Clinical trial NCT01832259
Conditions: Adenocarcinoma of the Prostate
Sponsor: University of Utah
Start date: 2013-08-01; Completion date: 2018-08-09
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The area around a tumor ("pre-metastatic niche") may be an area to which cancer cells are attracted. The study doctor will take blood and tumor samples to look for certain features linked with response to treatment so that they can predict which future patients may benefit from this therapy. The purpose of this study is to see if the drug pazopanib can be used to reduce the amount of pre-metastatic niche in the patient's lymph nodes (a common site for prostate cancer to spread). Down the line, this may help to prevent prostate cancer from coming back after surgery.

Detailed description:

Arms: arm 1: Participants receiving placebo arm 2: Participants receiving Pazopanib
Interventions: intervention 1: Pazopanib intervention 2: Placebo
Intervention descriptions: intervention 1: Pazopanib, 800 mg, orally daily for 28 days prior to radical prostatectomy. intervention 2: Placebo tablet orally, daily for 28 days prior to radical prostatectomy.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol name: Pazopanib in High-Risk Prostate Cancer Followed by Radical Prostatectomy and Pelvic Lymph Node Dissection 
Version Date: 22MAR2018 
Principal Investigator: Neeraj Agarwal, MD 
 
A Neoadjuvant, Randomized, Phase II Study of VEGF Tyrosine Kinase Inhibitor 
(Pazopanib) in Men with High-Risk Prostate Cancer Followed by Radical 
Prostatectomy and Pelvic Lymph Node Dissection  
 
Lead Org. ID: HCI63129/ IRB# 63129 
NCT01832259/ Novartis Study # CPZP034CUS02T 
 
 
Principal Investigator 
 
Neeraj Agarwal, MD 
 
 
 
 
 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope, Ste 2123 
 
Salt Lake City, Utah, 84112 
 
Sub-investigator(s)  
 
Will Lowrance, MD, MPH 
 
 
 
 
 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Christopher Dechet, MD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Robert Stephenson, MD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Jonathan Tward, MD, PhD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Julia Batten, APRN 
Huntsman Cancer Institute  
University of Utah 
2000 Circle of Hope (Room #2149.6) 
Salt Lake City, Utah, 84112 


Protocol name: Pazopanib in High-Risk Prostate Cancer Followed by Radical Prostatectomy and Pelvic Lymph Node Dissection 
Version Date: 22MAR2018 
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Jared Thorley, APRN 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Jamie Burnett, PA 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Jeff Linton, PA 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Sumati Gupta, MD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Benjamin Maughan, MD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
Mohamed Salama, MD (Pathology) 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah, 84112 
 
 
External Sub-investigator  
Sumanta Pal, MD 
Department of Medical Oncology  
& Experimental Therapeutics 
City of Hope Comprehensive Cancer Center 
1500 East Duarte Road 
Duarte, CA 91010 
 
 
 


Protocol name: Pazopanib in High-Risk Prostate Cancer Followed by Radical Prostatectomy and Pelvic Lymph Node Dissection 
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Drug Manufacturer  
 
Novartis Pharmaceuticals 
 
 
Investigational agent 
 
VotrientTM (pazopanib) 
 
 
IND Number   
 
 
118456 
 
 
 
 
 
Historical Protocol Versions 
Version 1: May 24, 2013 
Version 2: September 9, 2013  
Version 3: January 15, 2014 
Version 4: May 8, 2014 
Version 5: September 16, 2014 
Version 6: January 8, 2015 
Version 7: April 3, 2015 
Version 8: March 4, 2016 
Version 9: January 24, 2017 
Version 10: March 22, 2018 


Protocol name: Pazopanib in High-Risk Prostate Cancer Followed by Radical Prostatectomy and Pelvic Lymph Node Dissection 
Version Date: 22MAR2018 
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TABLE OF CONTENTS 
Page 
LIST OF ABBREVIATIONS ............................................................................................. 6 
1 
OBJECTIVES ........................................................................................................... 11 
1.1 
Primary Objectives and Endpoints ..................................................................... 11 
1.2 
Secondary Objectives and Endpoint .................................................................. 11 
1.3 
Exploratory Objectives and Endpoint ................................................................ 11 
2 
BACKGROUND ...................................................................................................... 11 
2.1 
Defining prognosis in prostate cancer. ............................................................... 11 
2.2 
Personalizing prognostic models in prostate cancer: The pre-metastatic niche. 12 
2.3 
VEGFR1+ Bone Marrow Derived Cells (BMDCs) initiate the pre-metastatic 
niche.  ............................................................................................................................ 12 
2.4 
MDSC recruitment may represent an early event in pre-metastatic niche 
formation. ...................................................................................................................... 12 
2.5 
Preliminary Data: VEGF-TKI therapy decreases MDSC accumulation in tumor 
tissue.  ............................................................................................................................ 13 
2.6 
Preliminary Data: The pre-metastatic niche is detectable in high-risk prostate 
cancer ............................................................................................................................ 13 
2.7 
Preliminary Data: VEGF-TKIs have demonstrable efficacy in the setting of 
prostate cancer, and have been employed in neoadjuvant trials. .................................. 14 
2.8 
Rationale for pazopanib therapy ........................................................................ 14 
3 
DRUG INFORMATION .......................................................................................... 15 
3.1 
Adverse Reactions .............................................................................................. 15 
4 
STUDY DESIGN...................................................................................................... 20 
4.1 
Description ......................................................................................................... 20 
4.2 
Number of Patients ............................................................................................. 21 
4.3 
Number of Study Centers ................................................................................... 21 
4.4 
Duration .............................................................................................................. 21 
5 
ELIGIBILITY CRITERIA........................................................................................ 21 
5.1 
Inclusion Criteria ................................................................................................ 21 
5.2 
Exclusion Criteria ............................................................................................... 23 
6 
TREATMENT PLAN ............................................................................................... 26 
6.1 
Administration Schedule .................................................................................... 26 
6.2 
Pazopanib/Placebo Treatment ............................................................................ 26 
6.3 
Concomitant Medications .................................................................................. 27 
6.4 
Duration of Therapy ........................................................................................... 30 
7 
TOXICITIES AND DOSEAGE MODIFICATION ................................................. 31 
7.1 
Dose Modifications ............................................................................................ 31 
7.2 
Supportive Care .................................................................................................. 34 
8 
STUDY CALENDARh ............................................................................................. 35 
9 
STUDY PROCEDURES .......................................................................................... 37 
10 CRITERIA FOR EVALUATION AND ENDPOINT .............................................. 39 
10.1 
Assessment of the pre-metastatic niche .......................................................... 39 
10.2 
Assessment of BMDCs and MDSCs .............................................................. 40 
10.3 
Time to Biochemical Recurrence ................................................................... 40 


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10.4 
Safety .............................................................................................................. 40 
10.5 
Stopping Rules ................................................................................................ 41 
11 STATISTICAL CONSIDERATIONS...................................................................... 42 
11.1 
Interim analysis for post-surgical complications ............................................ 42 
12 REGISTRATION GUIDELINES ............................................................................. 43 
13 DATA SUBMISSION SCHEDULE ........................................................................ 43 
14 SPECIAL INSTRUCTIONS .................................................................................... 43 
14.1 
Flow Cytometry Procedure ............................................................................. 43 
14.2 
Correlative Studies ......................................................................................... 44 
15 ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 45 
15.1 
Informed consent ............................................................................................ 45 
15.2 
Institutional Review ........................................................................................ 45 
15.3 
Data and Safety Monitoring Plan ................................................................... 45 
15.4 
Adverse Events / Serious Adverse Events ...................................................... 46 
15.5 
SAE Reporting Requirements ........................................................................ 50 
15.6 
Protocol Amendments .................................................................................... 52 
15.7 
Protocol Deviations ........................................................................................ 52 
15.8 
FDA Annual Reporting .................................................................................. 52 
15.9 
Clinical Trials Data Bank ............................................................................... 52 
16 BIBLIOGRAPHY ..................................................................................................... 52 
Appendix A: UPC ............................................................................................................. 55 
Appendix B: Drugs with risk to prolong QT interval sorted by generic name ................. 56 
APPENDIX C: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES .......... 57 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 


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Abbreviation or Term1 
Definition/Explanation 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IB 
Investigator’s Brochure 
i.e. 
Id est (that is) 
INR 
International normalized ratio 
IRB 
Institutional review board 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected  
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T4 
Thyroxine 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
WBC 
White blood cell 
All of these abbreviations may or may not be used in protocol.  


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PROTOCOL SIGNATURE 
 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein 
and according to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practice, and the applicable laws 
and regulations of the federal government.  I will promptly submit the protocol to the IRB 
for review and approval.  I understand that any modifications made during the course of 
the study must first be approved by the IRB prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study.  I will discuss this material with 
them to ensure that they are fully informed regarding the study treatment, the conduct of 
the study, and the obligations of confidentiality. 
 
Note: This document is signed electronically through submission and approval by the 
Principal Investigator in the University of Utah IRB Electronic Research Integrity and 
Compliance Administration (ERICA) system. 
 


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STUDY SUMMARY 
 
Title 
A Neoadjuvant Phase II Study of 
Pazopanib in Men With High-Risk Prostate 
Cancer Followed by Radical Prostatectomy 
and Pelvic Lymph Node Dissection 
Short Title 
Pazopanib in High-Risk Prostate Cancer 
Followed by Radical Prostatectomy and 
Pelvic Lymph Node Dissection 
Protocol Number 
IRB # 63129 
IND 
118456 
Phase 
Phase II 
Design 
Phase II, prospective, randomized, double 
blind, placebo controlled, two arm study.   
Study Duration 
Estimated duration for the main protocol is 
16 months (14 month enrollment period, 
study duration is 2 months) 
Study Center(s) 
Single-center  
Objectives 
1) To determine if pazopanib can decrease 
the extent of pre-metastatic niche 
formation in benign lymph nodes in 
patients with high-risk, localized 
prostate cancer. Hypothesis: Treatment 
with pazopanib (as compared to 
control) will result in a decrease in pre-
metastatic niche formation, as 
characterized by VEGFR1+ cell 
clusters, in pelvic lymph nodes 
Number of Subjects 
30 (15 patients per arm) 
Diagnosis and Main Eligibility Criteria 
1. Men ≥ 18 years of age 
2. Histological documentation of 
adenocarcinoma of the prostate, with 
available biopsy pathology. Biopsy 
material must be available for 
pathologic review.  
3. All patients must meet one or more of 
the following disease features: clinical 
stage ≥ T3; Primary Gleason score of 4 
OR Gleason score of 8, 9 or 10; serum 
PSA ≥ 20 ng/mL; Prostate MRI 
findings consistent with T3 disease; 
Any clinical stage and PSA >10 and 
Gleason score 7; A Kattan nomogram 
predicted probability of being free from 
biochemical progression at 5 years after 
surgery of < 60%. 


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4. Patients must have a PSA ≥ 2 ng/mL at 
the time of diagnosis of prostate cancer 
or later. 
5. No prior radiation or chemotherapy for 
prostate cancer treatment. 
6. Potential candidate for radical 
prostatectomy. 
7. ECOG Performance Status of 0 or 1. 
8. Patients may have been treated with up 
to 4 months of androgen deprivation 
therapy. 
9. No clinical evidence of metastatic 
prostate cancer, or enlarged pelvic 
lymph nodes in the imaging studies. 
10. Fresh resected lymph nodes must be 
provided for all subjects for biomarker 
analysis immediately (same day) after 
surgery (radical prostatectomy). 
Study Product, Dose, Route, Regimen and 
duration 
Treatment Arm: Pazopanib, 800 mg, orally 
daily for 28 days prior to radical 
prostatectomy. 
Reference therapy 
Placebo Arm: Placebo tablet orally, daily 
for 28 days prior to radical prostatectomy.  
Statistical Methodology 
With 15 subjects per arm (30 subjects in 
all) there will be 80% power to detect a 
difference of 1.33 in the mean number of 
VEGFR+1 clusters/hpf between the 
reference and experimental arms using a 
student’s t-test at the one-sided alpha = 
0.05 significance level.  
Progression-free survival will be a 
secondary efficacy endpoint. PFS will be 
analyzed descriptively using Kaplan-Meier 
methods and associated 95% confidence 
intervals. Exploratory biomarker endpoints 
will be compared between the arms using 
student’s t-tests (provided the data is 
normally distributed) or a non-parametric 
Wilcoxon test (if the data is non-normally 
distributed). Safety outcomes will be 
tabulated. 
An interim analysis will be done after 16 
patients have enrolled to assess post-
surgical toxicities. 


