Clinical trial NCT02926053
Conditions: Metastatic Renal Cell Carcinoma
Sponsor: Inge Marie Svane
Start date: 2016-12-01; Completion date: 2021-10-31
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. The TILs are isolated from patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in vivo.

Recent studies suggest, that TIL therapy works in other cancers than Metastatic Melanoma, including Renal Cell Carcinoma. In this study TIL therapy is administered to patients with metastatic Renal Cell Carcinoma.

Detailed description:
Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. The TILs are isolated from patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in vivo.

Objectives:

To evaluate safety and feasibility when treating patients with metastatic renal cell carcinoma with ACT with TILs.

To evaluate treatment related immune responses . To evaluate clinical efficacy.

Design:

Patients will be screened with a physical exam, medical history, blood samples, pulmonary function test, Cr-EDTA clearance, MUGA scan and ECG.

Patients will undergo surgery to harvest tumor material for TIL production.

Patients is admitted day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7.

On day 0 patients receive TIL infusion and shortly after starts IL-2 administration with high-dose bolus IL-2 every eight hour for up to 5 days (maximum of 15 doses).

The patients will followed until progression or up to 5 years.

Arms: arm 1: All patients receive the same treatment.

Surgical removal of tumor tissue for T cell production, which takes 4-6 weeks, is performed initially.

All patients are hospitalized during treatment (one week in advance of the T cell product being ready and for approximately 3 weeks in total) and receive treatment only once.

The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine on day -7 to day -1.

The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 5. Interleukin-2 is administered as high-dose i.v. bolus every eight hour starting approximately 6 hours after TIL infusion and for up to 5 days (maximum of 15 doses).
Interventions: intervention 1: Surgical removal of tumor tissue for T cell production intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: TIL infusion intervention 5: Interleukin-2
Intervention descriptions: intervention 1: Surgical removal of \> 1 cm3 tumor tissue chosen with regards to high rate of success and to minimize the general risks involved in a surgical procedure. intervention 2: Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6. intervention 3: Fludarabine 25 mg/m2 is administered on day -5 to day -1. Maximum dose of 50 mg per administration. intervention 4: The maximum number of expanded TILs are infused over 30-45 minutes on day 0. intervention 5: Interleukin-2 is administered as high-dose bolus infusions (600.000 IU/kg) over a 15 minute period every 8 hours and continuing for up to 5 days (maximum of 15 doses).

Protocol documents:
Prot_000.pdf: 
T Cell Therapy for Patients with Advanced Renal 
Cell Carcinoma. 
 
 
 
A pilot Study 
 
 
EudraCT nr.: 2016-001454-18 
 
 
 
 
The study will be conducted as described in this protocol and according to Good Clinical Practice 
(GCP) guidelines and regulatory requirements. The investigator allows direct access to data 
sources/documents (including patient charts) for monitoring, audit and/or inspection from the 
Danish Health and Medicines Authority, GCP-units or other national health authorities. 
 
 
 
Sponsor 
 
Inge Marie Svane, professor, M.D., ph.d. 
Date: _______________________________ 
Head of National Center for Cancer Immune Therapy (CCIT-DK), 
Department of Oncology (54B1) 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 25C, 5th floor, 2730 Herlev 
Phone: 38 68 21 31  
 
 
Inge Marie Svane: ____________________ 
 
 
Principal Investigator 
Troels Holz Borch, M.D., PhD 
 
Date: _______________________________ 
National Center for Cancer Immune Therapy (CCIT-DK), 
Department of Oncology (54B1) 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 25C, 5th floor, 2730 Herlev 
Phone: 38 68 17 56  
 
 
Troels Holz Borch:____________________ 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
2
Project Managers 
 
Sponsor 
Inge Marie Svane, professor, M.D., PhD 
Head of National Center for Cancer Immune Therapy (CCIT-DK), 
Department of Oncology (54B1) 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 25C, 5th floor, 2730 Herlev 
Phone: 38 68 21 31  
 
 
Principal Investigator 
Troels Holz Borch, M.D., PhD 
 
National Center for Cancer Immune Therapy (CCIT-DK), 
Department of Oncology (54B1) 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 25C, 5th floor, 2730 HerlevPhone: 38 68 17 56 
 
 
Sub-investigators 
Marco Donia, M.D., PhD 
National Center for Cancer Immune Therapy (CCIT-DK), 
Department of Oncology (54B1) 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 25C, 5th floor, 2730 HerlevPhone: 38 68 14 56 
 
Poul Geertsen, M.D., PhD 
Department of Oncology 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 1, 2730 Herlev 
Phone: 38 68 22 98 
 
Anne Kirstine Hundahl Møller, M.D., PhD 
Department of Oncology 
Herlev Hospital, University of Copenhagen 
Borgmester Ib Juuls Vej 1, 2730 Herlev 
Phone: 38 68 10 83 
 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
3
Monitoring 
 
GCP unit 
GCP-unit at University of Copenhagen 
Bispebjerg Hospital, Bygning 51, 3.sal 
Bispebjerg Bakke 23 
2400 København NV 
Phone: 35 31 38 90 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
4
Table of Contents 
 
PROJECT MANAGERS ................................................................................................................................................. 2 
MONITORING ................................................................................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................................................. 4 
LIST OF ABBREVIATIONS .......................................................................................................................................... 7 
SYNOPSIS ....................................................................................................................................................................... 10 
INDICATION AND TREATMENT ....................................................................................................................................... 10 
RATIONALE ................................................................................................................................................................... 10 
PURPOSE ....................................................................................................................................................................... 10 
STUDY DESIGN .............................................................................................................................................................. 10 
POPULATION ................................................................................................................................................................. 11 
TOXICITY ...................................................................................................................................................................... 11 
EVALUATION OF CLINICAL RESPONSE ........................................................................................................................... 11 
IMMUNOLOGICAL RESPONSE EVALUATION .................................................................................................................... 11 
INTRODUCTION AND RATIONALE ........................................................................................................................ 12 
RENAL CELL CARCINOMA ............................................................................................................................................. 12 
TUMOR IMMUNOLOGY................................................................................................................................................... 12 
TUMOR INFILTRATING LYMPHOCYTES (TILS) ............................................................................................................... 13 
T CELL THERAPY ........................................................................................................................................................... 13 
CCITS EXPERIENCE WITH T CELL THERAPY .................................................................................................................. 15 
 ...................................................................................................................................................................................... 19 
THE RATIONALE OF THE DRUGS USED IN THE STUDY ..................................................................................................... 19 
Lymphocyte depleting chemotherapy ....................................................................................................................... 19 
Cyclophosphamide ................................................................................................................................................... 19 
Fludarabine phosphate ............................................................................................................................................ 20 
Interleukin 2 ............................................................................................................................................................. 20 
THE RATIONALE OF THE TREATMENT REGIMEN USED IN THE STUDY ............................................................................. 20 
PURPOSE AND HYPOTHESIS ................................................................................................................................... 20 
PRIMARY ....................................................................................................................................................................... 20 
SECONDARY .................................................................................................................................................................. 20 
STUDY DESIGN ............................................................................................................................................................ 21 
STUDY POPULATION ................................................................................................................................................. 21 
CRITERIA OF IN- AND EXCLUSION .................................................................................................................................. 21 
Criteria of inclusion ................................................................................................................................................. 21 
Criteria of exclusion ................................................................................................................................................ 22 
Evaluation before entry in the study ........................................................................................................................ 23 
Examination plan during the course of treatment .................................................................................................... 24 
TREATMENT STRATEGY .......................................................................................................................................... 25 
T CELL THERAPY ........................................................................................................................................................... 25 
MEDICINAL PRODUCTS USED IN THE STUDY .................................................................................................................. 27 
Cyclophosphamide ................................................................................................................................................... 27 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
5
Fludarabine phosphate ............................................................................................................................................ 27 
TILs .......................................................................................................................................................................... 27 
Interleukin-2 ............................................................................................................................................................. 27 
TREATMENT PLAN ......................................................................................................................................................... 28 
CONCOMITANT TREATMENT .......................................................................................................................................... 28 
Guidelines for supportive care and treatment .......................................................................................................... 28 
Prophylactic treatment ............................................................................................................................................. 28 
Supportive treatment ................................................................................................................................................ 29 
Local radiotherapy ................................................................................................................................................... 30 
END OF TREATMENT ...................................................................................................................................................... 30 
Normal end of treatment .......................................................................................................................................... 30 
Follow-up ................................................................................................................................................................. 30 
Early termination of treatment ................................................................................................................................. 31 
Subsequent treatment ............................................................................................................................................... 32 
PRODUCTION OF TILS .............................................................................................................................................. 32 
ACQUISITION OF TUMOR TISSUE .................................................................................................................................... 32 
ESTABLISHMENT OF ”YOUNG TIL” CULTURES .............................................................................................................. 32 
RAPID EXPANSION PROTOCOL (REP) ............................................................................................................................ 33 
HANDLING AND TRANSPORTATION OF THE INFUSION PRODUCT .................................................................................... 33 
PHENOTYPE- AND CLONOTYPE DETERMINATION ........................................................................................................... 33 
ADVERSE EVENTS, POTENTIAL RISKS AND PRECAUTIONS ........................................................................ 33 
ADVERSE EVENTS ......................................................................................................................................................... 33 
Grading of Adverse Events ...................................................................................................................................... 34 
Serious Adverse Events ............................................................................................................................................ 34 
GUIDELINES FOR ADVERSE EVENTS POSSIBLE RELATION TO THE TREATMENT ........................................................................ 35 
Adverse Reactions .................................................................................................................................................... 35 
Reporting of Adverse Events and Adverse Reactions ............................................................................................... 35 
KNOWN ADVERSE REACTIONS ...................................................................................................................................... 36 
Chemotherapy .......................................................................................................................................................... 36 
Cyclophosphamide ................................................................................................................................................... 36 
Fludarabine phosphate ............................................................................................................................................ 37 
TILs .......................................................................................................................................................................... 37 
Interleukin-2 ............................................................................................................................................................. 37 
RISKS AND DISADVANTAGES REGARDING SURGERY AND TEST SAMPLING ..................................................................... 38 
Risks associated with removing tumor tissue ........................................................................................................... 38 
Risks associated with biopsies ................................................................................................................................. 38 
Risks associated with blood tests ............................................................................................................................. 38 
MONITORING AND PRECAUTIONS .................................................................................................................................. 39 
Hematological parameters ....................................................................................................................................... 39 
Kidney- and urine infections .................................................................................................................................... 39 
Cardiotoxicity .......................................................................................................................................................... 39 
Infertility .................................................................................................................................................................. 39 
Live vaccines ............................................................................................................................................................ 39 
Interactions .............................................................................................................................................................. 40 
EFFECT EVALUATION, DATA PROCESSING AND MONITORING ................................................................. 40 
EFFECT EVALUATION .................................................................................................................................................... 40 
Primary effect parameters ....................................................................................................................................... 40 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
6
Secondary effect parameters .................................................................................................................................... 40 
RESPONSE CRITERIA ..................................................................................................................................................... 40 
RECIST .................................................................................................................................................................... 40 
IMMUNOLOGICAL MONITORING ..................................................................................................................................... 41 
Blood samples for immunological monitoring ......................................................................................................... 41 
Tumor biopsies ......................................................................................................................................................... 41 
Specimens for Future Biomedical Research ............................................................................................................ 42 
ADDITIONAL RESEARCH ANALYSES ............................................................................................................................... 42 
Isolation of tumor cells ............................................................................................................................................ 42 
Cytokine Release Assay ............................................................................................................................................ 42 
Gene-based arrays ................................................................................................................................................... 42 
STATISTICS .................................................................................................................................................................... 44 
DATA REGISTRATION AND -ANALYSIS ........................................................................................................................... 44 
END OF STUDY REPORT ................................................................................................................................................. 45 
AMENDMENTS ............................................................................................................................................................... 45 
ETHICAL ASPECTS ..................................................................................................................................................... 45 
RECRUITMENT OF STUDY PATIENTS AND INFORMED CONSENT ...................................................................................... 45 
INSURANCE ................................................................................................................................................................... 46 
ETHICAL ASPECTS ......................................................................................................................................................... 46 
RESEARCH BIOBANK, INCLUDING FUTURE BIOMEDICAL RESEARCH BIOBANK ............................................................. 46 
REPORTING TO THE RESEARCH ETHICS COMMITTEE ..................................................................................................... 47 
ADMINISTRATIVE ASPECTS AND PUBLICATION ............................................................................................. 47 
PATIENT IDENTIFICATION .............................................................................................................................................. 47 
PUBLICATIONS .............................................................................................................................................................. 47 
ECONOMY ..................................................................................................................................................................... 48 
APPENDIX 1 ................................................................................................................................................................... 49 
RETNINGSLINJER FOR AFGIVELSE AF MUNDTLIG DELTAGERINFORMATION ................................................................... 49 
APPENDIX 2 ................................................................................................................................................................... 51 
ECOG-FUNKTIONSSTATUS/PERFORMANCE STATUS ...................................................................................................... 51 
APPENDIX 3 ................................................................................................................................................................... 52 
INTERNATIONAL MRCC DATABASE CONSORTIUM (IMDC) PROGNOSTIC MODEL ......................................................... 52 
APPENDIX 4 ................................................................................................................................................................... 53 
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION OF HEART FAILURE ......................................................... 53 
APPENDIX 5 ................................................................................................................................................................... 54 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) VERSION 4 ........................................................ 54 
APPENDIX 6 ................................................................................................................................................................... 55 
TREATMENT GUIDELINE FOR HIGH DOSE INTERLEUKIN-2 DURING T-CELL THERAPY ..................................................... 55 
APPENDIX 7 ................................................................................................................................................................... 63 
FEBRILE NEUTROPENIA DURING T-CELL THERAPI.......................................................................................................... 63 
APPENDIX 8 ................................................................................................................................................................... 64 
SUMMARY OF PRODUCT CHARACTERISTICS FOR CYCLOPHOSPHAMIDE.......................................................................... 64 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
7
APPENDIX 9 ................................................................................................................................................................... 85 
SUMMARY OF PRODUCT CHARACTERISTICS FOR FLUDARABINEPHOSPHAT .................................................................... 86 
APPENDIX 10 ............................................................................................................................................................... 103 
SUMMARY OF PRODUCT CHARACTERISTICS FOR É FOR PROLEUKIN ............................................................................. 103 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
List of Abbreviations 
ACT = Adoptive Cell Therapy 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
8
AE = Adverse Event 
ALAT = Alanine-Aminotransferase  
ASAT = Aspartate-Aminotransferase 
AR = Adverse Reaction 
ASAT = Aspartaet-Aminotransferase 
BMI = Body mass index 
CCIT = Center for Cancer Immune Therapy 
CD4+ Cells = Helper T cells 
CD8+ Cells = Cytotoxic T cells 
CLL = Chronic lymphatic leukemia 
CR = Complete Response 
CTC = Common Toxicity Criteria 
CTCAE = Common Terminology Criteria for Adverse Events 
CTL = Cytotoxic T lymphocyttes 
Cy = Cyclophosphamide 
DMSO = DiMethyl SulfOxide 
ECG = Electrocardiogram 
eCRF = Elektronic Case Report Form 
EF = Ejection fraction 
ELISA = Enzyme-Linked ImmunoSorbent Assay 
ELISpot = Enzyme-Linked ImmunoSpot 
Flu = Fludarabine phosphate 
FTC = Freshly disaggregated tumor cells 
GCP = Good Clinical Practice 
G-CSF = Granulocyte colony stimulating factor 
GFR = Glomerular filtration rate 
HLA = Human Leukocyte Antigen 
IFN = Interferon 
IFN-γ = Interferon-gamma 
IFN-α = Interferon alpha 
IMPD = Investigational Medical Product Dossier 
IL-2 = Interleukin-2 
KFE = Klinisk forskningsenhed / Clinical Research Unit  
LAK = Lymphokine-Activated Killer 
LDH = Lactate dehydrogenase 
MHC = Major Histocompatibility Complex 
MM = Malignant melanoma = skin cancer 
mRCC = Metastatic Renal Cell Carcinoma 
MUGA = Multigated acquisition 
NED = No evidence of disease 
NGS = Next generation sequencing 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
9
ORR = Overall Response Rate 
OS = Overall survival 
PBMC = Peripheral mononuclear blood cells 
PD = Progressive Disease 
Peginterferon = Pegylated interferon alpha 2b 
PET =Positron Emission Tomography  
PFS = Progression free survival 
PR = Partial Response 
PS = Performance status, ECOG scale 0-4 
RCC = Renal Cell Carcinoma 
RECIST = Response Evaluation Criteria In Solid Tumours 
REP = Rapid Expansion Protocol 
RR= Response rate 
SAE = Serious Adverse Event 
SAR = Serious Adverse Reaction 
SD = Stable Disease 
SUSAR = Suspected Unexpected Serious Adverse Reaction 
TAA = Tumor Associated Antigens 
TCL = Tumor cell line 
TIL = Tumor Infiltrating Lymphocyttes 
TKI = Tyrosine Kinase Inhibotor 
TNF = Tumor necrosis factor 
Treg = Regulatory T cells 
VEK = Videnskabsetisk Komité / Health Research Ethics Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
10
Synopsis 
 
Indication and treatment 
Patients with metastatic renal cell carcinoma (mRCC) will be treated in this pilot study. The 
treatment involves infusion of tumor-infiltrating lymphocytes (TILs) isolated from the patient’s 
own tumor tissue as well as administration of lymphodepleting chemotherapy and the immune-
stimulating cytokine, interleukin-2 (IL-2).  
 
Rationale 
T-cell therapy is an experimental personalized immunotherapy where TILs are isolated from the 
patient’s own tumor tissue, expanded in vitro to billions of cells and then administered to the 
individual patient with the purpose of eliminating the remaining cancer cells. Lymphodepleting 
chemotherapy with cyclophosphamide and fludarabine phosphate is administered to the patient 
before TIL infusion to reduce the number of irrelevant immune cells- as well as regulatory T-cells 
known to inhibit T-cell mediated cancer cell killing. IL-2 is administered after TIL administration to 
activate and stimulate further proliferation of the infused TILs.  
 
Purpose 
The primary objective is to evaluate the tolerability and safety of the treatment. The secondary 
objective is to characterize antitumor immune responses (immune monitoring) as well as to assess 
the clinical effect of the treatment by use of the objective response rate (using RECIST 1.1). In 
addition, overall survival (OS) and progression-free survival (PFS) will be described, but not 
included as endpoints. 
 
Study design 
The trial is a pilot study.  
Patients will be included and treated at the Department of Oncology at Herlev Hospital. Patients can 
be referred from other oncology or urology centers. 
 
All eligible patients will be treated during hospital admission and one series of treatment will span 
approximately 3 weeks. Treatment will be administered only once.  
It will take approximately 4-6 weeks from the tumor tissue is removed for TIL manufacturing to the 
start of treatment. In some cases, TILs will be isolated from tumor tissue in advance and cryo-
preserved for later treatment. After the end of treatment, the patients will be followed with clinical- 
and imaging controls for up to 5 years in a specialized immunotherapy unit at the Department of 
Oncology, Herlev Hospital. Patients will be excluded upon clinical or radiological progression.  


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
11
The inclusion period is expected to be approximately five years, starting in august 2016.  
The study will be monitored by the Good Clinical Practice (GCP)-unit, and reported to the Danish 
Health and Medicines Authority, the Research Ethics Committee and the Danish Data Protection 
Agency. 
 
