Clinical trial NCT01330966
Conditions: Chondrosarcoma Metastatic Chondrosarcoma
Keywords: surgically unresectable chondrosarcoma
Sponsor: Emerald Clinical Inc.
Start date: 2011-04-01; Completion date: 2018-02-01
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the effectiveness and safety of single agent pazopanib in subjects with chondrosarcoma.

Detailed description:
This research study is being conducted in adult subjects with a type of bone cancer called chondrosarcoma that has spread to other parts of the body and is not able to be removed with surgery. There is only one study drug that will be used in this study. It is a drug that interferes with cell communication and growth, taken orally. The study drug is called pazopanib.

Arms: arm 1: Pazopanib 800 mg orally once daily will be started on Cycle 1 Day 1 and will be administered continuously for a 28-day cycle.
Interventions: intervention 1: pazopanib
Intervention descriptions: intervention 1: Pazopanib 800 mg orally once daily will be started on Cycle 1 Day 1 and will be administered continuously for a 28-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol AAPSMCS1002 
 
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A Phase II Study of Pazopanib in the Treatment of Surgically Unresectable 
or Metastatic Chondrosarcoma  
 
PROTOCOL NUMBER: AAPSMCS1002 
 
Sponsor: 
Vector Oncology 
 
6555 Quince Road, Suite 400 
 
Memphis, TN USA 38119 
 
Phone: 901-435-5570 
 
Fax: 901-259-8276 
 
 
Study Chairs: 
Arthur Staddon, M.D., F.A.C.P. 
 
Warren Chow, M.D., F.A.C.P. 
 
 
Protocol Version: 
1 
 
Amendment 1 
 
Amendment 2 
 
Amendment 3 
 
Amendment 4 
 
Protocol Date:  
December 29, 2010 
 
November 7, 2012 
 
April 17, 2013 
 
September 15, 2014 
 
January 28, 2016 
 
 
 
 
 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of Vector Oncology and any unauthorized use 
or disclosure of such information without the prior written authorization of Vector Oncology is expressly prohibited. 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
For Vector Oncology protocol AAPSMCS1002, A Phase II Study of Pazopanib in the 
Treatment of Surgically Unresectable or Metastatic Chondrosarcoma, Amendment 4: 
I agree to conduct the study as detailed in the protocol and in compliance with ICH 
Guidelines for Good Clinical Practice. 
 
I acknowledge that I am responsible for overall study conduct, and I agree to personally 
conduct or supervise the described clinical study. 
 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations.  Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study. 
 
 
 
 
Principal Investigator printed name 
 
 
 
 
 
Principal Investigator signature 
 
Date 
 


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PROTOCOL SYNOPSIS 
Protocol Title: A Phase II Study of Pazopanib in the Treatment of Surgically 
Unresectable or Metastatic Chondrosarcoma 
Study Sites: 
The study will be conducted at approximately 7 oncology centers 
associated with Vector Oncology.   
Study Design: 
This is a Phase II, multicenter, prospective, open-label, single arm study. 
Study 
Schema: 
Pazopanib 800 mg orally once daily administered continuously for a 28-
day cycle.  Subjects may continue study treatment until they develop 
disease progression or unacceptable toxicity. 
Accrual Goal: 
47 subjects  
Accrual Rate: 
Estimated to be two subjects per month across approximately 7 sites 
Study 
Objectives: 
The primary objective is to determine the treatment efficacy of single 
agent pazopanib in subjects with chondrosarcoma.  Secondary objectives 
are to determine the safety profile of pazopanib in this population. 
Main 
Eligibility 
Criteria: 
Adults with histologically confirmed conventional chondrosarcoma of any 
grade that is metastatic or surgically unresectable.   
Criteria for 
Evaluation: 
CT or PET/CT scans will be repeated after every 2 cycles of treatment.  
Subjects may continue study treatment until they develop disease 
progression or unacceptable toxicity.  
Adverse events will be recorded and graded using the Common 
Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).  
Other safety assessments will include clinical laboratory values, 
electrocardiograms (EKGs), echocardiograms (ECHOs) or multiple gated 
acquisition (MUGA) scans, physical examinations, and vital sign 
measurements. 
 


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TABLE OF CONTENTS 
Page 
LIST OF IN-TEXT TABLES ................................................................................................................. 7 
LIST OF ABBREVIATIONS ................................................................................................................ 8 
1. 
INTRODUCTION ........................................................................................................................ 11 
1.1. 
Pazopanib Background .................................................................................................... 11 
1.2. 
Adverse Reactions ........................................................................................................... 13 
1.2.1. 
Clinical Trials Experience .............................................................................. 13 
1.2.2. 
Postmarketing Data......................................................................................... 18 
1.2.3. 
Warnings and  Precautions for use ................................................................. 19 
As of 09 september 2015 there have been 3 reports of pregnancy involving 2 female 
subjects who were enrolled in pazopanib clinical trials.  Both subjects became pregnant 
after pazopanib was discontinued. ................................................................................................ 25 
A 28-year-old enrolled in the ovarian cancer study veg110655 had a spontaneous abortion at 
8 weeks gestation, which was 155 days after the last pazopanib dose.  About2 years 
after her last pazopanib dose, the subject gave birth to a normal baby boy at 39 weeks 
gestation. ....................................................................................................................................... 25 
A 26-year-old enrolled in a gsk-supported rcc study had a positive pregnancy test 47 days 
after her last pazopanib dose.  On 08 august 2014, the patient underwent an elective 
caesarian section in order for her to receive chemotherapy due to malignancy 
progression.  An infant male was delivered uneventfully, although prematurely at27 
weeks gestation.  The investigator noted that no aes associated with the patient’s 
pazopanib treatment were observed.............................................................................................. 25 
In addition to the above reports, a spontaneous report of congenital anomalies in an infant 
whose mother received pazopanib is described in the marketing experience: ............................. 25 
1.3. 
Pazopanib Monotherapy Dose Rationale......................................................................... 26 
2. 
STUDY RATIONALE ................................................................................................................. 27 
3. 
OVERVIEW OF STUDY DESIGN AND EVALUATION ........................................................ 28 
4. 
STUDY OBJECTIVES ................................................................................................................ 29 
4.1. 
Primary Objective ............................................................................................................ 29 
4.2. 
Secondary Objectives ...................................................................................................... 29 
5. 
ELIGIBILITY CRITERIA ........................................................................................................... 29 
5.1. 
Inclusion Criteria ............................................................................................................. 29 
5.2. 
Exclusion Criteria ............................................................................................................ 31 
5.3. 
Other Eligibility Criteria Considerations ......................................................................... 34 
6. 
TREATMENT OF SUBJECTS .................................................................................................... 34 
6.1. 
Subject Enrollment .......................................................................................................... 34 
6.2. 
Study Treatment .............................................................................................................. 34 
6.3. 
Pazopanib Dose Interruptions and Modifications ............................................................ 35 
6.3.1. 
Dose Interruptions/Modifications for Specific, Non-liver Related, 
Toxicities ........................................................................................................ 35 
6.3.2. 
Dose Interruptions/Modifications for Hepatotoxicity .................................... 44 
6.4. 
Concomitant Medications and Non-Drug Therapies ....................................................... 47 
6.5. 
Prohibited and Permitted Medications During Study Treatment..................................... 48 


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6.5.1. 
Prohibited Medications ................................................................................... 48 
6.5.2. 
Permitted Medications – Use with Caution .................................................... 49 
7. 
STUDY ASSESSMENTS ............................................................................................................ 51 
7.1. 
Screening Assessments .................................................................................................... 52 
7.2. 
Efficacy Assessments ...................................................................................................... 53 
7.2.1. 
Tumor Measurement ....................................................................................... 54 
7.2.2. 
Baseline Documentation of Target and Non-target Lesions ........................... 55 
7.2.3. 
Response Criteria ............................................................................................ 55 
7.3. 
Safety Assessments ......................................................................................................... 59 
7.3.1. 
Laboratory Tests During Treatment ............................................................... 59 
7.3.2. 
Physical Examinations .................................................................................... 60 
7.3.3. 
Vital Signs, Weight, and Performance Status ................................................. 60 
7.3.4. 
12-lead Electrocardiogram ............................................................................. 61 
7.3.5. 
ECHO or MUGA ............................................................................................ 63 
8. 
REMOVAL OF SUBJECTS FROM TREATMENT OR THE STUDY ..................................... 63 
8.1. 
Criteria for Removal from Treatment .............................................................................. 63 
8.2. 
Criteria for Removal from Study ..................................................................................... 64 
8.3. 
Procedures for End of Treatment and Follow-up ............................................................ 64 
9. 
INVESTIGATIONAL PRODUCT .............................................................................................. 65 
9.1. 
Description of Investigational Product ............................................................................ 65 
9.1.1. 
Dosage and Administration ............................................................................ 66 
9.1.2. 
Dispensing ...................................................................................................... 66 
9.2. 
Drug Ordering and Accountability .................................................................................. 66 
9.2.1. 
Initial Orders and Resupply Requests............................................................. 66 
9.2.2. 
Accountability ................................................................................................ 67 
9.2.3. 
Destruction ..................................................................................................... 67 
10. ADVERSE EVENTS ................................................................................................................... 67 
10.1. 
Definitions ....................................................................................................................... 67 
10.2. 
Reporting Procedures for Adverse Events ....................................................................... 69 
10.2.1. 
All Adverse Events ......................................................................................... 69 
10.2.2. 
Relationship to Study Drug ............................................................................ 70 
10.2.3. 
Serious Adverse Events .................................................................................. 71 
11. STATISTICAL METHODOLOGY ............................................................................................. 74 
11.1. 
Introduction ..................................................................................................................... 74 
11.2. 
Analysis Populations ....................................................................................................... 74 
11.3. 
Endpoints ......................................................................................................................... 75 
11.3.1. 
Primary ........................................................................................................... 75 
11.3.2. 
Secondary ....................................................................................................... 75 
11.4. 
Sample Size ..................................................................................................................... 75 
11.5. 
Statistical Analysis .......................................................................................................... 75 
11.5.1. 
Baseline Demographic and Clinical Characteristics ....................................... 75 
11.5.2. 
Efficacy Analysis, Primary Endpoint ............................................................. 76 
11.5.3. 
Efficacy Analysis, Secondary Endpoints ........................................................ 76 
11.5.4. 
Toxicity Analysis ............................................................................................ 76 
11.5.5. 
Other Planned Analyses .................................................................................. 76 
11.5.6. 
Exploratory Analyses ..................................................................................... 76 
12. STUDY ADMINISTRATION ..................................................................................................... 77 
12.1. 
Ethics Review .................................................................................................................. 77 


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12.2. 
Ethical Conduct of the Study ........................................................................................... 77 
12.3. 
Compliance with the Protocol and Protocol Revisions ................................................... 77 
12.4. 
Informed Consent ............................................................................................................ 77 
12.5. 
Records and Reports ........................................................................................................ 78 
12.6. 
Subject Data Protection ................................................................................................... 78 
12.7. 
Records Retention ........................................................................................................... 78 
12.8. 
Data Management ............................................................................................................ 79 
13. REFERENCES ............................................................................................................................. 80 
Appendix 1 
Time and Events Schedule ............................................................................. 82 
Appendix 2 
ECOG Performance Status Criteria ................................................................ 84 
Appendix 3 
Determination of Creatinine Clearance (ClCR) ............................................... 85 
Appendix 4 
Urine Protein Creatinine Ratio (UPC) ............................................................ 86 
Appendix 5 
New York Heart Association Classification of Cardiac Disease .................... 87 
 


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LIST OF IN-TEXT TABLES 
Page 
Table 1. Adverse Reactions Occurring in > 10% of Patients with RCC who Received 
Pazopanib…………………………………………………………………………… 
14 
 Table 1. Selected Laboratory Abnormalities Occurring in ≥ 15% of Patients with RCC who 
Received Pazopanib and More Commonly (> 5%) in Patients who Received 
Pazopanib Versus 
Placebo…………………………………………………………………. ............................. 15 
Table 3. Adverse Reactions Occurring in > 10% of Patients with STS who Received 
Pazopanib .............................................................................................................................. 16 
Table 4. Selected Laboratory Abnormalities Occurring in ≥ 15% of Patients with STS who 
Received Pazopanib and More Commonly (> 5%) in Patients who Received 
Pazopanib versus Placebo ..................................................................................................... 17 
Table 5. Definitions for Adequate Organ Function .............................................................................. 30 
Table 6.  Dose Modification Algorithms for Potential Treatment-Related Adverse Events ................ 35 
Table 7.  Guidelines for Management of Treatment Emergent Hepatotoxicity ................................... 44 
Table 8. Response Criteria for Target Lesions ..................................................................................... 56 
Table 9. Response Criteria for Non-target Lesions .............................................................................. 56 
Table 10. Evaluation Criteria for Best Overall Response: Subjects with Target Disease, with 
or without Non-target Disease .............................................................................................. 57 
Table 11. Evaluation Criteria for Best Overall Response: Subjects with Non-target Disease 
Only ...................................................................................................................................... 58 
 


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LIST OF ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate transaminase 
AUC 
Area under the plasma concentration curve 
BP 
Blood pressure 
BS 
Bone sarcomas 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
ClCR 
Calculated creatinine clearance 
Cmax 
Maximum plasma concentrations 
CMP 
Comprehensive metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE v4.0 
Common Terminology Criteria for Adverse Events Version 4.0 
CYP1A2 
Cytochrome P450 1A2 
CYP2A6 
Cytochrome P450 2A6 
CYP2B6 
Cytochrome P450 2B6 
CYP2C8 
Cytochrome P450 2C8 
CYP2C9 
Cytochrome P450 2C9 
CYP2C19 
Cytochrome P450 2C19 
CYP2D6 
Cytochrome P450 2D6 
CYP2E1 
Cytochrome P450 2E1 
CYP3A4 
Cytochrome P450 3A4 
DBP 
Diastolic blood pressure 
DVT 
Deep venous thrombosis 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EC50 
Half maximal effective concentration 
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FSH 
Follicle stimulating hormone 
F/U 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 


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GSK 
GlaxoSmithKline 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRT 
Hormone replacement therapy 
HUS 
Hemolytic uremic syndrome 
ICH 
International Conference on Harmonisation 
iCRF 
Internet case report form 
ID 
identification 
IND 
Investigational New Drug (Application) 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LD 
Longest diameter 
LFT 
Liver function test 
LLN 
Lower limit normal 
LT 
Long-term 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multiple gated acquisition scan 
NCI 
National Cancer Institute 
Novartis 
Novartis Pharmaceuticals 
NYHA 
New York Heart Association 
OS 
Overall survival 
P 
Pulse 
PD 
Progressive disease 
PET/CT 
Positron emission tomography/Computed tomography 
PFR12 weeks 
Progression-free rate at 12 weeks 
PFS 
Progression-free survival 
P-gp 
Permeability glycoprotein 
PK 
Pharmacokinetics 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PRES 
Posterior reversible encephalopathy syndrome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
(Taken) once daily 
QTc 
Corrected QT interval 
QTcB 
Corrected QT interval using Bazett's formula 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPLS 
Reversible posterior leukoencephalopathy syndrome 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Stable disease 


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STS 
Soft-tissue sarcoma 
T 
Body temperature 
TIA 
Transient ischemic attack 
TSH 
Thyroid stimulating hormone 
TTP 
Thrombotic thrombocytopenic purpura 
ULN 
Upper limit normal 
UPC 
Urine protein to creatinine ratio 
USA 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WOCBP 
Women of child-bearing potential 


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1. 
INTRODUCTION 
1.1. 
Pazopanib Background 
Angiogenesis, the process of new blood vessel formation, plays an important role in the 
development of malignancy as well as the growth and progression of metastatic lesions.  The 
molecular pathways involved in angiogenesis have been targeted for anti-tumor therapy.  
Numerous growth factors and cytokines are involved in the angiogenic process.  Among 
these factors, vascular endothelial growth factor (VEGF) has a predominant role as a central 
mediator of tumor-related angiogenesis, and its expression has been shown to be an adverse 
prognostic factor for a number of solid tumors [Folkman, 1971; Folkman 1997; Ferrara, 
1997]. 
Pazopanib is an orally-bioavailable, ATP-competitive tyrosine kinase inhibitor of VEGFR (-
1, -2, and -3), PDGFR (- and -), and c-Kit [Kumar, 2007].  Pazopanib is being developed 
by GlaxoSmithKline (GSK) for the treatment of a variety of cancers.  In nonclinical 
experiments, pazopanib has demonstrated encouraging potency and selectivity for VEGF 
receptors: for example, pazopanib demonstrated significant inhibition of VEGF-induced 
VEGFR-2 phosphorylation in human umbilical vein endothelial cells and was 3- to 400-fold 
selective for VEGF receptors compared to 23 other kinases tested.  Pazopanib showed 
significant growth inhibition of a variety of human tumor xenografts in mice, and also 
inhibited angiogenesis in several different models of angiogenesis (e.g., the Matrigel plug 
assay, the cornea micropocket, and the laser-induced choroidal neovascularization models).  
Further physico-chemical characteristics of pazopanib as well as more detailed results of 
nonclinical studies are described in the Investigator’s Brochure (IB) [Ariazi, 2014]. 
As of the clinical data cut-off date for the current IB, 09 September 2013, 47 GSK-sponsored 
studies of pazopanib (plus 1 additional study initiated by the NCI) have been conducted or 
are in progress in adult subjects with cancer including renal cell cancer (RCC), non-small cell 
lung cancer (NSCLC), ovarian cancer, breast cancer, soft tissue sarcoma (STS), cervical 
cancer, colorectal cancer, hepatocellular cancer (HCC), multiple myeloma (MM), and 
glioma. Approximately 5000 subjects have received pazopanib as monotherapy or in 
combination out of approximately 7000 subjects enrolled in pazopanib oncology clinical 
studies as of the cut-off.  Data collected to date show that oral pazopanib is absorbed after 
administration and that pazopanib administration at 800 mg daily is associated with a 
reasonable safety profile and encouraging efficacy in various oncology settings [Ariazi, 
2014]. 
 
Clinical data indicate that (a) pazopanib is absorbed after oral administration, (b) the 800 mg 
daily dosing regimen is an active monotherapy dose for subjects with cancer, providing 
optimal biologic and clinical effects associated with VEGFR inhibition, (c) pazopanib is 
generally well-tolerated at the 800 mg daily dosing regimen, and (d) pazopanib has 
encouraging efficacy in specific tumor settings such as RCC, sarcoma, NSCLC, cervical and 


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ovarian cancer.  In 2009, pazopanib was approved by the U.S. Food and Drug Administration 
(FDA) for the treatment of patients with advanced renal cell carcinoma (RCC) [Votrient PI, 
2014].  In 2012, pazopanib was FDA-approved for the treatment of patients with advanced 
soft tissue sarcoma who have received prior chemotherapy.  However, the efficacy of 
pazopanib for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal 
stromal tumors has not been demonstrated [Votrient PI, 2014]. 
 
