Conditions: Carcinoma, Renal Cell
Keywords: metastatic renal cell carcinoma sunitinib Sutent cardiopulmonary function
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effect of a sunitinib administration schedule 2/1 (2 weeks of treatment followed by 1 week without) compared to a schedule 4/2 (4 weeks of treatment followed by 2 weeks without) on cardiopulmonary function in subjects with renal cell carcinoma. Subjects will be randomized 1:1 to one of two arms: 4/2 schedule of sunitinib administration or 2/1 schedule of sunitinib administration. Cardiopulmonary function will be assessed at baseline, week 4 (4/2 schedule only), week 5 (2/1 schedule only) and week 12. The investigators hypothesize that schedule 2/1 of sunitinib is not only better tolerated but will be associated with less fatigue and functional cardiovascular/muscular toxicity than the 4/2 schedule.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Sunitinib intervention 2: Sunitinib
Intervention descriptions: intervention 1: Patients randomized to sunitinib schedule 4/2 will receive sunitinib at 50 mg daily for 4 weeks on, followed by 2 weeks off, per standard of care. Cardiopulmonary Exercise Testing (CPET) will be performed at baseline, 4 weeks and 12 weeks. intervention 2: Patients randomized to sunitinib schedule 2/1 will receive sunitinib 50 mg daily for 2 weeks on, followed by 1 week off. Cardiopulmonary Exercise Testing (CPET) will be performed at baseline, 5 weeks and 12 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
Cover Page for Protocol 
 
 
Sponsor Name 
Duke Cancer Institute  
NCT Number 
NCT03109015 
Official title of Study 
ASSET:  Alternative Schedule Sunitinib in Metastatic Renal Cell 
Carcinoma ‒ Cardiopulmonary Exercise Testing 
Document date 
27 July 2020 
 


Pro00072588:  Exercise Testing & Sunitinib 2/1 vs. 4/2 (ASSET) 
 
 
 
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CONFIDENTIAL 
A Phase II Randomized Controlled Trial 
 
ASSET:  Alternative Schedule Sunitinib in Metastatic Renal Cell 
Carcinoma ‒ Cardiopulmonary Exercise Testing 
 
 
 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Pfizer, Inc. 
 
 
Protocol Source: 
PI – Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00072588 
 
 
IND#: 
 
Exempt 
 
 
Principal Investigator 
Michael R. Harrison, MD 
DUMC 103861 
Durham, NC  27110 
(919) 668‐4667 (Office) 
(919) 660‐0178 (Fax) 
michael.harrison@duke.edu  
 
v 1:  08Feb2017 
v2:  14Feb2017 
v3:  21Mar2017 
v4:  30May2017 
v5:  12Jul2017 
v6:  10Aug2017 
v7:  27Feb2018 
v8:  27Jul2020 
 
Sub‐Investigator(s) 
Andrew J. Armstrong, MD, MSc 
andrew.armstrong@duke.edu 
 
Daniel J. George, MD 
daniel.george@duke.edu 
 
Tian Zhang, MD 
tian.zhang2@duke.edu 
 
 Michel G. Khouri, MD 
michel.khouri@duke.edu 
 
Rajan Gupta, MD 
Rajan.Gupta@duke.edu 
 
David Bartlett, Ph.D. 
David.bartlett@duke.edu 
 
 
 
Statistician 
Yuan Wu, PhD 
yuan.wu@duke.edu 
 
Lead Study Coordinator 
Marco Reyes Martinez 
marco.reyes‐martinez@duke.edu 
    
Data Manager 
Monika Anand, PhD, CCRP 
monika.anand@dm.duke.edu 
 
Regulatory Coordinator 
Nancy Hight 
Nancy.Hight@duke.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS ..................................................................................................5 
 
STUDY SCHEMA ...................................................................................................................7 


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BACKGROUND AND SIGNIFICANCE ...............................................................................8 
3.1 
Renal Cell Carcinoma:  Background and Standard Treatments ....................................8 
3.2 
Study Agent – Sunitinib in Renal Cell Carcinoma ........................................................8 
3.3 
Study Purpose/Rationale ................................................................................................9 
 
OBJECTIVES AND ENDPOINTS ........................................................................................10 
 
INVESTIGATIONAL PLAN ................................................................................................12 
5.1 
Study Design ................................................................................................................12 
5.1.1 
Dose Modification ...................................................................................................12 
5.1.2 
Dose Modifications and Management of Liver Toxicity .........................................18 
5.2 
Subject Monitoring and Management Guidelines for Certain Treatment-
Emergent Adverse Events (AEs) of Interest ................................................................19 
5.2.1 
Fatigue and  Generalized Muscle Weakness ....................................................................19 
5.2.2 
Abdominal Pain .......................................................................................................19 
5.3 
Treatment Compliance .................................................................................................19 
5.3.1 
Missed Doses ...........................................................................................................19 
5.3.2 
Concomitant Medications ........................................................................................19 
5.3.3 
Randomization .........................................................................................................21 
5.4 
Rationale for Selection of Dose, Regimen, and Treatment Duration ..........................21 
5.5 
Rationale for Correlative Studies .................................................................................21 
5.6 
Definition of Evaluable Subjects .................................................................................23 
5.7 
Early Study Termination ..............................................................................................23 
 
STUDY DRUG:  SUNITINIB ...............................................................................................24 
6.1 
Names, Classification, and Mechanism of Action .......................................................24 
6.2 
Packaging and Labeling ...............................................................................................24 
6.3 
Supply, Receipt, and Storage .......................................................................................25 
6.4 
Dispensing....................................................................................................................25 
6.5 
Compliance, Accountability, Reconciliation, and Return ...........................................25 
 
SUBJECT ELIGIBILITY .......................................................................................................25 
7.1 
Inclusion Criteria .........................................................................................................25 
7.2 
Exclusion Criteria ........................................................................................................26 
 
SCREENING, REGISTRATION, AND ON-STUDY TESTS AND PROCEDURES .........27 
8.1 
Screening Examination ................................................................................................29 
8.1.1 
Subject Registration .................................................................................................30 


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8.2 
Exercise Testing Days A and B ...................................................................................30 
8.3 
Randomization .............................................................................................................31 
8.4 
Treatment Period:  Day 1 .............................................................................................31 
8.5 
Treatment Period (Schedule 4/2:  Day 29; Schedule 2/1:  Day 36) .............................32 
8.6 
Treatment Period:  Day 85 ...........................................................................................32 
8.7 
Off Study and End of Study .........................................................................................33 
8.8 
Early Withdrawal of Subject(s) ...................................................................................33 
8.8.1 
Criteria for Early Withdrawal(s) ..............................................................................33 
8.8.2 
Follow-up Requirements for Early Withdrawal(s) ..................................................33 
8.8.3 
Replacement of Early Withdrawal(s) .......................................................................34 
8.9 
Study Assessments .......................................................................................................34 
8.9.1 
Medical History .......................................................................................................34 
8.9.2 
Physical Exam ..........................................................................................................34 
8.9.3 
Correlative Evaluations ............................................................................................34 
 
SAFETY MONITORING AND REPORTING .....................................................................36 
9.1 
Adverse Events (AEs) ..................................................................................................37 
9.1.1 
AEs of Special Interest.............................................................................................37 
9.1.2 
Expected AEs with Exercise Testing (CPET) .........................................................37 
9.2 
Serious Adverse Events (SAEs) ...................................................................................37 
9.2.1 
Reporting of SAEs ...................................................................................................38 
9.3 
Procedure in Case of Pregnancy ..................................................................................39 
9.4 
Safety Oversight Committee (SOC) ............................................................................40 
 QUALITY CONTROL AND QUALITY ASSURANCE .....................................................40 
10.1 
DCI Monitoring Team .................................................................................................40 
10.2 
Data Management and Processing ...............................................................................40 
10.2.1 Study Documentation...............................................................................................40 
10.2.2 Case Report Forms (CRFs) ......................................................................................41 
10.2.3 Data Management Procedures and Data Verification ..............................................41 
10.2.4 Study Closure ...........................................................................................................41 
 STATISTICAL METHODS AND DATA ANALYSIS ........................................................41 
11.1 
Analysis Sets ................................................................................................................41 
11.2 
Subject Demographics and Other Baseline Characteristics .........................................42 
11.3 
Treatments....................................................................................................................42 


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11.4 
Primary Objective ........................................................................................................42 
11.4.1 Variable ....................................................................................................................42 
11.4.2 Statistical Hypothesis, Model, and Method of Analysis ..........................................42 
11.4.3 Handling of Missing Values, Censoring, and Discontinuations ... Error! Bookmark 
not defined. 
11.5 
Secondary and Exploratory Objectives ........................................................................42 
11.6 
Sample Size Calculation ..............................................................................................43 
 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ..............................................43 
12.1 
Regulatory and Ethical Compliance ............................................................................43 
12.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ..................43 
12.3 
Informed Consent.........................................................................................................44 
12.4 
Privacy, Confidentiality, and Data Storage..................................................................44 
12.5 
Data and Safety Monitoring .........................................................................................44 
12.6 
Protocol Amendments ..................................................................................................45 
12.7 
Records Retention ........................................................................................................45 
12.8 
Conflict of Interest .......................................................................................................45 
 APPENDICES ........................................................................................................................46 
 REFERENCES .......................................................................................................................61 
 
 


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 LIST OF ABBREVIATIONS 
6MWD 
6 Minute Walk Distance 
AE 
Adverse Event 
BMI 
Body Mass index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Comprehensive Metabolic Panel 
COPD 
Chronic Obstructive Pulmonary Disease 
CrCl 
Creatinine Clearance 
CRF 
Case Report Forms 
CPC 
Cancer Protocol Committee 
CPET 
Cardiopulmonary Exercise Testing 
CSA 
Cross‐Sectional Area 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTQA 
Duke Clinical Trials Quality Assurance 
DBP 
Diastolic Blood Pressure 
DCI 
Duke Cancer Institute 
DE 
Dimensional Echocardiography 
DSMB 
Data Safety Monitoring Board 
DUHS 
Duke University Health System 
 
FACIT‐F 
Functional Assessment of Chronic Illness Therapy – Fatigue 
FDA 
Federal Drug Administration 
FKSI‐19 
Functional Assessment of Cancer Therapy‐Kidney Symptom Index ‐19 
GCP 
Good Clinical Practice 
GLS 
Global Longitudinal Strain 
HADS  
Hospital Anxiety and Depression Scale 
HIF 
Hypoxia‐Inducible Factor alpha 
HRQL 
Health‐related Quality of Life 
ICH 
International Conference on Harmonization 
IFN 
Interferon alpha 
IMDC 
International Metastatic Database Consortium 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
KPS 
Karnofsky Performance Status 
LDH 
Lactate Dehydrogenase 
LVCF 
Last Value Carried Forward 
LVEF 
Left ventricular ejection fraction 
mOS 
Median Overall Survival 
mPFS 
Median Progression Free Survival 
mRCC 
Metastatic Renal Cell Carcinoma 
MSKCC 
Memorial Sloan Kettering Cancer Center  
mTOR 
Mammalian Target Of Rapamycin 
NCCN 
National Comprehensive Cancer Network 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PDGFR 
Platelet‐derived Growth Factor Receptor 


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PI 
Principal Investigator 
QOL 
Quality Of Life 
RCC 
Renal Cell Carcinoma 
RTKs 
Receptor Tyrosine Kinases 
SBP 
Systolic Blood Pressure 
SI 
International System of Units 
SOC 
Safety Oversight Committee 
SOP 
Standard Operating Procedures 
TFT 
Thyroid Function Test 
TKI 
Tyrosine Kinase Inhibitor 
TUP 
Timed Get Up and Go 
ULN 
Upper Limit of Normal 
UPC 
Urine Protein Creatinine Ratio 
U.S. 
United States 
VEGF 
Vascular Endothelial Growth Factor 
VO2peak 
Peak Oxygen Uptake 
 
 
 
 
 


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 STUDY SCHEMA 
 
Objective: To investigate changes in cardiopulmonary function in patients treated with sunitinib for metastatic renal 
cell carcinoma (RCC) on schedule 4/2 and schedule 2/1.  
 
Design: Patients with histologically confirmed, treatment‐naive metastatic RCC (mRCC), good or intermediate Heng 
Risk, and Karnofsky Performance Status (KPS) ≥ 80will be enrolled. To be eligible, patients must also have no 
contraindications to maximal exercise testing and must complete satisfactory exercise testing at baseline. 
 
Cardiopulmonary exercise testing (CPET) will be performed at baseline, as well as during sunitinib 
treatment, in order to document changes in peak oxygen consumption (VO2peak) on each arm.   
 
Primary determinants of VO2peak, dose intensity of sunitinib, treatment‐emergent adverse events (AE), 
and patient‐reported outcomes will also be assessed at similar time points. 
 
Subjects will be randomly allocated to sunitinib treatment at 50 mg daily on one of the two following arms:   
A. Schedule 4/2 (n=15) or 
B. Schedule 2/1 (n=15) 
 
 
 
 
 
 
Weeks
Sunitinib
4/2
2/1
CPET and Other Assessments
0
3
1
2
4
5
7
10
9
12
6
8
11
Radiographic Evaluation


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 BACKGROUND AND SIGNIFICANCE 
3.1 Renal Cell Carcinoma:  Background and Standard Treatments 
Renal cell carcinoma accounts for ~3% of all cancers in the United States. This translates to 63,000 new cases a 
year with 14,000 associated deaths.1 Metastatic disease is found in 30% of subjects at diagnosis. Close to 90‐
95% of metastatic disease is of the clear‐cell histology.2 Multiple scoring systems are available to characterize 
prognosis in treatment‐naive RCC. Two of the most commonly used scoring systems are the Memorial Sloan‐
Kettering Cancer Center (MSKCC) and the International Metastatic RCC Database Consortium (IMDC).3,4 Each 
of these systems categorizes patients as favorable, intermediate, or poor risk based on how many adverse 
prognostic factors are present (0: favorable risk; 1‐2: intermediate risk; 3 or more: poor risk).  
The five parameters included in the MSKCC prognostic score are KPS, nephrectomy status, hemoglobin value, 
LDH, and corrected calcium concentration. Time from diagnosis to treatment is often used in place of 
nephrectomy status. The six parameters of importance for IDMC prognostic score classification are Karnofsky 
Performance Status (KPS), time from diagnosis to treatment, hemoglobin value, corrected calcium 
concentration, absolute neutrophil count, and platelet count. With each system, total number of adverse 
prognostic factors present has been shown to correlate with overall survival. Approximately 25% of patients 
are in the favorable‐risk group, 50% are in the intermediate‐risk group, and 25% are in the poor‐risk group. In 
an analysis of 1028 patients scored using the IMDC system, median OS for favorable‐, intermediate‐, and poor‐
risk patients is 43.2 months, 22.5 months, and 7.8 months, respectively.5 
 
Until recently, the cytokines IL‐2 and IFN‐were the only active treatments for advanced or metastatic RCC. 
However, due to each of these agents’ limited clinical benefit and substantial toxicity profile, newer targeted 
agents have largely replaced cytokines in the treatment of advanced or mRCC.6‐8 The recognition of the 
importance of hypoxia‐inducible factor alpha (HIF signaling in the pathogenesis of clear‐cell RCC has led to 
widespread study of two classes of targeted therapies:  anti‐angiogenic agents and mTOR inhibitors.9 
Targeting of angiogenesis is rational because constitutive HIF activation leads to the upregulation or 
activation of several proteins including vascular endothelial growth factor (VEGF), which can subsequently 
lead to tumor proliferation and neovasculature formation. Targeting of the mTOR pathway is important 
because activation of the upstream PI3K/Akt/mTOR signaling pathway is one method by which constitutive 
HIFactivation or upregulation occurs.  
There are 8 targeted agents approved for the treatment of RCC in the United States: 5 that target angiogenesis 
(i.e., the VEGF‐receptor tyrosine kinase inhibitors sorafenib, sunitinib, pazopanib, axitinib, and the VEGF‐
binding monoclonal antibody bevacizumab), 2 that target the mTOR pathway (i.e., everolimus and 
temsirolimus), and 1 that targets an immune checkpoint (i.e., the PD‐1 inhibitor nivolumab). Among these 
approved agents, none have demonstrated a statistically significant improvement in overall survival (OS) 
except for temsirolimus poor‐risk patients and nivolumab in VEGF‐refractory patients. According to National 
Comprehensive Cancer Center Network (NCCN) guidelines, sunitinib, temsirolimus (poor risk only), 
bevacizumab plus interferon, and pazopanib are Category 1 recommendations for first‐line therapy of mRCC.10  
 
3.2 Study Agent – Sunitinib in Renal Cell Carcinoma 
Sunitinib is a VEGF receptor TKI that is approved and recommended for the treatment of mRCC across 
prognostic groups.10 In a randomized Phase 3 trial of sunitinib vs. IFN in treatment‐naive subjects, median 
progression free survival (mPFS) and median OS (mOS) were greater in the sunitinib group than in the IFN 
group (mPFS:  11 mo vs. 5 mo, HR = 0.539; p = < .001); mOS:  26.4 mo vs. 21.8 mo, HR = 0.821; p = .051).11 The 
overall response rate (ORR) was also greater in the sunitinib group (47%) than in the IFN group (12%). More 
recently, sunitinib was compared to pazopanib in treatment‐naïve subjects in the Phase 3 COMPARZ study.12 
In this non‐inferiority study, sunitinib and pazopanib demonstrated similar mPFS (8.4 mo for pazopanib vs. 9.5 


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mo for sunitinib, HR = 1.05) and mOS (28.4 mo for pazopanib vs. 29.3 mo for sunitinib, HR = 0.91; p = 0.28). 
The ORR of pazopanib and sunitinib was 31% and 24%, respectively. The most common (≥ 20) adverse 
reactions include fatigue,  generalized muscle weakness, fever, diarrhea, nausea, mucositis/stomatitis, 
vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand‐foot 
syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, 
extremity pain, cough, dyspnea, anorexia, and bleeding [Sunitinib (Sutent®) U.S. Prescribing Information, April 
2015]. Other important adverse reactions include hepatotoxicity, QT prolongation (including Torsades de 
Pointes), osteonecrosis of the jaw, tumor lysis syndrome, and thyroid dysfunction. 
 
