after receiving all protocol 
related therapy.  
  
13. More than four weeks has elapsed since the patient received any prior systemic therapy at 
the time of enrollment. Patients must have stable or progressing disease after prior 
treatment. 
Note: Patient may have undergone minor surgical procedures within the past 3 weeks, as 
long as all toxicities from surgery have recovered to grade 1 or less. 
 
14. Patient has recovered to ≤ Grade 1 or baseline from adverse events due to prior therapy. 
 
15. Patient has stable or progressing disease after at least one prior treatment. 
 
16. Six weeks or more have elapsed since the patient received any prior anti-CTLA4 antibody 
therapy to allow antibody levels to decline.  
Note: If patient has previously received ipilimumab or tremelimumab, anti- PD1 or anti-
PD-L1 antibodies, and have documented GI toxicity, the patient must have completely 
recovered to baseline and more than six weeks off steroid therapy.  
 
17. A subset of head and neck squamous cell carcinoma subjects (N ≤ 5) will have the TIL 
product labeled with CS-1000. Subjects in this subset must meet the additional eligibility 
criteria below: 
a. Patients with neck recurrence should have solid (rather than cystic) masses 
below the angle of the mandible (e.g. levels 3-5). 
b. No evidence of hepatic metastases 
 
6.1.2 Exclusion Criteria 
Patients meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
 
1. Patient is currently using investigational agents. 
 
2. Patient had prior cell transfer therapy which included a non-myeloablative or myeloablative 
chemotherapy regimen. 
 
3. Patient is a female of child-bearing potential who is pregnant or breastfeeding because of 
the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. 
 
4. Patient requires immune suppressive therapy including but not limited to greater than 
physiologic steroid replacement. 
 

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5. Active systemic infections, coagulation disorders or other active major medical illnesses of 
the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium 
or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive 
pulmonary disease. 
 
6. Patient has any form of primary immunodeficiency (such as Severe Combined 
Immunodeficiency Disease and AIDS). 
 
7. Patient has opportunistic infections. 
 
8. Patient has a history of severe immediate hypersensitivity reaction to any of the agents used 
in this study. 
 
9. Patient has a history of coronary revascularization or ischemic symptoms. 
 
10. Patient is known to have an LVEF ≤ 45%. 
 
11. Patients with clinically significant atrial and/or ventricular arrhythmias including but not 
limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block. 
 
12. Patient has documented FEV1 ≤ 60% predicted. 
 
13. Patient with untreated brain metastases. 
 
6.2 Eligibility Evaluation 
Prior to initiation of study treatment (within 2 Months prior to chemotherapy): 
 
a. HIV antibody titer and HBsAG determination, anti HCV (must be performed within 2 
months of chemotherapy start date). 
 
b. Anti CMV antibody titer, HSV serology, and EBV panel. (must be performed within 2 
months of chemotherapy start; patients who are known to be positive for any of the 
above do not need to be retested.)  
 
c. Verification that HLA typing is completed (testing is permitted to be conducted at any 
time prior to this point). 
 
d. Stress cardiac (MUGA or echocardiogram) 
 
e. Pulmonary evaluation (PFTs) (must be performed within 2 months of chemotherapy 
start) 
 
f. 
Histologic confirmation of metastatic cancer. This can be done anytime prior to study 
participation on archived samples OR sample collected for TIL production.  
 

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g. For melanoma patients, limited molecular profiling will be documented including but not  
limited to mutation analysis for BRAF. Head and neck cancer patients will have HPV 
status confirmed utilizing either p16 immune histochemistry stains or HPV DNA analysis. 
The BRAF status (melanoma patients) and HPV status (HNSCC patients) will be 
recorded during screening.  
 
Within 2 weeks prior to initiation of study treatment: 
Note: the following evaluations should be repeated for safety if treatment will not begin within 3 
weeks of eligibility confirmation. 
 
a. Complete physical examination including height, weight, vital signs and eye exam, 
noting in detail the exact size and location of any lesions that exist. (Patient medical 
history may be obtained within 8 weeks) 
b. Chest x-ray. 
c. ECG. 
d. Baseline CT of the chest, abdomen and pelvis, and brain MRI to evaluate the status of 
disease. Additional scans and x-rays may be performed if clinically indicated based on 
patients’ signs and symptoms. 
e. Complete Metabolic Panel (CMP): 
o albumin  
o alkaline phosphatase  
o aspartate aminotransferase (ALT) 
o alanine aminotransferase (AST) 
o bicarbonate (CO2) 
o blood urea nitrogen (BUN)  
o calcium  
o chloride 
o creatinine 
o glucose  
o potassium  
o sodium 
o total protein 
o total bilirubin  
f. 
Magnesium, phosphorus 
g. CK, LDH, Uric acid 
h. Thyroid stimulating hormone (TSH), free thyroxine (fT4) 
i. 
Complete Blood Count (CBC) with differential: 
o hemoglobin,  
o hematocrit,  

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o platelet count,  
o white blood cell count,  
o percentage or absolute differential count 
j. 
 PT/PTT 
k. Urinalysis and culture, if indicated 
 
Within 7 days prior to treatment: 
 
a. β-HCG pregnancy test (serum or urine) on all women of child-bearing potential. 
b. ECOG 
 
7.0 
STUDY IMPLEMENTATION 
7.1 
Overall Schema 
Patients will have TIL generated under protocol HRPP 190787. TIL will be grown and 
expanded for this trial according to standard operating procedures submitted in the IND. TIL 
cultures will be monitored regularly and when approximately 5x108 cells are available the cells 
will undergo a rapid expansion. Prior to the start of the preparative regimen (approximately one 
week prior to infusion) TIL will be assessed for potency by interferon gamma release as 
specified in the Certificate of Analysis (COA) shown in the Laboratory Manual. TIL for a subset 
of HNSCC subjects will be labeled with CS-1000 before final harvest. 
 
Once cells exceed the potency requirement and are projected to exceed the minimum number 
specified in the COA (approximately 7 days after the rapid expansion protocol (REP) procedure 
has been initiated), the patient will receive the lymphocyte depleting preparative regimen, 
followed by infusion of between 1x109 to 3x1011 lymphocytes and the administration of high-
dose IL-2. The non-myeloablative chemotherapy (NMA) consists of 60 mg/kg/day 
cyclophosphamide for 2 days followed by 5 days of 25 mg/m2/day fludarabine. On the day 
following the preparative regimen, patients will receive a bolus intravenous infusion of TIL and 
start high-dose IL-2 therapy. Patients will receive the FDA approved standard regimen of IL-2 at 
720,000 IU/kg every eight hours to tolerance starting within 24 hours of cell infusion. Patients 
will be evaluated for response approximately 4-6 weeks following the completion of IL-2. 
 
7.2 
Drug Administration 
Drug Administration Treatment schedule will be according to the following schedule (Table 1). 
Administration of diuretics, electrolyte monitoring and replacement, and hydration should all be 
performed as clinically indicated. Communication between the ACTL principal investigator and 
treatment team will occur per Appendix 5. 
 
7.2.1 Preparative Regimen  
A preparative regimen with cyclophosphamide, mesna and fludrabine will be provided on 
Days -8 through Day -2. Additional information can be found in the Pharmacy Manual.  

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Day -8 and -7:  
Cyclophosphamide 60 mg/kg/day X 2 days IV per institutional standard or per MD 
discretion. .  
 
Mesna therapy will also be provided per institutional standard or MD discretion.  
 
Day -6 to Day --2: 
Fludarabine 25 mg/m2/day IVPB daily per institutional standard or MD discretion.  
 
