A Phase II Study of Propranolol Plus Sunitinib in First-line Treatment of Metastatic Renal Cell Carcinoma (ProSun Study)
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Sponsor: Military Institute od Medicine National Research Institute

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CLINICAL TRIAL PROTOCOL 
 
TITLE: 
A Phase II Study of Propranolol Plus Sunitinib in First-line Treatment 
of Metastatic Renal Cell Carcinoma (ProSun Study) 
 
 
PROTOCOL IDENTIFYING NUMBER: 
PS-001 
 
PROTOCOL VERSION NUMBER: 
v1.0 
 
PROTOCOL DATE: 
10 Sep 2017 
 
PROTOCOL AUTHOR: 
Paweł Chrom 
 
DEVELOPMENT PHASE 
2 

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Table of Contents 
CLINICAL TRIAL PROTOCOL ...................................................................................................................... 1 
Table of Contents .................................................................................................................................... 2 
List of Abbreviations ................................................................................................................................ 5 
Statement of Compliance ........................................................................................................................ 8 
Study Contact List .................................................................................................................................... 9 
Clinical Trial Summary ........................................................................................................................... 11 
1. Background ........................................................................................................................................ 13 
1.1 Renal Cell Carcinoma ................................................................................................................... 13 
1.1.1 Epidemiology ........................................................................................................................ 13 
1.1.2 The Role of VHL-HIF Axis in the Pathogenesis of RCC .......................................................... 13 
1.1.3 The Role of Beta-adrenergic Receptors in Carcinogenesis ................................................... 14 
1.1.4 The Place of Sunitinib in Treatment of Metastatic RCC ....................................................... 15 
1.2 Propranolol .................................................................................................................................. 16 
1.2.1 Pharmacology ....................................................................................................................... 16 
1.2.2 Current Indications and Dosing ............................................................................................ 17 
1.2.3 Antineoplastic Potential ....................................................................................................... 17 
1.2.4 Safety Results ....................................................................................................................... 19 
1.3 Study Rationale ............................................................................................................................ 20 
2. Study Objectives ................................................................................................................................ 23 
2.1 Primary Objective ........................................................................................................................ 23 
2.2 Secondary Objectives .................................................................................................................. 23 
3. Study Design ...................................................................................................................................... 23 
3.1 Summary of Study Design ........................................................................................................... 23 
3.2 Length of the Study ..................................................................................................................... 24 
3.3 Study Extension ........................................................................................................................... 24 
4. Study Population ............................................................................................................................... 24 
4.1 Number of Patients Planned ....................................................................................................... 24 
4.2 Recruitment of Patients .............................................................................................................. 24 
4.3 Inclusion Criteria .......................................................................................................................... 24 
4.4 Exclusion Criteria ......................................................................................................................... 25 
4.5 Discontinuations .......................................................................................................................... 27 
4.5.1 Discontinuation of Patients .................................................................................................. 27 
4.5.2 Replacement of Patients ...................................................................................................... 27 
4.5.3 Discontinuation of the Study ................................................................................................ 27 
5. Study Interventions ........................................................................................................................... 27 
5.1 Investigational Products .............................................................................................................. 27 
5.1.1 Sunitinib (SUTENT® by Pfizer Inc.) ........................................................................................ 27 
5.1.2 Propranolol (Propranolol Accord® by Accord Healthcare Ltd.) ............................................ 28 
5.2 Concomitant Treatment .............................................................................................................. 29 
5.2.1 Prohibited Concomitant Treatment ..................................................................................... 29 
5.2.2 Permitted Concomitant Treatment ...................................................................................... 30 
5.3 Storage, Accountability and Compliance .................................................................................... 30 

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6. Study Measures ................................................................................................................................. 30 
6.1 Definitions of Efficacy Measures ................................................................................................. 30 
6.1.1 Objective Response Rate ...................................................................................................... 30 
6.1.2 Progression-free Survival...................................................................................................... 30 
6.1.3 Overall Survival ..................................................................................................................... 30 
6.1.4 Disease Control Rate ............................................................................................................ 30 
6.2 Safety Measures .......................................................................................................................... 30 
6.3 Health-related Quality of Life Measures ..................................................................................... 31 
6.4 Disease-related Stress Measures ................................................................................................ 31 
6.5 Tumour Tissue and Serum Biomarkers Assessments .................................................................. 31 
6.6 Timing and Methods of Measurements ...................................................................................... 31 
6.6.1 Pre-treatment Period ........................................................................................................... 31 
6.6.2 Treatment Period ................................................................................................................. 32 
6.6.3 Postdiscontinuation Period .................................................................................................. 33 
6.6.4 Unscheduled Visits or Assessments ..................................................................................... 34 
7. Adverse Events .................................................................................................................................. 34 
7.1 Adverse Events Definitions .......................................................................................................... 34 
7.2 Expected Adverse Events ............................................................................................................ 34 
7.2.1 Expected Adverse Events for Sunitinib ................................................................................. 34 
7.2.2 Expected Adverse Events for Propranolol ............................................................................ 36 
7.3 Adverse Events Management ..................................................................................................... 38 
7.4 Adverse Events Monitoring and Reporting ................................................................................. 38 
8. Statistical Considerations .................................................................................................................. 38 
8.1 Study Hypotheses ........................................................................................................................ 38 
8.2 Sample Size Calculation ............................................................................................................... 39 
8.3 General Considerations ............................................................................................................... 39 
8.4 Primary and Secondary Endpoints Analyses ............................................................................... 39 
8.4.1 ORR and DCR Analysis .......................................................................................................... 39 
8.4.2 PFS and OS Analysis .............................................................................................................. 40 
8.4.3 Safety Analysis ...................................................................................................................... 40 
8.4.4 Health-related Quality of Life Analysis ................................................................................. 40 
8.4.5 Disease-related Stress Analysis ............................................................................................ 40 
8.4.6 Biomarker Analyses .............................................................................................................. 41 
8.5 Interim Analysis ........................................................................................................................... 41 
8.6 Statistical Software ...................................................................................................................... 41 
9. Ethical and Regulatory Standards ...................................................................................................... 41 
9.1 Ethics Review ............................................................................................................................... 41 
9.2 Ethical Conduct of the Study ....................................................................................................... 41 
9.3 Subject Information and Consent................................................................................................ 41 
9.4 Laws and Regulations .................................................................................................................. 41 
9.5 Conditions for Modifying the Protocol ........................................................................................ 42 
9.6 Insurance ..................................................................................................................................... 42 
10. Bibliographic References ................................................................................................................. 42 
Appendix A: Schedule of Assessments .................................................................................................. 48 

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Appendix B: Karnofsky Performance Status (KPS) Scale ....................................................................... 50 
Appendix C: Memorial Sloan Kettering Cancer Center (MSKCC) Criteria ............................................. 51 
Appendix D: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 ................................. 52 
Appendix E: The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C30 Version 3) .......................................................................................... 57 
Appendix F:  FACT-Kidney Symptom Index - 15 (FKSI-15) Questionnaire ............................................. 59 
Appendix G: The Perceived Stress Scale (PSS) Questionnaire ............................................................... 60 
 

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List of Abbreviations 
AC - adenyl cyclase 
AE - adverse event 
ALP - alkaline phosphatase 
ALT - alanine transaminase 
ANA - antinuclear antibodies 
ANOVA - analysis of variance 
AP-1 - activator protein 1 
APTT - activated partial thromboplastin time 
AST - aspartate aminotransferase 
AV - atrioventricular 
BAD - BCL2-associated death protein 
cAMP - cyclic 3′–5′ adenosine monophosphate 
ccRCC - clear-cell renal cell carcinoma 
CI - confidence Interval 
COX - cyclooxygenase 
CR - complete response 
CRF - Case Report Form 
CREB/ATF - cAMP response element binding protein/activating transcription factor 
crRCC - chromophobe renal cell carcinoma 
CSF-1R - colony stimulating factor 1 receptor 
CT - computed tomography 
CTLA-4 - cytotoxic T-lymphocyte-associated antigen 4 
CYP - cytochrome P 
D - day 
DCR - disease control rate 
DRS - disease-related stress 
E - epinephrine 
ECG - electrocardiography 
EGF - epidermal growth factor 
ELISA - enzyme-linked immunosorbent assay 
EMA - European Medical Agency 
EMT - epithelial-mesenchymal transition 
EORTC - European Organisation for Research and Treatment of Cancer 
EPAC - exchange protein activated by adenylyl cyclase 
EPO - erythropoietin 
ERK - extracellular signal-regulated kinase 
FAK - focal adhesion kinase 
FDA - Food and Drug Administration 
FGF - fibroblast growth factor 
FGFR - fibroblast growth factor receptor 
FKSI-15 - FACT-Kidney Symptom Index - 15 

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FLT-3 - fms-related tyrosine kinase 3 
GCP - Good Clinical Practice 
HER-2 - human epidermal growth factor receptor 2 
HGF - hepatocyte growth factor 
HIF - hypoxia-inducible factor 
HIV - human immunodeficiency virus 
HLQoL - health related quality of life 
HLRCC - hereditary leiomyomatosis and renal cell cancer 
HR - hazard ratio 
IFN-α - Interferon alpha 
IH - infantile haemangioma 
IL - interleukin 
INR - international normalized ratio 
IRB - Institutional Review Board 
IV - intravenous 
KIT - v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 
LMWH - low molecular weight heparin 
MAPK - mitogen-activated protein kinase 
MEK - mitogen-activated protein kinase kinase 
MMP - matrix metalloproteinase 
MRI - magnetic resonance imaging 
MSKCC - Memorial Sloan-Kettering Cancer Center 
mTOR - mammalian target of rapamycin 
MU - million units 
NA - not applicable 
NE - norepinephrine 
NFκB - nuclear factor kappa B 
NK - natural killer 
OS - overall survival 
PD - progressive disease 
PD-1 - programmed death-1 
PDGF - platelet-derived growth factor 
PDGFR - platelet-derived growth factor receptor 
PET - positron emission tomography 
PFS - progression-free survival 
PI3K - phosphoinositide 3-kinase 
PKA - protein kinase A 
PSS - Perceived Stress Scale 
PR - partial response 
pRCC - papillary enal cell carcinoma 
QoL - quality of life 
RANKL - receptor activator of nuclear factor kappa-B ligand 
RCC - renal cell carcinoma 
RECIST - Response Evaluation Criteria in Solid Tumors 

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RET - rearranged during transfection proto-oncogene 
SAE - serious adverse event 
SD - stable disease 
SDH - succinate-dehydrogenase 
SICF - Subject Information and Consent Form 
SoD - sum of the diameters 
SNAI2 - snail family transcriptional repressor 2 
SNS - sympathetic nervous system 
STAT-3 - signal transducer and activator of transcription-3 
TGFα - transforming growth factor alpha  
TKI - tyrosine kinase inhibitor 
TNFα - tumour necrosis factor alpha 
TPR - time point response 
TSH - thyroid-stimulating hormone 
UE - unable to evaluate 
VEGF - vascular endothelial growth factor 
VEGFR - vascular endothelial growth factor receptor 
vHL - von Hippel-Lindau 
W - week 

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Statement of Compliance 
I ensure that the trial will be conducted in compliance with the protocol and with Good Clinical 
Practice (GCP).  
I ensure that no deviation from, or changes to the protocol will take place without prior agreement 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. 
I ensure the trial will be registered on the www.clinicaltrials.gov website and wherever appropriate. 
I ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
 
Principal Investigator: 
 
Paweł Chrom  
Print/Type Name 
 
_____________________________________ 
Signed: 
 
 
Date (DD/MM/YYYY): 10/09/2017 

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Study Contact List 
Organization:  
 
 
Military Institute of Medicine 
Address: 
 
 
 
Szaserów 128, 04-141 Warsaw, Poland 
 
Principal investigator 
and study coordinator: Paweł Chrom   
 
M.D.  
Department: 
 
 
Oncology 
 
 
 
E-mail:  
 
 
pawel.chrom@gmail.com 
 
 
 
E-mail:  
 
 
pchrom@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 600057413  
 
 
 
 
 
Fax: 
 
 
 
+48 261817248 
Co-investigator: 
Cezary Szczylik   
 
M.D., Ph.D., Professor of Medicine 
Department: 
 
 
Oncology 
 
 
 
E-mail:  
 
 
cszczylik@wim.mil.pl 
 
 
 
Telephone: 
 
 
+48 261817235 
 
 
Co-investigator:  
Lubomir Bodnar  
 
M.D., Ph.D.  
Department: 
 
 
Oncology 
E-mail:  
 
 
lbodnar@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 261817240  
 
Co-investigator: 
Andrzej Skrobowski 
 
M.D., Ph.D., Professor of Medicine  
Department: 
 