3.3 Study Purpose/Rationale 
Schedule 2/1: An Important Alternative Dosing Regimen of Sunitinib 
A key challenge with sunitinib therapy for mRCC is to maximize quality of life (QOL) by minimizing toxicity 
without compromising efficacy.  Specifically, maintenance of sunitinib dose intensity is related to improved 
clinical outcomes.13  A recent Phase III trial provides an example of these difficulties:  fatigue was one of the 
most common treatment‐emergent adverse events (AEs), with 63% of sunitinib‐treated patients experiencing 
fatigue, including 17% with grade 3/4 fatigue.12  Interestingly, 49% of sunitinib‐treated patients required dose 
interruptions of ≥7 days, and 51% required dose reductions; 20% discontinued treatment due to AEs.  More 
work is clearly needed to achieve this delicate balance. 
 
Preliminary evidence suggests that the alternative schedule 2/1 of sunitinib may maximize both efficacy and 
tolerability. In theory, schedule 2/1 (2‐weeks on, 1‐week off) results in more frequent dose interruptions than 
the standard schedule 4/2 (4‐weeks on, 2‐weeks off) without affecting dose intensity over the same six‐week 
period.  In practice, however, schedule 2/1 may achieve better dose intensity. Multiple retrospective studies 
comprising over 700 patients have suggested that switching from the standard 4/2 schedule to the alternative 
2/1 schedule is associated with both improved outcomes and toxicity profile.14‐18  Four sets of observations 
may explain these findings.   
 
First, maximizing the dose intensity of sunitinib is associated with improved clinical outcomes (PFS and 
OS).13   
 
Second, both steady state of sunitinib and optimal inhibition of vascular perfusion are reached after 2 
weeks.17,19   
 
Third, an increased compensatory angiogenic response (proliferation of endothelial cells) has been 
associated with increased time off of sunitinib therapy.20,21   
 
Fourth, AEs such as fatigue were typically the impetus for dose/schedule modification from schedule 4/2 
in the retrospective studies.  AEs improved with modification, potentially resulting in fewer dose 
interruptions and discontinuations due to toxicity.14‐18   
For example, Atkinson et al demonstrated that the most common AE associated with schedule modification 
was fatigue (64%), which was reduced to 29% upon follow up after schedule modification.14 In this study 
alternative schedule sunitinib, comprised mostly of schedule 2/1 (82%), was also associated with at least 
comparable time on treatment, PFS, and OS. Further prospective evaluation of sunitinib schedule 2/1 is clearly 
warranted. 
To this end, two prospective single‐arm studies are ongoing: (1) to evaluate the tolerability of the 2/1 schedule 
compared with historical controls (NCT02060370), and (2) to study individualized dosing of sunitinib, including 
dose reduction to the 2/1 schedule in those who experience treatment‐emergent toxicity (NCT01499121).  
While these studies will provide prospective safety and efficacy data on schedule 2/1, neither trial is 
comparative or quantitates the functional consequences of treatment‐emergent AEs.   


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Clinical Importance of VO2peak 
Cardiorespiratory fitness testing provides a unique way to measure the tolerability and physiological effects of 
cancer therapy.  The gold standard for direct assessment of cardiorespiratory fitness is peak oxygen 
consumption (VO2peak). As measured by an objective exercise tolerance test (CPET), VO2peak reflects the 
integrative ability of the cardiopulmonary system to deliver adequate oxygen and substrate to metabolically 
active skeletal muscles for ATP resynthesis.22  Measured or estimated VO2peak is a well‐established 
independent predictor of mortality in a broad range of non‐cancer populations.23,24  In a series of studies, 
measurement of VO2peak has also been demonstrated to be safe and well‐tolerated in a wide range of cancer 
patients both during and following therapy.25‐28 Both a diagnosis of cancer and its associated therapeutic 
management are associated with significant impairments in VO2peak,29‐31 while low VO2peak is a significant 
predictor of physical and functional QOL domains, fatigue, and other patient reported outcomes (PROs).32,33  
For example, for a given age group (i.e., 60 year olds), compared with healthy women with no diagnosis of 
breast cancer, patients with breast cancer reached a given VO2peak value about 20 to 30 years earlier.  This 
amounts to “physiologic aging” of several decades in the women with cancer. Finally, VO2peak was 
demonstrated to be a significant predictor of overall mortality in cancer patients, providing prognostic 
information beyond established factors including performance status.25,34  In summary, VO2peak may be an 
important quantitative marker of change in function due to cancer therapy and is associated with survival in 
patients with cancer. 
 
Summary:  Rationale & Hypothesis 
While 4/2 is the recommended starting sunitinib dosing schedule in mRCC, retrospective evidence exists 
suggesting that schedule 2/1 may be at least as efficacious with an improved safety profile.  However, no 
prospective data exists comparing the two schedules in terms of tolerability.  Studies are needed to quantitate 
the functional cardiovascular and muscular changes induced by these two regimens.  Specifically, the 
phenomenology of fatigue in this setting needs to be better understood. Our overall hypothesis is that 
schedule 2/1 of sunitinib is not only better tolerated but will be associated with less fatigue and functional 
cardiovascular/muscular toxicity than the 4/2 schedule. In this study, the first in a continuum of research, we 
will obtain data on the magnitude of VO2peak decline (mean, median, standard deviation, etc.) in each arm in 
order to design a more definitive study to test this hypothesis.  Because future studies will include exercise 
training as a component, data on physiological determinants of VO2peak will be useful to design an optimal 
exercise training program.   
 
 OBJECTIVES AND ENDPOINTS 
All endpoints will be evaluated at the time points specified in the Schedule of Events at the beginning of Section 8. 
See Section 11 for Statistical Methods and Data Analysis. Key comparisons will be the change from Day 1 (week 1) 
to Day 85 (through week 12).  
 
 
Objective 
Endpoint 
Analysis 
Primary 
To estimate the change in VO2peak 
after 12 weeks from baseline in 
treatment‐naïve mRCC patients 
treated with sunitinib on schedule 
4/2 and 2/1 
Change in VO2peak with sunitinib on schedule 
4/2 or 2/1 after 12 weeks from baseline 
See Section 11.1 to 
Section 11.4 
Key Secondary 
To assess the effects on the primary 
physiological determinants of 
VO2peak (e.g., resting and stress 
cardiac function and muscle function, 
defined as cross‐sectional area, 
 Rest and Exercise Left Ventricular Ejection 
Fraction (LVEF) and Cardiac Function by 2‐D 
and 3‐D echocardiography (2DE/3DE) 
including Global Longitudinal Strain (GLS) 
See Section 11.5 


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Objective 
Endpoint 
Analysis 
strength endurance and maximal 
strength) 
 Upper and lower extremity maximal 
muscular strength: 
o voluntary one‐repetition maximum (1‐
RM) 
o muscular endurance (number of 
repetitions to fatigue at 70% of 1‐RM) 
 Muscle cross‐sectional area (CSA) of the 
major muscles near L3 (CT scans and Slice‐
O‐Matic® software) 
Other 
Secondary 
To evaluate changes in other 
measures of physical 
functioning/functional capacity and 
correlate with changes in VO2peak 
Objective assessments (i.e., chair‐stand test, 
timed up and go, 6‐minute walk distance) of 
functional capacity 
See Section 11.5 
Other 
Secondary 
To estimate the effects on patient‐
reported outcomes (i.e., fatigue and 
QOL) 
Functional Assessment of Chronic Illness 
Therapy (FACIT)‐Fatigue and Functional 
Assessment of Cancer Therapy‐Kidney 
Symptom Index‐19 (FKSI‐19)‐ Godin 
Leisure Time Exercise Questionnaire 
 
See Section 11.5 
Other 
Secondary 
To evaluate co‐existent depression 
Hospital Anxiety and Depression Scale (HADS) 
See Section 11.5 
Exploratory 
To evaluate safety and tolerability of 
both: (a) Sunitinib and (b) Exercise 
testing 
Eligibility rate, attrition rate, and adverse 
event rate (CTCAE v4.0) in each arm 
See Section 11.5 
Exploratory 
To determine the dose intensity of 
sunitinib 
Patient‐ reported drug diaries 
See Section 11.5 
Exploratory 
To estimate early change in VO2peak 
at 4‐5 weeks compared with baseline 
Change in VO2peak from baseline to 4‐5 weeks 
See Section 11.5 
Exploratory 
To collect plasma angiome samples 
for analysis and correlation with 
primary and key secondary endpoints 
Plasma angiome multiplex ELISA 
See Section 11.5 
Exploratory 
To use real‐time electronic 
monitoring to describe the following 
over the study period (subset of 
patients): 
(a) Changes in daily physical activity 
(b) Changes in daily blood pressure 
(a) Steps per day  
(b) Daily blood pressure (mmHg) reading 
See Section 11.5 
 
 
 
 
 
 
 


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 INVESTIGATIONAL PLAN 
5.1 Study Design 
Proposed is a randomized (1:1) prospective trial to determine changes in VO2peak in patients with treatment‐
naïve mRCC treated with sunitinib therapy on two different common schedules (see Section 2).  Patients 
randomized to sunitinib schedule 4/2 (Arm A) will receive sunitinib at 50 mg daily for 4 weeks on, followed by 
2 weeks off, per standard of care. Patients randomized to sunitinib schedule 2/1 (Arm B) will receive sunitinib 
50 mg daily for 2 weeks on, followed by 1 week off. All subjects will undergo detailed functional capacity 
assessments at baseline, 4‐5 weeks, and after 12 weeks. 
Specific recommendations for management of possible AEs, along with guidelines for dose delay/modification 
or discontinuation from study treatment are provided in this section, based on best evidence from 
contemporary trials and retrospective studies.12,15   
5.1.1 Dose Modification 
Dose interruptions or reductions of sunitinib may be required following potential drug‐related toxicities. 
Fatigue,  generalized muscle weakness, mucositis/stomatitis, hypertension, hand‐foot syndrome, bleeding, 
vascular thrombosis, thrombocytopenia/neutropenia, and other AEs have been reported in response to 
treatment with sunitinib.35 
 
At each visit during the Treatment Period, subjects should first be evaluated for the occurrence of AEs 
and laboratory abnormalities. Specific recommendations for management of possible AEs, other than 
hepatoxicity, along with guidelines for dose delay/modification or discontinuation of study treatment, are 
adapted from Kollmannsberger et al.,36 and are provided in Table 1. In the event of treatment‐emergent 
hepatotoxicity, please follow the guidelines for management hepatotoxicity provided in Table 2.  For 
toxicities unrelated to sunitinib, dose modifications and holds are per the discretion of the investigator. 
 
If dose reduction is necessary, two dose reductions are permitted in a stepwise fashion (initially to 37.5 mg 
and subsequently to 25 mg if necessary); however, the schedule (4/2 vs. 2/1) will not be changed during the 
study period. If the toxicity does not recur or worsen, the dose can then be increased stepwise back to the 
next dose level (37.5 mg or 50 mg as appropriate) at the start of the next treatment cycle. Increases to the 
next dose level should only be initiated at the start of the next treatment cycle, not during a treatment cycle. 
 