Population 
Patients with histologically verified mRCC will be eligible for treatment if they meet the inclusion 
criteria, including an acceptable performance status, acceptable kidney- and liver function, and the 
absence of major co-morbidities. A total of 6 patients will be included and treated. The treatment 
will only be completed in patients with successful manufacturing of TILs.  
Prior clinical trials have shown that the success rate of TIL manufacturing from metastatic 
melanoma exceeds 90% 1. To date, we have successfully generated viable TIL cultures from 23 out 
of 25 tumor samples from patients with renal cell carcinoma who have undergone radical or partial 
nephrectomy (our internal observation).  
The actual success rate of TIL manufacturing in this trial may depend on additional factors e.g. 
previous treatments, but major difficulties in manufacturing TILs from the majority of patients are 
not envisaged.  
 
Toxicity 
A phase II trial of T-cell based immunotherapy for patients with metastatic melanoma, administered 
in combination with the same lymphodepleting chemotherapy and  IL-2 (intravenous decrescendo 
regimen) has shown acceptable safety and toxicity at the Department of Oncology, Herlev 
Hospital1. Several other studies in metastatic melanoma have used the same lymphodepleting 
chemotherapy regimen and high-dose bolus IL-2 administration,(e.g. Dudley et al.2), with an 
acceptable safety profile. 
Recently, a Phase III study with an identical regimen was initiated at the Department of Oncology, 
Herlev Hospital. So far toxicity has been acceptable. 
Evaluation of clinical response 
The patients will be clinically evaluated 6 and 12 weeks after treatment with TILs and every 3 
months for 2 years and semiannually hereafter. Evaluation by diagnostic imaging will take place 
before the treatment and in connection with the clinical evaluations starting from 6 weeks after TIL 
treatment. 
 
Immunological response evaluation 
Blood samples of 110 ml will be collected at the time of surgery, before TIL infusion, at discharge 
and in connection with the clinical evaluations. Serum samples (10 ml blood samples) will be 
collected during hospitalization at day 0 before TIL infusion, 2 hours after TIL infusion and every 2 
days hereafter until discharge. Immune cells will be isolated from the collected blood samples by 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
12
standard gradient centrifugation and cryo-preserved for later analysis. Flow-cytometric analyses 
will be used to assess the quantity and function of different immune cell subsets (e.g. CD4+, CD8+) 
before and after treatment at several time points. 
 
Introduction and rationale 
 
Renal Cell Carcinoma  
Renal Cell Carcinoma (RCC) constituted 2,1% of cancers worldwide in 2008 and estimated 1,5% of 
cancer related deaths3. In Denmark, 800-900 patients are diagnosed each year with RCC with an 
increasing incidence over the last 10 years (21,1 in 100.000 for men and 11,05 in 100.000 for 
women). Patients typically range from 60-70 years of age with <25% having metastatic disease at 
the time of debut. Approximately 30% of patients undergoing surgery with a curative intent will 
develop locally recurrent or metastatic disease4.  
Younger patients with metastatic disease, and a suitable general condition, can be treated with IL-2, 
Interferon (INF) and sometimes surgery with a curative intent. The remaining patients with 
metastatic disease will be treated with different biological targeted agents, mainly Tyrosine Kinase 
Inhibotors (TKIs), in a palliative setting. Metastatic RCC is resitant to chemotherapy5. Therefore, 
there is an unmedt need for new and improved treatments in mRCC. 
 
Tumor immunology 
Substantial progress has been made in the understanding of the reactions of the immune system 
against cancer in recent years. It has become clear that the immune system reacts against certain 
tumors in vivo and that immunological response against cancer cells are associated with a better 
prognosis6,7. In addition, it has been shown that a small percentage of patients with widely 
metastatic cancers can be cured with a variety of immune-activating approaches, including transfer 
of T cells8.  
 
In RCC, several clinical trials have investigated cell-based therapy. Infusion of IL-2 and 
lymphokine-activated killer (LAK) cells were administered in several clinical trials with more than 
500 RCC patients, but did not find clinical response rate or overall survival significantly greater 
than treatment with IL-2 alone9. Treatment with TIL based adoptive cell therapy (ACT) has been 
tried in several other clinical trials, but only with modest success and highly varying response 
rates9. This is decribed in further details below (p. 14-15). 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
13
Tumor infiltrating lymphocytes (TILs) 
Tumors are often infiltrated by large amounts of T-cells (TILs) that specifically recognize tumor 
antigens but typically are inactive, or not sufficiently active, in the tumor microenvironment. The 
inactive state of the T-cells in the tumor tissue is characterized by abnormal intracellular signaling, 
apoptosis and reduced proliferative capability, which are probably caused by various immune 
inhibiting factors in the tumor environment10,11. However, it is possible to amplify and reactivate 
such TILs for tumor cell killing in vitro by use of activating factors like IL-212,13.  
 
 
T cell therapy 
T cell therapy, which is also called ”Adoptive T cell Therapy” (ACT), is an immunotherapeutic 
cancer treatment that has shown very promising results, especially in metastatic melanoma (MM). 
This treatment, which uses the patient’s own T cells for tumor cell killing, was developed at the 
American National Institute of Health and in recent years several studies from research centers in 
other countries in both USA and Europe have been published with more than 500 patients having 
received the treatment in total2,14–18.  
 
The treatment is defined as the infusion of T cells isolated from the patient’s own  
tumor tissue after ex vivo activation and several rounds of expansion, and takes advantage of the 
high number of tumor reactive T cells in tumor tissue compared to peripheral blood19. 
 
Briefly, tumor-infiltrating T-lymphocytes are harvested from freshly resected tumor material from 
an individual patient and initially expanded ex vivo over a period of 2-4 weeks by growing T cells in 
high concentrations of the T cell growth factor IL-2. Upon TIL isolation and initial growth, cells are 
further expanded to around 5x1010 cells in a standard 14 days rapid expansion protocol (REP), 
where TILs are cultured in the presence of allogeneic or autologous irradiated PBMCs (“feeder 
cells”), soluble anti-CD3 antibodies and IL-2. Prior to infusion of the TIL product, patients receive 
in-hospital lymphodepleting chemotherapy for 7 days as a conditioning treatment. This last step has 
no direct impact on tumor growth, but is crucial for subsequent in vivo TIL persistence and 
expansion. Following intravenous administration of the T-cell product, IL-2 is administered to 
support the growth and survival of the infused T cells. The patients remain in hospital for a total of 
14-21 days (see Figure 1 for an overview of the procedure). When an autologous and polyclonal 
tumor specific T cell population is infused under these conditions, migration of anticancer T cells to 
the tumor site leads to a broad and patient-specific recognition of both defined and undefined 
antigens expressed on tumor cells leading to tumor cell killing and, eventually, tumor regression.  
 
This makes T cell therapy a highly specialized and individualized form of cancer immune therapy. 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
14
 
Figure 1: Course of treatment with T cell therapy 
Tumor tissue for manufacturing of the T cell infusion product is removed immediately after 
inclusion. Treatment with Cyclophosphamide (C) and fludarabine phosphate (F) is commenced a 
week before the T cells are ready for infusion and are followed by infusion of the T cells and 
administration of IL-2 (I). Duration and dosage of IL-2 varies among protocols. 
 
T cell therapy has shown very promising results in MM with overall response rates (ORR) around 
50%, which has been confirmed in several phase I/II “single institution” studies15–17,20,21.  Complete 
response (CR) has been observed in about 20% of the treated patients of which most CR are of long 
duration and with patients being free of disease more than 7 years after the treatment14. Thus, TIL 
based T cell therapy seems to have the potential of curing a significant number of the treated 
patients with MM. 
 
Previous experiences with more than 500 patients with metastatic MM treated with T cell therapy 
has shown that the treatment is safe to administer to patients in a good performance status and 
adequate organ function, despite considerable - but temporary - toxicity. The observed acute side 
effects are reversible and consist of known and expected side effects to lymphodepleting 
chemotherapy and high dose IL-2. 
So far, treatment with TIL based ACT in metastatic renal cell carcinoma (mRCC) has only been 
given with modest success and highly varying response rates. Furthermore, all the clinical trials are 
of an elder date. Importantly, none of the clinical trials investigating T cell therapy in mRCC used 
the same preparative chemotherapy regimen used today and the ex vivo methods for lymphocyte 
expansion have changes considerably since then9. 
The TIL/IL-2 conducted studies in mRCC patients are summarized in table 1 below: 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
15


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
16
CCITs experience with T cell therapy 
Clinical trial 
The complicated methods of manufacturing TILs has been established at the Center for Cancer 
Immune Therapy (CCIT), Herlev Hospital, as one of the few places in the world22, and a clinical 
trial has been conducted1, with 31 patients with metastatic MM treated so far. 
All patients were treated with classic lymphodepleting chemotherapy with cyclophosphamide and 
fludarabine phosphate followed by TIL infusion with approximately 100x109 cells followed by the 
administration of IL-2. 
In the original “T cell regimen” described by Dudley et al15 very high dosages of IL-2 (720.000 
IU/kg i.v.) where given as bolus injection every 8 hours until treatment limiting toxicity. It is 
unknown how high a dosage of IL-2 is necessary to maintain T cell expansion, and consequently 
CCIT has tested the treatment with low and intermediate doses of IL-2 to investigate whether 
clinical efficacy can be maintained while toxicity is decreased. 
Low dosage subcutaneous IL-2 was given to 6 patients in a pilot study initiated in the summer of 
2009 and the results are now published15.  Two of the six treated patients achieved CR and are 
presently without evidence of disease (NED). 
To achieve a higher response rate (RR), the dosage of IL-2 was then increased to an intermediary 
dosage and administered after the decrescendo-regimen equal to the decrescendo regimen used in 
Denmark as standard treatment of metastatic MM. 
Additionally 25 patients have been treated after the increase in IL-2 dosage. Of the 31 treated 
patients, five achieved CR (48 (NED), 13 (NED), 47+, 32+ and 22+ months) and 7 patients 
achieved partial PR (45+ (NED), 12, 28+, 36+ (NED), 11, 11 and 8), of which 6 are having ongoing 
responses varying from 8-45 months. Thirteen patients had stable disease (SD) for 4-6 months and 5 
patients progressed immediately after treatment. An ORR of 39% has been observed, which is 
comparable to other studies administering high dosage of IL-2. The lymphodepleting chemotherapy 
induced, as anticipated, myelosuppression with anemia, leucopenia and thrombocytopenia and all 
patients received prophylactic antibiotics and blood transfusions. All patients experienced transient 
grade III-IV toxicities during the 3 weeks of hospitalization but recovered quickly after the 
treatment. The above mentioned results have recently been published23. Recently, a Phase III trial 
comparing high-dose bolus IL-2 receiving T cell therapy and Ipilimumab in patients with MM has 
begun at CCIT with international collaborators. So far, 6 patients have been treated with TILs and 
high-dose bolus IL-2 and only expected and manageable toxicities have been observed (our internal 
observation).  
In mRCC, the use of high-dose IL-2 is a well established first line treatment since the 90’s24. Thus, 
in this trial we will combine infusion of TILs with high-dose IL-2. 
 
Translational research 
Further development of T cell therapy with optimizing and expansion to other cancer forms has a 
high priority at CCIT. Our already established platform for T cell therapy for MM gives us an 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
17
unique opportunity to study the interactions between tumor and immune system and thereby 
identify possible methods for optimization of T cell therapy, as well as extension to other tumor 
histologies.  
 
Several studies has shown that the following T cell characteristics are important for achieving a 
clinical response after T cell therapy: long telomeres, short time spent in culture, a favorable T cell 
phenotype (CD27+, CD28+), a high absolute number of T cells and a high number of cytotoxic  
tumor-reactive T cells in the infusion product25 as well as an increased persistence of T cell in the 
peripheral blood after infusion14,22,26. At CCIT, we have modified the original T cell expansion 
method from ”Standard TIL expansion” to ”Young TIL expansion” based on these characteristics 
and leading to a reduction of the length of cell manufacturing from 4-7 weeks to 2-4 weeks. A 
decreased amount of time in culture (Young TIL) provides the TILs with longer telomere sequences 
and more favorable phenotypes (CD27+, CD28+) with the ability of increased proliferation, an 
increased persistence in vivo and a higher antitumor activity, all of which are correlated to an 
increased clinical response14,22. This optimization of TIL production has made it possible to produce 
clinically usable TIL infusion products from more than 90% of the patients27–30. Furthermore, 
during the final expansion phase, the Rapid Expansion Protocol (REP), we have introduced the use 
of the Wave® bioreactor31, which optimizes the conditions of proliferation of T cells and has made 
it possible to achieve a higher total number of cells as well as tumor reactive T cells in the TIL 
infusion product. We have standardized and harmonized TIL production methods between 3 
European cancer research centers based on these TIL production protocols developed at CCIT and 
have initiated a randomized, multicenter TIL-based phase III trial with T cell therapy versus 
standard immunotherapy (clinicaltrials.gov identifier: NCT02278887) with the purpose of the 
approval of T cell therapy as standard treatment for patients with MM.  
 
Recent studies suggest that TIL based ACT potentially can be used with success in other cancer 
forms including colon, breast, head and neck, kidney, ovary and sarcoma32–37. It has been shown 
that a high intratumoral presence of T cells is correlated with longer survival and functional analysis 
has shown that tumor infiltrating T cells show in vitro anti-tumor activity (Figure 2). We have 
successfully manufactured TILs from 23/25 samples obtained from RCC patients undergoing 
radical or partial nephrectomy, and in vitro expansion was similar characteristics as in MM (Figure 
3.  
 
 
 
 
 
 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
18
 
 
Figure 2: Anti-tumor reactivity of in vitro expanded CD8+ TILs in RCC 
(A) and (B) Bars show the proportion of tumor-reactive CD8+ T cells in (A) minimally expanded 
TIL cultures (Y-TIL) or (B) TIL cultures expanded to clinical numbers (Y-REP). Each bar shows 
one individual patient. The frequency of tumor reactive TILs was established by co-culture with 
autologous freshly disaggregated tumor cells (FTC) or short-term cultured tumor cell lines (TCL), 
with or without 72 hours of pre-treatment with IFN (IFN TCL)which increases antigen 
presentation.. If autologous TCLs were not available TILs were only tested against FTC (RCC3, 
RCC5, RCC8, RCC10 and RCC11). Dotted line: limit of sensitivity. (C) and (D) Flow cytometry 
plots gated on CD8+ T cells showing cytokine expression (IFN and TNF) and CD107a up-
regulation, which is a marker of T cell killing, from a representative patient (RCC26) after 
stimulation with autologous short-term cultured TCL and increased recognition after IFN pre-
treatment of the TCL. 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
19
 
 
Figure 3. Clinical expansion in the REP with standard static conditions. 
Fold expansion in 14 days REP of minimally expanded TILs from RCC and MM was performed in 
parallel.  (A) Fold expansion curves from 15 RCC patients in duplicates (n = 30) and 11 MM 
patients (n = 22). (B) No difference in median fold expansion on day 7 (P = 0.16) and day 14 (P = 
0.46) for RCC (n = 30) and MM (n = 22). 
 
The rationale of the drugs used in the study 
Lymphocyte depleting chemotherapy 
Activating cytokines (the signal molecules IL-2, IL-7, IL-15, IL-21 etc.) need to be available for the 
tumor specific T cells to sustain an immunological response against tumor tissue. A large number of 
“irrelevant” T cells will decrease the availability of these cytokines for the relevant T cells through 
competition. Thus, a high number of tumor specific T cells with a high specificity as well as a 
reduction of irrelevant T cells and regulatory T cells (Tregs) are needed to create an environment 
that facilitates the T cell mediated antitumor response. 
This study will use combination chemotherapy with two days treatment with cyclophosphamide and 
5 days with fludarabine phosphate to create such an environment. This combination has been 
chosen based on earlier studies where it was shown safe and effective38,39. 
 
Cyclophosphamide 
Cyclophosphamide is an alkylating drug that works by creating covalent bindings with biologically 
important macromolecules. Of special interest is the creation of a binding and linkage to DNA. Cell 
division can be prevented if the linkage is not canceled by the cells repair systems. The binding to 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
20
important proteins in the cell can damage important cellular functions and lead to cell death. 
Cyclophosphamide is among others used to treat breast cancer and in the treatment of hematological 
diseases as myelomatosis40.  
 
Fludarabine phosphate 
Fludarabine phosphate is a pro-drug that is converted to the active triphosphate 2-fluoro-ara-ATP. It 
is an anti metabolite which inhibits DNA synthesis while simultaneously reducing RNA and protein 
synthesis. Fludarabine phosphate is used in the treatment hematological diseases as CLL among 
others41.  
 
Interleukin 2 
IL-2 is physiologically produced by activated T-lymphocytes and stimulates the antigen specific 
and non-specific immune system through specific receptors42. 
Intermediate-dose interleukin-2 (IL-2) administered intravenously according to the decresendo-
regimen43 is used in Denmark as standard treatment for suitable patients with metastatic MM. 
Moreover, low-dose IL-2 is used for the treatment of metastatic RCC. As mentioned above, a Phase 
III trial comparing high-dose bolus IL-2 receiving T cell therapy and Ipilimumab in patients with 
MM has begun recently at CCIT with international collaborators. 
In the present pilot study, IL-2 will be given as high-dose bolus infusions as mentioned above and 
which has been used in several other phase II studies2,16,44. 
 
 
The rationale of the treatment regimen used in the study 
The ACT regimen has been determined according to our previous study carried out in MM1.  
 
Purpose and hypothesis 
Primary 
1) To assess tolerability and feasibility of the treatment. 
Secondary 
1) To clarify whether T cell therapy for patients with mRCC can induce a measurable immune 
response against tumor cells. 
 
2) To describe objective responses using RECIST 1.1 
 
Furthermore, overall survival (OS) and progression-free survival (PFS) will be described. 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
21
Study design 
The study is a pilot study for patients with advanced renal cell carcinoma. All patients will be 
included and treated at the Department of Oncology, Herlev Hospital. Patients can be referred to 
treatment from other centers in Denmark. 
We expect to include and treat 6 patients within four years. Patients will only receive one course of 
treatment.  
 The patients will be evaluated for objective response after 6 and 12 weeks and approximately every 
3 months for 2 years and the semiannually until disease progression. 
The course of treatment can vary between patients depending on the time period from surgery to 
treatment. In most cases (e.g. TILs undergoing massive expansion and infusion without 
cryopreservation of intermediate products), the patients will receive treatment approximately 4-6 
weeks after the operation and in these cases the course of treatment from surgery until the first 
evaluation with diagnostic imaging (6 weeks after treatment) will span across approximately 3 
months. 
Study population 
Patients with histological verified mRCC will be candidates for this study. The patients need to 
have a good performance status, no major co-morbidities and acceptable organ functions. 
Only patients in which it is possible to grow T cells from their tumor tissue will be offered 
treatment with T cells in the study and only patients receiving treatment will be included in the final 
study population. 
 
Criteria of in- and exclusion 
Criteria of inclusion 
All of the criteria listed in the following need to be met for patient inclusion. 
 