 
Cardiology and Internal Medicine 
E-mail:  
 
 
askrobowski@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 261816389  
 
Co-investigator: 
Robert Wierzbowski 
 
M.D., Ph.D. 
Department: 
 
 
Cardiology and Internal Medicine 
E-mail:  
 
 
rwierzbowski@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 261816389  
 
Co-investigator: 
Beata Uziębło-Życzkowska 
M.D., Ph.D. 
Department: 
 
 
Cardiology and Internal Medicine 
E-mail:  
 
 
rwierzbowski@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 261816362  
 
Co-investigator: 
Agnieszka Jurek 
 
M.D. 
Department: 
 
 
Cardiology and Internal Medicine 
E-mail:  
 
 
ajurek1@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 261816362  
 
 

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Co-investigator: 
Agnieszka Dancewicz 
 
M.Psych. 
Department: 
 
 
Oncology 
E-mail:  
 
 
adancewicz@wim.mil.pl 
 
 
 
Telephone:  
 
 
+48 261817248  

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Clinical Trial Summary 
TITLE 
A Phase II Study of Propranolol Plus Sunitinib in First-line Treatment of 
Metastatic Renal Cell Carcinoma (ProSun Study) 
PRINCIPAL INVESTIGATOR 
Pawel Chrom, M.D. 
TRIAL LOCATION 
Military Institute of Medicine 
Szaserów 128, 04-141 Warsaw, Poland 
STUDY OBJECTIVES 
Primary objective: To assess an effectiveness of therapy with 
propranolol plus sunitinib in terms of objective response rate in 
patients with metastatic renal cell carcinoma. 
Secondary objectives: To assess the following outcomes: overall 
survival, progression-free survival, disease control rate, incidence and 
severity of adverse events, changes from baseline in vital signs and 
laboratory results, health-related quality of life, disease-related stress, 
characterization of relationship between the primary tumour tissue 
and serum biomarkers with treatment and clinical outcomes. 
STUDY DESIGN 
It is a single-arm, single-center, open-label, phase II study. Eligible 
patients will be included in the single investigational cohort treated 
with: 
- oral sunitinib at a starting dose of 50 mg once daily in 6-weeks cycles 
consisting of 4 weeks of treatment followed by 2 weeks off the drug,  
- oral propranolol at a starting dose of 40 mg two times daily to a 
maximum dose of 240 mg a day 
 
Physical examination, laboratory findings, electrocardiography and 
filling health-related quality of life and disease-related stress 
questionnaires 
will 
take 
place 
every 
6 
weeks; 
computed 
tomography/magnetic resonance imaging scan will be performed 
every 12 weeks. The study treatment will last until disease 
progression, unacceptable toxicity or withdrawal of consent. Each 
patient will have a summary visit at the time of discontinuation from 
study treatment. The postdiscontinuation period will continue until 
death or the end of study data collection. 
STUDY POPULATION 
Main inclusion criteria:  
 
 
 
 
 
 
 
 
 
1. Histological diagnosis of clear-cell renal cell carcinoma or mixed-
type renal cell carcinoma with more than 60% of clear-cell component 
in the primary tumor. 
2. Diagnosis of stage IV renal cell carcinoma (primary metastatic or 
recurrence after surgical procedure). 
3. Prior nephrectomy (complete or partial). 
4. Presence of measurable disease. 
5. Karnofsky performance status: 80-100%. 
6. Favorable or intermediate risk according to Memorial Sloan-

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Main exclusion criteria: 
 
 
 
 
 
 
 
 
 
 
Expected number of 
patients: 
Kettering Cancer Center Score. 
7. Adequate organ function, including the following: 
 - hepatic: total bilirubin ≤ 2 times the upper limit of normal (excluding 
patients with Gilbert syndrome), AST and ALT ≤ 5 times the upper limit 
of normal, 
- renal: serum creatinine ≤ 2 times the upper limit of normal, 
- bone marrow: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 
100000/mm3, hemoglobin ≥ 9,5 g/dl. 
8. Normal thyroid function (natural or with supplementation of thyroid 
hormones). 
9. Age ≥ 18 years. 
10. Written informed consent prior to study entry. 
 
1. Prior systemic therapy of renal cell carcinoma. 
2. Treatment with propranolol within 6 months of study entry. 
3. Metastases in the central nervous system (patients who had brain 
metastases that were surgically resected or treated with radiotherapy 
in the past and now are without neurological symptoms, are allowed 
on protocol). 
4. Female patients who are pregnant or breast feeding. 
5. Presence of other malignancies (patients with carcinoma in situ of 
the cervix or basal cell carcinoma of the skin are allowed on protocol). 
6. Presence of any severe and/or uncontrolled medical conditions. 
7. Presence of any contraindication to propranolol. 
 
33 
INVESTIGATIONAL 
PRODUCTS 
Formulations: 
 
 
 
Tablets for oral administration, containing: 
- 
sunitinib: 50 mg, 37,5 mg, 25 mg, or 12,5 mg: 
- 
propranolol: 40 mg 
STATISTICAL 
CONSIDERATIONS 
The optimal two-stage Simon design. 
Under the conditions of: α level of 0.050, β level of 0.200, the increase 
in objective response rate from 0.30 for sunitinib monotherapy to 0.55 
for propranolol plus sunitinib combination, a minimum of 15 patients 
will be included in the first stage. The trial will be terminated if 6 or 
fewer patients achieve objective response rate. If the trial goes on to 
the second stage, a total of 33 patients will be studied. If the total 
number of patients achieving objective response rate is less than or 
equal to 13, the combination is rejected. 
 
 

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1. Background 
1.1 Renal Cell Carcinoma 
1.1.1 Epidemiology 
Kidney cancer accounts for approximately 2-3% of adult malignancies with 337860 new cases and 
143406 deaths worldwide [1]. The American Cancer Society estimates that there will be 62700 new 
cases (39650 in males, 23050 in females) of malignant tumors of the kidney, with 14240 deaths (9240 
in males, 5000 in females) in United States in 2016. The most common type of kidney cancer - renal 
cell carcinoma (RCC) – is expected to account for 80-90% of this incidence and mortality [2]. 
RCC is more common in populations of Northern Europe and North America than in those of other 
parts of the world. It is diagnosed more often in men than in women (1,6:1) and with blacks than in 
whites in United States. The patient’s median age at the time of diagnosis was 64 years, according to 
a 4-year observation (2010-2014) [3]. Newly diagnosed patients with a metastatic disease (stage IV, 
according to TNM Classification of Malignant Tumors) accounted for 16% during the period of 2007-
2013. The 5-year survival rate in that group was 11.7 % [3]. 
1.1.2 The Role of VHL-HIF Axis in the Pathogenesis of RCC 
The most frequent histological subtypes of RCC include clear-cell RCC (ccRCC), papillary RCC (pRCC), 
and chromophobe RCC (crRCC) that together represent more than 90% of all RCCs [4]. 
The knowledge of the genetic basis of RCC starts more than 100 years ago with reports of Collins, von 
Hippel and Lindau, who observed vascular-appearing growths involving the retina and occurring in a 
familial context [5-7]. The disease the researchers referred to was an autosomal-dominant dominant 
condition predisposing carriers to the development of hemangioblastomas, pheochromocytomas as 
well as RCCs, named further the von Hippel-Lindau disease (vHL). The sequencing of human von 
Hippel-Lindau gene (VHL) in 1993 was a mile-step in understanding the molecular basis of RCC [8]. Its 
germline inactivating mutation causes vHL disease [9]. The gene, mapped to 3p25, contains three 
exons and encodes 2 proteins by virtue of 2 alternative, start codons. Both forms are referred to as 
“pVHL” because they behave similarly in biochemical and biological aspects, as well as VHL mutations 
in RCC affect both pVHL isoforms [10]. pVHL is the substrate recognition component of an E3 
ubiquitin ligase complex that facilitates the oxygen-dependent ubiquitnation of the hypoxia-inducible 
factors (HIFs). HIF is a heterodimeric DNA-binding transcription factor consisting of an unstable α 
subunit and a stable β subunit. It regulates the expression of more than 1,000 target genes through 
binding to hypoxia response elements. The target genes include those encoding vascular endothelial 
growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), 
transforming growth factor alpha (TGFα), erythropoietin (EPO), cyclin D, hepatocyte growth factor 
(HGF), interleukin-6 (IL-6) and mammalian target of rapamycin (mTOR). Additionally, HIF upregulates 
the nuclear factor kappa B (NFκB) which is a transcription factor that contributes to ccRCC 
development and may be responsible for resistance of the tumour to many forms of therapy [11]. 
pVHL also inhibits a pro-carcinogenic Wnt/β-catenin pathway by promoting the ubiquitination of the 
Wnt signaling protein Disheveled [12]. In the presence of normal oxygen tension in the tissue 

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microenvironment, the HIFα subunits are recognized by pVHL, polyubiquitinated, and then destroyed 
by the proteasome. Under low oxygen conditions or in the absence of functional pVHL, the α subunit 
is stabilized and dimerizes with a β subunit. Further, HIF heterodimer accumulates within the 
cytoplasm, translocates to the nucleus where targets hypoxia responsive genes. Using this pathway, 
HIF is involved in numerous processes, including cell proliferation, angiogenesis, extracellular matrix 
degradation, vascular tone, and erythropoiesis - all the processes involved in cancer development. 
Therefore, when VHL gene performs in a normal pattern, it acts as a tumour-supressor [13, 14]. 
One of the recent studies reported the prevalence of VHL loss in ccRCC to be as high as 91%. VHL 
mutation occurred in 83.4% of cases, whereas methylation of multiple promoter sites inactivating 
VHL was observed in another 8.3% of cases, none containing VHL mutations [15]. Multiple studies 
showed that VHL loss occurred early in the development of ccRCC. The intratumoural heterogeneity 
of ccRCC and the discovery of differential HIFα expression patterns in pVHL-defective ccRCC results in 
suspicion that VHL loss may set the stage for a branched evolution of tumorigenesis in which HIF 
family members can become deregulated in different ways, leading to varying phenotypes of disease 
[16]. 
1.1.3 The Role of Beta-adrenergic Receptors in Carcinogenesis 
Sympathetic nervous system (SNS) that innervates every major organ system of the body is 
responsible for fight-or-flight stress responses. Due to physiological, psychological, and 
environmental threats to homeostasis it releases catecholamine neurotransmitters: norepinephrine 
(NE) via neural junctions and epinephrine (E) from chromaffin cells of the adrenal medulla into 
circulating blood. Seconds after an acute stress-evoking event NE and E levels may increase by more 
than 10-fold. However, basal levels also slightly vary over time and differ in solid tissues versus blood 
[17]. NE and E act via α1, α2, β1, β2, and β3 receptors which are distributed distinctly across different 
types of tissues where are responsible for numerous physiological processes. The activation of the β1 
receptor include increased cardiac output, renin release from juxtaglomerular cells of the kidney, 
increased ghrelin form the stomach. The activation of the β2 receptor results in actions such as 
smooth muscle relaxation in bronchi, gastrointestinal tract, and vessels, anabolism in skeletal 
muscles, insulin secretion, glycogenolysis, whereas the β3 receptor is responsible for lipolysis in 
adipose tissue. Binding NE and E to β receptors stimulates adenyl cyclase (AC) to synthesize cyclic 3′–
5′ adenosine monophosphate (cAMP). cAMP regulates multiple cellular processes via two major 
pathways. The first pathway is based on activation of protein kinase A (PKA) that phosphorylates 
serine or threonine residues on target proteins. The regulation of cellular processes via PKA includes 
metabolism, differentiation, morphology, motility, secretion, neurotransmission, and gene 
transcription. The effect on gene expression is mediated by PKA-induced phosphorylation of the 
cAMP response element binding protein/activating transcription factor (CREB/ATF) family. These 
transcription factors engage approximately 20% of human genes [18, 19]. The second, PKA-
independent pathway uses the guanine nucleotide exchange protein activated by adenylyl cyclase 
(EPAC) activates the Ras-like guanine triphosphatase Rap1A that results in stimulation of mitogen-
activated protein kinase pathway (MAPK). The effect of this stimulation is an engagement of 
downstream effectors such as B-Raf kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and 
extracellular signal-regulated kinases (ERK) 1/2. All these factors play important role in cell growth, 
proliferation, morphology, motility, and secretion dynamics [20]. 