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Table 1           Dose Modification Algorithms for Potential Treatment-Related Adverse Events (AEs) 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Sunitinib 4/2 
Sunitinib 2/1 
Hypertension (Scenario) 
(A). Asymptomatic and persistent systolic 
blood pressure (SBP) of ≥150 and <170 
mmHg, or diastolic blood pressure (DBP) of 
≥90 and <110 mmHg, or a clinically significant 
increase in DBP of ≥20 mmHg. 
Step 1. Continue study treatment at same dose. 
Step 2. Adjust current dose of or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well‐controlled1 blood pressure (BP). If BP is 
not well‐controlled within 2 weeks, follow Step 1 in scenario (B) below. 
Step 1. Continue study treatment at same dose. 
Step 2. Adjust current dose of or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well‐controlled1 blood pressure (BP). If BP is 
not well‐controlled within 2 weeks, follow Step 1 in scenario (B). 
(B). Symptomatic, or SBP ≥170 mmHg, or 
DBP ≥110 mmHg, or failure to achieve well‐
controlled BP within 2 weeks in scenario 
(A). 
Step 1. Interrupt study treatment. 
Step 2. Adjust current or initiate new antihypertensive medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well‐controlled BP. 
Step 4. Restart study treatment at same dose or lower dose at 
discretion of investigator2 once BP is well‐controlled.1 Dose 
adjustment or discontinuation of antihypertensive medication(s) 
may be necessary during scheduled 2‐week off treatment period. 
Step 1. Interrupt study treatment. 
Step 2. Adjust current or initiate new antihypertensive medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well‐controlled BP. 
Step 4. Restart study treatment at same dose or lower dose at discretion of 
investigator2 once BP is well‐controlled.1 Dose adjustment or 
discontinuation of antihypertensive medication(s) may be necessary during 
scheduled 1‐week off treatment period. 
(C). Two or more symptomatic episodes 
of hypertension despite modification of 
antihypertensive medication(s) and 
reduction of study medication dose. 
Discontinue study treatment and follow up per protocol. 
Discontinue study treatment and follow up per protocol. 
Cardiac Toxicity 
Grade 1 
Continue at same dose level 
Continue at same dose level 
Grade 2 
Continue at same dose level.  OR 
If asymptomatic decrease of LVEF by absolute value of 20% and to 
<LLN or nonurgent ventricular paroxysmal dysrhythmia requiring 
intervention:  
Step 1. Interrupt study treatment until toxicity reduced 
to ≤ Grade 1.  
Step 2. Restart treatment with lower dose2; monitor as clinically indicated. 
Continue at same dose level.  OR 
If asymptomatic decrease of LVEF by absolute value of 20% and to 
<LLN or nonurgent ventricular paroxysmal dysrhythmia requiring 
intervention:  
Step 1. Interrupt study treatment until toxicity reduced 
to ≤ Grade 1.  
Step 2. Restart treatment with lower dose2; monitor as clinically indicated. 
Grade 3 
Step 1. Interrupt study treatment until toxicity reduced to ≤ Grade 1.  
Step 2. Restart treatment with lower dose2; monitor as clinically 
indicated. 
Step 1. Interrupt study treatment until toxicity reduced to ≤ Grade 1.  
Step 2. Restart treatment with lower dose2; monitor as clinically 
indicated. 
Grade 4 
Discontinue study treatment and follow up per protocol. 
Discontinue study treatment and follow up per protocol. 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Sunitinib 4/2 
Sunitinib 2/1 
Proteinuria 
Urine Protein Creatinine Ratio (UPC) <3 
Continue study treatment at same dose. Monitor as clinically 
indicated. 
Continue study treatment at same dose. Monitor as clinically 
indicated. 
UPC ≥3 
Step 1:  Obtain a 24‐hr urine protein. 
Step 2:  If 24‐hour urine protein is <3 g, subject may continue 
treatment at same dose. 
OR 
If 24‐hour urine protein is ≥3 g, interrupt treatment until UPC returns. 
to <3. Restart therapy at lower dose.2 Monitor UPC for the remainder 
of the overall treatment period. If UPC ≥3, obtain a 24‐ hour urine 
protein. 
Step 3:  If 24‐hour urine protein is ≥3 g, following repeat dose reductions, 
discontinue treatment and follow up per protocol. 
Step 1:  Obtain a 24‐hr urine protein. 
Step 2:  If 24‐hour urine protein is <3 g, subject may continue 
treatment at same dose. 
OR 
If 24‐hour urine protein is ≥3 g, interrupt treatment until UPC returns. 
to <3. Restart therapy at lower dose.2 Monitor UPC for the remainder 
of the overall treatment period. If UPC ≥3, obtain a 24‐ hour urine 
protein. 
Step 3:  If 24‐hour urine protein is ≥3 g, following repeat dose reductions, 
discontinue treatment and follow up per protocol. 
Hemorrhage/Bleeding/Coagulopathy 
Grade 1 
Continue study treatment at same dose.  Monitor as clinically 
indicated. 
Continue study treatment at same dose.  Monitor as clinically 
indicated. 
Grade 2 
Step 1. Interrupt study treatment until the AE resolves to ≤ Grade 1.  
Step 2. Restart treatment with lower dose2; monitor as clinically indicated. 
Step 1. Interrupt study treatment until the AE resolves to ≤ Grade 1.  
Step 2. Restart treatment with lower dose2; monitor as clinically indicated. 
Grade 3 or 4, or 
Recurrent ≥Grade 2 event after dose 
interruption/reduction. 
Discontinuation of study treatment and follow up per protocol. 
Note: If abnormality is not clearly associated with clinical consequences, 
contact the Duke PI to discuss the potential for continuation of study 
treatment. If agreed, subject may restart treatment at lower dose.2 
Discontinuation of study treatment and follow up per protocol. 
Note: If abnormality is not clearly associated with clinical consequences, 
contact the Duke PI to discuss the potential for continuation of study 
treatment. If agreed, subject may restart treatment at lower dose.2 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Sunitinib 4/2 
Sunitinib 2/1 
Venous Thrombosis 
Grade 2 
Continue study treatment with same dose; monitor as clinically 
indicated. 
Continue study treatment with same dose; monitor as clinically 
indicated. 
Grade 3 or 
asymptomatic Grade 4 
Step 1. Interrupt study treatment. 
Step 2. Start to treat the subject with an anticoagulant. 
Step 3. Resume study treatment at same dose during the period of full‐
dose anticoagulation if all of the following criteria are met: 
 
The subject must have been treated with anticoagulant for at 
least one week. 
 
No Grade 3 or 4 hemorrhagic events have occurred while on 
anticoagulation treatment. 
 
Subject should be monitored as clinically indicated during 
anticoagulation treatment and after resuming study treatment.  
Step 1. Interrupt study treatment. 
Step 2. Start to treat the subject with an anticoagulant. 
Step 3. Resume study treatment at same dose during the period of full‐
dose anticoagulation if all of the following criteria are met: 
 
The subject must have been treated with an anticoagulant for at 
least one week. 
 
No Grade 3 or 4 hemorrhagic events have occurred 
while on anticoagulation treatment. 
 
Subject should be monitored as clinically indicated 
during anticoagulation treatment and after resuming 
study treatment. 
Symptomatic Grade 4 
Discontinuation of study treatment and follow up per protocol. 
Discontinuation of study treatment and follow up per protocol 
Arterial Thrombosis 
Any Grade 
Discontinuation of study treatment and follow up per protocol. 
Discontinuation of study treatment and follow up per protocol 
Neutropenia 
Grade 1 or 2 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Grade 3 lasting ≥5 days 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2.  
Step 2. Restart study treatment at same dose., 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2.  
Step 2. Restart study treatment at same dose. 
Grade 4 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lower dose.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment  with lower dose.2 
Recurrent Grade 3/4 event after initial 
dose reduction 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lowest dose (25 mg/day). 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lowest dose (25 mg/day). 
 
 
 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Sunitinib 4/2 
Sunitinib 2/1 
Thrombocytopenia 
Grade 1 or 2 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Grade 3 lasting ≥5 days 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lower dose.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment  with lower dose.2 
Grade 4 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lower dose.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment  with lower dose.2 
Recurrent Grade 3/4 event after initial 
dose reduction 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lowest dose (25 mg/day). 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lowest dose (25 mg/day). 
Fatigue (lethargy, malaise, generalized 
muscle weakness)3 
 
Grades 1 and 2 
Continue study treatment at same dose; monitor as clinically 
indicated 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Grades 3 and 4 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment  at lower dose.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment  at lower dose.2 
Hand‐foot Syndrome 
Grades 1 and 2 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Grade 3 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 1. 
Step 2. Restart study treatment at same dose or lower dose at 
discretion of investigator.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 1. 
Step 2. Restart study treatment at same dose or lower dose at 
discretion of investigator.2 
Grade 4 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment at lower dose or discontinue at 
discretion of investigator.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment at lower dose or discontinue at 
discretion of investigator.2 
Anemia:  Note: No dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding as noted above 
 
 
 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Sunitinib 4/2 
Sunitinib 2/1 
Other Clinically Significant Adverse Events4 
Grade 1 or 2 
Continue study treatment at same dose; monitor as clinically 
indicated. 
Continue study treatment at same dose; monitor as clinically 
indicated 
Grade 3 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 1. 
Step 2. Restart study treatment at same dose or lower dose at 
discretion of investigator.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 1. 
Step 2. Restart study treatment at same dose or lower dose at 
discretion of investigator.2 
Recurrent Grade 3 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 1. 
Step 2. Restart study treatment at  lower dose.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 1. 
Step 2. Restart study treatment at  lower dose.2 
Grade 4 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment at lower dose or discontinue at 
discretion of investigator.2 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment at lower dose or discontinue at 
discretion of investigator.2 
1. 
Well‐controlled BP defined as mean SBP <150 mmHg and mean DBP <90 mmHg. See Appendix F:  Recommendations for Management of Hypertension. 
2. 
Sunitinib dose should be reduced by 12.5 mg (i.e., 50 mg to 37.5 mg or 37.5 mg to 25 mg), but the schedule (i.e., 4/2 or 2/1) MUST be maintained. 
3. 
See Section 5.2.1 for additional guidelines on management of fatigue and generalized muscle weakness. 
4. 
Adverse events are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure. 
 
 


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5.1.2 Dose Modifications and Management of Liver Toxicity 
In the event of treatment‐emergent hepatotoxicity, potential contributing factors such as 
concomitant medications, viral hepatitis, choledocholithiasis, and hepatic metastases should be 
investigated. Concomitant medications known to be hepatotoxic that may be contributing to liver 
dysfunction should be discontinued or replaced with alternative medications to allow for 
recovery of liver function. As generally understood, ALT >3 x upper limit of normal (ULN) and 
concomitant bilirubin ≥2.0 x ULN (>35% direct bilirubin), in the absence of elevated alkaline 
phosphatase or biliary injury, suggest significant liver injury. See Table 2:  Guidelines for 
Management of Treatment‐Emergent Hepatotoxicity. 
 
Table 2           Guidelines for Management of Treatment-Emergent Hepatotoxicity 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
(A). ALT of ≤3.0 x ULN 
Continue study treatment with full‐panel liver function tests (LFTs)1 monitored 
as per protocol. 
(B). ALT >3.0 x ULN to  ≤8.0 x ULN 
without bilirubin elevation (defined as 
total bilirubin <2.0 x ULN or direct 
bilirubin ≤35%) and without 
hypersensitivity symptoms (e.g., 
fever, rash) 
Continue study treatment. 
Perform the following assessments for excluding hypersensitivity and other 
contributing factors: 
 
Eosinophil count 
 
Viral serology for hepatitis A, B, and C  
 
Liver imaging 
Monitor subject closely for clinical signs and symptoms; perform full‐panel 
LFTs1 weekly or more frequently if clinically indicated until ALT/AST reduced to 
Grade 1. 
If the subject is withdrawn from study treatment, follow up per protocol. 
(C). ALT >3.0 x ULN with 
concomitant elevation in bilirubin 
(defined as total bilirubin ≥2.0 x ULN; 
with direct bilirubin >35%) or with 
hypersensitivity symptoms (e.g., fever, 
rash) 
 
Or 
 
(D). ALT >8.0 x ULN without concomitant 
elevation in bilirubin (defined as total 
bilirubin ≥2.0 x ULN; with direct bilirubin 
>35%) 
Discontinue study treatment immediately. 
Consult a hepatologist, and perform the following assessments to identify co‐ 
contributing factors: 
 
Eosinophil count 
 
Viral serology for hepatitis A, B, C, and E; cytomegalovirus (CMV); 
Epstein‐Barr virus (EBV IgM antibody, or heterophile antibody, or 
monospot testing); anti‐nuclear antibody (ANA); anti‐smooth muscle 
antibody (SMA); and anti‐ mitochondrial antibody 
 
Serum creatinine phosphokinase (CPK) for possible muscle injury 
 
LFT elevation 
 
Liver imaging (ultrasound or CT scan) 
Monitor subject closely for clinical signs and symptoms; perform full‐panel LFTs1 
weekly or more frequently if clinically indicated until LFTs reduced to Grade 1. 
Isolated total bilirubin elevation 
without concurrent ALT elevation 
(defined as ALT <3 x ULN) 
Step 1.  Perform bilirubin fractionation at any time when total bilirubin is ≥1.5 
X ULN. Continue dosing at full dose, and perform weekly LFT assessments1 
until total bilirubin return to ≤1.5 x ULN. 
1. 
Full‐panel LFTs include: AST, ALT, alkaline phosphatase, γ‐GT, and total bilirubin. If at any time the total bilirubin is > 1.5 x 
ULN, perform bilirubin fractionation for direct and indirect bilirubin. 
Note: Because many subjects are taking multiple concurrent medications, it is critical to do a thorough evaluation of the 
subject’s concurrent medications, identify and discontinue those with known hepatotoxicity, and replace with a non‐
hepatotoxic equivalent for the same indication if necessary.


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5.2 Subject Monitoring and Management Guidelines for Certain Treatment‐
Emergent Adverse Events (AEs) of Interest 
5.2.1 Fatigue and Generalized Muscle Weakness 
Fatigue and generalized muscle weakness are commonly reported symptoms in patients with cancer. Both fatigue 
and generalized muscle weakness have been reported with sunitinib and other angiogenesis inhibitors in this class. 
Although the etiology of these events is generally unknown, hypothyroidism has been reported with this class of 
agents [Rini, 2007] and may be a contributing factor in some patients with fatigue and  generalized muscle 
weakness. 
 
To avoid any delay in the treatment of easily manageable conditions such as electrolyte disorders and to quickly 
recognize possible serious conditions such as cardiac dysfunction, the following steps are recommended when 
caring for subjects with fatigue and  generalized muscle weakness.  Subjects complaining of grade 2, 3, or 4 fatigue 
and/or  generalized muscle weakness should be investigated as appropriate including the following suggested 
workup outlined below. 
 
• 
Subjects with grade 3 or more fatigue and/or  generalized muscle weakness should be seen immediately. 
• 
A workup should include a detailed history and physical examination, measurement of serum electrolytes, 
liver function tests, an electrocardiogram, chest X‐ray, thyroid function tests, and an early‐morning cortisol. 
• 
Electrolyte abnormalities should be supplemented and adrenal insufficiency or hypothyroidism should be 
treated with replacement therapy. 
• 
An ACTH stimulation test should be performed if the cortisol concentration is <10 mcg/dL (280 nmol/L). 
• 
If the subject's history or physical examination points toward symptoms or signs of congestive heart failure, 
the appropriate investigations should be performed including an echocardiogram. 
• 
Subjects should be closely monitored on a weekly basis or more frequently if clinically indicated for duration 
of severe fatigue and  generalized muscle weakness. 
• 
Sunitinib dose (but not schedule) should be adjusted according to the dose adjustment guidelines in Table 1:  
Dose Modification Algorithms for Potential Treatment‐Related Adverse Events (AEs).  
 
Please contact the Duke PI if you require further guidance. 
5.2.2 Abdominal Pain 
Abdominal pain is a common symptom with vascular endothelial growth factor (VEGF) receptor antagonists, 
including sunitinib.  Bowel perforations have been reported in clinical trials of pazopanib, sunitinib, and with 
other agents in this class.  Bowel perforations have been associated in some patients with tumor in the bowel 
wall, or diverticulitis, while in others there has been no clear explanation. 
 
Although bowel perforation is a rare event, investigators and study staff at the site are advised to be vigilant 
of this potential complication in subjects receiving sunitinib.  Please contact the Duke PI if you need further 
guidance or would like to discuss an event involving abdominal pain or bowel perforations. 
5.3 Treatment Compliance 
5.3.1 Missed Doses 
Missed doses of sunitinib will be skipped, the subject should resume dosing the next day, and this 
should be recorded in the Pill Diary. 
5.3.2 Concomitant Medications 
All concomitant medications must be recorded on the appropriate case report form (CRF) and will be 
assessed at each study‐related clinic visit.  


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5.3.2.1 Effects of Sunitinib on Exposure to Other Drugs 
In vitro studies indicated that sunitinib does not induce or inhibit major cytochrome P450 (CYP) 
enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP 
isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, 
and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have 
any clinically relevant drug‐drug interactions with drugs that may be metabolized by these 
enzymes.35 
 
See the sunitinib package insert35 for full details:  
http://www.labeling.pfizer.com/ShowLabeling.aspx?id=607#S7.1 
5.3.2.2 Drugs That May Affect Exposure to Sunitinib 
CYP3A4 Inhibitors 
Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. 
Selection of an alternate concomitant medication with no or minimal enzyme inhibition 
potential is recommended. Concurrent administration of sunitinib with the strong CYP3A4 
inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + 
primary active metabolite) Cmax and AUC0–∞ values, respecƟvely, aŌer a single dose of 
sunitinib in healthy volunteers. Co‐administration of sunitinib with strong inhibitors of the 
CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase 
sunitinib concentrations. Grapefruit may also increase plasma sunitinib concentrations. A dose 
reduction for sunitinib should be considered when it must be co‐administered with strong 
CYP3A4 inhibitors.35 
 
CYP3A4 Inducers 
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of 
an alternate concomitant medication with no or minimal enzyme induction potential is 
recommended. Concurrent administration of sunitinib with the strong CYP3A4 inducer, 
rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active 
metabolite) Cmax and AUC0–∞ values, respecƟvely, aŌer a single dose of sunitinib in healthy 
volunteers. Co‐administration of sunitinib with inducers of the CYP3A4 family (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. 
John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib 
plasma concentrations unpredictably. Patients receiving sunitinib should not take St. John's 
Wort concomitantly. A dose increase for sunitinib should be considered when it must be co‐
administered with CYP3A4 inducers.35 
5.3.2.3 Precautions Regarding Concomitant Medications 
Refer to the following links for updated lists of CYP inhibitors and inducers:  
 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm#potency 
 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
See also the sunitinib package insert:35  
http://www.labeling.pfizer.com/ShowLabeling.aspx?id=607#S7.1 
 


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5.3.3 Randomization 
When the subject has been registered, has completed screening, and has been found eligible post‐
baseline testing, the study coordinator will request the subject’s random assignment to one of the two 
treatment arms from the Medidata RAVE database.   
 