7.2.2 Cell Infusion and IL-2 Administration 
Day 0 (one to three days after the last dose of agent in the preparative regimen): 
Autologous TIL infusion will be administered intravenously over 20 to 30 minutes 
(minimum 1 X 109 and up to a maximum of 3 X 1011 lymphocytes). Administer at 
an initial rate of 60mL/hr for 5 minutes. If well tolerated, increase and continue at 
a rate of 600mL/hr. Administer peripherally via gravity. 
After at least 3 hours but within 24 hours of cell infusion administration of IL-2 will 
be initiated. 
 
Day 0-5 (Day 0 is the day of cell infusion): 
• 
Standard IL-2 given at approximately 720,000 IU/kg IV (based on total body 
weight) over 15 minute every eight hours (+/- 1 hour) for up to 5 days (max 
15 doses). Dosing guidelines and supportive medications will be followed as 
outlined in Section 7.5 and per package insert. 
• 
Beginning on Day 1: Filgrastim will be started at 300 mcg per day. 
 

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 Table 1. Schedule of Study Treatment Administration 
Day 
Preparative Regimen 
Cell Infusion and IL-2 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
01 
1 
2 
3 
4-5 21 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
60 mg/kg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 
25 mg/m2 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
TIL Cells 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
IL-2 
 
 
 
 
 
 
 
 
X2 
X 
X 
X 
X 
 
Filgrastim3 
300mcg/day 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
TMP/SMX4 
160mg/800mg 
(example) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Fluconazole5 
100 mg po 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Valacyclovir or 
Acyclovir 6 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
1. One to three days after the last dose of agent in the preparative regimen. 
2. Initiate within 24 hours after cell infusion. 
3. Continue until neutrophils count > 1000 x 2 consecutive days. Zarxio may be used 
4. The TMP/SMX schedule should be adjusted to BID, twice a week. Until ALC >1000 for at least 60 
days.  
5. Continue until ANC > 1000/mm3. 
6. Continue until Day +100 and ALC > 1000. 
 
7.3 Infection Prophylaxis 
Note: Other anti infective agents may be substituted at the discretion of the treating investigator. 
 
7.3.1 Pneumocystis Jirovecii Pneumonia 
All patients will receive the fixed combination of trimethoprim [TMP] and 
sulfamethoxazole [SMX] as double strength (DS) tab (DS tabs = TMP 160 mg/tab, and 
SMX 800 mg/tab) p.o. twice daily twice weekly on non-consecutive days starting Day 
+21  and stopping when the absolute lymphocyte count is >1000/mm3 for at least 60 
days. 
 
Pentamidine or Atovaquone will be substituted for TMP/SMX-DS in patients with sulfa 
allergies. Pentamidine will be administered aerosolized at 300 mg per nebulizer within 
one week prior to admission and continued monthly until the absolute lymphocyte count 
is >1000/mm3 and for at least 60 days. Atovaquone will be administered at 1500mg by 
mouth daily after the first dose of chemotherapy on or after Day +21 and stopping when 
absolute lymphocyte count is >1000/mm3 for at least 60 days. 

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7.3.2 Herpes Virus Prophylaxis 
Patients with positive HSV serology will be given valacyclovir or acyclovir. Prophylaxis 
will be provided per institutional standard until absolute lymphocyte count count is 
greater than 1000/mm3. Reversible renal insufficiency has been reported with IV but not 
oral acyclovir. Neurologic toxicity including delirium, tremors, coma, acute psychiatric 
disturbances, and abnormal EEGs have been reported with higher doses of acyclovir. 
Should this occur, a dosage adjustment will be made or the drug will be discontinued. 
Acyclovir will not be used concomitantly with other nucleoside analogs which interfere 
with DNA synthesis, e.g. ganciclovir. In renal disease, the dose is adjusted as per 
product labeling. 
 
7.3.3 Fungal Prophylaxis (Fluconazole) 
Patients will start Fluconazole 100 mg orally after TIL administration on Day +1 and 
continue until the absolute neutrophil count is greater than 1000/mm3. The drug may be 
given IV at a dose of 100mg in 0.9% sodium chloride USP daily in patients unable to 
take it orally. 
 
7.3.4 Empiric Antibiotics 
Patients will start on broad-spectrum antibiotics, either a 3rd or 4thh generation 
cephalosporin or a quinolone for fever of 38.3°C once or two temperatures of 38.0°C or 
above at least one hour apart, AND an ANC <500/mm3. Aminoglycosides should be 
avoided unless clear evidence of sepsis. 
 
7.4 
Blood Product Support 
Using daily CBC’s as a guide, the patient will receive platelets and packed red blood 
cells (PRBC’s) as needed. Attempts will be made to keep Hgb >7gm/dl, and platelets 
>20,000/mm3. All blood products with the exception of the stem cell product will be 
irradiated and leukocyte reduced. 
7.5 
IL-2: Intravenous Administration 
IL-2 will be administered at a dose of approximately 720,000 IU/kg (based on total body 
weight) as an intravenous bolus over a 15 minute period every eight hours (+/- 1 hour) 
beginning within 24 hours after the cell infusion and continuing for up to 5 days 
(maximum 15 doses) per institutional practice. Doses may be delayed or skipped 
depending on patient tolerance if this is determined to be clinically indicated in the 
judgment of the attending physician. Doses will be skipped if patients reach Grade 3 or 4 
toxicity due to IL-2 except for the reversible Grade 3 toxicities common to IL-2 such as 
diarrhea, nausea, vomiting, hypotension, skin changes, anorexia, mucositis, dysphagia, 
or constitutional symptoms and laboratory changes as detailed in Appendix 2. Toxicities 
will be managed as outlined in Appendix 3 and adapted from the experience of the 
cytokine working group18. If these toxicities can be easily reversed within 24 hours by 
supportive measures then additional doses may be given. If greater than two doses of 
IL-2 are skipped, IL-2 administration will be stopped. In addition, dosing may be held or 
stopped at the discretion of the treating investigator. 

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Table 2. Schedule of Study Assessments 
 
Procedure 
Prior to 
treatment 
Within 2 
weeks  
(+/-1 week) 
prior to 
treatment 
Preparative 
Regimen 
During and After 
Infusion and IL-
2 Until Hospital 
Discharge 
Post-
Discharge 
Following Administration of Cell Product 
Eligibility 
 
Days -8 to 
-1 
Days 0 to 4 through 
Day of Discharge 
Day 7 (+7 days) 
after discharge 
Week 6 
(+/- 2 
wks) 
Week 
12 (+/- 
2 wks) 
Every 3 
Months (+/- 1 
MO) X 3 visits 
Every 6 Months 
(+/- 1 MO) X 5 
years 
Physical Exam 
 
X 
X (at least 3 
times/ week) 
X 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
 
 
 
 
 
Review of Systems 
 
 
X (at least 3 
times/ week) 
X 
X 
X 
X 
X 
X 
HLA Typing 
X 
 
 
 
 
 
 
 
 
Antibody Titers and 
Serology 
X+ 
 
X++ 
 
 
 
 
 
 
Stress Cardiac 
X^^ 
 
 
 
 
 
 
 
 
Pulmonary Evaluation 
X^^ 
 
 
 
 
 
 
 
 
Histologic 
Confirmation 
X 
 
 
 
 
 
 
 
 
BRAF Status 
(melanoma only) 
X 
 
 
 
 
 
 
 
 
HPV Status (HNSCC 
only) 
X 
 
 
 
 
 
 
 
 
Chest X-Ray 
 
X 
 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
Imaging, as clinically 
indicated 
 
X* 
 
 
X 
X 
X 
X 
X 
CMP 
 
X 
X 
X 
X 
X 
X 
X 
X 
CBC  
 
X 
X 
X 
 
 
 