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In the preclinical studies, activation of β-adrenergic receptors by stress hormones has been found to 
play significant role in tumour progression. The AC-cAMP-PKA pathway enables phosphorylation of 
CREB that induces the transcription of genes encoding numerous factors responsible for angiogenesis 
(VEGF), tissue invasion (matrix metalloproteinases [MMPs] 2/9), and inflammation (IL-6, IL-8). The 
cAMP/PKA/phosphoinositide 3-kinase (PI3K)/Akt/mTOR/p70S6 kinase stimulates VEGF expression 
dependent on HIF1α [21-24]. The PKA-independent pathway was reported to induce NFκB and 
activator protein 1 (AP-1) that regulate the translation of VEGF, MMPs and interleukins [25]. The 
stimulation of β2-adrenoceptors activates actin-related proto-oncogene tyrosine-protein kinase Src 
and subsequently phosphorylation of focal adhesion kinase (FAK) that results in lower level of anoikis 
[26]. Furthermore, β2-adrenoceptor stimulation by adrenaline leads to PKA-dependent BCL2-
associated death protein (BAD) phosphorylation which results in resistance to chemotherapy-
induced apoptosis [27]. The activation of PKA-dependent pathway by NE results in Src and signal 
transducer and activator of transcription-3 (STAT-3) stimulation that may drive the growth, invasion 
and metastasis process in ovarian cancer [28, 29]. On the other hand, a metastatic switch may be 
triggered by the tumour-infiltrating macrophages that produce various pro-metastatic factors after 
stress hormones release [30]. The β-adrenergic signaling may also inhibit p53-mediated DNA repair 
[31], suppress cytotoxic T lymphocyte and natural killer (NK) cell responses [32], inhibit expression of 
interferons [33], upregulate the human epidermal growth factor receptor 2 (HER2) signaling pathway 
[34] and induce the snail family transcriptional repressor 2 (SNAI2) which regulates the epithelial-
mesenchymal transition (EMT) [35]. 
Theoretically, the β-adrenergic tumour growth might be driven via circulating catecholamines or via 
NE local release from SNS nerve fibers. Recent studies, however, suggest that the second option is 
most possible. In ovarian cancer tissues E is not detectable and concomitantly NE levels are higher 
than those in circulating blood. What is more, intratumour NE levels correlate with patient 
psychosocial risk factors and with tumor gene expression profiles, whereas NE and E blood levels do 
not [36, 37]. Human breast and ovarian cancer tissues are extensively innervated by peri-vascular 
fibers that may supply tumour and stromal cells with NE [30, 38]. It was also found that social stress 
enhances sympathetic innervation of primate lymph nodes [39] and similar phenomenon in tumour 
tissues cannot be excluded. 
1.1.4 The Place of Sunitinib in Treatment of Metastatic RCC 
Surgical resection remains the only known effective treatment for localized renal cell carcinoma, but 
it also is used for palliation in metastatic disease. Clinical studies showed that nephrectomy increases 
effectiveness of further systemic therapies [40, 41]. Moreover, if the metastases are singular and 
resectable, metastasectomy should be also performed. Resection of single metastases from lung, 
brain or liver can provide a long time without starting a systemic treatment [42, 43]. 
For decades, treatment with classic chemotherapy was unsuccessful in patients with metastatic 
disease. Interleukin-2 (Il-2) and Interferon alpha (IFN-α) introduced in 1990s were the first drugs that 
were able to evoke dramatic and durable tumor regression, however in small percentage of patients 
with significant toxic side effects [44]. Sequencing of human VHL (von Hippel-Lindau) gene and the 
discovery that its abnormalities are found in majority of clear-cell RCC cases were a mile-step in 
development of active agents. Currently, they include VEGFR-targeted tyrosine kinase inhibitors 
(sorafenib, sunitinib, pazopanib, axitinib, lenvatinib and cabozantinib), VEGF antibody (bevacizumab), 

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mTOR pathway inhibitors (temsirolimus and everolimus) and programmed death-1 (PD-1) antibody 
(nivolumab) [45]. All these agents demonstrated clinical benefit in many investigational studies and 
have been approved by the US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA). 
Sunitinib is an orally administrated drug that was approved by FDA in 2005. It is an inhibitor of 
platelet-derived growth factor receptor (PDGFR) -α, -β, vascular endothelial growth factor receptor 
(VEGFR) -1, -2, -3, KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog), FLT-3 (fms-
related tyrosine kinase 3), CSF-1R (colony stimulating factor 1 receptor) and rearranged during 
transfection (RET) proto-oncogene. In a large phase III registration study (NCT00098657) sunitinib 
was superior in efficacy when compared to IFN-α in the control arm. There were 750 previously 
untreated patients with metastatic disease enrolled into the trial, with randomization ratio 1:1 in 
both arms. Patients in investigational arm received sunitinib at a dose of 50 mg daily for four weeks, 
then two weeks without medication (a six-week cycle). In control arm IFN-α was given as a 
subcutaneous injection three times per week on nonconsecutive days at 3 million units (MU) per 
dose during the first week, 6 MU per dose the second week, and 9 MU per dose thereafter. A dose 
reduction was allowed due to severe or uncontrolled adverse effects (to 37.5 mg and then to 25 mg 
daily for sunitinib, and to 6 MU and then to 3 MU three times per week for IFN-α). Median 
progression-free survival (PFS) was 11.0 months for sunitinib vs 5.0 months for IFN-α (Hazard Ratio 
[HR]=0.42, 95% Confidence Interval [CI]: 0.32-0.54, p<0.001). Median overall survival (OS) was 24.6 
vs. 21.8 (HR=0.821, 95% CI: 0.673-1.001, p=0.051) and objective response rate (ORR) was 31% (95% 
CI: 26 to 36) vs. 6% (95% CI: 4% to 9%) for sunitinib and IFN-α, respectively. All-grade adverse events 
occurred more frequently in the sunitinib group than in the IFN-α group. Patients in the sunitinib 
group, as compared with those in the IFN-α group, had higher rates of grade 3 diarrhea (5% vs. no 
cases), vomiting (4% vs. 1%), hypertension (8% vs. 1%), and the hand–foot syndrome (5% vs. no 
cases, p<0.05 for all comparisons). Treatment-related grade 3 or 4 fatigue was significantly higher 
among patients in the IFN-α group than in the sunitinib group (12% vs. 7%, p<0.05). Grade 3 or 4 
leukopenia, neutropenia, and thrombocytopenia occurred more often in the sunitinib group than in 
the IFN-α group (p<0.05 for all comparisons) [46]. In a retrospective, population-based analysis, 
efficacy of sunitinib was similar as in the registration study. Based on data of 6159 sunitinib-treated 
patients, median OS was 22.3 months (95% CI: 21.4-23.2), whereas median PFS was 8.4 months (95% 
CI 8.2-8.7). Response to sunitinib therapy was assessed in 5561 patients of whom 1687 (30%) 
achieved complete response (CR) or partial response (PR) [47]. Recent retrospective analysis of 
Bracarda et al. showed improved safety profile of patients who moved to a modified 2/1 schedule of 
sunitinib compared with that observed during the initial 4/2 schedule, without sacrifice the efficacy 
[48]. In a randomized phase II study of Lee et al., sunitinib administered with a 2/1 schedule was 
associated with less toxicity and higher 6-month failure-free survival than a 4/2 schedule, without 
compromising the efficacy in terms of ORR and time-to-progression [49]. 
1.2 Propranolol 
1.2.1 Pharmacology 
Propranolol (1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol), firstly developed in the 1960s, 
is a non-cardioselective sympatholytic β-adrenergic blocker with a similar binding affinity for β1- and 

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β2- and a much lower affinity (approximately 100-fold) for the β3-adrenoreceptor [50]. It possesses 
no other autonomic nervous system activity. After complete β-adrenoreceptor blockage, the NE 
release in synapsis may only result in α-adrenoceptor activation, and thus propranolol is considered 
as a weak indirect α-adrenoceptor agonist [51]. At dosages greater than required for β blockade it 
presents with strong membrane stabilizing activity. There is also an evidence that propranolol may 
function as an antagonist of 5-HT1A and 5-HT1B serotonin receptors [52]. 
After oral intake, propranolol undergoes rapid absorption in the intestine. It is highly lipophilic and 
more than 90% bound with plasma proteins. Peak plasma concentrations occur about 1 to 4 hours 
after an oral dose. Plasma half-life is 3 to 6 hours following single dose or 10 hours for extended 
release tablets. Mean peak plasma concentration following a single oral dose of 40 mg and 160 mg is 
38 ng/ml and 200-245 ng/ml, respectively. The extended release tablets result in a peak of 18-50 
ng/ml. Bioavailability after oral administration is within the range of 25-35% due to extensive first-
pass hepatic clearance and may be increased up by 50% during concomitant food intake with no 
further change in time to peak concentration, plasma binding, half-life, or the amount of unchanged 
drug in the urine. Propranolol crosses the blood-brain barrier and the placenta, and is distributed 
into breast milk. Its volume of distribution is approximately 4 liters/kg. The metabolism of 
propranolol takes place mainly in the liver and involves cytochromes P (CYPs) CYP2D6, CYP1A2 and 
CYP2C19. Propranolol is also a substrate for the intestinal efflux transporter, p-glycoprotein. 
Excretion is primarily renal, but about 1-4% of a dose is found in the faeces as unchanged drug and 
metabolites. Propranolol plasma clearance is reduced in elderly and Caucasians, as well as in patients 
with chronic renal failure and cirrhosis. Blood levels of propranolol may be increased by co-
administration with substrates or inhibitors of CYP2D6 (i.e. amiodarone, cimetidine, delavudin, 
fluoxetine, paroxetine, quinidine, and ritonavir), CYP1A2 (i.e. imipramine, cimetidine, ciprofloxacin, 
fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan), and CYP2C19 
(i.e. fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide). Blood levels of 
propranolol may be decreased by co-administration with CYP inducers such as rifampin, ethanol, 
phenytoin, phenobarbital and cigarette smoking. Propranolol is not significantly dialyzable [53-56]. 
1.2.2 Current Indications and Dosing 
Currently, propranolol is used in the treatment of hypertension, angina pectoris, cardiac 
dysrhythmias, tachycardia, anxiety, thyrotoxicosis, infantile hemangiomas (IH), and essential tremor. 
It is used in prophylaxis of migraine and upper gastrointestinal tract bleeding in patients with portal 
hypertension as well as for the long term prevention of sudden cardiac death in patients who have 
shown evidence of dysrhythmias during the acute phase of myocardial infarction.  
Usually, the initial propranolol dose in adults is 40 mg two or three times daily and may be increased 
by the same amount at weekly intervals to a maximum daily dose of 320 mg (immediate-release 
tablets). If it is necessary to withdraw propranolol, this should be done gradually, or another β-
adrenergic receptor blocker should be substituted [53, 57].  
1.2.3 Antineoplastic Potential 
Pre-clinical studies revealed wide antineoplastic potential of propranolol that includes inhibiton of 
proliferation, migration, invasion and angiogenesis, as well as induction of apoptosis, treatment 
sensitization and immunomodulation. Propranolol decreased proliferation rate associated with 