For this pilot study, subjects will be randomly assigned (randomized) with equal probability to either 
sunitinib schedule 4/2 or 2/1.    This study is open label, meaning that neither subjects nor study 
personnel will be blinded to treatment assignment.   
 
Note:  For subjects who are not eligible and fail the screening process, no further action is necessary 
and no additional information will be collected.  However, the number of screen failures and reason for 
screen failure will be collected and tallied at the end of the study.  
 
Case report forms will only be completed for those registered and randomized subjects, including those 
who do not receive treatment.  However, subjects who do not receive the assigned treatment will be 
replaced and not counted toward the overall study sample size. Data limited to demographics and 
reason for screen failure will be collected for screen failures. 
5.4 Rationale for Selection of Dose, Regimen, and Treatment Duration 
Sunitinib has an indication for the treatment of advanced RCC.35 The FDA‐approved dose of sunitinib for 
advanced RCC is one 50 mg oral dose taken once daily, on a treatment schedule of 4 weeks on followed by 2 
weeks off (schedule 4/2), which is the dose that will be used in Arm A for this study. 
 
Sunitinib packaging (4/2015) states, “In patients with advanced RCC who are unable to tolerate Schedule 4/2, 
consider the dose reduction described in the FDA‐approved label or, as an alternative, consider modifying the 
schedule to 2 weeks on treatment followed by 1 week off (Schedule 2/1) using the same dose. 
—“Studies supporting Schedule 2/1 have not been reviewed by the FDA. For most studies, the patient 
population was small and/or analysis was post hoc, and therefore susceptible to bias. The efficacy of any 
particular alternative dosing schedule has not been established.” 
https://www.pfizerpro.com/product/sutent/advanced‐rcc/dosing#dm 
 
Schedule 2/1 will be used in Arm B for this study.  Note:  The dose intensity for a 6‐week period is the same 
for schedule 4/2 and 2/1 (50 mg/day * 28 days = 1400 mg). 
5.5 Rationale for Study Evaluations 
PRIMARY PHYSIOLOGICAL DETERMINANTS OF VO2peak 
Rest and Exercise Left Ventricular Ejection Fraction and Cardiac Function will be measured by 2‐D and 3‐D 
echocardiography including Global Longitudinal Strain as described previously.37 The rate of cardiac 
dysfunction was approximately 11% in a recent large randomized trial of sunitinib in which schedule 4/2 was 
utilized.12 However, to date, testing for cardiac dysfunction in clinical trials has only been performed at rest. 
We hypothesize that the addition of stress echocardiography will reveal other abnormalities. 
Muscle Function will be evaluated by two outcomes: (1) upper and lower extremity maximal muscular 
strength will be assessed as a voluntary one‐repetition maximum (1‐RM) and muscular endurance (number of 
repetitions to fatigue at 70% of 1‐RM); and (2) muscle cross‐sectional area (CSA) of the major muscles near L3 
will be assessed using standard of care restaging computed tomography (CT) scans and Slice‐O‐Matic software 
(TomoVision; Magog, Canada), as described previously. Standard‐of‐care CT scans at baseline and after 12 
weeks will be used for the muscle CSA analysis. Sarcopenia, reflected as loss of muscle CSA, is known both to 
predict toxicity from and to develop on VEGF receptor TKI therapy.  Therefore, sarcopenia may contribute to 
decline in cardiopulmonary function.38‐40 
 


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PHYSICAL FUNCTIONING/FUNCTIONAL CAPACITY 
Chair‐Stand Test provides a reliable and valid indicator of functional performance of lower body strength in 
generally active, community‐dwelling older adults.41 Jones et al. examined the test‐retest reliability and 
construct validity of the 30‐second chair stand as a measure of lower body strength in 70 adults over 60 years 
of age (in comparison to a two maximum leg press test). There was a high correlation between chair‐stand 
performance and maximum weight‐adjusted, leg‐press performance for both men and women (r = .78 and 
.71, respectively) supporting the criterion‐related validity of the chair stand as a measure of lower body 
strength. Chair‐Stand Test performance decreased significantly across age groups in decades ‐ from the 60s to 
the 70s to the 80s ‐ and was significantly lower for participants reporting low levels of exercise behavior 
compared to participants reporting higher levels of exercise behavior. To date, the Chair‐Stand Test has not 
been assessed in patients with mRCC. However, this test, in combination with the Timed Get Up and Go and 
6MWD, is widely established as the gold standard for assessment of functional performance in older adults 
and will complement the performance‐based primary outcome of cardiopulmonary function (VO2peak).   
 
Timed Up and Go is field‐based test that assesses a person’s mobility. Specifically, the TUG measures the time 
that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down. 
This test has been found to be feasible in the majority of older adults.42 Scores of 10 seconds or less indicate 
normal mobility, 11 – 20 seconds are within normal limits for frail, elderly, and disabled subjects, and greater 
than 20 seconds suggests that further examination is required. To indicate normal vs. below‐normal 
performance, a recommended, practical cut‐off value for the TUG is 12 seconds.43  TUG performance 
decreases with the presence of mobility impairments.43 To our knowledge, the TUG test has not been assessed 
in patients with mRCC. This test, in combination with other functional performance measures, is widely 
established as the gold standard for assessment of functional performance in older adults and will 
complement the performance‐based primary outcome of cardiopulmonary function (VO2peak).   
 
6‐Minute Walk Distance (6MWD): Six‐minute walk testing (6MWT) is a simple, clinically feasible, and 
objective assessment of functional capacity that is practical even in severely deconditioned clinical populations 
(e.g., chronic heart failure, chronic obstructive pulmonary disease (COPD), and organ transplant recipients). 
6MWT is a robust predictor of mortality in non‐cancer settings;44‐47 only three studies to date have 
investigated the prognostic importance of 6MWT in the oncology setting.48,49  
 
Specifically, Kasymjanova et al. investigated the association between 6MWD and survival in 64 subjects with 
inoperable non‐small cell lung cancer (NSCLC).48 Relative to <400 m, a 6MWD ≥400 m was associated with a 
56% reduction in the risk of death after adjustment for important covariates. Similarly, in recent work among 
118 subjects with histologically confirmed metastatic NSCLC, Jones et al. found that compared with subjects 
achieving a 6MWD <358.5m, the adjusted hazard ratio (HR) for all‐cause mortality was 0.61 (95% CI, 0.34 to 
1.07) for a 6MWD of 358.5 – 450 m, and 0.48 (95% CI, 0.24 to 0.93) for a 6MWD >450 m.50 Interestingly, 
further work by the same group demonstrated that 6MWD was not an independent predictor of prognosis in 
243 subjects with grade III/IV recurrent malignant glioma,49 suggesting that 6MWD may not be an appropriate 
clinical tool for objectively assessing physical functioning in all cancer populations.  
 
PATIENT REPORTED OUTCOMES END POINTS (FACIT‐F, FKSI‐19, Godin Leisure Time Exercise Questionnaire) 
Sunitinib treatment causes fatigue and worse QOL; however, the changes that occur with sunitinib on 
schedule 2/1 and 4/2 have not been prospectively described.  Therefore, we propose to describe the changes 
that occur in this setting. 
 
Because fatigue is a patient reported outcome (PRO) of interest, we will evaluate it using the Functional 
Assessment of Chronic Illness Therapy – Fatigue (FACIT‐F) questionnaire. The FACIT‐F measures severity and 
impact of fatigue on functioning and health‐related quality of life (HRQL) experienced in past seven days 
[Cella, 2002]. It has been used previously to evaluate fatigue with anti‐angiogenesis treatments, including 
assessments for sunitinib [Motzer, 2005; Beaumont, 2006; Motzer, 2013]. The Functional Assessment of 
Cancer Therapy‐Kidney Symptom Index ‐19 (FKSI‐19) is a disease‐specific measure that measures disease and 


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treatment‐related symptoms specifically in renal cancer patients [Rosenbloom, 2007; Rosenbloom, 2008; Rao, 
2008]. It includes patient self‐reports on experience of symptoms in the past seven days such as lack of 
energy, pain, bone pain, shortness of breath, fatigue, blood in urine, etc. FKSI‐19 has been used in a 
contemporary trial of sunitinib in mRCC.12  Finally, because it will be important for interpretation of our data 
to understand activity levels in both arms, we will evaluate leisure time exercise habits with the simple Godin 
Leisure Time Exercise Questionnaire. 
 
DEPRESSION (HADS) 
 
Depression will be evaluated as described previously using the Hospital Anxiety and Depression Scale 
(HADS).51 Fatigue may be difficult to distinguish versus depression in patients with cancer.52 Understanding the 
prevalence of depression is necessary to evaluate the FACIT‐Fatigue and other related measures because 
there are high, positive correlations between fatigue and depression. 
 
EXPLORATORY ENDPOINTS  
 
Blood for use in the plasma angiome multiplex ELISA will be collected at the same time points as the 
cardiopulmonary function studies for correlation with primary and secondary endpoints as described 
previously.53 Samples will be processed in the Phase I Biomarker Laboratory at Duke (Director: Andrew Nixon, 
PhD), Molecular Reference Laboratory for the Alliance Oncology Cooperative Group, a national clinical trial 
research group sponsored by the National Cancer Institute. In cancer patients on therapy, circulating 
angiogenic factors may be modulated by exercise training during systemic therapy.54 Therefore, angiogenic 
biomarker signatures may also predict changes in exercise capacity with therapy. 
Changes in Daily Physical Activity will be recorded in a subset of patients (up to 16 total, on either arm) using 
Bluetooth‐enabled fitness trackers (Garmin Ltd) paired with the patients’ smartphones. Physical activity will be 
reported in steps per day. This will allow real‐time continuous evaluation of a measure of physical functioning 
that could be scalable to outpatient oncology clinics. We have shown the feasibility of transferring daily step 
counts from the patient’s device to the investigator through setting up an on‐line account with a data 
transferring service known as Self‐Generated Health Information exchange (SGHIx, https://sghix.org) in a 
previously IRB approved protocol (Duke Pro00063108, unpublished data). 
Self‐Generated Health Information Exchange (SGHIx) is a web based health information platform 
(https://app.sghix.org/), developed and managed by Promantus Inc., which specializes in providing a service 
for patients to set up an account where they can securely integrate their own health data into one platform.  
Patients can decide who, including their physicians, has access to their own patient generated health data.  
Access to data can be turned on and off by the patient through this web service.  SGHIx was selected as it gives 
patients the privacy to determine how and when others have access to their patient data. 
Changes in Blood Pressure will also be recorded in the same subset of patients using Bluetooth‐enabled blood 
pressure cuffs (iHealth, Inc.) paired with the patients’ smartphones. Blood pressure will be reported in mmHg 
on a daily basis. This will allow real‐time continuous evaluation of BP, which is both a pharmacodynamic 
marker of benefit and a key toxicity that may contribute to declines in VO2peak. Blood pressure data will also 
be transferred through SGHIx as detailed in the previous paragraph. 
 
5.6 Definition of Evaluable Subjects 
For the primary analysis of change in VO2peak, patients with measurements at baseline and after 12 weeks are 
evaluable. 
5.7 Early Study Termination 
This study can be terminated at any time for any reason by the Duke PI‐sponsor.  If this occurs, all subjects on 
study should be notified by the appropriate study personnel as soon as possible.  Additional procedures 


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and/or follow up should occur in accordance with Section 8.8, Early Withdrawal of Subject(s), which describes 
procedures and process for prematurely withdrawn subjects. 
 STUDY DRUG:  SUNITINIB 
6.1 Names, Classification, and Mechanism of Action 
Sunitinib (Sutent®) is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), including 
platelet‐derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors 
(VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms‐like tyrosine kinase‐3 (FLT3), colony‐
stimulating factor receptor Type 1 (CSF‐1R), and the glial cell line‐derived neurotrophic factor receptor (RET). 
6.2 Packaging and Labeling 
SUTENT, an oral multi‐kinase inhibitor, is the malate salt of sunitinib. Sunitinib malate is described chemically 
as Butanedioic acid, hydroxy‐, (2S)‐, compound with N‐[2‐(diethylamino)ethyl]‐5‐[(Z)‐(5‐fluoro‐1,2‐dihydro‐2‐
oxo‐3H‐indol‐3‐ylidine)methyl]‐2,4‐dimethyl‐1H‐pyrrole‐3‐carboxamide (1:1). The molecular formula is 
C22H27FN4O2 ∙ C4H6O5, and the molecular weight is 532.6 Daltons. 
 
The chemical structure of sunitinib malate is: 
 
 
 
Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of sunitinib malate in aqueous 
media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient 
(octanol/water) at pH 7 is 5.2. 
SUTENT (sunitinib malate) capsules are supplied as printed hard‐shell capsules containing sunitinib malate 
equivalent to 12.5 mg, 25 mg, 37.5 mg, or 50 mg of sunitinib together with mannitol, croscarmellose sodium, 
povidone (K‐25), and magnesium stearate as inactive ingredients. 
The orange gelatin capsule shells contain titanium dioxide and red iron oxide. The caramel gelatin capsule 
shells contain titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide. The yellow gelatin 
capsule shells contain titanium dioxide and yellow iron oxide. The white printing ink contains shellac, 
propylene glycol, sodium hydroxide, povidone, and titanium dioxide. The black printing ink contains shellac, 
propylene glycol, potassium hydroxide, and black iron oxide. 
 
See the sunitinib package insert for full details: 
http://www.labeling.pfizer.com/ShowLabeling.aspx?id=607#S7.1 
 
 
 


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6.3 Supply, Receipt, and Storage 
No study drug (i.e., sunitinib) is being provided by the study.  Investigators are responsible for ensuring 
subjects receive commercially available supplies of sunitinib for the entire duration of study participation. 
6.4 Dispensing  
Not applicable 
6.5 Compliance, Accountability, Reconciliation, and Return 
Not applicable 
 SUBJECT ELIGIBILITY 
7.1 Inclusion Criteria 
1. Age ≥ 18 years. 
2. Histologically confirmed renal cell carcinoma (RCC)  
3. One of the two following populations: 
a. High risk for recurrence of RCC after nephrectomy, in the opinion of the investigator, OR 
b. Locally advanced, unresectable or metastatic disease, in the opinion of the investigator, and good 
or intermediate risk by IDMC Heng Criteria (see Appendix I).4 
4. Karnofsky Performance Status (KPS) ≥ 80 (see Appendix A) 
5. Appropriate for treatment with sunitinib in the opinion of the treating physician. 
6. Able to swallow sunitinib and comply with study requirements. 
7. Able to walk and jog on a treadmill, in the opinion of the treating physician. 
8. Must be able to complete an acceptable cardiopulmonary exercise test (CPET) at baseline defined 
as at least one of the following: 
 
Achieving a plateau in oxygen consumption concurrent with an increase in power output;  
 
Respiratory exchange ratio ≥ 1.1 (RER); 
 
Volitional exhaustion with a rating of perceived exertion ≥17 (RPE). 
9. Subjects must have normal organ and marrow function as defined below: 
 
Absolute neutrophil count ≥1,200/µL 
 
Hemoglobin ≥9 g/dL 
 
Platelets ≥75,000/µL 
 
Total bilirubin ≤1.5 x institutional upper limit of normal 
 
AST(SGOT)/ALT(SGPT) <2.5 x institutional upper limit of normal 
 
Urine protein creatinine (UPC) ratio of <1 (see Appendix G schedule of events footnote) 
 
Creatinine ≤2.0 OR creatinine clearance >30 mL/min/1.73 m2 for subjects with creatinine levels 
above institutional normal (see Appendix H). 
 