1. Histological proven mRCC with the possibility of surgical removal of tumor tissue of > 1 
cm3. Histology must include a clear cell component with or without a sarcomatoid 
dedifferentiation. 
2. Metastatic disease irrespective of number of previous treatment lines. Treatment naïve pt’s 
can be included.  
3. Age: 18 – 70 years. 
4. ECOG performance status of ≤1 (Appendix 2). 
5. IMDC prognostic group ‘Favorable’ or ‘Intermediary’ (Appendix 3) 
6. Life expectancy of > 6 months. 
7. At least one measurable parameter after surgery in accordance with RECIST 1.1 –criteria’s. 
8. No significant toxicities or side effects (CTC ≤ 1) from previous treatments. 
9. Normal ejection fraction (EF) measured by a multigated acquisition (MUGA) scan. 
10. Crom EDTA clearance >40 ml/min 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
22
11. Sufficient organ function, including:  
System 
Laboratory value 
Hematological 
 
ANC (Absolute Neutrophil Count) 
≥ 1.500/µl 
Leukocytes 
≥ normal limit 
Platelets 
≥ 100.000/µl and < 700.000/µl 
Hemoglobin 
> 6,0 mmol/l (after blood transfusion if 
necessary) 
Liver 
 
Total serum bilirubin 
≤ 1,5 times upper normal limit 
ASAT/ALAT 
≤ 2,5 times upper normal limit 
Alkaline phosphatase 
≤ 5 times upper normal limit 
Coagulation 
 
PP 
> 40 unless the patient receives therapeutic anti-
coagulation treatment.  
INR 
< 1,5 unless the patient receives therapeutic 
anti-coagulation treatment. 
12. LDH ≤ 5 times upper normal limit as a measure of tumor burden 
13. Women in the fertile age must use effective contraception. Likewise, men included in the 
study, as well as their partners, must use effective contraception. This applies from inclusion 
and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, 
subdermal implantation, hormonal vaginal ring and transdermal depot patch are all 
considered safe contraceptives. 
14. Signed statement of consent after receiving oral and written study information. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research 
15. Willingness to participate in the planned controls. 
 
 
Criteria of exclusion 
Patients will be excluded if they meet one of the criteria listed below. 
 
1. A history of prior malignancies, exept curatively treated non-melanoma skin cancer and CIS 
of the cervix uteri. Patients treated for another malignancy can participate if they are without 
signs of disease for a minimum of 3 years after treatment. 
2. Patients with cerebral metastases. 
3. Patients with widespread bone or bone only metastases. 
4. Known hypersensitivity to one of the active drugs or one or more of the excipients. 
5. Severe medical conditions, such as severe asthma/COLD, ischemic hearth 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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Authorities chart nr. 2016072152. 
23
disease/significant cardiac disease (e.g. NYHA class ≥2, also see appendix 4), poorly 
regulated insulin dependent diabetes mellitus among others, which can interfere with patient 
compliance and/or significantly increase the risk of side effects upon investigators clinical 
judgement. 
6. Acutte/chronic infection with HIV, hepatitis, tuberculosis among others. 
7. Severe allergies or previous anaphylactic reactions. 
8. Active autoimmune disease, such as autoimmune neutropenia/thrombocytopenia or 
hemolytic anemia, systemic lupus erythematosis, Sjögren’s syndrome, sclerodermia, 
myasthenia gravis, Goodpasteur’s disease, Addison’s disease, Hashimotos thyroiditis, active 
Graves disease. 
9. Pregnant women and women breastfeeding. 
10. Simultaneous treatment with systemic immunosuppressive drugs (including prednisolone, 
methotrexate among others). 
11. Simultaneous treatment with other experimental drugs. 
12. Simultaneous treatment with other systemic anti-cancer treatments. 
13. Patients with active and uncontrollable hypercalcaemia. 
 
Evaluation before entry in the study 
The following need to be carried out before the start of treatment: 
- 
Medical history and clinical examination 
- 
Performance status in accordance to the ECOG-scale 
- 
Electrocardiogram 
- 
Multigated acquisition (MUGA) scan. Can be supplemented with an exertion test if 
indicated. 
- 
Cr-EDTA clearance* 
- 
Pulmonary function tests 
- 
Urine sample 
- 
Laboratory analyses:  
A) Hematology: hemoglobin, leukocytes, granulocytes and platelets 
B) Blood chemistry: Sodium, potassium, magnesium, carbamide, creatinine, LDH, alkaline 
phosphatase, ASAT, ALAT, bilirubin, ionized calcium, CRP, TSH, Ca-ion, INR, PP 
C) Infections: Hepatitis B, Hepatitis C (IgG), HIV, HTLV-1(IgG), EBV, Syphilis and CMV 
- 
Pregnancy test: Women in the fertile age must take a pregnancy test. This includes women 
who are not surgically sterilized, who are not postmenopausal and who have not used safe 
contraception’s regularly within the last 6 months.  
- 
Baseline tumor evaluation: A CT scan of the brain, chest, abdomen and pelvis is mandatory. 
Brain MRI scan is performed if brain metastases are suspected.  
- 
Reviewing the checklist for inclusion/exclusion for treatment. 
* If not performed before primary surgery/if potential entry in the study is due to progressive or 
recurrent disease. Is to be repeated within 2 weeks before hospitalization for T cell therapy if 
creatinine levels rises >20% after inclusion. 
 


 
 
 
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EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
24
Examination plan during the course of treatment 
 
Inclusion 
Operation 
Befrore 
admission 
Before 
T-cell infusion  
 
Before discharge 
Day 
 
 
-8 
0 
Approx. 
10 
Performance 
Status
x 
 
x 
x 
x 
Clinical 
examination
x 
 
x 
x 
x 
Weight
x
x
x
x
Adverse events 
(CTC)
 
 
x 
x 
x 
Screening blood 
testsa
x 
 
 
 
 
Immunological 
blood testsb 
 
x 
x 
 
x 
Random 
blood testsc
 
 
x 
x 
x 
ECG
x
x
MUGA
x
Cr EDTAd
(x)
(x)
Pulmonary 
function tests
x 
 
 
 
 
Urine sample
x
Biopsye
x
Tumor 
Evaluationf 
x 
 
x 
 
 
Examination plan  
a: 
Screening blood samples: T-cell screening (blood sample-package): hemoglobin, 
platelets, leukocytes, differential-count, sodium, potassium, magnesium, carbamide, 
creatinine, ALAT, ASAT, alkaline phosphatase, bilirubin, LDH, INR, APTT, PP, 
ionized calcium, CRP, TSH, albumine, phosphate, T3, T4, Hepatitis B virus s-antigen 
(HBVSAG), Hepatitis B virus s-antibody (HBVSAB), Hepatitis B virus c-antibody 
(HBVCAB), Hepatitis C virus-antibody (HCVAB), Human immune defect virus type 
1og 2 antibody and antigen (HIVCOMBO), HTLV type I-antibody + HTLV type II-
antibody (IgG) (HTLVIGG), Ebstein-Barr virus-antibody (EBV), P-Treponema 
pallidum-antibody (TREPONE), Cytomegalovirus (CMV) 
b: 
Immunological blood samples: HEREKS11.  See the section about “Blood samples for 
immunological monitoring”. 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
25
c:  
Random blood samples (are taken daily during hospital admission and until 
discharge):  Hemoglobin, leukocyttes, diff.-count, platelets, creatinine, sodium, 
potassium, magnesium, carbamide, phosphate, LDH, ASAT, ALAT, bilirubin, alkaline 
phosphatase, albumin, ionized calcium, TSH, CRP, INR, PP, APTT.  
d: 
Is to be performed before inclusion if not performed before primary surgery/if 
potential entry in the study is due to progressive or recurrent disease. Is to be 
repeated within 14 days prior to admission if a >20% rise in creatinine is observed. 
e: 
Biopsy with core- or fine needle if possible and depending on location and accesibility  
f: 
CT and MR scans can be used as mentioned above (page 23). The scan(s) before 
chemotherapy should preferably be performed within two week prior to admission.  
 
Treatment strategy 
T cell therapy 
The course of treatment consists of two steps followed by clinical controls and evaluation-scans as 
follow-up. 
 
Step 1: Screening, inclusion and surgical removal of tumor material followed by production and 
growth of TILs in the laboratory.  
 
Step 2: Treatment during hospitalization with chemotherapy, TIL infusion and IL-2 administration.  
 
Follow-up: Evaluation of the effect of treatment during follow-up.  
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
26
 
Figure 4: Shows a schematic presentation of TIL isolation from tumor tissue followed by T cell 
expansion and treatment with T cell therapy.  
Tumor tissue (metastasis or primary tumor) of minimum 1 cm3 is surgically removed from the 
patient and transported to the laboratory under sterile conditions where the tumor is separated into 
suitable fragments of 1-3 mm3 and placed in growth wells with a growth media and IL-2. TILs are 
then initially grown for 2-4 weeks until a cell-number of minimum 50 x 106. At this point the cells 
can be cryo-preserved for later use or pass on to the Rapid Expansion Protocol (REP) in which the 
T cells for 2 weeks are stimulated with anti-CD 3 antibody, allogeneic, radiated PBMC (peripheral 
mononuclear blood cells), feeder cells and IL-2. After stimulation, the expanded TILs (now billions) 
are then washed, pooled and re-infused intravenously back in to the patient. Seven days of 
lymphodepleting chemotherapy is given to the patient before TIL infusion with cyclophosphamide 
(C) on day -7 to day -6 and Fludarabine (F) on day -5 to day -1 with the purpose of removing all 
existing lymphocytes in the patient to make room for the infused TILs and remove regulatory T cells 
(Tregs). High-dosage bolus IL-2 will be administered every eight hour from the day of T cell 
infusion (day 0) for up to 5 days (maximum of 15 doses) in order to active and stimulate the infused 
TILs for further expansion within the patient.  
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
27
Medicinal products used in the study 
The medicinal products used in this study are cyclophosphamide, fludarabine phosphate and 
interleukin-2. Mixing and storage of the products is carried out according to existing standard 
guidelines at the Department of Oncology. 
 
Cyclophosphamide 
Cyclophosphamide is given as an intravenous infusion for two consecutive days in a dosage of 60 
mg per kg of body weight. The treatment takes place during hospital admission and with 
supplementary hydration and Mesna injections. Dosage is to be calculated based on the ideal body 
weight (male: 50 kg + 0,9 kg per cm above 150 cm, woman: 45 kg + 0,9 kg per cm above 150 cm) 
if Body Mass Index (BMI) is > 35. Dosage is to be reduced with up to 75% if renal function is 
reduced to GFR 30-70 ml/min and is contraindicated if GFR < 30 ml/min. 
 
Fludarabine phosphate 
Fludarabine phosphate is given as an intravenous infusion for 5 consecutive days in a dosage of 25 
mg per m2 body surface (starting the day after the last dosage of cyclophosphamide). The treatment 
takes place during hospital admission. Dosage is to be reduced with up to 80% if renal function is 
reduced to GFR 30-70 ml/min and is contraindicated if GFR < 30 ml/min.  
 
TILs 
The tumor specific T cells are infused intravenously back in to the patient on the day after the last 
dosage of fludarabine phosphate (day 0). The number of T cells in the product depends on the 
possible in vitro degree of expansion and is therefore variable, but will normally consist of 
approximately 1010 cells. See the attached Investigational Product Medicinal Dossier (IMPD) for 
more information. 
The treatment takes place during hospital admission. 
 
Interleukin-2 
Interleukin-2 will be administered at a dose of 600.000 IU/kg as an intravenous bolus over a 15-
minute period every eight hours beginning 4-24 hours following the  T cell infusion (day 0) and 
continuing for up to 5 days (maximum of 15 doses). Start of IL-2 administration depends on 
whether the patient has recovered from the TIL infusion. 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
28
Treatment plan 
Year:          Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 
-2 
-1 
0 
1 
Treatment day
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
7 
14
Time 
(indic. time)
Pt. is admitted  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide  
60 mg/kg iv 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabinephos-phate 
25 mg/m2 iv
 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
TILs iv 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Pegfilgrastime 
6 mg sc* 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Interleukin-2, 600.000 
IU/kg/dose every eight 
hour bolus/i.v. (200 
ml/hour)**
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
 
 
Treatment plan 
* See the section”Prophylactic treatment” 
** Only one dose on day 0 
 
Concomitant treatment 
Guidelines for supportive care and treatment 
Supportive treatment is given on ordinary medical indications estimated by the physician 
responsible for the treatment. Any measures should be specified in the patient chart and flow sheet. 
The following is meant as guidance and other medications can be administered as it is seen fit. One 
exception is systemic corticosteroid which cannot be administered during treatment. 
 
Prophylactic treatment 
T cell therapy: Prophylactic treatment includes fluid therapy during cyclophosphamide treatment as 
well as supportive treatment. 
 
In order to protect the mucosa of the bladder the following is administered: 
 Tabl. Mesna (25% of the cyclophosphamide dosage i.v. x 4 daily on day -7 and -6).  
 
In order to prevent deranging of electrolytes as well as low blood pressure during IL-2 treatment the 
following is administered:  
 Fluid therapy in accordance with appendix 4. 
 
In order to prevent opportunistic infections the following is administered:  


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
29
 Tabl. Sulfamethizole with Trimethoprime, 400/80 mg, 1 tabl. Daily on day -7 and 6 months 
ahead. 
 Tabl. Aciclovir, 400 mg x 2 daily on day 0 and 6 months ahead. 
 Tabl. Diflucan, 100 mg daily on day 0 and until the neutrophile count is > 1000/µl. 
 
In order to prevent and relieve nausea during chemotherapy (day -7 to -1) the following is 
administered:  
 Inj. Aloxi 250 μg i.v. on day -7 and -5. 
 Tabl. Emend 125 mg on day -7, 80 mg on day -6, 80 mg on day -5. 
 Tabl. Motilium 20 mg x 3. 
 Tabl. Temesta 1-2 mg max x 4 if needed. 
 Tabl. Pantoloc 40 mg x 1-2 daily. 
 
In order to prevent and relieve nausea during IL-2 treatment (day 0 to 5) the following is 
administered: 
 Tabl. Motilium 20 mg x 3. 
 Ondansetron 8 mg x 1 if needed max x 2. 
 Imolope 2 mg if needed max x 8. 
 
In order to reduce the length of neutropenia, Pegfilgrastime, which is a human granulocyte 
stimulating factor (G-CSF), is administered in a dosage of 6 mg s.c. on day 0 approximately 2 hours 
after TIL infusion. 
 
Supportive treatment 
T cell therapy: During the infusion with T cells the patient can experience shivering which can be 
relieved with the administration of subcutaneous Pethidin in a dosage of 25 mg max x 4 if needed. 
Also, light breathing difficulties can be observed with a possible decrease in saturation which can 
be treated with oxygen by nasal catheter.  
 
Neutropenia: 
If simultaneous neutropenia and fever occurs it will be treated in accordance with the local 
instruction for “Febril neutropeni under T-celleterapi” (appendix 5). 
 
Diarrhea: 
Diarrhea will be treated immediately with the necessary supportive care and treatment, including 
Loperamide. Loperamide is to be withdrawn if blood or slime is observed in the feces during the 
diarrhea. If this occurs, suitable diagnostic microbiological samples should be collected to exclude 
an infectious cause. Patients should also be instructed in the intake of plentiful amounts of fluids to 
prevent dehydration following the diarrhea. 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
30
Anemia:  
Transfusions with blood should be administered if hgb ≤ 6.0 mmol/L or if it is otherwise clinically 
indicated. Radiated and filtered blood will be given from day -7 and 6 months ahead. 
 
Thrombocytopenia: 
Transfusion with platelets is indicated if platelets <20/μl or if it is otherwise clinically indicated. 
 
Interleukin-2: Doses may be skipped depending on patient tolerance. Toxicities will be managed, 
however the attending physician may elect to skip doses or discontinue treatment based on clinical 
judgement. If toxicities are easily reversed within 24 hours by supportive measurements then 
additional doses may be given. If more than 2 doses of interleukin-2 are skipped, interleukin-2 
administration will be stopped. A detailed description of the IL-2 treatment and pausing/stopping 
rules can be found in appendix 5. 
 
Local radiotherapy 
Local radiotherapy can be prescribed for bone pains and soft tissue metastasesor if otherwise 
clinically indicated.  Radiotherapy is preferably to be avoided within the 3 weeks period where the 
treatment takes place for the interest of the patient. Radiated areas cannot be used as parameters in 
the assessment of treatment response. If possible, not all evaluable areas should be included in the 
radiated area. If this is not possible it is no longer possible to evaluate a response to treatment and 
the patient is withdrawn from the study.  
 
End of treatment 
Normal end of treatment 
Patients only receive one series of treatment consisting of a week of chemotherapy followed by one 
infusion of T cells (day 0) and up to 5 days of high-dose bolus IL-2. Patients will be followed at the 
department of oncology, Herlev Hospital, for up to 5 years or until progression. 
 
Follow-up 
Patients will be followed with clinical controls and diagnostic imaging at 6 and 12 weeks after 
treatment and every 3 months hereafter. After 2 years the controls will change to every 6 months for 
a total of up to 5 years or until progression. End of study is defined as 6 months after the last 
patients’ treatment or after progression. OS and PFS will subsequently be followed for up to 5 
years. 
A clinical examination, toxicity assessment, blood samples including immunological blood samples 
and a PET/CT scan will be performed in connection with every control. 
A tumor biopsy will be performed at the first control after treatment if the patient has remaining 
accessible tumor tissue and on progression. 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
31
 
Follow-up schedule 
 
1) Blood samples (T-cell follow-up): hemoglobin, platelets, leukocytes, differential-count, sodium, 
potassium, creatinine, ALAT, ASAT, alkaline phosphatase, bilirubin, albumin, LDH, INR, APTT, 
PP, ionized calcium,phosphate, magnesium, carbamide, CRP, TSH, T3, T4, immunological blood 
samples – HEREKS11 (See the  section about “Blood samples for immunological monitoring”) 
2) See the section about “Tumor biopsies”. 
3) CT and MR scans can be used as mentioned above (page 23). 
Early termination of treatment 
Not possible to grow TILs: The patient cannot be offered treatment if it is not possible to grow 
TILs. 
 
Patients own wish: The treatment can be stopped at any time the patient wishes so.  
 
Medical decision: The treatment can be stopped because of medical conditions at any time the 
investigator finds it in the patients’ best interest. 
 
Other treatment: Patients will be excluded at any time a new treatment with an experimental drug or 
other systemic anticancer treatment is initiated after inclusion in this protocol. The patient will be 
Year:          
Date:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week nr. 
6 
12 
24 
 
 
 
 
 
 
 
 
 
 
 
 
Month nr. 
1,5
3 
6 
9 
12
15
18
21
24
30
36 
42 
48
54
60
Clinical 
ex. and 
subjective 
complaint
s
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Toxicity 
assessmen
t
0 
0 
0 
 
 
 
 
 
 
 
 
 
 
 
 
Weigth 
0 
0 
0 
 
 
 
 
 
 
 
 
 
 
 
 
PS 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Blood 
samples: 
T-cell 
follow-
up1)
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Biopsy 2) 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor-
evaluation 
3) 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
32
excluded if systemic treatment with corticosteroids is initiated unless it is on vital indication an in 
agreement with the physician responsible for the protocol. 
 
Adverse events: Treatment is terminated if adverse events of a degree that makes completion of the 
study impossible do occur. 
 
Patients who stop IL-2 treatment prematurely will still be followed in accordance with the protocol. 
 
If a patient is excluded before infusion of TILs a replacement subject will be found. They will be 
followed until end of adverse events caused by the treatment, but will not be followed with 
subsequent controls. 
 
Subsequent treatment 
Patients that are excluded from the study can receive other treatment freely. If patients progress they 
can receive other treatment. 
 
Production of TILs 
Acquisition of tumor tissue 
The patients will receive oral and written information as described elsewhere and a written consent 
will be obtained before surgery. A tumor biopsy will be performed after sufficient tissue material 
for pathological examination has been removed. The biopsy will be labeled with date and patient 
code, placed in a sterile container and transported to the GMP facilities 54J7 or 54I6 at Herlev 
Hospital for further processing. See the IMPD for more details 
 
 
Establishment of ”Young TIL” cultures 
T cells are expanded using a recently established method for ”Young TILs”22. The tumor mass will 
be isolated with a scalpel, and cut into small 1-3 mm3 fragments. Fragments (typically from 24 to 
72 fragments in total) will be placed separately in the wells of a 24 well/plate. A TIL culture is 
established from each fragment by passive migration of T cells from tumor tissue in the IL-2 based 
media. IL-2 belongs to the group of homeostatic cytokines which are characterized by having a 
positive effect on the activation of tumor specific T cell and thereby tumor cell killing. T cell 
density is kept at about 1x106 cells/ml growth media containing the immune stimulating cytokine 
IL-2. Cell cultures from the different fragments are pooled to a single cell culture. T cell expansion 
is performed unselected to produce a polyclonal TIL repertoire targeted against multiple epitopes to 
potentially achieve more effective tumor cell destruction in vivo. The establishment of ”Young TIL” 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
33
cultures usually takes 2-4 weeks with a rate of success more than 90%. See the IMPD for more 
details. 
 