Renal Cell Carcinoma   
The safety and efficacy of pazopanib in renal cell carcinoma (RCC) were evaluated in a 
randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial. Patients (N = 435) 
with locally advanced and/or metastatic RCC who had received either no prior therapy or one 
prior cytokine-based systemic therapy were randomized (2:1) to receive pazopanib 800 mg 
once daily or placebo once daily. The primary objective of the trial was to evaluate and 
compare the 2 treatment arms for progression-free survival (PFS); the secondary endpoints 
included overall survival (OS), overall response rate (RR), and duration of response. 
Of the total of 435 patients enrolled in this trial, 233 patients had no prior systemic therapy 
(treatment-naïve subgroup) and 202 patients received one prior IL-2 or INFα-based therapy 
(cytokine-pretreated subgroup). The baseline demographic and disease characteristics were 
balanced between the pazopanib and placebo arms. The majority of patients were male (71%) 
with a median age of 59 years. Eighty-six percent of patients were Caucasian, 14% were 
Asian, and less than 1% were other. Forty-two percent were ECOG performance status 0 and 
58% were ECOG performance status 1. All patients had clear cell histology (90%) or 
predominantly clear cell histology (10%). Approximately 50% of all patients had 3 or more 
organs involved with metastatic disease. The most common metastatic sites at baseline were 
lung (74%), lymph nodes (56%), bone (27%), and liver (25%). 
A similar proportion of patients in each arm were treatment-naïve and cytokine-pretreated. In 
the cytokine-pretreated subgroup, the majority (75%) had received interferon-based 
treatment. Similar proportions of patients in each arm had prior nephrectomy (89% and 88% 
for pazopanib and placebo, respectively). 
The analysis of the primary endpoint PFS was based on disease assessment by independent 
radiological review in the entire trial population.  At the protocol-specified final analysis of 
OS, the median OS was 22.9 months for patients randomized to pazopanib and 20.5 months 
for the placebo arm [HR = 0.91 (95% CI: 0.71, 1.16)]. The median OS for the placebo arm 
includes 79 patients (54%) who discontinued placebo treatment because of disease 
progression and crossed over to treatment with pazopanib. In the placebo arm, 95 (66%) 
patients received at least one systemic anti-cancer treatment after progression compared to 88 
(30%) patients randomized to pazopanib [Votrient PI, 2014]. 
Soft Tissue Sarcoma 
 


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The safety and efficacy of pazopanib in patients with STS were evaluated in a Phase III, 
randomized, double-blind, placebo-controlled, multicenter trial. Patients (N = 369) with 
metastatic STS who had received prior chemotherapy, including anthracycline treatment, or 
were unsuited for such therapy, were randomized (2:1) to receive pazopanib 800 mg once 
daily or placebo. Patients with gastrointestinal stromal tumors (GIST) or adipocytic sarcoma 
were excluded from the trial. Randomization was stratified by the factors of WHO 
performance status (WHO PS) 0 or 1 at baseline and the number of lines of prior systemic 
therapy for advanced disease (0 or 1 versus 2+). Progression-free survival (PFS) was 
assessed by independent radiological review. Other efficacy endpoints included overall 
survival (OS), overall response rate, and duration of response.  
 
The majority of patients were female (59%) with a median age of 55 years. Seventy-two 
percent of patients were Caucasian, 22% were Asian, and 6% were Other. Forty-three percent 
of patients had leiomyosarcoma, 10% had synovial sarcoma, and 47% had other soft tissue 
sarcomas. Fifty-six percent of patients had received 2 or more lines of prior systemic therapy 
and 44% had received 0 or 1 lines of prior systemic therapy. The median duration of 
treatment was 4.5 months for patients on the pazopanib arm and 1.9 months for patients on 
the placebo arm. At the protocol-specified final analysis of OS, the median OS was 12.6 
months for patients randomized to pazopanib and 10.7 months for the placebo arm [HR = 
0.87 (95% CI: 0.67, 1.12)] [Votrient PI, 2014]. 
 
1.2. 
Adverse Reactions 
The following safety data is from the Prescribing Information for pazopanib, revised 
September 2015, and from the Investigator’s Brochure for pazopanib, version number 14 
dated January 7, 2016. 
1.2.1. Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical 
trials of another drug and may not reflect the rates observed in practice. 
Potentially serious adverse reactions with pazopanib included: 
 Hepatotoxicity 
 QT prolongation and torsades de pointes 
 Cardiac dysfunction 
 Hemorrhagic events 
 Arterial and venous thromboembolic events 
 Thrombotic microangiopathy 


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 Gastrointestinal perforation and fistula 
 Posterior Reversible Encephalopathy Syndrome (PRES) / Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) 
 Hypertension 
 Hypothyroidism 
 Proteinuria 
 Infection 
 Interstitial Lung Disease (ILD)/Pneumonitis 
 Increased toxicity with other cancer therapies 
 
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 1 presents the most common adverse reactions occurring in ≥ 10% of patients who 
received pazopanib. 
Table 2. Adverse Reactions Occurring in > 10% of Patients with RCC who Received Pazopanib  
Adverse Reactions 
Pazopanib 
(N=290) 
Placebo 
(N=145) 
All Gradesa 
Grade 3 
Grade 4 
All Gradesa 
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 


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Headache 
10 
0 
0 
5 
0 
0 
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
Other adverse reactions observed more commonly in patients treated with pazopanib than 
placebo and that occurred in < 10% (any grade) were alopecia (8% versus < 1%), chest pain 
(5% versus 1%), dysgeusia (altered taste) (8% versus < 1%), dyspepsia (5% versus < 1%), 
dysphonia (4% versus < 1%), facial edema (1% versus 0%), palmar-plantar 
erythrodysesthesia (hand-foot syndrome) (6% versus < 1%), proteinuria (9% versus 0%), 
rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 
3%). 
Additional adverse reactions from other clinical trials in RCC patients treated with pazopanib 
are listed below: 
Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms. 
Table 3. Selected Laboratory Abnormalities Occurring in ≥ 15% of Patients with RCC who 
Received Pazopanib and More Commonly (> 5%) in Patients who Received Pazopanib 
Versus Placebo 
Parameters 
Pazopanib 
(N=290) 
Placebo 
(N=145) 
All 
Gradesa 
Grade 3 
Grade 4 
All 
Gradesa 
Grade 3 
Grade 4 
% 
% 
% 
% 
% 
% 
Hematologic 
 
Leukopenia 
37 
0 
0 
6 
0 
0 
Neutropenia 
34 
1 
< 1 
6 
0 
0 
Thrombocytopenia 
32 
< 1 
< 1 
5 
0 
< 1 
Lymphocytopenia 
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 
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
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, 


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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. 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 4. Adverse Reactions Occurring in > 10% of Patients with STS who Received Pazopanib 
Adverse Reactions 
Pazopanib 
(N=240) 
Placebo 
(N=123) 
All 
Gradesa 
Grade 3 
Grade 4 
All 
Gradesa 
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 
Musculoskeletal pain 
23 
2 
0 
20 
2 
0 
Myalgia 
23 
2 
0 
9 
0 
0 
Gastrointestinal pain 
23 
3 
0 
9 
4 
0 
Dyspnea 
20 
5 
< 1 
17 
5 
1 
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 disorderb 
11 
2 
0 
1 
0 
0 
Skin hypopigmentation 
11 
0 
0 
0 
0 
0 
Stomatitis 
11 
< 1 
0 
3 
0 
0 
Chest pain 
10 
2 
0 
6 
0 
0 
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia. 
 


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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 4 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 5. Selected Laboratory Abnormalities Occurring in ≥ 15% 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 
Gradesa 
Grade 3 
Grade 4 
All 
Gradesa 
Grade 3 
Grade 4 
% 
% 
% 
% 
% 
% 
Hematologic 
 
Leukopenia 
44 
1 
0 
15 
0 
0 
Lymphocytopenia  
43 
10 
0 
36 
9 
2 
Thrombocytopenia 
36 
3 
1 
6 
0 
0 
Neutropenia 
33 
4 
0 
7 
0 
0 
Anaemia 
27 
5 
2 
23 
<1 
 
Chemistry 
 
AST increased 
51 
5 
3 
22 
2 
0 
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 
increased 
32 
3 
0 
23 
1 
0 
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 
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
 
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% 


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(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. 
Bradycardia: In the randomized trial of pazopanib for the treatment of RCC, bradycardia 
based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated 
with pazopanib and in 11% (16/144) of patients on the placebo arm.  Bradycardia was 
reported as an adverse reaction in 2% (7/290) of patients treated with pazopanib compared to 
<1% (1/145) of patients treated with placebo.  In the randomized trial of pazopanib for the 
treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 
19% (45/238) of patients treated with pazopanib and in 4% (5/121) of patients on the placebo 
arm.  Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with 
pazopanib compared to <1% (1/123) of patients treated with placebo. 
1.2.2. Postmarketing Data 
The following adverse reactions presented in Table 5 have been identified during post- 
approval use of pazopanib. This includes spontaneous case reports as well as serious 
adverse events from ongoing studies, clinical pharmacology studies and exploratory 
studies in unapproved indications. 
 
 
 
Table 5.       Post Marketing Data 
 
System Organ Class 
Frequency and MedDRA event Preferred 
Term
Infections and infestations 
Uncommon: Infections (with or without 
neutropenia; see Special Warnings and Special 
Blood and lymphatic system disorders 
Rare: Thrombotic microangiopathy (including 
thrombotic thrombocytopenic purpura and 
haemolytic uraemic syndrome; see Special 
W
i
d S
i l P
i
f
U
)


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Nervous system disorders 
Uncommon: Posterior reversible 
encephalopathy syndrome (see Special 
System Organ Class 
Frequency and MedDRA event Preferred 
Term
Eye disorders 
Uncommon: Retinal detachment/tear 
Respiratory, thoracic and mediastinal 
disorders 
Rare: Interstitial lung disease/pneumonitis (see 
Special Warnings and Special Precautions for 
Gastrointestinal disorders 
Common: Flatulence 
U
P
i i
Hepatobiliary disorders 
Common: Gamma-glutamyl transpeptidase 
i
d
Musculoskeletal and connective tissue 
di
d
Very common: Arthralgia 
C
M
l
 
 
1.2.3. Warnings and  Precautions for use 
1.2.3.1. 
Hepatic Toxicity and Hepatic Impairment 
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, aspartate aminotransferase [AST]) and bilirubin were observed (see Undesirable 
Effects). In the majority of the cases, isolated increases in ALT and AST have been 
reported, without concomitant elevations of alkaline phosphatase or bilirubin.  Patients 
over 60 years of age may be at greater risk for ALT >3 X ULN. Patients who carry the 
HLA-B*57:01 allele also have an increased risk of pazopanib-associated ALT elevations. 
Liver function should be monitored in all subjects receiving pazopanib, regardless of 
genotype or age.  The vast majority (over 90%) of all transaminase elevations of any grade 
occurred in the first 18 weeks.  Grades are based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 3 (NCI CTCAE). 
Monitor serum liver tests before initiation of treatment with pazopanib and at Weeks 3, 5,7 
and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic 
monitoring should then continue after Month 4. 
 The following guidelines are provided for patients with baseline values of total bilirubin 
1.5 X ULN, and AST and ALT 2 X ULN. 


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 
Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be 
continued on pazopanib with weekly monitoring of liver function until ALT return to 
Grade 1 (NCI CTCAE, defined in Version 3 as <2.5 X ULN) or baseline. 
 
 
Patients with ALT of >8 X ULN should have pazopanib interrupted until they return to 
Grade 1 (NCI CTCAE) or baseline. If the potential benefit for reinitiating pazopanib 
treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce 
pazopanib at a reduced dose of 400 mg once daily and measure serum liver tests 
weekly for 8 weeks (see Posology and Method of Administration). Following 
reintroduction of pazopanib, if ALT elevations >3 X ULN recur, then pazopanib 
should be permanently discontinued. 
If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X 
ULN pazopanib should be permanently discontinued.  Patients should be monitored 
until return to Grade 1 (NCI CTCAE) or baseline.  Pazopanib is a UGT1A1 
inhibitor. Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients 
with Gilbert’s syndrome.  Patients with only a mild indirect hyperbilirubinaemia, 
knownor suspected Gilbert’s syndrome, and elevation in ALT >3 X ULN should be 
managed as per the recommendations outlined for isolated ALT elevations. 
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see 
Interactions) and should be undertaken with caution and close monitoring. 
Beyond recommending that patients with mild hepatic impairment are treated with 800 mg 
pazopanib once daily and reducing the initial starting dose to 200 mg per day for 
patients with moderate impairment, no further dose modification guidelines based on 
results of serum liver tests during therapy have been established for patients with pre- 
existing hepatic impairment. Pazopanib is not recommended for patients with severe 
hepatic impairment  
The safety and pharmacokinetics of pazopanib in patients with pre-existing hepatic 
impairment have not been fully established (see Warnings and Precautions for Use). 
 
No dose adjustment is required in patients with mild hepatic impairment as defined by 
alanine aminotransferase (ALT) and bilirubin (see Clinical Pharmacology). 
 
The dose of pazopanib should be reduced to 200 mg per day in patients with moderate 
hepatic impairment. 
 
There are insufficient data in patients with severe hepatic impairment (total bilirubin >3 
times the upper limit of normal [X ULN] regardless of any level of ALT); therefore, 
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1.2.3.2. 
QT Prolongation and Torsades de Pointes 
In the RCC trials of pazopanib, QT prolongation (> 500 msec) was identified on routine 
electrocardiogram monitoring in 2% (11/558) of patients.  Torsades de pointes occurred in < 
1% (2/977) of patients who received pazopanib in the monotherapy trials. 
In the randomized RCC and STS trials, 1% (3/290) of patients and 0.2% (1/240) of patients, 
respectively, who received pazopanib had post-baseline values between 500 to 549 msec.  
Post-baseline QT data were only collected in the STS trial if ECG abnormalities were 
reported as an adverse reaction.  None of the 268 patients who received placebo on the two 
trials has post-baseline QTc values > 500 msec. 
Pazopanib should be used with caution in patients with a history of QT interval prolongation, 
in patients taking antiarrhythmics or other medications that may prolong QT interval, and 
those with relevant pre-existing cardiac disease.  
When using pazopanib, baseline and periodic monitoring of electrocardiograms and 
maintenance of electrolytes (calcium, magnesium, potassium) within normal range is 
recommended. 
1.2.3.3. 
Cardiac Dysfunction 
In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart 
failure and decreased left ventricular ejection fraction (LVEF) have occurred.  In a 
randomised RCC trial of pazopanib compared with sunitinib, in subjects who had baseline 
and follow-up LVEF measurements, myocardial dysfunction was observed in 13% 
(47/362) of subjects in the pazopanib arm compared to 11% (42/369) of subjects in the 
sunitinib arm.  Congestive heart failure was observed in 0.5% of subjects in each 
treatment arm. In the phase III STS clinical trial, congestive heart failure was reported in 3 
out of 240 subjects (1%).  In this trial decreases in LVEF in subjects who had post-
baseline measurement were detected in 11% (16/142) in the pazopanib arm compared with 
5% (2/40) in the placebo arm. Fourteen of the 16 subjects in the pazopanib arm had 
concurrent hypertension which may have exacerbated cardiac dysfunction in patients at 
risk (e.g., those with prior anthracycline therapy) by increasing cardiac after-load.  Blood 
pressure should be monitored and managed promptly using a combination of anti-
hypertensive therapy and dose modification of pazopanib (interruption and re-initiation at 
a reduced dose based on clinical judgment). Patients should be carefully monitored for 
clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of 
LVEF is recommended in patients at risk of cardiac dysfunction. 
1.2.3.4. 
Hemorrhagic Events 
Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials; there were no reports of fatal 
hemorrhage in the STS trials.  In the randomized RCC trial, 13% (37/290) of patients treated 
with pazopanib and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic 


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event.  The most common hemorrhagic events in the patients treated with pazopanib were 
hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%).  Nine of 37 
patients treated with pazopanib who had hemorrhagic events experienced serious events 
including pulmonary, gastrointestinal, and genitourinary hemorrhage.  One percent (4/290) of 
patients treated with pazopanib died from hemorrhage compared with no (0/145) patients on 
placebo.  In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage 
was observed in < 1% (2/586) of patients treated with pazopanib. 
In the randomized STS trial, 22% (53/240) of patients treated with pazopanib compared to 
8% (10/123) treated with placebo experienced at least 1 hemorrhagic event.  The most 
common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal 
hemorrhage (2%).  Grade 4 hemorrhagic events in the STS population occurred in 1% 
(3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage, and 
peritoneal hemorrhage.   
Pazopanib has not been studied in patients who have a history of hemoptysis, cerebral, or 
clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used 
in those patients. 
1.2.3.5. 
Arterial Thromboembolic Events 
Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC 
trials and in no patients in the STS trials.  In the randomized RCC trial, 2% (5/290) of 
patients receiving pazopanib experienced myocardial infarction or ischemia, 0.3% (1/290) 
had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack.  In 
the randomized STS trial, 2% (4/240) of patients receiving pazopanib experienced a 
myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there 
were no incidents of transient ischemic attack.  No arterial thrombotic events were reported 
in patients who received placebo in either trial.  Pazopanib should be used with caution in 
patients who are at increased risk for these events or who have had a history of these events.  
Pazopanib has not been studied in patients who have had an arterial thrombotic event within 
the previous 6 months and should not be used in those patients. 
1.2.3.6. 
Venous Thromboembolic Events 
In RCC and STS trials of pazopanib, venous thromboembolic events including venous 
thrombosis and fatal pulmonary embolus have occurred.  In the randomized STS trial, venous 
thromboembolic events were reported in 5% of patients treated with pazopanib compared to 
2% with placebo.  In the randomized RCC trial, the rate was 1% in both arms.  Fatal 
pulmonary embolus occurred in 1% (2/240) of STS patients receiving pazopanib and in no 
patients receiving placebo.  There were no fatal pulmonary emboli in the RCC trial.  Monitor 
for signs and symptoms of VTE and PE. 