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1 
OBJECTIVES 
1.1 Primary Objectives and Endpoints 
 
1.1.1  To evaluate if pazopanib can decrease the extent of pre-metastatic 
niche formation in benign lymph nodes in patients with high-risk, 
localized prostate cancer. Hypothesis: Treatment with pazopanib (as 
compared to control) will result in a decrease in pre-metastatic niche 
formation, as characterized by VEGFR1+ cell clusters, in pelvic lymph 
nodes. 
 
1.2 Secondary Objectives and Endpoint 
1.2.1 Progression free survival, in terms of PSA recurrence 
 
1.2.2  Safety and tolerability (adverse events during pazopanib treatment, 
and during intraoperative and post-operative period). 
 
1.3 Exploratory Objectives and Endpoint 
 
1.3.1    To evaluate if pazopanib therapy decreases the number of bone 
marrow derived cells (BMDCs), which initiate pre-metastatic niches in 
the benign pelvic lymph nodes.  Hypothesis: Treatment with 
pazopanib will reduce the number of BMDCs in pelvic lymph nodes. 
 
1.3.2  To evaluate if pazopanib therapy decreases levels of MDSCs and 
Tregs, immune cells that potentially suppress the antitumor immune 
response and thereby contribute to pre-metastatic niche formation, in 
benign lymph nodes. Hypothesis: VEGF-TKIs stifle recruitment of 
myeloid derived suppressor cells (MDSCs) to tumor tissue in murine 
xenografts models, and we thus suspect that pazopanib therapy will 
reduce MDSC recruitment. 
 
1.3.3  To evaluate if pazopanib therapy results in improved clinical outcome. 
Hypothesis: Through impeding pre-metastatic niche formation, we 
suspect that pazopanib therapy will yield improvement in clinical 
endpoint such as progression free survival 
2 
BACKGROUND 
2.1 
Defining prognosis in prostate cancer. 
Prostate cancer represents the most common malignancy in males. More than 241,000 
men were diagnosed with prostate cancer in 2012 cancer, and 28, 170 were estimated 
to  die of their disease, mainly because of progression to metastatic disease.[1] The 
incidence of prostate cancer rose sharply between 1990 and 1995, likely attributable to 


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an increase in widespread adoption of PSA screening.  PSA screening has also resulted 
in a drastic stage migration in prostate cancer, with far fewer patients presenting with 
de novo metastatic disease.[2]  While these data are encouraging, the increasing 
proportion of patients with localized disease underscores the need to develop accurate 
predictive tools to determine the risk of metastatic progression.  Clinical guidelines, 
such as those published by the NCCN, employ risk stratification tools combining stage, 
grade and PSA to determine the risk of biochemical recurrence after definitive local 
therapy.[3]  These tools have been validated in several series and provide a superior 
basis for treatment recommendations compared to clinical stage alone.[4,5] However, 
no currently available risk stratification schema has perfect accuracy, and furthermore, 
only a limited number can predict outcomes outside of biochemical recurrence, such as 
the risk of metastases and cancer-specific death.[6,7] Appropriate identification of 
patients at higher likelihood for such outcomes may provide an opportunity for 
therapeutic interventions to mitigate this risk.  
2.2 
Personalizing prognostic models in prostate cancer: The pre-metastatic 
niche. 
The ‘seed-and-soil’ hypothesis was proposed by Paget in 1889, and suggests that the 
biological characteristics of certain tissues may foster invasion and growth of 
metastases.[8]  Identification of these susceptible areas, termed pre-metastatic niches, 
has numerous potential clinical applications.  For instance, patients with more 
abundant niches may have increased metastatic potential – niche prevalence could 
therefore serve as a personalized supplement to current prognostic models.[9]  
Alternatively, the pre-metastatic niche could act as a target of anticancer therapy, 
preventing metastases from developing.  A necessary precursor to clinical use of the 
pre-metastatic niche is accurate molecular characterization of this entity.  The seminal 
studies defining the composition of the pre-metastatic niche are described herein.  
2.3 
VEGFR1+ Bone Marrow Derived Cells (BMDCs) initiate the pre-metastatic 
niche.  
Kaplan et al assessed mice injected with either LLC or B16 melanoma cells.  While 
LLC cells have a predilection for pulmonary spread, B16 melanoma cells metastasize 
in a more widely disseminated fashion.  At day 14 after tumor inoculation, it was 
observed that deposition and clustering of VEGFR1+ BMDCs occurred in terminal 
bronchioles prior to arrival of tumor cells.  By day 23, tumor micrometastases were 
visible.  Sites of BMDC clustering appeared to be tumor specific; while LLC cells 
deposited only in the lungs and liver, B16 cells deposited in a range of tissues, such as 
the lung, liver, testis and spleen.  VEGFR1+ BMDCs recruited to pre-metastatic niche 
sites had increased expression of the fibronectin receptor VLA-4 (integrin 41), 
implicating the role of fibronectin in BMDC clustering.   
2.4 
MDSC recruitment may represent an early event in pre-metastatic niche 
formation.  
Amongst the VEGFR1+ BMDCs that populate the pre-metastatic niche, a proportion 
are MDSCs, characterized by a Gr-1+/MAC1+ immunophenotype.[9]  Recent evidence 
suggests that MDSCs play a critical role in inhibition of the antitumor immune 
response.[13] The recruitment of MDSCs to tumor sites appears to be driven by Stat3, 


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and work done in Dr Hua Yu’s laboratory at City of Hope institution suggests that 
Stat3 may further activate tumor angiogenesis, promoting a functional tumor micro-
environment.[14]  Thus, abrogation of Stat3-mediated MDSC recruitment to the pre-
metastatic niche may reduce metastatic potential.  As discussed in the subsequent 
section, therapy with a VEGF-TKI could potentially inhibit these Stat3-mediated 
effects.     
2.5 
Preliminary Data: VEGF-TKI therapy decreases MDSC accumulation in 
tumor tissue.   
Our external collaborator, Dr. Pal’s group have previously reported a series of 
experiments in Renca-tumor bearing mice suggesting an antitumor effect of sunitinib 
that is Stat3 dependent.[15]  Specifically, these studies demonstrate a reduction in 
Stat3 activation in MDSCs with sunitinib therapy.  This reduction correlated with a 
decrease in expression of Stat3-mediated pro-angiogenic factors, such as VEGF and 
CXCL2 (the latter inhibits endothelial progenitor cell recruitment).[16] Furthermore, 
treatment with sunitinib decreased recruitment of MDSCs to tumor tissue.  
2.6 
Preliminary Data: The pre-metastatic niche is detectable in high-risk 
prostate cancer  
To determine the role of the pre-metastatic niche in prostate cancer, a separate 
retrospective study, specifically examining the predictive role of the niche in the 
benign lymph nodes of men with high risk prostate cancer was undertaken.  In COH 
IRB 09213, the City of Hope Prostate Cancer Database (COH Database) was used to 
identify 46 patients with high-risk PCa (baseline PSA > 20, pT3a-4 disease, or biopsy 
Gleason 8-10) who had undergone radical prostatectomy and pelvic lymph node 
dissection (PLND).  The COH PCR prospectively collects clinical data associated with 
patients undergoing prostatectomy at the institution, and warehouses available clinical 
specimens.  Benign tissue specimens (paraffin-embedded) derived from PLND were 
acquired for each patient, and were stained for VEGFR1 expression.  VEGFR1+ cell 
clusters were counted within 8 distinct 40x fields, and the cluster count was averaged. 
The average cluster count was 3.13 (standard deviation, 1.43), and ranged from 0-6.25 
(see Figure 1).  VEGFR1+ clustering in PLND specimens was a significant predictor 
of biochemical recurrence on multivariate Cox proportional hazards analysis, and 
outperformed other variables including established prognostic factors such as age, 
extracapsular spread, seminal vesicle invasion, and the aforementioned high-risk 
features.  Patients with increased VEGFR1+ clustering pelvic lymph node tissue had a 
shorter interval to biochemical recurrence (HR 0.18, P<0.10). These preliminary 
results indicate that increased VEGFR1+ cell clustering in benign nodal tissue may 
predict poorer clinical outcome in patients with high-risk PCa.  This dataset is 
consistent with a recent report from Fujita et al (Cancer Sci 2009; 100(6):1047-50), 
which also suggested that VEGFR1 staining in pelvic lymph nodes predicted the risk 
of biochemical recurrence after radical prostatectomy in a more heterogeneous group.  
Together with this dataset, there is emerging rationale for examining VEGFR1 as a key 
component of the pre-metastatic niche.  


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2.7 
Preliminary Data: VEGF-TKIs have demonstrable efficacy in the setting of 
prostate cancer, and have been employed in neoadjuvant trials.   
Data has emerged for the agent sunitinib in the setting of metastatic, hormone 
refractory prostate cancer.  In one phase II study, patients who had received no prior 
cytotoxic therapy (Group A) or prior docetaxel therapy (Group B), (n=17 in each 
group), were treated with daily sunitinib.[17]  One patient in each group had a 
documented PSA response.  Furthermore, 7 and 8 patients had a stable PSA at 12 
weeks in groups A and B, respectively.  Interestingly, radiographic responses were 
observed in the absence of PSA responses.  A separate phase II study assessed 
sunitinib specifically in the setting of docetaxel failure, and elicited similar response 
rates.[18]  Preclinical studies have suggested potential synergy between sunitinib and 
docetaxel; this combined regimen is being further explored.[19,20]  At least two 
studies have assessed sunitinib prior to prostatectomy.[21,22]  An experience reported 
by the M.D. Anderson Cancer Center exploring three cycles of sunitinib (37.5 mg oral 
daily) prior to surgery enrolled a total of 44 patients.[22]  Thus far, in 30 patients that 
have completed surgery, 1 CR has been reported.  However, 3 patients were 
characterized as treatment failures (defined by unresectable pelvic nodal disease, 
confirmed post-operative PSA ≥ 0.2ng/mL, or administration of post-operative 
radiation or ADT.  Thus, while sunitinib appears to be relatively safe in the 
neoadjuvant setting (no grade 4 toxicities or toxicity-related discontinuations were 
observed), there may be rationale to explore more potent agents in this setting, such as 
axitinib.   
2.8 
Rationale for pazopanib therapy 
Pazopanib (Novartis) has been chosen because it is a novel, orally available, small 
molecule tyrosine kinase inhibitor of VEGF receptor-1,-2,-3 and is already approved 
for treatment of metastatic renal cell carcinoma after favorable results in a randomized 
phase III trial[7]. 


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3 
DRUG INFORMATION 
 
Pazopanib (Novartis) is a novel, orally available, small molecule tyrosine kinase inhibitor 
of VEGF receptor-1,-2,-3 and is already approved for treatment of metastatic renal cell 
carcinoma after favorable results in a randomized phase III trial [28]. Further detailed 
results from nonclinical studies, as well as additional physical and chemical 
characteristics of pazopanib are available in the Investigator’s Brochure (IB) [29]. 
 
As of the clinical data cut-off date for the current IB, 09 September 2010, a total of 42 
clinical studies have been performed or are in progress in adult subjects with cancer.  
These studies include renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC, 
ovarian cancer, breast cancer, soft tissue sarcoma, cervical cancer, colorectal cancer, 
hepatocellular cancer, multiple myeloma, and glioma. As of the cutoff, over 6000 
subjects have enrolled on these clinical studies.  Data collected to date show that oral 
pazopanib is absorbed after administration and that pazopanib administration at 800mg 
daily dose is associated with a reasonable safety profile and encouraging efficacy in 
various oncology settings [29].  
3.1 
Adverse Reactions 
The following safety data is from the Prescribing Information for pazopanib, revised 
April 2012 [30].  
3.1.1 
Clinical Trials Experience 
 
Renal Cell Carcinoma:  
The safety of pazopanib has been evaluated in 977 patients in the monotherapy 
trials which included 586 patients with RCC at the time of NDA submission. 
With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most 
commonly observed adverse reactions (≥ 20%) in the 586 patients were 
diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and 
vomiting. 
 
The data described below reflect the safety profile of pazopanib in 290 RCC 
patients who participated in a randomized, double-blind, placebo-controlled 
trial. The median duration of treatment was 7.4 months (range 0 to 23) for 
patients who received pazopanib and 3.8 months (range 0 to 22) for the placebo 
arm. Forty-two percent of patients on pazopanib required a dose interruption. 
Thirty-six percent of patients on pazopanib were dose reduced. Table 3.1 
presents the most common adverse reactions occurring in ≥ 10% of patients who 
received pazopanib.  
 