 
 
Magnesium, 
Phosphorus 
 
X 
X 
X 
X 
X 
X 
X 
X 
Calcium 
 
 
 
X 
 
 
 
 
 
CK, Uric Acid 
 
X 
X 
 
X 
X 
X 
X 
X 
LDH 
 
X 
 
 
X 
X 
X 
X 
X 
TSH, T4 
 
X 
 
 
X- 
X- 
X- 
X- 
X- 
PT/PTT 
 
X 
 
 
 
 
 
 
 
ECOG 
 
X** 
 
 
 
 
 
 
 

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Procedure 
Prior to 
treatment 
Within 2 
weeks  
(+/-1 week) 
prior to 
treatment 
Preparative 
Regimen 
During and After 
Infusion and IL-
2 Until Hospital 
Discharge 
Post-
Discharge 
Following Administration of Cell Product 
Eligibility 
 
Days -8 to 
-1 
Days 0 to 4 through 
Day of Discharge 
Day 7 (+7 days) 
after discharge 
Week 6 
(+/- 2 
wks) 
Week 
12 (+/- 
2 wks) 
Every 3 
Months (+/- 1 
MO) X 3 visits 
Every 6 Months 
(+/- 1 MO) X 5 
years 
Pregnancy Test   
 
X** 
 
 
 
 
 
 
 
Urinalysis 
 
X@ 
X 
 
 
 
 
 
 
Blood Culture 
 
 
 
X^ 
 
 
 
 
 
Optional MRI*** 
 
 
 
 
X 
 
 
 
 
+ HIV antibody titer, HBsAG determination, HCV, CMV antibody titer, HSV serology, and EBV panel. Must be performed within 2 months of chemotherapy start 
date.  
++ CMV antigen assay only, if clinically indicated. 
* Baseline CT of chest, abdomen, and pelvis and brain MRI. Other imaging scans and x-rays as clinically indicated. 
** Within 7 days prior to treatment. 
*** Optional for subset of HNSCC participants who received CS-1000 labeled cellular product.  A repeat MRI may be performed 1-2 weeks after the first MRI. 
@ If clinically indicated.  
^ Up to 48 hours following the last IL2 infusion 
^^ Must be performed within 2 months of chemotherapy start.  
Note: Patients may be seen more frequently, as clinically indicated. 
 
 
 

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7.6 
On study Evaluation 
7.6.1 Prior to starting the Preparative Regimen (before Day -8) 
Within 2 weeks prior to starting the preparative regimen (day -8) and 3 weeks from the 
cell infusion (day 0), patients will have the following: 
• CBC with differential 
• CMP 
• Magnesium, phosphorus 
• CK, LDH, Uric acid 
If any results are beyond the criteria established for eligibility, the patient will not proceed 
until the abnormalities can be resolved. 
 
7.6.2 During the Preparative Regimen (daily) 
• CBC with differential 
• CMP 
• Magnesium, phosphorus 
• CK, Uric acid 
• Urinalysis 
• CMV antigen assay will be assessed if clinically indicated (e.g. unexplained fevers, 
pulmonary changes) 
• Review of systems and physical exam at least 3 times/week 
• Vital signs as per routine 
 
7.6.3 During and After Cell Infusion 
Vital signs (including heart rate, blood pressure, pulse oximetry, and respiratory rate) will 
be monitored hourly (+/- 15 minutes) for four hours and then routinely (every 4 -8 
hours) unless otherwise clinically indicated until discharged. The subject will be 
monitored for acute infusion reactions during and after autologous TIL infusion. 
Supportive care, including appropriate emergency medications (eg, epinephrine and 
diphenhydramine), will be available at bedside and institutional emergency guidelines 
will be followed as necessary. 
 
7.6.4 During and after IL-2 administration until hospital discharge (daily) 
• CBC with differential 
• CMP 
• Magnesium, phosphorus, calcium 
• Review of systems and physical exam 
• Vital signs as per routine 

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• Routine blood culture from central line up to 48 hours following the last IL2 infusion. 
 
After the last dose of IL-2, patients will be discharged from the hospital once they are 
considered medically stable. The exact day will be dependent on their tolerance of the 
study procedures. The laboratory results and vitals above will be collected until hospital 
discharge. These results must be within a clinically acceptable limit to proceed with 
discharge.   
 
7.7 
Post Treatment Evaluation 
The initial post treatment evaluation will be conducted approximately 7-14 days post-discharge. 
 
Following administration of the cell product, patients who experience stable disease, a partial 
response, or a complete response or have unresolved toxicities will be evaluated as noted 
below:  
• 
Week 6 (+/- 2 weeks)  
• 
Week 12 (+/- 2 weeks)  
• 
Every 3 months (+/- 1 month) x3  
• 
Every 6 months (+/- 1 month) x 5 years  
• 
As per PI discretion for subsequent years  
Note: Patients may be seen more frequently as clinically indicated 
 
At each scheduled evaluation patients will undergo: 
• 
Physical examination 
• 
CMP 
• 
Magnesium, phosphorus 
• 
CK, LDH, Uric acid 
• 
TSH, free T4 if clinically indicated 
• 
Toxicity assessment, including review of systems 
• 
CT of the chest, abdomen and pelvis as clinically indicated. If clinically indicated, other 
scans or x-rays may be performed (e.g., brain MRI, bone scan). 
• 
Visual symptoms will be evaluated and if changes have occurred from baseline, i.e. 
changes in visual acuity, an ophthalmologic consult will be performed.  
Immune monitoring per separate protocol and consent (HRPP #) 
• 
Patients who develop renal failure will undergo a nephrology consultation and a renal 
biopsy, if indicated. 
 
Note: Patients who develop progressive disease or patients who are unwilling or unable 
to return for follow up evaluation will not be required to undergo the above but will be 
contacted by phone approximately every 3-6 months for the first two years, and yearly 
thereafter.  
 

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The following information may be requested from the patient: 
• 
Summary of treatment received, including adverse events, since previous contact 
• 
Estimation of performance status 
• 
Request for imaging studies, physical exam and laboratory reports to be sent to 
the PI 
 
• 
Optional MRI.  A subset of HNSCC subjects (≤ 5 ) will be offered CS-1000 labled cellular 
product followed by MRI scans of known metastases and the liver after discharge 
(estimated Day 14 to 21).  MRIs will be performed per research protocol at the Center for 
Functional MRI, WM Keck Building, Osler Lane, UCSD School of Medicine Campus 
 
7.7.1 Off Treatment Criteria 
Patients will be taken off treatment (and followed for survival) for the following: 
• 
Completion of treatment. 
• 
Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, brain, eye, 
liver, colon, adrenal gland, lungs). 
• 
If a patient experiences grade 3 or 4 toxicity due to cell infusion as referred to under 
section 7.5 and appendix 2 occurring within 24 hours post cell infusion that does not 
reverse to grade 2 or less within 8 hours with 2 doses of 650 mg p.o. of acetaminophen 
or two dose of 50 mg p.o. of diphenhydramine the patient will receive no further cells but 
may continue to receive IL-2. 
• 
Grade 2 or greater allergic reaction including bronchospasm or generalized urticaria. 
• 
Grade 3 or greater toxicity due to cytokines (as referred to under Appendix 3) that does 
not decrease to grade 2 or less within 96 hours of management according to study site 
standard institutional practices. 
• 
Patients with progressive disease who elect not to undergo further active treatment. 
• 
If the PI determines that continued treatment is not in the best interest of the patient. 
 
7.7.2 Off Study Criteria 
Patients can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
• 
Patient withdraws consent. 
• 
There is significant noncompliance. 
• 
General or specific changes in the patient’s condition render continued participation 
unacceptable for further follow up in the judgment of the investigator. 
• 
Patient becomes pregnant.  
• 
Death. 
• 
Lost to follow-up.  
 

