A Phase II, Single-Arm Study of Pazopanib and Paclitaxel as First-Line Treatment for Subjects With Unresectable Stage III and Stage IV Melanoma
Phase: PHASE2
Conditions: Stage III Melanoma, Stage IV Melanoma, Unresectable Melanoma
Sponsor: University of California, Irvine

 
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Information Type: Clinical Protocol 
 
Title: 
A Phase II, Single-Arm Study of Pazopanib and Paclitaxel as 
First-Line Treatment for Subjects with Unresectable Stage III 
and Stage IV Melanoma 
Compound Number: GW786034 
Development Phase 
II 
Effective Date:  29 September 2016 
Repressed versions: 
29 September 2016 
30 Jan, 2014 
15 July, 2013 
18 Aug, 2010 
09 Aug, 2010 
1 Feb, 2010 
 
Description:  
This is a Phase II single-arm, open-label, clinical trial evaluating the efficacy and safety of 
pazopanib in combination with paclitaxel as first line therapy for subjects with unresectable 
Stage III and Stage IV melanoma.  Previous cytokine therapy is permitted.  Subjects must have 
measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).  Subjects who 
are not candidates for curative intent treatments are eligible for this study.   
Treatment on study will be administered in 4-week cycles.  Paclitaxel will be administered 
intravenously at a starting dose of 80mg/m2 weekly for 3 weeks followed by a 1-week rest.  
Pazopanib will be administered orally, in a continuous regimen, with a starting dose of 800mg 
daily.     Approximately 60 eligible subjects will be enrolled.  Twenty-one subjects will be 
entered into the first stage of a 2-stage Simon Minimax design.  If there are 3 responses, 39 
additional subjects will be enrolled in Stage 2.  The minimum number of responses required to move 
to the second stage, > 3, were noted after the first 9 patients on treatment, and the study then 
proceeded towards the goal of accruing 60 total patients. Subjects are permitted to receive supportive 
care throughout the study including transfusion of blood and blood products, treatment with 
antibiotics, anti-emetics, anti-diarrheal agents, analgesics, erythropoietin, filgramostim 
(Neupogen), or bisphosphonates, when appropriate.  Subjects should continue treatment on study 
until objective disease progression is documented according to RECIST or withdrawal from the 
study for other reasons.  Subjects discontinuing treatment with paclitaxel prior to disease 
progression should continue treatment with pazopanib.  Subjects discontinuing both agents prior 
to PD will be followed for tumor assessment until PD, or until the initiation of a subsequent anti-
cancer therapy in the absence of documented PD, or until death, whichever occurs first.  Subjects 

 
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may continue treatment beyond the time of RECIST-defined progression at the discretion of the 
investigator if the subject is perceived to be experiencing clinical benefit.  Overall survival will 
be assessed for 2 years from first study treatment. 
The primary objective of the study is to evaluate the 6-month progression-free survival (6- month 
PFS) in this patient population. The secondary objectives are to evaluate 1- and 2- year survival, 
the objective response rate (ORR), clinical benefit rate (CBR), duration of response (DR) , 
incidence and severity of adverse events (AE), serious adverse events (SAEs) and other safety 
parameters. Safety and efficacy assessments will be regularly performed on all subjects. 
Exploratory objectives are to observe angiogenic marker modulation by the drug combination, 
and when possible, to identify intra-tumoral biomarkers that correlate with or are predictive of 
clinical response/benefit to pazopanib and to identify gene and/or protein expression in tumor 
tissue that may be associated with clinical outcomes or response to therapy.  Other exploratory 
objectives, when possible, will correlate PD effects (increased diastolic blood pressure), plasma 
proteins (serum VEGF, soluble VEGF receptor 2, serum HIF and serum TSP1) to tumor biopsy 
expression levels and clinical outcome.   
 
Subject: melanoma, pazopanib (GW786034), anti-angiogenesis 
Lead Investigator/Author: 
John P. Fruehauf, MD, PhD 
Director Clinical Pharmacology and Developmental Therapeutics 
University of California Irvine  
Chao Family Comprehensive Cancer Center 
101 The City Drive, Bld 55, Rm 324 
Orange, CA 92868 
 

 
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TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS ........................................................................................................... 6 
PROTOCOL SUMMARY ................................................................................................. 8 
1. 
INTRODUCTION ................................................................................................... 11 
1.1. 
Background ................................................................................................ 11 
1.1.1. 
Epidemiology ............................................................................... 11 
1.1.2. 
Current Treatment Options for Advanced Melanoma ................... 11 
1.1.2.1. 
Chemotherapy ............................................................ 11 
1.1.2.2. 
Immunotherapy .......................................................... 12 
1.1.2.3. 
Anti-angiogenesis Therapy ......................................... 12 
1.1.3. 
Pazopanib: Preclinical and Clinical Experience ........................... 12 
1.1.3.1. 
Preliminary Safety Summary ...................................... 13 
1.1.3.2. 
Preliminary Efficacy Summary .................................... 16 
1.1.4. 
Paclitaxel: Safety Summary ......................................................... 18 
1.1.5. 
Preliminary Safety and Efficacy Summary- Pazopanib and 
Paclitaxel ..................................................................................... 19 
1.2. 
Rationale .................................................................................................... 20 
2. 
OBJECTIVES ......................................................................................................... 21 
2.1. 
Primary ....................................................................................................... 21 
2.2. 
Secondary .................................................................................................. 21 
2.3. 
Exploratory Objectives ................................................................................ 21 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 21 
3.1. 
Study Design .............................................................................................. 21 
3.2. 
Discussion of Design .................................................................................. 22 
3.2.1. 
Dose Rationale for Pazopanib ..................................................... 22 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 23 
4.1. 
Number of Subjects .................................................................................... 23 
4.2. 
Inclusion Criteria ......................................................................................... 23 
4.3. 
Exclusion Criteria ........................................................................................ 26 
4.4. 
Withdrawal Criteria ..................................................................................... 28 
4.4.1. 
Subject Withdrawal from Study Treatment ................................... 28 
4.4.2. 
Subject Withdrawal from Study Participation ............................... 28 
4.5. 
Screen and Baseline Failures ..................................................................... 28 
5. 
STUDY TREATMENTS .......................................................................................... 29 
5.1. 
Description of Investigational Product ......................................................... 29 
5.1.1. 
Pazopanib ................................................................................... 29 
5.1.2. 
Paclitaxel ..................................................................................... 29 
5.2. 
Dosage and Administration ......................................................................... 29 
5.2.1. 
Pazopanib ................................................................................... 29 
5.2.2. 
Paclitaxel ..................................................................................... 29 

 
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5.3. 
Dose Modifications for Toxicity ................................................................... 30 
5.3.1. 
Pazopanib Dose Modifications..................................................... 30 
5.3.2. 
Paclitaxel Dose Reduction ........................................................... 35 
5.4. 
Packaging and Labeling ............................................................................. 37 
5.5. 
Handling and Storage ................................................................................. 37 
5.6. 
Product Accountability ................................................................................ 38 
5.7. 
Treatment Compliance ............................................................................... 38 
5.8. 
Concomitant Medications and Non-Drug Therapies .................................... 38 
5.8.1. 
Permitted Medications and Non-Drug Therapies ......................... 38 
5.8.1.1. 
Hematopoietic Growth Factors ................................... 38 
5.8.2. 
Prohibited Medications ................................................................ 40 
5.8.3. 
Concomitant Anti-cancer Therapies ............................................. 41 
5.9. 
Treatment after the End of the Study .......................................................... 41 
5.10. 
Treatment of Investigational Product Overdose .......................................... 41 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 42 
6.1. 
Screening and Baseline Assessments ........................................................ 46 
6.1.1. 
Assessments within 4 Weeks of the First Dose ........................... 46 
6.1.2. 
Assessments within 2 Weeks of the First Dose ........................... 46 
6.1.3. 
Pre-dose Assessments on Day 1 ................................................. 47 
6.2. 
Efficacy ....................................................................................................... 47 
6.2.1. 
Primary Endpoint ......................................................................... 47 
6.2.2. 
Secondary Endpoints .................................................................. 47 
6.2.3. 
Methods, Scope and Schedules of Disease Assessments ........... 48 
6.2.3.1. 
Measurability of Tumor Lesions at Baseline ............... 49 
6.2.3.2. 
Determination of Target and non-Target Lesions ....... 50 
6.2.3.3. 
Response Evaluation of Measurable Disease ............ 50 
6.2.3.4. 
Evaluation of Disease Progression ............................. 52 
6.2.3.5. 
Survival Assessment .................................................. 52 
6.3. 
Safety ......................................................................................................... 52 
6.3.1. 
Physical Examination .................................................................. 52 
6.3.2. 
Vital Signs and Blood Pressure Monitoring .................................. 53 
6.3.3. 
ECOG PS .................................................................................... 53 
6.3.4. 
Clinical Laboratory Assessments ................................................. 53 
6.3.5. 
12-Lead Electrocardiogram ......................................................... 54 
6.3.6. 
Pregnancy Test ........................................................................... 55 
6.3.7. 
Safety Assessments upon Discontinuation of Study Treatment ... 55 
6.3.8. 
Adverse Events ........................................................................... 55 
6.3.8.1. 
Definition of an AE ..................................................... 55 
6.3.8.2. 
Definition of a SAE ..................................................... 56 
6.3.9. 
Clinical 
Laboratory 
Abnormalities 
and 
Other 
Abnormal 
Assessments as AEs and SAEs .................................................. 57 
6.3.10. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs ...................................................................... 58 
6.3.11. 
Time Period, and Frequency of Detecting AEs and SAEs ............ 58 
6.3.12. 
Pregnancy ................................................................................... 58 
6.3.12.1. Time period for collecting pregnancy information ....... 58 
6.3.12.2. Action to be taken if pregnancy occurs ....................... 58 
6.3.12.3. Action to be taken if pregnancy occurs in a female 
partner of a male study subject .................................. 59 
6.3.13. 
Prompt Reporting of SAEs to Novartis ......................................... 59 