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1.2.3.7. 
Thrombotic Microangiopathy 
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) 
and hemolytic uremic syndrome (HUS), has been reported in clinical trials of pazopanib as 
monotherapy, in combination with bevacizumab, and in combination with topotecan. 
Pazopanib is not indicated for use in combination with other agents.  Six of the 7 TMA cases 
occurred within 90 days of the initiation of pazopanib.  Improvement of TMA was observed 
after treatment was discontinued.  Monitor for signs and symptoms of TMA.  Permanently 
discontinue pazopanib in patients developing TMA. Manage as clinically indicated. 
1.2.3.8. 
Gastrointestinal Perforation and Fistula 
In the RCC and STS trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of 
patients and 1% (4/382) of patients receiving pazopanib, respectively.  Fatal perforations 
occurred in 0.3% (2/586) of these patients in the RCC trials and in 0.3% (1/382) of these 
patients in the STS trials.  Monitor for signs and symptoms of gastrointestinal perforation or 
fistula. 
1.2.3.9. 
Posterior Reversible Encephalopathy Syndrome / Reversible Posterior 
Leukoencephalopathy Syndrome 
Posterior Reversible Encephalopathy Syndrome (PRES) / Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving pazopanib 
and may be fatal.   
PRES/RPLS is a neurological disorder which can present with headache, seizure, lethargy, 
confusion, blindness, and other visual and neurologic disturbances.  Mild to severe 
hypertension may be present.  The diagnosis of PRES/RPLS is optimally confirmed by 
magnetic resonance imaging.  Permanently discontinue pazopanib in patients developing 
PRES/RPLS. 
1.2.3.10. 
Hypertension 
In clinical trials, hypertension (systolic blood pressure > 150 or diastolic blood pressure > 
100 mm Hg) and hypertensive crisis were observed in patients treated with pazopanib.  
Blood pressure should be well controlled prior to initiating pazopanib.  Hypertension occurs 
early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred 
in the first 18 weeks).  Blood pressure should be monitored early after starting treatment (no 
longer than one week) and frequently thereafter to ensure blood pressure control.  
Approximately 40% of patients who received pazopanib experienced hypertension.  Grade 3 
hypertension was reported in 4% to 7% of patients receiving pazopanib. 
Increased blood pressure should be treated promptly with standard anti-hypertensive therapy 
and dose reduction or interruption of pazopanib as clinically warranted.  Pazopanib should be 
discontinued if there is evidence of hypertensive crisis or if hypertension is severe and 


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persistent despite anti-hypertensive therapy and dose reduction.  Approximately 1% of 
patients required permanent discontinuation of pazopanib because of hypertension.   
1.2.3.11. 
Wound Healing 
No formal trials on the effect of pazopanib on wound healing have been conducted.  Since 
vascular endothelial growth factor receptor (VEGF) inhibitors such as pazopanib may impair 
wound healing, treatment with pazopanib should be stopped at least 7 days prior to scheduled 
surgery.  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. 
1.2.3.12. 
Hypothyroidism 
Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was 
reported in 7% (19/290) of patients treated with pazopanib in the randomized RCC trial and 
in 5% (11/240) of patients treated with pazopanib in the randomized STS trial.  No patients 
on the placebo arm of either trial had hypothyroidism.  In RCC and STS trials of pazopanib, 
hypothyroidism was reported as an adverse reaction in 4% (26/586) and 5% (20/382) of 
patients, respectively.  Proactive monitoring of thyroid function tests is recommended.  
1.2.3.13. 
Proteinuria 
In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) 
of patients receiving pazopanib and in no patients receiving placebo.  In 2 patients, 
proteinuria led to discontinuation of treatment with pazopanib.  In the randomized STS trial, 
proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic 
syndrome was reported in 1 patient treated with pazopanib compared to none in patients 
receiving placebo.  Treatment was withdrawn in the patient with nephrotic syndrome.  
Baseline and periodic urinalysis during treatment is recommended with follow up 
measurement of 24-hour urine protein as clinically indicated.  Interrupt pazopanib and dose 
reduce for 24-hour urine protein > 3 grams; discontinue pazopanib for repeat episodes 
despite dose reductions. 
1.2.3.14. 
Infection 
Serious infections (with or without neutropenia), including some with fatal outcome, have 
been reported.  Monitor patients for signs and symptoms of infection.  Institute appropriate 
anti-infective therapy promptly and consider interruption or discontinuation of pazopanib for 
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1.2.3.15.  Intersitial Lung Disease (ILD)/Pneumonitis:  ILD which can be fatal, has been 
reported in association with pazopanib.  Monitor patients for pulmonary symptoms indicative 
of ILD/pneumonitis and discontinue pazopanib in patients developing ILD or pneumonitis. 
1.2.3.16. 
Increased Toxicity with Other Cancer Therapy 
Pazopanib is not indicated for use in combination with other agents.  Clinical trials of 
pazopanib in combination with pemetrexed and lapatinib were terminated early due to 
concerns over increased toxicity and mortality.  The fatal toxicities observed included 
pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death.  A safe and effective 
combination dose has not been established with these regimens. 
1.2.3.17. 
Increased Toxicity in Developing Organs 
The safety and effectiveness of pazopanib in pediatric patients have not been established.  
Pazopanib is not indicated for use in pediatric patients.  Based on its mechanism of action, 
pazopanib may have severe effects on organ growth and maturation during early post-natal 
development.  Administration of pazopanib to juvenile rats less than 21 days old resulted in 
toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than 
the clinically recommended dose or doses tolerated in older animals.  Pazopanib may 
potentially cause serious adverse effects on organ development in pediatric patients, 
particularly in patients younger than 2 years of age. 
1.2.3.18. Pregnancy 
As of 09 september 2015 there have been 3 reports of pregnancy involving 2 female subjects 
who were enrolled in pazopanib clinical trials.  Both subjects became pregnant after 
pazopanib was discontinued. 
A 28-year-old enrolled in the ovarian cancer study veg110655 had a spontaneous abortion at 
8 weeks gestation, which was 155 days after the last pazopanib dose.  About2 years after her 
last pazopanib dose, the subject gave birth to a normal baby boy at 39 weeks gestation. 
A 26-year-old enrolled in a gsk-supported rcc study had a positive pregnancy test 47 days 
after her last pazopanib dose.  On 08 august 2014, the patient underwent an elective caesarian 
section in order for her to receive chemotherapy due to malignancy progression.  An infant 
male was delivered uneventfully, although prematurely at27 weeks gestation.  The 
investigator noted that no aes associated with the patient’s pazopanib treatment were 
observed. 
In addition to the above reports, a spontaneous report of congenital anomalies in an infant 
whose mother received pazopanib is described in the marketing experience: 
One report describing the use of pazopanib up to the first trimester of pregnancy, for an 
unapproved indication (off-label use) has been received up to 09 September 2015.  A 19- 
year-old female began pazopanib for treatment of thyroid cancer at age 16 in August2011.  


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Pazopanib was discontinued in January 2014, during the first trimester of pregnancy.  
About 7 months after the last pazopanib dose, in August 2014, the patient delivered a baby 
boy at 38 weeks gestation.  The baby’s APGAR scores were 8 at 1 minute and 9 at 5 
minutes after birth.  At an unspecified period after birth, the baby was diagnosed with 
congenital heart disease, characterised by a subaortic septal defect, aortic coarctation, and 
partial anomalous pulmonary venous return.  The baby underwent surgery and was 
described as “doing well and thriving” post-surgery.  The patient resumed pazopanib 
following delivery until about 5 months later, in January 2015, when pazopanib was 
stopped for an unspecified reason. 
There are no adequate and well-controlled studies of pazopanib in pregnant women.  If this 
drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus.  Women of childbearing 
potential should be advised to avoid becoming pregnant while taking pazopanib. 
1.2.3.19. 
Interactions 
Concomitant treatment with strong inhibitors of CYP3A4 or P-gp should be avoided due to 
risk of increased exposure to pazopanib.  Selection of alternative concomitant medicinal 
products with no or minimal potential to inhibit CYP3A4 or P-gp should be considered. 
 
1.3. 
Pazopanib Monotherapy Dose Rationale 
Pazopanib 800 mg once daily is the recommended monotherapy dose based on clinical and 
preclinical results.  Once daily doses of 50 mg to 2000 mg pazopanib were investigated in the 
“First Time in Human”, Phase I Study VEG10003.  Increases in the pazopanib dose above 
800 mg once daily when administered in the fasted state did not result in a consistent increase 
in systemic exposure at steady-state.  Therefore, no further benefit is expected at pazopanib 
doses above 800 mg once daily. 
Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg once daily, 
results in effects consistent with inhibition of the VEGF receptors it was designed to target.  
Concentration-effect relationships were observed between trough plasma pazopanib 
concentrations and the development of hypertension in Study VEG10003 and the percent 
change from baseline in sVEGFR2 nadir in Study VEG102616.  The trough plasma 
pazopanib concentrations associated with one-half the maximal effect (EC50) in both 
concentration-effect relationships were similar (21.3 g/mL and 15.3 g/mL) and 
demonstrate that there is a consistent inhibition of VEGF receptor(s) in subjects with cancer 
when plasma pazopanib concentrations are maintained above 15 g/mL.  The plasma 
pazopanib EC50 values for biologic effects observed in the clinical studies are similar to the 
plasma concentration of 40 M (17.5 g/mL) required for optimal inhibition of VEGFR-2 
phosphorylation in mice [GSK Report RH2003/00005/00]. 


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Progression Free Survival (PFS) in subjects with renal cell cancer in study VEG102616 was 
compared between subjects whose trough plasma pazopanib concentrations at Week 4 were 
above or below selected threshold values that were distributed evenly across the observed 
predose concentrations.  Subjects with trough concentrations above the threshold values had 
significantly better PFS, compared to the remaining subjects, when the threshold 
concentrations were 12.6 g/mL, 17.4 g/mL, and 20.7 g/mL.  Use of thresholds higher 
than 21 g/mL did not result in a significant difference in PFS between subjects above and 
below the threshold.  Using thresholds of 15 g/mL and 20.7 g/mL, subjects with trough 
concentrations above the thresholds also had significantly better response rate and tumor 
shrinkage than the remaining subjects. 
Pazopanib C24 at steady-state was greater than 15 g/mL in 93% of subjects who received 
800 mg once daily in Study VEG10003.  Individual subjects receiving pazopanib doses 
below 800 mg once daily can achieve plasma concentrations over 15 g/mL, albeit at a lower 
frequency compared with what is observed at 800 mg once daily.  Therefore, the 
pharmacokinetic and pharmacodynamic results across clinical studies demonstrate that 
pazopanib 800 mg once daily results in plasma concentrations that provide optimal biologic 
effects associated with VEGFR inhibition in the greatest proportion of subjects. 
Additional support for an 800 mg once daily pazopanib dose comes in results from Study 
VEG105192, a 435-subject Phase III study of pazopanib (800 mg once daily) versus placebo 
in treatment-naïve and cytokine-pretreated subjects with RCC.  In this study, the median 
progression-free survival in the pazopanib arm was 9.2 months (95% CI, 7.4, 12.9) compared 
to 4.2 months (95% CI, 2.8, 4.2) in the placebo arm.  This finding represented a statistically 
significant improvement in PFS in response to pazopanib monotherapy (HR 0.46, 95% CI 
0.34 to 0.62, p<0.0000001).  In addition, the response rate (defined as the percentage of 
subjects achieving either a confirmed complete or partial response according to RECIST) in 
the pazopanib arm was 30% versus 3% in the placebo arm, and the median duration of 
response in pazopanib-treated subjects was 58.7 weeks.  Results from Study VEG105192 
therefore clearly indicate that an 800 mg once daily dose of pazopanib is highly effective in 
treating subjects with advanced RCC. 
2. 
STUDY RATIONALE 
Bone sarcomas (BS) are uncommon mesenchymal malignancies. In 2009, the estimated 
number of new cases of BS in the United States will be 2,570, which will account for only 
0.2% of all newly diagnosed cancers [Jemal, 2006; Fletcher, 2002]. 
Chondrosarcoma is the second most common malignant primary tumor of bone, with about 
400 new cases per year [Yasko, 2008].  Chondrosarcomas are generally indolent, malignant 
tumors of bone that are characterized by the formation of cartilaginous neoplastic tissue.  
More than 90% are designated conventional chondrosarcomas.  Approximately 90% of these 
are low-grade to intermediate-grade tumors (grade 1 to 2), which have indolent clinical 
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grade 3 lesions, which have high metastatic potential [Dorfman, 1998]. Chemotherapy is 
generally recognized to be ineffective in conventional chondrosarcomas [Chow, 2007]. 
The growth, migration, and dissemination of sarcomas depend upon angiogenesis. 
Neovascularization allows for growth of the primary tumor as well as a pathway for 
migrating tumor cells to gain access to the systemic circulation and establish distant 
metastases. 
BS, unlike carcinomas, disseminate almost exclusively through the blood; bones lack a 
lymphatic system [Malawer, 2001]. Consequently, unlike most other cancers, BS almost 
universally metastasize to the pulmonary parenchyma as their first, and most commonly, only 
site of distant spread [Malawer, 2001]. Further, more than most other organs, the lungs 
possess a rich arterial and venous vascular supply. Additionally, elevated tumor and 
circulating VEGF levels are associated with the development of lung metastases [Shor, 
2008]. Accordingly, inhibiting neovascularization in BS, which have a unique proclivity to 
metastasize solely to this receptive organ, is appealing. 
Pazopanib is known to have a high degree of activity in soft-tissue sarcoma (STS).  In a 
phase II trial of pazopanib for relapsed or refractory advanced STS, the primary end point of 
progression-free rate at 12 weeks (PFR12 weeks) of 40% was achieved or nearly achieved in 
three out of four cohorts (26% liposarcomas, 44% leiomyosarcomas, 49% synovial sarcomas, 
and 39% in other STS) [Sleijfer, 2009].   
In a phase I study of pazopanib in subjects with advanced cancer, two subjects 
with chondrosarcoma achieved stable disease for 7.6 and 19.8 months [Hurwitz, 2009].  The 
chondrosarcoma subject who achieved stable disease for 19.8 months also had a 23% 
reduction in tumor [GSK data on file]. A treatment that reliably leads to stable disease in this 
population would represent a significant improvement over existing treatment options.  This 
study is designed to evaluate treatment with pazopanib in subjects with surgically 
unresectable or metastatic chondrosarcoma.  
3. 
OVERVIEW OF STUDY DESIGN AND EVALUATION 
This is a Phase II, multicenter, prospective, open-label, single arm study.  The primary 
endpoint of the study is disease control at week 16 defined as CR + PR + SD, where tumor 
response is defined by RECIST guidelines version 1.1.  The secondary endpoints include 
progression free survival (PFS) according to RECIST guidelines version 1.1, overall survival 
(OS), and toxicity assessment through the reporting of adverse events.   
Pazopanib 800 mg once daily will be started on Cycle 1 Day 1 and will be administered 
continuously for a 28-day cycle.  Subjects may continue study treatment until they develop 
disease progression or unacceptable toxicity. 


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The study will include a Screening Phase, a Treatment Phase, and a Follow-up Phase of 6 
months.  The study will be conducted at approximately 7 oncology centers associated with 
Vector Oncology.  Planned enrollment is approximately 47 subjects. 
4. 
STUDY OBJECTIVES 
4.1. 
Primary Objective 
The primary objective of the study is to determine the treatment efficacy of single agent 
pazopanib in subjects with chondrosarcoma.   
4.2. 
Secondary Objectives 
The secondary objectives of this study are to determine the safety profile of pazopanib in this 
population. 
5. 
ELIGIBILITY CRITERIA 
5.1. 
Inclusion Criteria 
A subject must meet each of the following criteria to be considered eligible for inclusion in 
this study: 
1. 
Subjects must provide written informed consent prior to performance of study-specific 
procedures or assessments, and must be willing to comply with treatment and 
follow-up.  
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) 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. 
2. 
Age ≥ 18 years. 
3. 
Histologically confirmed diagnosis of conventional chondrosarcoma of any grade. 
4. 
Surgically unresectable or metastatic disease. 
5. 
Any number of prior treatment regimens, including treatment naïve subjects.  Prior 
treatment with tyrosine kinase inhibitors is permitted. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
(Appendix 2). 
7. 
Measurable or evaluable (non-measurable) disease per RECIST guidelines version 1.1. 
8. 
Adequate organ system function as defined in Table 5 determined within 14 days prior 
to the first dose of study treatment. 


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Table 6. Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematologic 
 
Absolute neutrophil count (ANC) 
 1.5 X 109/L 
Hemoglobina  
 9 g/dL (5.6 mmol/L) 
Platelets 
 100 X 109/L 
Prothrombin time (PT) or international 
normalized ratio (INR)b  
 1.2 X ULN 
Activated partial thromboplastin time (aPTT) 
 1.2 X ULN 
Hepatic 
 
Total bilirubin 
 1.5 X ULN 
Alanine amino transferase (ALT) and Aspartate 
aminotransferase (AST)c  
 2.5 X ULN 
Renal 
 
Serum creatinine 
 1.5 mg/dL (133 µmol/L) 
Or, if serum creatinine is > 1.5 mg/dL: 
Calculated creatinine clearance (ClCR) (Appendix 
3) 
 50 mL/min 
Urine Protein to Creatinine Ratio (UPC; 
Appendix 4)d  
< 1 
a. 
Subjects may not have had a transfusion within 7 days of Screening assessment. 
b. Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended 
range for the desired level of anticoagulation. 
c. 
Concomitant elevations in bilirubin and AST/ALT above the ULN (upper limit of normal) are not 
permitted. 
d. 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. 
 
9. 
Left ventricular ejection fraction (LVEF) > 50% or the institutional LLN within 28 
days prior to the first dose of study treatment. 
10. A female is eligible to enter and participate in this study if she is of: 
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including 
any female who has had: 
 A hysterectomy 
 A bilateral oophorectomy (ovariectomy) 
 A bilateral tubal ligation 
 Is post-menopausal 
Subjects not using hormone replacement therapy (HRT) must have experienced total 
cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in questionable 
cases, have a follicle stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value 
< 40pg/mL (< 140 pmol/L). 