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catecholamines or isoproterenol in colorectal, pancreatic and lung adenocarcinoma cancer cells [58-
60]. In oral squamous cell carcinoma cells proliferation was induced via β2 signalling pathway 
activated by IL-6 after stimulation of NE and isoproterenol. Then the proliferation rate was inhibited 
by IL-6 specific antibody and propranolol [61]. Similarly, a decreased level of IL-6 concomitantly with 
inhibition of metastatic growth was reported in a murine melanoma model after propranolol 
treatment [62]. Propranolol was more potent in reducing the proliferation, migration, and invasion of 
non-stimulated breast, colon, and hepatocellular cancer cells than the selective β1 receptor agonist, 
atenolol [63]. Propranolol inhibited the NE-induced upregulation of MMP-2 and MMP-9 which are 
responsible for tissue remodeling process. This resulted in decreased tumour invasion of breast 
cancer, ovarian cancer, nasopharyngeal carcinoma, pancreatic cancer, gastric adenocarcinoma, 
melanoma, prostate cancer and IH [64-71]. NE induces EMT via TGF-β-adrenoreceptor pathway that 
leads to increased metastatic potential and this effect was shown to be inhibited in colorectal cancer 
cell lines by propranolol [72]. In breast cancer cell lines, isoproterenol reduced Rap1-dependent cell-
cell adhesion and promoted cell migration, whereas propranolol reduced the level of migration [73]. 
Catecholamine signaling was also reported to increase breast cancer cell colonization of bone via 
upregulation of receptor activator of nuclear factor kappa-B ligand (RANKL), which was reversed by 
propranolol or the RANKL inhibitor denosumab [74]. Propranolol induced cell cycle arrest and 
apoptosis in gastric carcinoma cell lines that was associated with a decrease of NF-κB, VEGF, 
cyclooxygenase (COX) 2, MMP-2 and MMP-9 expression [68]. The pro-apoptotic effect of propranolol 
was observed in head and neck squamous cell carcinoma and neuroblastoma cell lines and was 
connected to increased expression of p53 and p73 proteins [75, 76]. In another study on 
hemangioblastoma cells from vHL patients, propranolol decreased the viability and increased 
apoptosis that was associated with a decreased the expression of HIF protein and its target genes 
[77]. In ovarian cancer cell lines, propranolol blocked the angiogenesis by decreasing the VEGF 
expression which was previously stimulated by β-adrenergic agonists. Catecholamine induction of 
PKA-dependent signaling pathway was identified as a major mechanism by which behavioural stress 
enhanced tumour angiogenesis [78]. Propranolol inhibited brain endothelial cells tubulogenesis and 
matrix MMP-9 secretion in human glioblastoma [79]. HIF-1α expression was reported to be 
upregulated by NE, via the cAMP/PKA/Akt/p70S6K pathway, whereas propranolol completely 
abolished induction of VEGF expression and HIF-1α protein amount by NE and resulted in decreased 
angiogenesis in various cancer cell lines [80]. Propranolol also exhibited a potential to revert drug 
resistance of some leukemia cell lines to doxorubicin and revealed synergistic role with paclitaxel and 
5-fluorouracil in number of human cancer and non-cancer cell lines [81, 82]. Catecholamines were 
reported to reduce NK cell and cytotoxic T lymphocyte numbers as well as tumour necrosis factor 
alpha (TNFα) and IFN-γ levels and this could be reversed by propranolol [83-85]. 
A positive effect of propranolol on cancer has been observed in epidemiological studies that assessed 
hypertensive and non-hypertensive patients. The study of Chang et al. compared 12119 patients 
treated with propranolol for more than 6 months to 12119 non-propranolol users over a 12 year 
period. Overall, the incidence for developing cancer was lower in the propranolol cohort (HR: 0.75; 
95% CI: 0.67-0.85; p<0.001). Site specific analysis showed a decreased risk in head and neck cancers 
(HR=0.58; 95% CI: 0.35-0.95), oesophagus (HR=0.35; 95% CI: 0.13-0.96), stomach (HR=0.54; 95% CI: 
0.30-0.98), colon (HR=0.68; 95% CI: 0.49-0.93), and prostate cancers (HR=0.52; 95% CI: 0.33-0.83) 
[86]. The study of Nkontchou showed that the use of propranolol in patients with cirrhosis due to 

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hepatitis C was associated with a decreased risk of hepatocellular carcinoma (HR=0.25; 95% CI: 0.09-
0.65; p=0.004) [87]. In the study of Barron et al. women treated with propranolol (n=70) or atenolol 
(n=525) in the year prior to breast cancer diagnosis were matched with women not receiving β-
blocker treatment (n=4738). Patients in the propranolol group had lower risk of having T4 (odds ratio 
[OR]=0.24, 95% CI: 0.07-0.85) or N2/N3/M1 (OR=0.20; 95% CI: 0.04-0.88) tumor compared with 
matched non-users. The cumulative probability of breast cancer-specific mortality was significantly 
lower for propranolol users compared with matched nonusers (HR=0.19; 95% CI: 0.06-0.60). There 
was no difference in T4 or N2/N3/M1 tumor incidence or breast cancer-specific mortality between 
atenolol users and matched non-users [88]. 
Propranolol was also assessed in small interventional studies. In a series of seven cases of advanced 
angiosarcoma, propranolol (40 mg twice daily) was combined with weekly vinblastine (intravenous 
[IV] 6 mg/m2 to a maximum of 10 mg) and methotrexate (35 mg/m2 to a maximum of 50 mg) for up 
to 12 months followed by maintenance of propranolol (40 mg twice daily), oral etoposide (50 
mg/day) and oral cyclophosphamide (50 mg/day) for 20 consecutive days in cycles of 30 days. The 
treatment was well tolerated and resulted in ORR of 100%. Median PFS and OS were 11 months 
(range 5-24) and 16 months (range 10-30), respectively [89]. A combination of propranolol (20 mg 
twice daily, then titrated to maintain heart rate around 80 per minute) plus etodolac (400 mg twice 
daily) with metronomic temozolomide was compared to temozolomide monotherapy in 32 patients 
with recurrent glioblastoma. Patients treated with combination therapy had greater median time to 
progression (8.8 months versus 5.2 months), 6-months survival rate (63% versus 40%) and 1-year 
survival rate (22% versus 12%) than those treated with temozolomide monotherapy, respectively 
[90]. The same combination of propranolol and etodolac was tested with concomitant nab-paclitaxel 
plus gemcitabine in advanced pancreatic cancer. Patients randomized to four-drug therapy had 
greater PFS (11.8 months versus 7.2 months) and OS (15.9 months versus 10.5 months) than those 
receiving standard two-drug, respectively. Additionally, patients receiving propranolol plus etodolac 
experienced reduced pain and neuropathy and increased weight gain [91]. As a β-blocker, 
propranolol may also reduce the level of emotional distress, measured in terms of the number and 
rate of intrusive thoughts, associated with a cancer diagnosis [92]. 
1.2.4 Safety Results 
Propranolol is generally a well tolerated drug. Its adverse effects are listed in Section 7.2.2. The 
initiation of propranolol may lead to initial adverse effects which may resolve during dose titration to 
a maintenance dose. Sudden termination of treatment is not advised. The dose should be tapered 
rather than stopped abruptly. There are no reports of increased toxicity of propranolol in patients 
with cancer likewise during combining propranolol with other antineoplastic agents mentioned in 
Section 1.2.3. 
Because sunitinib can prolong the PR interval of the electrocardiogram in some patients, 
theoretically, its coadministration with propranolol, which also prolongs the PR interval, may result in 
increased risk of conduction disturbances and atrioventricular block. Thus, caution is advised if 
sunitinib is used concomitantly with propranolol, especially in the elderly and patients with known 
conduction problems (e.g., marked first-degree atrioventricular [AV] block; second-degree or higher 
AV block; sick sinus syndrome without pacemaker) or severe cardiac disease such as myocardial 
ischemia or heart failure. Despite the presence of sunitinib for more than 10 years in clinical practice, 

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no serious cardiac and other type toxicity was reported for coadministration of sunitinib and 
propranolol. 
1.3 Study Rationale 
Nowadays, first-line treatment with sunitinib is standard of care in patients with metastatic RCC who 
are classified into favourable- or intermediate-risk group according to Memorial Sloan-Kettering 
Cancer Center (MSKCC) criteria. However, disease progression occurs in most cases as cancer cells 
are primary or secondary resistant to sunitinib. Therefore, new strategies are needed to provide an 
improved option with maximal curative potential. New therapeutic approaches include combining 
sunitinib with autologous dendritic cell immunotherapy, AGS-003 (NCT01582672), PD-L1 inhibitor 
atezolizumab with VEGF inhibitor bevacizumab (NCT02420821), PD-L1 inhibitor avelumab with 
VEGFR inhibitor axitinib (NCT02684006), VEGFR/fibroblast growth factor receptor (FGFR) inhibitor 
lenvatinib with PD-1 inhibitor pembrolizumab (NCT02811861), and dual checkpoint inhibition: PD-1 
inhibitor nivolumab with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor ipilimumab 
(NCT02231749).  
Other directions in development of improved treatment options in metastatic RCC are focused on 
drugs available on the market for years that are prescribed primarily for non-malignant diseases. 
Their antitumor activity was confirmed in preclinical studies and now they are being investigated in 
clinical trials. These studies include dalteparin, a low molecular weight heparin (LMWH) in 
combination with sunitinib in first-lline setting (NCT01061411); prednisone, a glucocorticoid, in 
combination with everolimus in VEGFR pre-treated patients (NCT02479490); hydroxychloroquine, 
antimalaric drug, in combination with IL-2 (NCT01550367); metformin, an anti-diabetic biguanide, in 
combination with vandetanib in hereditary leiomyomatosis and renal cell cancer (HLRCC), succinate-
dehydrogenase (SDH) mutation-associated RCC (SDH-RCC) or sporadic papillary RCC (NCT02495103); 
a monotherapy with low dose naltrexone, an opioid antagonist, for metastatic melanoma, castrate 
resistant prostate cancer or RCC (NCT01650350). 
Since 1960s, propranolol is used worldwide in different indications, mostly for treatment of 
cardiovascular diseases. Despite numerous pre-clinical and clinical studies that described its 
antineoplastic potential, it was not studied extensively as a pure anti-cancer agent in RCC. In the 
current clinical practice, its anti-tumour activity is limited to benign tumour - IH. Due to favourable 
toxicity profile and 82-100% overall response rate, oral propranolol is first-line option in treatment of 
IH, particularly for complicated and ulcerated forms. It has early, intermediate and long-term 
pharmacological effect on IH. The early effect is a visible change in colour and softening of the lesion 
that occurs 1-3 days since the therapy initiation. This is related to the β2 inhibition which results in 
vasoconstriction due to decreased concentration of vasodilators, such as nitric oxide. The 
intermediate effect involves inhibition of proangiogenic cascade and angiogenesis as a consequence 
of VEGF and fibroblast growth factor (FGF) downregulation. The long term effect is due to cell 
apoptosis resulting in regression of haemangiomas [93]. In the recent consensus, a target daily dose 
of 1-3 mg/kg has been recommended [94]. Based on a randomized controlled trial performed by 
Hogeling et al., the treatment should last for at least 6 months which can be modified according to 
the morphological subtypes [95]. 

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Successful treatment of IH with propranolol leads us to investigate whether this drug is able to 
present similar anti-tumour activity in RCC that, in fact, is a highly vascularized neoplasm. Its 
molecular mechanisms of action involve inhibition of signaling pathways that are crucial in RCC 
development and may be exacerbated by intra-tumour release of stress-related hormones. 
Propranolol not only inhibits a catecholamine-dependent cancer cell growth and expansion, but 
simultaneously inhibits VEGF-dependent angiogenesis that is also a main target for currently used 
drugs in RCC, including sunitinib. Therefore, a combination of propranolol and sunitinib may result in 
synergistic anti-tumour effect. It is also worthwhile to mention other molecular actions of 
propranolol that include inhibition of cancer cell proliferation, migration and invasion (Figure 1). 
Together with reduction of emotional stress related to cancer diagnosis, propranolol may bring 
multidirectional benefit for RCC patients treated with sunitinib. Additionally, in colon 
adenocarcinoma, lung adenocarcinoma and melanoma cell lines and mouse models, exogenous NE 
and chronic stress attenuated the efficacy of sunitinib, primarily through promoting expression of 
VEGF, IL-6 and IL-8 that was chiefly mediated by β-adrenergic/cAMP/PKA signaling pathway. This 
negative impact of stress/NE on sunitinib efficacy was blocked by propranolol [96, 97]. 
All the data mentioned above imply that propranolol may increase efficacy of first-line sunitinib in 
patients with metastatic RCC. As a safe and well tolerant medication it is widely prescribed in 
treatment of non-malignant diseases, also within a subgroup of patients with metastatic RCC treated 
with sunitinib. Furthermore, no significant negative interactions (including life-threatening) between 
propranolol and sunitinib were reported in the literature. As a hypotensive drug, propranolol would 
be concomitant and suitable option in management of sunitinib-induced hypertension. Finally, the 
potential benefit of adding propranolol to a standard-of-care sunitinib would not lead to financial 
overload as the monthly cost of propranolol is only about $2.  
To conclude, the molecular antineoplastic profile of propranolol, its potential synergism with 
sunitinib, favourable safety profile, hypotensive potential for sunitinib-induced hypertension, ability 
to reduce cancer-associated anxiety and low cost of intervention encourage us to assess 
prospectively the combination of propranolol and sunitinib in first-line treatment of metastatic RCC. 

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Figure 1. Theoretical model of synergistic anti-tumour activity of propranolol plus sunitinib in RCC. 