Rapid Expansion Protocol (REP) 
When the TIL cultures are expanded to approximately 5x107 cells they are either frozen for later use 
or transferred directly for further expansion by use of the Rapid Expansion Protocol (REP) in which 
TIL are grown with radiated (40 Gy) allogeneic PBMCs (peripheral blood mononuclear cells) that 
work as “feeder cells”, IL-2 and anti-CD3 antibody that activates the TILs. In this way it is possible 
to reach a large number of activated tumor specific T cell with a high level of activity against tumor 
associated antigens (TAA) and tumor in 14 days. Ultimately, the autologous T cells are 
concentrated in a 400 ml infusion bag for intravenous infusion. See the IMPD for further details. 
 
Handling and transportation of the infusion product 
The infusion bag is labeled with patient ID and a patient specific transport schedule is filled out and 
both are then placed in a secure hatch. A trained physician controls the information on the infusion 
product and transport schedule, signs the latter and transports the infusion product to the patient. 
Before administration, the infusion product is controlled again by the treatment staff and matched to 
the ID of the patient through patient identification. 
 
Phenotype- and clonotype determination 
The prevalence of T cell types (e.g. CD4+ and CD8+) as well as characterization of T cell stages in 
both Young TILs and REP TILs will be determined by use of flow cytometric analysis. See the 
IMPD for more details. 
 
Adverse events, potential risks and precautions 
Adverse Events 
Adverse events (AE) are defined as any undesirable experience occurring to a subject during a 
clinical trial, whether or not considered related to the investigational treatment. All AEs reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded and 
described in the patient chart and the electronic Case Report Form (eCRF). The severity and 
consequences will be recorded for each AE. The severity and relation to the study medication will 
be assessed in accordance with the guidelines described in the following. 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
34
The investigator must attempt to identify all clinical and objective events from patients receiving 
treatment and determine their relation to the study medication. The investigator determines the 
relationship between AEs and treatment using the following guidelines: 
 
Grading of Adverse Events 
The severity of an AE refers to the intensity of the reaction. 
 
Events are graded using CTCAE version 4.0 (appendix 3)45. The following scale can be used if this 
grading is not applicable:  
 
1 = light 
2 = moderate 
3 = severe 
4 = life threatening 
5 = lethal 
 
Patients experiencing AEs will be monitored with the relevant clinical evaluations and laboratory 
investigations assessed by the attending physician. All AEs must be monitored until satisfactory 
restitution or stabilization. Results of the monitoring must be recorded in the patient chart and 
eCRF. 
Abnormal laboratory tests are not to be recorded in the eCRF unless they have caused a clinical 
event, resulted in termination of the treatment or otherwise meet the criteria of a serious adverse 
event (see the following). 
 
Serious Adverse Events 
A serious adverse event (SAE) is to be reported to sponsor within 24 hours and is defined as any 
medical occurrence or effect that occurs at any dose: 
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing patients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
leads to a congenital anomaly or birth defect; 
- 
is a significant medical event 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
35
Guidelines for adverse events possible relation to the treatment 
0  
No relation– no temporal relation, other etiologies very likely the cause 
 
1  
Possible relation – less clear temporal relation, other etiologies likely the cause 
 
2  
Probably related – clear temporal relation with recovery at termination of treatment, and not 
reasonably explained by the patient’s known clinical condition 
 
3 
Related – clear temporal relation with laboratory confirmation or a positive retreatment test 
 
If the event is assessed as being caused by the investigational treatment it is classified as an adverse 
reaction (AR) or a serious adverse reaction (SAR). 
 
Adverse Reactions 
An adverse reaction (AR) can be expected if it is described in the IMPD or the relevant product 
summary, or unexpected if the grade or severity does not correlate with the product information in 
the before mentioned documents. 
If the AR is unexpected, meets the criteria of a serious adverse reaction (SAR) and is found related 
to the investigational treatment it is classified as a suspected unexpected serious adverse reaction 
(SUSAR). 
 
Reporting of Adverse Events and Adverse Reactions 
Investigator reports SAEs, SARs and SUSARs to sponsor within 24 hours. Sponsor reports 
SUSARs to the Danish Health and Medicines Authority within 7 days if considered life threatening 
or fatal, and otherwise within 15 days. Consequences for the study must be reported. Sponsor 
submits a yearly list that summarizes any SAEs and SUSARs as well as a report regarding the study 
patients’ safety to the Danish Health and Medicines Authority and the Research Ethics Committee 
(investigator can report to the Research Ethics Committee as well). 
Sponsor submits a final report to the Danish Health and Medicines Authority at the end of the 
study, with a description of all SAEs, SARs and SUSARs. 
 
The following is not to be reported: 
- 
deaths caused by the malignant disease or progression 
- 
hospitalizations or prolongation of current hospitalization caused by the malignant disease: 
o weight loss 
o fatigue 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
36
o electrolyte derangement 
o pain management 
o anxiety 
o palliative hospitalization 
o stay at hospice or terminal care 
o progression of the underlying disease 
- 
hospitalizations or prolongation of current hospitalization if the sole reason for 
hospitalization or prolongation is: 
o fluid treatment or treatment of nausea 
o blood transfusion 
o platelet transfusion 
o febrile leucopenia/neutropenia 
o administration of investigational procedures 
o placement of a permanent intravenous catheter 
These events are to be registered in the eCRF. 
 
Known Adverse Reactions 
Chemotherapy 
The adverse reactions to chemotherapy described in the following are all general adverse reactions 
seen when the drugs are given as the primary treatment for oncological and hematological diseases. 
In these cases the treatment is often given over several series. In this study, the treatment will be 
given as a single dose, why we expect a milder adverse reactions profile. 
 
Cyclophosphamide 
The dose limiting toxicities in patients’ receiving treatment with cyclophosphamide are 
myelosuppression (neutropenia, thrombocytopenia and anemia) and urotoxicity (cystitis, haematuria 
and hemorrhagic cystitis). Sufficient treatment with Mesna alongside rehydration markedly reduces 
the frequency and severity of the urotoxicity. 
Other common adverse reactions are alopecia, nausea and vomiting. 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
37
Patients receiving treatment with Cyclophosphamide can experience the following adverse reactions 
described in appendix 8. 
 
Fludarabine phosphate 
The adverse reactions are myelosuppression (neutropenia, thrombocytopenia and anemia), infection 
including pneumonia, coughing, fatigue, limpness, nausea, vomiting and diarrhea. Other common 
adverse reactions are shivering, edema, malaise, peripheral neuropathy, visual disturbances, 
anorexia, mucositis, stomatitis and rash. Severe opportunistic infections have occurred in patients 
receiving treatment with fludarabine phosphate. Deaths have been recorded as a cause of severe 
adverse reactions. 
 
Patients receiving treatment with fludarabine phosphate can experience the following adverse 
reactions described in appendix 9. 
 
TILs 
No SARs are expected due to TIL infusion. The patients might experience transient fever, shivering 
and mild dyspnoea with a few cases of an observed light decrease in saturation.  
There is a theoretical risk of the development of allergic reactions/anaphylactic shock. This has not 
yet been observed according to literature.  
See the IMPD for more details on previous human exposure and anticipated risks. 
 
Interleukin-2 
Frequency and severity of adverse reactions to IL-2 has generally shown to be related to the route of 
administration, dose and frequency of treatment. Most adverse reactions are self-limiting and will 
disappear within 1-2 days after cessation of treatment. 
 
For further information see appendix 5 ”Vejledning til behandling med høj-dosis bolus interleukin-2 i 
forbindelse med T-celle terapi”.  
 
Patients receiving treatment with IL-2 can experience the following adverse reactions described in 
appendix 6. Also see appendix 10 for a summary of product characteristics. 
 
Leukoencephalopathy 
Rare cases of leukoencephalopathy related to administration of proleukine have been described in 
the literature, especially in patients treated for HIV. In some cases, other risk factors such as 
opportunistic infections, co administration of interferons and multiple series of chemotherapy had 
predisposed the patients.  
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
38
Capillary leak-syndrome 
Arrhythmia (supraventricular and ventricular), angina pectoris, myocardial infarction, respiratory 
insufficiency requiring intubation, organ dysfunction, gastrointestinal bleeding or kidney infarction, 
edema and change of mental state can be associated with capillary leak-syndrome.  
 
Severe manifestations of eosinophilia 
Most patients will experience lymphocytopenia and eosinophilia during treatment with reactive 
lymphocytosis within 24-48 hours after the treatment has ended. These manifestations are not 
considered as adverse reactions but can be explained by the anti-tumor activity mechanism of 
Proleukine. 
 
Cerebellar vasculitis 
Cerebellar vasculitis has been reported both isolated and in combination with other manifestations. 
Cutaneous and leukocytoplastic hypersensitivity vasculitis has also been reported. Some of these 
cases respond well to treatment with corticosteroids. 
 
Bacterial infection 
Bacterial infection or worsening of infection, including septicemia, bacterial endocarditis, septic 
thrombophlebitis, peritonitis, pneumonia and local infections surrounding catheters has been 
reported, mainly in relation to intravenous administration.  
 
Risks and disadvantages regarding surgery and test sampling 
Risks associated with removing tumor tissue 
Prior to inclusion it will be assessed whether it is possible to remove some of the patients own 
tumor tissue in a minor operative procedure. Surgery will mainly be performed by physicians at the 
Urology Department at Herlev Hospital or by physicians from other specialties if necessary. The 
patient will not be able to participate in the study if no tumor tissue is available for removal or if 
removal will put the patient at a too large risk.  
 
Risks associated with biopsies 
There is a slight risk of infection and/or bleeding when performing a biopsy. Pain and bruising 
might also occur in the area. 
 
Risks associated with blood tests 
Pain and bruising can occur in the area. Blood testing will involve frequent hospital visits.  
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
39
Monitoring and precautions 
Hematological parameters 
Careful hematological monitoring of blood counts is indicated for all patients during treatment. 
Leukocyte count, platelet count and hemoglobin values will be controlled at fixed intervals. 
Measurements will be made before start of chemotherapy, IL-2 and daily during treatment until 
neutrophile counts is > 500/μl and leukocyte count is > 1000/μl. Chemotherapy will not be given to 
patients with a leukocyte count < 500/μl and/or platelet number < 50.000/ μl before the start of 
chemotherapy. 
 
Kidney- and urine infections 
Any obstruction of the efferent urinary tracts, cystitis or infection will be resolved before start of 
treatment. Patients will be treated with Mesna and fluid therapy to decrease the frequency and 
severity of bladder toxicity. Treatment will be terminated if cystitis associated with micro- or 
macroscopic haematuria occurs during treatment with Cyclophosphamide. The patients’ urine will 
be controlled for the presence of microscopic haematuria before start of treatment with 
Cyclophosphamide. 
 
Cardiotoxicity 
Cardiotoxicity is especially seen when administrating high doses of Cyclophosphamide (120-240 
mg/kg body weight). An electrocardiogram will be performed before the start of treatment. Patients 
with known heart disease will not be included in the study. Necessary investigational procedures 
will be performed if the patients experiences symptoms from the cardiovascular system (e.g. chest 
pains, shortness of breath). Myocarditis has been described following high dose Il-2 treatment, if 
suspected CKMB, TPN, ECG and cardiology consult should be performed. 
 
Infertility 
Women receiving chemotherapeutic treatment have a risk of affecting their fertility in the future. It 
is not known whether T cell therapy increases the risk of cross reaction from T cells to normal 
ovarian tissue. 
 
Live vaccines 
Vaccination with live vaccines is to be avoided prior to- and immediately after treatment with 
chemotherapy because of the immunosuppressive effect. 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
40
Interactions 
Cyclophosphamide inhibits cholinesterase activity which increases the effect of depolarizing muscle 
relaxants such as Suxamethoniumchloride. This can results in prolonged apnea when anesthetized. 
The anesthesiologist is to be informed if the patient has received treatment with Cyclophosphamide 
within 10 days before treatment with Suxamethoniumchloride. The combination should be avoided.  
 
The patient is to avoid eating grapefruit or drinking grapefruit juice since grapefruit contains a 
substance that can impair the activation of Cyclophosphamide and thereby its effect. 
 
Transfusion related graft-versus-host reactions have been observed in patients receiving treatment 
with fludarabine phosphate after transfusion with non-radiated/non-filtered blood. Patients requiring 
blood transfusion within ½ a year from treatment with fludarabine phosphate is therefore to receive 
only radiated or filtered blood. An agreement with the blood bank at Herlev Hospital has been made 
so that there will be ordered radiated blood only for these patients for ½ a year after treatment. All 
blood in the Capital Region is filtered. 
 
Effect evaluation, data processing and monitoring 
Effect evaluation 
Primary effect parameters 
Paraclinical evaluation: Patients will be followed continually with in vitro analysis of the specific T 
cell reactivity against tumor antigens to evaluate the immunological effect of treatment. The 
immunological response against tumor antigens before and after treatment will be compared. These 
analyses will be done on blood samples and tumor biopsies. 
 
Secondary effect parameters 
Clinical evaluation: The clinical effect of treatment will be rated using the objective response rate in 
accordance with RECIST 1.1, overall survival (OS) and progression-free survival (PFS). 
 
Response Criteria 
RECIST 
Clinical evaluation will be done in accordance with RECIST 1.1 Guidelines46:  
 
Complete response (CR): All lesions disappear. 
Partial response (PR): Defined as a ≥ 30 % reduction in the sum of all measurable parameters 
longest diameter. 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
41
Stabile disease (SD): Defined as a < 30 % reduction in the sum of all measurable parameters longest 
diameter or a < 20 % increase in the sum of all measurable parameters longest diameter. 
Progression (PD): Defined as a > 20 % increase in the sum of all measurable parameters longest 
diameter or the appearance of new lesions. 
 
Complete and partial response is to be verified by examination at a minimum of 4 weeks after 
documentation of the response at the earliest. 
 
Immunological monitoring 
Blood samples for immunological monitoring 
Blood samples with 100 ml heparinized blood for immunological monitoring and 10 ml blood in a 
dry glass for freezing of serum are taken: at surgery, before start of treatment (at ”baseline”), at 
hospital discharge (approximately 1 week after T cell infusion) and 6 and 12 weeks after T cell 
infusion (see the examination plan and follow-up schedule). Blood samples will be taken for 
immunological monitoring every 3rd month at evaluation hereafter until the patient is withdrawn 
from the study. In addition, serum samples (10 ml blood sample) will be taken at day 0 before TIL 
infusion, 2 hours after TIL infusion and every 2nd day until hospital discharge. 
A total of 500 ml of blood will be collected for research purposes in the period from time of surgery 
until the patient meet for the first evaluation after treatment. These blood samples are taken to 
assess the effect of treatment on the immune system for research purposes. The amount of blood 
taken during the course of the study does not exceed what the body itself is capable of producing 
between each test. Blood samples for research purposes will not be taken if the blood count is not 
acceptable (> 6 mmol/l). 
 
Mononuclear cells from the peripheral blood (PBMCs) are isolated using Lymfoprep/Leucosep 
density gradient technique. The mononuclear cells are washed and resuspended in a freezing media 
consisting of 90% heat inactivated humane AB serum and 10 % DMSO. The cells are frozen at -
150°C until analysis. A panel of relevant immunological assays for testing of antigen specific 
immune reactivity will be applied, including measurements of cytokine production (multimeric 
fluorescence coloring, ELISpot and ELISA), proliferative- and cytotoxic potential. 
 
Tumor biopsies 
Biopsies are sought taken from accessible tumor lesions or involved lymph nodes depending on 
localization and accessibility. Biopsies are preferred at evaluation 6 weeks after treatment and at 
progression if possible (see the examination plan and follow-up schedule).  
Biopsies will be performed guided by ultrasound and under sterile conditions by the Ultrasound 
Department, Herlev Hospital, if the involved areas are not directly accessible. The procedure will be 
performed in the outpatient clinic and the size will be approximately 5 mm3. 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
42
 
Biopsies will be examined for the concentration of immune cells. Furthermore, TILs will be isolated 
from the lesions and analyzed for clonotype and specificity. 
 
Establishment of autologous short term in vitro cultured tumor cell lines (as in 49, 50, or equivalent 
methods) and lymphocyte cultures (as in 51 or equivalent methods) will be attempted using these 
samples. These cultures will be primarily used to perform correlates of tumor-recognition in vitro 
(as in 51) with immune parameters and clinical outcomes following therapy on an exploratory basis. 
The informed consent sheet will contain information about the possibility to generate cell lines and 
cell cultures, that under pseudonymized or anonymized form can be used for health research 
purposes in multiple countries, according to the Danish National Ethics Committee guidelines. 
 
Specimens for Future Biomedical Research 
Only leftovers from analyses specifically described in the protocol will be transferred to the biobank 
for future biomedical research, as described on page 46 “Research biobank including Future 
Biomedical Research Biobank”. There will be no extra samples to be obtained during this study. 
These specimens may be used to study various causes for how subjects may respond to the 
immunotherapy. These speciemens will be stored to provide a resource for future trials conducted 
by CCIT focused on the study of biomarkers responsible for how immunotherapy works, other 
pathways immunotherapy may interact with, or other aspects of disease. 
 
Additional research analyses 
Isolation of tumor cells 
Tumor cells are isolated from the tumor fragments by the use of enzymatic processing or seeding of 
cells from the tumor fragments and are then frozen for later use in determining T cell anti tumor 
activity. This exploratory analysis will not influence any prior or subsequent surgical decisions or 
medical treatment of the patients enrolled. 
 
Cytokine Release Assay 
TIL cultures is screened for activity against TAA and autologous tumor by determining their 
production of the activating cytokines (INF-γ + TNF-α). The production of the activating cytokines 
is quantified by use of ELISpot technique and intracellular flow cytometric analysis. 
 
Gene-based arrays 
The aim of the planned gene analyses is to learn more about; 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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Authorities chart nr. 2016072152. 
43
1. Differences among patients in expression level of a panel of relevant normal genes in the 
tumor microenvironment which could influence the chance of benefit from treatment 
2. Expression of tumor/patient specific mutated genes which could influence the chance of 
benefit from treatment 
Analysis for identifying specific tumor gene expression signatures47 and mutations in the tumor 
cells, leading to patient-specific neo-antigens derived from these mutations48, will be performed.  
These analyses will contribute to the identification of patients that are most likely to respond to 
treatment as well as contribute to the optimization of T cell therapy based on the selection of neo-
antigen specific T cells. 
Methods 
Tumor tissue gene expression profiles will be analysed on FFPE tumor tissue. Using Illumina 
targeted RNA sequencing applicable to degraded RNA we will retrieve gene expression data on 
approximately 500 cancer/immunity related genes. 
Next Generation Sequencing (NGS) of tumors and normal cells of the individual patient will be 
used to obtain information on tumor-specific mutations. Gene sequencing will be performed on 
tumor cells (tumor gene profile) and leukocytes (normal gene profile). Tumor specific gene 
expression (neo antigens) will be performed by subtracting the two gene profiles from each other. 
Data regarding potential disease causing genes will be generated as a byproduct of this analysis, but 
this data will not be used or explored further upon, since only data regarding tumor specific genes 
will be processed more closely. Therefore, we do not expect to obtain explicit knowledge regarding 
disease causing genes. Furthermore, ‘Targeted sequencing’ on a limitied number of defined genes 
will be performed on the tumor tissue to obtain a ‘immune profile’ to determine which genes- and 
consequently which proteins- are expressed in the tumor tissue. Data will be handled according to 
national laws.  
If by chance these analyses will discover known mutations with potential significant impact on 
patient’s health, the case will be discussed with the Clinical Genetics Department, Rigshospitalet, 
unles the patient has chosen not to be informed as stated in the patient information. The following 
criteria will determine if further actions are indicated. 
  There is a reasonable degree of possibility that a genetic disposition is present, 
 there is solid documentation of a link between the genetic disposition and the development 
of disease, 
 the tests used to determine the genetic disposition are well established, 
 the disease in question can be prevented or treated, and 


 
 
 
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 the link between the genetic disposition and the development of disease has considerable 
importance for the patient. 
If indicated, the patient will be contacted and asked for permission to referral to such Department 
for additional information and testing. 
In case that a patient dies/is dead, or do not want information regarding significant health issues, a 
medical assessment, using the 5 above mentioned criteria (p. 43), will determine whether relatives 
to the patient is to be informed, in accordance with Danish law (sundhedslovens § 43, stk. 2, nr.2.). 
 