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Subjects using HRT must have experienced total cessation of menses for ≥ 1 year and be 
greater than 45 years of age, OR, have had documented evidence of menopause based on 
FSH and estradiol concentrations prior to initiation of HRT. 
Childbearing potential, including any female who has had a negative serum pregnancy test 
within 7 days prior to the first dose of study treatment, preferably as close to the first dose as 
possible, and agrees to use adequate contraception.  Acceptable contraceptive methods, when 
used consistently and in accordance with both the product label and the instructions of the 
physician, are as follows: 
 Complete abstinence from sexual intercourse for 14 days before exposure to 
investigational product, through the dosing period, and for at least 21 days after the 
last dose of investigational product [Hatcher, 2004] 
 Oral contraceptive, either combined or progestogen alone [Hatcher, 2004] 
 Injectable progestogen [Hatcher, 2004] 
 Implants of levonorgestrel [Hatcher, 2004] 
 Estrogenic vaginal ring [Hatcher, 2004] 
 Percutaneous contraceptive patches [Hatcher, 2004] 
 Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate 
of less than 1% per year [Hatcher, 2004]. 
 Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject [Hatcher, 2004]. 
 Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) 
Female subjects who are lactating should discontinue nursing prior to the first dose of study 
drug and should refrain from nursing throughout the treatment period and for 14 days 
following the last dose of study drug. 
5.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be considered not eligible for 
inclusion in this study: 
1. 
Prior treatment with pazopanib. 
2. 
Mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes. 
3. 
Prior malignancy.  Note: Subjects who have had another malignancy and have been 
disease-free for 3 years, or subjects with a history of completely resected non-
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4. 
History or clinical evidence of central nervous system (CNS) metastases or 
leptomeningeal carcinomatosis, except for individuals who have previously-treated 
CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-
seizure medication for 6 months prior to first dose of study drug.  Screening with CNS 
imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is 
required only if clinically indicated or if the subject has a history of CNS metastases. 
5. 
Clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding including, but not limited to: 
 Active peptic ulcer disease 
 Known intraluminal metastatic lesion(s) with risk of bleeding 
 Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other 
gastrointestinal conditions with increased risk of perforation 
 History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days prior to beginning study treatment. 
6. 
Clinically significant gastrointestinal abnormalities that may affect absorption of 
investigational product including, but not limited to: 
 Malabsorption syndrome 
 Major resection of the stomach or small bowel. 
7. 
Presence of uncontrolled infection. 
8. 
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula. 
9. 
History of any one or more of the following cardiovascular conditions within the past 6 
months: 
 Cardiac angioplasty or stenting 
 Myocardial infarction 
 Unstable angina 
 Coronary artery bypass graft surgery 
 Symptomatic peripheral vascular disease 
 Class III or IV congestive heart failure, as defined by the New York Heart 
Association (NYHA) [Appendix 5]. 
10. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥ 140 
mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. 
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to 
study entry.  BP must be re-assessed on two occasions that are separated by a minimum 
of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from 
each BP assessment must be < 140/90 mmHg in order for a subject to be eligible for 


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the study (see Section 7.1 for details on BP control and re-assessment prior to study 
enrollment). 
11. History of cerebrovascular accident including transient ischemic attack (TIA), 
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 
months.  
Note: Subjects with recent DVT who have been treated with therapeutic anti-
coagulating agents for at least 6 weeks are eligible. 
12. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or 
presence of any non-healing wound, fracture, or ulcer.  Major surgery is defined by the 
use of general anesthesia; however, endoscopic examinations with diagnostic intent are 
not considered major surgery.  Insertion of a vascular access device is exempt from this 
exclusion criterion.  Subjects must have recovered from all surgery-related 
complications. 
13. Evidence of active bleeding or bleeding diathesis. 
14. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that 
increase the risk of pulmonary hemorrhage.   
 Lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are 
excluded; however, the presence of a tumor that is 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. 
15. Hemoptysis of red blood in excess of 2.5 mL (or one half teaspoon) within 8 weeks of 
first dose of study drug. 
16. 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. 
17. Unable or unwilling to discontinue use of prohibited medications (see lists in Section 
6.5.1) 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 treatment. 
18. Treatment with any of the following anti-cancer therapies: 
 radiation therapy, surgery (except major surgery, as described above) or tumor 
embolization within 14 days prior to the first dose of study drug, OR 
 chemotherapy, immunotherapy, biologic therapy, investigational therapy or 
hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) 
prior to the first dose of study drug. 


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19. Administration of any non-oncologic investigational drug within 30 days or five half-
lives (whichever is longer) prior to receiving the first dose of study drug. 
20. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is 
progressing in severity, except alopecia. 
21. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to pazopanib or excipients that contraindicates participation. 
5.3. 
Other Eligibility Criteria Considerations 
To assess any potential impact on subject eligibility with regard to safety, the Investigator 
must refer to the current Prescribing Information and Investigator’s Brochure for pazopanib 
for detailed information regarding warnings, precautions, contraindications, adverse events, 
and other significant data pertaining to the investigational product being used in this study. 
6. 
TREATMENT OF SUBJECTS 
6.1. 
Subject Enrollment 
Participating sites will be instructed on the procedure for enrolling subjects with Vector 
Oncology during site training.  Subject numbers will be assigned in sequential order across 
all participating sites.   
6.2. 
Study Treatment 
 Pazopanib 800 mg once daily will be started on Cycle 1 Day 1 and will be administered 
continuously for a 28-day cycle.  Subjects may continue study treatment until they develop 
disease progression or unacceptable toxicity. 
During the treatment prior of the study, a visit window of + / - 3 business days is allowed.  
Assessments may be performed within 3 business days before the actual visit to allow 
flexibility in scheduling with the exception of the BP measurements required at Cycle 1 Day 
8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 15, and Cycle 3 Day 15, which have a 
window of +/- 1 business day.  Other vital signs are not required at these time points, and BP 
can be assessed by any method (e.g., at home or by another physician) as long as the 
Investigator is informed of the measurement, verifies any measurement that is not normal, 
and takes appropriate action. 
Treatment will be administered on an outpatient basis.  No investigational or commercial 
agents or therapies other than those described in this section may be administered with the 
intent to treat the subject's malignancy. 
Pazopanib should be taken orally without food at least one hour before or two hours after a 
meal.  The tablets should be swallowed whole and must not be crushed or broken. The time 


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of day the tablets are taken should be relatively consistent. If a dose is missed, it should not 
be taken if it is less than 12 hours until the next dose. 
6.3. 
Pazopanib Dose Interruptions and Modifications  
Guidelines for pazopanib dose interruptions/modifications in case of specific treatment-
emergent AEs are provided in the following sections.  
If pazopanib is interrupted for 5 days or more, Vector Oncology must be notified. 
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, 
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.  
Pazopanib Starting Dose 
800 mg once daily 
Dose Reduction 1 
600 mg once daily 
Dose Reduction 2 
400 mg once daily 
Dose Reduction 3 
200 mg once daily 
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).  
If a subject’s treatment is interrupted for more than 28 days, for any reason, the subject must 
be removed from study treatment. 
6.3.1. Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities 
Guidelines for pazopanib dose interruptions/modifications in case of specific treatment-
emergent AEs are provided in Table 6.  If an AE is considered unlikely to be related to 
pazopanib per Investigator’s clinical judgment, then these dose modification rules will not 
apply. 
 
Table 7.  Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
(A). Asymptomatic and persistenta 140 < 
SBP < 160 mmHg, or 90 < DBP < 100 
mmHg, or a clinically significant increase 
in DBP of 20 mmHg (but still below 100 
Step 1. Continue pazopanib at the current dose.  
Step 2. Adjust current or initiate new antihypertensive 
medication(s) to achieve and maintain a BP level of < 140/90 


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AE Terms & Descriptions 
Dose Modification Algorithms 
mmHg). 
mmHg. 
If BP cannot be controlled to < 140/90 mmHg within 2 weeks 
after 2 or more different antihypertensive medication adjustments, 
dose reduction of pazopanib by 200 mg should be considered. 
(B). Asymptomatic SBP  160 mmHg, or 
DBP  100 mmHg. 
Step 1. Dose reduce by 200 mg or interrupt pazopanib as per 
clinical judgment. 
Step 2. Adjust current or initiate new antihypertensive 
medication(s) to achieve and maintain a BP level of < 140/90 
mmHg.  
If BP cannot be controlled to < 140/90 mmHg within 2 weeks and 
pazopanib has been interrupted, it can be resumed with dose-
reduced by 200 mg from pre-event dose. 
If BP cannot be adequately controlled with these measures, 
consider referring the subject to a specialist for further evaluation 
and management. 
(C). Symptomatic hypertension or 
recurring SBP  160 mmHg, or DBP  
100 mmHg, despite modification of 
antihypertensive medication(s) 
Step 1. Interrupt pazopanib.  
Step 2. Strongly recommend referring the subject to a specialist 
for further evaluation and management. 
Once BP is controlled to < 140/90 mmHg via adjustment of 
current or initiation of new antihypertensive medication(s), 
pazopanib can be resumed with dose-reduced by 200 mg.  BP 
should be monitored as clinically indicated. 
(D). Refractory hypertension unresponsive 
to above interventions including 
malignant hypertension, hypertensive 
crisis, transient or permanent neurological 
deficit related to uncontrolled 
hypertension. 
Permanently 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. Weekly UPC or 24-hr urine protein monitoring until UPC 
is < 3 or 24-hr urine protein is < 3 grams.  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 ≥ 3g recurs and the 
pazopanib dose can no longer be reduced, discontinue pazopanib 
and continue follow-up per protocol. 
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AE Terms & Descriptions 
Dose Modification Algorithms 
Grade 1 
For hemoptysis, interrupt pazopanib and contact Vector Oncology 
to discuss whether further treatment with pazopanib is appropriate. 
For other Grade 1 hemorrhage/bleeding events, continue 
pazopanib at the current dose; monitor as clinically indicated. 
Grade 2 
For pulmonary or GI bleed (other than hemorrhoidal bleeding), 
discontinue pazopanib and continue follow-up per protocol.  
For other Grade 2 hemorrhage/bleeding events, interrupt 
pazopanib until the AE resolves to < Grade 1.  Restart pazopanib 
dose-reduced by 200 mg and monitor as clinically indicated. 
Grade 3 or 4, or Recurrent  Grade 2 
event after dose interruption/reduction. 
Permanently discontinue pazopanib and follow-up per protocol. 
Venous Thrombosis (DVT, PE) 
Grade 1 
Continue pazopanib at the current dose; monitor as clinically 
indicated 
Grade 2 or 3   
Step 1. Interrupt pazopanib.  
Step 2. Initiate and monitor anticoagulation as clinically indicated.  
Step 3. Resume pazopanib dose-reduced by 200 mg only if all of 
the following criteria are met:  
 
The subject must have been treated with anticoagulant at 
the desired level of anticoagulation for at least one week. 
 
No Grade 3 or 4 or clinically significant Grade 2 
hemorrhagic events have occurred while on 
anticoagulation treatment. 
Subject should be monitored as clinically indicated during 
anticoagulation treatment and after resuming study treatment. 
When treating with warfarin, international normalized ratio (INR) 
should be monitored within three to five days after any change in 
pazopanib (e.g., re-initiating, escalating/de-escalating, or 
discontinuing pazopanib), and then at least weekly until the INR is 
stable. The dose of warfarin (or its derivatives) may need to be 
adjusted to maintain the desired level of anticoagulation. 
AE Terms & Descriptions 
Dose Modification Algorithms 
Venous Thrombosis (DVT, PE) 
Grade 4  
Permanently discontinue pazopanib and follow-up per protocol. 
Arterial Thrombosis/Ischemia 
Any Grade 
Permanently discontinue pazopanib and follow-up per protocol. 
Palmar-Plantar Erythrodysesthesia Syndrome 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Grade 1 
Minimal skin changes or dermatitis 
without pain (erythema, edema, 
hyperkeratosis) 
Step 1. Continue pazopanib at present dose. 
 
Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily living 
(ADLs) (peeling, blisters, edema, bleed, 
hyperkeratosis) 
Step 1. Interrupt pazopanib. 
Step 2. Treat as clinically appropriate. 
Step 3. Upon resolution to < Grade 1, restart pazopanib dose-
reduced by 200 mg; monitor as clinically indicated. 
Step 4. If recurrent, consider a further dose reduction, or 
discontinue. 
Grade 3 
Severe skin changes with pain and 
limiting self-care ADLs 
Step 1. Permanently discontinue pazopanib. 
Thrombocytopenia: Investigate and document underlying cause 
Grade 1 or 2 
Continue pazopanib at current dose; monitor as clinically 
indicated. 
Grade 3 or 4 
Step 1. Interrupt pazopanib until toxicity resolves to ≤ Grade 2. 
Step 2. Restart pazopanib dose-reduced by 200 mg and monitor as 
clinically indicated.  
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 
thrombocytopenia, permanently discontinue pazopanib and 
follow-up per protocol 
Anemia:  No specific dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding as 
noted above. 
Other Clinically Significant Non-Liver Related Adverse Events 
Grade 1 
Step 1. Continue pazopanib at current dose. 
Step 2. Manage the side effects with appropriate medical 
treatments/supportive care.  A dose reduction of 200 mg may be 
considered if a subject experiences multiple Grade 1 AEs and 
cannot tolerate the current pazopanib dose. 
Grade 2  
Step 1. Manage the side effects with appropriate medical 
treatments/supportive care. 
Step 2. A dose reduction of 200 mg or interruption of pazopanib 
may be considered if a subject experiences a clinically significant 
Grade 2 AE or multiple Grade 1 and 2 AEs and cannot tolerate the 
current pazopanib dose. 
If AEs are fully resolved or recover to Grade 1, the dose can be 
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AE Terms & Descriptions 
Dose Modification Algorithms 
For subjects with dose interruption, dose can be resumed at the 
pre-event level or dose-reduced by 200 mg based on clinical 
judgment. 
Grade 3 
Step 1. Interrupt pazopanib. 
Step 2. Manage the side effects with appropriate medical 
treatments/supportive care. 
If AEs fully recover or recover to Grade 1, restart pazopanib with 
dose-reduced by 200 mg.  Monitor as clinically indicated for AE 
recurrence. 
Dose can be interrupted or further reduced for recurrent Grade 3 
AEs.    
Grade 4 
Permanently discontinue pazopanib and follow-up per protocol. 
Prolongation of QTc Interval: If a QTc reading is > 500 msec, the EKG should be manually read to ensure 
accuracy of the reading.  The values below refer to manually-read EKGs. 
480 < QTc < 500 msec 
Continue pazopanib; monitor as clinically indicated. 
QTc  500 msec (see Section 7.3.4) 
Step 1. Perform 2 additional EKGs to confirm the abnormality. 
Step 2. Manually evaluate each EKG tracing to obtain RR and QT 
intervals for QTc calculation. 
Step 3. Determine the average QTc from the 3 EKG tracings by 
manual evaluation. 
Step 4. If the average QTc is < 500 msec, the subject may 
continue therapy.  If the average QTc is > 500 msec, interrupt 
pazopanib and refer to Section 7.3.4 of the protocol. 
a. 
Persistent SBP and/or DBP is defined as SBP > 140 or DBP > 90 for at least 24 hours per NCI CTCAE 
v4.0. 
b. Recommendation of antihypertensive agents for treatment-emergent BP elevations: ACE inhibitors, 
angiotensine receptor blocking agents, beta blockers, calcium channel blockers, and diuretics have all been 
shown to reduce blood pressure in subjects treated with pazopanib. 
Abbreviations: AE, adverse event; ADLs, activities of daily living; BP, blood pressure; DBP, diastolic blood 
pressure; DVT, deep venous thrombosis; EKG, electrocardiogram; GI, gastrointestinal; INR, international 
normalized ratio; PE, pulmonary embolism; SBP, systolic blood pressure; UPC, urine protein to creatinine ratio. 
 
Diarrhea  
In cancer patients, diarrhea can be debilitating and potentially life threatening, with 
dehydration, renal insufficiency, and electrolyte imbalances. Pazopanib as a monotherapy has 
been associated with an increased incidence of diarrhea, which is grade 1 or 2 in the majority 
with grade 3/4 diarrhea occurring in approximately 4% of subjects.  The incidence and 
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Early identification and intervention is critical for the optimal management of diarrhea.  A 
subject’s Baseline bowel pattern should be established so that changes in that pattern can be 
identified.  In addition, subjects should be educated on signs and symptoms of diarrhea with 
instructions to report any changes in bowel pattern to the physician. 
The NCI CTCAE Version 4.0 criteria for defining diarrhea are provided below. 
Toxicity 
Grade 
Diarrhea  
(includes diarrhea of small bowel or colonic origin and/or ostomy diarrhea) 
1 
Increase of <4 stools/day over Baseline; mild increase in ostomy output compared to 
Baseline 
2 
Increase of 4-6 stools/day over Baseline; moderate increase in ostomy output 
compared to Baseline 
3 
Increase of 7 stools/day over Baseline; incontinence; hospitalization indicated; severe 
increase in ostomy output compared to Baseline; limiting self-care ADL 
4 
Life threatening consequences; urgent intervention indicated 
5 
Death 
 
Uncomplicated diarrhea is considered mild to moderate and defined as CTCAE Grade 1 to 2 
with no complicating signs or symptoms. 
Complicated diarrhea is severe and defined as CTCAE Grade 3 or 4 or Grade 1 or 2 with 1 or 
more of the following signs or symptoms: cramping, nausea/vomiting ≥ Grade 2, decreased 
performance status, fever, sepsis, neutropenia Grade 3 or 4, frank bleeding, and/or 
dehydration.  If complicated diarrhea goes unrecognized or untreated, it may lead to death. 
Experience thus far suggests that, when pazopanib is used as monotherapy, uncomplicated 
CTCAE Grade 1 or 2 diarrhea may ensue.  In rare cases, subjects treated with monotherapy 
pazopanib may develop debilitating and potentially life-threatening diarrhea with 
dehydration, renal insufficiency, and electrolyte imbalances.  The pathophysiologic 
mechanism of diarrhea with pazopanib is not known. 
The following broad general management principles are recommended as means by which a 
subject with diarrhea may avoid more serious complications. Guidelines such as these should 
never replace sound clinical judgment.  Standardized and universal guidelines have been 
developed by an American Society of Clinical Oncology (ASCO) panel for treating 
chemotherapy-induced diarrhea [Benson, 2004].  The guidance provided here is a 
modification of the ASCO guidelines. 
Early identification and intervention is critical for the optimal management of diarrhea.  
 A subject’s Baseline bowel pattern should be established so that changes in that 
pattern can be identified.   
 Subjects should be educated on the signs and symptoms of diarrhea with instructions 
to report any changes in bowel pattern to the physician. 


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 At the initiation of diarrhea, an assessment of frequency, consistency, duration and 
other symptoms such as fever, cramping pain, nausea, vomiting, dizziness and thirst 
should be taken to identify subjects at high risk of complications. 
Management Guidelines 
Uncomplicated diarrhea of CTCAE Grade 1 or 2: 
 
Hydration:  have subject drink 8 to 10 large glasses (approximately 2 liters) of clear 
non-caffeinated liquids a day (e.g., broth or electrolyte-containing sports drinks).  
 
If Grade 2 diarrhea, consider dose reduction of investigational product. 
 
Dietary modifications:  have subject stop all lactose-containing products and eat 
frequent, small meals. 
 
Pharmacologic intervention using loperamide: 
o 
Begin loperamide at initial dose of 4 mg followed by 2 mg every 4 hours or after 
every unformed stool. The recommended maximum daily dose of loperamide is 16 
mg/day. 
o 
Continuation of loperamide is suggested until diarrhea-free for 12 hours. 
o 
If mild to moderate diarrhea persists for more than 24 hours, administer loperamide 
2 mg every 2 hours and pursue evaluation for other treatable causes. 
o 
If mild to moderate diarrhea persists after 48 hours total treatment with loperamide, 
discontinue study drug(s) and consider initiation of second-line agents (lomotil, 
octreotide). 
 
Complicated diarrhea of CTCAE Grade 3 or 4 or Grade 1 or 2 with complicating 
features requires aggressive management: 
 
Subject must call study site physician immediately in response to any event of severe 
diarrhea with or without complications as listed above.  
o Hospitalization may be required for subjects most at risk for life-threatening 
complications. 
 
Interrupt investigational products until symptoms resolve; consider reintroducing at a 
reduced dose (discuss with Vector Oncology). 
 