 
 
 
 
 


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Table 3.1. Adverse Reactions Occurring in > 10% of Patients with RCC who 
Received Pazopanib Adverse Reactions 
 
Pazopanib  
(N=290) 
Placebo  
(N=145)  
All 
Grades 
Grade 3  
Grade 4  
All 
Grades  
Grade 3  
Grade 4  
% 
%  
%  
%  
%  
%  
Diarrhea  
52  
3  
< 1  
9  
< 1  
0  
Hypertension  40  
4  
0  
10  
< 1  
0  
Hair color 
changes  
38  
< 1  
0  
3  
0  
0  
Nausea  
26  
< 1  
0  
9  
0  
0  
Anorexia  
22  
2  
0  
10  
< 1  
0  
Vomiting  
21  
2  
< 1  
8  
2  
0  
Fatigue  
19  
2  
0  
8  
1  
1  
Asthenia  
14  
3  
0  
8  
0  
0  
Abdominal 
pain  
11  
2  
0  
1  
0  
0  
Headache  
10  
0  
0  
5  
0  
0  
Neutropenia  
34  
1  
< 1  
6  
0  
0  
Thrombocyto
penia  
32  
< 1  
< 1  
5  
0  
< 1  
Lymphocyto
penia  
31  
4  
< 1  
24  
1  
0  
Chemistry  
ALT 
increased  
53  
10  
2  
22  
1  
0  
AST 
increased  
53  
7  
< 1  
19  
< 1  
0  
Glucose 
increased  
41  
< 1  
0  
33  
1  
0  
Total 
bilirubin 
increased  
36  
3  
< 1  
10  
1  
< 1  
Phosphorus 
decreased  
34  
4  
0  
11  
0  
0  
Sodium 
decreased  
31  
4  
1  
24  
4  
0  
Magnesium 
decreased  
26  
< 1  
1  
14  
0  
0  
Glucose 
decreased  
17  
0  
< 1  
3  
0  
0  
 
 
 


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Soft Tissue Sarcoma:  
The safety of pazopanib has been evaluated in 382 patients with advanced soft 
tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). 
The most commonly observed adverse reactions (≥ 20%) in the 382 patients were 
fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, 
vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, 
dysgeusia, dyspnea, and skin hypopigmentation.  
 
The data described below reflect the safety profile of pazopanib in 240 patients 
who participated in a randomized, double-blind, placebo-controlled trial of 
patients with soft tissue sarcoma. The median duration of treatment was 4.5 
months (range 0 to 24) for patients who received pazopanib and 1.9 months 
(range 0 to 24) for the placebo arm. Fifty-eight percent of patients on pazopanib 
required a dose interruption. Thirty-eight percent of patients on pazopanib had 
their dose reduced. Fourteen percent of patients who received pazopanib 
discontinued therapy due to adverse reactions. Table 3 presents the most common 
adverse reactions occurring in ≥ 10% of patients who received pazopanib.  
 
Table 3.2:  Adverse Reactions Occurring in > 10% of Patients with STS who 
Received Pazopanib Adverse Reactions 
 
 
Pazopanib (N=240) 
Placebo  
(N=123)  
All 
Grades 
Grade 3  Grade 4  
All 
Grades  
Grade 3  
Grade 4  
% 
%  
%  
%  
%  
%  
Fatigue  
65  
13  
1  
48  
4  
1  
Diarrhea  
59  
5  
0  
15  
1  
0  
Nausea  
56  
3  
0  
22  
2  
0  
Weight 
decreased  
48  
4  
0  
15  
0  
0  
Hypertension  
42  
7  
0  
6  
0  
0  
Appetite 
decreased  
40  
6  
0  
19  
0  
0  
Hair color 
changes  
39  
0  
0  
2  
0  
0  
Vomiting  
33  
3  
0  
11  
1  
0  
Tumor pain  
29  
8  
0  
21  
7  
2  
Dysgeusia  
28  
0  
0  
3  
0  
0  
Headache  
23  
1  
0  
8  
0  
0  
Musculoskelet
al pain  
23  
2  
0  
20  
2  
0  
Myalgia  
23  
2  
0  
9  
0  
0  
Gastrointestin
al pain  
23  
3  
0  
9  
4  
0  
Dyspnea  
20  
5  
< 1  
17  
5  
1  


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Exfoliative 
rash  
18  
< 1  
0  
9  
0  
0  
Cough  
17  
< 1  
0  
12  
< 1  
0  
Peripheral 
edema  
14  
2  
0  
9  
2  
0  
Mucositis  
12  
2  
0  
2  
0  
0  
Alopecia  
12  
0  
0  
1  
0  
0  
Dizziness  
11  
1  
0  
4  
0  
0  
Skin disorder  
11  
2  
0  
1  
0  
0  
Skin 
hypopigmenta
tion  
11  
0  
0  
0  
0  
0  
Stomatitis  
11  
< 1  
0  
3  
0  
0  
Chest pain  
10  
2  
0  
6  
0  
0  
 
Other adverse reactions observed more commonly in patients treated with 
pazopanib that occurred in ≥ 5% of patients and at an incidence of more than 2% 
difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% 
versus 0), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular 
dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus 
<1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder 
(5% versus 0%).  
 
Table 3.3 presents the most common laboratory abnormalities occurring in >10% 
of patients who received pazopanib and more commonly (≥ 5%) in patients who 
received pazopanib versus placebo.  
 
Table 3.3:  Selected Laboratory Abnormalities Occurring in > 10% of Patients with 
STS who Received Pazopanib and More Commonly (> 5%) in Patients who 
Received Pazopanib versus Placebo Parameters 
 
Pazopanib(N=240) 
Placebo  
(N=123)  
All 
Grades 
Grade 3  
Grade 4  
All 
Grades  
Grade 3  Grade 4  
% 
%  
%  
%  
%  
%  
Hematologic  
Leukopenia  
44  
1  
0  
15  
0  
0  
Lymphocyto
penia  
43  
10  
0  
36  
9  
2  
Thrombocyto
penia  
36  
3  
1  
6  
0  
0  
Neutropenia  
33  
4  
0  
7  
0  
0  
Chemistry  
AST 
increased  
51  
5  
3  
22  
2  
0  


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ALT 
increased  
46  
8  
2  
18  
2  
1  
Glucose 
increased  
45  
< 1  
0  
35  
2  
0  
Albumin 
decreased  
34  
1  
0  
21  
0  
0  
Alkaline 
phosphatase  
32  
3  
0  
23  
1  
0  
increased  
Sodium 
decreased  
31  
4  
0  
20  
3  
0  
Total 
bilirubin 
increased  
29  
1  
0  
7  
2  
0  
Potassium 
increased  
16  
1  
0  
11  
0  
0  
 
Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in 
severity in both the RCC and STS clinical trials. Patients should be advised how to 
manage mild diarrhea and to notify their healthcare provider if moderate to severe 
diarrhea occurs so appropriate management can be implemented to minimize its impact.  
 
Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 
27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 
4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the 
RCC trials of pazopanib, clinical pancreatitis was observed in <1% (4/586) of patients.  
 
Pneumothorax: Two of 290 patients treated with pazopanib and no patient on the placebo 
arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of 
pazopanib for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients 
treated with pazopanib and in no patients on the placebo arm. 
 
3.1.2 
Post marketing Experience 
Potentially serious adverse reactions with pazopanib during post market 
experience included the following [8]:  
 
- 
Hepatic effects: Cases of hepatic failure (including fatalities) have been 
reported during the use of pazopanib. In clinical trials with pazopanib, 
increase in serum transaminases (ALT, AST) and bilirubin were observed. In 
the majority of the cases, isolated increases in ALT and AST have been 
reported, without concomitant elevations of alkaline phosphatase or 
bilirubin. The vast majority (92.5%) of all transaminase elevations of any 
grade occurred in the first 18 weeks.  
 


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- 
Hypertension: In clinical studies with pazopanib, events of hypertension 
including hypertensive crisis have occurred. Hypertension (systolic blood 
pressure ≥ 150 or diastolic blood pressure ≥ 100 mm Hg) occurs early in the 
course of treatment (39% of cases occurred by Day 9 and 88% of cases 
occurred in the first 18 weeks).  
 
- 
QT Prolongation and Torsade de Pointes: In clinical studies with pazopanib, 
events of QT prolongation or Torsade de Pointes have occurred. 
 
- 
Arterial Thrombotic Events: In clinical studies with pazopanib, myocardial 
infarctions, angina, ischemic stroke and transient ischemic attack were 
observed. Fatal events have been observed. Pazopanib has not been studied 
in patients who have had an event within the previous 6 months.  
 
- 
Haemorrhagic Events: In clinical studies with pazopanib haemorrhagic 
events have been reported. Fatal haemorrhagic events have occurred. 
Pazopanib has not been studied in patients who had a history of 
haemoptysis, cerebral, or clinically significant gastrointestinal haemorrhage 
in the past 6 months.  
 
- 
Gastrointestinal Perforations and Fistula: In clinical studies with pazopanib, 
events of gastrointestinal (GI) perforation or fistula have occurred.  Fatal 
perforation events have occurred.  
 
- 
Wound Healing: No formal studies on the effect of pazopanib on wound 
healing have been conducted. Vascular Endothelial Growth Factor (VEGF) 
inhibitors may impair wound healing. The decision to resume pazopanib 
after surgery should be based on clinical judgment of adequate wound 
healing. Pazopanib should be discontinued in patients with wound 
dehiscence. 
 
- 
Hypothyroidism: In clinical studies with pazopanib, events of 
hypothyroidism have occurred. 
 
- 
Proteinuria: In clinical studies with pazopanib, proteinuria has been reported. 
4 
STUDY DESIGN 
4.1 Description 
This is a phase II, prospective, randomized, double blind (investigator and study 
subject will be blinded to treatment assignment; Investigational Pharmacy will 
be un-blinded) placebo controlled, two arm study. This study will assess 
biomarkers in post treatment samples (surgically resected lymph nodes) in the 
pazopanib group and placebo group. The objective is to compare the post 
treatment VEGFR1 (and other biomarker) levels between treatment and placebo 
groups. We also plan to compare these levels with those reported in previous 


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studies [4, 5].  This study will also assess progression free survival for a total of 
2 years post prostatectomy.  
 
4.2 Number of Patients 
Approximately 30 patients will be enrolled in the study. 15 patients will be 
enrolled onto the treatment arm, and 15 patients will be enrolled to the placebo 
arm.  
 
4.3 Number of Study Centers 
This is a single-center study to be conducted at Huntsman Cancer Institute.  
4.4 Duration  
Enrollment is expected to be completed within 14 months.  Patients will remain 
on study for 2 months. Subjects will be treated with either pazopanib or a 
placebo for 28 days until 2-7 days prior to radical prostatectomy.  Post-surgery, 
subjects be followed for progression free survival for two years.  
5 
ELIGIBILITY CRITERIA 
 
This eligibility checklist is used to determine patient eligibility and filed with 
signature in the patient research chart.  
  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Men ≥ 18 years of age 
5.1.2 _____ Histological documentation of adenocarcinoma of the prostate, 
with available biopsy pathology. Biopsy material must be available for 
pathologic review.  
5.1.3 _____ All patients must meet one or more of the following disease 
features: clinical stage ≥ T3; Primary Gleason score of 4 OR Gleason 
score of 8, 9 or 10; serum PSA ≥ 20 ng/mL; Prostate MRI findings 
consistent with T3 disease; Any clinical stage and PSA >10 and Gleason 
score 7; A Kattan nomogram predicted probability of being free from 
biochemical progression at 5 years after surgery of < 60%. 
5.1.4 _____ Patients must have a PSA ≥ 2 ng/mL at the time of diagnosis of 
prostate cancer or later. 
5.1.5 _____ No prior radiation or chemotherapy for prostate cancer treatment. 


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5.1.6 _____ Scheduled for radical prostatectomy surgery. 
5.1.7 _____ ECOG Performance Status of 0 or 1. 
5.1.8 _____ Patients may have been treated with up to 4 months of androgen 
deprivation therapy. 
5.1.9 _____ No clinical evidence of metastatic prostate cancer, or enlarged 
pelvic lymph nodes in the imaging studies. 
 