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Patients must be followed until all adverse events have resolved to grade 2 or less with the 
exception of lymphopenia and alopecia. If an adverse event is not expected to resolve to grade 
2 or less this will be noted in the patient medical record and the patient may be taken off study. 
 
If a patient becomes pregnant, treatment must be discontinued as soon as possible. Pregnant 
patients will be withdrawn from the study entirely. Patients who become pregnant will be 
monitored until the outcome of the pregnancy is known. Any adverse events or serious adverse 
events related to the pregnancy will be reported as described in Section 11. 
 
8.0 
SUPPORTIVE CARE 
Patients will have blood transfusions in order to maintain a minimum hemoglobin of greater than 
7 g/dL. Concomitant medications to control side effects of therapy will be given. Meperidine (25-
50 mg) will be given intravenously if severe chills develop. Other supportive therapy will be 
given as required and may include acetaminophen (650 mg q4h), ibuprofen (600 mg q8h) and 
ranitidine (150 mg q12h) or equivalent per MD discretion. Patients who require transfusions will 
receive irradiated blood products. Additional antiemetic therapy will be administered for 
breakthrough nausea and vomiting. Patients will receive supportive care as indicated for IL-2 
toxicities as listed in Appendix 3. 
 
9.0 
MEASUREMENT OF EFFECT 
9.1 
Toxicity Criteria 
Careful evaluation to ascertain the toxicity, immunologic effects and anti-tumor efficacy of 
the treatment regimens will be performed.  The study will use the CTCAE version 5.0 
(http://ctep.cancer.gov/reporting/ctc.html) for reporting of toxicity and adverse events. 
 
Over 100 patients have been treated in the Surgery Branch, NCI with TIL. Early toxicities related 
specifically to the infusion of the cells (those which are seen immediately following cell infusion 
and prior to aldesleukin administration) are generally mild and include fevers, chills, headache, 
and malaise. Toxicities which occur following administration of IL-2 but are thought to be related 
to the cells include immune mediated events such as vitiligo, transient uveitis, hearing loss and 
vestibular dysfunction. The use of the non-myeloablative regimen prior to cell administration 
increases the toxicity of this treatment as profound myelosuppression occurs in all patients. In 
93 patients treated with TIL using the non-myeloablative chemotherapy regimen with or without 
total body irradiation, there was one treatment related death (NMA + 200 cGy TBI) due to an 
unexpected but preexisting diverticular abscess. 
 
The standard approach to the administration of IL-2 in all studies is to continue dosing until 
grade 3 or 4 events occur. The most commonly seen grade 4 events are pulmonary and renal 
impairment, and mental status changes. These toxicities may sometimes require intubation for 
protection of the patient’s airway. It is important to note that although these patients require 
significant supportive measures during this period, all toxicities are reversible and the 
overwhelming majority of patients have suffered no long term sequelae following this treatment 
regimen. However, fatal complications are possible and it is therefore only appropriate to carry 
out this experimental treatment in the context of life threatening metastatic cancer. 
 

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Toxicities seen on protocols using this non-myeloablative regimen and IL-2 that occur during the 
follow up period are rare but have included EBV lymphoma following prolonged lymphopenia, 
herpes zoster infection, and sensory neuropathy likely related to fludarabine. 
 
The major discomforts of the research are those of nausea and vomiting, mucositis, anorexia, 
diarrhea, fever and malaise. Side effects of common drugs used in this regimen include: 
• 
Cyclophosphamide: Marrow suppression, nausea, mucositis, rash, hemorrhagic cystitis, 
myocardial damage, alopecia, infertility, nausea and vomiting, SIADH. 
• 
Fludarabine: Myelosuppression, fever and chills, nausea and vomiting, malaise, fatigue, 
anorexia, weakness, neurologic toxicity, and interstitial pneumonitis. Serious 
opportunistic infections have occurred in CLL patients treated with fludarabine. 
• 
Antimicrobials in general: Allergic reactions, renal impairment, nausea, vomiting, hepatic 
damage, marrow suppression, photosensitivity. 
• 
High-dose IL-2 administration: A listing of these side effects in 652 patients who received 
1,039 treatment courses are listed in Appendix 2.  
9.2 
Response Criteria 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. See Appendix 4. A minimum of 1 and up 
to 5 lesions in total will be considered target lesions that fulfill the criteria for reproducibility and 
not previously treated with radiation.  No more than 2 lesions per organ system (e lung or liver 
or skin or LN). Target lesions will be identified, recorded and measured at baseline. 
 
10.0 
STATISTICAL SECTION 
10.1 
Study Design 
This is a Phase I trial of safety and activity of autologous cell therapy in metastatic melanoma 
and head and neck cancer patients. Up to 12 patients will be enrolled in each cancer type ( a 
melanoma study arm and a head and neck cancer study arm).  Patients will be enrolled in 
cohorts of size 3.  There will be a safety assessment after each cohort, prior to enrollment of the 
next cohort.  There will be an efficacy assessment after the first 6 patients in each cancer type. 
 
The primary objective is to establish a low rate of Dose Limiting Toxicity of adoptive cell transfer 
(ACT) using cultured autologous tumor infiltrating lymphocytes (TIL) following non-myeloablative 
chemotherapy plus IL-2 treatment for treating patients with cancer. 
 
The secondary objectives are to determine safety and tolerability, and the overall and complete 
response rate in head and neck cancer and melanoma patients receiving ACT plus IL-2. We will 
also assess progression free survival and overall survival in cancer patients treated with ACT 
plus IL-2. 
 

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10.2 
Endpoints 
The primary safety endpoint is the rate of Dose Limiting Toxicity, defined as 
 
• 
Any treatment related death 
• 
Neutropenia (grade 4 ANC) 4 weeks following treatment. 
• 
Thrombocytopenia (grade 3 or 4 platelets) 4 weeks following treatment. 
• 
Grade 4 infection. 
• 
Grade 3 creatinine level at 4 weeks post treatment.  
• 
Grade 4 acute respiratory distress syndrome. 
• 
Any grade 3 or higher AE, except as described above, at least possibly related to study 
treatment that does not resolve within 48 hours 
 
 
The primary efficacy endpoint is objective response rate using RECIST criteria.  
 
Secondary Endpoints: 
• 
Adverse events related to ACT plus IL-2 treatment (description, timing, grade [CTCAE 
v5.0], severity, seriousness, and relatedness). 
• 
Overall and complete response rate assessed according to RECIST v1.1. 
• 
Progression free survival and overall survival. 
 
10.3 
Sample size 
There will be up to 4 cohorts of size 3 in each indication (melanoma and HNSCC).  The total 
sample size will be 24 patients or less. 
 
10.4 
Safety stopping rule and safety reporting 
For each of the first 3 patients in cohort 1, we will generate a safety report listing AEs by attribution 
at 30 days post TIL infusion and enrollment will be suspended. The trial will not enroll the next 
patient prior to receiving DSMB approval. After the first 3 patients, this safety report will be 
generated for each cohort of size 3 at 30 days post TIL infusion, prior to enrolling the next cohort.  
Each safety report will be filed with the DSMB and the FDA. The DSMB will approve enrollment 
of the next patient or cohort, as appropriate, or will stop the trial.  The trial will suspend within 48 
hours if one or more DLT’s are observed in any cohort, and a safety report will be forwarded for 
discussion with the DSMB and the FDA.  
 