Statistics 
 
The study is non-blinded and non-comparative. Descriptive statistics will be used to estimate the 
immunological- and clinical response rate. Descriptive statistics will also be used to sum up the 
duration of response and patient characteristics. The study is designed as a pilot study and the 
primary aim is to determine safety and toxicity to the treatment. A required sample size that allows 
determination of primary- as well as secondary- and tertiary end points can therefore not formally 
be calculated. A phase II study is planned if the pilot study does not give rise to SUSARs. 
 
Data registration and -analysis 
The patients are given a patient number at inclusion in the study to secure patient anonymity. 
Clinical personnel and selected persons in the laboratory will have access to patient information to 
secure proper treatment. 
The principal investigator has access to patient charts to obtain information regarding the cancer 
disease to be able to compare this information with the project specific analysis performed on 
cancer tissue and blood tests.  
 
All relevant data is registered in the eCRF (electronic Case Report Form) developed in cooperation 
with the clinical research unit, KFE. The principal investigator has the responsibility of 
manufacturing the eCRF and subsequent recording of data when the investigational treatment is 
finished and eCRFs are reported to sponsor. Sponsor and principal investigator are responsible for 
data analysis on all included patients. Patient data and eCRF will be stored for 5 years in accordance 
with current guidelines for storage of personal information. Drafting of a final report will be 
conducted in collaboration between the members of the study group. 
 
Analyses will include: 
 Toxicity (CTC registration) 
 Immunological response  
 Clinical effect parameters 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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45
Personal data and remaining tests will be coded at the end of the study. All patients receiving T cell 
therapy will be included in the statistical analyses. Patients excluded for one of the following 
reasons will not be included in the statistical analyses: 
 Not enough tissue to produce tumor TIL 
 Unable to produce TILs in the laboratory  
 Withdrawal of consent 
 Started other treatment 
 
End of study report 
Sponsor will inform the Danish Health and Medicines Authority and Research Ethics Committee 
within 90 days of study completion. The definition of study completion is 6 months after the last 
patients’ treatment or after exclusion due to progression. In addition, patients will be followed for 
PFS and OS for up to 5 years. If the study is prematurely terminated, the Danish Health and 
Medicines Authority will be informed of the reason(s) for the termination. Sponsor will submit a 
final study report to the Danish Health and Medicines Authority and the Research Ethics Committee 
with the study results including publications based on the study within a year of study completion. 
 
Amendments 
An application to the Danish Health and Medicines Authority and the Research Ethics Committee 
will be made if substantial changes to the protocol are to be made. These can be implemented when 
approved. Changes to the protocol are considered substantial in accordance with ‘Vejledning om 
anmeldelse, indberetningspligt m.v. (sundhedsvidenskabelige forskningsprojekter)’, paragraph 6.0. 
on www.dnvk.dk and the schedule ’Skema om ændringer (ammendmendts) til kliniske forsøg’ on 
sundhedsstyrelsen.dk.  
 
Ethical aspects 
Recruitment of study patients and informed consent 
Eligible patients with advanced renal cell carcinoma will be referred from the Oncological 
Department at Herlev Hospital or other Oncological centers in Denmark treating patients with these 
cancers. Information about the study will be given at scientific meetings for physicians at the 
relevant departments. 
Referral of patients is to be made to the uro-gynecological (UG team) visitation office, Department 
of Oncology, Herlev Hospital. 
Contact to eligible patients will be done in accordance with the Danish Health Act, § 46, paragraph 
3. 
 
All patients will be informed about the study according to appendix 1. 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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46
Insurance 
Patients’ participation in the study will be covered by “Patienterstatningen”. 
 
Ethical aspects 
Despite advances, especially with biological targeted treatments, there is no recommended adjuvant 
treatment for RCC at the moment, and up to half of the operated patients will develop metastasic 
disease at some point. Only a few patients with metastatic disease can be treated with a curative 
intent. The remaining patients will be treated in a palliative setting. Furthermore, metastatic RCC is 
resistant to chemotherapy5..Based on the current knowledge and the lack of treatment options, the 
risks and downsides associated with this study are assessed to be acceptable.  
Participation is voluntary and is preceded by oral and written information and the treatment will be 
stopped in case of unacceptable adverse reactions or if the patient wishes so at any time. 
The patient will receive treatment after the current guidelines at the department if she does not wish 
treatment according to the protocol. The study is therefore assessed as ethical proper.  
 
The study follows the Helsinki agreement and the principal investigator is to obtain permission 
from the Danish Health and Medicines Authority and the Research Ethics Committee. 
 
For future biomedical research, risks to the subject have been minimized. Risks include those 
associated with venipuncture to obtain the whole blood specimen. This specimen will be obtained at 
the time of routine blood specimens drawn in the main trial. 
 
Research biobank, including Future Biomedical Research Biobank 
In connection with the current study, blood samples (110 ml/blood sample) and tumor biopsies will 
be stored in coded form at -150 °C in a research biobank at the CCIT in room PA102 until all 
analysis concerning the study is performed or for a maximum of 15 years, after which the remaining 
material will be destroyed.  
 
Analyses will be primarily performed at CCIT. However, some special analyses on tumor tissue or 
blood test samples may be performed at a partner institution after establishing a specific written 
agreement. All patient relevant information will be sent in an anonymous way. In case the patient’s 
cells will be sent to partner institutions located abroad, these will be handled according to national 
laws and regulations of the specific nation where these have been sent. In such a case, all patient 
information will be communicated in coded form. A written data processing agreement will be 
signed between the data controllers and the data processors abroad. If any gene analysis are to be 
performed abroad, the data processing agreement will include the 5 criteria (p. 42-43) regarding the 
discovery of known mutations with potential significant impact on patient’s health, as well as the 
requirement, that the partner abroad reports back to the primary project managers in Denmark so 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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Authorities chart nr. 2016072152. 
47
that relevant actions can be taken as described on p. 43. If data processing is to be performed in a 
third-country, permission wil be applied for at the Danish Data Protection Agency, or one of the 
agencies standard contracts will be used. 
 
Samples that are not used in the study will be transferred to a biobank at CCIT for future biomedical 
research for up to 15 years and if accepted by the Danish Data Protection Agency. If additional 
studies in other research areas are to be performed on any samples obtained during the conduct of 
this study/samples are transferred to a new biobank, a request to do so will be submitted to the 
Scientific Ethics Committee, Capital Region of Denmark, as per the ‘Act of Processing of Personal 
Data’ §§ 5 and § 10, paragraph 2 and 3. After 15 years, any remaining tissue samples will be 
disposed of according to the local guidelines for destruction of biohazardous waste. 
If a patient withdraws his/her informed consent, all biological material is to be destroyed if the 
patient wishes so.  
 
Reporting to the Research Ethics Committee 
The study is reported to the Research Ethics Committee. The law dealing with personal data will be 
respected. Information concerning study patients is protected according to the law concerning 
personal data and the Act on Research Ethics Review of Health Research Projects.  
Administrative aspects and publication 
Patient identification 
Patients will be given a number after enrollment in the study. This number will be used to identify 
the patient and will be used in the Case Report Forms (eCRFs). Data and patient materials will be 
treated in code and confidentially. The number is given sequentially after enrollment in the study 
and is not based on the patients’ initials or birthday.   
 
Publications 
The primary project managers are Inge Marie Svane and Magnus Pedersen. The members of the 
project group have joint copyright of the obtained results, given that the Vancouver rules are met. 
Positive as well as negative results will be published in international journals. Manuscripts will be 
produced in cooperation with the project managers and other members of the study group, with the 
project managers as primarily responsible for the preparation. The project managers are co-authors 
on publications made on the basis of this study. Author succession will be determined based on the 
individual contributions. Use of study data, oral as well as written, at congresses, teaching or the 
likes, is only to take place if accepted by the project managers. The project managers are obliged to 
publish results from the study and are naturally interested in the propagation and implementation of 
the results in clinic. Publications are expected to be completed in 2018. 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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Economy 
The study is initiated by Center for Cancer Immune Therapy in cooperation with the Department of 
Oncology, Herlev Hospital, and is partially financed by these two departments. In addition, 
operational- and salary funding is applied for ongoing. At the current stage, research grants have 
been obtained from ’knæk cancer’ and ‘Danielsens fond’.  
 
The Research Ethics Committees will be informed if/when new funds support is obtained. None of 
the physicians involved in the study have any economic interests in the study and there is no 
potential economic gain for the departments or of personnel in connection with the study. There are 
no economic attachments between the financial supporters and the project managers. 
The study is part of the principal investigator Magnus Pedersen’s PhD project. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Appendix 1 
 
Guidelines for verbal information regarding participation in a clinical trial 
The verbal information regarding the clinical trial “T-cell therapy for patients with advanced renal 
cell carcinoma” will be provided at Department of Oncology, Herlev Hospital. The information will 
be given by a medical doctor involved in the clinical trial. The verbal information will be 
accompanied by written participant information leaflet. The consultation will be conducted 
according to the guidelines from the ethical committee: 
 
Before the consultation 
 A time and place for the consultation are agreed upon. 
 Beforehand, the participant is informed that the consultation will be about participation in a 
clinical trial. 
 The participant is informed of his/her right to have time to consider the participation in the 
clinical trial and the option to bring an assessor to the consultation.   
 
Consultation regarding participation in the clinical trial 
 Must be scheduled. 
 Must take place in a place with no interruptions. 
 The participant must be given adequate time to read the written information, listen to the 
verbal information and ask questions. 
 Must contain an understandable presentation of the clinical trial without use of technical or 
value-laden terms, and must be given in consideration of the participant’s individual 
prerequisites in terms of age, maturity, experience etc. 
 Must contain information about any foreseeable risks, side effects, complications and 
disadvantages, as well as that there may be unforeseeable risks and burdens linked to 
participation in a clinical trial. 
 Must contain information on alternative treatment options. 
 Must contain information that information about health conditions, purely private conditions 
and other confidential information can be passed on to and processed by persons who must 
carry out a statutory quality control of the trial. 
 Must contain information that the participants have the right to renounce knowledge of their 
health conditions. 
 The information is provided by the medical doctor responsible for the project or by an 
authorized person involved in the trial. 
 
Consideration period and obtaining consent 
 The consideration period depends on the nature of the clinical trial. As a rule of thumb, the 
consideration periode should be at least one day. 


 
 
 
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 There must be a clear connection between information and consent. This implies that 
consent to trial participation is generally given as soon as possible after providing 
information, however taking into account the necessary consideration period. 
 
After the information interview, the subject will be informed, 
 If, during the implementation of the trial, new information about effect, risks, side effects, 
complications or disadvantages emerges. 
 If the experimental design of the research project is changed significantly in relation to the 
subject’s safety (applies to subjects who actively participate in the experiment). 
 If, during the implementation of the trial, significant information about the subject’s state of 
health emerges, unless he subject has unequivocally expressed that the subject does not want 
this. 
 About the results that have been achieved, as well as about any consequences for the 
individual. This assumes that it is practically possible and the subject wants this. 
 If the trial is interrupted, the subject must be informed of the reason for this. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Appendix 2 
ECOG-funktionsstatus/Performance status 
 
ECOG-FUNKTIONSSTATUS* 
Niveau 
ECOG 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physical strenous activity, but ambulatory and able to carry out 
work of a light and sedentary nature (e.g. light house work, office work) 
2 
Ambulatory and capable of self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead 
* Udgivet af Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Appendix 3 
International mRCC Database Consortium (IMDC) prognostic model 
IMDC prognostic model* 
Prognostic factor 
Observation 
Score 
Karnofsky performance score 
80 to 100 % 
70% or lower 
0 
1 
Interval from diagnosis to treatment 
≥ 1 year 
≤ 1 year 
0 
1 
Hemoglobin 
≥ LLN 
< 1 LLN 
0 
1 
Ionized calcium 
≥ ULN 
< ULN 
0 
1 
Neutrophil count 
≥ ULN 
≤ ULN 
0 
1 
Platelet count 
≥ ULN 
≤ ULN 
0 
1 
LLN: lower limit of normal, ULN: upper limit of normal. 
Prognostic group: 
- 
Favorable prognostic group: 0 risk factors 
- 
Intermediary prognostic group: 1-2 risk factors 
- 
Bad prognostic group: ≥ 3 risk factors 
* Heng D et al: Prognostic Factors for Overall Survival in Patients With Metastatic Renal Cell 
Carcinoma Treated With Vascular Endothelial Growth Factor–Targeted Agents: Results From a 
Large, Multicenter Study. J Clin Oncol 2009 Dec 1;27(34):5793-9. 
 
 
 


 
 
 
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Appendix 4 
New York Heart Association (NYHA) classification of heart failure 
 
 Class I: No symptoms with normal physical activity. Normal functional status. 
 
 Class II: Mild symptoms with normal physical activity. Comfortable at rest. Slight limitation 
of physical status. 
 
 Class III: Moderate symptoms with less than normal physical activity. Comfortable only at 
rest. Marked limitation of physical status. 
 
 Class IV: Severe symptoms with features of heart failure with minimal physical activity 
even at rest. Severe limitation of functional status.  
 
* Symptoms – Fatique, palpitations, chest pain, dyspnea, syncope 
 
(The Criteria Committee of the New York Heart Association: Diseases of the Heart and Blood 
Vessels; Nomenclature and Criteria for Diagnosis, 6th ed Boston, Little, Brown 1964) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Appendix 5 
Common Terminology Criteria for Adverse Events (CTCAE) version 4 
 
CTCAE45 is a descriptive terminology used for reporting of adverse events. Adverse events (AE) 
are graded as follows: 
 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe or medcially significant AE 
 Grade 4: Lifethreatening AE  
 Grade 5: Death 
 
 


 
 
 
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Appendix 6 
Treatment guideline for high dose interleukin-2 during T-cell therapy 
 
Introduction 
 
High dose interleukin 2 (HD IL-2, 600,000 to 720,000 IU/kg)(HD IL-2) is registered in the USA as 
treatment for advanced melanoma and clear cell renal cell carcinoma patients, resulting in 15% 
objective response rate, of which about half the patients experience a durable complete remission. 
This treatment was however, never registered in Europe because of lack of randomized controlled 
studies (showing improvement in overall survival for HD IL-2) and the severity of adverse events 
accompanying this treatment.  
Here, HD IL- 2 is used as a concomitant treatment with the TIL (tumor infiltrating lymphocytes) 
treatment.  
IL-2 has been discovered as a T cell growth factor. In vivo IL-2 leads to lymphocytosis, and when 
given as high dose intravenously IL-2 causes severe capillary leak syndrome, high fever, rigors, 
nausea, diarrhea, hypotension, renal insufficiency, dyspnea, severe fluid retention and weight gain, 
erythrodermia and sometimes mental disturbances. In addition, IL-2 stimulates other blood cells of 
the native immune system, such as natural killer cells. 
 
Treatment schedule 
 
HD IL-2 is given as 15 min bolus infusions of 720,000 IU/kg in 50 mL saline, every 8 hours for a 
maximum of 15 doses. Basic intake should be minimal (i.v. 50 ml saline per hour plus oral intake). 
The first HD IL-2 dose is infused as early as 4 hours after the TIL infusion, depending on whether 
the patient has recovered from the TIL infusion. HD IL-2 should be started within 24 hours after 
TIL administration.  
Before initiation of HD IL-2 patients anti-hypertensive drugs will be discontinued. Patients will 
start paracetamol 6 times daily, and ranitidine 150 mg twice daily (orally). One hour before infusion 
granisetron 1 mg is administered to prevent nausea. HD IL-2 is given via a CVC. 
Prior to and following every infusion of HD IL-2, the blood pressure, pulse, temperature and O2-
saturation needs to be measured (during the first 4 hours every 60 min, thereafter before 
administration of the following dose. , Urine production and total intake every 8 hours. The patients 
should be weighed every 8 hours. Every 8 hours a physician needs to check the patient’s condition 
(vital signs, heart, lungs, stomach, skin and extremities) and mental condition. During 
hospitalization a dedicated nurse (practitioner) is the first person of contact. He or she will inform 
the treating physician every 8 hours or sooner in case of changes in the patient’s condition.  
Toxicity can rapidly start within hours after the infusion, especially rigors and fever. In order to 
prevent rigors, patients may require indomethacin and/or pethidin (25-50 mg) prior to every 
infusion.  Capillary leak syndrome, resulting in edema, weight gain and progressive dyspnea will 


 
 
 
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increase gradually during treatment. Hypotension and oliguria may start about 24 hours after 
initiation of IL-2. Nausea, anorexia and vomiting may occur later during the treatment. As soon as 
patients clearly experience insufficiency in fluid intake, the basic [basis] infusion will be adjusted to 
maximal 100 mL/hr. 
The most significant blood abnormalities are an increase in creatinin and thrombocytopenia. Most 
adverse events will disappear soon after the last dose of IL-2.  
When within 8 hours after infusion the patient has not recovered from toxicity despite the 
measurements taken, the next dose IL-2 will be skipped. When the patient does not recover 
within 24 hours, IL-2 dosing will be discontinued. Importantly, there is no correlation 
between the number of IL-2 infusions and response to treatment! 
 
Table 1 - Schedule for monitoring 
 
  
No vasopressors needed 
ICU admission 
Vital signs 
Every hour during first 4 hours, then 
every 4 hours
Every hour 
Intake and output 
Every 8 hours 
Every hour 
Weight 
Every 8 hours  
Daily 
Mental status 
Every 8 hours 
Every 8 hours 
Infusion site 
CVC: every 8 hours 
Every 8 hours 
Laboratory tests 
  
  
Hb, Ht, L, diff, Thr
Daily 
Daily 
Na, K, Creat, Ur, Glu
Daily 
Daily 
ASAT, ALAT, tot bili
Daily 
Daily 
Ca++ Mg++ fosfate
Daily 
Daily 
INR, APTT
Daily from day 2 
Daily 
CK, bicarbonate
Daily 
Daily 
TSH, FT4
Once during HD IL-2 period 
 
Urine analyses 
Once during HD IL-2 period or if 
indicated
if indicated 
ECG 
Once duirng HD IL-2 period or if 
indicated
if indicated 
X-thorax 
Once during HD IL-2 period or if 
indicated 
if indicated 
 
 
 


 
 
 
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Toxicity 
 
Blood pressure  
Systolic blood pressure of the patient prior to start of IL-2 is: 
< 100 mmHg: 
 
target BP during IL-2: > 80 mmHg systolic 
100-120 mmHg: 
 
target BP during IL-2: > 85 mmHg systolic 
> 120 mmHg: 
 
target BP during IL-2: > 90 mmHg systolic 
 
If the blood pressure drops below these target values, the first action to take is fluid challenge. 
Hypotension should in this case (the HD IL-2 treatment) be treated with Ringer’s lactate solution. 
(RCT have shown that colloidal fluid resuscitation is not superior over crystalline fluid 
resuscitation). Do not give more than 1-1,5 L per 24 hours, which means two to three 500 mL of 
Ringer’s solution in 30 minutes on top of the basic intake (50 mL/hr + oral intake, or 100 mL/hr 
without oral intake), because of capillary leak syndrome. When the patient stays hypotensive in 
spite of the fluid challenges, vasopressors are the next treatment to use (in ICU setting). This should 
be prevented as much as possible.  
NB. Hypotension after IL-2 administration is cyclic and surges 4-6 hours after IL-2 administration. 
This should be taken into consideration in the calculation of the vasopressors.  
 