5.1.10 _____ Resected lymph nodes must be provided for all subjects for 
biomarker analysis immediately (same day) after surgery (radical 
prostatectomy). 
5.1.11 _____ Adequate organ system function as defined by Table 5 
 
Table 5: Definitions of Adequate Organ Function: 
System 
Laboratory Values 
Hematology 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobin a 
9 g/dL (5.6 mmol/L) 
Platelets 
100 X 109/L 
Prothrombin time (PT) or 
international normalized ratio (INR)  
1.2 X ULN 
Activated partial thromboplastin time 
(aPTT) 
1.2 X ULN 
Hepatic 
Total bilirubin 
1.5 X ULN  
Alanine aminotransferase (ALT) and 
Aspartate aminotransferase (AST)  
Below the institutional upper 
limits of normal 
Renal 
Serum creatinine 
1.5 mg/dL (133 µmol/L) 
Or, if >1.5 mg/dL: Calculated 
creatinine clearance (ClCR) (reference 
appropriate appendix) 
30 mL/min to 50 mL/min   
Urine Protein to Creatinine Ratio 
(UPC; refer to Appendix A)b  
<1 
Or, 24-hour urine protein 
<1g 
a. Subjects may not have had a transfusion within 7 days of screening 
assessment. 


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b. If UPC 1, then a 24-hour urine protein must be assessed.  Subjects 
must have a 24-hour urine protein value <1 g to be eligible.   
5.1.12 _____ Subjects must provide written informed consent within one month 
prior to performance of study-specific procedures or assessments and 
must be willing to comply with treatment and follow up. 
Note:  Informed consent will be obtained after establishing the diagnosis 
of high risk, localized prostate cancer, and may be obtained prior to start 
of the specified screening window. 
Note:  Procedures conducted as part of the subject’s routine clinical 
management (e.g., blood count, imaging study such as bone scan) and 
obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided these procedures are conducted 
as specified in the protocol   
5.2 Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible 
5.2.1 _____ Clinical evidence of metastatic prostate cancer. 
5.2.2 _____ Prior malignancy. No other prior malignancy is allowed except 
for the following: adequately treated basal cell or squamous cell skin 
cancer, adequately treated Stage I or II cancer from which the patient is 
currently in complete remission, or any other cancer from which the 
patient has been disease-free for 5 years.   
5.2.3 _____ 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, 
Chrohn’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.  
5.2.4 _____ Clinically significant gastrointestinal abnormalities that may 
affect absorption of investigational product including, but not limited to: 
 Malabsorption syndrome or  
 Major resection of the stomach or small bowel. 
5.2.5 _____ Corrected QT interval (QTc) > 480 msecs  
  Note:  Correction method should be reported  
5.2.6 _____ History of any one or more of the following cardiovascular 


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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 C for 
description) 
5.2.7 _____ No evidence of preexisting uncontrolled hypertension.  If the 
patient has a history of or elevated blood pressure at baseline then they 
must have controlled hypertension documented and confirmed by 2 
consecutive blood pressure readings taken within 1 hour.  The baseline 
systolic blood pressure readings must be 140 mm Hg, and the baseline diastolic blood pressure readings must be 90 mm Hg.
   
Note: Initiation or adjustment of antihypertensive medication(s) is 
permitted prior to study entry.  Following antihypertensive medication 
initiation or adjustment, blood pressure (BP) must be re-assessed three 
times at approximately 2-minute intervals.  At least 24 hours must have 
elapsed between anti-hypertensive medication initiation or adjustment 
and BP measurement.  These three values should be averaged to obtain 
the mean diastolic blood pressure and the mean systolic blood pressure.  
The mean SBP / DBP ratio must be <140/90 mmHg (OR 150/90 mm Hg, 
if this criterion is approved by the HCI DSMC Chair or Co-chair) in 
order for a subject to be eligible for the study (see Table 7.1 for details 
on BP control and re-assessment prior to study enrollment). 
5.2.8 _____ History of cerebrovascular accident including transient ischemic 
attack (TIA), pulmonary embolism or untreated deep venous thrombosis 
(DVT) within the past 6 months. 
5.2.9 _____ 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 not considered 
to be major surgery). 
5.2.10 _____ Evidence of active bleeding or bleeding diathesis. 
5.2.11 _____ Patients on active therapeutic anticoagulation.   
5.2.12 _____ Known endobronchial lesions and/or lesions infiltrating major 
pulmonary vessels that increase the risk of pulmonary hemorrhage 
Note:  Lesions infiltrating major pulmonary vessels (contiguous tumour 
and vessels) are excluded; however, the presence of a tumor that is 


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touching, but not infiltrating (abutting) the vessels is acceptable (CT with 
contrast is strongly recommended to evaluate such lesions). 
 Large protruding endobronchial lesions in the main or lobar 
bronchi are excluded; however, endobronchial lesions in the 
segmented bronchi are allowed.  
 Lesions extensively infiltrating the main or lobar bronchi are 
excluded; however, minor infiltrations in the wall of the bronchi 
are allowed. 
5.2.13 _____ Recent hemoptysis ( ½ teaspoon of red blood within 8 weeks 
before first dose of study drug). 
5.2.14 _____ Any serious and/or unstable pre-existing medical, psychiatric, or 
other condition that could interfere with subject’s safety, provision of 
informed consent, or compliance to study procedures.  
5.2.15 _____Unable or unwilling to discontinue use of prohibited medications 
listed in Section 6.3.5 for at least 14 days or five half-lives of a drug 
(whichever is longer) prior to the first dose of study drug and for the 
duration of the study. 
5.2.16 _____ Treatment with any of the following anti-cancer therapies:  
 radiation therapy, chemotherapy, immunotherapy, biologic 
therapy, investigational therapy 
 surgery or tumor embolization within 14 days prior to the first dose 
of pazopanib OR 
 hormonal therapy within 14 days or five half-lives of a drug 
(whichever is longer) prior to the first dose of Pazopanib 
5.2.17 _____  Administration of any non-oncologic investigational drug within 
30 days or 5 half lives whichever is longer prior to receiving the first 
5.2.18 _____ Any ongoing toxicity from prior hormonal therapy that is >Grade 
1 and/or that is progressing in severity 
5.2.19 _____ Known active viral infection.  
• 
Note: Viral hepatitis testing is required at screening for all patients 
 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this 
study.  
 
______________________________ 
_________ 
_______ 
PI Signature   
 
 
 
Date  
Time 


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6 
TREATMENT PLAN 
Treatment will be administered in an outpatient setting.  Randomization will take 
place by the Investigational Pharmacy at Huntsman Cancer Institute. Patients who 
are enrolled will be randomized to either pazopanib experimental arm, or the 
placebo arm. Patients will take either 800 mg pazopanib or a placebo tablet orally 
for 28 days of therapy.  
 
The initiation of pazopanib or placebo will be contingent upon the date selected 
for radical prostatectomy and pelvic lymph node dissection, with 28 days of 
planned therapy to conclude at least 48 hours prior to surgical intervention.  
6.1 Administration Schedule 
 
Treatment Arm: 
Pazopanib 800 mg orally daily for 28 days prior to radical prostatectomy. 
 
Placebo Arm: 
Placebo, orally, daily for 28 days prior to radical prostatectomy 
 
One cycle = 28 days 
 
Only one cycle of pazopanib or placebo will be instituted for this protocol. 
 
Surgery 
Radical prostatectomy with pelvis lymph node dissection will be 
performed as standard of care after ~ 7 days of completion of the 28 days 
of treatment with either pazopanib or placebo. A 48 hour washout period 
from treatment is required prior to surgery.  Prostatectomy may be 
performed via any accepted methodology (open, laparoscopic, robotic-
assisted, etc.).  Notably, standard wait times for prostatectomy at 
Huntsman Cancer Institute vary between 5-6 weeks from the time of 
seeing the surgeon for prostatectomy.  Thus, it is not anticipated that the 
current protocol will delay standard of care therapies on the control or 
experimental arms.  Surgery will not be delayed longer than 8 weeks from 
the time of randomization.  
 
6.2 Pazopanib/Placebo Treatment 
6.2.1 
How Supplied, Stored, Packaged and Labeled 
Pazopanib tablets are manufactured and provided by Novartis.  The 
tablets are supplied as 50 mg, 100 mg, 200 mg, 400 mg and 500 mg 
(as free base) tablets for oral administration to support oncology 
indications. The 200 mg and 400 mg tablets are oval-shaped white 
tablets and will be used for this purpose of this study.  
 


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Placebo tablets will match the oval-shaped 200 mg and 400 mg tablets 
and will also be provided by Novartis. 
 
All tablets will be packaged in white high density polyethylene 
(HDPE) bottles with white plastic, induction seal, child-resistant caps. 
 
Huntsman Cancer Institute Investigational Pharmacy will randomize 
patients to either arm.  
6.2.2 
Preparation and Administration 
800 mg (2x400mg or 4x200mg) Pazopanib per day should be taken 
orally without food at least one hour before or two hours after a meal. 
 
Placebo tablets should also be taken orally without food at least one 
hour before or two hours after a meal.  
 
Patients should be instructed NOT to crush tablets. The consumption 
of crushed pazopanib tablets leads to increases in the extent of oral 
absorption and may result in increased toxicities. 
6.2.3 
Accountability and Compliance 
Patients will be instructed to keep a diary of daily medication 
compliance.  The study team will collect the diary at the completion of 
28 days of pazopanib/placebo treatment prior to radical prostatectomy.  
 
6.3 Concomitant Medications 
All subjects will be asked to provide a complete list of prescription and over-
the-counter medications that have been taken within the 4 weeks prior to 
Screening.  The investigator must be informed as soon as possible about any 
new medication(s) taken from the time of Screening until the completion of the 
post-treatment follow-up visit.   
 
Subjects should receive full supportive care during the study, including 
transfusion of blood and blood products, and treatment with antibiotics, 
analgesics, erythropoietin, or bisphosphonates, when appropriate.   
 
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT 
antagonists) may be administered prophylactically in the event of nausea.  Anti-
diarrheals, such as loperamide, may be administered as needed in the event of 
diarrhea.  Although acetaminophen at doses of 2 g/day is permitted, it should 
be used with caution in subjects with impaired liver function.   
 
6.3.1 
 Permitted Medications – Use with Caution 
 
Specific recommendations regarding anticoagulants: 


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Subjects taking concomitant anticoagulant therapy at “baseline” are excluded 
from the study.  Results from drug-drug interaction studies conducted in 
subjects with cancer suggest that pazopanib has no effect on the metabolism of 
S-warfarin.  Hemorrhagic events, however, have been reported in clinical 
studies with pazopanib; therefore, pazopanib should be used with caution in 
subjects with increased risk of severe bleeding or who are receiving 
concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low 
molecular weight heparin, unfractionated heparin).  Therefore, patients may 
only be on concomitant anticoagulant therapy if such therapy is deemed 
necessary by the investigator “after” study commencement and is monitored 
closely while on study treatment. 
6.3.2 
Specific recommendations regarding hypoglycemic therapy including 
insulin: 
Results from drug-drug interaction studies conducted in subjects with cancer 
suggest that there will be no clinically relevant pharmacokinetic interaction 
between pazopanib and hypoglycemic agents.  Transient decreases in serum 
glucose (mainly Grade 1 and 2, rarely Grade 3) have been observed in clinical 
studies with pazopanib.  In addition, decreases in blood sugar have been 
recently reported in subjects treated with another small molecule tyrosine 
kinase inhibitor, sunitinib [10].  Such changes may require an adjustment in the 
dose of hypoglycemic and/or insulin therapy.  Subjects should be advised to 
report symptoms of hypoglycemia (e.g., confusion, visual disturbances, 
palpitations, sweating).  Serum glucose should be tested during treatment with 
pazopanib as outlined in the protocol and as clinically indicated. 
 