If loperamide has not been initiated, begin loperamide usage immediately at an initial 
dose of 4 mg followed by 2 mg every 2 hours or after every unformed stool. The 
recommended maximum daily dose of loperamide is 16 mg/day. 
 
If no improvement in severity after 24-hours of maximal loperamide dosing, subject 
must visit study site and be evaluated: 


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o For dehydration, use intravenous fluids as appropriate.   
 
Antibiotic therapy should be considered in patients who present with signs and 
symptoms of bacterial diarrhea such as fever, bloody diarrhea, and presence of fecal 
leukocytes. Investigators should have a low threshold to start such treatment in patients 
with Grade 3 or Grade 4 neutropenia.  
 
Before initiation of antimicrobial therapy, stool cultures should be obtained. When 
bacterial etiology for diarrhea is suspected, study-treatment and anti-motility agents 
(loperamide or others) should be held. 
 
Intervention should be continued until diarrhea free for 24 hours. 
 
Alternative Pharmacologic Intervention for Uncomplicated and Complicated Diarrhea 
 
Lomotil (diphenoxylate 2.5 mg + atropine 0.025 mg) can be used. The recommended 
dose is 2 tablets 4 times daily. When diarrhea is under control, a dose reduction should 
be attempted. 
The synthetic octapeptide, octreotide, has been shown to be effective in the control of 
diarrhea induced by fluoropyrimidine-based chemotherapy regimens when administered as 
an escalating dose by continuous infusion or subcutaneous injection. Octreotide can be 
administered at doses ranging from 100 g twice daily to 500 g 3 times daily, with a 
maximum-tolerated dose of 2000 g 3 times daily in a 5-day regimen.  
Nausea and Vomiting 
Every attempt should be made to control nausea and vomiting in subjects who have emesis 
and are unable to retain pazopanib. 
Routine pre-medication for nausea is not necessary, but symptomatic subjects should be 
treated with standard anti-nausea/anti-emetic therapy as necessary. 
If a subject vomits after taking study medication, the subject should be instructed not to take 
a replacement dose on that same day.  The subject should resume taking pazopanib at the 
next scheduled dose on the following day.  If vomiting persists then the subject should 
contact their physician. 
To prevent or treat nausea and vomiting standard medications are recommended.  These may 
include:  
 5-HT3 receptor antagonist (granisetron, ondansetron, dolasetron mesylate);  
 NK-1 receptor antagonists such as aprepitant,  metoclopramide,  phenothiazines 
(prochlorperazine);  
 corticosteroids, (dexamethasones, prednisone); and  


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 cannabinoids (dronabinol). 
Wound Healing 
No formal studies on the effect of pazopanib on wound healing have been conducted.  Since 
vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may 
impair wound healing, treatment with pazopanib should be stopped at least 7 days prior to 
scheduled surgery.  The decision to resume pazopanib after surgery should be based on 
clinical judgment of adequate wound healing. Pazopanib should be discontinued in subjects 
with wound dehiscence. 
Overdose 
No maximum tolerated dose (MTD) was reached in the dose escalation study of pazopanib 
administered as a single agent at repeated doses of up to 2000 mg/day (Study VEG10003).  
Systemic exposure to pazopanib at steady-state appeared to plateau at doses greater than 800 
mg once daily.  Increases in the daily pazopanib dose above 800 mg in the fasted state 
resulted in a small or no increase in mean systemic exposure to pazopanib.     
A pazopanib overdose is defined as the administration of more than the protocol-specified 
dose.  Treatment of overdose of pazopanib should consist of general supportive care 
measures.  There is no specific antidote for overdosage of pazopanib.  Hemodialysis is not 
expected to enhance the elimination of pazopanib because pazopanib is not significantly 
renally excreted and is highly bound to plasma proteins.   
The Investigator must promptly report any overdose to Vector Oncology as an important 
medical event (see SAE Section 10.2.3).  Decisions regarding pazopanib dose modifications 
or interruptions will be made by the Investigator in consultation with Vector Oncology based 
on the clinical evaluation of the subject.    
Following an overdose, additional monitoring of the subject for AEs/SAEs and laboratory 
abnormalities should be considered.   
Information regarding the quantity of the excess dose, as well as the duration of overdosing, 
should be documented in the source documents and in the iCRF. 
Posterior Reversible Encephalopathy Syndrome / Reversible Posterior 
Leukoencephalopathy Syndrome 
Posterior Reversible Encephalopathy Syndrome (PRES) / Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving pazopanib 
and may be fatal.  PRES/RPLS is a neurological disorder which can present with headache, 
seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances.  Mild to 
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by magnetic resonance imaging.  Permanently discontinue pazopanib in patients developing 
PRES/RPLS. 
Thrombotic Microangiopathy 
Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as 
monotherapy, in combination with bevacizumab, and in combination with topotecan.  
Permanently discontinue pazopanib in patients developing TMA.  Reversal of effects of 
TMA has been observed after treatment was discontinued.  Pazopanib is not indicated for use 
in combination with other agents. 
6.3.2. Dose Interruptions/Modifications for Hepatotoxicity 
Note: Liver chemistry abnormalities meeting pre-defined criteria must be promptly reported 
to Vector Oncology as an important medical event (see SAE Section 10.2.3). 
Liver Chemistry Abnormalities Requiring Reporting: 
ALT > 3.0 x ULN with concomitant elevation in bilirubina (defined as total bilirubin  2.0 x ULN; with direct 
bilirubin > 35%) or with hypersensitivity symptoms (e.g., fever, rash). 
ALT > 8.0 x ULN without bilirubin elevation (defined as total bilirubina < 2.0 x ULN or direct bilirubin ≤ 
35%) and without hypersensitivity symptoms (e.g., fever, rash). 
a. 
Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject 
meets the criterion of total bilirubin > 1.5 x ULN, then the event should be promptly reported as a SAE. 
 
Guidelines for investigational product dose interruptions/modifications in case of liver-
related treatment-emergent AEs are provided in Table 7.  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.  Details on the subject’s alcohol use will be captured in the iCRF.  
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 
progression of malignancy. 
 
Table 8.  Guidelines for Management of Treatment Emergent Hepatotoxicity 
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x 
ULN 
Continue pazopanib at current dose with full panel LFTsa) monitored as per protocol. 
(B). ALT > 3.0 x ULN 
to ≤ 8.0 x ULN without 
bilirubin elevation 
Liver Event Monitoring Criteria: 
(1) Continue pazopanib at current dose levels.  
(2) Monitor subject closely for clinical signs and symptoms; perform full panel 


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Event 
Dose Modification Algorithms 
(defined as total 
bilirubinb) < 2.0 x ULN 
or direct bilirubin 
≤35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash)  
LFTsa weekly or more frequently if clinically indicated until ALT/AST is reduced 
to Grade 1. 


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Event 
Dose Modification Algorithms 
(C). ALT > 8.0 x ULN 
without bilirubin 
elevation (defined as 
total bilirubinb < 2.0 x 
ULN or direct bilirubin 
≤ 35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash) 
1st occurrence – Liver Event Interruption Criteria: 
(1) Interrupt pazopanib until toxicity resolves to  Grade 1 or Baseline.  Report the 
event to Vector Oncology as a SAE within 24 hours of learning of its occurrence 
and complete the iCRF.  Make every reasonable attempt to have subjects return to 
the clinic within 24 to 72 hours for repeat liver chemistries and liver event follow 
up assessments. 
(2) Liver imaging and other laboratory investigations should be considered as 
clinically appropriate.  
(3) Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTsa weekly or more frequently if clinically indicated until ALT/AST is reduced 
to Grade 1.   
(4) If the potential benefit for re-initiating pazopanib treatment is considered to 
outweigh the risk for hepatotoxicity, then re-introduce pazopanib at a reduced 
dose and measure serum liver tests weekly for 8 weeksc. Re-challenge may be 
considered if ALL following criteria are met:  
- ALT/AST reduced to Grade 1 
- Total bilirubin < 1.5 x ULN or direct bilirubin  35% 
- No hypersensitivity signs or symptoms 
- Subject is benefiting from therapy.  
 
Recurrence – Liver Event Stopping Criteria: 
Discontinue pazopanib permanently and monitor subject closely for clinical signs 
and symptoms; perform full panel LFTsa weekly or more frequently if clinically 
indicated until ALT/AST is reduced to Grade 1.  At the time of the recurrence, 
complete the appropriate iCRF.   
(D). ALT > 3.0 x ULN 
with concomitant 
elevation in bilirubinb) 
(defined as total 
bilirubin  2.0 x ULN; 
with direct bilirubin > 
35%) or with 
hypersensitivity 
symptoms (e.g., fever, 
rash). 
Liver Event Stopping Criteria: 
(1) Discontinue pazopanib immediately, report the event to Vector Oncology as a 
SAE within 24 hours of learning of its occurrence, and complete the appropriate 
iCRF.  Make every reasonable attempt to have subjects return to the clinic within 
24 hours for repeat liver chemistries and liver event follow up assessments. 
(2) Consult a gastroenterologist / hepatologist and perform the following 
assessments to identify potential co-factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, cytomegalovirus, Epstein-Barr virus 
(IgM antibody, heterophile antibody, or monospot testing) 
- Anti-nuclear antibody, anti-smooth muscle antibody, anti-mitochondrial 
antibody 
- Serum creatinine phosphokinase for possible muscle injury caused LFT 
elevation 
- Liver imaging 
-Consider toxicological blood screen for possible contributing chemical/medical 
entities  
(3) Monitor subject closely for clinical signs and symptoms; record the appearance 
or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia 
as relevant on the AE report form.  Perform full panel LFTsa weekly or more 
frequently if clinically indicated until LFTs are reduced to Grade 1.   
For isolated total 
bilirubinb) elevation 
without concurrent ALT 
increases (defined as 
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other 
signs/symptoms of liver injury) does not require dose modification.  Pazopanib 
inhibits UGT1A1 and OATP1B1, which can cause elevation of indirect 
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Event 
Dose Modification Algorithms 
ALT < 3 X ULN). 
 
(2) If bilirubin is > 1.5 x ULN in the absence of ALT elevation, fractionation of 
bilirubin elevation should be performed.  If the bilirubin is predominantly indirect 
(unconjugated), continue pazopanib at the same dose.  If bilirubin is > 35% direct 
(conjugated), further evaluation for underlying cause of cholestasis should be 
performed. 
a) Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.  Coagulation tests 
should be performed as clinically indicated. 
b) Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a 
subject meets the criterion of total bilirubin > 1.5 x ULN, then the event should be promptly reported as a 
SAE. 
c) Please refer to Investigator’s Brochure, Summary of Data and Guidance for Investigator, Warnings and 
Precautions, Hepatic Effects for information about rechallenge dose. 
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; iCRF internet case report form; 
LFT liver function tests; SAE serious adverse event; ULN upper limit of normal 
 
Laboratory Assessments:  Full Panel Liver Function Tests for Treatment Emergent 
Hepatotoxicity 
When full panel LFTs are conducted due to treatment emergent hepatotoxicity, this panel 
should include the following: ALT, AST, alkaline phosphatase, GGT, and total bilirubin.  A 
direct bilirubin level should be obtained if the total bilirubin level is greater than 1.5 x upper 
limit of normal (ULN).  Coagulation tests should be performed as clinically indicated.  Liver 
chemistry threshold stopping criteria and dose modification guidelines have been designed to 
assure subject safety.  Guidelines for evaluation of the LFTs are described in Table 7: 
Guidelines for Management of Treatment Emergent Hepatotoxicity. 
6.4. 
Concomitant Medications and Non-Drug Therapies 
All subjects will be asked to provide a complete list of prescription and over-the-counter 
medications they are taking at 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 30-day post-treatment Follow-up visit.   
All concomitant medications taken during the study will be recorded in the iCRF with 
indication, dose information, and dates of administration. 
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.   


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6.5. 
Prohibited and Permitted Medications During Study Treatment 
6.5.1. Prohibited Medications 
Subjects should not receive other anti-cancer therapy (cytotoxic, biologic, radiation, or 
hormonal) while on treatment in this study.  When pazopanib 800 mg was administered with 
lapatinib 1500 mg, the pazopanib AUC and Cmax increased approximately 50% to 60% 
compared with taking pazopanib alone.  Clinical trials of pazopanib in combination with 
pemetrexed (NSCLC) and lapatinib (cervical cancer) were terminated early due to concerns 
over increased toxicity and/or mortality, and a safe and effective combination dose has not 
been established with these regimens.  Pazopanib is not indicated for use in combination with 
other agents. 
Subjects should avoid grapefruit and grapefruit juice while receiving treatment in this 
study.  Plasma pazopanib concentrations may be elevated, increasing the pharmacologic 
effects and risk of adverse reactions. 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations, 
increasing the pharmacologic effects and risk of adverse reactions.  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 treatment.  Strong CYP3A4 
inhibitors include (but are not limited to): 
 Antibiotics: clarithromycin, telithromycin, troleandomycin 
 HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir, atazanavir) 
 Antifungals:  itraconazole, ketoconazole, voriconazole, fluconazole 
 Antidepressants:  nefazodone 
Medications that inhibit permeability glycoprotein (P-gp) may result in increased plasma 
pazopanib concentrations, increasing the pharmacologic effects and risk of adverse reactions.  
Therefore, concomitant administration of strong P-gp inhibitors is PROHIBITED beginning 
14 days prior to the first dose of study drug until discontinuation from the study treatment.  
Strong P-gp inhibitors include (but are not limited to): 
 Antiarrhythmics: amiodarone, dronedarone, quinidine, verapamil 
 Antibiotics: clarithromycin 
 Antifungals:  itraconazole, ketoconazole 
 Immune modulators: cyclosporine, tacrolimus 


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In general, as far as pazopanib is concerned, subjects should not receive any other 
investigational drug within 15 days of the last dose of pazopanib and until end of treatment 
blood draws are completed. 
6.5.2. Permitted Medications – Use with Caution 
Although acetaminophen at doses of  2 g/day is permitted, it should be used with 
caution in subjects with impaired liver function. 
Specific recommendations regarding the use of simvastatin and other statins: 
Concomitant use of pazopanib and simvastatin (Zocor) increases the risk of ALT elevations 
and should be undertaken with caution and close monitoring.  If a subject receiving 
concomitant simvastatin develops ALT elevations, follow the Guidelines for Management of 
Treatment Emergent Hepatotoxicity and discontinue simvastatin.  Insufficient data are 
available to assess the risk of concomitant administration of alternative statins and 
pazopanib. 
Specific recommendations regarding drugs that raise gastric pH: 
In a drug interaction trial in patients with solid tumors, concomitant administration of 
pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of 
pazopanib by approximately 40% (AUC and Cmax).  Therefore, concomitant use of pazopanib 
with drugs that raise gastric pH should be avoided.  If such drugs are needed, short-acting 
antacids should be considered in place of PPIs and H2 receptor antagonists.  Pazopanib 
should be administered at least 1 hour before or 2 hours after administration of short-acting 
antacids. 
Specific recommendations regarding anticoagulants: 
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).  Subjects taking concomitant anticoagulant therapy should 
be monitored regularly for changes in relevant coagulation parameters as clinically indicated, 
as well as for any clinical bleeding episodes. 
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 
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blood sugar have been recently reported in subjects treated with another small molecule 
tyrosine kinase inhibitor, sunitinib [Billemont, 2008].  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. 
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): 
 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, propafenone (potential 
increased risk for QT interval prolongation and Torsade de Pointes) 
 Immune modulators: sirolimus (potential increased risk for nephrotoxicity and 
neurotoxicity) 
 Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 


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In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 
with IC50 of 1.2 and 0.79 µM, respectively.  Pazopanib may increase concentrations of drugs 
primarily eliminated through UGT1A1 and OATP1B1. 
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, 
increasing the pharmacologic effects and risk of adverse reactions.  Co-administration of 
strong CYP3A4 inhibitors is prohibited (see Section 6.5.1 Prohibited Medications); therefore, 
selection of an alternate concomitant medication with no or minimal potential to inhibit 
CYP3A4 is recommended.  
Medications that inhibit P-gp may result in increased plasma pazopanib concentrations, 
increasing the pharmacologic effects and risk of adverse reactions.  Co-administration of 
strong P-gp inhibitors is prohibited (see Section 6.5.1 Prohibited Medications); therefore, 
selection of an alternate concomitant medication with no or minimal potential to inhibit P-gp 
is recommended. 
CYP3A4 inducers may reduce plasma pazopanib concentrations, decreasing the efficacy.  
Selection of an alternate concomitant medication with no or minimal enzyme induction 
potential is recommended.  Pazopanib should not be given to patients who cannot avoid long-
term use of strong CYP3A4 inducers.  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, carbamazepine, phenobarbital, oxcarbazepine 
 HIV antivirals:  efavirenz, nevirapine 
 Antibiotics:  rifampin (rifampicin), rifabutin, rifapentine 
 Miscellaneous:  St. John’s Wort, modafinil, pioglitazone, troglitazone 
7. 
STUDY ASSESSMENTS 
A Time and Events Schedule is provided in Appendix 1.  During the treatment portion of the 
study, a visit window of +/- 3 business days is allowed.  Assessments may be performed 
within 3 business days before the actual visit to allow flexibility in scheduling with the 
exception of the BP measurements required at Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 


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22, Cycle 2 Day 15, and Cycle 3 Day 15, which have a window of +/- 1 business day.  Other 
vital signs are not required at these time points, and BP can be assessed by any method (e.g., 
at home or by another physician) as long as the Investigator is informed of the measurement, 
verifies any measurement that is not normal, and takes appropriate action. 
7.1. 
Screening Assessments 
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.  Procedures conducted as part of the subject’s 
routine clinical management (e.g., blood count, imaging study) and obtained prior to signing 
of informed consent may be utilized for Screening purposes provided these procedures are 
conducted as specified in the protocol.  The study assessment schedules and visit windows 
are summarized in the Time and Events Schedule (Appendix 1). 
Screening assessments must be conducted within the specified time frame prior to start of 
protocol therapy and will include the following:   
 
obtain written informed consent within 28 days prior to start of protocol therapy; 
 
record demographics and medical and disease history within 28 days prior to start of 
protocol therapy.  (Disease history must include date of diagnosis, prior treatment [i.e., 
chemotherapy, surgery, radiotherapy], and if applicable sites of metastases.  Medical 
history must include documentation about alcohol use and note if the subject is hepatitis 
B or C positive.); 
 
perform serum pregnancy test for WOCBP within 7 days prior to start of protocol 
therapy; 
 
perform FSH and estradiol to assess childbearing potential, if applicable (see Section 
5.1, Inclusion Criterion # 10) within 14 days prior to start of protocol therapy; 
 
perform physical examination, vital signs [blood pressure, temperature, and pulse], 
weight, and ECOG performance status within 14 days prior to start of protocol therapy 
(If Screening physical exam is performed within 7 days prior to start of protocol therapy, 
the Cycle 1 Day 1 physical exam is not required.); 
Note:  At the Screening visit, blood pressure should be measured three times at 
approximately 2-minute intervals. All three blood pressure values should be recorded 
on the iCRF. These three values should be averaged to obtain mean diastolic blood 
pressure and mean systolic blood pressure. The mean diastolic and the mean systolic 
blood pressures are to be used to determine if the subject’s blood pressure is within 
the well-controlled range; or if the subject needs medical attention.  
At all later visits, a single blood pressure is measured. If both the systolic and the 
diastolic blood pressure is within the well- controlled range (defined as blood 
pressure below 140/90 mmHg) this value is recorded on the iCRF. If either the 
systolic or the diastolic pressure is outside the well-controlled range, three blood 
pressures are measured as described for the Screening visit and the mean blood 