10.5 
Futility stopping rule 
There will be 2 study arms:  a melanoma arm and a head and neck cancer arm. After the first 6 
patients have been enrolled in a study arm, enrollment will pause in that arm until response has 
been assessed. If there are one or fewer responses at 8 weeks post TILs, enrollment will 
cease in that arm due to a low response rate. 
 

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In the NCI experience the overall objective response rate using RECIST criteria in 93 
patients with metastatic melanoma was 56%.  Thus we expect the true response rate to be 
at least 50%.  With this futility stopping rule if the true response rate is 50% the chance of 
stopping early is only 11%.  However  if the response rate is only 30%, there is a 42% 
chance of stopping for futility.  If the response rate is 20%, or 10%, the chance of early 
stopping is 66% and 88% respectively.  Thus there is a high chance of stopping early if the 
response rate is low. The intention is to protect the patients from the considerable toxicity of 
this treatment regime in the absence of the expected level of efficacy. 
 
10.6 
Evaluable populations 
Efficacy analyses will be intent to treat, and will use all subjects who have received any study 
related treatment.  Safety analysis will use subjects who have undergone at least one day of 
preparative regimen. 
 
10.7 
Analysis plan 
Safety and efficacy will be summarized overall and by study arm. Safety analyses will include 
Adverse events by attribution including description, timing, grade [CTCAE v5.0], severity, 
seriousness, and relatedness.  Efficacy results will be descriptive and will include overall and 
complete response rate assessed according to RECIST v1.1. and progression free survival and 
overall survival. 
 
11.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention. Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the investigational agent, is also an AE. 
 
Pregnancy, although reportable, will not be considered an AE or SAE unless the pregnant 
patient experiences signs or symptoms of pregnancy complications. A follow up pregnancy 
report form will be completed to document the outcome of the pregnancy. If there is a 
complication, which qualifies as an SAE, the event will be reported as described in section 11.6. 
 
Exclusions to Routine Adverse Event Reporting:  
Patients will be receiving multiple agents which include commercially available agents 
(fludarabine, cyclophosphamide and supportive medications) in combination with the 
investigational agents. Therefore, Grade 2 adverse events ‘unrelated’ or ‘unlikely related’ to 
the investigational agent, and ‘possibly’, ‘probably’ or ‘definitely’ related to the commercially 
available agents as specified in the package inserts do not require reporting/recording. In 
addition all grade 1 events and all expected grade 2 events unrelated to the cell product will 
not be reported/recorded. 
 

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Interleukin-2: 
Expected toxicities of aldesleukin are listed in the product labeling. No expedited reporting of 
expected grade 3 toxicities or grade 4 laboratory toxicities clearly related to aldesleukin, 
expected, easily managed, and reversed to less than grade 3 within 48 hours is required. 
Aldesleukin toxicities that must be reported in an expedited fashion include: need for 
endotracheal intubation, renal dialysis, coma, myocardial infarction, myocarditis, bowel 
perforation, sustained ventricular tachycardia, death or any grade 4 toxicity that is not listed in 
the package insert. 
 
Reporting of laboratory events  
Laboratory results (including grade 3 and 4) that support the diagnosis of a reportable 
adverse event or that reflect major organ function will be considered adverse events. For 
example grade 3 and 4, creatinine, liver function tests, hemoglobin, ANC, ALC, platelets, 
and lipase and amylase as indicated will be captured as adverse events; electrolytes, BUN, 
albumin, total protein, uric acid etc, and the remainder of the CBC differential will not be 
captured as adverse events. For reportable adverse events: the adverse event start date 
will be the date the event reaches a grade 3; the event will be considered resolved once it 
reaches grade 2. The highest grade the event reaches in that period will be considered the 
grade of the event. For hematological toxicities, the event will not be considered resolved 
until it reaches grade 2 without the support of transfusions or growth factors. 
 
Reporting of non-laboratory events  
For reportable expected adverse events: the adverse event start date will be the date the 
event reaches a grade 3; the event will be considered resolved once it reaches grade 2. 
The highest grade the event reaches in that period will be considered the grade of the 
event. For unexpected adverse events, the adverse event start date will be the date the 
event reaches a grade 2; the event will be considered resolved once it reaches grade 1 or 
baseline. 
 
Reporting Infection  
Febrile neutropenia will be captured as follows: The start date will be the date the fever of 
38.5C or greater was first recorded. The end date will be the date the patient has been 
afebrile greater than 48 hours or the date the patient develops a clinically significant 
infection. If a patient has a positive culture during the period of febrile neutropenia, the 
event will be captured as “infection with neutropenia” with the start date as the date the 
fever of 38.5C was first recorded. Infection will only be captured once in any given period 
regardless of the number of organisms cultured or sites involved. Positive cultures seen on 
routine surveillance cultures with no clinical symptoms will not be captured as infections 
regardless of whether anti-infective agents are given.  
 
Progression of the cancer under study or events which are unequivocally due to disease 
progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 
 

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11.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins at the time of initiating study treatment through 30 days 
following the last administration of study treatment or study discontinuation/termination, 
whichever is earlier. 
 
All patients experiencing an adverse event at least possibly related to study treatment will be 
monitored until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;  
• 
any clinically significant abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes observed; or 
• 
death. 
 
11.2 
Severity 
All adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. The CTCAE v5.0 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death. 

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11.3 
Seriousness 
A “serious” adverse event (SAE) is defined in regulatory terminology as any untoward medical 
occurrence that: 
 
1. Results in death. 
If death results from (recurrence of) the disease, the disease should be reported as 
event (SAE) itself. 
 
2. Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe). 
 
3. Requires in-patient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalization (including hospitalization for an elective procedure) for a 
preexisting condition which has not worsened does not constitute a serious adverse 
event. 
4.  
5. Results in persistent or significant disability or incapacity. Substantial disruption of 
one’s ability to conduct normal life functions. 
6.  
7. Is a congenital anomaly/birth defect. 
8.  
9. Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that may not result in hospitalization; development of drug 
abuse or drug dependency. 
11.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
11.5 
Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered “unexpected”, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed as known adverse 
events in this protocol or the current Investigator’s Brochure. 

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11.6 
Reporting Requirements for Adverse Events 
11.6.1 Expedited Reporting 
• 
The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the study drug.  
• 
The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change to 
the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
 
11.6.2 Routine Reporting Requirements 
• 
The UCSD HRPP must be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.  
 
FDA REPORTING CRITERIA  
 
IND Safety Reports to the FDA (Refer to 21 CFR 312.32)  
 
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days of initial receipt of the 
information using the MedWatch Form 3500A. 
 
The Sponsor will also notify FDA within 15 calendar days of:  
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed 
to the drug  

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• 
Clinically important increase in the rate of a serious suspected adverse reaction over 
that listed in the protocol or Investigator’s Brochure. 
• 
If FDA requests any additional data or information, the sponsor must submit it to the 
FDA as soon as possible, but no later than 15 calendars days after receiving the 
request.  
 
FDA Annual Reports (Refer to 21 CFR 312.33)  
The study Sponsor will submit a brief report of the progress of the trial within 60 days of the 
anniversary date that the IND went into effect, then annually as indicated. 
 
12.0 
PHARMACEUTICAL INFORMATION 
12.1 
IL-2 (Aldesleukin, Interleukin-2, Proleukin, Recombinant Human Interleukin 2) 
Please refer to Product Label for more comprehensive information. 
 
How supplied: IL-2 is available from commercial sources. 
 
Formulation/Reconstitution: Aldesleukin is provided as single-use vials containing 22 million IU 
(~1.3 mg) IL-2 as a sterile, white to off-white lyophilized cake plus 50 mg mannitol and 0.18 mg 
sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic 
sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The vial is reconstituted with 1.2 mL of 
Sterile Water for Injection, USP, and the resultant concentration is 18 million IU/ml or 1.1 
mg/mL. Diluent should be directed against the side of the vial to avoid excess foaming. Swirl 
contents gently until completely dissolved. Do not shake. Since vials contain no preservative, 
reconstituted solution should be used with 24 hours. 
 