Left ventricular ejection fraction (LVEF) ≥lower limit of institutional normal as assessed by 
echocardiography. 
10. For the sixteen patients who elect to participate in the optional technology portion involving 
electronic step counts and blood pressure monitoring, the patient must have a Bluetooth‐enabled 
smart phone, which is compatible with the wireless health monitors. 
11. For women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to 
the start of the study. Women of childbearing potential (WOCBP) must agree to follow instructions 
for method(s) of contraception for the duration of the study. Medically acceptable contraceptives 
include: (1) surgical sterilization (such as a tubal ligation or hysterectomy), (2) approved hormonal 
contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods 
(such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD). 
Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. If you do become pregnant during this study or if you have 
unprotected sex, you must inform your study physician immediately. 


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12. For men who are sexually active, must agree to use a two medically acceptable forms of birth 
control (one of which must include a condom as a barrier method of contraception) in order to be 
in this study. Medically acceptable contraceptives include: (1) surgical sterilization (such as a 
vasectomy), or (2) a condom used with a spermicide.  Contraceptive measures such as Plan B (TM), 
sold for emergency use after unprotected sex, are not acceptable methods for routine use. Men 
must also agree to inform their partner of the potential for harm to an unborn child.  She should 
know that if pregnancy occurs, the subject will need to report it to the study doctor, and she should 
promptly notify her doctor. The study doctor will ask if the subject’s partner is willing to provide 
updates on the progress of the pregnancy and its outcome. If the subject’s partner agrees, this 
information will be provided to Pfizer, Inc. for safety monitoring follow‐up. 
 
7.2 Exclusion Criteria 
1. Any prior anti‐VEGF therapies (i.e., sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, 
bevacizumab, etc.), including in the adjuvant or neoadjuvant setting. 
2. Prior systemic therapy for advanced RCC; however, treatment with immunotherapy (i.e., high‐dose 
bolus IL‐2, ipilumumab + nivolumab, etc.) is allowed. 
3. Subjects who are receiving any other investigational agents. 
4. Subjects who are receiving strong CYP3A4 inhibitors or CYP3A4 inducers (see Section 5.3.2.2). 
5. Radiotherapy within 2 weeks prior to taking the first dose of study drug, or those who have not 
recovered from adverse events due to agents administered more than 2 weeks earlier. 
6. Central nervous system (CNS) metastases at baseline, with the exception of those subjects who 
have previously treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) 
and who meet both of the following criteria:  a) are asymptomatic, and b) have no requirement for 
steroids or enzyme‐inducing anticonvulsants in the prior 28 days. 
7. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal 
bleeding including, but not limited to: 
 
Active peptic ulcer disease 
 
Known intraluminal metastatic lesion(s) with risk of bleeding 
 
Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal 
conditions with increased risk of perforation  
 
History of abdominal fistula, gastrointestinal perforation, or intra‐abdominal abscess within 28 
days prior to beginning study treatment 
8. History of any one or more of the following cardiovascular conditions within the past 6 months: 
 
Cardiac angioplasty or stenting 
 
Myocardial infarction 
 
Unstable angina 
 
Coronary artery bypass graft surgery 
 
Symptomatic peripheral vascular disease 
 
Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) 
(see Appendix J)  
9. Absolute contraindications to cardiopulmonary exercise testing and/or aerobic training, as 
determined by the attending oncologist:  
Absolute Contraindications 
 
Uncontrolled arrhythmia causing symptoms or hemodynamic compromise 
 
Recurrent syncope 
 
Active endocarditis 
 
Acute myocarditis or pericarditis 
 
Symptomatic severe aortic stenosis 


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 
Uncontrolled heart failure 
 
Suspected dissecting aneurysm 
 
Uncontrolled asthma 
 
Pulmonary edema 
 
Room air desaturation at rest <85% 
 
Respiratory failure 
 
Acute non‐cardiopulmonary disorders that may affect exercise performance or be aggravated 
by exercise (i.e., infection, renal failure, thyrotoxicosis) 
 
Mental impairment leading to inability to cooperate. 
10. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >150 mmHg or diastolic 
blood pressure (DBP) of >90 mmHg]. 
11. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism, 
or untreated deep venous thrombosis (DVT) within the past 6 months. 
12. Major surgery or trauma within 28 days prior to first dose of investigational product and/or 
presence of any non‐healing wound, fracture, or ulcer (procedures such as catheter placement are 
not considered to be major surgery). 
13. Osseous metastatic disease with unacceptable risk of impending fracture due to study 
assessments, in the opinion of the investigator 
14. Evidence of active bleeding or bleeding diathesis.  
15.  Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase    
the risk of pulmonary hemorrhage. 
 
SCREENING, REGISTRATION, AND ON‐STUDY TESTS AND 
PROCEDURES 
In addition to assessment for the primary endpoint (VO2peak) by cardiopulmonary exercise testing (CPET), 
secondary and exploratory assessments for functional capacity, quantitative skeletal muscle function, patient‐
reported outcomes, and other endpoints will occur throughout the study as specified in Table 3, Schedule of 
Events. 
 
The important time periods [and windows] during the study include: 
 
Screening on Day ‐84 to ‐1 
 
Exercise Testing A [Day ‐28 to ‐1] 
 
Exercise Testing B [Day ‐28 to ‐1, at least 24 hours before or after the CPET as part of Exercise 
Testing A] 
 
Randomization on Day ‐1 [Day ‐28 to ‐1], may occur on the same day as Exercise Testing B but after 
Inclusion/Exclusion criteria have been completed  
 
Treatment Period: Sunitinib from Day 1 to 85 
 
End of Treatment Visit either 30 days after the last dose of sunitinib or on Day 85, whichever occurs 
first.  (There is no Safety Follow Up Visit in this study because the vast majority of patients are 
expected to continue sunitinib beyond Day 85 per standard of care.) 
 
All subjects will receive treatment with sunitinib according to the schedule to which they are randomized. 
 
 
 


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TABLE 3.  SCHEDULE OF EVENTS 
Phase 
 
Screen‐
ing 
Exercise 
Testing 
Ac,d 
Exercise 
Testing B 
and 
Random‐
izationc 
Treatment Period 
End of 
Treatment 
Visit 
Unscheduled 
Visita 
Day 
 
‐84 to  
‐1 
‐4 
‐2/‐1 
1 
4/2:  29 
2/1:  36 
85 
NA 
NA 
Week 
 
‐12 to  
‐1 
 
 
1 
4/2:  4 
2/1:  5 
13 
See Note 
NA 
Window (Days) 
 
NA 
‐28 to ‐1 
‐28 to ‐1 
NAd 
±3 
±3 
±7 
NA 
General 
Evaluations 
See 
Secti
on 
 
Informed Consentb 
8.1.1.
1 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
7 
X 
 
 
 
 
 
 
 
Medical History 
8.9.1 
X 
 
 
 
 
 
 
 
Randomizationc 
8.3 
 
 
Xc 
 
 
 
 
 
Physical Exame 
8.9.2 
X 
X 
 
Xo 
X 
X 
X 
X 
Height, Weight, 
BMIn 
8.9.2 
X 
X 
 
Xo 
X 
X 
X 
X 
Vital Signsf 
8.9.2 
X 
X 
 
Xo 
X 
X 
X 
X 
Performance 
Statusg 
App. 
A 
X 
X 
 
Xo 
X 
X 
X 
X 
Concomitant 
Medications 
5.3.2 
X 
X 
 
Xo 
X 
X 
X 
X 
Adverse Eventsh 
9.1 
X 
X 
x 
Xo 
X 
X 
X 
X 
Laboratory Evaluations 
CBC with Platelets 
8.1‐
8.6 
X 
X 
 
Xo 
X 
X 
X 
Xi 
Serum Chemistry 
8.1‐
8.6 
X 
X 
 
Xo 
X 
X 
X 
Xi 
Thyroid Functionj 
8.1‐
8.6 
X 
 
 
 
X 
X 
 
 
UPCk 
App. 
G 
X 
X 
 
Xo 
X 
X 
X 
Xi 
Serum Pregnancy 
Test (WOCBP Only) 
 
X  
 
 
 
 
 
 
 
Echo  
8.1 
X 
 
 
 
 
 
 
 
Disease 
Evaluations 
 
CT Chest, 
Abdomen, Pelvis 
 
Xl 
 
 
 
 
X 
 
 
Bone Scan (opt.) 
 
Xl 
 
 
 
 
 
 
 
Objective Evaluations 
CPET 
8.9.3 
 
X 
 
 
X 
X 
 
 
Rest and Exercise 
2‐D + 3‐D Echo 
8.9.3 
 
X 
 
 
 
X 
 
 
Muscular 
Strength/Muscular 
Endurance m 
8.9.3 
 
 
X 
 
X 
X 
 
 
Muscle CSAl 
8.9.3 
 
X 
 
 
 
X 
 
 
Chair Stand 
8.9.3 
 
 
X 
 
X 
X 
 
 
Timed Up and Go 
8.9.3 
 
 
X 
 
X 
X 
 
 
6 min walk distance 
8.9.3 
 
 
X 
 
X 
X 
 
 
FACIT‐Fatigue 
App. 
B 
 
X 
 
 
X 
X 
 
 
FKSI‐19 
App. 
C 
 
X 
 
 
X 
X 
 
 
Godin Leisure 
App. 
D 
 
X 
 
 
X 
X 
 
 


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HADS 
App. 
E 
 
X 
 
 
X 
X 
 
 
Drug Diaryp 
 
 
 
 
x 
X 
X 
X 
X 
Plasma Angiome 
Multiplex ELISA 
8.9.3 
 
X 
 
 
 
X 
 
 
Step Counts 
8.9.3 
 
X 
 
 
X 
X 
 
 
Blood Pressure 
8.9.3 
 
X 
 
 
X 
X 
 
 
Treatment 
 
Sunitinib 4/2 
5.1 
 
 
 
X 
X 
X 
 
 
Sunitinib 2/1 
5.1 
 
 
 
X 
X 
X 
 
 
Note: The End‐of‐Treatment Visit will occur approximately 30 days after the last dose of sunitinib or on Day 85, whichever occurs first. 
a. 
Unscheduled visits may be performed at any time during the study as clinically indicated to assess for or follow‐up on AEs. Unscheduled 
visits may also occur due to holidays or other scheduling difficulties. 
b. 
Informed consent may be performed within 84 days prior to enrollment (Day 1), but it must be obtained prior to the performance of any 
study‐specific procedures. 
c. 
Randomization should be performed after baseline testing (specifically, CPET) is completed from day ‐28 to ‐1, but only after eligibility is 
confirmed.  Note that the Baseline Exercise Testing  Visits are structured to take place over 1‐2 consecutive days. See also footnote d. 
below. 
d. 
Day 1 is defined as the day the patient begins taking sunitinib.  Because day 1 is defined by this activity, there is no window. The day 1 
Physical Exam, Weight, BMI, Vital Signs, PS, Con Meds, AEs, and labs have a ±3 day window.  
e. 
A complete physical examination is required at the Screening, Exercise Testing Day A, Day 29‐36, and Day 85 visits.  A brief symptom‐
directed physical examination should be performed at all other clinic visits. 
f. 
Vital signs (temperature, blood pressure, heart rate) are to be obtained at each visit.  SpO2 collected at baseline. 
g. 
Performance status measured by  KPS (as part of IDMC)  (see Appendix A) at screening. KPS will be used throughout the remainder of the 
study. 
h. 
All non‐serious adverse events will be collected from the time of first dose of study drug until the End of Treatment Visit. Serious adverse 
events that are related to study procedures are recorded from the time the informed consent form is signed until the End of Treatment 
Visit (or screen failure). In the event of no End of Treatment Visit, adverse event information will be collected through 30 days after the 
last dose of study drug. Subjects should be contacted by phone for adverse event follow‐up if they do not come to the clinic for the End of 
Treatment Visit. 
i. 
Clinical laboratory tests may be performed at unscheduled visits if clinically indicated. 
j. 
Thyroid function tests (TFTs) should include TSH and free T4. 
k. 
If UPC ≥1 (see Appendix G) at the baseline/ screening assessment, then a 24‐hour urine protein must be assessed. Subjects must have a 
24‐hour urine protein value <1 g to be eligible. 
l. 
Computed tomography (CT) chest, abdomen, and pelvis should be performed at the time of screening and  after 12 weeks (at day 1 of 
week 13).  PET/CT is allowed but should be performed at both timepoints for consistency. Muscle CSA will be calculated from these scans. 
Scans may be used to calculate Muscle CSA if they were collected within the window for collection of that scan, Bone scan is optional, 
based on clinical suspicion at baseline.   
m. 
Muscular Strength  and Muscular Endurance must be done at least 24 hours before or after CPET to allow adequate recovery time. 
n. 
Height is only required to be collected at screening. 
o. 
Physical Exam, Weight, BMI, Vital Signs, PS, Con Meds, AEs, and labs do not need to be repeated if performed within 14 days of day 1. 
p. 
Drug Diary given to subject on Treatment Day 1. Drug Diary collected on all other visits. 
 
BMI, body mass index; KPS, Karnofsky Performance Status; CBC, complete blood count; CT, computed tomography; opt., optional; CPET, 
cardiopulmonary exercise test; ; CSA, cross‐sectional area; FACIT, Functional Assessment of Chronic Illness Therapy; FKSI‐19, Functional 
Assessment of Cancer Therapy‐Kidney Symptom Index‐19. 
8.1 Screening Examination 
The screening examination will take place between Day ‐84 and ‐1.  The subject must sign an Informed 
Consent before any screening procedure takes place.  Subject data to be collected at the Screening 
Examination includes: 
 
Informed Consent 
 
Eligibility Criteria 
 
Medical History 
 
Physical Exam 
 
Height, Weight, BMI 
 
Vital Signs 
 
Performance Status (KPS) 
 
Concomitant Medications 
 
Adverse Events (baseline symptoms) 


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 
CBC with Platelets (hemoglobin, hematocrit, platelet count, white blood cell count, total [absolute] 
neutrophils) 
 
Serum Chemistry (sodium, potassium, chloride, total CO2 [bicarbonate], calcium, BUN, creatinine, 
glucose, albumin, total bilirubin, total protein, alkaline phosphatase, AST, ALT) 
 
Thyroid function (TSH and free T4) 
 
UPC (see Appendix G) 
 
Serum pregnancy test 
 
Echo  
 
CT chest, abdomen, and pelvis  
 
Bone scan (optional; if subject has known bone metastases then bone scan is required) 
8.1.1 Subject Registration 
After signing informed consent and completing eligibility screening, subjects who are selected to 
participate will be registered in the Duke clinical trial subject registry within 1 business day.  A record of 
subjects who fail to meet entry criteria (i.e., screen failures) will be maintained.  Note:  Subject 
registration must be complete before beginning any treatment. 
8.1.1.1 Informed Consent 
Authorized study personnel should fully explain the scope of the study to each subject before 
obtaining informed consent.  Subjects should be advised of any known risks inherent in the 
planned procedures, of any alternative treatment options, of their right to withdraw from the 
study at any time for any reason, and of their right to privacy.  
 
When obtaining informed consent, study personnel should complete the following steps: 
1. Confirm that the subject is a potential candidate for study participation. 
2. Obtain dated and signed informed consent. 
3. Confirm that the subject is eligible as defined in Section 7, Subject Eligibility.  A record of 
subjects who fail to meet entry criteria (i.e., screening failures) will be maintained. 
8.1.1.2 Subject Registration 
Subject registration for all subjects signing informed consent will be completed by Duke 
University Medical Center Genitourinary Oncology Group. Following consent and completion 
of the Eligibility Checklist, documents will be submitted for review and registration of subject. 
Enrolled subjects will be assigned a unique study ID.  
 
Refer to Subject Registration Instructions (see Section 8.1.1) for details.   
 