6.3.3 
  The Effects of Pazopanib on Other Drugs 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, 
CYP2C8, CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and 
CYP2E1.  Pregnane X receptor transient transfection assay suggested some 
potential for human CYP3A4 induction at high concentrations.  Results from 
drug-drug interaction studies conducted in subjects with cancer suggest that 
pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but 
had no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19 
metabolism.  Therefore, concomitant use of pazopanib with certain medications 
(substrates of CYP3A4, CYP2C8, and CYP2D6) with a narrow therapeutic 
window should be undertaken with CAUTION due to the potential for 
alterations in the pharmacologic effects of these medications or an increased 
risk for serious or life threatening adverse events associated with such 
medications (see below) secondary to the inhibition of specific CYP enzymes 
by pazopanib.  In addition, the potential for drug interaction with such 
medications, although diminished, may persist after the last dose of pazopanib 
due to its long half-life (i.e., mean 30.9 hours); therefore, continue to exercise 
CAUTION for at least 7 days and up to 15 days after the last dose of pazopanib 
when administering these medications.  These medications include (but are not 
limited to): 


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• 
Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, 
methylergonovine (potential increased risk for developing ergot 
toxicity that includes severe vasospasm leading to peripheral as well as 
cerebral ischemia) 
• 
Neuroleptics: pimozide (potential increased risk for QT interval 
prolongation, ventricular arrhythmia, and sudden death) 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, 
amiodarone, quinidine, propafenone (potential increased risk for QT 
interval prolongation and Torsade de Pointes) 
• 
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential 
increased risk for nephrotoxicity and neurotoxicity) 
• 
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
 
6.3.4 
The Effects of Other Drugs on Pazopanib 
Results from in vitro studies suggest that the oxidative metabolism of pazopanib 
in human liver microsomes is mediated primarily by CYP3A4, with minor 
contributions from CYP1A2 and CYP2C8.  Furthermore, in vitro data suggest 
that pazopanib is a substrate for p-glycoprotein.  Substances that induce or 
inhibit CYP3A4 may alter the pharmacologic effects of pazopanib and should 
be used with CAUTION.   
Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations.  Co-administration of strong CYP3A4 inhibitors is prohibited 
(see Section on Prohibited Medications); therefore selection of an alternate 
concomitant medication with no or minimal potential to inhibit CYP3A4 is 
recommended.   
CYP3A4 inducers may decrease plasma pazopanib concentrations.  Selection of 
an alternate concomitant medication with no or minimal enzyme induction 
potential is recommended.  Drugs that induce CYP3A4 and may decrease 
pazopanib plasma concentrations include (but are not limited to): 
• 
Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone (>10 mg), methylprednisolone (>8 mg), dexamethasone 
(>1.5 mg) 
• 
Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, 
oxcarbazepine 
• 
HIV antivirals:  efavirenz, nevirapine 
• 
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene 
• 
Miscellaneous:  St. John’s Wort, modafinil, pioglitazone 
 
6.3.5 
  Prohibited Medications 
 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is 
PROHIBITED beginning 14 days prior to the first dose of study drug until 
discontinuation from the study.  Strong CYP3A4 inhibitors include (but are 
not limited to): 


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• 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
• 
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, 
lopinavir) 
• 
Antifungals:  itraconzaole, ketoconazole, voriconazole 
• 
Antidepressants:  nefazodone 
 
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, 
radiation, or hormonal] while on treatment in this study.   
 
HMG-CoA Reductase Inhibitors (Statins) should be held during the treatment 
period and for one week after discontinuation to lower the risk for liver toxicity. 
 
Subjects taking concomitant anticoagulant therapy at baseline are excluded from 
the study. 
 
Drugs with known risk to induce torsades de pointes or prolong QT interval 
(refer to appendix B for a comprehensive list).  Drugs that have a possible risk 
of prolonging QT interval should be used with caution.  
 
Subjects should not receive any other investigational drug within 15 days of the 
last dose of pazopanib and until post-treatment blood draws are completed. 
 
Patients will be strongly discouraged from drinking alcohol during the treatment 
period. 
6.4 Duration of Therapy 
Patients will be randomized to either the pazopanib arm or the placebo arm.  
The duration of patient treatment will be 28 days until 2-7 days prior to radical 
prostatectomy.  Post-prostatectomy patients will be followed as per standard of 
care for ≥ 30 days to assess for post-operative complications.  Study treatment 
will be discontinued after one cycle or 28 days of treatment.  Patients will be 
removed from study after their 30 day post radical prostatectomy follow-up 
visit. Patients may also be removed from study for any of the following: 
intolerable toxicities, patient withdrawal, or PI decision.  
 
If a patient misses more than 7 consecutive days of study treatment they may be 
replaced at the discretion of the investigator.  Patients who are unable to have 
surgery will be considered not evaluable and will be replaced.  
 
Following prostatectomy, patients will be followed clinically for progression for 
a maximum of two years. PFS is defined in Section 10.2. 
 
 
 


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7 
TOXICITIES AND DOSEAGE MODIFICATION 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for 
Adverse Events) Version 4.0 for adverse event and serious adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded:  
(http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx). 
7.1 Dose Modifications 
The investigator should determine if an adverse event is related to study 
treatment, which is defined as possibly, probably, or definitely related to 
pazopanib.  If an adverse event is considered at least possibly related to 
pazopanib and requires a dose modification as described in this section, 
treatment will be un-blinded and the necessary dose modifications will be 
utilized.  Adverse events that are not related to pazopanib will be defined as 
unlikely related and unrelated.  
As a general rule, if dose reduction of pazopanib is necessary, the dose should 
be reduced stepwise by 200 mg at each step, and the subject should be 
monitored for approximately 10 to 14 days at each dose level.  If toxicity does 
not abate during this monitoring time, the pazopanib may need to be interrupted 
and/or the dose further decreased with continued monitoring for an additional 
10-14 days at each dose level, and so on.  
If the toxicity has abated with reduction of the dose and dose re-escalation is 
considered safe by the investigator, the pazopanib dose can then be increased 
step-wise back to the pre-event dose (in 200 mg increments, after monitoring for 
10-14 days at each dose level to ensure that toxicity did not recur or worsen).  
Subjects will be permanently discontinued from treatment for the following: 
a. Grade > or = 2 adverse events attributed by the investigator as related to 
pazopanib, and which do not resolve within 7 days after dose modification 
of pazopanib. 
b. Grade > or = 2 thrombocytopenia regardless of attribution 
c. Grade > or = 2 elevations in ALT or AST regardless of attribution 
 
d. Patients with toxicity that requires dose interruption for >7 days will be 
taken off treatment to avoid delaying curative surgery 
e. Any grade 3 or higher adverse event  
f. Any newly diagnosed DVT or PE or arterial thrombotic event  
 
Table 7.1 
Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Grade 2  Asymptomatic and 
persistent SBP of 140 and 
<170 mmHg, or DBP 90 and <110 
mmHg, or a clinically significant 
increase in DBP of 20 mmHg (but 
still below 110 mmHg). 
Step 1.  If the event is attributed by the investigator as related to 
pazopanib, decrease the dose of pazopanib by 200 mg.    
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 7 days as 
indicated to achieve well-controlleda blood pressure (BP). If BP is 
not well-controlled within 7 days, discontinue treatment and 
consider referral to a specialist. 
 
Grade 3 Asymptomatic SBP 170 
mmHg, or DBP 110 mmHg, or 
failure to achieve well-controlled BP 
within 7 days.   
Discontinue pazopanib and continue follow-up per protocol.  
Grade 4 or Refractory hypertension 
unresponsive to above interventions. 
Discontinue pazopanib and continue follow-up per protocol. 
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to ensure 
accuracy of the reading.  The values below refer to manually-read ECGs.  REFER READER TO ECG 
SECTION IN PROTOCOL 
Grade 2: QTc   481 - 500 msec 
If the event is attributed by the investigator as related to pazopanib, 
decrease pazopanib by 200 mg ; monitor as clinically indicated. If 
the event resolves to grade 1 or baseline in 7 days or less, continue  
pazopanib at the reduced dose. Repeat EKG in 7 days, if the event 
persists, discontinue pazopanib.  
Grade 3 or higher: QTc 501 msec 
Discontinue pazopanib and continue follow-up per protocol. 
Proteinuria 
UPC <3 
Continue pazopanib at the current dose; monitor as clinically 
indicated 
UPC ≥3 or 24-h urine protein 3g 
Step 1. Interrupt pazopanib. 
Step 2. Repeat UPC or 24-hr urine protein monitoring until UPC is 
<3 or 24-hr urine protein is <3 grams.  If the event resolves in 7 
days or less, then restart pazopanib dose-reduced by 200 mg. 
Step 3.  If UPC ≥3 or 24-h urine protein 3g recurs, repeat steps 1 
and 2. 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the 
pazopanib dose can no longer be reduced, discontinue 
pazopanib and continue follow-up per protocol. 
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding 
Grade 1 
For hemoptysis, interrupt pazopanib and contact the Novartis Study 
Physician to discuss whether further treatment with pazopanib is 
appropriate. 
For other Grade I hemorrhage/bleeding events, continue pazopanib 
at the current dose; monitor as clinically indicated. 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal 
bleeding), discontinue pazopanib and continue follow-up per 
protocol.  
Grade 3 or 4, or  
Recurrent  Grade 2 event after dose 
interruption/reduction. 
Discontinue pazopanib and continue with follow-up per protocol.  
   
Venous Thrombosis (DVT, PE) 
Any Grade 
Discontinue pazopanib and continue follow-up per protocol.  
 
Arterial Thrombosis/Ischemia 
 
Any Grade 
Discontinue pazopanib and continue follow-up per protocol.  
Thrombocytopenia: Investigate and document underlying cause 
Grade 1  
Continue pazopanib with current dose; monitor as clinically 
indicated.  
Grade > 2 
Discontinue pazopanib and continue with follow-up per protocol.  
 
Anemia:  No specific dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding 
as noted above. 
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or dermatitis 
without pain 
(erythema, oedema, hyperkeratosis) 
1. Continue pazopanib at present dose 
 Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily living 
(ADLs) (peeling, blisters, oedema, 
bleed, hyperkeratosis) 
1. Hold pazopanib  
2. Treat as clinically appropriate 
3. If resolution to grade 1 or better in 7 days or less, restart  
pazopanib with a dose reduction by 200 mg.  
4. If recurrent consider a further dose reduction to 200mg or 
discontinuation 
Grade 3 
Severe skin changes with pain and 
limiting self care ADLs 
1. Discontinue pazopanib 
Other Clinically Significant Adverse Eventsb  
Grade 1 
Continue pazopanib; monitor as clinically indicated. 
Grade 2  
The investigator will attribute whether the adverse event is 
attributed to pazopanib.  If the event is related to pazopanib, 


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AE Terms & Descriptions 
Dose Modification Algorithms 
decrease the dose of pazopanib by 200 mg, and if the event 
resolves in 7 days or less, continue at the decreased dose.  If the 
event does not resolve after 7 days, discontinue treatment with 
pazopanib. .If the event is attributed by the investigator as 
unrelated to pazopanib, continue pazopanib and monitor as 
clinically indicated. 
Grade 3 or 4 
Discontinue pazopanib and continue follow-up per protocol. 
a. 
Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. 
b. AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI 
CTCAE v4)  
       Abbreviations: BP, blood pressure;  
 
7.1.1 
Dose Modifications and Management of Liver toxicity 
Dose modifications for pazopanib in case of liver-related treatment-
emergent AEs are provided in Table 7.2.  As a general rule, since 
many subjects are taking multiple concurrent medications, it is critical 
to (a) do a thorough evaluation of the subject’s concurrent medications  
and (b) identify and discontinue those with known hepatotoxicity and 
replace with a non-hepatotoxic equivalent for the same indication if 
necessary.  Liver dysfunction must be fully evaluated even if clinical 
signs and symptoms indicate progression of liver tumor lesions.  
Imaging studies must be obtained to document potential progression of 
malignancy. 
 
Table 7.2 
Management of Treatment Emergent Hepatotoxicity 
Event 
Dose Modification Algorithms 
Grade 1 ALT or AST: > 
ULN – 3.0 x ULN 
Continue pazopanib at current dose and monitor LFTs closely. . 
 Grade 2 ALT or AST 
elevation (>3.0 x ULN)  
Permanently discontinue treatment with pazopanib, monitor the patient 
closely until LFTs resolve to baseline or grade 1.   
Grade 2 AST or ALT 
elevation in the setting of 
bilirubin elevation greater 
than 2.0 ULN 
Permanently discontinue treatment with pazopanib, monitor closely until 
LFTs resolve to baseline or grade 1.  
Grade 3 or higher AST or 
ALT elevation (>5.0 x 
ULN)  
Permanently discontinue treatment with pazopanib, monitor closely until 
LFTs resolve to baseline or grade 1.  
 