Urine production  
Oliguria (urine production below 10-20 ml/hour) will occur due to decreased intravascular volume 
and hypotension. Renal insufficiency with IL-2 is prerenal, transient and reversible. Primarily 
oliguria is treated with fluid challenge. When 1-1,5 L Ringer’s solution does not improve diuresis, 
the patient should get a urine catheter with urimeter to follow urine production closely and the 
patient should be transferred to ICU for vasopressors (preferably low dose dopamine). The urine 
production should be >10-20 mL/hr before the next bolus of IL-2 can be given. Do not treat with 
diuretics!  
Diuretics (furosemide) can be used after treatment with IL-2 has been discontinued completely and 
blood pressure is back to normal, to remove the sometimes severe peripheral edema (at least 1x 
daily 40 mg furosemide). 
 
Dyspnea  
Pulmonary edema can occur due to capillary leak syndrome, and by too much fluid administration. 
Measuring transcutaneous O2 saturation is useful during treatment with IL-2 (should be performed 
with determining other vital signs (blood pressure, pulse and temperature). O2 saturation should be 
kept at >95% during treatment, primarily through a nasal oxygen tube with a maximum of 4 
L/O2/min or with a oxygen mask with 40% O2. When O2 saturation cannot be kept at 95% or 
higher, the next bolus IL-2 can not be administered.  
Pulmonary edema usually leads to changes in pulmonary sounds, especially crackles. When 
crackles occurs over the upper lung areas in a patient with an O2 saturation of <95% (despite 
treatment), IL-2 should be discontinued and, depending on the blood pressure, furosemide should be 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
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administered for maximal fluid excretion. Artificial breathing is seldomly required, but should not 
be denied when needed. 
See table 2 and 3 for other toxicities and the actions to be taken. 
 
Infections 
During treatment with HD IL-2 it can be difficult to recognize an infection. TIL patients are during 
HD IL-2 infusion still neutropenic, have a central venous catheter (CVC) and often also diarrhea, 
which results in a high risk of infection. When a patient gets a high fever despite of prophylaxis 
with paracetamol or indometacin, or when a patient becomes hypotensive and does not respond to 
fluid challenges, an infection should certainly be considered. Broad spectrum antibiotics (according 
local guidelines for instances vancomycin/ceftazidim) should be started immediately after blood 
(from both CVC lines and peripherally) and other cultures have been taken. Check the renal 
function before defining the dose. 
 
After discontinuation of IL-2 treatment 
The patient should be closely observed until all vital signs have been stabilized. Intake/output and 
weight should be measured until release from the hospital. Lab values should also stabilized or 
improve. 
Halt the basic infusion within 8 hours after the last administration of IL-2, even when the patient 
still has an inadequate oral intake. Only in case of very severe gastro intestinal events (severe 
vomiting or diarrhea) or severe weight loss until below baseline weight it may be necessary to 
hydrate the patient i.v. 
Proceed with paracetamol or indometacin and ranitidine until at least 16-24 hours after 
discontinuing treatment with IL-2, because the patient can still get feverish. Make sure diuresis is 
adequate (> 20 ml/hr) after the blood pressure has stabilized (without treatment). Monitor the 
reaction to furosemide and repeat dose until the diuresis is high (200 mL/hour). 
 
 


 
 
 
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Table 2 – expected toxicity 
 
Expected toxicity 
Grade 
Supportive measures 
Discontinue 
IL-2 
Cold chills 
3 
Pethidin 25-50 mg IV, q 1 hr, as needed 
no 
Fever 
3 
Paracetamol 500 mg po, q 4 hr or  
indometacin 50-75 mg, po, q 8 hr 
no 
Pruritus 
3 
Hydroxyzine HCL (Atarax) 10-20 mg po, q 
6 hr, as needed
no 
Skin 
3 
Carbomer hydrogel with 1% menthol 
no 
Nausea/vomiting/ 
anorexia 
3 
Granisetron 1 mg IV/day, as needed or 
Ondansetron 8 mg IV, q 8 hr, as needed 
no 
Diarrhea 
3 
Loperamide 2 mg po, q 3 hr, as needed or  
codeine 20 mg po, q 6 hr, as needed 
no 
Malaise 
3 or 4 
Bed rest or minimal activity 
no 
Blood bilirubin 
increased
3 or 4 
Observation 
no 
Anemia 
3 or 4 
Blood transfusion 
no 
Platelet count  
decreased 
3 or 4 
Thrombocyte transfusion 
When grade 4 
despite of 
transfusion 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
60
Table 3 - Criteria for delaying or stopping IL-2 dosage 
 
For each relative criterium: 
Take action and possibly delay dose (depending on recovery) 
More than 3 relative criteria: Take action and always delay dose. Stop treatment if patient 
recovers too slowly 
Each absolute criterium: 
Take action and always delay dose. Stop treatment if patient 
recovers too slowly 
Organ 
Relative criteria 
Absolute criteria 
Heart 
Sinus tachycardia (120-130/min)
No recovery of sinus tachycardia 
(>130/min)
Atrial fibrillation
Supraventricular tachycardia
Ventricular arrhythmia (frequent PVC)
Elevated cardiac enzymes (troponin, CK)
Ischemia on ECG
Skin 
Moist desquamation
Gastro-
intestinal 
Diarrhea, 1 L/8hr
Diarrhea 2 L/8hr
Ileus/increased abdominal girth
Vomiting not responding to anti-emetics
Bilirubin > 125 mmol/L
Severe abdominal bloating
Severe stomach ache
Coagulation 
Slight hemoptysis, hematemesis, 
blood in stools
Severe hemoptysis, hematemesis, rectal loss 
of blood or melaena
Thrombocytes: 30-50 x 10^9/L
Thrombocytes: <30 x 10^9/L
Infection 
Strong clinical suspicion or proven
Musculoskeletal
Weight gain > 15%
Tightness extremities (edema)
Sensory disturbance in extremities
Neurological 
Vivid dreams
Hallucinations
Emotionally labile 
Persistent crying
Changes in mental status that do not recover 
within 2 hours
Cannot apply 'serial sevens' (100-7 etc)
Disoriented
Lungs 
Dyspnea at rest
4 L O2/min or O2 40% cap to keep O2 
saturation >95%
3-4 L O2/min to keep O2 
saturation >95%
Need for intubation
Crackles over 1/3 of the lung
Crackles over 1/2 of the lung
Pleural fluid for which drainage is needed
Kidneys 
Urine production 80-160 ml/8 hr
Urine production < 80 ml/8hr
Urine production 10-20 ml/hr
Urine production < 10 ml/hr
Creatinin 200-250 umol/L
Creatinin > 250 umol/L
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
61
Table 4 – Grading symptoms according to CTCAE v. 4.0 
 
Symptom 
Grade 1 
2 
3 
4 
Cold 
chills 
Mild sensation of 
cold; shivering; 
chattering of teeth
Moderate tremor of the 
entire body; narcotics 
indicated
Severe or prolonged, 
not responsive to 
narcotics
- 
Fever 
38.0-39.0ºC 
>39.0-40.0ºC 
>40.0ºC for ≤24 
hours
>40.0ºC for 
>24 hours
Pruritus 
Mild or localized; 
topical intervention 
indicated 
Intense or widespread; 
intermittent; skin 
changes from 
scratching (e.g. edema, 
papulation, 
excoriations, 
lichenification, 
oozing/crusts); oral 
intervention indicated; 
limiting instrumental 
ADL
Intense or 
widespread; constant; 
limiting self care 
ADL or sleep; oral 
corticosteroid or 
immunosuppressive 
therapy indicated 
- 
Nausea/ 
vomiting/ 
anorexia 
Loss of appetite 
without alteration 
in eating habits 
Oral intake altered 
without significant 
weight loss or 
malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight 
loss or malnutrition 
(e.g., inadequate oral 
caloric and/or fluid 
intake); tube feeding 
or TPN indicated
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Diarrhea 
Increase of <4 
stools per day over 
baseline; mild 
increase in ostomy 
output compared to 
baseline 
Increase of 4 - 6 stools 
per day over baseline; 
moderate increase in 
ostomy output 
compared to baseline 
Increase of >=7 stools 
per day over baseline; 
incontinence; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self 
care ADL
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Malaise 
Uneasiness or lack 
of well being 
Uneasiness or lack of 
well being; limiting 
instrumental ADL
 
 
Blood 
bilirubin 
increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Anemia 
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 
mmol/L; <LLN - 
100 g/L 
Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L; 
<100 - 80g/L 
Hgb <8.0 - 6.5 g/dL; 
<4.9 - 4.0 mmol/L; 
<80 - 65 g/L; 
transfusion indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
62
Platelet 
count  
decreased 
<LLN - 
75,000/mm3; 
<LLN - 75.0 x 
10e9 /L
<75,000 - 50,000/mm3; 
<75.0 - 50.0 x 10e9 /L 
<50,000 - 
25,000/mm3; <50.0 - 
25.0 x 10e9 /L 
<25,000/mm3; 
<25.0 x 10e9 
/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
63
Appendix 7 
Febrile neutropenia during T-cell therapy 
Neutrophils < 0,5 mia./l 
Fever = temperature > 38º C (rectal measurement > 38,5º C) 
Note: Clinical suspicion of or confirmed infection in a neutropenic and febrile patient should be 
treated as sepsis. 
Patients receiving T-cell therapy expectedly develops neutropenia from approximately day 0 lasting 
7 days with considerable individual variation. Either from infusion of T-cells or interleukin-2, the 
patient develops fever lasting until about 24 hours after stopping IL-2. 
Adverse events related to IL-2 are clinically hard to distinguish from sepsis, thus, patients should be 
treated as per local guidelines for febrile neutropenia with empiric antibiotics, thorough 
microbiological testing and radiological examinations as needed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
64
Appendix 8 
 
Summary of product characteristics for cyclophosphamide 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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)*+,	
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!&
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 1
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)*+,	
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	
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BCDEFGHFIGHJKLMNOPDFQRJLQLQSODCDEFGHFIGHJKLMNTOUNDFQIRLRVRNMOLQOWJRNUOLIOHCGFRFQLDOJQMOIHFVEMOQFROXNOLQYNDRNM
MLUNDRECZ
/ #  # # !1.# #
 !&@!A! [\]\\*[	^,\*_ &/
 #!.  1! 8 1`[	a,&   !#
.. & !2.3"&#&# $ 
! A#! A!!!  !! !&-  #!
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Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
85
Appendix 9 
 
Summary of product characteristics for fludarabinephosphat 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


	

 !"#$!"%&'"&!'() "% *+,-,./*0123456
789	:	
5; </=)> %';"&?&?@%!"&?&?'&?A
B8CDED	
F!$G&;!?"&?'</=; H&?%)$')$"%A
4?%;%!?'"&""% ';"&?!?"&?'.<=; H&?%)$')$"%A
5"$%;;;&'"%I!&)&%?"'J'%%'%!"&?KA*A
L8M:		
> %';"&?&?@%!"&?&?'&?A
N$&"%;)$&;&'"%%!?'"&""&?A
O8P
O87Q:
R%"%?"S,!%;;!$?&!;)$!"&!;%T%&U#VVW&? ;")"&%?"'>&"$'&!&%?"H?%>%'%G%'A
5&'";&?%"%"%?">&"$5; '$; ?;H%&?&"&"% &? ;")"&%?"'>&"$ G?!%  &'%'%JX&'"=%'666Y6ZUS&?%"
'"=%#WJX&'"=%'6Y66US&?%"'"=%2YSW>$%%"$%)"&%?"$' &'%'%%;"% ')"'%G& %?!%)=%''&G%
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';=
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R$%%]&%  '%U!;!;"% ?"$%H'&'"$%)"&%?"^
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&?'&?J"$%%]&%  '% >?)&?'&?=%H% &;"% &?*//;' &!$;& %0=Y;U/A0_W? &?'% G%
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R$% "&?"%"%?" %)%? '?"$%"%"%?"'!!%''? "$%";%H&;&""$% =A
6?#VV)"&%?"'J5; '$; H% &?&'"%% )""$%!$&%G%%?"H%'"%')?'%U!);%"%)"&;%&''&?J
';;K!!;%'W? "$%?"$% ='$; H% &'!?"&?% A
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o'%''$; H% @'"% )"&%?"'>&"$% !% T& ?%?!"&?A6!%"&?&?%!;%?!%&'H%">%%?`/? p/;Y&?J"$%
 '%'$; H%% !% H)"</_? !;'%$%";=&!;?&"&?='$; H%'% "''%''"I&!&"U'%%'%!"&?
qAqWA
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abcdefcghidcjhjenbcdshdmnbdkmefc
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'$; H%'% >&"$!"&?A
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%!%? % '%&?!$&; %?A
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Protocol UG1617: T-cell therapy for patients with renal cell carcinoma. Version 6. Date: 23-12-2020. 
EudraCT nr.2016-001454-18. Research Ethics Committee file nr. 1607343. Danish Health and Medicines 
Authorities chart nr. 2016072152. 
102
Appendix 10 
Summary of product characteristics for proleukin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROLEUKIN® (aldesleukin) 
for injection, for intravenous infusion 
Rx Only 
WARNINGS 
Therapy with Proleukin® (aldesleukin) should be restricted to patients with 
normal cardiac and pulmonary functions as defined by thallium stress testing 
and formal pulmonary function testing. Extreme caution should be used in 
patients with a normal thallium stress test and a normal pulmonary function test 
who have a history of cardiac or pulmonary disease. 
Proleukin should be administered in a hospital setting under the supervision of 
a qualified physician experienced in the use of anticancer agents. An intensive 
care facility and specialists skilled in cardiopulmonary or intensive care 
medicine must be available. 
Proleukin administration has been associated with capillary leak syndrome 
(CLS) which is characterized by a loss of vascular tone and extravasation of 
plasma proteins and fluid into the extravascular space. CLS results in 
hypotension and reduced organ perfusion which may be severe and can result 
in death. CLS may be associated with cardiac arrhythmias (supraventricular and 
ventricular), angina, myocardial infarction, respiratory insufficiency requiring 
intubation, gastrointestinal bleeding or infarction, renal insufficiency, edema, 
and mental status changes. 
Proleukin treatment is associated with impaired neutrophil function (reduced 
chemotaxis) and with an increased risk of disseminated infection, including 
sepsis and bacterial endocarditis. Consequently, preexisting bacterial 
infections should be adequately treated prior to initiation of Proleukin therapy. 
Patients with indwelling central lines are particularly at risk for infection with 
gram positive microorganisms. Antibiotic prophylaxis with oxacillin, nafcillin, 
ciprofloxacin, or vancomycin has been associated with a reduced incidence of 
staphylococcal infections. 
Proleukin administration should be withheld in patients developing moderate to 
severe lethargy or somnolence; continued administration may result in coma. 
Reference ID: 3165255 


 
 
 
 
DESCRIPTION 
Proleukin® (aldesleukin), a human recombinant interleukin-2 product, is a highly purified 
protein with a molecular weight of approximately 15,300 daltons. The chemical name is des­
alanyl-1, serine-125 human interleukin-2. Proleukin, a lymphokine, is produced by 
recombinant DNA technology using a genetically engineered E. coli strain containing an 
analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify 
the human IL-2 gene, and the resulting expression clone encodes a modified human 
interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) 
Proleukin is not glycosylated because it is derived from E. coli ; b) the molecule has no N-
terminal alanine; the codon for this amino acid was deleted during the genetic engineering 
procedure; c) the molecule has serine substituted for cysteine at amino acid position 125; this 
was accomplished by site specific manipulation during the genetic engineering procedure; 
and d) the aggregation state of Proleukin is likely to be different from that of native 
interleukin-2. 
The in vitro biological activities of the native nonrecombinant molecule have been reproduced 
with Proleukin.1,2 
Proleukin is supplied as a sterile, white to off-white, lyophilized cake in single-use vials 
intended for intravenous administration. When reconstituted with 1.2 mL Sterile Water for 
Injection, USP, each mL contains 18 million International Units (1.1 mg) Proleukin, 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 
manufacturing process for Proleukin involves fermentation in a defined medium containing 
tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. 
Proleukin contains no preservatives in the final product. 
Proleukin biological potency is determined by a lymphocyte proliferation bioassay and is 
expressed in International Units as established by the World Health Organization 1st 
International Standard for Interleukin-2 (human). The relationship between potency and 
protein mass is as follows: 
18 million International Units Proleukin = 1.1 mg protein 
CLINICAL PHARMACOLOGY 
Proleukin® (aldesleukin) has been shown to possess the biological activities of human native 
interleukin-2.1,2 In vitro studies performed on human cell lines demonstrate the 
immunoregulatory properties of Proleukin, including: a) enhancement of lymphocyte 
mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; 
b) enhancement of lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated 
(LAK) and natural (NK)) activity; and d) induction of interferon-gamma production. 
The in vivo administration of Proleukin in animals and humans produces multiple 
immunological effects in a dose dependent manner. These effects include activation of 
cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the 
production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. 3 In vivo 
experiments in murine tumor models have shown inhibition of tumor growth.4 The exact 
mechanism by which Proleukin mediates its antitumor activity in animals and humans is 
unknown. 
Reference ID: 3165255 


 
 
 
 