Storage: Intact vials are stored in the refrigerator (2° - 8°C) protected from light. Each vial bears 
an expiration date. 
 
Dilution/Stability: Reconstituted IL-2 should be further diluted with 50 mL of dextrose 5% water.  
Avoid diluting to a concentration <0.03mg/mL or >0.07mg/mL. IL-2 is chemically stable for 48 
hours when refrigerated, 2° –8°C. Use immediately or within one hour when stored at room 
temperature.  
 
Administration: The dosage will be calculated based on total body weight. The final dilution of 
aldesleukin will be infused over 15 minutes. IL-2 will be administered as an inpatient. Do not use 
in-line filter during administration. Infusion will be performed per standard inpatient infusion 
treatment plan established at UCSD. 
 
Toxicities: Expected toxicities of IL-2 are listed in the product label and in Appendix 2 and 3. 
Grade 3 toxicities common to aldesleukin include diarrhea, nausea, vomiting, hypotension, skin 
changes, anorexia, mucositis, dysphagia, or constitutional symptoms and laboratory changes as 
detailed in Appendix 2. Additional grade 3 and 4 toxicities seen with IL2 are detailed in Appendix 
2.. 
12.2 
Fludarabine 
Please refer to Product Label for more comprehensive information. 
 

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Description: Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic 
nucleosides in that the sugar moiety is arabinose instead of ribose or deoxyribose. Fludarabine 
is a purine antagonist antimetabolite. 
 
How Supplied: Fludarabine is available from commercial sources and is supplied in a 50 mg vial 
as fludarabine phosphate powder in the form of a white, lyophilized solid cake. 
 
Stability: Following reconstitution with 2 mL of sterile water for injection to a concentration of 25 
mg/ml, the solution has a pH of 7.7. Administer finished dose within 8 hours of preparation. 
Store finished doses at room temperature.  
 
Storage: Intact vials should be stored refrigerated (2-8°C). 
 
Administration: Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium chloride, 
USP over 30 minutes. The doses will be based on body surface area (BSA).  
 
Toxicities: At doses of 25 mg/m2/day for 5 days, the primary side effect is myelosuppression; 
however, thrombocytopenia is responsible for most cases of severe and life-threatening 
hematologic toxicity. Serious opportunistic infections have occurred in CLL patients treated with 
fludarabine. Hemolytic anemia has been reported after one or more courses of fludarabine with 
or without a prior history of a positive Coomb’s test; fatal hemolytic anemia has been reported. 
In addition, bone marrow fibrosis has been observed after fludarabine therapy. Other common 
adverse effects include malaise, fever, chills, fatigue, anorexia, nausea and vomiting, and 
weakness. Irreversible and potentially fatal central nervous system toxicity in the form of 
progressive encephalopathy, blindness, and coma is only rarely observed at the currently 
administered doses of fludarabine. More common neurologic side effects at the current doses of 
fludarabine include weakness, pain, malaise, fatigue, paresthesia, visual or hearing 
disturbances, and sleep disorders. Adverse respiratory effects of fludarabine include cough, 
dyspnea, allergic or idiopathic interstitial pneumonitis. Tumor lysis syndrome has been rarely 
observed in fludarabine treatment of CLL. Treatment on previous adoptive cell therapy protocols 
in the NCI Surgery Branch have caused persistently low (below 200) CD4 counts, and one 
patient developed polyneuropathy manifested by vision blindness, and motor and sensory 
defects. 
 
12.3 
Cyclophosphamide 
Please refer to Product Label for more comprehensive information. 
 
Description: Cyclophosphamide is a nitrogen mustard-derivative alkylating agent. Following 
conversion to active metabolites in the liver, cyclophosphamide functions as an alkyating agent; 
the drug also possesses potent immunosuppressive activity. The serum half-life after IV 
administration ranges from 3-12 hours; the drug and/or its metabolites can be detected in the 
serum for up to 72 hours after administration. 
 
How Supplied: Cyclophosphamide will be obtained from commercially available sources. 
 
Stability: Following reconstitution as directed with sterile water for injection, cyclophosphamide 
is stable for 24 hours at room temperature or 36 hourswhen kept at 2-8°C. 
 
Administration: It will be diluted in D5W (concentration </=2mg/mL) and infused over one hour. 
The dose will be based on the patient’s body weight.  

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Toxicities: Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia 
and thrombocytopenia. Anorexia, nausea and vomiting, rash and alopecia occur, especially 
after high-dose cyclophosphamide; diarrhea, hemorrhagic colitis, infertility, and mucosal and 
oral ulceration have been reported. Sterile hemorrhagic cystitis occurs in about 20% of patients; 
severity can range from microscopic hematuria to extensive cystitis with bladder fibrosis. 
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide appears to be 
lower than that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has 
been used prophylactically as a uroprotective agent in patients receiving cyclophosphamide. 
Prophylactic mesna is not effective in preventing hemorrhagic cystitis in all patients. Patients 
who receive high dose cyclophosphamide may develop interstitial pulmonary fibrosis, which can 
be fatal. Hyperuricemia due to rapid cellular destruction may occur, particularly in patients with 
hematologic malignancy. Hyperuricemia may be minimized by adequate hydration, alkalinization 
of the urine, and/or administration of allopurinol. If allopurinol is administered, patients should be 
watched closely for cyclophosphamide toxicity (due to allopurinol induction of hepatic 
microsomal enzymes). At high doses, cyclophosphamide can result in a syndrome of 
inappropriate antidiuretic hormone secretion; hyponatremia with progressive weight gain without 
edema occurs. At high doses, cyclophosphamide can result in cardiotoxicity. Deaths have 
occurred from diffuse hemorrhagic myocardial necrosis and from a syndrome of acute 
myopericarditis; in such cases, congestive heart failure may occur within a few days of the first 
dose. Other consequences of cyclophosphamide cardiotoxicity include arrhythmias, potentially 
irreversible cardiomyopathy, and pericarditis. Other reported adverse effects of 
cyclophosphamide include headache, dizziness, and myxedema; faintness, facial flushing, and 
diaphoresis have occurred following IV administration. Mesna (sodium 2- 
mercaptoethanesulfonate; given by IV injection) is a synthetic sulfhydryl compound that can 
chemically interact with urotoxic metabolites of cyclophosphamide (acrolein and 4-
hydroxycyclophosphamide) to decrease the incidence and severity of hemorrhagic cystitis. 
 
12.4 
Mesna (Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex,) 
Please refer to Product Label for more comprehensive information. 
 
How Supplied: Mesna will be obtained from commercial sources and is supplied as a 100 mg/ml 
solution. 
 
Storage: Intact vials are stored at room temperature. 
 
Stability: Mesna is chemically stable at room temperature for 24hours when diluted in dextrose 
5% water or 0.9% sodium chloride. See package insert for additional information.  
 
Administration: Dilute to concentrations less than or equal to 20 mg mesna/ml fluid in D5W or 
0.9% NaCl. Administer intravenously as a continuous infusion.  
 
Toxicities: Nausea, vomiting and diarrhea. 
 
12.5 
Filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF, Neupogen, Zarxio) 
 
How Supplied: Filgrastim and filgrastim-sndz will be obtain from commercial sources. See 
approved labeling for availability, storage and dosing. 