 
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6.3.13.1. Timeframes for Submitting SAE Reports to Novartis .. 59 
6.3.13.2. AE 
and 
SAE 
Documentation 
and 
Follow-up 
Procedures ................................................................. 60 
6.4. 
Biomarker(s) ............................................................................................... 60 
6.5. 
Biomarker Research ................................................................................... 60 
7. 
DATA MANAGEMENT ........................................................................................... 62 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................. 62 
8.1. 
Hypotheses ................................................................................................ 62 
8.2. 
Study Design Considerations...................................................................... 62 
8.2.1. 
Sample Size Assumptions ........................................................... 62 
8.2.2. 
Analysis Populations ................................................................... 62 
8.2.3. 
Analysis Data Sets ...................................................................... 63 
8.2.4. 
Early Stopping Rule ..................................................................... 63 
8.2.5. 
Key Elements of Analysis Plan .................................................... 63 
8.2.5.1. 
Efficacy Analyses ....................................................... 65 
8.2.5.1.1. 
Primary Analysis ..................................... 65 
8.2.5.1.2. 
Secondary Analyses ............................... 65 
8.2.5.2. 
Safety Analyses ......................................................... 66 
8.2.5.3. 
Biomarker(s) Analyses ............................................... 67 
9. 
STUDY CONDUCT CONSIDERATIONS ............................................................... 67 
9.1. 
Safety Data Review .................................................................................... 67 
9.2. 
Regulatory and Ethical Considerations, Including the Informed Consent 
Process ...................................................................................................... 68 
10. REFERENCES ...................................................................................................... 69 
11. APPENDICES ........................................................................................................ 73 
11.1. 
Appendix 1: American Joint Committee on Cancer (AJCC) Tumor Node 
Metastasis (TNM) Classification of Melanoma ............................................ 73 
11.2. 
Appendix 2: The Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) Scales ..................................................................................... 75 
11.3. 
Appendix 3: Cockcroft and Gault Formula for Estimated Creatinine 
Clearance (CrCl)......................................................................................... 76 
11.4. 
Appendix 4: New York Heart Association (NYHA) Classification of 
Congestive Heart Failure ............................................................................ 77 
11.5. 
Appendix 5: Recommendations for Management of Hypertension .............. 78 
11.6. 
Appendix 6: Procedures for Obtaining Urine Protein/Creatinine Ratio ........ 79 
11.7. 
Appendix 7:  Blood Samples for Soluble protein assessments: Procedures 
for Sampling, Handling, Storage, and Shipment ......................................... 80 
11.8. 
Appendix 8:  Fresh Tissue Samples: Procedures for Sampling, Handling, 
Storage, and Shipment ............................................................................... 81 
11.9. 
Appendix 9:  Biomarker Analysis ................................................................ 82 
 

 
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ABBREVIATIONS 
ACTH 
Adrenocorticotropic hormone  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BP 
Blood pressure  
C24 
Concentration 
at 
24 
hr 
following 
single-dose 
administration 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine Clearance  
CT 
Computerized tomography 
CYP 
Cytochrome P450 (subtypes 3A, 3A4, 2D6) 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
ECOG performance status 
CRF 
Electronic Case Report Form 
EMEA 
European Medicines Agency 
EIAC 
Enzyme-inducing anticonvulsants 
EQ-5D 
EuroQoL-5 Dimension 
FDA 
Food and Drug Administration  
Flt-3 
Fms-like tyrosine kinase-3 
FKSI 
FACT-Kidney Symptom Index 
FU 
Follow up 
GCP 
Good Clinical Practice 
GIST 
Gastrointestinal stromal tumors 
GSK 
GlaxoSmithKline 
HIF-1 
Hypoxia-inducible factor-1 
HRT 
Hormone Replacement Therapy 
IC50 
Half-maximal inhibition 
IFN 
Interferon  
IL-2 
Interleukin-2 
IND 
Investigational New Drug  
INR 
International 
normalized 
ratio 
(anticoagulant 
level 
description) 
IEC/IRB 
Independent Ethic Committee /Institutional Review Board 
ITT 
Intend-to-treat 
LD 
Longest diameter 
LMWH 
Low Molecular Weight Heparin 
MM 
Metastatic Melanoma 

 
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MRI 
Magnetic resonance imaging 
msec 
Millisecond(s) 
MTD 
Maximum tolerated dose  
mTOR 
mammalian Target of Rapamycin 
MUGA 
Multigated acquisition 
NCI-CTC  
National Cancer Institute-common toxicity criteria 
OS 
Overall survival 
PD 
Progressive disease  
PDGF 
Platelet-derived growth factor  
PDGFR 
Platelet-derived growth factor receptor 
PFS 
Progression-free survival 
PR 
Partial response 
PTT 
Partial thromboplastin time 
QD 
Once daily 
QTc 
Corrected QT interval 
RAP 
Report and analysis plan 
RAMOS 
Registration and Medication Ordering System 
RCC 
Renal cell carcinoma  
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event  
SBP 
Systolic blood pressure 
SD 
Stable disease 
SPM 
Study Procedures Manual 
T3 
Triiodothyronine 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
M 
Micromolar 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
VHL 
Von Hippel-Lindau  
 
 

 
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PROTOCOL SUMMARY 
Rationale 
Metastatic melanoma (MM) is a devastating and incurable disease lacking effective therapies.  
Despite treatment options, which include palliative chemotherapy and immunotherapy, the 
majority of patients succumb to their disease within 6 to 9 months of diagnosis [Homsi, 2005].  
Because of the lack of treatment capable of prolonging the survival for patients with MM, many 
patients are treated with experimental therapy on clinical trials or with supportive care. 
 
Chemotherapy options for MM currently include dacarbazine (DTIC), temozolomide, platinum-
based therapies, and taxanes. However, only DTIC is approved by the U.S Food and Drug 
Administration (FDA) for use in palliative treatment for MM, based on studies performed in the 
1970s [Eggermont, 2004].  Despite a response rate in MM of 13%–20% [Jelic, 2002], no 
significant benefit in progression-free survival (PFS) or overall survival has been demonstrated 
with DTIC treatment. Temozolomide is an oral therapy related to DTIC that crosses the blood–
brain barrier. This property may be of benefit, given the high rate of brain metastases seen in 
melanoma [Middleton, 2000]. Temozolomide has not been approved by the FDA for the 
treatment of MM, but has become the most common chemotherapy option for palliation in this 
disease. Taxanes, such as paclitaxel, which have been associated with a response rate in MM 
similar to that of DTIC, are another treatment option that has not been approved by the FDA 
[Gogas et al. 2004]. 
 
Combination regimens, including cisplatin, vinblastine, and DTIC (Dartmouth regimen or CVD), 
are associated with a higher response rate and increased toxicity compared with single-agent 
chemotherapy, but also lack a benefit in PFS and overall survival [Legha, 1989; Danson, 2005; 
Flaherty,  2006].  The combination of paclitaxel and carboplatin has moderate activity against 
malignant melanoma, with expected reversible hematologic toxicities.  Although not 
prospectively compared with single agents, this combination may be a treatment option for some 
patients [Hodi et al. 2002]. Use of combination chemotherapy remains a treatment option that 
some oncologists continue to use, owing to anecdotal reports of long-term responses. An 
immunotherapeutic treatment, high-dose interleukin-2, is the only other approved treatment for 
MM. This highly toxic treatment requires regular hospitalization in a specialized intensive care 
unit. This treatment is associated with a response rate of 10%–20% and long-term disease-free 
survival (DFS) of 5% [Atkins, 2000]. However, it is also associated with a treatment morbidity 
rate of > 45% and a mortality rate of 2% [Atkins, 1999]. Combinations of chemotherapy and 
immunotherapy, referred to as bio-chemotherapy, are an alternative treatment for highly selected 
patients, although a large Phase III study showed higher toxicity and efficacy similar to that of 
single-agent chemotherapy [Atkins, 2006]. 
 
As the result of the rapid rate of progressive disease seen in patients with MM and the lack of 
proven therapies that change the course of the disease, MM is a disease for which a first-line 
experimental 
approach 
is 
reasonable 
(NCI 
website, 
http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page9. 