Subjects will be enrolled only after all pre‐treatment screening evaluations are completed and 
all eligibility criteria are met. When the subject has signed consent and been found to meet all 
eligibility criteria, the subject will be enrolled, and a unique patient study identification number 
will be assigned.  Treatment must not commence until the subject has received their 
identification number . 
8.2 Exercise Testing Days A and B 
An informed consent must be signed by the subject before any screening procedure takes place. Baseline 
exercise testing will take place between Day ‐28 and ‐1, over approximately 2 days (CPET and Muscular 
Strength must be at least 24 hours apart).    Subject data to be collected at Baseline Exercise Testing includes: 
 
Examination and procedures include: 
 
Physical Exam 
 
Weight, BMI 


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 
Vital Signs 
 
Performance Status (KPS) 
 
Concomitant Medications 
 
Adverse Events (SAE’s) 
 
CBC with Platelets (hemoglobin, hematocrit, platelet count, white blood cell count, total [absolute] 
neutrophils) 
 
Serum Chemistry (sodium, potassium, chloride, total CO2 [bicarbonate], calcium, BUN, creatinine, glucose, 
albumin, total bilirubin, total protein, alkaline phosphatase, AST, ALT) 
 
UPC (see Appendix G) 
 
CPET  
 
Rest and exercise 2‐D and 3‐D echocardiography 
 
Muscular Strength (must be at least 24 hours before or after CPET to allow for adequate recovery) 
 
Muscular Endurance (must be at least 24 hours before or after CPET to allow for adequate recovery) 
 
Muscle CSA (CT) 
 
Chair Stand 
 
Timed Up and Go 
 
6 Minute Walk Distance 
 
FACIT‐Fatigue 
 
FKSI‐19  
 
Godin Leisure Time Exercise Questionnaire 
 
HADS 
 
Plasma angiome multiplex ELISA 
 
Step counts (give device to subject, optional) 
 
Blood pressure (give device to subject, optional) 
 
8.3 Randomization 
Subjects will be randomized after inclusion/exclusion criteria are met, exercise testing is complete and subject 
has completed an acceptable CPET and Muscular Strength.  Exercise Testing Day B and Randomization may 
occur on the same day if eligibility is confirmed prior to randomization.  Randomization and related activities 
can occur between days ‐28 to ‐1. 
8.4 Treatment Period:  Day 1 
Day 1 is defined as the day on which the subject begins taking sunitinib.   
Note:  Subjects should start treatment with sunitinib according to the schedule to which they are randomized. 
 
Examinations include: 
 
Physical Exam 
 
Weight, BMI 
 
Vital Signs 
 
Performance Status (KPS) 
 
Concomitant Medications 
 
Adverse Events 
 
CBC with Platelets (hemoglobin, hematocrit, platelet count, white blood cell count, total [absolute] 
neutrophils) 
 
Serum Chemistry (sodium, potassium, chloride, total CO2 [bicarbonate], calcium, BUN, creatinine, glucose, 
albumin, total bilirubin, total protein, alkaline phosphatase, AST, ALT) 
 
UPC (see Appendix G) 
 
Note:  Many of these activities do not need to be repeated if they are performed within 14 days of day 1 
(see Schedule of Events). 
 
Drug diary (give to subject) 


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8.5 Treatment Period (Schedule 4/2:  Day 29; Schedule 2/1:  Day 36) 
Subject data to be collected includes: 
 
Physical Exam 
 
Weight, BMI 
 
Vital Signs 
 
Performance Status (KPS) 
 
Concomitant Medications 
 
Adverse Events 
 
CBC with Platelets (hemoglobin, hematocrit, platelet count, white blood cell count, total [absolute] 
neutrophils) 
 
Serum Chemistry (sodium, potassium, chloride, total CO2 [bicarbonate], calcium, BUN, creatinine, 
glucose, albumin, total bilirubin, total protein, alkaline phosphatase, AST, ALT) 
 
Thyroid function (TSH and free T4) 
 
UPC (see Appendix G) 
 
CPET 
 
Chair Stand 
 
Timed Up and Go 
 
6 Minute Walk Distance 
 
FACIT‐Fatigue 
 
FKSI‐19  
 
Godin Leisure Time Exercise Questionnaire 
 
HADS  
 
Drug diary (collect) 
 
Step counts (record, optional) 
 
Blood pressure (record, optional) 
  
Note:  Remind subject to re‐order sunitinib so that he/she has adequate supply. 
 
8.6 Treatment Period:  Day 85 
Subject data to be collected includes: 
 
Physical Exam 
 
Weight, BMI 
 
Vital Signs 
 
Performance Status (KPS) 
 
Concomitant Medications 
 
Adverse Events 
 
CBC with Platelets (hemoglobin, hematocrit, platelet count, white blood cell count, total [absolute] 
neutrophils) 
 
Serum Chemistry (sodium, potassium, chloride, total CO2 [bicarbonate], calcium, BUN, creatinine, 
glucose, albumin, total bilirubin, total protein, alkaline phosphatase, AST, ALT) 
 
Thyroid function (TSH and free T4) 
 
UPC (see Appendix G) 
 
CT chest, abdomen, and pelvis  
 
Bone scan (if ordered at baseline) 
 
CPET  
 
Rest and exercise 2‐D and 3‐D echocardiography 
 
Muscular Strength  (must be at least 24 hours before or after CPET to allow for adequate recovery) 
 
Muscular Endurance (must be at least 24 hours before or after CPET to allow for adequate recovery) 


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 
Muscle CSA (CT) 
 
Chair Stand 
 
Timed Up and Go 
 
6 Minute Walk Distance 
 
FACIT‐Fatigue 
 
FKSI‐19  
 
Godin Leisure Time Exercise Questionnaire 
 
HADS  
 
Drug diary (collect) 
 
Plasma angiome multiplex ELISA 
 
Step counts (record, optional) 
 
Blood pressure (record, optional) 
 
8.7 Off Study and End of Study 
The End of Treatment Visit will occur approximately 30 days after the last dose of sunitinib or on Day 85, 
whichever occurs first.  Note:  There is no Safety Follow Up Visit in this study because the vast majority of 
patients are expected to continue sunitinib beyond Day 85 per standard of care (see Table 3. Schedule of 
Events). 
 
A subject is considered off study when he/she has completed the End of Treatment Visit. All subjects 
discontinuing study drug for any reason will have an End Of Treatment Visit approximately 30 days after their 
last dose of study drug or prior to initiation of cytotoxic or investigational therapy, whichever occurs first.  
 
Reasonable effort should be made to contact any subject lost to follow‐up during the course of the study in 
order to complete study‐related assessments and retrieve any outstanding data and study drug. Following 
unsuccessful telephone contact, an effort to contact the subject by mail using a method that provides proof of 
receipt should be attempted. Such efforts should be documented in the source documents.  
 
The end of the study will occur when the last enrolled subject has completed his/her End of Treatment Visit. A 
database lock will occur when the data has been cleaned to the specifications in the data quality plan. The 
database will then be frozen, and no further changes will be permitted. 
8.8 Early Withdrawal of Subject(s) 
8.8.1 Criteria for Early Withdrawal(s) 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject from 
the study at any time based on his/her discretion.  Reasons for PI‐initiated withdrawal may include, but 
is not limited to, the following: 
 
Adverse events 
 
Abnormal laboratory values 
 
Abnormal test procedure results 
 
Protocol deviation 
 
Administrative issues 
 
Disease progression, defined as follows: 
o 
Clinical progression (in the opinion of the investigator) 
o 
Radiographic progression (in the opinion of the investigator) 
8.8.2 Follow‐up Requirements for Early Withdrawal(s) 
After early withdrawal, the subject must complete the End of Treatment Visit. All subjects discontinuing 
study drug for any reason will have an End of Treatment Visit approximately (1) 30 days after their last 


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dose of study drug or (2) prior to initiation of cytotoxic or investigational therapy, whichever occurs 
first. 
8.8.3 Replacement of Early Withdrawal(s) 
Subjects who withdraw prior to completing the baseline assessment for the primary endpoint will be 
replaced. Note:  See Section 7.1, Inclusion Criteria. 
8.9 Study Assessments 
8.9.1 Medical History 
Medical history, such as previous treatments, procedures, and conditions, will be collected during the 
screening period. 
8.9.2 Physical Exam 
Evaluations should be performed by the same evaluator throughout the study whenever possible. 
Weight will be recorded at every visit. Height will be recorded at screening visit only. Body mass index 
(BMI) will be calculated at every visit. Vital signs include temperature, blood pressure, and heart rate. A 
complete physical examination is required at the Screening, Day 1, Day 29‐37, and Day 85 visits.  A brief 
symptom‐directed physical examination should be performed at all other clinic visits. 
8.9.3 Evaluations 
Cardiopulmonary Exercise Testing (CPET) 
Exercise Capacity will be assessed using a symptom‐limited CPET on a motorized treadmill with expired 
gas analysis to determine VO2peak, according to guidelines for clinical populations.55 All CPET data will 
be recorded as the highest 30 second value elicited during the CPET. During exercise, heart rate and 
rhythm will be monitored continuously using a 12‐lead ECG. Equipment with similar technical 
specifications will be used across the study sites to ensure reasonably accurate and precise results.   
 
Rest and Exercise 2‐D and 3‐D Echocardiography 
Resting left ventricular (LV) function will be assessed by LVEF using 2‐dimensional echocardiography 
(2DE) and 3‐dimensional echocardiography (3DE), as well as by global longitudinal strain (GLS) using 2‐
dimensional speckle‐tracking echocardiography (2D‐STE) as previously described.37 After resting 
assessments, subjects will complete cardiopulmonary exercise testing as above with stress 2DE 
immediately post‐CPET. 
 
Skeletal Muscle Function 
 
Muscle Cross‐Sectional Area (CSA) will be assessed using standard‐of‐care CT scans. Slice‐O‐Matic 
(Tomovision, Magog, QC, Canada) software will be used to measure muscle cross‐sectional area and 
adipose tissue (subcutaneous, visceral) cross‐sectional area by analysis of axial CT cross‐sectional 
images at the time points described (see Table 3. Schedule of Events), as has been done previously.56  
Average muscle and adiposity measurements will be made between 2 separate axial image cuts from 
each CT scan at the level of L3 by two separate reviewers who will be trained by a radiologist.  The 
major muscles measured near L3 will include the rectus abdominis, latissimus dorsi, external and 
internal oblique, psoas major, erector spinae, transversospinalis, and quadratus lumborum.  
Muscle Strength of the upper and lower body will be assessed as a one‐repetition maximum (1‐RM).  A 
1‐RM is defined as the greatest resistance that can be moved through the full range of motion in a 
controlled manner. This dynamic strength assessment will be conducted using the following exercises: 


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leg press, chest press, and row. The heaviest weight lifted while adhering to the strict technique and 
form will be used to score the assessment. A certified exercise physiologist or trained designee will 
conduct this assessment in a controlled environment. Mean percentage of age and sex‐predicted 
muscle strength will be obtained from available normative data.  
 
Muscular Endurance of the upper and lower body will be assessed as the number of repetitions to 
fatigue at 70% of the 1‐RM.  The same exercises and methods will be used as in the 1‐RM determination 
detailed above.  Subjects will continue until technique, tempo, volition, or inability to complete two 
consecutive repetitions cause finality (per discretion of the exercise physiologist or trained designee). 
 
Physical Functioning/Functional Capacity 
Physical Functioning/Functional Capacity will be assessed using the following assessments:  Chair‐Stand 
Test, Timed Up and Go, and 6‐Minute Walk Distance outcomes as described previously.57 41,58,59These 
measures will complement the exercise capacity measure. 
 
Chair‐Stand Test:  The 5‐repetition Chair‐Stand Test measures the time taken to complete 5 repetitions 
of the sit‐to‐stand maneuver. All sit‐to‐stand maneuvers will be performed from a chair without an arm 
rest at 43 cm in height and 47.5 cm in depth. Standardized instructions will be provided as follows: “By 
the count of 3, please stand up and sit down as quickly as possible for 5 times. Place your hands on your 
lap, and do not use them throughout the procedure. Lean your back against the chair's backrest at the 
end of every repetition.”  Note:  Timing will start when the subject's back left the backrest and will be 
stopped once the back touched the backrest. 
 
Timed Up and Go:  Subjects will be required to stand up from a chair with armrests, walk 3 meters (9.8 
feet), turn around, return to the chair, and sit down.  Note:  The time taken to complete this task will be 
measured in seconds with a stopwatch.59  
 
6‐Minute Walk Test: The 6‐minute Walk Test will be conducted according to the guidelines of the 
American Thoracic Society (ATS) to determine the 6MWD.60 Subjects will be instructed to cover the 
longest distance possible in 6 minutes under the supervision of an exercise physiologist or trained 
designee. The walked distance will be determined in a measured corridor between 2 cones that were 
placed 30 meters apart. Age‐ and sex‐predicted 6MWD will be calculated from the equation of Gibbons 
et al.61 
 
Patient‐Reported Outcomes 
Data on patient‐reported changes in fatigue will be collected using the Functional Assessment in 
Chronic Illness Therapy – Fatigue Questionnaire (FACIT‐F) that can be found in Appendix B.  Data on 
kidney cancer symptoms will be collected using the Functional Assessment of Cancer Therapy‐Kidney 
Symptom Index‐19 (FKSI‐19)that can be found in Appendix C.  Data on leisure time exercise habits will 
be collected using the 4‐item Godin Leisure Time Exercise Questionnaire that can be found in 
Appendix D.62  Data on depression will be collected using the Hospital Anxiety and Depression Survey 
(HADS) that can be found in Appendix E.   
 
Plasma Angiome Multiplex ELISA 
PROCESSING INSTRUCTIONS:    
 
Biomarker assays are time sensitive.  Samples must be processed within one hour of collection.   
 
For plasma samples: 
 


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1.    Draw one 10ml lavender top (K2EDTA) tube (BD Vacutainer, Catalog no. 366643). Please fill the 
tube completely. 
2.    Invert tubes 10 times to mix blood 
3.    Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge manufacturer’s 
instructions) 
4.    Remove plasma from tube and transfer equally into two separate clean 15ml polypropylene tubes 
5.    Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
6.     Aliquot approximately 1.0ml of plasma from each tube into each 2.0 ml pink capped cryovial.  Total 
of 5 pink capped cryovials needed for EDTA plasma.  
7.     Label and freeze at ‐80°C* (see labeling instructions below) 
 
LABELING INSTRUCTIONS:   
 
Plasma‐containing tubes need to be labeled with the following information (label template to be sent 
electronically): 
 
1.            Protocol Name  
2.            Subject Study Number 
3.            Subject Initials 
4.            Sample Date and Time 
5.            Sample Type (ie. EDTA plasma) 
 
Step Counts and Blood Pressure Monitoring (both optional; up to N=16) 
 
Subjects in this portion of the study must have Bluetooth‐enabled smart phone.  
 
Each subject who elects to participate in this optional assessment will be provided a Garmin wrist‐
worn accelerometer and will be taught to download the Garmin smart phone application. 
 
Subjects will also be provided an iHealth BP cuff that will allow the patient to monitor his or her BP.  
 
Each subject will be taught by a trained staff member regarding general use of the activity tracker 
(Garmin Ltd) and wireless BP cuff (iHealth, Inc) to monitor the patient’s step and blood pressure 
respectively.    Both the activity monitor and wireless BP cuff are commercially available devices, 
with easy‐to‐use instruction manuals.  The patient will need to set up an SGHIx account (web‐based 
software platform, developed and managed by Promantus Inc., which will securely transmit device 
data to the investigator; http://sghix.org).  A trained staff member will help the patient set up this 
account, which will allow the patient to send their activity tracker and blood pressure data 
electronically directly to the investigators. 
 
The patients will be recommended to monitor their activity and blood pressure on a daily basis, but 
the patient will have full autonomy regarding usage of these devices as well as the data they will 
wish to share with the investigators through the online data transferring website SGHIx. 
 
All patient health data from SGHIx will be downloaded by the investigators or study personnel and 
transferred to the study’s Medidata RAVE database. 
 
 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events (AEs) and serious adverse events 
(SAEs).  At each study visit, the PI or trained designee must assess, through non‐suggestive inquiries of the subject 
or evaluation of study assessments, whether an AE or SAE has occurred. 


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9.1 Adverse Events (AEs) 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and that does not 
necessarily have a causal relationship with this treatment.  For this protocol, the definition of AE also includes 
worsening of any pre‐existing medical condition.  An AE can therefore be any unfavorable and unintended or 
worsening sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of sunitinib, whether or not related to use of the sunitinib.  Abnormal laboratory findings without 
clinical significance (based on the PI’s judgment) should not be recorded as AEs.  Note:  Laboratory value 
changes that require therapy or adjustment in prior therapy are considered adverse events. 
 