 
7.2 Supportive Care 
7.2.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
 
 


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8 
STUDY CALENDARh 
 
 
Screeninga Wk 1 Wk 2 
Wk 3 
Wk 4 
Wk 5 
(surgery) 
Week 9(1 
month Post-
Surgery)i 
Post Study 
Assessmentsj 
Informed Consent 
X 
 
 
 
 
 
 
 
History/Progress 
Notes 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
 
 
 
Physical Exam 
X 
X 
 
 
X 
 
X 
 
Vitals signs 
Xl 
X 
Xb 
 
X 
 
X 
 
ECOG Performance 
Status 
X 
X 
 
 
X 
 
X 
 
Safety Assessments 
 
 
X 
X 
X 
X 
X 
 
CBCc 
X 
X 
 
 
X 
 
X 
 
CMPd 
X 
X 
X 
X 
X 
 
X 
 
UPCk 
X 
 
 
 
X 
 
X 
 
TSH, Free T4e 
X 
 
 
 
X 
 
 
 
Coagulation test 
X 
 
 
 
 
 
 
 
PSA 
X 
 
 
 
 
 
X 
X 
Viral Hepatitis Panelf 
X 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
X 
 
 
CT or MRI scang 
X 
 
 
 
 
 
 
 
Bone scang 
X 
 
 
 
 
 
 
 
Pazopanib or Placebo  
 
X 
X 
X 
X 
 
 
 
Prostatectomy/ 
PLND 
 
 
 
 
 
X 
 
 
Collection of Tumor 
specimens 
 
 
 
 
 
X 
 
 
aALL Pre-study/Screening procedures should be completed within 28 days, with the exception of CT or MRI scan 
which need to be performed within 8 weeks prior to study enrollment and  laboratory tests which need to be 
completed within 2 weeks prior to study enrollment. Week 1 laboratory assessments do not need to be repeated if 
screening labs were performed within 7 days of Week 1 Day 1.  The week 1 physical exam, vitals and ECOG do not 
need to be repeated if done within 15 days of week 1 day 1, unless determined clinically indicated per treating 
physician.  
bMonitoring of BP only:  A measurement of BP should be taken at day 7+/- 3 days.  BP can be assessed by any method 
(i.e., at home or by another physician) as long as the study physician is informed of the measurement, verifies any 
measurement that is not normal and takes appropriate action. 
c CBC with differential and platelets.  Permanently discontinue pazopanib for any grade > 2 thrombocytopenia 
d  CMP includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total 
Bilirubin, Calcium, Carbon Dioxide, Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen. If 
clinically indicated, correction of electrolytes (most importantly, potassium, magnesium and calcium) to within 
normal ranges should take place prior to study entry and during study conduct as standard of care. Permanently 
discontinue pazopanib for grade > 2 elevation of AST or ALT.  


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e TSH and free T4 laboratory assessment will be repeated at week 4 only if the patient shows clinical signs of abnormal 
thyroid function tests at screening 
f All patients must be screened for Viral Hepatitis. These laboratory assessments include the following: Hepatitis A 
Virus Antibody,  Hepatitis B Virus Core Antibody, and Hepatitis C Virus Antibody. 
g Axial imaging of the pelvis (either by CT or MRI) will be done as part of preoperative staging evaluation.  A bone 
scan will be done if clinically indicated per investigator discretion. 
h All visits have a +/- 3 day window, with the exception of the prostatectomy/PLND which must be performed within 2 
– 7 days of the completion of 28 days of treatment.  Prostatectomy must be completed no later than 8 weeks post 
randomization. 
i The post-surgery visit will occur per standard of care practices but should occur > 30 days after surgery to assess for 
any post-operative complications 
j Patients will be followed as standard of care until progression in PSA levels >0.2 ng/mL for two years post 
prostatectomy 
k For the baseline UPC:  If UPC 1, then a 24-hour urine protein must be assessed.  Subjects must have a 24-hour urine 
protein value <1 g to be eligible.  At the four week visit, a UPC must be done to assess for proteinuria. 
l  If the subject has a history of or elevated blood pressure  (> 140/90 mmHg) at baseline, 2 consecutive blood pressure 
readings should be done within 1 hour to confirm eligibility. Please refer to exclusion criteria 5.2.7. 


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9 
STUDY PROCEDURES 
 
Screening: 
- 
Informed Consent 
- 
Physical exam 
- 
Review of medical history/baseline symptoms 
- 
Vital Signs- If the subject has a history of or elevated blood pressure (> 140/90 
mmHg) at baseline, 2 consecutive blood pressure readings should be done within 
1 hour to confirm eligibility. 
- 
Concomitant Medication Assessment 
- 
ECOG Performance status 
- 
Labs to be performed within two weeks prior to enrollment: 
o CBC w/diff 
o CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, and Urea 
Nitrogen 
o Coagulation test – PT, PTT, INR 
o PSA 
o Thyroid function – TSH, Free T4 
o UPC:  If UPC 1, then a 24-hour urine protein must be assessed.  Subjects 
must have a 24-hour urine protein value <1 g to be eligible.    
o Viral Hepatitis Panel: Hepatitis A Virus Antibody, Hepatitis B Virus Core 
Antibody, and Hepatitis C Virus Antibody. 
- 
CT or MRI of the pelvis to evaluate disease to be completed within 8 weeks of 
enrollment 
- 
Bone Scan, if clinically indicated, to evaluate disease to be completed within 8 
weeks of enrollment 
- 
EKG 
- 
Verification of an operative date for prostatectomy/pelvic lymph node dissection 
that allows for the 28 day therapeutic period as well as a 48 hour washout period 
prior to surgery.  Prostatectomy may be performed via any accepted methodology 
(open, laparoscopic, robotic-assisted, etc.).  
 
 
Week 1 (Day 1): 
- 
Physical Exam-if clinically indicated per investigator discretion.  Not required if 
screening physical was done within 15 days of Week 1 Day 1. 
- 
ECOG Performance Status.  Not required if done within 15 days of Week 1 Day 
1. 
- 
Vital Signs.  Not required if done within 15 days of Week 1 Day 1. 
- 
Labs: (do not need to be repeated if screening labs performed within 7 days of 
W1D1) 
o CBC w/diff 
o CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 


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Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, and Urea 
Nitrogen 
- 
Safety Assessment: Monitoring and recording all adverse events and serious 
- 
Concomitant medication assessment 
- 
Treatment with pazopanib or Placebo  
 
Week 2 (Day 7 +/- 3 days): 
- 
Vital Signs - Monitoring of BP only:  A measurement of BP should be taken at 
day 7+/- 3 days.  BP can be assessed by any method (i.e., at home or by another 
physician) as long as the study physician is informed of the measurement, verifies 
any measurement that is not normal and takes appropriate action. 
- 
CMP: Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, and Urea Nitrogen. Permanently 
discontinue pazopanib for > grade 2 elevations in ALT, AST 
- 
Concomitant medication assessment 
- 
Safety assessment - Monitoring and recording all adverse events and serious 
adverse events using the CTCAE version 4.   
o Safety and Con/Med Assessments may be done over the phone.  
- 
Treatment with pazopanib or Placebo 
 
Week 3 (Day 15 +/- 3 days): 
- 
Treatment with pazopanib or Placebo 
- 
CMP: Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, and Urea Nitrogen:  Permanently 
discontinue pazopanib for > grade 2 elevations in ALT or AST. 
- 
Safety Assessments: Monitoring and recording all adverse events and serious.  
o Safety and Con/Med Assessments may be done over the phone 
 
Week 4 (Day 22 +/- 3 days): 
- 
Physical Exam 
- 
ECOG Performance Status 
- 
Vitals 
- 
Labs:  
o CBC w/diff: Permanently discontinue pazopanib for grade > 2 
thrombocytopenia 
o CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, and Urea 
Nitrogen: Permanently discontinue pazopanib for > grade 2 elevations of 
ALT or AST  
o TSH, Free T4: laboratory assessment will only be repeated at week 4 if the 
patient shows clinical signs of abnormal thyroid function tests at screening 
o UPC evaluation 


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- 
Treatment with pazopanib daily or Placebo until Day 28.  Medication Compliance 
must be documented. 
- 
Concomitant Medication assessment 
- 
Safety assessment - Monitoring and recording all adverse events and serious 
adverse events using the CTCAE version 4 
 
Week 5: Day 30 – Day 37 (Surgery) 
- 
EKG prior to surgery 
- 
Prostatectomy with Pelvic Lymph Node Dissection: to be performed after the 
completion of 48hour washout period from treatment/placebo (NOTE: Surgery 
must not be delayed longer than 8 weeks from the time of randomization).  
o Collection of benign lymph tissue samples from prostatectomy and pelvic 
lymph node dissection 
o Refer to Section 14.1 for more details on collection, processing and 
storage 
 
 
Week 9 (1 Month Post-op) 
This visit will occur as standard of care, however should occur ≥30 days after 
surgery to assess all toxicities and post-surgery complications.  
- 
Physical Exam 
- 
ECOG Performance Status 
- 
Labs:  
o CBC w/diff 
o CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, and Urea 
Nitrogen 
o Urinalysis 
o PSA 
- 
Safety assessment - Monitoring and recording all adverse events and serious 
adverse events using the CTCAE version 4 
 
Follow-up 
- 
PSA will be performed as clinically indicated post prostatectomy for 2 years or 
until the development of biochemical metastatic recurrence.  
10 
CRITERIA FOR EVALUATION AND ENDPOINT 
 
10.1 Assessment of the pre-metastatic niche 
Normal lymph node tissue will be assessed for pre-metastatic niche density, 
characterized as the average number of VEGFR1-positive clusters in 8 distinct 
40x microscopic fields.  This assessment will be performed through previously 
defined techniques at City of Hope Medical Center.  


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10.2  Assessment of BMDCs and MDSCs 
Normal lymph node tissue will also be assessed by flow cytometry for the 
number of bone marrow derived cells (BMDCs) as well as myeloid derived 
suppressor cells (MDSCs) and Tregs. 
  
10.3 Time to Biochemical Recurrence 
Progression Free Survival will use the time to biochemical recurrence which is 
defined as the number of days elapsed between prostatectomy and the first 
recording of a PSA value ≥ 0.2 ng/mL.  Patients will be followed for 
progression free survival for two years.  
 
10.4 Safety 
Routine safety and tolerability will be evaluated from the results of reported 
signs and symptoms, scheduled physical examinations, vital sign measurements, 
and clinical laboratory test results. More frequent safety evaluations may be 
performed if clinically indicated or at the discretion of the investigator.  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a 
licensed physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be 
obtained in the sitting position. Patients should be sitting for 3-5 minutes prior 
to obtaining vital signs. 
 
Safety Laboratory Determinations 
 
Laboratory assessments should be performed as indicated in Section 8 and 9: 
Study Calendar and Procedures.  These assessments may be carried out within 3 
days before the actual visit to allow flexibility in scheduling.  Assessments may 
be performed more frequently if clinically indicated.  Correction of electrolytes 
(most importantly, potassium, magnesium and calcium) to within normal ranges 
should take place prior to study entry and during study conduct as clinically 
indicated. 
All laboratory tests with values that become abnormal and clinically significant 
while the subject is participating in the study or within 28 days after the last 
dose of study drug should be repeated until the values return to normal or 
baseline.  See Section 7 for guidance on subject follow-up and dose 
management in response to specific laboratory abnormalities.   


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Table 10.3.1 shows the clinical laboratory assessments that should be reported. 
 
Table 10.3.1 Clinical Laboratory Assessments 
Clinical 
Chemistry 
 
Renal function 
 Urea, Creatininea 
Liver function test 
(LFT) Panel  
Albumin, Alkaline phosphatase,  Alanine aminotransferase 
(ALT), Aspartate aminotransferase (AST) and Bilirubin 
(total)b 
Electrolytes and 
others 
Calcium, Potassium, Sodium, Magnesium, Inorganic 
phosphate, Glucose, and Lactate Dehydrogenase (LDH) 
Hematology 
Hematocrit, Hemoglobin, White Blood Cell Count, Red 
Blood Cell Count, Neutrophils, and Platelets 
Coagulation Tests 
Activated partial thromboplastin (aPTT) and International 
Normalization Ratio (INR)c 
Urinalysis for 
Proteinuria 
UPCd 
Thyroid Function 
Test 
TSHe 
 
 
a) Estimated creatinine clearance should be calculated using the Cockroft and Gault method. 
Alternatively, creatinine clearance can be measured directly by 24-hour urine collection.  
b) A direct bilirubin level should be obtained if the total bilirubin level is greater than 1.5 X upper 
limit of normal (ULN).  See Section 7 for stopping criteria and dose modification guidelines 
for treatment-emergent liver function abnormality. 
c) Coagulation tests may also be performed in response to an AE/SAE of bleeding and as 
clinically indicated.   
d) UPC should be evaluated as described in Appendix A or by 24-hour urine protein.  If UPC  3 
or if urine protein is 3g, then the dose modification table guidelines should be followed 
(7.1).    
e) Unscheduled thyroid function tests [TSH and thyroxine (free T4)] should be performed if 
clinically indicated (e.g., if a subject develops signs and symptoms suggestive of 
hypothyroidism). 
10.5 Stopping Rules 
A delay in surgery exceeding 7 days as a consequence of pazopanib-related 
toxicity will be considered an unacceptable toxicity.   If the number of 
unacceptable toxicities exceeds 1 in the first 3 patients, or exceeds 2 in the first 
6 patients or more than 25% thereafter, the study will hold accrual for an 
amendment regarding treatment modifications or study termination. Toxicity 
will be graded and recorded for each patient in this population according to 
CTCAE 4.0.   
 