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2. Study Objectives 
2.1 Primary Objective 
To assess the efficacy of first-line systemic therapy with propranolol plus sunitinib in patients with 
metastatic RCC. 
Primary endpoint:  
• 
objective response rate. 
2.2 Secondary Objectives 
To assess the efficacy, safety, influence on health-related quality of life and disease-related stress, 
and relationship between tumour tissue markers and serum biomarkers with treatment and clinical 
outcomes of first-line systemic therapy with propranolol plus sunitinib in patients with metastatic 
RCC. 
Secondary endpoints: 
• 
overall survival, 
• 
progression-free survival, 
• 
disease control rate, 
• 
incidence of adverse events and serious adverse events, 
• 
changes from baseline in vital signs and laboratory results, 
• 
changes in patient-reported outcomes using The European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, version 3) and FACT-Kidney 
Symptom Index - 15 (FKSI-15), 
• 
changes in patient-reported outcomes using the 10-point Perceived Stress Scale (PSS), 
• 
relationship of the primary tumour tissue and serum biomarkers with treatment and clinical 
outcomes. 
3. Study Design 
3.1 Summary of Study Design 
The present study is designed as a prospective, interventional, single-arm, single-center, and open-
label phase II trial. 
The study is planned to have 3 periods (illustrated in Figure 1.): 
1. 
A pre-treatment period – starts at the time of patient’s screening, giving him information of the 
study and writing consent. 
2. 
A treatment period – starts at application of first dose of interventional products under medical 
supervision and lasts until discontinuation of study treatment. 

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3. 
A postdiscontinuation period – starts at the time of discontinuation from study treatment; this 
period includes a summary (end-of-treatment) visit and will continue until death or the end of 
study data collection. 
 
 Pre-treatment period  
Treatment period  
 
Postdiscontinuation period 
 
 
 
     Arm I (sunitinib + propranolol) 
(propranolol continuation if eligible) 
 
 
 
 
Screening 
Start of treatment 
 
 
End of treatment 
  
End of study 
Figure 1. The illustration of study design for Protocol PS-001. 
3.2 Length of the Study 
Total length of the study is planned to be at least 18 months, including 12 months of accrual time, 
and then at least 6 months of follow-up time since the last patient recruitment. 
3.3 Study Extension 
After data final analysis, all remaining on-study patients without disease progression will be 
permitted to transition into the extension phase of the study to continue to receive treatment until 
disease progression, death, unacceptable toxicity, patient refusal, or start of any new anticancer 
treatment, whichever occurs first. 
4. Study Population 
4.1 Number of Patients Planned 
According to the sample size calculation (Section 8.2), maximum number of 33 patients will be 
enrolled in the study. 
4.2 Recruitment of Patients 
Candidates for the trial will be recruited from a general population of patients with metastatic RCC, 
who are planned to start first-line systemic anticancer therapy with sunitinib. 
4.3 Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
1. Histological diagnosis of ccRCC or mixed-type RCC with more than 60% of clear-cell component. 
2. Diagnosis of stage IV RCC (primary metastatic or recurrence after surgical procedure). 
3. Prior nephrectomy (complete or partial). 

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4. Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1. 
5. Karnofsky performance status (KPS) score of 80-100%. 
6. Favourable- or intermediate-risk according to MSKCC criteria. 
7. Adequate organ function, including the following: 
a. hepatic: total bilirubin ≤ 2 times the upper limit of normal (excluding patients with 
Gilbert syndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤  5 times the upper limit of normal, 
b. renal: serum creatinine ≤ 2 times the upper limit of normal, 
c. bone marrow: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100000/mm3, 
hemoglobin ≥ 9,5 g/dl. 
8. Normal thyroid function (natural or with supplementation of thyroid hormones) defined as 
thyroid-stimulating hormone (TSH) within limits of normal. 
9. Age eighteen years or older on the day of consent. 
10. Written informed consent prior to study entry. 
4.4 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Prior systemic pharmacotherapy of renal cell carcinoma. 
2. Treatment with propranolol within 6 months of study entry. 
3. Metastases in central nervous system (patients who had central nervous system metastases that 
were surgically resected and/or treated with radiotherapy in the past and now are without 
neurological symptoms, are allowed on protocol). 
4. Female patients who are pregnant or breast feeding or adults of reproductive potential who are 
not using effective birth control methods. 
5. Presence of other malignancies (patients with carcinoma in situ of the cervix or basal cell 
carcinoma of the skin are allowed on protocol). 
6. Presence of any severe and/or uncontrolled medical conditions or other conditions that could 
affect their participation in the study such as: 
a. heart failure of New York Heart Association Class III or IV, significant cardiac arrhythmia 
or any other clinically significant cardiovascular disease, 
b. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
within 6 months of entering the study,  

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c. severely impaired respiration as defined as 02 saturation that is ≤ 90% at rest on room 
air, 
d. uncontrolled diabetes as defined by fasting serum glucose > 1,5 times the upper limit of 
normal, 
e. ejection fraction less than 40% (measured at echocardiography), 
f. 
significant liver disease such as cirrhosis, active hepatitis or chronic persistent hepatitis, 
g. active (acute or chronic) infections requiring antimicrobial intervention. 
7. Concomitant treatment with: 
a. chronic, systemic corticosteroids or another immunosuppressive agent; topical or 
inhaled corticosteroids are allowed, 
b. strong CYP3A4 inducers/inhibitors: carbamezepine, phenytoin, rifabutin, rifampin, 
nafcillin, phenobarbital, St John’s wort, itraconazole, ketoconazole, erythromycinum, 
clarithromycinum, nefazodone. 
8. Known allergy/sensitivity to sunitinib and/or propranolol. 
9. Galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 
10. Immunization with attenuated live vaccines within 30 days of study entry. 
11. Human immunodeficiency virus (HIV) sero-positivity at the study entry or in the past. 
12. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the 
absorption of sunitinib and/or propranolol (e.g., ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome or small bowel resection). 
13. Presence of active, bleeding diathesis. 
14. Major surgery (defined as requiring general anesthesia) and/or significant traumatic injury 
(requiring > 28 days to heal) within 28 days of the study entry; presence of side effects due to 
any surgery or probable requirement of major surgery during the course of the study. 
15. Present contraindications to propranolol, that include: bronchial asthma, prolonged fasting, 
acidosis, hypotension (systolic blood pressure less than 90 mmHg, diastolic blood pressure less 
than 60 mmHg), severe peripheral arterial circulatory disturbance, cardiogenic shock, 
bradycardia, Prinzmetal’s angina, uncontrolled heart failure, second or third degree heart block, 
untreated phaeochromocytoma, sick sinus syndrome. 
16. Inability or unwillingness of subject or legal guardian/representative to give written informed 
consent. 

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4.5 Discontinuations 
4.5.1 Discontinuation of Patients 
Patients will be discontinued from the study in the following circumstances: 
1. 
Withdrawal of informed consent. 
2. 
Evidence of progressive disease (PD) including patient’s death. 
3. 
Recurrent or unacceptable toxicity grade ≥ 3 according to The Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. 
4. 
Karnofsky performance status < 70 observed in three assessment points (visits) in a row. 
5. 
Development of exclusion criteria or other safety reasons. 
6. 
Use of illicit drugs or other substances that may, in the opinion of the investigator, have a 
reasonable chance of contributing to toxicity or otherwise skewing results. 
7. 
Discontinuation of sunitinib and/or propranolol for more than 14 days (excluding the 2-week 
rest period for each cycle of sunitinib). 
8. 
Protocol non-compliance. 
In all cases, the reason for withdrawal must be recorded in the Case Report Form (CRF) and in the 
subject's medical records. All patients who discontinue because of adverse events or clinical 
laboratory abnormalities should be followed up until they recover or stabilize, and the subsequent 
outcome recorded. 
4.5.2 Replacement of Patients 
Patients who discontinue due to toxicity related to one or both study drugs will not be replaced. 
Patients who discontinue during the first two weeks due to reasons other than toxicity will be 
replaced. 
4.5.3 Discontinuation of the Study 
The study will be discontinued if the Investigators judge it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP. 
5. Study Interventions 
5.1 Investigational Products 
5.1.1 Sunitinib (SUTENT® by Pfizer Inc.) 
Marketing Authorisation Holder: 
Pfizer Limited  
Ramsgate Road  

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Sandwich, Kent CT13 9NJ  
United Kingdom 
 
Presentation of sunitinib 50 mg: gelatin capsules with caramel cap and caramel body, printed with 
white ink “Pfizer” on the cap, “STN 50 mg” on the body and containing yellow to orange granules. 
Presentation of sunitinib 37.5 mg: gelatin capsules with yellow cap and yellow body, printed with 
black ink “Pfizer” on the cap, “STN 37.5 mg” on the body and containing yellow to orange granules. 
Presentation of sunitinib 25 mg: gelatin capsules with caramel cap and orange body, printed with 
white ink “Pfizer” on the cap, “STN 25 mg” on the body and containing yellow to orange granules. 
Presentation of sunitinib 12.5 mg: Gelatin capsules with orange cap and orange body, printed with 
white ink “Pfizer” on the cap, “STN 12.5 mg” on the body, and containing yellow to orange granules. 
Modalities of administration: 1 capsule (50 mg or 37.5 mg [alternatively: 1 capsule 25 mg + 1 capsule 
12.5 mg] or 25 mg) every day during the treatment period. Capsule must be administered orally, with 
or without food. 
Dosage: starting dose is 50 mg taken once daily, for 4 consecutive weeks, followed by a 2-week rest 
period (schedule 4/2) to comprise a complete cycle of 6 weeks. The schedule may be changed by the 
Investigator to 2 weeks on / 1 week off to decrease the level of toxic effects. Dose modifications in 
12.5 mg steps may be applied based on individual safety and tolerability. Daily dose cannot be either 
decreased below 25 mg or increased over 50 mg. If there are suspicions of its unacceptable toxicity, 
it must be withdrawn immediately. 
There is no specific antidote for overdose with sunitinib and treatment of overdose should consist of 
general supportive measures. If indicated, elimination of unabsorbed active substance may be 
achieved by emesis or gastric lavage. 
5.1.2 Propranolol (Propranolol Accord® by Accord Healthcare Ltd.) 
Marketing Authorisation Holder: 
Accord Healthcare Limited 
319, Pinner Road, 
North Harrow, 
Middlesex HA1 4HF, 
United Kingdom 
 
Presentation of propranolol 40 mg: white to off-white round, biconvex film-coated tablets imprinted 
with 'AL' on one side and a score line on the other side. Diameter of the tablet is 9.0 mm. The score 
line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. 
Modalities of administration: prespecified number of propranolol tablets every day during treatment 
period. In case of administration two times a day, tablet(s) must be administered orally in the 
morning and in the evening. In case of administration three times a day, tablet(s) must be 
administered orally in the morning, in the afternoon and in the evening. 

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Dosage: it is obligatory to follow the schedule presented below: 
1. the starting dose is 40 mg (one tablet) two times a day (total daily dose of 80 mg); if the drug is 
well tolerated the dose should be increased to a dose mentioned in point 2., but not faster than 
7 days of the current dose; if the drug is badly tolerated, the drug should be withdrawn and the 
patient should discontinue propranolol treatment; 
2. the next dose is 80 mg (two tablets) two times a day (total daily dose of 160 mg); if the drug is 
well tolerated the dose should be increased to a dose mentioned in point 3., but not faster than 
7 days of the current dose; if the drug is badly tolerated, the dose should be decreased to that 
mentioned in point 1. or withdrawn in case of severe toxicity; 
3. the next dose is 80 mg (two tablets) three times a day (total daily dose of 240 mg); if the drug is 
well tolerated the dose may not be increased; if the drug is badly tolerated, the dose should be 
decreased to that mentioned in point 2. or point 1. or withdrawn in case of severe toxicity. 
In case of propranolol overdose, atropine 1 to 2 mg intravenously can counter excessive bradycardia. 
If necessary this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this 
may be followed or repeated by an intravenous infusion of glucagon 1 to 10 mg/hour depending on 
response. If no response is received to the glucagon or if glucagon is unavailable, a beta-
adrenoceptor stimulant e.g. dobutamine 2.5 to 10 microgram/kg/minute by intravenous infusion 
may be given. Bronchospasm may be treated by nebulized salbutamol or intravenous aminophylline 
or salbutamol. Severe cases may require the use of oxygen or artificial ventilation. 
When it has been decided to interrupt a β-blockade in preparation for surgery, therapy should be 
discontinued for at least 48 hours. Continuation of beta-blockade reduces the risk of arrhythmias 
during induction and intubation; however the risk of hypotension may be increased as well. If 
treatment is continued, caution should be observed with the use of certain anaesthetic drugs. The 
patient may be protected against vagal reactions by intravenous administration of atropine. 
5.2 Concomitant Treatment 
5.2.1 Prohibited Concomitant Treatment 
• 
Any drugs that have been approved in antitumor therapies or any new potentially antineoplastic 
agents that are being investigated (e.g. IL-2, IFN, cabozantinib, sorafenib, axitinib, dovitinib, 
pazopanib, lenvatinib, everolimus, temsirolimus, nivolumab, ipilimumab). 
• 
CYP3A4 
inducers/inhibitors: 
carbamezepine, 
phenytoin, 
rifabutin, 
rifampin, 
nafcillin, 
phenobarbital, St John’s wort, itraconazole, ketoconazole, erythromycinum, clarithromycinum, 
nefazodone. 
• 
Immunosuppressors and immunomodulators including chronic systemic corticosteroids. 
• 
β-agonists, β-blockers other than propranolol, bronchodilators, calcium channel blockers 
(verapamil, diltiazem or bepridil), fingolimod, barbiturates, propafenone, monoamine oxidase 
inhibitors. 