 
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Angiogenesis plays a role in melanoma progression and metastasis. [Mahabeleshwar, 2007].  A 
phase II study of axitinib, an orally available small-molecule inhibitor of VEGFR-1, 2, and 3, in 
metastatic melanoma demonstrated an ORR of 19% in 32 patients Median overall survival was 
6.8 months with a median progression free survival of 2.3 months [Fruehauf, 2008]. A recent 
study of carboplatin + paclitaxel chemotherapy combined with sorafenib biologic therapy 
resulted in progression-free survival (PFS) of 8.8 months (historical controls have PFS of 2−4 
months) in a 100-patient, single-arm, Phase II study [Flaherty, 2006].  Bevacizumab, in 
combination chemotherapies including paclitaxel, has also demonstrated antitumor in metastatic 
melanoma.  In a Phase II study evaluating carboplatin, weekly paclitaxel and bevacizumab, nine 
(17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at 
least 8 weeks. Median progression-free survival and median overall survival were 6 months and 
12 months, respectively [Perez, 2009].   
Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT. [Harris, 2008] 
In vitro and in vivo, pazopanib has demonstrated antiangiogenic activity as well as inhibition of 
xenograft tumor growth.  Established as tolerable, a randomized phase III trial to evaluate PFS in 
advanced RCC for pazopanib 800mg daily compared with placebo was initiated given a partial 
response (PR) rate at week 12 of 27% in a randomized discontinuation phase II trial of pazopanib 
in metastatic RCC. [Hutson, 2008] In melanoma, a single agent phase II study with pazopanib is 
planned. In light of the relevance of angiogenesis in melanoma and possible additive or 
synergistic benefit of other antiangiogenesis agents in combination with chemotherapy, a Phase 
II study of pazopanib in combination with chemotherapy in advanced stage melanoma is 
warranted. 
Objective(s) 
The primary objective of the study is to evaluate the 6-month progression-free survival (PFS) in 
subjects with unresectable Stage III and Stage IV melanoma.  
The secondary objectives are to evaluate 1- and 2- year survival, objective response rate (ORR), 
clinical benefit rate (CBR), duration of response (DR) , incidence and severity of adverse events 
(AE), serious adverse events (SAEs) and other safety parameters.  Safety and efficacy 
assessments will be regularly performed on all subjects.  
Exploratory objectives are to observe angiogenic marker modulation by the drug combination, 
and when possible, to identify intra-tumoral biomarkers that correlate with or are predictive of 
clinical response/benefit to pazopanib and to identify gene and/or protein expression in tumor 
tissue that may be associated with clinical outcomes or response to therapy.  Other exploratory 
objectives, when possible, will correlate PD effects (increased diastolic blood pressure), plasma 
proteins (serum VEGF, soluble VEGF receptor 2, serum HIF and serum TSP1) to tumor biopsy 
expression levels and clinical outcome.   
Study Design 
This is a Phase II single-arm, open-label, clinical trial evaluating the efficacy and safety of 
pazopanib in combination with paclitaxel as first line therapy for subjects with unresectable 

 
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Stage III and Stage IV melanoma.  Previous cytokine therapy is permitted.  Subjects must have 
measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).  Subjects who 
are not candidates for curative intent treatments are eligible for this study.   
Approximately 60 eligible subjects will be enrolled.  Twenty-one subjects will be entered into 
the first stage of a 2-stage Simon Minimax design [Simon, 1989].  If there are 3 responses, 39 
additional subjects will be enrolled in this study.   
The study includes a Screening/Baseline Period, a Treatment Period and a post-treatment 
Follow-Up Period for progression-free survival and survival. After signing the informed consent, 
candidate subjects will be screened against all the eligibility criteria.  
All subjects will receive paclitaxel IV at 80mg/m2 and pazopanib 800mg oral daily dosing.  
Subjects are permitted to receive supportive care throughout the study including transfusion of 
blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrheal agents, 
analgesics, erythropoietin, or bisphosphonates, when appropriate. Study treatment will continue 
until a subject dies, or experiences disease progression, unacceptable toxicity, or withdraws 
consent for study participation. Dose interruptions or reductions may be required following 
potential drug-related toxicities. After discontinuation of study treatment, subjects will be 
followed until death, withdrawal of consent, or lost to follow up or until 2 years following the 
last subject enrolled, whichever comes first. 
Study Endpoints/Assessments 
Primary Endpoint 
 
The primary endpoint is 6-month progression free survival (6-month PFS)  
Secondary Endpoints 
 1-and 2-year Survival 
 Objective response rate (ORR) 
 Clinical benefit response (CBR) 
 Duration of response (DR) 
 Incidence, severity of adverse events (AE), serious adverse events (SAEs) and other 
safety parameters. 
Exploratory Endpoints 
 Concentrations of plasma proteins (serum VEGF, soluble VEGF receptor 2, serum HIF 
and serum TSP1) that may be associated to angiogenesis and tumor proliferation.  

 
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 Tissue levels of angiogenic markers  
1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Epidemiology 
Melanoma accounts for approximately 5% of all cancers in the United States, with 62,480 new 
cases and 8,420 deaths expected to occur in 2008 with an increasing death rate since 1990.  A 
619% increased incidence of melanoma has been reported between 1950 and 2000, with a 165% 
increased mortality rate. Melanoma affects younger patients and is the second leading cause of 
lost productive years. It is the most common cancer in women 20 to 29 years of age. There is a 
slightly higher incidence in men than women, with 34,950 cases in men (5%) and 27,530 (4%) in 
women [SEER database, 2009] 
1.1.2. 
Current Treatment Options for Advanced Melanoma 
1.1.2.1. 
Chemotherapy 
The prognosis for patients with advanced and metastatic melanoma classified as Stage III and IV 
according to the Staging System of the American Joint Committee on Cancer (AJCC) [See 
Section 11.1, Appendix 1], is poor with a 5-year survival rate of less than 10 percent [Jamal 
2008].  Chemotherapy options for MM currently include dacarbazine (DTIC), temozolomide, 
platinum-based therapies, and taxanes. However, only DTIC is approved by the U.S Food and 
Drug Administration (FDA) for use in palliative treatment for MM, based on studies performed 
in the 1970s [Eggermont, 2004]. Despite a response rate in MM of 13%–20% [Jelic, 2002), no 
significant benefit in progression-free survival (PFS) or overall survival has been demonstrated 
with DTIC treatment. Temozolomide is an oral therapy related to DTIC that crosses the blood–
brain barrier. This property may be of benefit, given the high rate of brain metastases seen in 
melanoma [Middleton, 2000]. Temozolomide has not been approved by the FDA for the 
treatment of MM, but has become the most common chemotherapy option for palliation in this 
disease. Taxanes, such as paclitaxel, which have been associated with a response rate in MM 
similar to that of DTIC, are another treatment option that has not been approved by the FDA 
[Gogas, 2004]. Combination regimens, including cisplatin, vinblastine, and DTIC (Dartmouth 
regimen or CVD), are associated with a higher response rate and increased toxicity compared 
with single-agent chemotherapy, but also lack a benefit in PFS and overall survival [Legha, 
1989; Danson, 2005; Flaherty, 2006]. The combination of paclitaxel and carboplatin has 
moderate activity against malignant melanoma, with expected reversible hematologic toxicities. 
Although not prospectively compared with single agents, this combination may be a treatment 
option for some patients [Hodi, 2002]. Use of combination chemotherapy remains a treatment 
option that some oncologists continue to use, owing to anecdotal reports of long-term responses. 
 

 
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1.1.2.2. 
Immunotherapy 
An immunotherapeutic treatment, high-dose interleukin-2, is the only other approved treatment 
for MM. This highly toxic treatment requires regular hospitalization in a specialized intensive 
care unit. This treatment is associated with a response rate of 10%–20% and long-term disease-
free survival (DFS) of 5% [Atkins, 2000]. However, it is also associated with a treatment 
morbidity rate of > 45% and a mortality rate of 2% [Atkins, 1999]. Combinations of 
chemotherapy and immunotherapy, referred to as bio-chemotherapy, are an alternative treatment 
for highly selected patients, although a large Phase III study showed higher toxicity and efficacy 
similar to that of single-agent chemotherapy [Atkins, 2006]. 
 
As the result of the rapid rate of progressive disease seen in patients with MM and the lack of 
proven therapies that change the course of the disease, MM is a disease for which a first-line 
experimental 
approach 
is 
reasonable 
[NCI 
website, 
http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional /page9]. 
 
1.1.2.3. 
Anti-angiogenesis Therapy 
Axitinib, a potent oral VEGFR 1,2, and 3 inhibitor demonstrated single-agent activity with an 
ORR of 19% in a study of 32 patients with metastatic melanoma as first or second line therapy.  
Additionally, an unplanned subset analysis demonstrated a survival benefit in patients with an 
increase in diastolic blood pressure during study therapy [Fruehauf, 2007].   
 
In a study of 32 patients with Stage IV MM who received either bevacizumab or bevacizumab 
plus low-dose interferon, one patient experienced a partial response and eight patients 
experienced prolonged disease stabilization (24–146 weeks) [Varker, 2007].  In a Phase II study 
evaluating carboplatin, weekly paclitaxel and bevacizumab, nine (17%) patients achieved partial 
remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median 
progression-free survival and median overall survival were 6 months and 12 months, 
respectively [Perez, 2009].   
A recent study of carboplatin plus paclitaxel chemotherapy combined with sorafenib biologic 
therapy resulted in progression-free survival (PFS) of 8.8 months (historical controls have PFS of 
2−4 months) in a 100-patient, single-arm, Phase II study [Flaherty, 2006]. This study has led to 
two ongoing Phase III studies using the same regimen and has renewed interest in the carboplatin 
+ paclitaxel chemotherapy regimen in this disease setting [Rao, 2006; Hodi , 2002].  
 