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pressure values are entered on the iCRF and used to determine if the subject needs 
medical attention. 
 
perform CT chest, abdomen, and pelvis or PET/CT scan within 28 days prior to start of 
protocol therapy; 
 
perform CNS imaging studies (CT or MRI) if clinically indicated or if subject has a 
history of CNS metastases within 28 days prior to start of protocol therapy; 
 
document target and non-target lesions to be followed by RECIST guidelines during 
study within 28 days prior to start of protocol therapy; 
 
perform complete blood count (CBC) with differential within 14 days prior to start of 
protocol therapy;  
 
perform comprehensive metabolic panel (CMP) including magnesium and phosphorus 
within 14 days prior to start of protocol therapy; 
 
calculate creatinine clearance (if serum creatinine is > 1.5 mg/dL) using Cockcroft and 
Gault method within 14 days prior to start of protocol therapy (see Appendix 3); 
 
calculate UPC ratio and if applicable obtain 24-hour urine protein within 14 days prior to 
start of protocol therapy (see Appendix 4); 
 
perform PT/INR and PTT within 14 days prior to start of protocol therapy; 
 
perform TSH and Lipase within 14 days prior to start of protocol therapy; 
 
perform 12-lead EKG with documented QTc measurement using Bazett’s formula 
within 28 days prior to start of protocol therapy.  If the QTc interval is > 480 msecs 
using Bazett’s formula, then 2 additional EKGs must be obtained over a brief period of 
time (e.g., within 15-20 minutes) to confirm the abnormality.  The average QTc interval 
will be determined from the 3 EKG tracings by manual evaluation and will be used to 
determine if the subject will be excluded from the study.  If the average QTc interval is > 
480 msec, then the subject is not eligible to participate in the study (see Section 7.3.4).; 
 
perform ECHO or MUGA with documented LVEF measurement within 28 days prior to 
start of protocol therapy (see Section 7.3.5); 
 
record concomitant medications within 14 days prior to start of protocol therapy 
ensuring adequate washout of prohibited medications, if necessary (see Section 6.5.1). 
7.2. 
Efficacy Assessments 
Tumor response will be assessed using RECIST guidelines version 1.1.  Subjects will be 
staged for response after every 2 cycles of treatment at the end of Cycles 2, 4, 6, 8, etc. 
(approximately every 8 weeks).  Imaging should be conducted at the end of the indicated 
cycles or prior to treatment on Day 1 of the next cycle (3, 5, 7, 9, etc.) taking into account 
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Repeat imaging should include all affected areas by CT or PET/CT and any other appropriate 
imaging studies.  Contrast should be used for all scans unless contraindicated.  Confirmation 
of PR or CR is required by repeat measurements that should be performed 4 weeks after the 
criteria for response are first met.  EOT tumor assessments should be made within 30 days of 
study treatment discontinuation.  Subjects may continue study treatment in the absence of 
disease progression or unacceptable toxicity.    
7.2.1. Tumor Measurement 
The procedures for solid tumor measurement are as follows: 
 
Measurable disease:  the presence of at least one measurable lesion.  If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
 
Measurable lesions: lesions that can be accurately measured in at least one dimension 
(the longest diameter), and with a minimum size of 10 mm by CT scan, or 10 mm by 
caliper measurement during clinical exam, or 20 mm by chest X-ray. 
o A malignant lymph node may be considered pathologically enlarged and 
measurable if it is  15 mm in short axis by CT scan. 
o A lytic or mixed blastic-lytic bone lesion, with identifiable soft tissue component 
which is evaluable by CT or MRI, may be considered as measurable lesion if the 
soft tissue component meets the criteria for measurable lesions. 
o Cystic metastases may be considered as measurable lesions if they meet the 
criteria for measurable lesions, however, non-cystic lesions, if present, are 
preferred as target lesions. 
o Tumor lesions in an area previously subjected to loco-regional treatment, may be 
considered measurable if there has been demonstrated progression.  
 
Non-measurable lesions: all other lesions, including simple cysts, small lesions (longest 
diameter < 10 mm or pathological lymph nodes with  10 to < 15 mm short axis) and 
other truly non-measurable lesions. These include: leptomeningeal disease; ascites; 
pleural/pericardial effusion; inflammatory breast disease; lymphangitis cutis/pulmonis; 
abdominal masses that are not measurable by reproducible imaging techniques; blastic 
bone lesions.  
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All Baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at Baseline and during Follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
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Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes), and > 10 mm diameter using calipers.  In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended. 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint.  The measurability of lesion by CT scan is based on the assumption that CT slice 
thickness is < 5 mm.   
7.2.2. Baseline Documentation of Target and Non-target Lesions 
 
When more than one measurable lesion is present at Baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and recorded and measured 
at Baseline. 
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter) and their suitability for accurate repetitive measurements (either by imaging 
techniques or clinically). 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the Baseline sum diameters. The 
Baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at Baseline. Measurements 
are not required and these lesions should be followed as ‘present’ ‘absent’, or in rare 
cases ‘unequivocal progression’. Multiple non-target lesions involving the same organ 
may be recorded as a single item. 
7.2.3. Response Criteria 
Response and progression will be evaluated in this study using RECIST guidelines version 
1.1 [Eisenhauer, 2009].   
7.2.3.1. 
Evaluation of Target Lesions 
The criteria for evaluating target lesions are summarized in Table 8. 


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Table 9. Response Criteria for Target Lesions 
Response Category 
Criteria 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph nodes 
must have reduction in short axis to < 10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of the target lesions 
taking as reference the Baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of the target lesions 
taking as reference the smallest sum on study, and an absolute increase 
of at least 5 mm. The appearance of one or more new lesions is also 
considered progression. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum diameters while 
on the study. 
 
7.2.3.2. 
Evaluation of Non-target Lesions 
The criteria for evaluating non-target lesions are summarized in Table 9. 
Table 10. Response Criteria for Non-target Lesions 
Response Category 
Criteria 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological (< 10 mm 
short axis). 
Non-complete Response  
(non-CR)/Non-progression 
(non-PD): 
Persistence of one or more non-target lesion(s) or/and maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD): 
Unequivocal appearance of one or more new malignant lesions. 
Unequivocal progression of existing non-target lesions. Although a 
clear progression of non-target lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail 
and the progression status should be confirmed later on by a review 
panel or study chair/primary Investigator. 
 
Note:  If tumor markers are initially above the ULN, they must normalize for a subject to be 
considered in complete clinical response. 


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7.2.3.3. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  In general, the subject’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
Table 10 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at Baseline. When subjects have non-measurable 
(therefore non-target) disease only, Table 11 should be used. 
 
Table 11. Evaluation Criteria for Best Overall Response: Subjects with Target Disease, with or 
without Non-target Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD or not at all 
evaluated 
No 
PR 
SD 
Non-PD or not at all 
evaluated 
No 
SD 
Not at all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; Non-CR = non-complete response; Non-PD = non-progression; 
PR = partial response; SD = stable disease; PD = progressive disease 
 


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Table 12. Evaluation Criteria for Best Overall Response: Subjects with Non-target Disease 
Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not at all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; Non-CR = non-complete response; Non-PD = non-progression; 
PR = partial response; SD = stable disease; PD = progressive disease 
a 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
 
 When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  
 Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. FDG-PET may be used to upgrade a response to 
a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality 
is thought to represent fibrosis or scarring. 
 For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
7.2.3.4. 
Confirmation 
 
In non-randomized trials where response is the primary endpoint, confirmation of PR or 
CR must be confirmed by repeat measurements that should be performed no less than 
4 weeks after the criteria for response are first met. 
 
In randomized trials or studies where the primary endpoints are stable disease or 
progression, confirmation of response is not required. Elimination of the requirement for 


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response confirmation may increase the importance of central review to protect against 
bias, particularly in studies which are not blinded.  
 
In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 6-8 weeks. 
7.3. 
Safety Assessments 
The definitions for an AE and SAE and the procedures for collecting and reporting these 
events are provided in Section 10.  Toxicities will be graded using the Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) (see 
http://ctep.cancer.gov/reporting/ctc.html). 
7.3.1. Laboratory Tests During Treatment 
Laboratory tests will be performed as indicated in the Time and Events Schedule (Appendix 
1).  
Participating sites will use their local laboratory to perform all clinical laboratory 
assessments.  Laboratory tests will be performed during Screening, at specified visits during 
study treatment, and at the end of treatment visit, all as specified in the Time and Events 
Schedule.  Laboratory assessments may be performed within 3 business days before the 
actual visit to allow flexibility in scheduling.  These assessments may be performed more 
frequently if clinically indicated. 
Hematology and Chemistry 
A complete blood count (CBC) with differential, a comprehensive metabolic panel (CMP), 
phosphorus, and magnesium will be assessed on Day 1 of each cycle (approximately every 4 
weeks).  
A separate liver function test (LFT) panel will be assessed on Day 15 of Cycle 1 and Cycle 2.  
This panel must include ALT, AST, and bilirubin. 
Full Panel Liver Function Tests for Treatment Emergent Hepatotoxicity 
When full panel LFTs are conducted due to treatment emergent hepatotoxicity, this panel 
should include the following: ALT, AST, alkaline phosphatase, GGT, and total bilirubin.  A 
direct bilirubin level should be obtained if the total bilirubin level is greater than 1.5 x upper 
limit of normal (ULN).  Coagulation tests should be performed as clinically indicated.  Liver 
chemistry threshold stopping criteria and dose modification guidelines have been designed to 
ensure subject safety.  Guidelines for interpretation of LFT values are described in Section 
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Evaluation of Protein 
Proteinuria will be evaluated using the urine protein to creatinine ratio (UPC) as described in 
Appendix 4.  UPC will be assessed on Day 1 of each cycle (approximately every 4 weeks).   
If UPC > 3, then the dose modification table guidelines should be followed (see Section 
6.3.1, Table 7). 
Thyroid Stimulating Hormone 
Thyroid function tests to assess thyroid stimulating hormone (TSH) will be assessed after the 
first 2 cycles of treatment and then after every 4 cycles of treatment on Day 1 of Cycles 3, 7, 
11, 15, etc. (approximately every 16 weeks). 
Lipase 
Lipase will be assessed after the first 2 cycles of treatment and then after every 4 cycles of 
treatment on Day 1 of Cycles 3, 7, 11, 15, etc. (approximately every 16 weeks). 
7.3.2. Physical Examinations 
Physical examinations will be performed on Day 1 of each cycle (approximately every 4 
weeks).  If Screening physical exam is performed within 7 days prior to start of protocol 
therapy, the Cycle 1 Day 1 physical exam is not required. 
Physical examinations will be performed per standard clinical practice and should, at least, 
include head, eyes, ears, nose, throat, neck, chest, heart, abdomen, skin, and nodes (cervical, 
axillary, inguinal) with other areas examined as clinically indicated. 
7.3.3. Vital Signs, Weight, and Performance Status 
Vital signs, weight, and ECOG performance status will be assessed on Day 1 of each cycle 
(approximately every 4 weeks).  Vital sign measurements will include pulse, temperature, 
and blood pressure.  For ECOG performance status, refer to Appendix 2.  
As hypertension is a common drug-related AE observed from other pazopanib studies, blood 
pressure monitoring is mandatory.  Blood pressure must be monitored weekly during Cycle 1 
and every 2 weeks during Cycles 2 and 3.  Note that only a BP measurement is required at 
Cycle 1 Day 8 (+/- 1 business day), Cycle 1 Day 15 (+/- 1 business day), Cycle 1 Day 22 (+/- 
1 business day), Cycle 2 Day 15 (+/- 1 business day), and Cycle 3 Day 15 (+/- 1 business 
day).  Other vital signs are not required at these time points, and BP can be assessed by any 
method (e.g., at home or by another physician) as long as the Investigator is informed of the 
measurement, verifies any measurement that is not normal, and takes appropriate action.   
After Cycle 3, if BP is controlled (defined as blood pressure below 140/90 mmHg), then BP 
may be monitored once monthly.  After Cycle 3, if BP is uncontrolled (defined as blood 


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pressure > 140/90 mmHg), then continue with every 2 week monitoring or more frequently if 
clinically indicated. 
The following instructions must be followed for cuff measurement of blood pressure: 
Sitting blood pressure should be measured after the subject has been sitting quietly for at 
least 10 minutes.  The same cuff method should be used to measure blood pressure 
throughout the study.  All measurements will be made on the same arm using the same cuff 
size and the same equipment.  Diastolic blood pressure will be measured at the disappearance 
of Korotkoff sounds - phase V.  If possible, measurements will be taken by the same staff 
member at each visit.  
At the Screening visit, blood pressure should be measured three times at approximately 2-
minute intervals.  All three blood pressure values should be recorded on the iCRF. These 
three values should be averaged to obtain mean diastolic blood pressure and mean systolic 
blood pressure. The mean diastolic and the mean systolic blood pressures are to be used to 
determine if the subject’s blood pressure is within the well-controlled range; or if the subject 
needs medical attention.   
At all later visits, a single blood pressure is measured.  If both the systolic and the diastolic 
blood pressure is within the well-controlled range (defined as blood pressure below 140/90 
mmHg) this value is recorded on the iCRF.  If either the systolic or the diastolic pressure is 
outside the well-controlled range, three blood pressures are measured as described for the 
Screening visit and the mean blood pressure values are entered on the iCRF and used to 
determine if the subject needs medical attention. Refer to Section 6.3.1, Table 7 for the 
algorithm of dose modification of study medication in the event that hypertension occurs. 
7.3.4. 12-lead Electrocardiogram 
In clinical studies of pazopanib, events of QT prolongation have occurred.  A 12-lead EKG 
will be obtained on all subjects at the end of Cycle 1, and then after every 4 cycles of 
treatment at the end of Cycles 5, 9, 13, 17, etc. (approximately every 16 weeks).  EKGs may 
be performed before the start of treatment on Day 1 of the next cycle as long as results are 
available prior to treatment. 
QTc must be measured using the Bazett’s formula and the result documented.  Additional 
EKGs should be done at the Investigator’s discretion to ensure the subject’s safety, and in 
case the subject experiences a non-study drug treatment modification with a potentially QT 
prolonging medication.  
Prior to each EKG test, the subject should be at rest for approximately 10 minutes.  The 
subject should be in the semi-recumbent or supine position; the same position must be used 
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All EKGs must include QTc measurements either manually or machine calculated using 
Bazett’s formula, and recorded in the iCRF.  The Bazett’s formula is: 
QTcB (msec) = QT interval (msec) / √(RR interval) 
Screening/Baseline 
If the QTc interval is > 480 msecs using Bazett’s formula, then 2 additional EKGs must be 
obtained over a brief period of time (e.g., within 15-20 minutes) to confirm the abnormality.  
The average QTc interval will be determined from the 3 EKG tracings by manual evaluation 
and will be used to determine if the subject will be excluded from the study.  If the average 
QTc interval is > 480 msec, then the subject is not eligible to participate in the study. 
During Treatment 
If a QTc > 500 msec is noted on a scheduled or unscheduled EKG, then 2 additional EKGs 
must be obtained over a brief period of time (e.g., within 15-20 minutes) to confirm the 
abnormality.  Each EKG tracing must be evaluated manually to obtain RR and QT intervals 
for QTc calculation.  The average QTc will be determined from the 3 EKG tracings by 
manual evaluation and will be used to determine appropriate next steps.  If the average QTc 
is ≤ 500 msec, the subject may continue therapy.   
If the average QTc is > 500 msec, the following steps must be taken: 
 Study treatment must be interrupted immediately. 
 Electrolytes, particularly potassium and magnesium, must be checked and corrected if 
abnormal. 
 Concomitant medications with a potential for QTc interval prolongation must be 
discontinued if clinically appropriate. 
 The subject must be treated appropriately for QTc prolongation and monitored until 
resolution is documented by a repeat EKG with QTc interval returning to ≤ 480 msec. 
 Communicate findings to Vector Oncology. 
NOTE: If the QTc prolongation > 500 msec is clearly and causally associated with an 
underlying situation that is clearly reversible (e.g., a subject with severe diarrhea and 
hypokalemia with QTc prolongation that resolves once the diarrhea improves and potassium 
is corrected), then the subject may restart study drug once the underlying situation has been 
corrected (e.g., electrolytes supplemented), the QTc interval prolongation has resolved, and a 
discussion with Vector Oncology has taken place.   


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If the QTc prolongation > 500 msec is not clearly and causally associated with an underlying 
situation that is clearly reversible, then the subject must have study drug permanently 
discontinued and be removed from the treatment portion of the study. 
7.3.5. ECHO or MUGA 
An ECHO or MUGA is required at the end of Cycle 3 for all subjects.     
After Cycle 3, if BP is controlled (defined as blood pressure below 140/90 mmHg) and left 
ventricular ejection fraction (LVEF) is within institutional normal range, then repeat ECHO 
or MUGA per treating Investigator’s discretion as clinically indicated.   
After Cycle 3, if BP is uncontrolled (defined as blood pressure > 140/90 mmHg) or LVEF is 
abnormal, an ECHO or MUGA must be repeated after every 3 cycles of treatment.   
The ECHO or MUGA may be done before the start of treatment on Day 1 of the next cycle 
as long as results are available prior to treatment.   
To enable comparison, the same assessment method must be used throughout the study.  
8. 
REMOVAL OF SUBJECTS FROM TREATMENT OR THE 
STUDY 
Subjects who do not start study treatment, but who sign the informed consent and undergo at 
least some of the Screening procedures will be considered Screening failures.  Screening 
information on any subject who signs the informed consent must be entered into the EDC. 
8.1. 
Criteria for Removal from Treatment 
The criteria for stopping therapy are as follows: 
 
Interruption in pazopanib administration for more than 28 days for any reason. 
 
Permanent discontinuation of pazopanib for any reason.  
 
Substantial noncompliance with the requirements of the study. 
 
Progression of the underlying cancer. 
 
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of 
the Investigator, indicates that continued treatment with study therapy is not in the best 
interest of the subject. 
 
Excessive toxicity despite dose reduction. 
 
Request by the subject or a legal representative/relative to stop the treatment. 
 
At the specific request of the Sponsor (Vector Oncology). 
 
Pregnancy 


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o All WOCBP should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation.  Institutional policy and local regulations should determine 
the frequency of on-study pregnancy tests for WOCBP enrolled in the study. 
o The Investigator must immediately notify Vector Oncology in the event of a 
confirmed pregnancy in a subject participating in the study. 
 