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• 
attenuated live vaccines. 
5.2.2 Permitted Concomitant Treatment 
Any drugs other than those listed above are allowed, and should be administered, as necessary for 
the treatment of the patient, when possible with a stable dose, at the discretion of the Investigator. 
All treatment with these drugs should be recorded on the appropriate CRF. 
5.3 Storage, Accountability and Compliance 
All study drugs must be kept in a secure place under adequate storage conditions – protected from 
moisture and light. The patient will record the use of study medications in the Patient’s Diary on a 
daily basis and the adherence to the prescribed treatment will be checked at every clinic visit. If there 
are at least 14 days without study drugs intake (excluding a 14 days off the sunitinib in each cycle), 
patient should be discontinued from the study. 
6. Study Measures 
6.1 Definitions of Efficacy Measures 
6.1.1 Objective Response Rate 
Objective Response Rate (ORR) is defined as the percentage of patients who have achieved partial 
response (PR) and complete response (CR) according to RECIST guidelines (version 1.1). 
6.1.2 Progression-free Survival 
Progression-Free Survival (PFS) is defined as the time from the date of first dose investigational 
products administration to the first date of objectively determined progressive disease (PD) 
according to RECIST guidelines (version 1.1) or death from any cause. For patients not known to have 
died as of the data cut-off date and who do not have objective PD, PFS will be censored at the date of 
the last RECIST (version 1.1) assessment. 
6.1.3 Overall Survival 
Overall Survival (OS) is defined as the time from the date of first dose investigational products 
administration to the date of death from any cause. For patients not known to have died as of the 
data cut-off date, OS will be censored at the last contact date. 
6.1.4 Disease Control Rate 
Disease Control Rate (DCR) is defined as the percentage of patients who have achieved partial 
response (PR), complete response (CR) and stable disease (SD) according to RECIST guidelines 
(version 1.1). 
6.2 Safety Measures 
Safety evaluation will rely on capturing all adverse events reported on vital signs, physical 
examinations and laboratory tests. The CTCAE (version 4.0) will be used to standardize reported 
adverse events of any kind.  

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6.3 Health-related Quality of Life Measures 
The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30 version 3) and FACT-Kidney Symptom Index - 15 (FKSI-15) are validated and reliable 
self-administered instruments that will be used to assess health-related quality of life.  
6.4 Disease-related Stress Measures 
The 10-point Perceived Stress Scale (PSS) is validated and reliable self-administered instrument that 
will be used to assess Disease-related Stress (DRS). 
6.5 Tumour Tissue and Serum Biomarkers Assessments 
Formalin-fixed paraffin embedded primary tumour tissue (archival or recently biopsied) and serum 
biomarkers will be used for exploratory analysis of potential pathway components or modulators 
associated with RCC or the mechanism(s) of action of the study drugs. 
6.6 Timing and Methods of Measurements 
6.6.1 Pre-treatment Period 
The protocol presents scheduled timelines for study procedures by abbreviated references to week 
(W) and day (D) (eg, W1D1, W3D1 etc) relative to the date of the first dose of study treatment 
(defined as W1D1). 
Patients will be examined within 7 days prior to the first ingestion of the investigational products 
during a screening visit to assess their eligibility to participate. Each subject will consent in writing to 
the screening process before the start of the examination. The consent form will also include the 
study information leaflet. The examinations and investigations will include: 
• 
medical history, including history of concomitant chronic diseases, allergies, use of medications, 
demographics (date of birth, sex, race), alcohol and tobacco consumption patterns, family 
history of cancer, 
• 
physical examination including assessment of general appearance, mouth, throat, 
cardiovascular, lungs, abdomen and measurement of height and body weight. The examination 
will be made in accordance with the normal clinical routines at the trial center, 
• 
vital signs: systolic and diastolic blood pressure, heart rate, pulse, respiratory rate, 02 saturation 
and body temperature, 
• 
KPS score, 
• 
electrocardiography (ECG): standard 12-lead, 
• 
24-hour Holter ECG monitoring, 
• 
echocardiography, 
• 
cardiology consultation, 

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• 
laboratory tests: 
 hematology: a complete blood count with hemoglobin level, 
 serum biochemistry including levels of: creatinine, urea, bilirubin, AST, ALT, LDH, TSH, 
alkaline phosphatase (ALP) albumin, sodium, potassium, calcium (total),  
 coagulation: Activated Partial Thromboplastin Time (APTT), International Normalized 
Ratio (INR) 
 routine urine analysis, 
 serum β-HCG pregnancy test in fertile females, 
 HIV testing by the enzyme-linked immunosorbent assay (ELISA) +/- Western blot. 
• 
filling in EORTC QLQ-C30 and FKSI questionnaires, 
• 
filling in the PSS questionnaire, 
• 
collection of blood samples for serum biomarkers, 
• 
collection of formalin-fixed paraffin embedded primary tumour tissue whenever available. 
Corrected calcium level will be calculated using formula: 
Corrected calcium level [mg/dl] = total calcium level [mg/dl] + 0.8 x (4.0 - albumin level [g/dL]) 
Within 4 weeks before the start of therapy, baseline tumor measurement(s) will be performed on 
each patient. Computed tomography (CT) and magnetic resonance imaging (MRI) are allowed 
methods of measurement. The study will not permit ultrasound, chest-X-ray or positron emission 
tomography (PET) scans as methods of tumor measurement. 
6.6.2 Treatment Period 
During every day of the treatment period, patient will have to collect blood pressure and pulse 
measures two times a day (in the morning and in the evening) and to record the results in the 
Patient’s Diary. 
The examinations and investigations during control visits, that will take place every 6 weeks of 
treatment, will include:  
• 
physical examination,  
• 
vital signs measurement,  
• 
laboratory tests: 
 hematology: a complete blood count with hemoglobin level, 

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 serum biochemistry including levels of: creatinine, urea, bilirubin, AST, ALT, ALP, LDH, 
albumin, sodium, potassium, calcium (total), 
• 
standard 12- lead ECG, 
• 
filling in the EORTC QLQ-C30 and FKSI-15 questionnaires, 
• 
filling in the PSS questionnaire. 
 
At the start of the second and third week of the treatment (W2D1 and W3D1), additional visit is 
planned to assess safety of propranolol and to define further propranolol dose and will include 
physical examination, vital signs measurement, verification of ambulatory blood pressure and pulse 
measures, ECG (12-lead) and optional cardiology consultation.  
Blood samples for serum biomarkers will be obtained at W7D1. 
The method used at baseline to assess tumor measurement(s) must be used consistently and will be 
repeated every 12 weeks (± 2 weeks). Tumor responses will be measured and recorded using the 
RECIST guidelines (version 1.1). 
6.6.3 Postdiscontinuation Period 
Patients will continue treatment until they require discontinuation of study drugs for any reason 
mentioned in Section 4.5.1 of this document (including disease progression). Each enrolled patient 
will enter a postdiscontinuation period once study treatment is discontinued. The end-of-treatment 
visit will take place within 30 days after discontinuation of the study drugs and will include: 
• 
physical examination,  
• 
vital signs measurement,  
• 
laboratory tests: 
 hematology: a complete blood count with hemoglobin level, 
 serum biochemistry including levels of: creatinine, urea, bilirubin, AST, ALT, ALP, LDH, 
TSH, albumin, sodium, potassium, calcium (total), 
 coagulation: APTT, INR, 
• 
standard 12- lead ECG, 
• 
24-hour Holter ECG monitoring, 
• 
echocardiography, 
• 
cardiology consultation, 
• 
filling in the EORTC QLQ-C30 and FKSI-15 questionnaires, 

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• 
filling in the PSS questionnaire, 
• 
blood samples for serum biomarkers. 
During the postdiscontinuation period, information about date of disease progression, death, 
adverse events, subsequent anticancer systemic therapy, radiotherapy, or surgical intervention will 
be collected. 
In case of disease progression and the need for second-line anticancer therapy, propranolol may be 
continued beyond first-line progression if the drug is well tolerated and there are other indications to 
continue β-adrenergic blockade. It may be also replaced by other β-blocker, if necessary. Cessation of 
propranolol therapy should be gradual. 
6.6.4 Unscheduled Visits or Assessments 
If the investigator determines that a subject should be monitored more frequently or with additional 
laboratory parameters assessments than indicated by the protocol-defined visit schedule, 
unscheduled visits or assessments are permitted. Unscheduled visits for radiographic evaluations are 
allowed at any time as clinically indicated. 
7. Adverse Events 
7.1 Adverse Events Definitions 
An adverse event (AE) is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition during treatment. However, it does not necessarily have to have a 
causal relationship with this treatment. 
A Serious Adverse Event (SAE) is an adverse event occurring during any phase of the study and at any 
dose of the investigational product which fulfils one or more of the following criteria: 
• 
results in death, 
• 
is life-threatening (it refers to an event in which the patient was at risk of death at the time of 
the event), 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity. 
7.2 Expected Adverse Events 
7.2.1 Expected Adverse Events for Sunitinib 
Adverse reactions related to sunitinib are listed below by system organ class and frequency. 
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 
to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); Frequency not known (cannot be 
estimated from the available data). 
The following undesired events, listed by body system, have been reported: 

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Blood and lymphatic system disorders  
Very common: neutropoenia, thrombocytopenia, anaemia, leucopoenia. 
Common: lymphopoenia. 
Uncommon: pancytopenia. 
Rare: thrombotic microangiopathy. 
Immune system disorders 
Uncommon: hypersensitivity. 
Rare: angioedema. 
Endocrine disorders 
Very common: hypothyroidism. 
Uncommon: hyperthyroidism. 
Rare: thyroiditis. 
Infections and infestations 
Common: viral infections, respiratory infections, abscess, fungal infections, urinary tract infection, 
skin infections, sepsis. 
Uncommon: necrotising fasciitis, bacterial infections. 
Metabolism and nutrition disorders 
Very common: decreased appetite. 
Common: dehydration, hypoglycaemia. 
Rare: tumour lysis syndrome. 
Psychiatric disorders 
Very common: insomnia. 
Common: depression. 
Nervous system disorders 
Very common: dizziness, headache, taste disturbance. 
Common: neuropathy peripheral, paraesthesia, hypoaesthesia, hyperaesthesia. 
Uncommon: cerebral haemorrhage, cerebrovascular accident, transient ischaemic attack. 
Rare: posterior reversible encephalopathy syndrome. 
Eye disorders 
Common: periorbital oedema, myelid oedema, lacrimation increased. 
Cardiac disorders 
Common: myocardial ischemia, ejection fraction decreased. 
Uncommon: cardiac failure congestive, myocardial infarction, cardiac failure, cardiomyopathy, 
pericardial effusion, ECG QT prolonged. 
Rare: left ventricular failure, torsade de pointes. 
Vascular disorders 
Very common: hypertension. 
Common: deep vein thrombosis, hot flush, flushing. 
Uncommon: tumour haemorrhage. 
Respiratory, thoracic and mediastinal disorders 
Very common: dyspnoea, epistaxis, cough. 
Common: pulmonary embolism, pleural effusion, haemoptysis, dyspnoea exertional, oropharyngeal 
pain, nasal congestion, nasal dryness. 
Uncommon: pulmonary haemorrhage, respiratory failure. 