1.1.3. 
Pazopanib: Preclinical and Clinical Experience 
Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor (TKI) of 
VEGFR-1, -2, -3, PDGFR-α and -β and c-kit, with half-maximal inhibition 
(IC50) values of 10, 30, 47, 71, 84 and 74 nM, respectively. It inhibits VEGF-
induced VEGFR-2 phosphorylation in human umbilical vein endothelial cells 
(HUVEC) as well as in mouse lungs in a dose-dependent manner. Data from 
preclinical studies show pazopanib has significant growth inhibition of a 

 
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variety of human tumor xenografts in mice, and also inhibits basic fibroblast 
growth factor- (bFGF-) and VEGF-induced angiogenesis in two mouse models of 
angiogenesis, viz., the Matrigel™ plug assay and the cornea micropocket model 
[GSK Pazopanib Investigator’s brochure version 7.0]. 
 
GlaxoSmithKline initiated the clinical development of pazopanib in December 
2002. As of April, 2007, five Phase I, one Phase I/II, six Phase II, and one Phase III 
clinical studies had been initiated to evaluate the pharmacokinetics, pharmacodynamics, safety, 
clinical benefit, and efficacy of pazopanib alone or in combination with other compounds in 
patients with various types of cancer including renal cell carcinoma, ovarian, breast, 
multiple myeloma, and soft tissue sarcoma. 
 
1.1.3.1. 
Preliminary Safety Summary 
As of 09 September 2012, approximately 5000 subjects have received pazopanib 
as monotherapy or in combination out of approximately 7000 subjects enrolled 
in pazopanib oncology clinical studies. 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.  
In VEG105192 a randomized, double-blind, placebo-controlled Phase III study of 
pazopanib monotherapy in subjects with advanced RCC), the median time on 
treatment was approximately twice that on placebo (7.4 months versus 3.8 
months) [Sternberg, 2010]. The overall frequency of AEs reported during the 
study was higher in the pazopanib arm (92%) compared with placebo (74%). Most 
common AEs reported in >20% subjects in the pazopanib arm (as of 23 May 2008) 
were diarrhea (52%), hypertension (40%), hair color change (depigmentation; 
38%), nausea (26%), anorexia (22%), and vomiting (21%).  These AEs were all 
reported at a higher incidence than in the placebo arm. Most of these events 
were Grade 1 or 2 using the National Cancer Institute Common Toxicity Criteria 
for Adverse Events (NCI CTCAE) Version 3.0. More Grade 3 AEs were reported in 
the pazopanib arm (33%) compared with the placebo arm (14%). The frequency of 
Grade 4 AE and Grade 5 event was similar between the pazopanib and placebo 
arms: Grade 4 in 7% and 6% respectively; Grade 5 in 4% and 3% respectively. At 
the time of the final overall survival (OS) analysis, a subsequent review of 
safety data did not reveal any changes to the previously observed safety 
profile; no new safety signals were detected. [Sternberg, 2013] 
 
Based on the analysis of the safety data integrated across the 3 RCC studies 
VEG102616, (a Phase II study of pazopanib monotherapy in subjects with 
advanced RCC), VEG105192, and VEG107769 (a single arm Phase III extension 

 
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study of pazopanib monotherapy in subjects with advanced RCC) as of 09 January 
2009 (N=593), the most common AEs and SAEs were similar to those observed in 
the pazopanib arm of VEG105192.   
Study VEG108844 was a randomized, open-label, parallel group Phase III non-
inferiority study to evaluate the efficacy and safety of pazopanib compared 
with sunitinib in subjects with advanced RCC who had not received prior 
systemic therapy for advanced or metastatic RCC. Approximately 876 eligible 
subjects (approximately 438 per treatment arm) were planned to be enrolled 
over the course of the study. However, due to higher than expected withdrawal 
rates and discordance rates between Independent Review Committee (IRC) and 
investigator assessments of progression, the protocol was amended to increase 
the number of subjects to approximately 1100 total by including all subjects 
enrolled in VEG108844 and VEG113078 (a substudy of VEG108844). VEG113078 was 
conducted in China, Korea, and Taiwan; enrolled the same subject population as 
VEG108844; and is almost identical in study design and conduct to allow 
integration of efficacy and safety data. 
 
A total of 1102 subjects were included in the safety population (pazopanib 554 
subjects; sunitinib 548 subjects). The median time on treatment was 8 months 
for pazopanib and 7.6 months for sunitinib. The overall frequency of AEs 
reported during the study was similar for each treatment group; 552 subjects 
(>99%) had AEs in the pazopanib arm and 544 subjects (>99%) had AEs in the 
sunitinib arm. However, differential safety profiles were observed between the 
treatment arms, with a statistically significant difference in frequencies 
(unadjusted for multiplicity) for many AEs. The most common AEs (>35% in 
either treatment arm) were diarrhea (63% in pazopanib arm, 57% in sunitinib 
arm), fatigue (55% in pazopanib arm, 63% in sunitinib arm), hypertension (46% 
in pazopanib arm, 41% in sunitinib arm), nausea (45% in pazopanib arm, 46% in 
sunitinib arm), decreased appetite (37% in pazopanib arm, 37% in sunitinib 
arm), dysgeusia (26% in pazopanib arm, 36% in sunitinib arm), and palmar-
plantar erythrodysesthesia (PPE) syndrome (or hand-foot syndrome [HFS]) (29% 
in pazopanib arm, 50% in sunitinib arm). Of these AEs, fatigue, HFS, and 
dysgeusia occurred more frequently in the sunitinib arm compared with the 
pazopanib arm based on 95% confidence interval (CI; unadjusted for 
multiplicity) for relative risk excluding 1. The proportion of subjects with 
diarrhea and hypertension was higher in pazopanib compared with sunitinib, but 
the 95% CI did not exclude a relative risk of 1. The proportion of subjects 
with maximum Grade 3 and 4 AEs was similar between the treatment arms, with no 
difference in the relative risk. Grade 3 AEs of increased ALT, increased 
aspartate aminotransferase (AST), and headache occurred more frequently in the 
pazopanib arm compared with the sunitinib arm. Grade 3 AEs of fatigue, 

 
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decreased appetite, HFS, neutropenia, mucosal inflammation, thrombocytopenia, 
leukopenia, decreased platelet count, anemia, and decreased neutrophil count 
occurred more frequently in the sunitinib arm compared with the pazopanib arm. 
Grade 5 AEs were reported in 13 (2%) subjects in the pazopanib arm and 19 (3%) 
subjects in the sunitinib arm. 
 
 
In VEG110727 (a randomized placebo-controlled Phase III study of pazopanib 
monotherapy in subjects with STS), the median time on pazopanib was 19.4 
weeks, as compared with 8.1 weeks in the placebo arm. The most common AEs 
(≥20%) reported in the pazopanib arm (as of 23 May 2011) were fatigue (65%), 
diarrhea (59%), nausea (56%), weight decreased (51%), hypertension (42%), 
decreased appetite (40%), hair color changes (39%), vomiting (33%), tumor pain 
(30%), dysguesia (28%), headache (23%), musculoskeletal pain (23%), myalgia 
(23%), gastrointestinal (GI) pain (23%), and dyspnea (20%). Twenty-eight 
percent of subjects on placebo and 63% of subjects on pazopanib experienced an 
AE of maximum Grade 3 or higher. The proportion of subjects who experienced 
maximum Grade 4 and Grade 5 AEs was similar in both treatment arms. 
 
An analysis of integrated safety data from VEG110727 and VEG20002 (a single 
arm Phase II study of pazopanib monotherapy in subjects with STS) showed a 
safety profile similar to that observed in the pazopanib arm of VEG110727 
alone. Increased rates of myocardial dysfunction, venous thrombo-embolic 
events, and pneumothorax were newly observed in the STS studies as compared to 
RCC. 
 
Rare but severe AEs previously described for VEGFR inhibitors, such as 
cardiac/cerebral ischemia, hemorrhage, and bowel perforation, were observed 
with pazopanib treatment. 
 
The most common SAEs occurring in subjects enrolled in all pazopanib oncology 
studies regardless of treatment assignment include diarrhea, abdominal pain, 
vomiting, dyspnea,hypertension (including 1 SAE of hypertensive crisis), 
pyrexia, 
anemia, 
dehydration, 
fatigue, 
pneumonia, 
pleural 
effusion, 
neutropenia, pulmonary embolism, increased ALT, and nausea. 
 
In study VEG105192 in subjects with RCC, the most common chemistry 
abnormalities, occurring almost twice as frequently on pazopanib compared with 
placebo included ALT (53% versus 22%), AST (52% versus 19%) and bilirubin 
elevations (36% versus 10%), hypophosphatemia (34% versus 11%), hypomagnesemia 
(26% versus 14%), hypoglycemia (17% versus 3%) and hypokalemia (9% versus 2%). 

 
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Most of these were Grade 1/2. The most common Grade 3/4 abnormalities were ALT 
and AST elevations.  Although leukopenia, neutropenia, and thrombocytopenia 
were more common on pazopanib than placebo, Grade 3/4 cytopenias were 
uncommon. 
 
In subjects with RCC,, the major laboratory abnormality appears to be 
elevation of hepatic enzymes, which typically occurred during the first 18 
weeks of treatment. As of 09 January 2009, the transaminase elevations were 
reversible in 96 (91%) of 106 subjects with elevated ALT ≥3×ULN; 7 of the 
remaining 10 subjects had limited or no follow-up to determine recovery and 3 
died of cancer progression with no follow-up ALT data.It was noted early in 
development that some of the subjects with elevated hepatic enzymes remained 
on study drug despite these elevations and had normalization of their 
transaminases while remaining on pazopanib (“adaptation”). Most subjects 
with transaminase elevations in whom dosing was interrupted could be 
successfully re-challenged. 
 