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Toxicities: Side effects of filgrastim are skin rash, myalgia and bone pain, an increase of 
preexisting inflammatory conditions, enlarged spleen with occasional associated low platelet 
counts, alopecia (with prolonged use) elevated blood chemistry levels. 
 
12.6 
Trimethoprim and Sulfamethoxazole Double Strength (TMP/SMX DS) 
TMP/SMX DS will be obtained from commercial sources and used for the prevention of PCP 
pneumonia. The oral dose is 1 tablet PO twice daily two times a week (on NON-consecutive 
days) beginning on Day +21and continuing until the ALC is greater than 1000 for at 60 days. 
Like other sulfa drugs, TMP/SMX DS can cause allergies, fever, photosensitivity, nausea, and 
vomiting. Allergies typically develop as a widespread itchy red rash with fever eight to fourteen 
days after beginning the standard dose. Neutropenia, a reduction in the number of neutrophils, 
can also occur. 
 
12.6.1 Aerosolized Pentamidine or Oral Atovaquone in Place of TMP/SMX DS 
Pentamidine or Atovaquone will be substituted for TMP/SMX-DS in patients with sulfa allergies. 
Pentamidine 300 mg per nebulizer within one week prior to admission and continued monthly 
until the CD4 count is above 200 on two consecutive follow up lab studies and and for at least 
60 days. Pentamidine Isethionate will be obtained from commercial sources. It will be used to 
prevent the occurrence of PCP infections. It is supplied in 300 mg vials of lyophilized powder 
and will be administered via nebulizer. Toxicities reported with the use of Pentamidine include 
metallic taste, coughing, bronchospasm in heavy smokers and asthmatics; increased incidence 
of spontaneous pneumothorax in patients with previous PCP infection or pneumatoceles, or 
hypoglycemia.  Atovaquone will be administered at 1500mg by mouth daily after the first dose of 
chemotherapy on or after Day +21 and stopping when absolute lymphocyte count is 
>1000/mm3 for at least 60 days. Atovaquone is commercially available and supplied as 
750mg/5mL suspension. Known side effects include rash, diarrhea, nausea, vomiting, 
headache, insomnia and, in rare cases, increase in liver enzymes, Stevens-Johnson and 
methhemoglobinemia. See FDA approved package insert for additional information. . 
 
12.7 
Herpes Virus Prohpylaxis 
12.7.1 Valacyclovir (Valtrex) 
Valocyclovir will be obtained from commercial sources. It will be used orally to prevent the 
occurrence of herpes virus infections in patients with positive HSV serology. See package insert 
for dosing, storage and additional information. Common side effects include headache, upset 
stomach, nausea, vomiting, diarrhea or constipation. Rare serious side effects include hemolytic 
uremic syndrome and thrombotic thrombocytopenic purpura. 
 
12.7.2 Acyclovir  
Acyclovir will be obtained from commercial sources. Acyclovir will not be used concomitantly 
with other nucleoside analogs which interfere with DNA synthesis, e.g. gancyclovir. In renal 
disease, the dose is adjusted as per product labeling. Prepare and administer per institutional 
standard. See package insert for additional information.  
 

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12.8 
Fluconazole 
Fluconazole will be obtained from commercial sources. It will be used to prophylax against 
fungal infections. Prepare and administer per institutional standard. See package insert for more 
information. 
 
12.9 
Cell Preparation 
The procedure for growing and expanding the autologous TIL and the Certificate of Analysis are 
similar to those approved by the Food and Drug Administration and used at the NCI in protocol 
07-C-0176. This product will be provided for investigational use only under a sponsor-
investigator IND. The Certificate of Analysis and the Standard Operating Procedures for the 
growth of TIL are included in the IND. 
 
12.10 Support Medication 
Odansetron hydrochloride 
Odansetron hydrochloride will be obtained from commercial sources. It 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, pruritis, constipation and urinary retention. Consult the package insert 
for specific dosing instructions. 
 
Furosemide 
Furosemide will be obtained from commercial sources. It 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 
pruritis. Consult the package insert for a complete list of all side effects. 
 
 
13.0 
STUDY MANAGEMENT 
13.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed according to UCSD conflict of interest policy. 
 
13.2 
Institutional Review Board (IRB) Approval and Consent  
The IRB should approve the consent form and protocol prior to any study-related activities.  It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 

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regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
 
13.3 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
 
13.4 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the principal investigator and 
co-investigators, quality assurance of the study may be performed by the Moores Cancer 
Center Clinical Trials Office internal monitor. Monitoring intervals will be dependent upon the 
number of patients enrolled and the complexity of the study.  
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board 
(DSMB) to provide oversight in the event that this treatment approach leads to unforeseen 
toxicities. Data from this study will be reported every six months and will include: 
1) The protocol title, IRB protocol number, and the activation date of the study.  
2) The number of patients enrolled to date. 
3) The date and site of patients’ enrollment. 
4) A summary of all adverse events regardless of grade and attribution, as well as toxicities 
presented in individual tables as follows: 
• 
all toxicities attributed to the cells, 
• 
all incidences of intubation including the duration of and reason for intubation, 
• 
all grade 2 unexpected adverse events, and all grade 3 or greater events regardless 
of attribution. 
 
13.5 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 

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Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
13.6 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
 
 

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14.0 
APPENDICES 
Appendix 1. CS-1000 labeling of TIL 
 
1 
Summary 
 
TIL were cultured and expanded according to clinical TIL protocols in the UCSD Advanced Cell 
Therapy Lab.  4 flasks of TIL were labeled at 10mg/mL of CS-1000 for the final 24 hours of 
culture (days 13-14).  A fifth flask was maintained as a control.  Individual flasks were sampled 
and a pool of the 4 labeled flasks was also analyzed.  Labeled TIL, both individual flasks and 
pooled sample, had comparable viability to the unlabeled control.  The labeling across the 
individual flasks was comparable to the pooled sample.  All TIL, labeled and unlabeled, met the 
clinical release criteria of viability, yield, and IFN ɣ potency.   
 
2 
Viability 
 
 
*all samples met release parameters 
 
3 
Label uptake 
 
 
 
Labeling efficiency will be measured for each batch of TIL.  F/c = Fluorine atoms per cell, this 
number is used to quantify the number of cells in a MRI region of interest. 
 

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4 
Phenotype 
 
 
 
Phenotype was assessed on a pooled sample of the labeled TIL compared to unlabeled control 
TIL. Phenotyping is not measured for release, but was assessed along with the IFNɣ potency 
testing.  
 
5 
IFN ɣ potency  
 
 
 
IFNɣ potency performed on a pooled sample of the labeled TIL compared to unlabeled control 
TIL. 
 