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Gastrointestinal disorders 
Very common: stomatitis, abdominal pain, vomiting, diarrhea, dyspepsia, nausea, constipation. 
Common: gastro-oesophageal reflux disease, dysphagia, gastrointestinal haemorrhage, oesophagitis, 
abdominal distension, abdominal discomfort, rectal haemorrhage, gingival bleeding, mouth 
ulceration, proctalgia, cheilitis, haemorrhoids, glossodynia, oral pain, dry mouth, flatulence, oral 
discomfort, eructation. 
Uncommon: gastrointestinal perforation, pancreatitis, anal fistula. 
Hepatobiliary disorders 
Uncommon: hepatic failure, cholecystitis, hepatic function abnormal. 
Rare: hepatitis. 
Skin and subcutaneous tissue disorders 
Very common: skin discolourations, palmar-plantar erythrodysaesthesia syndrome, rash, hair colour 
changes, dry skin. 
Common: skin exfoliation, skin reaction, eczema, blister, erythema, alopecia, acne, pruritus, skin 
hyperpigmentation, skin lesion, hyperkeratosis, dermatitis, nail disorder. 
Rare: erythema multiforme, Stevens-Johnson syndrome, pyoderma gangrenosum, toxic epidermal 
necrolysis. 
Musculoskeletal and connective tissue disorders 
Very common: pain in extremity, arthralgia, back pain. 
Common: musculoskeletal pain, muscle spasms, myalgia, muscular weakness. 
Uncommon: osteonecrosis of the jaw, fistula. 
Rare: rhabdomyolysis, myopathy. 
Renal and urinary disorders 
Common: renal failure, renal failure acute, chromaturia, proteinuria. 
Uncommon: haemorrhage urinary tract. 
Rare: nephrotic syndrome. 
General disorders and administration site conditions 
Very common: mucosal inflammation, fatigue, oedema, pyrexia. 
Common: chest pain, pain, influenza like illness, chills. 
Uncommon: impaired healing. 
Investigations 
Common: Weight decreased, white blood cell count decreased, lipase increased, platelet count 
decreased, haemoglobin decreased, amylase increased, aspartate aminotransferase increased, 
alanine aminotransferase increased, blood creatinine increased, blood pressure increased, blood uric 
acid increased. 
Uncommon: blood creatine phosphokinase increased, blood thyroid stimulating hormone increased. 
7.2.2 Expected Adverse Events for Propranolol 
Adverse reactions related to propranolol are listed below by system organ class and frequency. 
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 
to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); Frequency not known (cannot be 
estimated from the available data). 
The following undesired events, listed by body system, have been reported: 
Blood and lymphatic system disorders  

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Rare: thrombocytopenia. 
Frequency not known: agranulocytosis. 
Immune system disorders  
Rare: angioedema. 
Endocrine disorders  
Frequency not known: masking signs of thyrotoxicosis. 
Metabolic and nutritional disorders  
Frequency not known: hypoglycaemia in neonates, infants, children, elderly patients, patients on 
haemodialysis, patients on concomitant antidiabetic therapy, patients with prolonged fasting and 
patients with chronic liver disease has been reported. Changes in lipid metabolism (changes in blood 
concentrations of triglycerides and cholesterol). Severe hypoglycemia may rarely lead to seizures or 
coma. 
Psychiatric disorders  
Common: sleep disturbances, nightmares. 
Rare: Hallucinations, psychoses, mood changes 
Frequency not known: depression. 
Nervous system disorders  
Rare: confusion, memory loss, dizziness, paraesthesia. 
Very rare: Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis 
have been reported. 
Frequency not known: headache, seizure linked to hypoglycaemia. 
Eye disorders  
Rare: visual disturbances, dry eyes. 
Frequency not known: conjunctivitis. 
Cardiac disorders  
Common: bradycardia. 
Rare: Heart failure deterioration, precipitation of heart block, postural hypotension which may be 
associated with syncope. 
Frequency not known: worsening of attacks of angina pectoris. 
Vascular disorders  
Common: cold extremities, Raynaud's syndrome. 
Rare: exacerbaction of intermittent claudication. 
Respiratory thoracic and mediastinal disorders  
Common: breathlessness. 
Rare: Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic 
complaints, sometimes with fatal outcome. 
Frequency not known: dyspnoea. 
Gastrointestinal disorders  
Uncommon: diarrhoea, nausea, vomiting. 
Frequency not known: constipation, dry mouth. 
Skin and subcutaneous tissue disorders  
Rare: alopecia, purpura, psoriasiform skin reactions, exacerbation of psoriasis, rash. 
Very rare: isolated cases of hyperhidrosis have been reported. 
Musculoskeletal system and connective tissue disorders  

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Frequency not known: arthralgia. 
Renal and urinary disorders  
Frequency not known: reduced renal blood flow and GFR. 
Reproductive system and breast disorders  
Frequency not known: impotence. 
General disorders and administration site conditions  
Common: fatigue and/or lassitude (often transient). 
Investigations:  
Very rare: An increase in antinuclear antibodies (ANA) has been observed with many β-blockers, 
however the clinical relevance of this is not clear. 
7.3 Adverse Events Management 
If any adverse event occurs, all appropriate measurements to ensure the safety of the patients must 
be taken. The investigator has to care about patient with best medical knowledge and available 
methods of treatment and should follow up the outcome of adverse events (clinical signs, laboratory 
values or other, etc) until the return to normal or stabilization of the patient's condition. Dose 
modification for drug induced toxicity should be kept with accordance to Summary of Product 
Characteristics of all used drugs.  
7.4 Adverse Events Monitoring and Reporting 
All Adverse Events regardless of seriousness or relationship to investigational products have to be 
recorded on the corresponding page(s) included in the CRF. The Investigator should specify the date 
of onset, intensity, action taken with respect to investigational products, corrective 
treatment/therapy given, outcome and his/her opinion as to whether there is a reasonable 
possibility that the AE was caused by the investigational products. 
In the case of a SAE the Investigator must send the signed and dated corresponding page(s) in the 
CRF to the representative of the Monitoring Team and attach a copy of all examinations carried out 
with dates on which these examinations were performed. 
8. Statistical Considerations 
8.1 Study Hypotheses 
Primary hypothesis is whether addition of oral propranolol to sunitinib in first-line treatment of 
metastatic RCC can increase its antitumor efficacy and it is related to analyses of: ORR, PFS, OS, and 
DCR. 
Secondary hypothesis is whether addition of oral propranolol to sunitinib in first-line treatment of 
metastatic RCC is safe and has an influence on patient-reported quality of life and disease-related 
stress and it is referred to analyses of: adverse events, vital signs, physical examinations, laboratory 
tests, health-related quality of life and disease-related stress. 

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8.2 Sample Size Calculation 
According to registration study for sunitinib and a recent population-based study, the ORR of 
sunitinib monotherapy is estimated to be around 30% [46, 47]. Because strong potential bias exists 
due to single-center and phase II study design, we assume an increase to 55% of the ORR under 
propranolol plus sunitinib therapy as a combination worthwhile for further investigation. 
The optimal two-stage Simon design is to test the null hypothesis that P ≤ 0.300 versus the 
alternative that P ≥ 0.550 has an expected sample size of 17.36 and a probability of early termination 
of 0.869. If the combination of propranolol and sunitinib is actually not effective, there is a 0.050 
probability of concluding that it is (the target for this value [α level] was 0.050). If the combination is 
actually effective, there is a 0.195 probability of concluding that it is not (the target for this value [β-
level] was 0.200). After testing the combination on 15 patients in the first stage, the trial will be 
terminated if 6 or fewer achieve ORR. If the trial goes on to the second stage, a total of 33 patients 
will be studied. If the total number achieving ORR is less than or equal to 13, the combination is 
rejected. 
8.3 General Considerations 
The analyses will be performed on all patients who received at least one dose of study medications.  
Descriptive statistics, including the mean, standard deviation, median, interquartile range, minimum, 
and maximum values will be provided for continuous variables as well as frequencies and 
percentages for categorical variables. 
Characteristics such as patient age, gender, height, weight, medical history, and Karnofsky 
performance status, concomitant therapies, as well as baseline signs and symptoms will be 
tabulated. 
Study drug administration will be described in terms of the total number of cycles administered, the 
median (range) of cycles administered, dose intensity, and reasons for the deviations from planned 
therapy. 
A detailed description of patient disposition will be provided. It will include: summary of patients 
screened, total number of patients enrolled, total number of patients discontinuing the study. A 
detailed summary of reasons for patient discontinuation from study treatment will be provided. 
8.4 Primary and Secondary Endpoints Analyses 
8.4.1 ORR and DCR Analysis 
The response (CR, PR, SD, PD, ORR, and DCR according to RECIST guidelines (version 1.1)) will be 
summarized for studied patients as frequency and percentages with 2-sided 95% CI calculated using 
the Clopper-Pearson method.  
To indirectly compare ORR and DCR of patients treated with propranolol and sunitinib combination 
versus sunitinib monotherapy, a group of patients treated with sunitinib monotherapy will be drawn 
from the institution historical cohort. This control group will consist of 33 consecutive patients that 
started sunitinib monotherapy just before the beginning of the present study. The comparison will be 

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made using unstratified Pearson χ2 test or the Fisher’s exact test (in case of no more than 5 expected 
frequencies in each cell of a studied contingency table) and the Cochran-Mantel-Haenszel test 
stratified by the MSKCC risk group (favourable versus intermediate). This additional analysis is 
planned only if the trial goes on to the second stage. 
8.4.2 PFS and OS Analysis 
PFS and OS will be summarized using Kaplan-Meier method and displayed graphically as cumulative 
probability of survival (Y axis) versus time since treatment initiation (X axis). The median event time 
and corresponding 2-sided 95% CI for the median will be provided using log-log transformation. 
In an exploratory analysis that aims to identify independent prognostic factors for OS and PFS, the 
multivariable Cox proportional hazards regression will be used. The variables with p value less than 
0.05 will be assumed as independently affecting OS and PFS. 
To indirectly compare OS and PFS of patients treated with propranolol and sunitinib combination 
versus sunitinib monotherapy, a group of patients treated with sunitinib monotherapy will be drawn 
from the institution historical cohort. This control group will consist of 33 consecutive patients that 
started sunitinib monotherapy just before the beginning of the present study. The comparison will be 
made using the unadjusted log-rank test and the adjusted log-rank test based on the inverse 
probability of treatment weighting [97]. The unstratified and stratified by the MSKCC risk group 
(favourable versus intermediate) multivariable Cox proportional hazards regression will be used to 
assess the impact of the drug combination on OS and PFS. 
8.4.3 Safety Analysis 
Summary tables will present the number of patients observed with adverse events and 
corresponding percentages. Additionally, the following safety-related outcomes will be summarized: 
study treatment discontinuations due to adverse events, deaths during the study treatment period, 
severe adverse events during the study treatment period, hospitalizations and transfusions during 
the study treatment period. 
Each vital sign will be summarized and presented by treatment group. Patients with significant 
changes in vital signs will be listed. 
8.4.4 Health-related Quality of Life Analysis 
Descriptive statistics including the mean, standard deviation and 95% CI will be used to summarize 
absolute scores for EORTC QLQ-C30 and FKSI-15 questionnaires.  
A non-parametric Friedman’s Analysis of Variance (ANOVA) will be performed to assess the 
differences in HRQoL outcomes at all studied time-points. In case of significant result Friedman’s 
ANOVA, the difference between two prespecified time-points will be assessed using Nemenyi post-
hoc test. 
8.4.5 Disease-related Stress Analysis 
Descriptive statistics including the mean, standard deviation and 95% CI will be used to summarize 
absolute scores for 10-point PSS questionnaire. 

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A non-parametric Friedman’s ANOVA will be performed to assess the differences in DRS outcomes at 
all studied time-points. In case of significant result Friedman’s ANOVA, the difference between two 
prespecified time-points will be assessed using Nemenyi post-hoc test. 
8.4.6 Biomarker Analyses 
The influence of primary tumour and serum biomarkers on efficacy and safety parameters will be 
additionally explored if the collection of biological material will be sufficient.  
8.5 Interim Analysis 
No interim analysis is planned. 
8.6 Statistical Software 
The sample size calculation was performed using PASS 14 Power Analysis and Sample Size Software, 
NCSS, LLC, USA. 
The remaining calculations will be performed using Stata Software, version 14.2, StataCorp, USA, and 
R, version 3.2.3, The R Foundation for Statistical Computing, Austria. 
9. Ethical and Regulatory Standards 
9.1 Ethics Review 
The final study protocol, including the final version of the Subject Information and Consent Form 
(SICF), must be approved in writing by an IRB. All Investigators are responsible for informing the IRB 
of any SAEs and amendment to the protocol as per regulatory requirement. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles in the Declaration of Helsinki 
and that are consistent with GCP and applicable regulatory requirements. 
9.3 Subject Information and Consent 
The Investigator will ensure that the patient is given full and adequate oral and written information 
about the nature, purpose, possible risk and benefit of the study.  The patients must also be notified 
that they are free to discontinue from the study at any time.  The patients should be given the 
opportunity to ask questions and allowed time to consider the information provided. The 
Investigator must store the original, signed patient informed SICF and a copy must be given to the 
patient. 
9.4 Laws and Regulations 
This clinical trial will be conducted in compliance with all international and national laws and 
regulations of the country in which the clinical trial is performed, as well as any applicable guidelines. 
The trial will be registered on www.clintrials.gov and on other sites, as appropriate. 