In Study VEG108844 in subjects with RCC, the worst-case toxicity grade changes 
from baseline for hematologic toxicity were higher in the sunitinib arm 
compared with the pazopanib arm and for chemistry worst-case toxicity grade 
changes were similar between the pazopanib and sunitinib arms. See the 
investigator brochure for details.  
 
1.1.3.2. 
Preliminary Efficacy Summary 
Pazopanib 800mg once daily has shown efficacy and/or encouraging efficacy 
signals in the following settings: 
 Renal Cell Carcinoma: In Study VEG102616, the primary analysis of the 
primary endpoint, progression-free survival (PFS), revealed a large and 
highly statistically significant improvement in PFS in the pazopanib-
treated subjects compared to placebo-treated subjects (HR 0.46, 95% 
confidence interval [CI] 0.34 to 0.62, p<0.0000001). The median PFS in 
the pazopanib arm was more than double that in the placebo arm: 9.2 
months (95% CI, 7.4, 12.9) versus 4.2 months (95% CI, 2.8, 4.2), 
respectively. The response rate (RR), defined as the percentage of 
subjects who achieved either a confirmed complete response (CR) or 
partial response (PR) according to Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria was significantly higher for the pazopanib arm 
compared with the placebo arm by Independent Review Committee (IRC) 
assessment (30% vs. 3%, p<0.001). In the pazopanib arm, the median 
duration of response was 58.7 weeks (95% CI, 52.1 to 68.1 weeks) and the 

 
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median time to response was 11.9 weeks (95% CI, 9.4 to 12.3 weeks) by 
IRC assessment [Sternberg, 2010]. The median overall survival (OS) at 
final analysis was 22.9 months in the pazopanib arm and 20.5 months in 
the placebo arm. The final OS was not statistically different between 
the pazopanib arm and the placebo arm in (HR = 0.91, stratified log-rank 
p-value, 0.224). Of note, 54% of subjects in the placebo arm received 
pazopanib, many starting early in the study, and an additional 12% 
received other systemic therapies.. 
 Soft Tissue Sarcoma: In the VEG110727 Study, a statistically significant 
improvement in PFS was observed in the pazopanib arm compared with the 
placebo arm.  The median PFS in the placebo arm was 7.0 weeks (95% CI: 
4.4, 8.1) and in the pazopanib arm was 20.0 weeks (95% CI: 17.9, 21.3), 
with a corresponding HR of 0.35 (95% CI: 0.26, 0.48, p<0.001) as 
assessed by independent radiology review.  The median OS at final 
analysis was 10.7 months in the placebo arm (95% CI:  9.0, 13.1) and 
12.6 months (95% CI: 10.9, 14.9) in the pazopanib arm; HR = 0.87 (97.57% 
CI: 0.67, 1.13, p=0.256).  In the VEG20002 Study, the rate of PFS at 12 
weeks, based on investigator assessment, was 18 of 41 subjects (43.9%) 
for leiomyosarcoma; 18 of 37 subjects (48.6%) for synovial sarcoma; 5 of 
19 (26.3%) for adipocytic sarcoma; and 16 of 41 subjects (39.0%) for 
other types of sarcoma 
 
 Ovarian cancer: 11 of 36 subjects (31%) experienced a cancer antigen-125 
(CA-125) response to pazopanib, with a median time to CA-125 response of 
29 days and median duration of response of 113 days. Excluding one 
subject whose CA-125 decreased before she received the first dose, the 
biochemical response was 28% (10 subjects). Overall response rate based 
on modified Gynecologic Cancer Intergroup (GCIG) criteria (incorporating 
CA-125, Response Evaluation Criteria in Solid Tumors (RECIST), and 
clinical assessment) was 18% in subjects with measurable disease at 
baseline, and was 21% in subjects without measurable disease at 
baseline. Median PFS was 84 days. 
 
 Advanced or metastatic soft tissue sarcoma: Rate of PFS at 12 weeks, based on 
investigator 
assessment, 
was 
18 
of 
41 
subjects 
(43.9%) 
for 
leiomyosarcoma; 18 of 37 subjects (48.6%) for synovial sarcoma; and 16 
of 41 subjects (39.0%) for other types of sarcoma [Sleijfer, 2008]. 
 
 Early-stage Non-Small Cell Lung Cancer (NSCLC): 30 of 35 subjects (86%) 
experienced a reduction in tumor volume after short-term use of 
pazopanib median duration of 16 days) as assessed by high-resolution 

 
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computed tomography (HRCT) after preoperative pazopanib treatment 
[Altorki, 2008]. 
 
 ErbB2-positive advanced or metastatic breast cancer: A higher response rate 
(36.2% versus 22.2%) by independent review at Week 12 was observed in 
subjects on combination lapatinib 1000mg once daily + pazopanib 400mg 
once daily compared with lapatinib 1500mg once daily as a monotherapy, 
respectively (VEG20007, [Slamon, 2008c]). 
 
 Inflammatory 
Breast 
Cancer: 
Investigator-assessed 
best 
ORR 
was 
numerically higher for combination lapatinib 1500 mg once daily + 
pazopanib 800 mg once daily compared with lapatinib 1500 mg once daily 
as a monotherapy [45% (90% CI: 30.9, 59.3) vs. 29% (90% CI: 17.2, 
43.3)], and for combination lapatinib 1000 mg once daily + pazopanib 400 
mg once daily compared with lapatinib 1500 mg once daily as a 
monotherapy [58% (90% CI: 43.3, 71.5) vs. 47% (90% CI: 32.8, 62.1)].  
However, no increase in PFS was observed compared to lapatinib alone 
 
 Cervical cancer: There was a 34% reduction in risk for progression for 
subjects receiving pazopanib relative to lapatinib (hazard ratio: 0.66; 
90% CI: 0.48, 0.91). The median time to investigator-assessed PFS was 
17.1 weeks in the lapatinib group and 18.1 weeks in the pazopanib (one-
sided p=0.013) 
 
1.1.4. 
Paclitaxel: Safety Summary 
Paclitaxel (TAXOL®) 
ADVERSE REACTIONS SIGNIFICANT—Percentages reported with single-agent therapy. 
Note: Myelosuppression is dose related, schedule related, and infusion-rate dependent (increased 
incidences with higher doses, more frequent doses, and longer infusion times) and, in general, 
rapidly reversible upon discontinuation. 
 >10%: 
Cardiovascular: Flushing (28%), ECG abnormal (14% to 23%), edema (21%), 
hypotension (4% to 12%) 
Dermatologic: Alopecia (87%), rash (12%) 
Gastrointestinal: Nausea/vomiting (52%), diarrhea (38%), mucositis (17% to 35%; 
grades 3/4: up to 3%), stomatitis (15%; most common at doses >390mg/m2), abdominal 
pain (with intraperitoneal paclitaxel) 
Hematologic: Neutropenia (78% to 98%; grade 4: 14% to 75%; onset 8-10 days, median 
nadir 11 days, recovery 15-21 days), leukopenia (90%; grade 4: 17%), anemia (47% to 
90%; grades 3/4: 2% to 16%), thrombocytopenia (4% to 20%; grades 3/4: 1% to 7%), 

 
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bleeding (14%) 
Hepatic: Alkaline phosphatase increased (22%), AST increased (19%) 
Local: Injection site reaction (erythema, tenderness, skin discoloration, swelling: 13%) 
Neuromuscular & skeletal: Peripheral neuropathy (42% to 70%; grades 3/4: up to 7%), 
arthralgia/myalgia (60%), weakness (17%) 
Renal: Creatinine increased (observed in KS patients only: 18% to 34%; severe: 5% to 
7%) 
Miscellaneous: Hypersensitivity reaction (31% to 45%; grades 3/4: up to 2%), infection 
(15% to 30%) 
 
 1% to 10%: 
Cardiovascular: Bradycardia (3%), tachycardia (2%), hypertension (1%), rhythm 
abnormalities (1%), syncope (1%), venous thrombosis (1%) 
Dermatologic: Nail changes (2%) 
Hematologic: Febrile neutropenia (2%) 
Hepatic: Bilirubin increased (7%) 
Respiratory: Dyspnea (2%) 
 
 <1% (Limited to important or life-threatening): Anaphylaxis, ataxia, atrial fibrillation, 
AV block, back pain, cardiac conduction abnormalities, cellulitis, CHF, chills, 
conjunctivitis, dehydration, enterocolitis, extravasation recall, hepatic encephalopathy, 
hepatic necrosis, induration, intestinal obstruction, intestinal perforation, interstitial 
pneumonia, ischemic colitis, lacrimation increased, maculopapular rash, malaise, MI, 
necrotic changes and ulceration following extravasation, neuroencephalopathy, 
neutropenic enterocolitis, ototoxicity (tinnitus and hearing loss), pancreatitis, paralytic 
ileus, phlebitis, pruritus, pulmonary embolism, pulmonary fibrosis, radiation recall, 
radiation pneumonitis, pruritus, renal insufficiency, seizure, skin exfoliation, skin 
fibrosis, skin necrosis, Stevens-Johnson syndrome, supraventricular tachycardia, toxic 
epidermal necrolysis, ventricular tachycardia (asymptomatic), visual disturbances 
(scintillating scotomata) 
 CONTRAINDICATIONS—Hypersensitivity 
to 
paclitaxel, 
Cremophor® 
EL 
(polyoxyethylated castor oil), or any component of the formulation 
1.1.5. 
Preliminary Safety and Efficacy Summary- Pazopanib and Paclitaxel 
Two dose-escalation phase I studies of pazopanib in combination with paclitaxel in subjects with 
advanced cancer have been completed.[Suttle, 2007; Tan, 2008] The first trial divided subjects 
into two groups, one receiving paclitaxel in combination with pazopanib, and the other receiving 
paclitaxel and carboplatin in combination with pazopanib.[Suttle, 2007] Paclitaxel administered 
D1, 8, 15 on a 28 day cycle was escalated (15-80mg/m2) with pazopanib daily starting on day 2, 
escalated from 400-800mg. The other group escalated every 3 week paclitaxel (80-225mg/m2) 
with carboplatin AUC 6 and pazopanib 800mg. Preliminary data on 9 subjects in the paclitaxel 
and pazopanib group yielded: grade 1/2 AEs of diarrhea, nausea, vomiting, fatigue, anorexia, 
dysguesia, rash, AST elevation, cough and hypertension except for one subject with grade 3 