All non‐serious adverse events will be collected from the time of first dose of study drug until the End of 
Treatment Visit.   Serious adverse events that are related to study procedures are recorded from the time the 
informed consent form is signed until the End of Treatment Visit (or screen failure).  These AEs must be 
recorded in the subject’s medical record and adverse events case report form. 
 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.  If 
CTCAE grading does not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), severe 
(3), life‐threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
 
Definite:  The AE is clearly related to the study drug or exercise testing. 
 
Probably:  The AE is likely related to the study drug or exercise testing. 
 
Possible:  The AE may be related to the study drug or exercise testing. 
 
Unlikely:  The AE is doubtfully related to the study drug or exercise testing. 
 
Unrelated:  The AE is clearly NOT related to the study drug or exercise testing.  
9.1.1 AEs of Special Interest 
“Fatigue” and “generalized muscle weakness” (regardless of site) are AEs of special interest. Care 
should be taken to appropriately identify, grade, and note the attribution of these AEs throughout the 
study.  Note:  There is no special reporting requirement for these AEs. 
9.1.2 Expected AEs with Exercise Testing (CPET) 
Anticipated (expected) side‐effects associated with a symptom‐limited cardiopulmonary exercise test 
include: 
 
Fatigue 
 
Muscle soreness 
 
Joint pain 
 
Lower back pain 
 
Leg cramps 
 
Unanticipated but possible side‐effects that are rare, but serious include: 
 
Cardiovascular:  angina, AV blocks, bradycardia, edema, hypotension, palpitations, rebound 
hypertension, shock, syncope    
 
Arrhythmias 
 
Myocardial ischemia 
 
Sudden cardiac death 
 
Cerebrovascular accident 
 
9.2 Serious Adverse Events (SAEs) 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 


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 
Fatal 
 
Life threatening 
 
Constitutes a congenital anomaly or birth defect 
 
A medically significant condition (defined as an event that compromises subject safety or may require 
medical or surgical intervention to prevent one of the three outcomes above). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption to conduct normal life functions 
 
SAE reporting criteria defined below 
 
A. Subset of SAEs Reportable for this Study. Because the Pfizer Product used in this 
Study is a  mature marketed product with a well‐established safety profile, only 
SAEs that fit into any of the following categories need to be reported to Pfizer: (1) a 
death, regardless of whether it is considered related to treatment with the Pfizer 
Product, (2) a non‐fatal SAE that occurs during the reporting period and that is 
assessed by the Principal Investigator as both related to treatment with the Pfizer 
Product and unexpected for that Product, (3) an SAE assessed by the Principal 
Investigator as related to the Pfizer Product that occurs after the SAE reporting 
period, or (4) an otherwise reportable event as described in paragraph B., below. 
An event should be considered "related" to the Pfizer Product if a relationship is at 
least a reasonable possibility, and "unexpectedness" should be based upon a 
single safety reference document identified by the Principal Investigator and 
documented in association with the study. 
 
B. Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure, 
and Lack Of Effect. Even though there may not be an associated SAE, exposure to 
the Pfizer Product during pregnancy, exposure to the Pfizer Product during 
lactation, and occupational exposure to the Pfizer Product are reportable, and lack 
of effect of the Pfizer Product may also be reportable.  
9.2.1 Reporting of SAEs 
Serious adverse events, whether or not considered drug related, should be reported within 24 hours of 
becoming aware of the event, using the provided DCI SAE Report Form and the SAE Report Review 
Form (Site Assessment). These documents should be sent to: 
 
 
The DCI Safety Desk – fax: (919) 681‐9357; phone: (919) 681‐9538; email: dcccsafe@dm.duke.edu  
 
Note:  If the DCI Safety Desk cannot be reached within 24 hours, the Principal Investigator should be 
contacted:  
 
 
Dr. Michael Harrison, phone: (919) 668‐4615; pager: (919) 684‐8111; email: 
michael.harrison@duke.edu 
 
The initial report for each SAE or death should include at minimum the following information: 
• 
Protocol # and title 
• 
Patient initials, study identification number, sex, age 
• 
Date the event occurred 
• 
Description of the SAE 
• 
Dose level and cycle number at the time the SAE occurred 
• 
Description of the patient’s condition 
• 
Indication whether the patient remains on study 


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• 
Causality 
 
Follow‐up information including severity, action taken, concomitant medications, and outcome should 
be communicated to Duke as soon as possible. 
 
Upon receipt of the DCI SAE Report form by the DCI Safety Desk, the PI will be notified and be required to 
complete the PI assessment of the DCI SAE Report Review Form.  The DCI Safety Desk will, in turn, report the event 
to Pfizer if the SAE is felt to be at least possibly related to sunitinib using the DCI SAE Report Form.  The 
Reportable Event Fax Cover Sheet provided by Pfizer must also be included with each SA_E submitted. 
 
The SAE documentation, including the DCI SAE Report Form and available source records, should be 
faxed to Pfizer per the instructions on the SAE cover sheet.   
 
The following minimum information is required for this documentation and report: 
• 
Study number/IIT regulatory identifier 
• 
Subject number, sex, and age 
• 
Report date 
• 
SAE description (event, seriousness of the event) 
• 
Causal relationship to the study drug 
 
Follow‐up information for the event should be sent promptly (within 7 days) as necessary. 
 
Fax and Phone numbers to report SAEs to Pfizer: 
 
Fax: Toll‐Free (local): 1 866 997‐8322 
(Clinical Trial, Compassionate Use , IIR reports) 
Tel: 800 752‐9737 (toll‐free)  
ONLY  for  technical support if fax number is not working 
 
9.3 Procedure in Case of Pregnancy 
Sunitinib is Pregnancy Category D. 
 
Sunitinib can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical 
component of embryonic and fetal development, inhibition of angiogenesis following administration of 
sunitinib should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats 
and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic.  
 
Subjects receiving sunitinib are advised to use 2 acceptable methods of birth control (one of which must 
include a condom as a barrier method of contraception) starting at the time of screening and continuing 
throughout the course of treatment and for at least three months after sunitinib is discontinued.  
 
If, during the conduct of the clinical trial, a male subject impregnates his partner, OR a female subject 
becomes pregnant, the subject should report the pregnancy to the Investigator. With the permission of the 
pregnant partner, the Investigator should report the pregnancy to Pfizer as an SAE within 24 hours of 
awareness of the event. The expected date of delivery or expected date of the end of the pregnancy, last 
menstruation, estimated fertility date, pregnancy result, and neonatal data, etc., should be included in this 
information. 
 
With the permission of the pregnant partner, the Investigator should report the outcome of the pregnancy 
(independent of outcome, e.g., full‐term delivery, pre‐term delivery, spontaneous abortion, induced abortion, 
stillbirth, death of newborn, congenital anomaly [including anomaly in a miscarried fetus, etc.]) in accordance 
with the same reporting procedure as for SAEs (see Section 9.2.1).  The date of outcome of the pregnancy, 


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gestational age, date of birth, and neonatal data, etc., should be included in this information. Informed 
consent will need to be obtained from the pregnant partner to document her permission to disclose this 
information to Pfizer. 
9.4 Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor‐
investigator Phase I and II, therapeutic interventional studies that do not have an independent Data Safety 
Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities, and new 
information that may affect subject safety or efficacy. Annual safety reviews include, but may not be limited 
to, review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference 
literature, and interim analyses as provided by the sponsor‐investigator.  The SOC in concert with the DCI 
Monitoring Team (see Section 10.1 for Monitoring Team description) oversees the conduct of DUHS cancer‐
related, sponsor‐investigator therapeutic intervention and prevention intervention studies that do not have an 
external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in 
accordance with the protocol, standard operating procedures (SOPs), Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 DCI Monitoring Team 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and 
that the protocol is conducted, recorded, and reported in accordance with the protocol, standard operating 
procedures, good clinical practice, and applicable regulatory requirements.  As specified in the DCI Data and 
Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third subject is 
enrolled, followed by annual monitoring of 1 – 3 subjects until the study is closed to enrollment and subjects 
are no longer receiving study interventions that are more than minimal risk.   
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious 
and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI 
leadership, the DCI Cancer Protocol Committee, Duke Clinical Trials Quality Assurance (CTQA), the Safety 
Oversight Committee (SOC), the Sponsor‐Investigator, the site’s Principal Investigator, or the IRB.  All study 
documents must be made available upon request to the DCI Monitoring Team and other authorized regulatory 
authorities, including, but not limited to, the National Institute of Health, National Cancer Institute, and the 
FDA.  Every reasonable effort will be made to maintain confidentiality during study monitoring. 
10.2 Data Management and Processing 
10.2.1 Study Documentation 
Study documentation includes, but is not limited to, source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI‐mandated “Regulatory 
Binder” that includes, but is not limited to, signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
 
Source documents are original records that contain source data that is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, X‐rays, subject files, and records kept at the pharmacy, at the 


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laboratories, and at medico‐technical departments involved in the clinical trial.  When possible, the 
original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
10.2.2 Case Report Forms (CRFs) 
The electronic CRF will be the primary data collection document for the study and will be updated in a 
timely manner following acquisition of new source data.  Only the research staff members listed on the 
delegation of authority log are permitted to make entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system (eCRF).  All 
users of this system will complete user training, as required or appropriate per regulations. 
10.2.3 Data Management Procedures and Data Verification 
Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, queries may be issued by the study data 
manager or project leader. Missing or implausible data will be queried for completion or correction (i.e., 
confirmation of data, correction of data, and completion or confirmation that data is not available, 
etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
10.2.4 Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
 
Data clarification and/or resolution 
 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
 
Review of site study records for completeness 
 
Shipment of all remaining laboratory samples to the designated laboratories (i.e., Nixon Lab at 
Duke) 
 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analysis will be performed under the direction of the statistician designated in key personnel.  Any 
data analysis carried out independently by the investigator must be approved by the statistician before publication 
or presentation. 
11.1 Analysis Sets 
The intent‐to‐treat (ITT) population will consist of all randomized patients.  The modified intent‐to‐treat (ITT) 
population will consist of all randomized patients who have both a baseline and after week 12 evaluation. In 
the ITT analyses and the modified ITT analyses patients will be analyzed according to the study arm to which 
they were randomized. The modified ITT population will be the primary analysis population. 
 
The per‐protocol population will consist of all randomized patients with both baseline and after week 12 
measurements for the primary endpoint and prior to any analysis:  have been deemed compliant and properly 
evaluated for efficacy per investigator, satisfied all inclusion and exclusion criteria, and correctly assigned 
treatment.    
 
The safety population will be all patients with at least one safety evaluation. 


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11.2 Subject Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the ITT population.  Mean, median, 
standard deviation, minimum, and maximum will be displayed by treatment arm for continuous variables.  
Categorical variables will be summarized by counts and percentages for each arm. 
11.3 Treatments 
Compliance with sunitinib will be described, for each treatment arm, by the number and percent of intended 
doses taken (dose intensity).  Deviations from the planned sunitinib schedule (i.e., 4/2 vs. 2/1) will be 
presented by numbers and percent of patients. In addition, the number and percent of patients having delays 
or dose reductions will be displayed by treatment arm. 
 
Numbers of patients discontinuing treatment and reasons for discontinuation will be displayed for each 
treatment arm.   Numbers of patients failing to complete full follow‐up (through week 12) and reasons for loss 
to follow‐up will be displayed for each treatment arm. 
11.4 Primary Objective 
The primary objective is to estimate the change in VO2peak at after 12 weeks from baseline in treatment‐naïve 
mRCC patients treated with sunitinib on schedules 4/2 and 2/1 separately. 
11.4.1 Variable 
The primary endpoint is the change in peak oxygen uptake (VO2peak) from week 1 to through week 12  
in each group. 
11.4.2 Statistical Hypothesis, Model, and Method of Analysis 
The primary analysis will be checking if there is a significant change in peak oxygen uptake (VO2 peak) 
from baseline to through week 12 for each schedule, using a paired t‐test.  The primary analysis will be 
done for complete cases, (i.e., patients with VO2peak measured at baseline and after week 12) in the 
ITT population. 
 
11.5 Secondary and Exploratory Objectives 
For subjects with VO2 peak measures at week 4 or week 5, descriptive statistics including mean, standard 
deviation, minimum and maximum of VO2peak changes from baseline to week 4 and to week 5 will also be 
reported to assess early effects of each sunitinib schedule. Descriptive statistics for other secondary and 
exploratory endpoints will also be reported for each sunitinib schedule.  
 
In addition, a random effects model will be used to assess the effect of different sunitinib schedules on the 
VO2 peak change. In the model repeated measurements of VO2 peak change at week 4, 5 and through week 12 
from baseline are outcomes, schedule indicator (0 for schedule 4/2, 1 for schedule 2/1) is chosen as the main 
factor, baseline VO2 peak value and patient characteristics are other included covariates. Similarly, random 
effects models with other continuous repeated measures (i.e., resting and stress cardiac function and muscle 
strength) as dependent variables will also be used to analyze the schedule effects. 
 
Sensitivity analyses will be performed for the  primary endpoint and key secondary endpoint  using Last Value 
Carried Forward (LOCF) methods. The intent of this sensitivity analysis is to assay the robustness of results 
observed in the modified ITT population. 
 
Eligibility rate, acceptance rate and adverse event rate will be reported descriptively.   
 
Eligibility rate is defined as the number of subjects eligible for the study divided by the number approached for 
the study (i.e., screen fail rate).     


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Acceptance rate is defined as the number of patients agreeing to participate divided by total number 
randomized.   
 
Rates of adverse events, classified by CTCAE v4.0, will be displayed by body system and preferred term for 
each arm.  
 
For analysis of the plasma angiome multiplex ELISA data, correlations among analytes will be evaluated by 
Spearman analysis. Analyte levels at baseline and changes on‐treatment will be correlated with baseline 
VO2peak and changes in VO2peak, respectively.  
 
Descriptive statistics and graphical reporting of group and individual patient data will be used to report 
changes in step counts and blood pressure over time (daily monitoring).  We will also determine if there is any 
association between steps/day and measurements of VO2peak and association between steps/day and blood 
pressure measurements of VO2peak.   
 
11.6 Sample Size Calculation 
The primary purpose of this study is to check if changes in cardiopulmonary function (VO2peak) in patients 
from baseline to through week 12 is significant for each sunitinib schedules.  
This is a pilot study in which 15 evaluable patients per arm will be randomized with equal probability to either 
the sunitinib 4/2 or 2/1 schedule. The estimated variance based on a previous pilot study is 3.2 (Lee W. Jones, 
PhD; unpublished data).  
Assuming 1) the same variance at baseline and 12 weeks, and 2) no correlation between the two VO2peak 
measurements at baseline and 12 weeks, based on 2‐sided, paired t‐test with 15 patients, the VO2peak mean 
difference of 2.0 ml kg‐1 min‐1 from baseline to after 12 weeks can be detected with 80% power and 
significance level 0.05. If we assume a correlation of 0.20 between the two VO2peak measurements, then the 
VO2peak mean difference of 1.8 ml kg‐1 min‐1 from baseline to after 12 weeks can be detected.  Note:  Because 
VO2peak typically declines by only about 1% per year in adults, this magnitude of decline is believed to be 
clinically significant. 
Because 1) the primary endpoint is mean difference in VO2peak at after 12 weeks) 30 total patients are 
required for adequate evaluation, patients who are not able to undergo CPET for determination of VO2peak at 
after 12 weeks will be replaced. We estimate a 20% dropout rate so that 36 patients will need to be accrued in 
order to have 30 total evaluable patients (15 evaluable in each arm). 
 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
12.1 Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
12.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol‐related documents must 
be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for 
review.  The study may be initiated only after the Principal Investigator has received written and dated 
approval from the CPC and IRB. 
 


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The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e., amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
 
The Principal Investigator must obtain protocol re‐approval from the IRB within 1 year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re‐approval from the CPC within 1 year of the 
most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
12.3 Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject population.  
Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of 
the research, methods, potential risks and benefits, subject concerns, and other study‐related matters.  This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility 
of coercion.  Appropriate accommodations will be made available for potential subjects who cannot read or 
understand English or are visually impaired.  Potential subjects will have the opportunity to contact the 
Principal investigator or authorized key personnel with questions, and will be given as much time as needed to 
make an informed decision about participation in the study. 
 