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9.5 Conditions for Modifying the Protocol 
Protocol modifications will be prepared, reviewed, and approved by the Investigators. All protocol 
modifications must be submitted to the IRB for information and approval in accordance with local 
requirements, and to regulatory agencies if required. Approval must be obtained before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to study 
subjects, or when the change involves only logistical or administrative aspects of the trial. 
9.6 Insurance 
All patients participating in the study will have insurance coverage by the National Health Fund. 
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Appendix A: Schedule of Assessments 
The schedule of required assessments is presented in this appendix. Assessments for safety and 
patient reported outcomes are to occur corresponding with study which are fixed from Week 1 Day 1 
(W1D1) defined as the date of the first dose of study treatment. In the absence of toxicity, all 
scheduled safety visits should occur within ± 2 days of the nominal time, unless otherwise indicated. 
Unscheduled safety assessments are to be performed weekly (or more frequently as clinically 
indicated). Other unscheduled visits or assessments are permitted whenever necessary. 
 

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Appendix A: Schedule of Assessments 
 
Pre-treatment period 
Treatment period 
Postdiscontinuation period 
Assessment 
Screening (≤ 7 days) 
W1D1
5 
W2D1 
W3D1 
W7D1 
W13D1 
W19D1 
W25D1 
After beginning 
of W25 
End-of-
treatment visit 
Follow-up 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
 
ECG 
X 
 
X 
X 
X 
X 
X 
X 
X3 
X 
 
24-hour Holter ECG monitoring 
X 
 
 
 
 
 
 
 
 
X 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
X 
 
Cardiology consultation 
X 
 
X2 
X2 
X 
 
 
 
 
X 
 
Hematology 
X 
 
 
 
X 
X 
X 
X 
X3 
X 
 
Biochemistry 
X 
 
 
 
X 
X 
X 
X 
X3 
X 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
X 
 
Urine analysis 
X 
 
 
 
 
 
 
 
 
 
 
β-HCG, HIV tests 
X 
 
 
 
 
 
 
 
 
 
 
CT/MRI 
X1 
 
 
 
 
X 
 
X 
X4 
 
 
Bone scan1,2 
X1,2 
 
 
 
 
 
 
 
 
 
 
Tumour tissue samples6 
X 
 
 
 
 
 
 
 
 
 
 
Serum biomarkers 
X 
 
 
 
X 
 
 
 
 
X 
 
EORTC QLQ-C30, FKSI-15, PSS  
questionnaires 
 
X 
 
 
X 
X 
X 
X 
X3 
X 
 
Sunitinib 
and 
propranolol 
administration record 
 
Since the first day of sunitinib/propranolol administration up to the end-of-treatment visit 
 
Blood 
pressure 
and 
pulse 
home monitoring (twice daily) 
 
Since the first day of sunitinib/propranolol administration up to the end-of-treatment visit 
 
Adverse events 
 
Since the first day of sunitinib/propranolol administration up to the end-of-treatment visit 
 
Dispense/return of study 
drugs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Further cancer treatment 
and survival status 
 
 
 
 
 
 
 
 
 
 
Every 8 weeks (±7 
days) until the end 
of study or death 
1 ≤ 28 days, 2 if clinically indicated, 3 every 6 weeks, 4 every 12 weeks, 5 prior to first dose of sunitinib/propranolol, 6 whenever available

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Appendix B: Karnofsky Performance Status (KPS) Scale 
 
100 – Normal; no complaints; no evidence of disease. 
90 – Able to carry on normal activity; minor signs or symptoms of disease. 
80 – Normal activity with effort; some signs or symptoms of disease. 
70 – Cares for self; unable to carry on normal activity or to do active work. 
60 – Requires occasional assistance, but is able to care for most of their personal needs. 
50 – Requires considerable assistance and frequent medical care. 
40 – Disabled; requires special care and assistance. 
30 – Severely disabled; hospital admission is indicated although death not imminent. 
20 – Very sick; hospital admission necessary; active supportive treatment necessary. 
10 – Moribund; fatal processes progressing rapidly. 
0 – Dead 

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Appendix C: Memorial Sloan Kettering Cancer Center (MSKCC) Criteria 
 
Criterion 
 
 
 
 
 
 
 
 
Points 
Karnofsky performance status ≤ 70% 
 
 
 
 
 
(No - 0; Yes - 1) 
Time from diagnosis to treatment < 1 year 
 
 
 
 
(No - 0; Yes - 1) 
Hemoglobin concentration < LLN 
 
 
 
 
 
(No - 0; Yes - 1) 
Serum corrected calcium concentration > 10 mg/dl (> 2.5 mmol/L) 
 
(No - 0; Yes - 1) 
Lactate dehydrogenase level > 1.5x ULN 
 
 
 
 
(No - 0; Yes - 1) 
 
 
Favorable risk group: 0 points. 
Intermediate risk group: 1-2 points. 
Poor risk group: 3-5 points. 

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Appendix D: Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 
Definitions 
Baseline: Baseline is defined as the most recent assessment performed prior to initiation of study 
treatment. 
Baseline assessments must be performed within the period defined in the protocol. 
Measurable lesions: Except for lymph nodes as described below, measurable lesions are defined as 
those that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥ 
10 mm with CT scan (if CT scans have slice thickness greater than 5 mm the minimum size for a 
measurable lesion is twice the slice thickness). 
• To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short 
axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). 
At baseline and in follow-up, only the short axis will be measured and recorded. 
• MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, but not for 
lesions in the lungs. The minimum size for measurability is the same as for CT (10 mm) as long as the 
scans are performed with slice thickness of 5 mm and no gap. If MRI is performed with thicker slices, 
the size of a measurable lesion at baseline should be twice the slice thickness. In the event there are 
interslice gaps, this also needs to be considered in determining the size of measurable lesions at 
baseline. 
 
Nonmeasurable lesions: All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥10 to < 15 mm short axis), are considered 
nonmeasurable. Lymph nodes that have a short axis < 10 mm are considered nonpathological and 
are not be recorded or followed. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/ pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as nonmeasurable. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, are to be identified as target lesions and measured and 
recorded at baseline. Target lesions are to be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, and be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which can 
be measured reproducibly should be selected. Target lesions will be measured at each assessment 
(longest axis for nonnodal lesions, shortest axis for measurable malignant nodal lesions). 
Nontarget lesions: All other lesions (or sites of disease) including all non-measurable lesions 
(including pathological lymph nodes with ≥ 10 to <15 mm short axis) and all measurable lesions over 
and above the 5 target lesions are to be identified as non-target lesions and recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each is to be recorded throughout follow-up. Lymph nodes that have a 
short axis < 10mm are considered non-pathological and are not to be recorded or followed. 
To be considered progression of non-target lesions in the presence of measurable disease, 
unequivocal progression is defined as substantial worsening in non-target disease such that, even in 

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the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of the therapy. 
 
Special Consideration 
Lesions by clinical examination will not be used for response in this study. 
Cystic lesions 
• Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts.  
• Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if noncystic lesions are present 
in the same patient, these are preferred for selection as target lesions.  
 
Bone lesions 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
• Blastic bone lesions are non-measurable. 
 
Lesions with prior local treatment 
• Lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are not considered measurable. 
 
Imaging Methods 
The same method of assessment and the same technique used to characterize each identified and 
reported lesions at baseline should be used during each follow-up assessment. All measurements 
should be taken and recorded in metric notation using a ruler or calipers. Imaging based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged 
but assessed by clinical examination (referring to biopsy-proven visible lesion(s) on the chest). 
 
Chest x-ray: Chest x-ray will not be used for response assessment in this study. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion is twice the slice thickness. MRI is also acceptable in 
certain situations (eg, for body scan) except for lung. 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences 

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used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, 
the same type of scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible.  
 
Positron emission tomography will not be used for response assessment in this study. 
Ultrasound: Ultrasound will not be used for response assessment in this study.  
Bone scans will be used to assess the presence or disappearance of the bone component of bone 
lesions. CT or MRI scan will be used to confirm ambiguous results of bone scans. Preferred method 
for confirmation is MRI. 
 
 
Time Point Assessments 
The frequency and schedule of tumor assessments is defined in the protocol. The schedule is to be 
maintained regardless of whether study treatment is held or discontinued. At baseline, tumors and 
lymph nodes are classified and documented as target or nontarget per the definitions provided 
above. It is possible to record multiple nontarget lesions involving the same organ as a single item 
(eg, ‘multiple liver metastases’). At all postbaseline (follow-up) evaluations the baseline classification 
(target, nontarget) is to be maintained and lesions are to be documented and described in a 
consistent fashion over time (eg, recorded in the same order on source documents). At each 
assessment, a sum of the diameters (longest for nonnodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and included in source documents. The baseline sum of the 
diameters (SoD) will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. The lowest SoD (nadir) since (and including) the baseline 
value will be used as reference for evaluating progression. 
After baseline, target lesions should have the actual size documented, if possible, even if the lesions 
become very small. If in the opinion of the radiologist the lesion has likely disappeared, 0 mm should 
be recorded. If the lesion is present but too small to measure, an indicator for ‘too small to measure’ 
this should be included in source documents.  
For target lesions, measurements should be taken and recorded in metric notation. All tumor 
measurements must be recorded in millimeters. 
Nontarget lesions are to be assessed qualitatively (present, resolved, or unequivocal progression) 
and new lesions, if any, are to be documented separately. 
At each evaluation, progression status is to be determined based upon the time point status for 
target lesions, nontarget lesions, and new lesions. 
Finding of new lesions should not be attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor. Necrosis of 
preexisting lesions as part of a response to treatment should be excluded before defining a ‘new’ 
cystic lesion. A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion. If a new lesion is equivocal because of its small size, repeat 

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scans need to confirm there is definitely a new lesion, and progression should be declared using the 
date of the initial scan. 
Time point progression can be based solely on bone scans if there is unequivocal evidence of new 
bone scan lesions. New bone scan lesions will be considered malignant in the absence of correlative 
imaging or clinical data that demonstrate lesions are not malignant. Follow up imaging may be 
required to ensure new lesions are unequivocal. Increases in the density or size of bone scan lesions 
present at baseline cannot be the basis of progression. 
 
Time point response (TPR) criteria 
Target Lesion TPR 
Complete Response (CR) - Disappearance of all target lesions. All pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR) - At least a 30% decrease in SoD of target lesions, taking as a reference the 
baseline SoD 
Stable Disease (SD) - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD. 
Progressive Disease (PD) - At least a 20% increase in the SoD of target lesions, taking as a reference 
the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the 
SoD must also demonstrate an absolute increase of at least 5 mm. 
Not Applicable (NA) - No target lesion identified at baseline. 
Unable to Evaluate (UE) - One or more target lesions are not imaged and the remainder of the SoD 
compared with the nadir SoD does not meet the criterion for PD. 
 
Non-Target Lesion TPR 
Complete Response (CR) - Disappearance of all non-target lesions. All lymph nodes must be 
nonpathological in size (<10 mm short axis) 
Non-CR / Non-PD - Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) - Unequivocal progression of non-target lesions. Unequivocal progression 
should normally trump target lesion status. It must be representative of overall disease status 
change, not a single lesion increase 
Not Applicable (NA) - No non-target lesions identified at screening 
Unable to Evaluate (UE) - One or more non-target lesions are not imaged and the remaining 
nontarget lesions do not meet the criterion for PD. 
 
New Lesion TPR 
Yes - Lesion present at follow-up visit either for the very first time or reappearing (ie, lesion was 
present at baseline, disappeared at a follow-up visit and re-appeared later). On bone scan, a single 
new lesion may not 
be sufficient to qualify as PD. Confirmation should be obtained by performing CT or MRI of the area 
of concern to confirm ambiguous results of bone scan. Preferred method for confirmation is MRI. 
No - No new lesions present at follow-up. 
Unable to Evaluate (UE) - Subject not assessed or incompletely assessed for new lesions. 
 
 

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Evaluation of Overall Time Point Response 
Target Lesion TPR 
Non-target Lesion TPR 
New Lesion TPR 
Overall TPR 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
UE 
No 
PR 
PR 
Non-PD or NA or UE 
No 
PR 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Non-PD 
No 
UE 
PD 
Any 
No or Yes or UE 
PD 
Any 
PD 
No or Yes or UE 
PD 
Any 
Any 
Yes 
PD 
NA 
CR 
No 
CR 
NA 
Non-CR/Non-PD 
No 
Non-Cr/Non-PD 
NA 
UE 
No 
UE 
Non-PD 
Non-PD 
UE 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, UE, unable 
to evaluate; NA, not applicable (no such lesions at screening); Any, CR, PR, SD, PD, NA, or UE. 

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Appendix E: The European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 Version 3) 
 
 

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Appendix F:  FACT-Kidney Symptom Index - 15 (FKSI-15) 
Questionnaire 
 

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Appendix G: The Perceived Stress Scale (PSS) Questionnaire