An interim analysis will occur after 16 patients have completed the 30 day post-
surgical evaluation period (see section 11.1).  The DSMC will review the results 
of the interim analysis to determine if the study should be allowed to continue 
or be stopped for excessive post-surgical toxicity due to pazopanib in the 
treatment arm. 


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11 
STATISTICAL CONSIDERATIONS 
In multivariate analysis, VEGFR1+ clustering in pelvic lymph nodes was an 
independent predictor of time to biochemical recurrence, with an optimal cutoff 
of1.65 clusters/hpf [4].The primary hypothesis for this study is that treatment with 
pazopanib (as compared to control) will result in a decrease in pre-metastatic 
niche formation, as characterized by VEGFR1+ cell clusters, in pelvic lymph 
nodes. The primary efficacy endpoint will be the mean number of VEGFR1+ 
clusters in pelvic lymph nodes. The mean number of VEGFR1+ clusters per high 
power field in the study described above was 3.13, with a standard deviation SD = 
1.43 and a range of 0 – 6.25.  With 15 subjects per arm (30 subjects in all) there 
will be 80% power to detect a difference of 1.33 in the mean number of 
VEGFR+1 clusters/hpf between the reference and experimental arms using a 
student’s t-test at the one-sided alpha = 0.05 significance level. Assuming the 
number of clusters/hpf follows a Gaussian distribution, this difference 
corresponds a substantial improvement from 15% of subjects with <1.65 
clusters/hpf in the standard therapy arm to 46% of subjects with <1.65 
clusters/hpf in the experimental therapy arm.  
 
Progression-free survival will be a secondary efficacy endpoint. PFS will be 
analyzed descriptively using Kaplan-Meier methods and associated 95% 
confidence intervals.  
 
Exploratory biomarker endpoints will be compared between the arms using 
student’s t-tests (provided the data is normally distributed) or a non-parametric 
Wilcoxon test (if the data is non-normally distributed). Safety outcomes will be 
tabulated. 
11.1 Interim analysis for post-surgical complications 
 
An interim analysis will be performed after 16 patients have completed the 
follow-up toxicity assessment at ≥30 days post-surgery. If the number of patients 
with Grade III-V surgical complications by the Clavien-Dindo system differs by 
two or more between the study arms then the study will be held until full review 
by the DSMC.  The operating characteristics of this stopping rule were assessed 
via simulation (100,000 simulations per condition). The proportion of patients 
with grade III or higher Clavien-Dindo complications is less than 15%. If the true 
proportion of grade III-V Clavien-Dindo complications in both arms is 10% the 
probability of stopping is 19%. If the true proportion of grade III-V Clavien-
Dindo complications are 10% and 40% in the two arms then the probability of 
stopping is 72%. 
 
For reference to Clavien-Dindo system: 
http://www.uroweb.org/fileadmin/livesurgery/Clavien-Dindo_Table.pdf 
 
 


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12 
REGISTRATION GUIDELINES 
Patients must meet all of the eligibility requirements listed in Section 5 prior 
to registration.   
 
Patients must not have any study procedures or begin protocol treatment 
prior to registration. 
 
Treatment should start within five working days after registration. 
 
To register eligible patients on study, complete a Clinical Trials Office Patient 
Registration Form and submit to: CTORegistrations@hci.utah.edu.  
 
13 
DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each 
patient that provides a record of the data generated according to the protocol.  
CRF’s should be created prior to the study being initiated and updated (if 
applicable) when amendments to the protocol are IRB approved.  These forms 
will be completed on an on-going basis during the study.  The medical records 
will be source of verification of the data.  During the study, the CRFs will be 
monitored for completeness, accuracy, legibility and attention to detail by a 
member of the Research Compliance Office. The CRFs will be completed by the 
Investigator or a member of the study team as listed on the Delegation of Duties 
Log. The data will be reviewed no less than annually by the Data and Safety 
Monitoring Committee.  The Investigator will allow the Data and Safety 
Monitoring Committee or Research Compliance Office personnel access to the 
patient source documents, clinical supplies dispensing and storage area, and study 
documentation for the above-mentioned purpose.  The Investigator further agrees 
to assist the site visitors in their activities. 
 
14 
SPECIAL INSTRUCTIONS  
14.1 Flow Cytometry Procedure 
Flow cytometric quantification of regulatory T cells, cytotoxic T cells and 
myeloid derived suppressor cells in pelvic lymph nodes form high risk prostate 
cancer patients 
 
13.1.2 Lymph nodes will be minced then dissociated by treatment with 
collagenase (Invitrogen) according to the manufacturer’s protocol to 
create single cell suspensions.  Subsequently, staining will be 
performed for cytotoxic T cells (CTCLs), regulatory T cells (Tregs) 
and myeloid derived suppressor cells (MDSC) as follows.  
Approximately 1x106 lymph node cells in 100 μL of Staining Buffer 
(PBS, 0.1% BSA, 0.1% NaN3) will be placed in each of three tubes.  
CTCLs will be evaluated by staining for CD45, CD3, CD8, and 


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granzyme B.  First, fluorochrome conjugated anti-human CD45, anti-
CD3 and ant-CD8 will be added to the cell suspensions then incubated 
for 20 min at room temperature in the dark. After incubation, cells will 
be washed with staining buffer, then fixed and permeabilized using a 
commercially available fixation and permeabilization kit (eBioscience) 
according manufacturer’s protocol and additionally stained with anti-
Granzyme B by incubating for 40 min at 4°C in the dark.  Cells will 
then be washed with staining buffer then resuspended in 500 μL of 
staining buffer and analyzed by flow cytometry. A second aliquot of 
lymph node cells will be stained for CD45, CD3, CD4 and FOXP3 to 
identify Tregs.  First, cells will be incubated with anti-CD45, anti-CD3 
and anti-CD4 for 20 min at room temperature in the dark. After 
incubation, cells will be washed with staining buffer, fixed and 
permeabilized using the above kit according manufacturer’s protocol 
and additionally stained with anti-FOXP3 by incubating for 40 min at 
4°C in the dark.  Subsequently, cells will be washed with staining 
buffer then resuspended in 500 μL of staining buffer and analyzed by 
flow cytometry.  MDSCs will be identified by staining cells for 
CD11b, CD33, CD14 and HLA-DR by incubating with fluorochrome 
conjugated antibodies for 20 min at room temperature in the dark. 
Cells will be washed with staining buffer, resuspended in 500 μL of 
staining buffer and analyzed by flow cytometry.  All flow cytometry 
antibodies will be purchased from eBioscience.  Tregs have the 
phenotype CD3+, CD4+, FOXP3+.  CTCLs have the phenotype, 
CD3+, CD8+, granzyme B+.  Monocytic MDSCs have the phenotype 
CD11b+, CD33+, HLA-DR low/-, CD14+ and granulocytioc MDSCs 
have the phenotype CD11b+, CD33+, HLA-DR low/-, CD14-.  For 
comparison between patients, all of these subsets will be expressed as 
percent of total lymph node cells. 
 
 
Lymph node samples (1-2 fresh, not frozen, benign pelvic lymph nodes) 
for Flow Cytometry should be sent to the following:  
Todd Kelley, PhD: 
Attn: Olga Efimova in Hematopathology 
University of Utah 
Department of Pathology 
15 North Medical Drive East  
Salt Lake City, UT 84112 
14.2 Correlative Studies 
Analysis of pre-metastatic niche density will take place through previously 
reported techniques.  Briefly, a total of 15  m sections of benign lymph node 
tissue (derived from paraffin-embedded sections) will be stained with monoclonal 
antibodies directed at VEGFR1 (ImClone Systems). VEGFR1 clustering will be 
counted within 8 distinct 40x fields, and the cluster count will be averaged.   
 


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14.3.1 Time Points for collection: 
 Tissue will be obtained at the time of prostatectomy/PLND. 
 
14.3.2 Required samples 
 Tissue: 15 paraffin-embedded slides derived from normal lymph 
node tissue will be requested.  These slides will be marked with a 
unique patient identifier number (UPIN) designated by the 
pathology core facility.  Only the study PI and biostatistician will 
have access to the data to correlate UPIN with patient 
identification; this data will be housed in a password-protected 
electronic database.   
 
Tissue will be stored by TRAC and may be batched and sent to the 
following: 
 
 
 
 
Sumanta Pal, MD 
Department of Medical Oncology & Experimental Therapeutics 
City of Hope Comprehensive Cancer Center 
1500 East Duarte Road 
Duarte, CA 91010 
 
 
15 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 Informed consent  
Informed consent will be obtained from all research participants prior to 
performing any study procedures using the most recent IRB approved version.  
15.2 Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
15.3  Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman 
Cancer Institute (HCI) and approved by the NCI to assure the well-being of 
patients enrolled on Investigator Initiated Trials that do not have an outside 
monitoring review.  Roles and responsibilities of the DSMC are set forth in the 
NCI approved plan.  The activities of this committee include a quarterly review 
of adverse events including SAEs, important medical events, significant 
revisions or amendments to the protocol, and approval of cohort/dose 
escalations.  If the DSMC and/or the PI have concerns about unexpected safety 
issues, the study will be stopped and will not be resumed until the issues are 
resolved. The DSMC also reviews and approves audit reports generated by the 
Research Compliance Office.  
 
 


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All phase II studies are reviewed by the full committee at each quarterly DSMC 
meeting. This includes a review of all serious adverse events (SAEs) occurring 
in patients treated at HCI or its affiliates as well as all grade 3 or greater 
toxicities for patients on treatment and within 30 day follow-up window (only if 
possibly, probably or definitely related).  
15.4 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for 
Adverse Events) Version 4.0 for AE and SAE reporting.  An electronic copy of 
the CTCAE Version 4.0 can be downloaded from:  
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 
15.4.1 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable 
sign, symptom, or medical condition occurring after starting the study 
drug even if the event is not considered to be related to study drug. For 
the purposes of this study, the terms toxicity and adverse event are 
used interchangeably. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen 
after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, or require therapy. 
 
Events meeting the definition of an AE include: 
1. Any abnormal laboratory test results (hematology, clinical chemistry, 
or urinalysis) or other safety assessments e.g., ECGs, radiological 
scans, vital signs measurements), including those that worsen from 
baseline, and felt to be clinically significant in the medical and 
scientific judgment of the investigator 
2. Exacerbation of a chronic or intermittent pre-existing condition 
including either an increase in frequency and/or intensity of the 
condition 
3. New conditions detected or diagnosed after investigational product 
administration even though it may have been present prior to the start 
of the study 
4. Signs, symptoms, or the clinical sequelae of a suspected interaction 
5. Signs, symptoms, or the clinical sequelae of a suspected overdose of 
either investigational product or a concomitant medication (overdose 
per se will not be reported as an AE/SAE) 
 
“Lack of efficacy” or “failure of expected pharmacological action” per 
se will not be reported as an AE or SAE. However, the signs and 


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symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfill the definition of an AE or SAE. 
 
Events that do not meet the definition of an AE include: 
1. Any clinically significant abnormal laboratory finding or other 
abnormal safety assessments that is associated with the underlying 
disease, unless judged by the investigator to be more severe than 
expected for the subject’s condition.  
2. The disease/disorder being studied, or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe 
than expected for the subject’s condition 
3. Medical or surgical procedure (e.g., prostatectomy); the condition that 
leads to the procedure is an AE 
4. Situations where an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital) 
5. Anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not 
worsen 
 
The collection of adverse events will begin after the first dose of study 
treatment.  Adverse event collection will end 1 month post-
prostatectomy. 
 
 
Information about all adverse events, whether volunteered by the 
subject, discovered by investigator questioning, or detected through 
physical examination, laboratory test or other means, will be collected 
and recorded and followed as appropriate. 
 