 
Pharmacokinetics 
Proleukin exists as biologically active, non-covalently bound microaggregates with an 
average size of 27 recombinant interleukin-2 molecules. The solubilizing agent, sodium 
dodecyl sulfate, may have an effect on the kinetic properties of this product. 
The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations 
following a short intravenous infusion, rapid distribution into the extravascular space and 
elimination from the body by metabolism in the kidneys with little or no bioactive protein 
excreted in the urine. Studies of intravenous Proleukin in sheep and humans indicate that 
upon completion of infusion, approximately 30% of the administered dose is detectable in 
plasma. This finding is consistent with studies in rats using radiolabeled Proleukin, which 
demonstrate a rapid (<1 min) uptake of the majority of the label into the lungs, liver, kidney, 
and spleen. 
The serum half-life (T 1/2) curves of Proleukin remaining in the plasma are derived from 
studies done in 52 cancer patients following a 5-minute intravenous infusion. These patients 
were shown to have a distribution and elimination T 1/2 of 13 and 85 minutes, respectively. 
Following the initial rapid organ distribution, the primary route of clearance of circulating 
Proleukin is the kidney. In humans and animals, Proleukin is cleared from the circulation by 
both glomerular filtration and peritubular extraction in the kidney.5-8 This dual mechanism for 
delivery of Proleukin to the proximal tubule may account for the preservation of clearance in 
patients with rising serum creatinine values. Greater than 80% of the amount of Proleukin 
distributed to plasma, cleared from the circulation and presented to the kidney is metabolized 
to amino acids in the cells lining the proximal convoluted tubules. In humans, the mean 
clearance rate in cancer patients is 268 mL/min. 
The relatively rapid clearance of Proleukin has led to dosage schedules characterized by 
frequent, short infusions. Observed serum levels are proportional to the dose of Proleukin. 
CLINICAL STUDIES 
Safety and efficacy were studied in a series of single and multicenter, historically controlled 
studies enrolling a total of 525 patients with metastatic renal cell carcinoma or melanoma. 
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 or 1 and normal organ function as determined by cardiac stress test, pulmonary 
function tests, and creatinine ≤1.5 mg/dL. Studies excluded patients with brain metastases, 
active infections, organ allografts and diseases requiring steroid treatment. 
The same treatment dose and schedule was employed in all studies demonstrating efficacy. 
Proleukin was given by 15 min intravenous infusion every 8 hours for up to 5 days (maximum 
of 14 doses). No treatment was given on days 6 to 14 and then dosing was repeated for up to 
5 days on days 15 to 19 (maximum of 14 doses). These 2 cycles constituted 1 course of 
therapy. Patients could receive a maximum of 28 doses during a course of therapy. In 
practice >90% of patients had doses withheld. Doses were withheld for specific toxicities 
(See “DOSAGE AND ADMINISTRATION” section, “Dose Modifications” subsection and 
“ADVERSE REACTIONS” section). 
Metastatic Renal Cell Cancer 
Two hundred fifty-five patients with metastatic renal cell cancer (metastatic RCC) were 
treated with single agent Proleukin in 7 clinical studies conducted at 21 institutions. 
Metastatic RCC patients received a median of 20 of 28 scheduled doses of Proleukin.  
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In the renal cell cancer studies (n=255), objective response was seen in 37 (15%) patients, 
with 17 (7%) complete and 20 (8%) partial responders (See Table I). The 95% confidence 
interval for objective response was 11% to 20%. Onset of tumor regression was observed as 
early as 4 weeks after completion of the first course of treatment, and in some cases, tumor 
regression continued for up to 12 months after the start of treatment. Responses were 
observed in both lung and non-lung sites (e.g., liver, lymph node, renal bed occurrences, soft 
tissue). Responses were also observed in patients with individual bulky lesions and high 
tumor burden. 
TABLE 1: Proleukin Clinical Response Data 
Number of 
Responding Patients 
(response rate) 
Median Response 
Duration in Months 
(range) 
Metastatic RCC 
CR’s 
17 (7%) 
80+* (7 to 131+) 
PR’s 
20 (8%) 
20 (3 to 126+) 
PR’s + CR’s 
37 (15%) 
54 (3 to 131+) 
(+) sign means ongoing 
* Median duration not yet observed; a conservative value is presented which represents the minimum median 
duration of response. 
Lack of efficacy with low dose Proleukin regimens  
Sixty-five patients with metastatic renal cell cancer were enrolled in a single center, open 
label, non-randomized trial that sequentially evaluated the safety and anti-tumor activity of 
two low dose Proleukin regimens.  The regimens administered 18 million International Units 
Proleukin as a single subcutaneous injection, daily for 5 days during week 1; Proleukin was 
then administered at 9 x106  International Units days 1-2 and 18 x106  International Units days 
3-5, weekly for an additional 3 weeks (n=40) followed by a 2 week rest or 5 weeks (n=25) 
followed by a 3 week rest, for a maximum of 3 or 2 treatment cycles, respectively.    
These low dose regimens yielded substantially lower and less durable responses than those 
observed with the approved regimen. Based on the level of activity, these low dose regimens 
are not effective. 
Metastatic Melanoma 
Two hundred seventy patients with metastatic melanoma were treated with single agent 
Proleukin in 8 clinical studies conducted at 22 institutions. Metastatic melanoma patients 
received a median of 18 of 28 scheduled doses of Proleukin during the first course of 
therapy. In the metastatic melanoma studies (n=270), objective response was seen in 43 
(16%) patients, with 17 (6%) complete and 26 (10%) partial responders (See Table II). The 
95% confidence interval for objective response was 12% to 21%. Responses in metastatic 
melanoma patients were observed in both visceral and non-visceral sites (e.g., lung, liver, 
lymph node, soft tissue, adrenal, subcutaneous). Responses were also observed in patients 
with individual bulky lesions and large cumulative tumor burden. 
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TABLE 2: Proleukin CLINICAL RESPONSE DATA 
Number of 
Responding Patients 
(response rate) 
Median Response 
Duration in Months 
(range) 
Metastatic Melanoma 
CR’s 
17 (6%) 
59+* (3 to 122+) 
PR’s 
26 (10%) 
6 (1 to 111+) 
PR’s + CR’s 
43 (16%) 
9 (1 to 122+) 
(+) sign means ongoing 
* Median duration not yet observed; a conservative value is presented which represents the minimum median 
duration of response. 
INDICATIONS AND USAGE 
Proleukin® (aldesleukin) is indicated for the treatment of adults with metastatic renal cell 
carcinoma (metastatic RCC). 
Proleukin is indicated for the treatment of adults with metastatic melanoma. 
Careful patient selection is mandatory prior to the administration of Proleukin. See 
“CONTRAINDICATIONS”, “WARNINGS” and “PRECAUTIONS” sections regarding patient 
screening, including recommended cardiac and pulmonary function tests and laboratory 
tests. 
Evaluation of clinical studies to date reveals that patients with more favorable ECOG 
performance status (ECOG PS 0) at treatment initiation respond better to Proleukin, with a 
higher response rate and lower toxicity (See “CLINICAL PHARMACOLOGY” section, 
“CLINICAL STUDIES” section and “ADVERSE REACTIONS” section). Therefore, selection 
of patients for treatment should include assessment of performance status. 
Experience in patients with ECOG PS >1 is extremely limited. 
CONTRAINDICATIONS 
Proleukin® (aldesleukin) is contraindicated in patients with a known history of hypersensitivity 
to interleukin-2 or any component of the Proleukin formulation.  
Proleukin is contraindicated in patients with an abnormal thallium stress test or abnormal 
pulmonary function tests and those with organ allografts. Retreatment with Proleukin is 
contraindicated in patients who have experienced the following drug-related toxicities while 
receiving an earlier course of therapy: 
 Sustained ventricular tachycardia (≥5 beats) 
 Cardiac arrhythmias not controlled or unresponsive to management 
 Chest pain with ECG changes, consistent with angina or myocardial infarction  
 Cardiac tamponade 
 Intubation for >72 hours 
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 Renal failure requiring dialysis >72 hours 
 Coma or toxic psychosis lasting >48 hours 
 Repetitive or difficult to control seizures 
 Bowel ischemia/perforation 
 GI bleeding requiring surgery 
WARNINGS 
See boxed “WARNINGS” 
Because of the severe adverse events which generally accompany Proleukin® (aldesleukin) 
therapy at the recommended dosages, thorough clinical evaluation should be performed to 
identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment in 
whom Proleukin is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, 
and CNS function may experience serious, life threatening or fatal adverse events. Adverse 
events are frequent, often serious, and sometimes fatal. 
Should adverse events, which require dose modification occur, dosage should be withheld 
rather than reduced (See “DOSAGE AND ADMINISTRATION” section, “Dose 
Modifications” subsection). 
Proleukin has been associated with exacerbation of pre-existing or initial presentation of 
autoimmune disease and inflammatory disorders. Exacerbation of Crohn’s disease, 
scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia 
gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson 
syndrome and bullous pemphigoid, has been reported following treatment with IL-2. 
All patients should have thorough evaluation and treatment of CNS metastases and have a 
negative scan prior to receiving Proleukin therapy. New neurologic signs, symptoms, and 
anatomic lesions following Proleukin therapy have been reported in patients without evidence 
of CNS metastases. Clinical manifestations included changes in mental status, speech 
difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and 
coma. Radiological findings included multiple and, less commonly, single cortical lesions on 
MRI and evidence of demyelination. Neurologic signs and symptoms associated with 
Proleukin therapy usually improve after discontinuation of Proleukin therapy; however, there 
are reports of permanent neurologic defects. One case of possible cerebral vasculitis, 
responsive to dexamethasone, has been reported. In patients with known seizure disorders, 
extreme caution should be exercised as Proleukin may cause seizures. 
PRECAUTIONS 
General 
Patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of 
therapy. (See “PRECAUTIONS” section, “Laboratory Tests” subsection). Capillary leak 
syndrome (CLS) begins immediately after Proleukin® (aldesleukin) treatment starts and is 
marked by increased capillary permeability to protein and fluids and reduced vascular tone. In 
most patients, this results in a concomitant drop in mean arterial blood pressure within 2 to 12 
hours after the start of treatment. With continued therapy, clinically significant hypotension 
(defined as systolic blood pressure below 90 mm Hg or a 20 mm Hg drop from baseline 
systolic pressure) and hypoperfusion will occur. In addition, extravasation of protein and fluids 
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into the extravascular space will lead to the formation of edema and creation of new 
effusions. 
Medical management of CLS begins with careful monitoring of the patient’s fluid and organ 
perfusion status. This is achieved by frequent determination of blood pressure and pulse, and 
by monitoring organ function, which includes assessment of mental status and urine output. 
Hypovolemia is assessed by catheterization and central pressure monitoring. 
Flexibility in fluid and pressor management is essential for maintaining organ perfusion and 
blood pressure. Consequently, extreme caution should be used in treating patients with fixed 
requirements for large volumes of fluid (e.g., patients with hypercalcemia). Administration of 
IV fluids, either colloids or crystalloids is recommended for treatment of hypovolemia. 
Correction of hypovolemia may require large volumes of IV fluids but caution is required 
because unrestrained fluid administration may exacerbate problems associated with edema 
formation or effusions. With extravascular fluid accumulation, edema is common and ascites, 
pleural or pericardial effusions may develop. Management of these events depends on a 
careful balancing of the effects of fluid shifts so that neither the consequences of 
hypovolemia (e.g., impaired organ perfusion) nor the consequences of fluid accumulations 
(e.g., pulmonary edema) exceed the patient’s tolerance. 
Clinical experience has shown that early administration of dopamine (1 to 5 mcg/kg/min) to 
patients manifesting capillary leak syndrome, before the onset of hypotension, can help to 
maintain organ perfusion particularly to the kidney and thus preserve urine output. Weight 
and urine output should be carefully monitored. If organ perfusion and blood pressure are not 
sustained by dopamine therapy, clinical investigators have increased the dose of dopamine 
to 6 to 10 mcg/kg/min or have added phenylephrine hydrochloride (1 to 5 mcg/kg/min) to low 
dose dopamine (See “ADVERSE REACTIONS” section). Prolonged use of pressors, either in 
combination or as individual agents, at relatively high doses, may be associated with cardiac 
rhythm disturbances. If there has been excessive weight gain or edema formation, 
particularly if associated with shortness of breath from pulmonary congestion, use of 
diuretics, once blood pressure has normalized, has been shown to hasten recovery. NOTE: 
Prior to the use of any product mentioned, the physician should refer to the package 
insert for the respective product. 
Proleukin® (aldesleukin) treatment should be withheld for failure to maintain organ perfusion 
as demonstrated by altered mental status, reduced urine output, a fall in the systolic blood 
pressure below 90 mm Hg or onset of cardiac arrhythmias (See “DOSAGE AND 
ADMINISTRATION” section, “Dose Modifications” subsection). Recovery from CLS begins 
soon after cessation of Proleukin therapy. Usually, within a few hours, the blood pressure 
rises, organ perfusion is restored and reabsorption of extravasated fluid and protein begins. 
Kidney and liver function are impaired during Proleukin treatment. Use of concomitant 
nephrotoxic or hepatotoxic medications may further increase toxicity to the kidney or liver. 
Mental status changes including irritability, confusion, or depression which occur while 
receiving Proleukin may be indicators of bacteremia or early bacterial sepsis, hypoperfusion, 
occult CNS malignancy, or direct Proleukin-induced CNS toxicity. Alterations in mental status 
due solely to Proleukin therapy may progress for several days before recovery begins. 
Rarely, patients have sustained permanent neurologic deficits (See “PRECAUTIONS” section 
“Drug Interactions” subsection). 
Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and 
inflammatory disorders has been reported following Proleukin alone or in combination with 
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interferon (See “PRECAUTIONS” section “Drug Interactions” subsection and “ADVERSE 
REACTIONS” section). Hypothyroidism, sometimes preceded by hyperthyroidism, has been 
reported following Proleukin treatment. Some of these patients required thyroid replacement 
therapy. Changes in thyroid function may be a manifestation of autoimmunity. Onset of 
symptomatic hyperglycemia and/or diabetes mellitus has been reported during Proleukin 
therapy. 
Proleukin enhancement of cellular immune function may increase the risk of allograft 
rejection in transplant patients. 
Serious Manifestations of Eosinophilia 
Serious manifestations of eosinophilia involving eosinophilic infiltration of cardiac and 
pulmonary tissues can occur following Proleukin. 
Laboratory Tests 
The following clinical evaluations are recommended for all patients, prior to beginning 
treatment and then daily during drug administration. 
 Standard hematologic tests-including CBC, differential and platelet counts 
 Blood chemistries-including electrolytes, renal and hepatic function tests 
 Chest x-rays 
Serum creatinine should be ≤1.5 mg/dL prior to initiation of Proleukin treatment. 
All patients should have baseline pulmonary function tests with arterial blood gases. 
Adequate pulmonary function should be documented (FEV1 >2 liters or ≥75% of predicted for 
height and age) prior to initiating therapy. 
All patients should be screened with a stress thallium study. Normal ejection fraction and 
unimpaired wall motion should be documented. If a thallium stress test suggests minor wall 
motion abnormalities further testing is suggested to exclude significant coronary artery 
disease. 
Daily monitoring during therapy with Proleukin should include vital signs (temperature, pulse, 
blood pressure, and respiration rate), weight, and fluid intake and output. In a patient with a 
decreased systolic blood pressure, especially less than 90 mm Hg, constant cardiac rhythm 
monitoring should be conducted. If an abnormal complex or rhythm is seen, an ECG should 
be performed. Vital signs in these hypotensive patients should be taken hourly. 
During treatment, pulmonary function should be monitored on a regular basis by clinical 
examination, assessment of vital signs and pulse oximetry. Patients with dyspnea or clinical 
signs of respiratory impairment (tachypnea or rales) should be further assessed with arterial 
blood gas determination. These tests are to be repeated as often as clinically indicated. 
Cardiac function should be assessed daily by clinical examination and assessment of vital 
signs. Patients with signs or symptoms of chest pain, murmurs, gallops, irregular rhythm or 
palpitations should be further assessed with an ECG examination and cardiac enzyme 
evaluation. Evidence of myocardial injury, including findings compatible with myocardial 
infarction or myocarditis, has been reported. Ventricular hypokinesia due to myocarditis may 
be persistent for several months. If there is evidence of cardiac ischemia or congestive heart 
failure, Proleukin therapy should be held, and a repeat thallium study should be done. 
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Drug Interactions 
Proleukin may affect central nervous function. Therefore, interactions could occur following 
concomitant administration of psychotropic drugs (e.g., narcotics, analgesics, antiemetics, 
sedatives, tranquilizers). 
Concurrent administration of drugs possessing nephrotoxic (e.g., aminoglycosides, 
indomethacin), myelotoxic (e.g., cytotoxic chemotherapy), cardiotoxic (e.g., doxorubicin) or 
hepatotoxic (e.g., methotrexate, asparaginase) effects with Proleukin may increase toxicity in 
these organ systems. The safety and efficacy of Proleukin in combination with any 
antineoplastic agents have not been established. 
In addition, reduced kidney and liver function secondary to Proleukin treatment may delay 
elimination of concomitant medications and increase the risk of adverse events from those 
drugs. 
Hypersensitivity reactions have been reported in patients receiving combination regimens 
containing sequential high dose Proleukin and antineoplastic agents, specifically, 
dacarbazine, cis-platinum, tamoxifen and interferon-alfa. These reactions consisted of 
erythema, pruritus, and hypotension and occurred within hours of administration of 
chemotherapy. These events required medical intervention in some patients. 
Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and 
severe rhabdomyolysis appear to be increased in patients receiving Proleukin and interferon­
alfa concurrently. 
Exacerbation or the initial presentation of a number of autoimmune and inflammatory 
disorders has been observed following concurrent use of interferon-alfa and Proleukin, 
including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory 
arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. 
Although glucocorticoids have been shown to reduce Proleukin-induced side effects including 
fever, renal insufficiency, hyperbilirubinemia, confusion, and dyspnea, concomitant 
administration of these agents with Proleukin may reduce the antitumor effectiveness of 
Proleukin and thus should be avoided.12 
Beta-blockers and other antihypertensives may potentiate the hypotension seen with 
Proleukin. 
Delayed Adverse Reactions to Iodinated Contrast Media 
A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with 
various interleukin-2 containing regimens who were subsequently administered radiographic 
iodinated contrast media experienced acute, atypical adverse reactions. The onset of 
symptoms usually occurred within hours (most commonly 1 to 4 hours) following the 
administration of contrast media. These reactions include fever, chills, nausea, vomiting, 
pruritus, rash, diarrhea, hypotension, edema, and oliguria. Some clinicians have noted that 
these reactions resemble the immediate side effects caused by interleukin-2 administration, 
however the cause of contrast reactions after interleukin-2 therapy is unknown. Most events 
were reported to occur when contrast media was given within 4 weeks after the last dose of 
interleukin-2. These events were also reported to occur when contrast media was given 
several months after interleukin-2 treatment.13 
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Carcinogenesis, Mutagenesis, Impairment of Fertility 
There have been no studies conducted assessing the carcinogenic or mutagenic potential of 
Proleukin. 
There have been no studies conducted assessing the effect of Proleukin on fertility. It is 
recommended that this drug not be administered to fertile persons of either gender not 
practicing effective contraception. 
Pregnancy 
Pregnancy Category C. 
Proleukin has been shown to have embryolethal effects in rats when given in doses at 27 to 
36 times the human dose (scaled by body weight). Significant maternal toxicities were 
observed in pregnant rats administered Proleukin by IV injection at doses 2.1 to 36 times 
higher than the human dose during critical period of organogenesis. No evidence of 
teratogenicity was observed other than that attributed to maternal toxicity. There are no 
adequate well-controlled studies of Proleukin in pregnant women. Proleukin should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
Nursing Mothers 
It is not known whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk and because of the potential for serious adverse reactions in nursing 
infants from Proleukin, a decision should be made whether to discontinue nursing or to 
discontinue the drug, taking into account the importance of the drug to the mother. 
Pediatric Use 
Safety and effectiveness in children under 18 years of age have not been established. 
Geriatric Use 
There were a small number of patients aged 65 and over in clinical trials of Proleukin; 
experience is limited to 27 patients, eight with metastatic melanoma and nineteen with 
metastatic renal cell carcinoma. The response rates were similar in patients 65 years and 
over as compared to those less than 65 years of age. The median number of courses and the 
median number of doses per course were similar between older and younger patients. 
Proleukin is known to be substantially excreted by the kidney, and the risk of toxic reactions 
to this drug may be greater in patients with impaired renal function. The pattern of organ 
system toxicity and the proportion of patients with severe toxicities by organ system were 
generally similar in patients 65 and older and younger patients. There was a trend, however, 
towards an increased incidence of severe urogenital toxicities and dyspnea in the older 
patients. 
ADVERSE REACTIONS 
The rate of drug-related deaths in the 255 metastatic RCC patients who received single-
agent Proleukin® (aldesleukin) was 4% (11/255); the rate of drug-related deaths in the 270 
metastatic melanoma patients who received single-agent Proleukin was 2% (6/270). 
The following data on common adverse events (reported in greater than 10% of patients, any 
grade), presented by body system, decreasing frequency and by preferred term (COSTART) 
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are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) 
treated with the recommended infusion dosing regimen. 
TABLE 3: ADVERSE EVENTS OCCURRING IN ≥10% OF PATIENTS (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 increase 
10 
Tachycardia 
23 
Nervous
  Vasodilation 
13 
Confusion 
34 
Supraventricular tachycardia 
12 
Somnolence 
22 
  Cardiovascular disordera 
11 
Anxiety 
12 
Arrhythmia 
10 
Dizziness 
11 
Digestive 
Respiratory
 Diarrhea 
67 
Dyspnea 
43 
Vomiting 
50 
  Lung disorderb 
24 
Nausea 
35 
Respiratory disorderc 
11 
Stomatitis 
22 
  Cough increase 
11 
Anorexia 
20 
Rhinitis 
10 
Nausea and vomiting 
19 
Skin and Appendages 
Hemic and Lymphatic
 Rash 
42 
Thrombocytopenia 
37 
Pruritus 
24 
Anemia 
29 
Exfoliative dermatitis 
18 
Leukopenia 
16 
Urogenital
 Oliguria 
63 
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
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b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
The following data on life-threatening adverse events (reported in greater than 1% of 
patients, grade 4), presented by body system, and by preferred term (COSTART) are based 
on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with 
the recommended infusion dosing regimen. 
TABLE 4: LIFE-THREATENING (GRADE 4) ADVERSE EVENTS (n= 525) 
Body System 
# (%) 
Patients 
Body System 
# (%) 
Patients 
Body as a Whole 
Metabolic and 
Nutritional Disorders
 Fever 
5 (1%) 
Bilirubinemia 
13 (2%) 
Infection 
7 (1%) 
  Creatinine increase 
5 (1%) 
Sepsis 
6 (1%) 
SGOT increase 
3 (1%) 
Cardiovascular
 Acidosis 
4 (1%) 
Hypotension 
15 (3%) 
Nervous
 Supraventricular tachycardia 
3 (1%) 
Confusion 
5 (1%) 
  Cardiovascular disordera 
7 (1%) 
Stupor 
3 (1%) 
Myocardial infarct 
7 (1%) 
Coma 
8 (2%) 
  Ventricular tachycardia 
5 (1%) 
Psychosis 
7 (1%) 
Cardiac arrest 
4 (1%) 
Respiratory 
Digestive
 Dyspnea 
5 (1%) 
Diarrhea 
10 (2%) 
Respiratory disorderc 
14 (3%) 
Vomiting 
7 (1%) 
Apnea 
5 (1%) 
Hemic and Lymphatic 
Urogenital
 Thrombocytopenia 
5 (1%) 
Oliguria 
33 (6%) 
  Coagulation disorderb 
4 (1%) 
Anuria 
25 (5%) 
  Acute kidney failure 
3 (1%) 
a Cardiovascular disorder: fluctuations in blood pressure.  
b Coagulation disorder: intravascular coagulopathy.  
c Respiratory disorder: ARDS, respiratory failure, intubation.  
The following life-threatening (grade 4) events were reported by <1% of the 525 patients: 
hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; 
hemorrhage; atrial arrhythmia; phlebitis; AV block second degree; endocarditis; pericardial 
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effusion; peripheral gangrene; thrombosis; coronary artery disorder; stomatitis; nausea and 
vomiting; liver function tests abnormal; gastrointestinal hemorrhage; hematemesis; bloody 
diarrhea; gastrointestinal disorder; intestinal perforation; pancreatitis; anemia; leukopenia; 
leukocytosis; hypocalcemia; alkaline phosphatase increase; BUN increase; hyperuricemia; 
NPN increase; respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; 
convulsion; grand mal convulsion; delirium; asthma, lung edema; hyperventilation; hypoxia; 
hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary disorder; kidney function 
abnormal; kidney failure; acute tubular necrosis. 
In an additional population of greater than 1,800 patients treated with Proleukin-based 
regimens using a variety of doses and schedules (e.g., subcutaneous, continuous infusion, 
administration with LAK cells) the following serious adverse events were reported: duodenal 
ulceration; bowel necrosis; myocarditis; supraventricular tachycardia; permanent or transient 
blindness secondary to optic neuritis; transient ischemic attacks; meningitis; cerebral edema; 
pericarditis; allergic interstitial nephritis; tracheo-esophageal fistula. 
In the same clinical population, the following fatal events each occurred with a frequency of 
<1%: malignant hyperthermia; cardiac arrest; myocardial infarction; pulmonary emboli; stroke; 
intestinal perforation; liver or renal failure; severe depression leading to suicide; pulmonary 
edema; respiratory arrest; respiratory failure. In patients with both metastatic RCC and 
metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment-related 
mortality and serious adverse events. 
Most adverse reactions are self-limiting and, usually, but not invariably, reverse or improve 
within 2 or 3 days of discontinuation of therapy. Examples of adverse reactions with 
permanent sequelae include: myocardial infarction, bowel perforation/infarction, and 
gangrene. 
Immunogenicity 
Serum samples from patients in the clinical studies were tested by enzyme-linked 
immunosorbent assay (ELISA) for anti-aldesleukin antibodies. Low titers of anti-aldesleukin 
antibodies were detected in 57 of 77 (74%) patients with metastatic renal cell carcinoma 
treated with an every 8-hour PROLEUKIN regimen and in 33 of 50 (66%) patients with 
metastatic melanoma treated with a variety of intravenous regimens. In a separate study, the 
effect of immunogenicity on the pharmacokinetics of aldesleukin was evaluated in 13 
patients. Following the first cycle of therapy, comparing the geometric mean aldesleukin 
exposure (AUC) Day 15 to Day 1, there was an average 68% increase in 11 patients who 
developed anti-aldesleukin antibodies and no change was observed in the antibody-negative 
patients (n=2). Overall, neutralizing antibodies were detected in 1 patient. The impact of 
antialdesleukin antibody formation on clinical efficacy and safety of PROLEUKIN is unknown. 
Immunogenicity assay results are highly dependent on several factors including assay 
sensitivity and specificity, assay methodology, sample handling, timing of sample collection, 
concomitant medications, and underlying disease. For these reasons, comparison of 
incidence of antibodies to PROLEUKIN with the incidence of antibodies to other products 
may be misleading. 
Post Marketing Experience 
The following adverse reactions have been identified during post-approval use of Proleukin.  
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
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always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. 
 Blood and lymphatic system: neutropenia, febrile neutropenia, eosinophilia,  
lymphocytopenia  
 Cardiac: cardiomyopathy, cardiac tamponade 
 Endocrine: hyperthyroidism 
 Gastrointestinal: gastritis, intestinal obstruction, colitis 
 General and administration site conditions: injection site necrosis 
 Hepatobiliary: hepatitis, hepatosplenomegaly, cholecystitis 
 Immune system: anaphylaxis, angioedema, urticaria 
 Infections and infestations: pneumonia (bacterial, fungal, viral), fatal endocarditis, 
cellulitis 
 Musculoskeletal and connective tissue: myopathy, myositis, rhabdomyolysis 
 Nervous system: cerebral lesions, encephalopathy, extrapyramidal syndrome, 
neuralgia, neuritis, demyelinating neuropathy 
 Psychiatric: insomnia 
 Vascular: hypertension, fatal subdural and subarachnoid hemorrhage, cerebral 
hemorrhage, retroperitoneal hemorrhage 
Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders 
have been reported (See “WARNINGS” section, “PRECAUTIONS” section, “Drug 
Interactions” subsection). Persistent but nonprogressive vitiligo has been observed in 
malignant melanoma patients treated with interleukin-2. Synergistic, additive and novel 
toxicities have been reported with Proleukin used in combination with other drugs. Novel 
toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity 
reactions to antineoplastic agents (See “PRECAUTIONS” section, “Drug Interactions” 
subsection). 
Experience has shown the following concomitant medications to be useful in the 
management of patients on Proleukin therapy: a) standard antipyretic therapy, including 
nonsteroidal anti-inflammatories (NSAIDs), started immediately prior to Proleukin to reduce 
fever. Renal function should be monitored as some NSAIDs may cause synergistic 
nephrotoxicity; b) meperidine used to control the rigors associated with fever; c) H2 
antagonists given for prophylaxis of gastrointestinal irritation and bleeding; d) antiemetics and 
antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these 
medications were discontinued 12 hours after the last dose of Proleukin. 
Patients with indwelling central lines have a higher risk of infection with gram positive 
organisms.9-11 A reduced incidence of staphylococcal infections in Proleukin studies has been 
associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin, 
ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used to control 
symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and 
ointments should be applied as needed for skin manifestations. Preparations containing a 
Reference ID: 3165255 