The subject uses illicit drugs or other substances that may, in the opinion of the 
Investigator, have a reasonable chance of contributing to toxicity or otherwise interfering 
with results. 
 
The development of a second malignancy that requires treatment, which would interfere 
with this study. 
 
The subject is lost to Follow-up. 
 
Development of an intercurrent illness or situation which would, in the judgment of the 
Investigator, affect assessments of clinical status and study endpoints to a significant 
degree. 
8.2. 
Criteria for Removal from Study 
Subjects will be removed from study treatment when any of the criteria listed in Section 8.1 
applies.  The subject should be entered into the Follow-up portion of the study unless the 
subject withdraws consent for Follow-up.  The Investigator should ensure that all subjects are 
followed every three months after discontinuing study treatment. 
The reason for study removal and the date the subject was removed must be documented in 
the subject’s source documents and in the iCRF. 
8.3. 
Procedures for End of Treatment and Follow-up 
The Investigator will make every reasonable effort to keep each subject in the study unless it 
is in the subject’s best interests to discontinue participation.  If a subject is removed from 
treatment or declines further participation, all End of Treatment evaluations should be 
performed if the subject is willing and able to be assessed (see Appendix 1 for the Time and 
Events Schedule).  The End of Treatment evaluations must be performed within 30 days of 
the subject discontinuing study treatment.  A description of the reason(s) for discontinuation 
from the study treatment must be recorded in the subject’s source documents and in the 
iCRF. 
Relevant visit data should be entered in the iCRF and any unused study medication will be 
accounted for and returned for all subjects participating in the study, even for a brief period 
of time.   
In general, as far as pazopanib is concerned, subjects should not receive any other 
investigational drug within 15 days of the last dose of pazopanib and until end of treatment 
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If any subject should die during the trial or within 30 days of stopping study treatment, the 
Investigator will inform Vector Oncology as soon as possible.  The cause of death should be 
recorded in detail on the SAE Report Form. 
After the end of treatment (whatever the reason for discontinuation), the subject will be 
followed for at least 30 days, during which time all procedures for the reporting of SAEs will 
be followed.  The 30-day safety Follow-up may be completed via a phone call, and it must be 
documented in the subject’s source documents. 
All subjects who discontinue treatment secondary to an AE should be followed until 
resolution, stabilization or return to a Baseline condition.  Subjects who discontinue 
treatment without documented tumor progression should be evaluated for extent of disease at 
the time of treatment discontinuation. 
Subjects will be in long-term Follow-up for 6 months.  These Follow-ups may be completed 
via a phone call, and they must be documented in the subject’s source documents.  Subjects 
who discontinue treatment due to disease progression will have Follow-ups conducted every 
3 months for survival for six months.    Subjects who discontinue treatment due to reasons 
other than disease progression will have Follow-ups conducted every 3 months to assess 
disease status.  During Follow-up, repeat imaging should be performed per the treating 
Investigator’s discretion, and assessment of the subject’s disease status should be based upon 
the most current information available at the time the Follow-up is due.  Once the subject has 
experienced disease progression, (s)he will be followed every 3 months for survival for six 
months.. 
The Investigator should ensure that all subjects are followed for disease status (as applicable) 
and survival status every 3 months for six months with the first Follow-up due 3 months from 
the date the 30-day safety Follow-up was completed.  
9. 
INVESTIGATIONAL PRODUCT 
9.1. 
Description of Investigational Product 
Pazopanib monohydrochloride salt is supplied as aqueous film-coated tablets containing 200 
mg or 400 mg of the free base of clinical supply.  The 200-mg and the 400 mg tablets are 
oval-shaped and white in color.  Refer to the pazopanib IB for information regarding the 
physical and chemical properties of pazopanib and a list of excipients. 
 
Votrient commercial available supply with auxiliary label will be also provided to the Central 
Pharmacy by Novartis.     All bottles are made of high-density polyethylene and have a child-
resistant closure. The study drug should be administrated and stored according to the 
instructions specified on the drug labels (refer to label, P I, and IB for detailed information). 
 


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9.1.1. Dosage and Administration 
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-
fold increase in area under the plasma drug concentration curve (AUC) and maximum 
observed plasma drug concentration (Cmax). 
Pazopanib should be taken orally without food at least one hour before or two hours after a 
meal. The tablets should be swallowed whole and must not be crushed or broken. The time of 
day the tablets are taken should be relatively consistent.  
If a dose is missed, the subject should take the dose as soon as possible, but only if there are 
12 or more hours remaining before the next dose is due.  If the next dose is due in less than 
12 hours, the subject should skip the missed dose and take the next dose as scheduled. 
If vomiting occurs after taking pazopanib, the subject should not take a replacement dose on 
that day because it is not possible to determine how much pazopanib has actually been 
absorbed.  The subject should resume taking pazopanib at the next scheduled dose on the 
following day.  If vomiting persists, the subject should be instructed to notify the 
Investigator. 
Refer to Section 6.5 Prohibited and Permitted Medications During Study Treatment. 
9.1.2. Dispensing 
It is the responsibility of the Investigator to ensure that pazopanib is only dispensed to study 
subjects.  Pazopanib must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper 
number of 200 mg tablets to the subject to satisfy dosing requirements for the study.  The 
containers provided to the subject should be labeled with proper instructions for use.  The lot 
numbers, dosing start dates and the number of tablets for each dosage  must be recorded on 
the drug accountability pages of record for the site.   
The subject will complete a pazopanib diary throughout study participation and must be 
instructed to return all empty bottles and all unused pazopanib in the provided packaging at 
each subsequent visit. 
9.2. 
Drug Ordering and Accountability 
9.2.1. Initial Orders and Resupply Requests 
Pazopanib will be provided to the Central Pharmacy by Novartis.  Participating sites should 
request pazopanib from the Central Pharmacy by completing the Investigational Product 


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Request Form and faxing it to the fax number provided on the form.  Pazopanib will not be 
automatically resupplied. 
9.2.2. Accountability 
It is the responsibility of the Investigator to ensure that a current record of pazopanib 
disposition is maintained at each study site where pazopanib are inventoried and disposed.  
Records or logs must comply with applicable regulations and guidelines, and should include: 
 
Amount received and placed in storage area.  
 
Amount currently in storage area. 
 
Label identification (ID) number or batch number and use date or expiry date. 
 
Dates and initials of person responsible for pazopanib inventory entry/movement. 
 
Amount dispensed to and returned by each subject, including unique subject identifiers. 
 
Amount transferred to another area/site for dispensing or storage. 
 
Non-study disposition (e.g., lost, wasted, broken). 
 
Amount returned to Central Pharmacy, if applicable. 
 
Amount destroyed at study site, if applicable. 
Pazopanib dispensing record/inventory logs and copies of signed packing lists must be 
maintained at the investigational site.  Label ID numbers or batch numbers for pazopanib 
must be recorded in the drug accountability records. 
Periodic drug accountability visits will be conducted by a Vector Oncology representative. 
9.2.3. Destruction 
It is the Investigator’s responsibility to ensure that arrangements have been made for disposal 
and that procedures for proper disposal have been established according to applicable 
regulations, guidelines, and institutional procedures.  Appropriate records of the disposal 
must be maintained.  
10. 
ADVERSE EVENTS 
Toxicities will be recorded as AEs in the subject’s source documents and on the Adverse 
Event iCRF and must be graded using the CTCAE v4.0. 
10.1. 
Definitions 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have to have a 


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causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of pazopanib whether or not considered related to pazopanib. 
Events meeting the definition of an AE include: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., EKGs, radiological scans, vital signs measurements), 
including those that worsen from Baseline, and are felt to be clinically significant in the 
medical and scientific judgment of the Investigator. 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after investigational product administration even 
though it may have been present prior to the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication. 
 
Events that do not meet the definition of an AE include: 
 
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.  
 
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. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
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. 
During clinical trials, AEs can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject.  (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more AEs.) 
Serious Adverse Event 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or side 
effect, regardless of the Investigator or Sponsor’s opinion on the relationship to 


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investigational product.  This includes, but may not be limited to, any event that (at any 
dose): 
 
Is fatal. 
 
Is life threatening (places the subject at immediate risk of death). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
(Note that complications that occur during hospitalization are AEs unless the 
complication prolongs hospitalization or fulfills any other serious criteria.) 
 
Is a persistent or significant disability/incapacity. 
 
Is a congenital anomaly/birth defect. 
 
All liver chemistry abnormalities meeting pre-defined criteria must be reported as SAEs. 
 
A hospitalization meeting the regulatory requirement for the “serious” criteria is any 
inpatient hospital admission that includes a minimum of an overnight stay in a health 
care facility. 
 
Any event that does not exactly meet this definition yet, in the Investigator’s opinion 
represents a significant hazard can be assigned the “other significant hazard” regulatory 
reporting serious criteria. 
 
Additionally, important medical events that may not be immediately life threatening or 
result in death or hospitalization but that may jeopardize the subject or require 
intervention to prevent one of the outcomes listed above, or result in urgent 
investigation, may be considered serious.  Examples include allergic bronchospasm, 
convulsions, and blood dyscrasias.  For reporting purposes, also consider the 
occurrences of pregnancy or overdose (regardless of adverse outcome) as events 
which must be reported as important medical events. 
 
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. 
10.2. 
Reporting Procedures for Adverse Events 
10.2.1.  All Adverse Events 
All AEs occurring after the start of study treatment observed by the Investigator or reported 
by the subject (whether or not attributed to pazopanib), will be reported on the iCRF.   
Medically significant AEs considered related to the investigational product by the 
Investigator or the Sponsor will be followed until resolved or considered stable.  The 


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Investigator must assign the following attributes:  description; dates of onset and resolution; 
severity; assessment of relatedness to investigational product, and action taken.  The 
Investigator may be asked to provide follow-up information. 
If any subject should die during the trial or within 30 days of stopping study treatment, the 
Investigator will inform Vector Oncology as soon as possible.  The cause of death should be 
recorded in detail on the SAE Report Form. 
Vector Oncology will notify the central IRB of IND Safety reports received from Novartis, if 
applicable.  The site will be responsible for reporting SAEs occurring at the site to the 
applicable IRB per the IRB’s reporting guidelines.  Sites that are required to utilize a local 
IRB will be responsible for their own local IRB submissions.   
It will be left to the Investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the subject’s removal from treatment.  A subject may also voluntarily 
discontinue treatment due to what he or she perceives as an intolerable AE.  If either of these 
occurs, the subject must undergo an end-of-treatment visit and be given appropriate care 
under medical supervision until symptoms cease or the condition becomes stable and returns 
for a safety Follow-up visit.  If the subject was permanently removed from the study or 
investigational product due to an SAE, this information must be included in either the initial 
or follow-up SAE Report Form and in the End of Treatment iCRF. 
10.2.2. Relationship to Study Drug 
The following categories and definitions of causal relationship to study drug should be 
considered: 
 
Certain: There is a known causal relationship between the study drug and the AE/SAE.  
The event responds to withdrawal of study drug (dechallenge), and recurs with 
rechallenge when clinically feasible. (>95% certainty of relatedness). 
 
Probable: There is reasonable causal relationship between the study drug and the 
AE/SAE.  The event responds to dechallenge. Rechallenge is not required. (65%-95% 
probability of relatedness). 
 
Possible: There is reasonable causal relationship between the study drug and the AE/ 
SAE.  Dechallenge information is lacking or unclear. (35%-65% probability of 
relatedness). 
 
Not likely: There is temporal relationship to study drug administration, but there is not a 
reasonable causal relationship between the study drug and the AE/SAE. (5-35% 
probability of relatedness). 
 
Not related: There is not a temporal relationship to study drug administration (too early, 
or late, or study drug not taken), or there is known causal relationship between the 
AE/SAE and another drug, concurrent disease, or other circumstance. (<5% chance of 
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10.2.3. Serious Adverse Events 
Site responsibility: 
Serious adverse events, overdoses, pregnancies, and liver chemistry abnormalities meeting 
pre-defined criteria must be reported immediately* to Vector Oncology via the SAE Report 
Form: 
 
Vector Oncology 
 
6555 Quince Road, Suite 400 
 
Memphis, TN  38119 USA 
 
Fax:  901-259-8292 
 
E-mail address: Safety@vectoroncology.com 
 
United Kingdom only: *Reporting “immediately” is clarified in European Commission 
guidance document 2011/C 172/01 (CT-3), Section 4.3, paragraph 29, which states 
“Immediate reporting should allow the sponsor to take the appropriate measures to address 
potential new risks in a clinical trial.  Therefore, the immediate report should be made by the 
investigator within a very short period of time and under no circumstances should this exceed 
24 hours following knowledge of the serious adverse event”. 
 
Site Responsibility: 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Documents to Vector Oncology 
Documents to Vector Oncology 
All SAEs, including overdose of 
study drug 
SAE Report Form 
SAE Report Form 
Pregnancy 
SAE Report Form 
SAE Report Form 
Liver chemistry abnormalities: 
ALT > 3.0 x ULN  
with concomitant elevation in 
bilirubina (defined as  
total bilirubin  2.0 x ULN;  
with direct bilirubin > 35%)  
or with hypersensitivity 
symptoms (e.g., fever, rash). 
SAE Report Form 
SAE Report Form 
ALT > 8.0 x ULN  
without bilirubin elevation 
(defined as total bilirubina < 2.0 
x ULN or direct bilirubin ≤ 
35%) and without 
hypersensitivity symptoms (e.g., 
fever, rash) 
SAE Report Form 
SAE Report Form 
a. 
Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject 
meets the criterion of total bilirubin > 1.5 x ULN, then the event should be promptly reported as a SAE. 
 
The site will complete the initial and follow-up SAE reports.  It is the Investigator’s 
responsibility to make sure follow-up information and supporting documentation are 
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All SAEs must be collected beginning at the start of study treatment until 30 days after 
discontinuation of treatment.  In addition, the Investigator should notify Vector Oncology of 
any SAE that may occur after this time period which they believe to be certainly, probably, 
or possibly related study treatment.  Vector Oncology will then notify Novartis of the event. 
SAE terminology and severity grading will be based on the CTCAE v4.0 guidelines. 
An overdose is defined as the accidental or intentional ingestion of more than the protocol-
specified dose.  For reporting purposes, an overdose, regardless of adverse outcome, is an 
important medical event. 
Any pregnancy that occurs during study participation must be reported to Vector Oncology.  
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child.  Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE.  Spontaneous abortions must be reported 
as an SAE.  Any SAE occurring in association with a pregnancy, brought to the 
Investigator’s attention after the subject has completed the study and considered by the 
Investigator as possibly related to the investigational product, must be promptly reported to 
Vector Oncology.  In addition, the Investigator must attempt to collect pregnancy 
information on any female partners of male study subjects who become pregnant while the 
subject is enrolled in the study. Pregnancy information must be reported to Vector Oncology 
for reporting to Novartis. 
Sponsor (Vector Oncology) responsibility: 
Vector Oncology 
Responsibility: 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time 
Frame 
Documents to Novartis 
Time 
Frame 
Documents to 
Novartis 
All SAEs, including overdose of 
study drug 
24 hours 
SAE Report Form 
As obtained 
SAE Report Form 
Pregnancy 
2 weeks 
SAE Report Form 
2 weeks 
SAE Report Form 
Liver chemistry abnormalities: 
ALT >3.0 x ULN  
with concomitant elevation in 
bilirubina (defined as  
total bilirubin 2.0 x ULN;  
with direct bilirubin >35%)  
or with hypersensitivity 
symptoms (e.g., fever, rash). 
24 hours 
SAE Report Form 
As obtained 
SAE Report Form 
ALT >8.0 x ULN  
without bilirubin elevation 
(defined as total bilirubina <2.0 
x ULN or direct bilirubin ≤35%) 
and without hypersensitivity 
symptoms (e.g., fever, rash) 
24 hours 
SAE Report Form 
As obtained 
SAE Report Form 
a. 
Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject 
meets the criterion of total bilirubin > 1.5 x ULN, then the event should be promptly reported as a SAE. 


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Vector Oncology will:  
 
Expeditiously handle and report all AEs classified as “serious” to Novartis in 
compliance with regulatory requirements.  
 
Immediately report all SAEs to Novartis within 24 hours of becoming aware of the 
event.  If only limited information is initially available, required follow-up reports will 
be sent.  SAE reports will be kept on file at Vector Oncology. 
All SAEs should be faxed to Novartis along with Novartis SAE fax cover 
sheet  at: 
 
US CPO DS&E  Fax #: (877) 778-9739 
 
Should the designated SAE Fax# be non-functional please send SAEs to the 
designated SAE mailbox: clinicalsafetyop.phuseh@novartis.com 
 
  
 
 
Any pregnancy that occurs during study participation must be reported to Novartis.  To 
ensure subject safety, each pregnancy must be reported to Novartis within 2 weeks of 
learning of its occurrence.  The pregnancy must be followed up to determine outcome 
(including premature termination) and status of the mother and child.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE 
or SAE.  Spontaneous abortions must be reported as an SAE. Any SAE occurring in 
association with a pregnancy, brought to the Investigator’s attention after the subject has 
completed the study and considered by the Investigator as possibly related to the 
investigational product, must be promptly reported to Novartis.  In addition, the 
Investigator must attempt to collect pregnancy information on any female partners of 
male study subjects who become pregnant while the subject is enrolled in the study. 
Pregnancy information must be reported to Novartis as described above. 
 
For studies conducted under an Investigator Investigational New Drug (Application) 
(IND), any event that is both serious and unexpected must be reported to the FDA as 
soon as possible and, in no event, later than 7 days (death or life-threatening event) or 15 
days (all other SAEs) after the Investigator’s or institution’s initial receipt of the 
information.  Novartis will be provided with a simultaneous copy of all adverse events 
filed with the FDA.  SAEs should be reported on the MedWatch Form 3500A, which can 
be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/  


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MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD  20852-9787 
Fax:  1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
 
 
United Kingdom only: Reporting of SAEs and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be in accordance not only with the USA FDA requirements 
but also with the European Directive 2001/20/EC and Statutory Instrument 2004 No. 
1031.  SUSAR reporting will be handled by the Sponsor or its designee. 
 
Collection of complete information concerning SAEs is extremely important.  Full 
descriptions of each event will be followed by Novartis. Thus, follow-up information 
which becomes available as the SAE evolves, as well as supporting documentation (e.g., 
hospital discharge summaries and autopsy reports), should be collected subsequently, if 
not available at the time of the initial report, and immediately sent using the same 
procedure as the initial SAE report. 
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious. This also applies to subjects experiencing AEs that cause interruption or 
discontinuation of study drug, or those experiencing AEs that are present at the end of 
their participation in study treatment; such subjects should receive post-treatment 
follow-up as appropriate. 
 