 
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diarrhea. The pazopanib 800mg daily and paclitaxel 80mg/m2 weekly dose level was expanded 
given one DLT of an abscess. Six (83%) subjects demonstrated SD as the best response. 
Concomitant treatment with pazopanib increased paclitaxel AUC and Cmax (20-35%). The most 
tolerable regimen has not yet been identified.  
 
A second trial evaluated safety and toxicity, PK and efficacy in 25 subjects with dose escalations 
of both weekly paclitaxel (D1, 8, and 15 on a 28 day cycle) from 15-80mg/m2 and pazopanib 
daily for 28 days from 400-800mg.[Tan, 2008] The optimally tolerated regimen (OTR) was 
defined as pazopanib 800mg daily and paclitaxel 80mg/m2 weekly. Subjects received a median 
of 2.5 cycles, range of 1-8. Tumor types included: breast, colon, non-small cell lung, and 
esophageal cancer. One DLT was seen at the OTR, a grade 3 groin abscess. Most adverse events 
were grade 1/2 and included: gastrointestinal toxicities (nausea/vomiting/diarrhea/constipation), 
systemic symptoms (fatigue/anorexia), as well as rash, alopecia, visual disturbance, and liver test 
elevations. Twelve of 16 subjects treated at the OTR had dose modifications, most commonly for 
liver test elevation; 10 subjects had dose interruptions (7) or reductions (3) of pazopanib, and 11 
subjects had interruptions/delays (11) or reductions (5) of paclitaxel.  Three subjects were 
withdrawn due to an adverse event. Again, increased AUC and Cmax of paclitaxel were 
observed with pazopanib. Of the sixteen subjects treated at the OTR, 5 (31%) evidenced a PR 
and 10 (63%) evidence SD for greater than 8 weeks. 
1.2. 
Rationale 
No therapy to date has improved overall survival in melanoma.  New treatment modalities are 
critically important for this disease, which is the 6th leading cause of cancer in men and the 7th in 
women.  Melanoma is a highly vascular tumor and VEGF has previously been implicated in the 
evolution of its pathogenesis, being directly associated with the transition from radial/horizontal 
to vertical growth phase. The expression of VEGF in MM is associated with a worse overall 
prognosis [Birck, 1999; Gorski, 2003; Lacal, 2000; Marcoval, 1997; Salven, 1997; Simonetti, 
2002; Straume, 2001; Ugurel, 2001; Vlaykova, 1999].   
 
A phase II study of axitinib, an orally available small-molecule inhibitor of VEGFR-1, 2, and 3, 
in metastatic melanoma demonstrated an ORR of 19% in 32 patients Median overall survival 
was 6.8 months with a median progression free survival of 2.3 months [Fruehauf, 2008]. A 
recent study of carboplatin + paclitaxel chemotherapy combined with sorafenib biologic therapy 
resulted in progression-free survival (PFS) of 8.8 months (historical controls have PFS of 2−4 
months) in a 100-patient, single-arm, Phase II study [Flaherty, 2006].  Bevacizumab, in 
combination chemotherapies including paclitaxel, has also demonstrated antitumor in metastatic 
melanoma.  In a Phase II study evaluating carboplatin, weekly paclitaxel and bevacizumab, nine 
(17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at 
least 8 weeks. Median progression-free survival and median overall survival were 6 months and 
12 months, respectively [Perez, 2009].   
Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT. [Harris, 2008] 
In vitro and in vivo, pazopanib has demonstrated antiangiogenic activity as well as inhibition of 
xenograft tumor growth.  Established as tolerable, a randomized phase III trial to evaluate PFS in 
advanced RCC for pazopanib 800mg daily compared with placebo was initiated given a partial 
response (PR) rate at week 12 of 27% in a randomized discontinuation phase II trial of pazopanib 

 
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in metastatic RCC. [Hutson, 2008] In melanoma, a single agent phase II study with pazopanib is 
planned. In light of the relevance of angiogenesis in melanoma and possible additive or 
synergistic benefit of other antiangiogenesis agents in combination with chemotherapy, a Phase 
II study of pazopanib in combination with chemotherapy in advanced stage melanoma is 
warranted. 
2. 
OBJECTIVES 
2.1. 
Primary 
 To evaluate the 6-month progression-free survival (PFS) for subjects with unresectable 
Stage III and Stage IV melanoma.  
2.2. 
Secondary 
The secondary objectives are: 
 
To evaluate 1- and 2-year survival, objective response rate, clinical benefit rate 
(SD+PR+CR), and duration of response of subjects treated with pazopanib and 
paclitaxel. 
 
To assess safety of the combination of pazopanib and paclitaxel in this patient 
population.   
2.3. 
Exploratory Objectives 
 To observe angiogenic marker modulation by the drug combination. 
 To identify intra-tumoral biomarkers that correlate with or are predictive of clinical 
response/benefit to pazopanib and to identify gene and/or protein expression in tumor 
tissue that may be associated with clinical outcomes or response to therapy.   
 To correlate PD effects (increased diastolic blood pressure), plasma proteins (serum 
VEGF, soluble VEGF receptor 2, serum HIF and serum TSP1) to tumor biopsy 
expression levels and clinical outcome.    
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is a Phase II single-arm, open-label, clinical trial evaluating the efficacy and safety of 
pazopanib in combination with paclitaxel as first line therapy for subjects with unresectable 
Stage III and Stage IV melanoma.  Previous cytokine therapy and immunotherapy is permitted.  
Subjects must have measurable disease per RECIST.  Subjects who are not candidates for 
curative intent treatments are eligible for this study. 

 
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Approximately 60 eligible subjects will be enrolled.  Twenty-one subjects will be entered into 
the first stage of a 2-stage Simon Minimax design.  If there are 3 responses, 39 additional 
subjects will be enrolled in Stage 2.   
A subject must first sign a written informed consent prior to any study related assessments or 
procedures. After signing the informed consent, candidate subjects will be screened against all 
the eligibility criteria. During the Screening/Baseline Period, a subject will be evaluated for 
study eligibility per protocol as defined in the inclusion/exclusion criteria [See Section 4.2 and 
Section 4.3]. Eligible subjects must complete all the required baseline safety assessments and 
disease assessments prior to enrollment and the first dose of study treatment [See Table 6 and 
Section 6.1 for Screening/Baseline assessments].  
The study consists of a Screening/Baseline Period, Treatment Period and a post-treatment 
Follow-Up Period.  
All subjects will be enrolled to receive pazopanib 800mg daily dosing in combination with 
paclitaxel. Subjects are permitted to receive full supportive care during the study, including 
transfusion of blood and blood products, treatment with antibiotics, anti-emetics, anti-diarrheal 
agents, analgesics, erythropoietin, or bisphosphonates, when appropriate. 
Study treatment will continue until subjects experience disease progression, death, unacceptable 
toxicity, or withdrawal of consent for any other reasons. During the Treatment Period, safety and 
disease assessments will be performed regularly according to schedules displayed in the Time 
and Events Table, Table 6.  
Subjects who progress following study treatment may continue to receive medical treatment 
according to the local standard of care as per the investigator’s discretion and at the subject’s 
wish.  
 