Before conducting any study‐specific procedures, the Principal Investigator must obtain written informed 
consent from the subject or a legally acceptable representative.  The original informed consent form will be 
stored with the subject’s study records, and a copy of the informed consent form will be provided to the 
subject.   
12.4 Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate Duke clinical research 
unit for the Duke site. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course 
of the study.  Prospective participants will be consented in an exam room where it is just the research staff, 
the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and 
study coordinators) regarding research activities will take place in a private exam room. All research related 
interactions with the participant will be conducted by qualified research staff who are directly involved in the 
conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key 
accessible only by the research staff.  Electronic records of subject data will be maintained using a dedicated 
database which is housed in an encrypted and password‐protected DCI file server.  Access to electronic 
databases will be limited to delegated personnel.  The security and viability of the IT infrastructure will be 
managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.    Subject 
names or identifiers will not be used in reports, presentations at scientific meetings, or publications in 
scientific journals. 
12.5 Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan.  
For a more detailed description of the DSMP for this protocol, refer to the DSMP document. 


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12.6 Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 
 
Though not yet required, the CPC should be informed about any protocol amendments that potentially affect 
research design or data analysis (i.e., amendments affecting subject population, inclusion/exclusion criteria, 
agent administration, etc.). 
12.7 Records Retention 
The Principal Investigator will maintain study‐related records at least six years after study completion. 
12.8 Conflict of Interest 
The Principal Investigator and Sub‐Investigators must comply with applicable federal, state, and local 
regulations regarding reporting and disclosure of conflict of interest.  Conflicts of interest may arise from 
situations in which financial or other personal considerations have the potential to compromise or bias 
professional judgment and objectivity.  Conflicts of interest include but are not limited to royalty or consulting 
fees, speaking honoraria, advisory board appointments, publicly‐traded or privately‐held equities, stock 
options, intellectual property, and gifts. 
 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages research‐
related conflicts of interest.  The Principal Investigator and Sub‐Investigators must report conflicts of interest 
annually and within 10 days of a change in status, and when applicable, must have a documented 
management plan that is developed in conjunction with the Duke RIO and approved by the IRB/IEC. 


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 APPENDICES 
 
Appendix A 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
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. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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Appendix B 
FACIT Fatigue Scale (version 4) 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of 
energy
 .......................................................................................... 
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 .......................................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my 
family
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have 
pain
 .......................................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 .......................................................................................... 
0 
1 
2 
3 
4 
GP6 
I feel 
ill
 .......................................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in 
bed
 .......................................................................................... 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my 
friends
 .......................................................................................... 
0 
1 
2 
3 
4 


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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel 
sad
 .......................................................................................... 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my 
family
 .......................................................................................... 
0 
1 
2 
3 
4 
GS3 
I get support from my 
friends
 .......................................................................................... 
0 
1 
2 
3 
4 
GS4 
My family has accepted my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex 
life
0 
1 
2 
3 
4 


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GE4 
I feel 
nervous
 .......................................................................................... 
0 
1 
2 
3 
4 
GE5 
I worry about 
dying
 .......................................................................................... 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at 
home)
 .......................................................................................... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is 
fulfilling
 .......................................................................................... 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 .......................................................................................... 
0 
1 
2 
3 
4 
GF4 
I have accepted my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well
 .......................................................................................... 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for 
fun
 .......................................................................................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now
 .......................................................................................... 
0 
1 
2 
3 
4 
 


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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
HI7 
I feel 
fatigued
 .......................................................................................... 
0 
1 
2 
3 
4 
HI12 
I feel weak all 
over
 .......................................................................................... 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed 
out”)
 .......................................................................................... 
0 
1 
2 
3 
4 
An2 
I feel 
tired
 .......................................................................................... 
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am 
tired
 .......................................................................................... 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am 
tired
 .......................................................................................... 
0 
1 
2 
3 
4 
An5 
I have 
energy
 .......................................................................................... 
0 
1 
2 
3 
4 
An7 
I am able to do my usual 
activities
 .......................................................................................... 
0 
1 
2 
3 
4 
An8 
I need to sleep during the 
day
 .......................................................................................... 
0 
1 
2 
3 
4 


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An12 
I am too tired to 
eat
 .......................................................................................... 
0 
1 
2 
3 
4 
An14 
I need help doing my usual 
activities
 .......................................................................................... 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want 
to 
do
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am 
tired
 .......................................................................................... 
0 
1 
2 
3 
4 
 
 
 


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Appendix C     FKSI‐19 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of 
energy
 .....................................................................  
0 
1 
2 
3 
4 
GP4 
I have 
pain
 .....................................................................  
0 
1 
2 
3 
4 
C2 
I am losing 
weight
 .....................................................................  
0 
1 
2 
3 
4 
HI7 
I feel 
fatigued
 .....................................................................  
0 
1 
2 
3 
4 
B1 
I have been short of 
breath
 .....................................................................  
0 
1 
2 
3 
4 
BRM3 
I am bothered by fevers (episodes of high 
body 
temperature)
 .....................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
BP1 
I have bone 
pain
 .....................................................................  
0 
1 
2 
3 
4 
L2 
I have been 
coughing
 .....................................................................  
0 
1 
2 
3 
4 
HI12 
I feel weak all 
over
 .....................................................................  
0 
1 
2 
3 
4 
D
R
S-
P 


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RCC
2 
I have had blood in my 
urine
 .....................................................................  
0 
1 
2 
3 
4 
C6 
I have a good 
appetite
 .....................................................................  
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well
 .....................................................................  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse
 .....................................................................  
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 .....................................................................  
0 
1 
2 
3 
4 
C5 
I have diarrhea 
(diarrhoea)
 .....................................................................  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 .....................................................................  
0 
1 
2 
3 
4 
GF1 
I am able to work (include work at 
home)
 .....................................................................  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 .....................................................................  
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life 
right 
now
 .....................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
 
T
S
E 
F 
W 
B 
D
R
S-
E 


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Appendix D     Godin Leisure Time Exercise Questionnaire 
 
1. During a typical 7-Day period (a week), how many times on the average do you do the 
following kinds of exercise for more than 15 minutes during your free time (write on each 
line the appropriate number). 
  
Times Per    Average                        
Week          Duration (mins) 
a) STRENUOUS EXERCISE 
 
(HEART BEATS RAPIDLY)                                                       __________ _______ 
 
(e.g., running, jogging, hockey, football, soccer, 
 
squash, basketball, cross country skiing, judo, 
 
roller skating, vigorous swimming, 
 
 vigorous long distance bicycling) 
 
 MODERATE EXERCISE 
 
(NOT EXHAUSTING)                                                                 __________ _______ 
 
(e.g., fast walking, baseball, tennis, easy bicycling, 
 
volleyball, badminton, easy swimming, alpine skiing, 
 
popular and folk dancing) 
 
b) MILD EXERCISE 
 
(MINIMAL EFFORT)                                                                   __________ _______ 
 
(e.g., yoga, archery, fishing from river bank, bowling, 
 
horseshoes, golf, snow-mobiling, easy walking) 
 
 
2. During a typical 7-Day period (a week), in your leisure time, how often do you engage in any 
regular activity long enough to work up a sweat (heart beats rapidly)? 
 
 
OFTEN  
SOMETIMES  
NEVER/RARELY 
 
1. 
2.                          
3.  


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APPENDIX E     HADS 
Instructions: Doctors are aware that emotions play an important part in most illnesses. If your doctor knows about 
these feelings he or she will be able to help you more. This questionnaire is designed to help your doctor know how you 
feel. Read each item and circle the reply which comes closest to how you have been feeling in the past week. Don’t take 
too long over your replies: your immediate reaction to each item will probably be more accurate than a long thought out 
response. 
 
D 
A 
D 
A 
I feel tense or 'wound up': 
I feel as if I am slowed down: 
3 
Most of the time 
3 
Nearly all the time 
2 
A lot of the time 
2 
Very often 
1 
From time to time, occasionally 
1 
Sometimes 
0 
Not at all 
0 
Not at all 
 
 
I still enjoy the things I used to 
enjoy: 
 
 
I get a sort of frightened feeling like 
'butterflies' in the stomach: 
0 
Definitely as much 
0 
Not at all 
1 
Not quite so much 
1 
Occasionally 
2 
Only a little 
2 
Quite Often 
3 
Hardly at all 
3 
Very Often 
 
 
I get a sort of frightened feeling as if 
something awful is about to 
happen: 
 
 
 
I have lost interest in my appearance: 
3 
Very definitely and quite badly 
3 
Definitely 
2 
Yes, but not too badly 
2 
I don't take as much care as I should 
1 
A little, but it doesn't worry me 
1 
I may not take quite as much care 
0 
Not at all 
0 
I take just as much care as ever 
 
 
I can laugh and see the funny side 
of things: 
 
 
I feel restless as I have to be on the 
move: 
0 
As much as I always could 
3 
Very much indeed 
1 
Not quite so much now 
2 
Quite a lot 
2 
Definitely not so much now 
1 
Not very much 
3 
Not at all 
0 
Not at all 
 
 
Worrying thoughts go through my 
mind: 
 
 
I look forward with enjoyment to 
things: 
3 
A great deal of the time 
0 
As much as I ever did 
2 
A lot of the time 
1 
Rather less than I used to 
1 
From time to time, but not too often 
2 
Definitely less than I used to 
0 
Only occasionally 
3 
Hardly at all 
I feel cheerful: 
I get sudden feelings of panic: 
3 
Not at all 
3 
Very often indeed 
2 
Not often 
2 
Quite often 
1 
Sometimes 
1 
Not very often 
0 
Most of the time 
0 
Not at all 
 
 
I can sit at ease and feel relaxed: 
 
 
I can enjoy a good book or radio or TV 
program: 
0 
Definitely 
0 
Often 
1 
Usually 
1 
Sometimes 
2 
Not Often 
2 
Not often 
3 
Not at all 
3 
Very seldom 
 
 
 


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APPENDIX F     Recommendations for Management of Hypertension 
The pathogenesis of hypertension induced by angiogenesis inhibitors is likely to be multi‐factorial. VEGF and 
VEGFR‐2 are involved in the proper maintenance, differentiation, and function of endothelial cells.   Arterial 
hypertension is characterized by reduced nitric oxide (NO) biosynthesis, activation of the renin‐angiotensin‐
aldosterone system (RAAS), increased vasoconstriction, and microvascular rarefaction of arterioles and capillaries. 
Microvascular rarefaction in hypertension is partly due to impaired angiogenesis. Hypertension observed with anti‐
angiogenic agents is thought to be due to decreased bioavailability of endothelium‐derived NO, which is a potent 
vasodilator, as a result of reduced endothelium function by anti‐angiogenesis. 
A.  Control of Hypertension Prior to Study Entry 
For subjects presenting with hypertension, their blood pressure (BP) must be adequately controlled to <150/90 
mmHg prior to the first dose of study medication. This can be achieved by adjusting the existing anti‐hypertensive 
medications or adding new one (see below for permitted anti‐hypertensive medications). 
B.  Control of Hypertension during Study Treatment 
In event hypertension is worsened or emerged during study treatment; the management of hypertension should 
include two parts:  
1. Dose modification of study medication, including interruption, reduction, re‐challenge, or discontinuation of 
study medication (see Table 1 for guidelines and algorithm)  
2. Management of hypertension with anti‐hypertensive medications 
The following antihypertensive medications are permitted by the protocol but should be used with caution: 
 
Dihydropyridine calcium channel blockers:  felodipine, nifedipine, nicardipine, nimodipine, nitrendipine, 
amlodipine, nisoldipine, and isradipine 
 
Angiotensin II blockers: losartan and irbesartan 
 
Beta‐blockers:  carvedilol, metoprolol, propafenone, propranolol, and timolol 
 
Non‐dihydropyridine calcium channel blockers: diltiazem and verapamil 
Based on consensus of experts in the field, we recommend the use of dihydropyridine calcium channel blockers 
(e.g., amlodipine) and ACE inhibitors (e.g., lisinopril) as the first line and second line of therapy, respectively, for 
treatment‐related hypertension. The use of non‐dihydropyridine calcium channel blockers diltiazem and 
verapamil are not encouraged.  
The Duke PI should be contacted if there is any concern or need for clarification. 
 


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APPENDIX G     Urine Protein Creatinine Ratio (UPC) 
Clinical meaning of UPC 
 
There is a good correlation between the ratio of urine protein to creatinine concentrations in a random urine 
sample and the amount of protein excreted in a 24‐hour urine collection period.  The creatinine excretion is 
fairly constant throughout the day regardless of changes in urine flow rate: 
 
 
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day  
 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day  
 
Normal protein excretion is <100 mg to 150 mg/24 hours 
 
The UPC ratio is roughly equal to the 24‐hour urine protein excretion in g/day 
 
Calculating (UPC) 
 
UPC ratio = (Urine protein mg/dl) / (urine creatinine mg/dl) = numerically equivalent to gm protein excreted 
in urine over 24 hours 
 
 
Example:  Patient has a urine protein = 90 mg/dl and urine creatinine = 30 mg/dl. UPC 
ratio= (90 mg/dl) / (30 mg/dl) = 3 
 
Result UPC is 3 (correlates to roughly 3 grams protein excretion in a 24‐hour period) 
 
Units for UPC Ratio 
 
Note:  Both the protein concentration and the creatinine concentration must be expressed in the same units 
(mg/dL or g/L) to perform the UPC calculation.  (Units will cancel out, such as protein mg/creatinine mg or as 
protein gm/creatinine gm) 
 
If protein was expressed in mg/dL and creatinine expressed in µmol/L, the UPC ratio would be in 
mg/µmol, thus, conversion of the units is required (see below): 
 
From 
To 
Conversion Factor 
Conventional Units: mg/dl 
SI Units: µmol/l 
Multiply by 88.4 
SI Units: µmol/l 
Conventional Units: mg/dl 
Divide by 88.4 
 
Reference: 
Xin G, Wang M, Jian L, Xu F, Wang H.  Protein‐to‐creatinine ratio in spot urine samples as a predictor of 
quantitation of proteinuria 2004. Clinica Chimica Acta 350:35‐39. 
 
 
 


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APPENDIX H     COCKCROFT AND GAULT FORMULA FOR ESTIMATED CREATININE CLEARANCE 
(CrCl) 
For US Units: 
 
Cockcroft-Gault CrCl for males (mL/min) =  
[(140 - age) * (Weight in kg1)] / (72 * Cr) 
 
Cockcroft-Gault CrCl for females (mL/min) =  
[(140 - age) * (Weight in kg1) * (0.85)] / (72 * Cr) 
 
1. If the subject is obese (> 30% over ideal body weight), use ideal body weight in calculation of estimate 
CrCl. 
 
 
 


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APPENDIX I     IDMC (Heng) Criteria4 
 
Step 1:  Calculate number of risk factors: 
 
 
Risk Factor 
KPS 
<80% 
Time from diagnosis to treatment 
<12 months 
Hemoglobin 
<LLN 
Corrected serum calcium* 
>ULN 
Neutrophil count 
>ULN 
Platelet count 
>ULN 
KPS = Karnofsky Performance Status 
LLN = lower limit of normal laboratory reference range 
ULN = upper limit of normal laboratory reference range 
 
*Corrected calcium (mg/dL) = measured total calcium (mg/dL) + [0.8 
(4.0 ‐ serum albumin [g/dL])], where 4.0 represents the average 
albumin level in g/dL 
 
Step 2:  Determine risk status: 
 
Number of Risk Factors 
Risk Status 
0 
Favorable (Good) 
1‐2 
Intermediate 
≥3 
Poor 
 
 
 
 
 
 


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APPENDIX J     New York Heart Association (NYHA) Classification of Congestive Heart Failure 
Class I 
Subjects with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II 
Subjects with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion. 
Class III 
Subjects with marked limitation of activity; they are comfortable only at rest. 
Class IV 
Subjects who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 
 
 
 
 
 
 
 
 


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