11. 
STATISTICAL METHODOLOGY 
11.1. 
Introduction 
Descriptive statistics will be generated for all study variables.  These will include means, 
standard deviations, medians, minimum and maximum values for continuous variables; and 
frequency and percentage for categorical variables; and survival function graphs for 
description of time to event endpoints.  Other details regarding analyses are presented below, 
under Statistical Analysis. 
11.2. 
Analysis Populations 
There is no randomization in this study.  Intent to treat is defined as occurring at first 
administration of Pazopanib on C1D1 to eligible subjects, regardless of subsequent subject 
discontinuation.  The intent to treat population includes all subjects who receive the first 
administration of Pazopanib on C1D1. 


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The population of subjects who are nonevaluable for disease control includes subjects in the 
intent to treat population who discontinue or are lost to follow-up prior to the first evaluation 
of disease control. 
11.3. 
Endpoints 
11.3.1. Primary 
The primary endpoint is disease control at week 16. defined as CR + PR + SD, where tumor 
response is defined by RECIST guidelines version 1.1. 
The analysis sample for primary endpoint of the study is the intent to treat population.  
Subjects who are not evaluable for disease control rate will be considered treatment failures 
for this endpoint. 
11.3.2. Secondary 
The secondary endpoints of this study are as follows: 
 
Progression free survival (PFS) according to RECIST guidelines version 1.1. 
 
Overall survival (OS). 
 
Toxicity assessment through the reporting of adverse events graded using the CTCAE 
v4.0. 
The analysis sample for secondary endpoints of the study is the intent to treat population.   
11.4. 
Sample Size 
The primary endpoint for this study is disease control at week 16 defined as CR + PR + SD, 
where tumor response is defined by RECIST guidelines version 1.1.  For sample size 
estimation, we assume a null hypothesis rate of 30%, and an alternative hypothesis rate of 
50%.  A sample of 47 subjects will provide power of 80% to detect this effect, with alpha = 
.05, two tailed. 
There will be no randomization in this study. 
Investigator-specific bias will be minimized through the use of multiple centers.   
11.5. 
Statistical Analysis 
11.5.1. Baseline Demographic and Clinical Characteristics 
Descriptive statistics will be used to characterize Baseline demographic and clinical 
characteristics of study subjects.  As above, these will include means, standard deviations, 
medians, minimum and maximum values for continuous variables; and frequency and 
percentage for categorical variables.  The disposition of subjects at end of treatment will be 


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reported, including the number discontinuing for toxicity, for disease progression, and for 
other reasons. 
11.5.2. Efficacy Analysis, Primary Endpoint 
Disease control at week 16 will be reported.  An Exact test of a single proportion will be used 
to test the hypothesis that the week 16 disease control rate in the sample does not differ from 
the null hypothesis rate of 30%.  Change from Baseline in sum of largest diameters of target 
lesions as of week 16 will be computed, with summary statistics reported.  A waterfall plot 
will be generated to descriptively characterize this statistic. 
11.5.3. Efficacy Analysis, Secondary Endpoints 
The Kaplan Meier product limit estimator will be used to estimate PFS and OS in the sample.  
The time origin for analysis of PFS and OS will be C1D1.  The Kaplan Meier survival 
function will be generated and displayed to descriptively characterize PFS and OS. 
Cox regression analysis may be employed to examine subject Baseline demographic or 
clinical characteristics as predictors of PFS and OS in the sample. 
11.5.4. Toxicity Analysis 
Treatment emergent adverse events will be reported by preferred term, by system organ 
class, by serious vs. nonserious status.  Events will be graded per CTCAE version 4.0.  The 
frequency and percentage of subjects experiencing events within preferred term, within 
system organ class, and for the entire sample, will be reported. 
11.5.5. Other Planned Analyses 
Number of cycles treated will be reported.  Descriptive statistics related to dose of study drug 
will be reported.  The frequency and percentage of subjects who had dose reductions and 
dose delays will be reported, overall, and by treatment cycle. 
11.5.6. Exploratory Analyses 
Exploratory analysis will examine disease control and time to event endpoints by tumor 
grade.  Depending on the distribution of tumor grade, Chi-square test or Fisher’s Exact test 
may be used to compare disease control rate across tumor grade.  Log rank tests will be used 
to compare time to event endpoints across tumor grades.   Logistic regression may be used to 
examine disease control by tumor grade, controlling for other subject characteristics. 
Other exploratory analyses may be conducted as indicated by preliminary findings from this 
study. 


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12. 
STUDY ADMINISTRATION 
12.1. 
Ethics Review 
Before study initiation, each Principal Investigator must have written and dated 
approval/favorable opinion from the Institutional Review Board (IRB) for the final protocol, 
informed consent, subject recruitment materials/process (e.g., advertisements), and any other 
written information to be provided to subjects.  Documentation of approval signed by the 
chairperson or designee of the IRB(s) must be sent to Vector Oncology. 
Vector Oncology will provide the central IRB with reports, updates, and other information 
(e.g., Safety Updates, Amendments, Administrative Letters) according to regulatory 
requirements and institution procedures.  Sites that are required to utilize a local IRB will be 
responsible for their own local IRB submissions.  The protocol must be re-approved by the 
IRB annually, as local regulations require.  
Progress reports and notifications of serious unexpected ADRs will be provided to the IRB 
according to local regulations and guidelines.  Vector Oncology will provide the central IRB 
with reports of any serious ADRs from any other study conducted with the investigational 
product.   
12.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP, applicable regulatory 
requirements. 
12.3. 
Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in the final approved protocol.   
All revisions will be submitted to Novartis by Vector Oncology.  The Investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB of an Amendment, except where necessary to 
eliminate an immediate hazard(s) to study subjects. 
See also 21Code of Federal Regulations (CFR) for definitions of amendment and 
requirements. 
12.4. 
Informed Consent 
Preparation of the consent form is the responsibility of Vector Oncology and will include all 
elements required by 21 CFR Part 50.25 and the local IRB, if applicable.  If modifications 


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are made to the consent form according to local requirements, the new version must be 
approved by Vector Oncology. 
The Investigator must ensure that the subject or his/her legally acceptable representative is 
given full and adequate oral and written information about the nature, purpose, possible risk 
and benefit, and other critical issues regarding clinical trials of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated informed consent(s) must be obtained before conducting any 
procedure specifically for the study.  The Investigator(s) must store the original, signed 
written Informed Consent Form(s).  A copy of the signed written Informed Consent Form(s) 
must be given to the subject. 
12.5. 
Records and Reports 
An Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation (e.g., iCRF) 
on each individual treated with the study drug or entered in the investigation.  The 
Investigator is required to retain, in a confidential manner, the data pertinent to the study. 
12.6. 
Subject Data Protection 
In accordance with HIPAA, the written Informed Consent Form must include a subject 
authorization to release medical information to Vector Oncology and/or allow Vector 
Oncology, a regulatory authority, or IRB access to subject’s medical information that 
includes all hospital records relevant to the study, including a subject’s medical history. 
12.7. 
Records Retention 
The Investigator must retain study drug disposition records, source documents, and case 
histories designed to record all observations and other data pertinent to the investigation (e.g., 
iCRF) for the maximum period required by applicable regulations and guidelines, or 
Institution procedures. 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another Investigator, IRB).  
Documentation of such transfer will be provided to Novartis by Vector Oncology. 


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12.8. 
Data Management 
Vector Oncology will manage all data management activities for the trial at the company’s 
Memphis, TN facility.  All sites will enter their data directly into the EDC.  Training on the 
EDC will be conducted as part of site initiation procedures.  EDC access will be password 
protected, and usage at each research site will be monitored by Vector Oncology. 
Investigators are responsible for the integrity of the data (accuracy, completeness, legibility, 
and timeliness) reported to Vector Oncology.  Data should be entered in the EDC within 14 
days of a subject’s visit.  
Clinical Data Management per the study specific plan will be performed by the Vector 
Oncology Data Management team in accordance with Good Clinical Data Management 
Practices (GCDMP) with the objective of removing errors and inconsistencies in the data 
which would otherwise impact the analysis and reporting objectives, or the credibility of the 
Clinical Study Report. 


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13. 
REFERENCES 
Ariazi J, Bryant T, Chagin K, et al. Investigator’s Brochure for pazopanib (GW786034) for 
Oncology and Other Indications. GlaxoSmithKline, 2014. 
 
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et al.  
Recommended Guidelines for the Treatment of Cancer Treatment-Inducted Diarrhea.  J Clin 
Oncol. 2004, 22; 2918-26. 
Billemont B, Medioni J, Tailade L, Helley D, Meric JB, Rixe O, Oudard S, Blood glucose 
levels in patients with metastatic renal cell carcinoma treated with sunitinib.  Br J Cancer.  
2008: 99, 1380-1382. 
Chow WA. Update on chondrosarcomas. Curr Opin Oncol. 19:371-376, 2007. 
Data on file - GSK Study VEG10003: A Phase I, Open-Label, Multiple Dose Escalation 
Study of GW786034 in Patients with Solid Tumors. 
Dorfman HD, Czerniak B. In: Bone tumors. Mosby, Inc., St Louis, MO, pp 353-440, 1998. 
Eisenhauer A, Therasse P., Bogaerts J., et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 
1997;18:4-25. 
 
Fletcher CDM, Unni KK, Mertens F (eds) Pathology and genetics of tumors of soft tissue 
and bone. IARC Press, Lyon, 2002. 
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-
1186. 
 
Folkman J. Antiangiogenic therapy, in DeVita VTJ, Hellman S, Rosenberg SA (eds): Cancer: 
Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997;3075-3085. 
 
Hatcher RA, Trussell J, Stewart F, Nelson AL, Cates W, Guest F, Kowal DD, editors. 
Contraceptive Technology.  New York: Ardent Media, 2004: 226.  Table 9-2, “% of Women 
Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First 
Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the 
First Year.  United States”, column entitled, “% of Women Experiencing an Unintended 
Pregnancy Within the First Year of Use.  Perfect Use”. 
Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced 
cancer. Clin Cancer Res. 15: 4220-4227, 2009. 


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Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2009. CA Cancer J Clin. Published 
Online: May 25, 2009. DOI: 10.3322/caac.2006. 
Kumar R, Knick VB, Rudolph SK, et al.  PK-PD correlation from mouse to human with 
pazopanib, a multi-kinase angiogenesis inhibitor with potent antitumor and antiangiogenic 
activity.  Mol Cancer Therapy. 2007; 6 2012-2021.  
 
Malawer MM, Link MP, Donaldson SS. Sarcomas of bone. In: DeVita VT, Jr., Hellman S, 
Rosenberg SA (eds) Cancer: principles and practice of oncology. Lippincott Williams & 
Wilkins, Philadelphia, PA. pp 1891-1935, 2001. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0. Available at: http://ctep.cancer.gov. 
Shor AC, Agresta SV, D’Amato GZ et al. Therapeutic potential of directed tyrosine kinase 
inhibitor therapy in sarcomas. Cancer Control.15:47-54, 2008. 
Sleijfer S, Ray-Coquard I, Papai Z et al. Pazopanib, a multikinase angiogenesis inhibitor, in 
patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the 
European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma 
Group (EORTC Study 62043). J Clin Oncol. Published Online: May 18, 2009. DOI: 
10.1200/JCO.2008.21.3223. 
Votrient® [prescribing information]; Research Triangle Park, NC: GlaxoSmithKline; June 
2014. 
 
Yasko AW, Chow WA, Frassica D. Bone Sarcomas. In: Pazdur R, Wagman LD, 
Camphausen KA, Hoskins WJ (eds). Cancer Management: A Multidisciplinary Approach. 
CMP Medica, Lawrence, KS. Pp 597-610, 2008. 
 
 
 
 


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Appendix 1 
Time and Events Schedule 
Assessments (see Section 7 of the protocol) 
Screening / 
Baseline 
Treatment Period 
EOT 
Visit 
30 
day 
F/U10 
LT 
F/U11 
(Cycle length = 28 days)   
Cycle 
1 
2 
3 
4 
5 
6, etc.9 
(Visit window during treatment =  
± 3 business days, except BP only ± 
1 business day3) 
Day 
1 
8 
15 
22 
1 
15 
22 
1 
15 
22 
1 
15 
22 
1 
15 
22 
1 
15 
22 
Informed Consent* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history*1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam**2 
X 
X2 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital signs (BP3, T, P) and weight** 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
BP only3 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X3 
 
 
X3 
 
 
X3 
 
 
 
 
ECOG** 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
CBC with differential** 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
PT/INR and PTT** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMP including magnesium and phosphorus** 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
LFT panel4 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculate creatinine clearance (if serum 
creatinine > 1.5 mg/dL)** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UPC ratio (24-hour urine protein, if 
applicable)** 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
TSH** and Lipase**5 
X 
 
 
 
 
 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum pregnancy test for WOCBP*** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and estradiol (if applicable)** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA with documented LVEF 
measurement*6 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X5 
 
 
 
12-lead EKG with documented QTc 
measurement using Bazett’s formula*7 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
X 
 
 
CT CAP or PET/CT*8 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X7 
X7 
 
 
CNS imaging studies (CT or MRI) if 
clinically indicated or if hx of CNS mets* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pazopanib administration and compliance 
(subject diary) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Assess concomitant medications** 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Assess adverse events 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Disease status and survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
* within 28 days prior to starting treatment 
** within 14 days prior to starting treatment 
*** within 7 days prior to starting treatment 
1. 
Disease history must include date of diagnosis, prior treatment, and if applicable sites of metastases. Medical history must include alcohol use and if the subject is hepatitis B or C positive. 
2. 
If Screening physical exam is performed within 7 days of starting treatment, the Cycle 1 Day 1 physical exam is not required. 
3. 
At the Screening visit, BP should be measured three times at approximately 2-minute intervals.  The three values will be averaged to determine if the subject’s BP is within the well-
controlled range (defined as BP < 140/90).  Blood pressure must be monitored weekly during Cycle 1 and every 2 weeks during Cycles 2 and 3. BP only at Cycle 1 Day 8 (+/- 1 business 
day), Cycle 1 Day 15 (+/- 1 business day), Cycle 1 Day 22 (+/- 1 business day), Cycle 2 Day 15 (+/- 1 business day), and Cycle 3 Day 15 (+/- 1 business day); other vital signs are not 
required at these time points.  BP measurement at these time points may be done at home or by another physician (see Section 7.3.3), but subject must report results to research staff.  After 
Cycle 3, if BP is controlled (defined as BP < 140/90), then BP may be monitored once monthly.  If BP is uncontrolled (defined as BP > 140/90), continue with every 2 week monitoring or 
more frequently if clinically indicated. 
4. 
LFT panel must include ALT, AST, and bilirubin. 
5. 
TSH and Lipase will be assessed after the first 2 cycles of treatment and then after every 4 cycles of treatment on Day 1 of Cycles 3, 7, 11, 15, etc. (approximately every 16 weeks). 


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6. 
An ECHO or MUGA is required at Screening and at the end of Cycle 3.  After Cycle 3, if BP is controlled (defined as BP < 140/90) and LVEF is within normal range, then repeat 
ECHO/MUGA per treating Investigator’s discretion as clinically indicated.  After Cycle 3, if BP is uncontrolled (defined as BP > 140/90) or LVEF is abnormal, an ECHO or MUGA must 
be repeated after every 3 cycles of treatment.  The ECHO or MUGA may be done before the start of treatment on Day 1 of the next cycle as long as results are available prior to treatment.  
The same test should be performed at all time points during the study (see Section 7.3.5). 
7. 
A 12-lead EKG will be obtained at the end of Cycle 1 and then after every 4 cycles of treatment at the end of Cycles 5, 9, 13, 17, etc. (approximately every 16 weeks).  EKGs may be done 
before the start of treatment on Day 1 of the next cycle as long as results are available prior to treatment.  QTc must be measured using the Bazett’s formula and the result documented.  If 
QTc > 500 msec is noted on scheduled or unscheduled EKG, then 2 additional EKGs should be obtained  to confirm the abnormality (see Section 7.3.4).    
8. 
Perform CT chest, abdomen, and pelvis or PET/CT on all subjects at Screening.  Repeat imaging would include a CT or other appropriate imaging studies of all affected areas after every 2 
cycles.  Imaging should be conducted at the end of the indicated cycle or prior to treatment on Day 1 of the next cycle taking into account time required for receipt and review of scan 
results.  Contrast should be used for all scans unless contraindicated.  Tumor response will be assessed per RECIST version 1.1 guidelines.  Tumor assessment should be repeated 4 weeks 
after initial response for confirmation.  EOT tumor assessments should be made within 30 days of study treatment discontinuation.  
9. 
Subjects may continue treatment in the absence of disease progression or unacceptable toxicity. 
10. The 30-day safety Follow-up may be conducted via a phone call, and it must be documented in the subject’s source documents. 
11. Long-term Follow-ups will be conducted every 3 months from 30-day Follow-up for disease status (in subjects discontinuing treatment for reasons other than progression) and survival 
status for 6 months..  The long-term Follow-ups may be conducted via a phone call, and they must be documented in the subject’s source documents.


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Appendix 2 
ECOG Performance Status Criteria 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
 
Reference:  As published in Oken MM, Creech RH, Tormey DC, et al.  Toxicity And Response     
                   Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol.  1982;5:649-655. 


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Appendix 3 
Determination of Creatinine Clearance (ClCR) 
 
Estimation of creatinine clearance using Cockcroft and Gault method:  
 
ClCR for males (mL/min) = 
 
[140 - age (years)] X [weight (kg)] 
 
 
 
                        (72) X [Serum creatinine (mg/dL)] 
ClCR for females (mL/min) =  
(0.85) X [140 - age (years)] X [weight (kg)] 
 
 
                 (72) X [Serum creatinine (mg/dL)] 
 
For SI units: 
ClCR for males (mL/min) =   
[140 - age (years)] X [weight(kg)] X (1.23) 
 
 
 
 
                     [serum creatinine (µmol/L)] 
ClCR for females (mL/min) =   
[140 - age(years)] X [weight(kg)] X (1.05) 
 
 
 
 
 
          [serum creatinine (µmol/L)] 
 


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Appendix 4 
Urine Protein Creatinine Ratio (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:  Subject 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 ration 
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  
References: 
Xin G, Wang M, Jian L, Xu F, Wang H.  Protein-to-creatinine ratio in spot urine samples as a 
predictor of quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39. 
NKF: NKF KDOQI Guidelines [Internet].  National Kidney Foundation; nd.  KDOQI 
Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and 
Stratification.  Available from 
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm 
 
 


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Appendix 5 
New York Heart Association Classification of Cardiac Disease 
The following table presents the NYHA Classification of Cardiac Disease: 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity.  Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients 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. 
Objective evidence of minimal 
cardiovascular disease. 
 
III 
Patients with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable at 
rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
 
IV 
Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort.  
Symptoms of heart failure or the anginal syndrome may 
be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease. 
 
 
Reference: The Criteria Committee of New York Heart Association.  Nomenclature and                
                   Criteria for Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed.  
                   Boston, MA: Little, Brown & Co; 1994:253-256.