Subjects who withdraw from study treatment due to unacceptable toxicity will continue to have 
regular disease assessments until disease progression or initiation of another anti-cancer 
treatment(s) [See Table 6 for assessments during disease progression follow-up (FU)].  
All study subjects will be followed until death due to any cause, withdrawal of consent, or until 2 
years following the last subject enrolled, whichever comes first. 
3.2. 
Discussion of Design 
3.2.1. 
Dose Rationale for Pazopanib 
Animal models (mice with human tumor xenografts and the Matrigel plug model of 
angiogenesis) using an osmotic pump to maintain a steady-state plasma concentration of 
pazopanib suggest that a concentration of >40 micromolar (μM) (>17,500ng/mL) was required 
for optimal in vivo activity. These results were further supported by studies showing that the 
inhibition of VEGF-stimulated receptor phosphorylation in mouse lungs also required similar 
plasma pazopanib concentrations for reproducible activity. The activity of pazopanib against 
human and mouse VEGFR-2 kinase is similar (IC50 of 23 and 9nM against human and mouse 

 
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VEGFR-2, respectively); therefore, similar effective concentrations are expected in humans.  In 
vitro and in vivo results, taken together, suggest that steady-state plasma pazopanib 
concentrations of at least 17,500 – 22,000ng/mL (40 to 50μM) were required to optimally inhibit 
VEGFR-2 activity. 
Evidence of biological activity associated with VEGFR inhibition was observed in cancer 
subjects in study VEG10003.  A concentration-effect relationship was demonstrated between the 
plasma pazopanib concentration 24 hours after administration (C24) on Day 22 and the 
probability of an increase in blood pressure.  The C24 at which there was a 50% probability of an 
in increase in blood pressure requiring a modification of antihypertensive therapy or a 15mmHg 
increase in mean MAP was approximately 21,000ng/mL.  Preliminary DCE-MRI data indicate 
that doses of 800mg once daily and 300mg twice daily demonstrated effects consistent with a 
decrease in tumor perfusion. Mean (%CV) pazopanib C24 values were 24,800ng/mL (42.0) and 
30,900ng/mL (31.5) in the 800mg once daily and 300mg twice daily dose groups, respectively. 
These results suggest that plasma pazopanib concentrations greater than 20,000ng/mL (46µM) 
maintained over the entire dosing interval are associated with biologic activity associated with 
VEGFR inhibition in cancer patients. 
Evidence of clinical activity after pazopanib treatment with 800mg OD has been observed in 
patients with metastatic RCC in study VEG102616. Pazopanib doses ranging from 50mg three 
time weekly to 2000mg once daily (QD) were evaluated in the Phase I dose-escalation study 
VEG10003.  Pazopanib 800mg QD dosing was relatively well tolerated and C24 concentrations 
were maintained above 40 μM in over 85% of patients who were treated at this dose in study 
VEG10003. No consistent increase in exposure was observed when the dose was increased from 
800mg QD up to 2000mg QD and no maximum tolerated dose (MTD) was established in this 
study. Thus, a dose of pazopanib of 800mg QD was selected as the dose to be tested in this trial. 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
Subjects who meet all of the following inclusion/exclusion criteria will be eligible for enrollment 
into the study. Approximately 60 subjects will be enrolled into the study. 
4.2. 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
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.  Note: It is not necessary that informed consent be obtained within the 
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2. Histologically confirmed cutaneous melanoma with 1) unresectable Stage III disease, or 
2) Stage IV disease by AJCC criteria. 
3. Must have measurable disease [i.e. with at least one measurable lesion, per RECIST]. A 
measurable lesion is defined as a lesion that can be accurately measured in at least one 
dimension with the longest diameter ≥20mm using conventional techniques or ≥10mm 
with spiral CT scan. 
Note: Subjects should be excluded if all baseline measurable lesions are within 
previously irradiated areas.  Subjects participating in the exploratory analysis shall not 
have the biospied lesion(s) as the only sites of measurable disease. 
4. ECOG performance status of 0 or 1 [See Section 11.2, Appendix 2 for a description] 
5. Age  18 years old 
6. 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).  
Subjects must discontinue HRT prior to study enrollment due to the potential for 
inhibition of Cytochrome P450 (CYP) enzymes that metabolize estrogens and progestins 
[See Section 5.8]. For most forms of HRT, at least 2-4 weeks must elapse between the 
cessation of HRT and determination of menopausal status; length of this interval depends 
on the type and dosage of HRT.  If a female subject is determined not to be post-
menopausal, they must use adequate contraception, as defined immediately below. 
Childbearing potential, including any female who has had a negative serum pregnancy 
test within 2 weeks 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 follow: 
 An intrauterine device with a documented failure rate of less than 1% per year. 
 Vasectomized partner who is sterile prior to the female subject’s entry and is the sole 
sexual partner for that female. 

 
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 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. 
 Double-barrier contraception (condom with spermicidal jelly, foam suppository, or 
film; diaphragm with spermicide; or male condom and diaphragm with spermicide). 
 
Note: Oral contraceptives are not reliable due to potential drug-drug interactions. 
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. 
A male with a female partner of childbearing potential is eligible to enter and participate 
in the study if he uses a barrier method of contraception or abstinence during the study.  
7. Adequate organ system functions as defined in Table 1. 
Table 1.  Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematologic 
 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobin1 
9 g/dL 
Platelets 
100 X 109/L 
International normalized ratio (INR) 
1.2 X upper limit of normal (ULN) 
Partial thromboplastin time (PTT) 
1.2 X ULN 
Hepatic 
 
Total bilirubin 
1.5 X ULN  
AST and ALT 
2.5 X ULN 
Renal 
 
Calculated creatinine clearance2 
30 mL/min 
Urine Protein to Creatinine Ratio (UPC)3 
<1 
1. 
Subjects may not have had a transfusion within 7 days of screening assessment.  
2. 
See Section 11.6, Appendix 6 
3. 
If UPC 1, then a 24-hour urine protein must be assessed.  Subjects must have a 24-hour urine 
protein value <1g to be eligible. 
 
8. Corrected serum calcium concentration within normal range per local clinical laboratory 
standard.  
9. Left ventricular ejection fraction (LVEF) lower limit of normal (LLN) as assessed by 
echocardiography or multigated acquisition (MUGA) scan. 
 

 
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4.3. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Prior treatment with cytotoxic anti-cancer therapy.  (Previous cytokine or investigational 
immunotherapy are permitted, but must be completed 28 days prior to first dose of study 
medication). 
2. Prior use of other investigational or licensed tyrosine kinase inhibitors (TKIs), or agents 
which target VEGF or VEGF receptors (ie bevacizumab, VEGF-Trap).  
3. Known history of dose-limiting hypersensitivity reactions to paclitaxel/Cremophor EL. 
4. Pregnant or lactating female. Female subjects who are lactating are eligible if they 
discontinue nursing prior to the first dose of study drug and refrain from nursing throughout 
the treatment period and for 14 days following the last dose of study drug. 
5. Melanoma of ocular origin. 
6. History of another 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-melanomatous skin carcinoma or 
successfully treated in situ carcinoma are eligible. 
7. Life expectancy < 3 months. 
8. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal 
carcinomatosis except for subjects who have previously-treated CNS metastases (surgery  
radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria: 
a. Are asymptomatic 
and, 
b. Have had no clinical evidence of active CNS metastases for 28 days prior to 
enrollment 
and, 
c. Have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC) 
9. Clinically significant gastrointestinal abnormalities including, but not limited to: 
a. Malabsorption syndrome  
b. Major resection of the stomach or small bowel that could affect the absorption of 
study drug 
c. Active peptic ulcer disease 
d. Inflammatory bowel disease  
e. Ulcerative colitis, or other gastrointestinal conditions with increased risk of 
perforation  
f. History of abdominal fistula, gastrointestinal perforation, or intra abdominal 
abscess within 28 days prior to beginning study treatment. 

 
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10. Presence of uncontrolled infection. 
11. Prolongation of corrected QT interval (QTc) >480 milliseconds (msecs). 
12. History of any one or more of the following cardiovascular conditions within the past 6 
months: 
a. Cardiac angioplasty or stenting 
b. Myocardial infarction 
c. Unstable angina 
d. Symptomatic peripheral vascular disease 
e. Class III or IV congestive heart failure, as defined by the New York Heart 
Association (NYHA) [See Section 11.4, Appendix 4] 
13. History of cerebrovascular accident, pulmonary embolism or untreated deep venous 
thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been 
treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.  
14. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150mmHg or 
diastolic blood pressure (DBP) of ≥ 90mmHg]. 
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to 
study entry.  Blood pressure must be re-assessed on two occasions that are separated by a 
minimum of 24 hours. The mean SBP/DBP values from each blood pressure assessment 
must be 150 systolic and 90 diastolic mmHg in order for a subject to be eligible for the 
study.  
15. Prior major surgery or trauma within 14 days of the first dose of study drug and/or presence 
of any non-healing wound, fracture, or ulcer.  
16. Evidence of active bleeding or bleeding diathesis 
17. Hemoptysis within 6 weeks of first dose of study drug. 
18. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could 
interfere with subject’s safety, obtaining informed consent or compliance to the study.  
19. Use of any prohibited medications within 14 days of the first dose of study medication.  
20. Radiation therapy within 28 days of the first dose of study drug. 
21. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is 
progressing in severity. 
22. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically 
related to pazopanib. 

 
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4.4. 
Withdrawal Criteria 
4.4.1. 
Subject Withdrawal from Study Treatment  
Study treatment will continue until subjects experience disease progression, death, unacceptable 
toxicity, or withdrawal of consent for any other reasons.  
Subjects whose disease progresses following study treatment may continue to receive medical 
treatment according to the local standard of care as per the investigator’s discretion and at the 
subject’s wish.  
Subjects who withdraw from study treatment due to unacceptable toxicity will continue to have 
regular disease assessments until disease progression or initiation of another anti-cancer 
treatment(s) [See Table 6 for assessments during disease progression follow-up]. 
4.4.2. 
Subject Withdrawal from Study Participation 
A subject may withdraw from study participation (i.e. withdraw consent) at any time for any 
reason.  
If a subject withdraws from study participation during the Treatment Period, the investigator 
must make every effort to perform all the assessments listed in the Study Treatment 
Discontinuation Visit in Table 6 Time and Events Table. Disease status should be assessed if not 
performed within the last 8 weeks.  
If the subject withdraws from study participation during the progressive disease (PD) Follow-Up 
period, the investigator must make every effort to have the following evaluations and document 
the results in the CRF: disease assessments, ECOG performance status (ECOG PS) and 
continuation or resolution of treatment-related AEs/serious adverse events (SAEs) [see Table 6].  
If the subject withdraws from study participation during the Survival Follow-Up period, the 
subject should be evaluated for continuation or resolution of treatment-related AEs/SAEs. 
For data collection purposes, subjects are considered as completing the study if they have died 
during the Study Treatment or Follow-Up Periods, are lost to follow-up, or withdraw consent. If 
a subject has been treated or followed until death, the death certificate should be obtained, if 
possible, and the cause of death should be evaluated and documented. 
4.5. 
Screen and Baseline Failures 
A subject is considered to be a screen/baseline failure if the subject signs the informed consent, 
but withdraws before study enrollment.  All potential subjects who are screened for enrollment in 
this study including screening/baseline failures will be listed on the Subject Screening 
Log/Identification List.  Reasons for exclusion will be recorded for potential subjects who do not 
enter the study. 