 
 
steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product 
mentioned, the physician should refer to the package insert for the respective product. 
OVERDOSAGE 
Side effects following the use of Proleukin® (aldesleukin) appear to be dose-related. 
Exceeding the recommended dose has been associated with a more rapid onset of expected 
dose-limiting toxicities. Symptoms which persist after cessation of Proleukin should be 
monitored and treated supportively. Life-threatening toxicities may be ameliorated by the 
intravenous administration of dexamethasone, which may also result in loss of the 
therapeutic effects of Proleukin.12 NOTE: Prior to the use of dexamethasone, the 
physician should refer to the package insert for this product. 
DOSAGE AND ADMINISTRATION 
The recommended Proleukin® (aldesleukin) treatment regimen is administered by a 15­
minute intravenous infusion every 8 hours. Before initiating treatment, carefully review the 
“INDICATIONS AND USAGE”, “CONTRAINDICATIONS”, “WARNINGS”, “PRECAUTIONS”, 
and “ADVERSE REACTIONS” sections, particularly regarding patient selection, possible 
serious adverse events, patient monitoring and withholding dosage. The following schedule 
has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or 
metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles 
separated by a rest period. 
600,000 International Units/kg (0.037 mg/kg) dose administered every 8 hours by 
a 15-minute intravenous infusion for a maximum of 14 doses. Following 9 days of 
rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses 
per course, as tolerated. During clinical trials, doses were frequently withheld for 
toxicity (See “CLINICAL STUDIES” section and “Dose Modifications” 
subsection). Metastatic RCC patients treated with this schedule received a 
median of 20 of the 28 doses during the first course of therapy. Metastatic 
melanoma patients received a median of 18 doses during the first course of 
therapy. 
Retreatment 
Patients should be evaluated for response approximately 4 weeks after completion of a 
course of therapy and again immediately prior to the scheduled start of the next treatment 
course. Additional courses of treatment should be given to patients only if there is some 
tumor shrinkage following the last course and retreatment is not contraindicated (See 
“CONTRAINDICATIONS” section). Each treatment course should be separated by a rest 
period of at least 7 weeks from the date of hospital discharge. 
Dose Modifications 
Dose modification for toxicity should be accomplished by withholding or interrupting a dose 
rather than reducing the dose to be given. Decisions to stop, hold, or restart Proleukin 
therapy must be made after a global assessment of the patient. With this in mind, the 
following guidelines should be used: 
Retreatment with Proleukin is contraindicated in patients who have experienced the 
following toxicities: 
Body System 
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Cardiovascular 
Sustained ventricular tachycardia (≥5 beats) 
Cardiac rhythm disturbances not controlled or unresponsive to management 
Chest pain with ECG changes, consistent with angina or myocardial infarction 
 
Cardiac tamponade 
Respiratory 
Intubation for >72 hours 
Urogenital 
Renal failure requiring dialysis >72 hours 
Nervous 
Coma or toxic psychosis lasting >48 hours 
Repetitive or difficult to control seizures 
Digestive 
Bowel ischemia/perforation 
GI bleeding requiring surgery 
Doses should be held and restarted according to the following: 
Body System 
Hold dose for 
Subsequent doses may be given if 
Cardiovascular 
Atrial fibrillation, supraventricular 
tachycardia or bradycardia that requires 
treatment or is recurrent or persistent 
Patient is asymptomatic with full recovery 
to normal sinus rhythm 
Systolic bp <90 mm Hg with increasing 
requirements for pressors 
Systolic bp ≥90 mm Hg and stable or 
improving requirements for pressors 
Any ECG change consistent with MI, 
ischemia or myocarditis with or without 
chest pain; suspicion of cardiac 
ischemia 
Patient is asymptomatic, MI and 
myocarditis have been ruled out, clinical 
suspicion of angina is low; there is no 
evidence of ventricular hypokinesia 
Respiratory 
O2 saturation <90% 
O2 saturation >90% 
Nervous 
Mental status changes, including 
moderate confusion or agitation 
Mental status changes completely 
resolved 
Body as a 
Whole 
Sepsis syndrome, patient is clinically 
unstable 
Sepsis syndrome has resolved, patient is 
clinically stable, infection is under 
treatment 
Urogenital 
Serum creatinine >4.5 mg/dL or a serum 
creatinine of ≥4 mg/dL in the presence 
of severe volume overload, acidosis, or 
hyperkalemia 
Serum creatinine <4 mg/dL and fluid and 
electrolyte status is stable 
Persistent oliguria, urine output of <10 
mL/hour for 16 to 24 hours with rising 
serum creatinine 
Urine output >10 mL/hour with a 
decrease of serum creatinine >1.5 mg/dL 
or normalization of serum creatinine 
Digestive 
Signs of hepatic failure including 
encephalopathy, increasing ascites, 
liver pain, hypoglycemia 
All signs of hepatic failure have resolved* 
Stool guaiac repeatedly >3-4+ 
Stool guaiac negative 
Skin 
Bullous dermatitis or marked worsening 
of pre-existing skin condition, avoid 
Resolution of all signs of bullous 
dermatitis 
Reference ID: 3165255 


 
 
topical steroid therapy 
* Discontinue all further treatment for that course. A new course of treatment, if warranted, should be initiated no 
sooner than 7 weeks after cessation of adverse event and hospital discharge. 
Reconstitution and Dilution Directions: Reconstitution and dilution procedures other 
than those recommended may alter the delivery and/or pharmacology of Proleukin and 
thus should be avoided. 
1. Proleukin® (aldesleukin) is a sterile, white to off-white, preservative-free, lyophilized 
powder suitable for IV infusion upon reconstitution and dilution. EACH VIAL 
CONTAINS 22 MILLION International Units (1.3 mg) OF PROLEUKIN AND 
SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 mL OF STERILE WATER 
FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH mL 
CONTAINS 18 MILLION International Units (1.1 mg) OF PROLEUKIN. The resulting 
solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use 
only and any unused portion should be discarded. 
2. During reconstitution, the Sterile Water for Injection, USP should be directed at the 
side of the vial and the contents gently swirled to avoid excess foaming. DO NOT 
SHAKE. 
3. The dose of Proleukin, reconstituted with Sterile Water for Injection, USP (without 
preservative) should be diluted aseptically in 50 mL of 5% Dextrose Injection, USP 
(D5W) and infused over a 15-minute period. 
In cases where the total dose of Proleukin is 1.5 mg or less (e.g., a patient with a body 
weight of less than 40 kilograms), the dose of Proleukin should be diluted in a smaller 
volume of D5W. Concentrations of Proleukin below 0.03 mg/mL and above 0.07 
mg/mL have shown increased variability in drug delivery. Dilution and delivery of 
Proleukin outside of this concentration range should be avoided. 
4. Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with 
comparable results. It is recommended that plastic bags be used as the dilution 
container since experimental studies suggest that use of plastic containers results in 
more consistent drug delivery. In-line filters should not be used when 
administering Proleukin. 
5. Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 
46°F). Do not freeze. Administer Proleukin within 48 hours of reconstitution. The 
solution should be brought to room temperature prior to infusion in the patient. 
6. Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium 
Chloride Injection, USP should be avoided because of increased aggregation. 
Proleukin should not be coadministered with other drugs in the same container. 
7. Parenteral drug products should be inspected visually for particulate matter and  
discoloration prior to administration, whenever solution and container permit.  
HOW SUPPLIED 
Proleukin® (aldesleukin) is supplied in individually boxed single-use vials. Each vial contains 
22 million International Units of Proleukin. Discard unused portion. 
NDC 65483-116-07 
Individually boxed single-use vial 
Reference ID: 3165255 


 
 
Store vials of lyophilized Proleukin in a refrigerator at 2° to 8°C (36° to 46°F). PROTECT 
FROM LIGHT. Store in carton until time of use. 
Reconstituted or diluted Proleukin is stable for up to 48 hours at refrigerated and room 
temperatures, 2° to 25°C (36° to 77°F). However, since this product contains no preservative, 
the reconstituted and diluted solutions should be stored in the refrigerator. 
Do not use beyond the expiration date printed on the vial. NOTE: This product contains no 
preservative. 
Rx Only 
REFERENCES 
1. Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human 
recombinant interleukin-2125 and native interleukin-2. J Biol Response Mod 1985; 4:96­
109. 
2. Ralph P, Nakoinz I, Doyle M, et al. Human B and T lymphocyte stimulating properties 
of interleukin-2 (IL-2) muteins. In: Immune Regulation By Characterized Polypeptides. 
Alan R. Liss, Inc. 1987; 453-62. 
3. Winkelhake JL and Gauny SS. Human recombinant interleukin-2 as an experimental 
therapeutic. Pharmacol Rev 1990; 42:1-28. 
4. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of established pulmonary 
metastases and subcutaneous tumor mediated by the systemic administration of high-
dose recombinant interleukin-2. J Exp Med 1985; 161:1169-88. 
5. Konrad MW, Hemstreet G, Hersh EM, et al. Pharmacokinetics of recombinant  
interleukin-2 in humans. Cancer Res 1990; 50:2009-17.  
6. Donohue JH and Rosenberg SA. The fate of interleukin-2 after in vivo administration. J 
Immunol 1983; 130:2203-8. 
7. Koths K, Halenbeck R. Pharmacokinetic studies on 35S-labeled recombinant 
interleukin-2 in mice. In: Sorg C and Schimpl A, eds. Cellular and Molecular Biology of 
Lymphokines. Academic Press: Orlando, FL, 1985;779. 
8. Gibbons JA, Luo ZP, Hansen ER, et al. Quantitation of the renal clearance of 
interleukin-2 using nephrectomized and ureter ligated rats. J Pharmacol Exp Ther 
1995; 272: 119-125. 
9. Bock SN, Lee RE, Fisher B, et al. A prospective randomized trial evaluating 
prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients 
treated with immunotherapy. J Clin Oncol 1990; 8:161-69. 
10.Hartman LC, Urba WJ, Steis RG, et al. Use of prophylactic antibiotics for prevention of 
intravascular catheter-related infections in interleukin-2-treated patients. J Natl Cancer 
Inst 1989; 81:1190-93. 
11.Snydman DR, Sullivan B, Gill M, et al. Nosocomial sepsis associated with interleukin­
2. Ann Intern Med 1990; 112:102-07. 
12.Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin-2-induced tumor 
necrosis factor release by dexamethasone: Prevention of an acquired neutrophil 
chemotaxis defect and differential suppression of interleukin-2 associated side effects. 
Blood 1990; 76:1933-40. 
Reference ID: 3165255 


 
 
 
 
 
 
 
 
 
 
 
13.Choyke PL, Miller DL, Lotze MT, et al. Delayed reactions to contrast media after 
interleukin-2 immunotherapy. Radiology 1992; 183:111-114. 
Manufactured by: 
Prometheus Laboratories Inc. 
San Diego, CA 92121 
U.S. License No. 1848 
At 
Bayer HealthCare Pharmaceuticals 
Emeryville, CA 94608 
For additional information, contact Prometheus Laboratories Inc. 1-877-PROLEUKIN (1-877­
776-5385) 
PROLEUKIN is a registered trademark of Novartis Vaccines and Diagnostics, Inc. 
© 2011 Prometheus Laboratories Inc. Prometheus Therapeutics & Diagnostics
REV: July 2012 
PR001E 
Reference ID: 3165255