The occurrence of adverse events should be sought by non-directive 
questioning of the patient at each visit or phone contact during the 
study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, 
each adverse event should be evaluated to determine: 
1. the severity grade based on CTCAE v.4 (grade 1-5) 
2. its relationship to the study drug(s) (definite, probable, possible, 
unlikely, not related)  
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage 
adjusted/temporarily interrupted; study drug permanently 
discontinued due to this adverse event; concomitant medication 


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taken; non-drug therapy given; hospitalization/prolonged 
hospitalization) 
5. whether it constitutes an SAE 
 
All adverse events will be treated appropriately. Such treatment may 
include changes in study drug treatment as listed in the dose 
modification section of this protocol (see section 7 for guidance). Once 
an adverse event is detected, it should be followed until its resolution, 
and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the 
study drug, the interventions required to treat it, and the outcome. 
 
Information about common side effects already known about the 
pazobanib is described in the Drug Information (section 3) and the 
most recent Investigator Brochure as well as the FDA-approved 
product labels. This information will be included in the patient 
informed consent and will be discussed with the patient during the 
study as needed. 
 
15.4.2 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and 
recorded. A serious adverse event is an undesirable sign, symptom or 
medical condition which: 
 is fatal or life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' 
refers to an event in which the subject was at risk of death at the 
time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
 results in persistent or significant disability/incapacity 
NOTE:  The term disability means a substantial disruption of a 
person’s ability to conduct normal life functions.  This definition is 
not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) 
which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
 is medically significant: medical or scientific judgment should be 
exercised in deciding whether reporting is appropriate in other 
situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the 
above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, 


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intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, or development of drug dependency or drug 
abuse. 
 causes congenital anomaly or birth defect 
 requires inpatient hospitalization or prolongation of existing 
hospitalization, unless hospitalization is for: 
NOTE:  In general, hospitalization signifies that the subject has 
been detained (usually involving at least an overnight stay) at the 
hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or out 
patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE 
should be considered serious 
 
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs: 
 Any abnormal laboratory test results (hematology, clinical 
chemistry, or urinalysis) or other safety assessments (e.g., ECGs, 
radiological scans, vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be 
recorded as AEs or SAEs. 
 All events meeting liver stopping criteria must be recorded as an 
SAE.  
 However, any clinically significant safety assessments that are 
associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs. 
 
Disease-Related Events and/or Disease-Related outcomes Not 
Qualifying as SAEs 
An event which is part of the natural course of the disease under study 
(i.e., disease progression) does not need to be reported as an SAE.  
However, if the progression of the underlying disease is greater than 
that which would normally be expected for the subject, or if the 
investigator considers that there was a causal relationship between 
treatment with investigational product or protocol design/procedures 
and the disease progression, then this must be reported as an SAE. 
 
Collection of SAEs  


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The collection of serious adverse events will begin after the first dose 
of study treatment.  Serious adverse event collection will end 1 month 
post-prostatectomy. 
 
Any death from any cause while a patient is receiving treatment on this 
protocol or up to 30 days after the last dose of protocol treatment, or 
any death which occurs more than 30 days after protocol treatment has 
ended but which is felt to be treatment related, must be reported. 
 
Toxicities which fall within the definitions listed above must be 
reported as an SAE regardless if they are felt to be treatment related or 
not.  Toxicities unrelated to treatment that do NOT fall within the 
definitions above, must simply be documented as AEs in the patient 
research chart.   
 
15.5 SAE Reporting Requirements 
 
SAEs must be reported to the DSMC, the FDA, the IRB, and Novartis, 
according to the requirements described below: 
 
A MedWatch 3500A form must be completed and submitted to 
compliance@hci.utah.edu as soon as possible, but no later than 10 days of first 
knowledge or notification of event (5 days for fatal or life threatening event).  
Please note that Novartis reporting is required within 24 hours of learning of the 
event.  In place of the Medwatch, the Novartis SAE report form may be used for 
DSMC reporting purposes.  If the SAE meets FDA reporting requirements, then 
a MedWatch 3500A must also be completed. 
 
*Medwatch 3500A form can be found at 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/ucm082728.pdf 
 
DSMC Notifications: 
 An HCI Research Compliance Officer (RCO) will process and submit the 
MedWatch form to the proper DSMC member as necessary for each 
individual study.  
 The RCO will summarize and present all reported SAEs according to the 
Data and Safety Monitoring Plan at the quarterly DSMC meeting. 
 
FDA Notifications: 
 Adverse events occurring during the course of a clinical study that meet the 
following criteria will be promptly reported to the FDA: 
 Serious 
 Unexpected 


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 Definitely, Probably or Possibly Related to the 
investigational drug 
 Fatal or life-threatening events that meet the criteria above will be reported 
within 7 calendar days after first knowledge of the event by the investigator; 
followed by as complete a report as possible within 8 additional calendar 
days. 
 All other events that meet the criteria above will be reported within 15 
calendar days after first knowledge of the event by the investigator. 
 The RCO will review the MedWatch report for completeness, accuracy and 
applicability to the regulatory reporting requirements. 
 The RCO will ensure the complete, accurate and timely reporting of the 
event to the FDA. 
 The Regulatory Coordinator will submit the report as an amendment to the 
IND application. 
 All other adverse events and safety information not requiring expedited 
reporting that occur or are collected during the course of the study will be 
summarized and reported to the FDA through the IND Annual Report. 
 IRB Notification: Events meeting the University of Utah IRB reporting 
requirements (http://www.research.utah.edu/irb/) will be submitted through 
the IRB’s electronic reporting system within 10 working days. 
 Novartis/Drug Manufacturer Notifications: Once an investigator determines 
that an event meets the protocol definition of an SAE, the SAE will be 
reported to Novartis within 24 hours of being notified of the event.  All 
SAEs regardless of relationship to investigational product will be collected 
from the first dose of investigational product to at least 30 days after the last 
dose of study treatment.  All SAEs regardless of causality will be collected 
until the end of the follow-up period.  From the time a subject consents to 
participate in and completes the study all SAEs assessed as related to study 
participation (e.g., protocol-mandated procedures, invasive tests, or change 
in existing therapy) or related to Novartis concomitant medication, will be 
reported promptly to Novartis.  Any SAE brought to the investigator’s 
attention after the subject has completed the study and considered by the 
investigator as possibly related to investigational product must be reported 
to Novartis. 
 
SAE’s should be reported to Novartis alone with the Novartis SAE Fax 
cover sheet.  All applicable sections of the form must be completed in order 
to provide a clinically thorough report.  The investigator must assess and 
record the relationship of each SAE to pazopanib treatment and sign the 
form.  The completed SAE form should be sent to the following with the 
Novartis FAX cover sheet: 
 
Oncology Novartis DS&E department 
 
 
Fax: 1-877-778-9739   


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15.6 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the 
period, for which the IRB approval has already been given, will not be initiated 
without submission of an amendment for IRB review and approval.    
 
These requirements for approval will in no way prevent any immediate 
action from being taken by the investigator in the interests of preserving 
the safety of all patients included in the trial.  
15.7 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures 
and treatment plans as outlined in the protocol version submitted and previously 
approved by the IRB. Protocol deviations have the potential to place 
participants at risk and can also undermine the scientific integrity of the study 
thus jeopardizing the justification for the research.  Protocol deviations are 
unplanned and unintentional events.  
 
Because some protocol deviations pose no conceivable threat to participant 
safety or scientific integrity, reporting is left to the discretion of the PI within 
the context of the guidelines below. The IRB requires the prompt reporting of 
protocol deviations which are: 
 
Exceptions to eligibility criteria. 
 
Intended to eliminate apparent immediate hazard to a research 
participant or  
 
Harmful (caused harm to participants or others, or place them at 
increased risk of harm - including physical, psychological, economic, 
or social harm), or  
 
Possible serious or continued noncompliance  
15.8 FDA Annual Reporting  
 
An annual progress report will be submitted to the FDA within 60 days of the 
anniversary of the date that the IND went into effect.  (21 CFR 312.33).  
Content of this report is listed in Appendix III. 
 
15.9 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP 
(Clinical Trials Reporting Program) by the Clinical Trials Office. 
16 
BIBLIOGRAPHY 
1. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin, 
62(1), 10-29 (2012). 
2. 
Ryan CJ, Elkin EP, Small EJ, Duchane J, Carroll P. Reduced incidence of bony 
metastasis at initial prostate cancer diagnosis: Data from CaPSURE(TM). 


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Urologic Oncology: Seminars and Original Investigations, 24(5), 396-402 
(2006). 
3. 
Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT. 
CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci, 
117(Pt 16), 3539-3545 (2004). 
4. 
D'Amico AV, Whittington R, Malkowicz SB et al. Pretreatment Nomogram for 
Prostate-Specific Antigen Recurrence After Radical Prostatectomy or External-
Beam Radiation Therapy for Clinically Localized Prostate Cancer. J Clin Oncol, 
17(1), 168- (1999). 
5. 
D'Amico AV, Whittington R, Malkowicz SB et al. Biochemical outcome after 
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Appendix A: UPC  
Clinical meaning of UPC 
There is a good correlation between the ratio of protein concentration to creatinine 
concentration in a random urine sample and the amount of protein excreted over 24 
hours.  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 and is similar for men and 
women. 
Calculating UPC 
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL).  
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs.  
Example:  Patient has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL.   
UPC ratio= (90 mg/dL) / (30 mg/dL) =  3   
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a 
24-hour period. 
Units for UPC ratio 
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the 
same units (mg/dL, g/L, or μmol/L).  If, for example, protein concentration is expressed 
in mg/dL and creatinine concentration is expressed in µmol/L, conversion of one of the 
concentration values is required.  Conversion factors are:  
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 88.4  


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Appendix B: Drugs with risk to prolong QT interval sorted by generic name 
Drugs with known risk 
Drugs with possible risk 
Drugs with conditional risk 
Amiodarone 
Alfuzosin 
Amantadine 
Arsenic trioxide 
Artenimol + piperaquine 
Amisulpride 
Azithromycin 
Atazanavir 
Amitriptyline 
Bepridil 
Bedaquiline 
Chloral hydrate 
Chloroquine 
Clozapine 
Ciprofloxacin 
Chlorpromazine 
Dolasetron 
Clomipramine 
Cisapride 
Dronedarone 
Desipramine 
Citalopram 
Eribulin 
Diphenhydramine 
Clarithromycin 
Famotidine 
Doxepin 
Disopyramide 
Felbamate 
Fluconazole 
Dofetilide 
Fingolimod 
Fluoxetine 
Domperidone 
Foscarnet 
Glantamine 
Droperidol 
Fosphenytoin 
Imipramine 
Erythromycin 
Gatifloxacin 
Intraconazole 
Escitalopram 
Gemifloxacin 
Ketoconazole 
Flecainide 
Granisetron 
Nortriptyline 
Halofantrine 
Iloperidone 
Paroxetine 
Haloperidol 
Indapamide 
Protriptyline 
Ibutilide 
Isradipine 
Quinine Sulfate 
Levomethadyl 
Lapatinib 
Ritonavir 
Mesoridazine 
Levofloxacin 
Sertraline 
Methadone 
Lithium 
Solifenacin 
Moxifloxacin 
Mirtazapine 
Trazodone 
Pentamidine 
Moexipril/HCTZ 
Trimethoprim-Sulfa 
Pimozide 
Nicardipine 
Trimipramine 
Probucol 
Nilotinib 
 
Procainamide 
Ofloxacin 
 
Quinidine 
Olanzapine 
 
Sevoflurane 
Ondansetron 
 
Sotalol 
Oxytocin 
 
Sparfloxacin 
Paliperidone 
 
Terfenadine 
Perflutren lipid microspheres 
 
Thioridazine 
Promethazine 
 
 
Quetiapine 
 
 
Ranolazine 
 
 
Risperidone 
 
 
Roxithromycin 
 
 
Saquinavir 
 
 
Sertindole 
 
 
Sunitinib 
 
 
Tacrolimus 
 
 
Tamoxifen 
 
 
Telithromycin 
 
 
Tizanidine 
 
 
Tolterodine 
 
 
Vardenafil 
 
 
Venlafaxine 
 
 
Voriconazole 
 
 
Ziprasidone 
 


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APPENDIX C: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES 
 
 
NYHA Classification 
 
 
Excerpted from Oxford Textbook of Medicine. Vol 2, p.2228. Oxford Press.1997. 
Class 
Description 
I 
Subjects with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
II 
Subjects with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain. 
IV 
Subjects with cardiac disease resulting in inability to carry on 
physical activity without discomfort.  Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present event 
at rest.  If any physical activity is undertaken, discomfort is 
increased.