 

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Appendix 2. Adverse Events Occurring in ≥ 10% of Patients Treated with IL-2  
Source: Proleukin® Prescribing Information – (n=525) 
 
Body System 
% Patients 
Body System 
% Patients 
Body as a Whole 
 
Metabolic and Nutritional Disorders 
Chills 
52 
Bilirubinemia 
40 
Fever 
29 
Creatinine increase 
33 
Malaise 
27 
Peripheral edema 
28 
Asthenia 
23 
SGOT increase 
23 
Infection 
13 
Weight gain 
16 
Pain 
12 
Edema 
15 
Abdominal pain 
11 
Acidosis 
12 
Abdomen enlarged 
10 
Hypomagnesemia 
12 
Cardiovascular 
 
Hypocalcemia 
11 
Hypotension 
71 
Alkaline phosphatase incr 
10 
Tachycardia 
23 
Nervous 
 
Vasodilation 
13 
Confusion 
34 
Supraventricular tachycardia 
12 
Somnolence 
22 
Cardiovascular Disorder a 
11 
Anxiety 
12 
Arrythmia 
10 
Dizziness 
11 
Digestive 
 
Respiratory 
 
Diarrhea 
67 
Dyspnea 
43 
Vomiting 
50 
Lung disorder b 
24 
Nausea 
35 
Respiratory disorder c 
11 
Stomatitis 
22 
Cough increase 
11 
Anorexia 
20 
Rhinitis 
10 
Nausea and vomiting 
19 
Skin and Appendages 
 
Hemic and Lymphatic 
 
Rash 
42 
Thrombocytopenia 
37 
Pruritis 
24 
Anemia 
29 
Exfoliative dermatitis 
18 
Leukopenia 
16 
Urogenital 
 
 
 
Oliguria 
63 
 
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
 
 

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Appendix 3. Expected IL-2 Toxicities and their Suggested Management 
 
Expected 
Toxicity 
Expected 
Grade 
Supportive 
Measures 
Stop Cycle* 
Stop 
Treatment** 
Chills 
3 
IV Meperidine 25-50 
mg, IV q15min  prn 
chills or rigors 
No 
No 
Fever 
3 
Acetaminophen 650 
mg, po, q4h; 
Indomethacin 50- 75 
mg, po, q8h 
No 
No 
Pruritis 
3 
Hydroxyzine HCL 10-
20 mg po q6h, prn; 
Diphenhydramine 
HCL25-50 mg, po, 
q4h, prn 
No 
No 
Nausea/ 
Vomiting/ 
Anorexia 
3 
Ondansetron 8mg, IV, 
q8h, prn; Granisetron 
0.01 mg/kg IV daily 
prn; 
Droperidol 1 mg, IV 
q4- 
6h, prn; 
Prochlorperazine 
25 mg q4h p.r., prn or 
10 mg IV q6h prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg, po, 
q3h, prn; 
Diphenoxylate HCl 
2.5 mg and atropine 
sulfate 25 mcg, po, 
q3h, prn; 
codeine sulfate 30-60 
mg, po, q4h, prn 
If uncontrolled after 
24 hours despite all 
supportive measures 
No 
Malaise 
3 or 4 
Bedrest interspersed 
with activity 
If other toxicities 
occur 
simultaneously 
No 
Hyperbilirubinemia 3 or 4 
Observation 
If other toxicities 
occur 
simultaneously 
No 
Anemia 
3 or 4 
Transfusion with 
PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytopenia 3 or 4 
Transfusion with 
platelets 
If uncontrolled 
despite all 
supportive measures 
No 
Edema/ 
Weight gain 
 
3 
Diuretics prn 
No 
No 

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Expected 
Toxicity 
Expected 
Grade 
Supportive 
Measures 
Stop Cycle* 
Stop 
Treatment** 
Hypotenstion 
3 
Fluid resuscitation 
Vasopressor support 
If uncontrolled 
despite all 
supportive measures 
No 
Dyspnea 
3 or 4 
Oxygen or ventilatory 
support 
If requires ventilatory 
support 
No 
Oliguria 
3 or 4 
Fluid boluses or 
dopamine at renal 
doses 
If uncontrolled 
despite all 
supportive measures 
No 
Increased 
creatinine 
3 or 4 
Observation 
Yes (grade 4) 
No 
Renal failure 
3 or 4 
Dialysis 
Yes 
Yes 
Pleural effusion 
3 
Thoracentesis 
If uncontrolled 
despite all 
supportive measures 
Yes 
Bowel perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4 
Intubation for airway 
protection 
Yes 
Yes 
Arrythmia 
3 
Correction of fluid and 
electrolyte 
imbalances; 
chemical conversion 
or 
electrical conversion 
therapy 
If uncontrolled 
despite all 
supportive measures 
No 
Elevated Troponin 
levels 
3 or 4 
Observation 
Yes 
If changes 
in LV 
function 
have not 
improved to 
baseline by 
next dose 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
Elevated 
transaminases 
3 or 4 
Observation 
For grade 4 without 
liver metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Electrolyte 
imbalances 
3 or 4 
Electrolyte 
replacement 
If uncontrolled 
despite all 
supportive measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours 
** Unless the toxicity is not reversed to grade 2 or less by next re-treatment.  
 

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Appendix 4. Response Evaluation Criteria in Solid Tumors (RECIST) 
Tumor assessments will be made according to the schedule of assessments. Response and 
progression will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 guidelines [Eisenhauer et al. 2009]. 
1 
Definitions 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
1.1 
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 
mm with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 

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those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
1.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI . This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of scanner should 
be used and the image acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning techniques, if possible. 
 

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PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-
488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, 
the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-

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PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
1.3 
Response Criteria 
1.3.1 Evaluation of target lesions 
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study.  
1.3.2 Evaluation of non-target lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10mm short axis). 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must 
be representative of overall disease status change, not a single 
lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 

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1.3.3 Evaluation of best overall response  
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 

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1.3.4 Duration of overall response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 
1.3.5 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
 

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Appendix 5 Communication Plan 
Purpose: The purpose of this plan is to define communication practices at the time patients 
initiate lymphodepletion chemotherapy and final product sterility testing. 
 
Scope: The Advanced Cell Therapy Lab (ACTL) is a Good Manufacturing Process (GMP) 
facility providing the autologous cell product and testing as outlined by the standard operating 
protocols (SOPs) detailed in the Chemistry, Manufacturing and Control (CMC) section of the 
IND. The principle investigator (PI) is the holder of the IND and responsible for the safe and 
faithful implementation of the IND. The treating physician is the attending physician for the 
patient and responsible for writing orders for patient care. This plan formalizes the 
communication during the time patients begin preparative chemotherapy to the time of final 
product sterility testing between the ACTL, PI and the attending physician. 
 
Methods of communication: 
1. List Serve email list. The email listserv will be updated and acknowledged by the PI with 
the start of each product initiation. The listserv will be maintained by the project manager 
for the Cutaneous team. The updating and use will be documented on the eligibility 
check list. The email list will minimally include the treating physician, principal 
investigator, investigational pharmacy, the ACTL, the primary study coordinator and the 
project manager 
2. Medical record 
3. Treatment plan orders 
 
Communication plan: 
1. An initial “list serve email” will be sent when a consented patient in deemed eligible. 
Confirmation of receipt from investigational pharmacy, the principal investigator, treating 
physician and ACTL will be requested and documented by the research coordinator. 
 
2. A second email will be sent when product expansion is confirmed and a date for 
lymphodepletion has been tentatively set. This email will include the cell phones for the 
principal investigator (Dr. Daniels), Dr. Cohen (back up to Dr. Daniels) and the attending 
physician (if different). 
 
3. Prior to initiating lymphodepletion, the principal investigator or sub-investigator will verify 
with ACTL that there is no concern for infection and document that the patient is ready to 
proceed in the medical record. The infusion nurse and pharmacy will verify this 
documentation prior to infusion of chemotherapy per treatment plan order for that day.  
 

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4. The principal investigator or sub-investigator will verify daily with the ACTL that there is 
no concern for infection during lymphodepletion and document this communication in the 
medical record. The infusion nurse will verify this documentation prior to infusion of 
chemotherapy per treatment plan order for that day. 
 
5. Prior to cell product release from the ACTL and patient infusion, the preliminary release 
certificate will be signed by the principal investigator (approx. 1 week after 
lymphodepletion begins). The final release certificate may take up to 28 days after 
product infusion. The investigator will confirm weekly with the ACTL until the final 
certificate is generated. 
 
Notes: The product release form has a specific line indicating the communication time that 
product release was determined. If the product is deemed not meeting release parameters, a 
verbal notification will be documented and acknowledged by either Dr. Daniels or Dr. Cohen.  
 
 
 

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15.0 
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