 
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5. 
STUDY TREATMENTS 
5.1. 
Description of Investigational Product 
5.1.1. 
Pazopanib 
The investigational product, pazopanib monohydrochloride salt (coded as GW786034B) tablets 
are provided as 200mg and 400mg tablets, which contain pazopanib monohydrochloride salt 
equivalent to 200mg and 400mg of the free base, respectively. 
5.1.2. 
Paclitaxel 
Paclitaxel used in this study will be supplied from commercial sources. 
5.2. 
Dosage and Administration 
5.2.1. 
Pazopanib 
Pazopanib is provided as an open-label study medication. Starting on Day 1 of the Treatment 
Period, each subject will receive 800mg (2 X 400mg tablets) of study medication administered 
once daily by mouth. The 200mg tablets of study medication are provided to subjects who need 
dose adjustments during the study [see Section 5.3.1 for instructions on dose modification.] 
Study medication should be taken without food at least one hour before or at least two hours 
after a meal. The time of day for administration of study medication should be relatively 
constant. If a subject misses a dose, the subject should take the dose as soon as possible, but not 
less than 12 hours 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. In the event of vomiting 
at any time after taking a dose of study medication, subjects should wait until the time of the next 
scheduled dose to take study medication. 
5.2.2. 
Paclitaxel 
Paclitaxel will be administered intravenously as approximately 1-hour infusions weekly for 3 
weeks followed by a 1-week rest period.  The starting dose will be 80mg/m2 weekly.  All 
patients should receive pretreatment for paclitaxel infusions, with oral or IV corticosteroids, 
diphenhydramine or equivalent histamine H1 antagonists, and cimetidine or equivalent histamine 
H2 antagonists, according to standard of care.  The weekly paclitaxel dose may be reduced to 
65mg/m2 for individual infusions or future cycles based on tolerability; guidelines for re-
escalation to 80mg/m2 upon recovery of toxicity are provided.  Paclitaxel may be discontinued at 
the discretion of the investigator due to achievement of maximum benefit or tolerability.   
The ideal duration of treatment cycles in this study is 4 weeks, with paclitaxel administered 
weekly during the first 3 weeks of each cycle, and pazopanib administered daily, continuously.  
In the event of paclitaxel interruption of at least one week due to reversible toxicity, a new cycle 
should begin, with the plan to deliver 3 consecutive weekly paclitaxel doses to prevent 

 
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unnecessary reduction in paclitaxel dose-intensity.  Therefore, after each rest from paclitaxel 
(including those due to toxicity), a new cycle should begin, with the plan to deliver 3 consecutive 
weekly paclitaxel doses.   
5.3. 
Dose Modifications for Toxicity 
5.3.1. 
Pazopanib Dose Modifications 
Dose interruptions or reductions may be required following potential drug-related toxicities. 
Hypertension, 
proteinuria, 
hepatotoxicity, 
bleeding 
events, 
vascular 
thrombosis, 
thrombocytopenia/neutropenia, and other adverse events have been reported in response to 
treatment with pazopanib. 
 
At each visit during the Treatment Period, subjects should first be evaluated for the occurrence of 
AEs and laboratory abnormalities. Specific recommendations for management of these possible 
AEs along with guidelines for dose delay/modification or discontinuation of study treatment are 
provided in Table 2. Dose-adjustments are to be exercised whenever clinically indicated. If dose 
reduction is necessary, two dose reductions are permitted in a stepwise fashion (initially to 
600mg and subsequently to 400mg if necessary) to achieve resolution of toxicity to grade 1 or 
baseline. If the toxicity does not recur or worsen, the dose can then be increased step-wise back 
to 600mg and 800mg after monitoring for 10-14 days at each step if toxicity does not recur or 
worsen. 
Interruptions for more than 14 days due to toxicity or to reasons other than toxicity (unplanned 
travel or vacation, or lack of transportation to the site), should be avoided. 
 

 
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Table 2. Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
AE Terms & Descriptions  
Dose Modification Algorithms 
Hypertension 
 
(A). Asymptomatic and persistent 
SBP of 150 and <170 mmHg, or 
DBP 90 and <110 mmHg, or a 
clinically significant increase in DBP 
of 20 mmHg. 
Step 1. Continue study treatment with 800mg dose.  
Step 2. Adjust current dose of or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled1 blood pressure (BP). If BP is not well-
controlled within 2 weeks, follow Step 1 in scenario (B). 
(B). Symptomatic, or SBP 170 
mmHg, or DBP 110 mmHg, or 
failure to achieve well-controlled BP 
within 2 weeks in scenario (A).  
Step 1. Interrupt study treatment. 
Step 2. Adjust current or initiate new antihypertensive medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled BP.  
Step 4. Restart study treatment at lower dose2 once BP is well-controlled1.  
(C). Two or more symptomatic 
episodes of hypertension despite 
modification 
of 
antihypertensive 
medication(s) and reduction of study 
medication dose. 
Discontinuation of study treatment and follow-up per protocol. 
Proteinuria 
UPC <3g 
Continue study treatment with 800mg per day dose. Monitor as clinically 
indicated. 
UPC ≥3g 
Step 1:  Obtain a 24-hr urine protein. 
Step 2:  If 24-hour urine protein is <3g, subject may continue treatment at 
800mg/day. 
OR 
If 24-hour urine protein is ≥3g, interrupt treatment until UPC returns to <3g. 
Restart therapy at  lower dose2. Monitor the subject by collecting 24-hour 
urine samples at the start of each 28-day treatment interval for the 
remainder of the overall treatment period.  
Step 3:  If 24-hour urine protein is ≥3g following repeat dose reductions, 
discontinue treatment and follow-up per protocol. 

 
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AE Terms & Descriptions  
Dose Modification Algorithms 
Hemorrhage/Bleeding/Coagulopathy 
Grade 1 
Continue study treatment with 800mg dose; monitor as clinically indicated. 
Grade 2 
Step 1. Interrupt study treatment until the AE resolves to  Grade 1.  
Step 2. Restart treatment with lower dose1; monitor as clinically indicated. 
Grade 3 or 4, or  
Recurrent Grade 2 event after 
dose interruption/reduction. 
Discontinuation of study treatment and follow-up per protocol.  
Note: If abnormality is not clearly associated with clinical consequences, 
contact the Lead Investigator to discuss the potential for continuation of 
study treatment. If agreed, subject may restart treatment at lower dose2.  
Vascular Thrombosis 
Grade 2 
Continue study treatment with 800mg dose; monitor as clinically indicated. 
Grade 3 or  
asymptomatic Grade 4 
Step 1. Interrupt study treatment.  
Step 2. Start to treat the subject with Low Molecular Weight Heparin 
(LMWH). Note: Coumadin® is prohibited per protocol. 
Step 3. Resume study treatment at 800mg during the period of full-dose 
anticoagulation if all of the following criteria are met:  
The subject must have been treated with LMWH for at least one week. 
No Grade 3 or 4 hemorrhagic events have occurred while on 
anticoagulation treatment. 
Subject should be monitored as clinically indicated during anticoagulation 
treatment and after resuming study treatment. 
Symptomatic Grade 4 
Discontinuation of study treatment and follow-up per protocol.  
Thrombocytopenia /Neutropenia   
Grade 1 or 2 
Continue study treatment with 800mg dose; monitor as clinically indicated.  
Grade 3 or 4 
Step 1. Interrupt study treatment until toxicity reduced to ≤Grade 2. 
Step 2. Restart study treatment with lower dose.2, 
Recurrent Grade 3/4 event after 
dose reduction 
Discontinuation of study treatment and follow-up per protocol.   
Note: If subject is benefiting from study treatment contact the Lead 
Investigator to discuss course of action.  
Anemia:  Note no dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding as noted 
above 
Other Clinically Significant Adverse Events4 
Grade 1 
Continue study treatment with 800mg dose; monitor as clinically indicated. 
Grade 2 or 3, if clinically significant  
Step 1. Interrupt study treatment until toxicity resolves to  Grade 1. 
Step 2. Restart study treatment at a lower dose2; monitor as clinically 
indicated3.  
Recurrent Grade 2/3, if clinically 
significant 
Discontinuation of study treatment and follow-up per protocol.   
 
Grade 4 
Discontinuation of study treatment and follow-up per protocol.   
Note: If the subject is benefiting from therapy contact the Lead Investigator 
to discuss course of action.   
1. Well-controlled BP defined as mean SBP <150mmHg and mean DBP <90mmHg.  
2. Dose should be reduced by 200mg (ie 800mg to 600mg or 600mg to 400mg)  
a. 
Adverse events are graded according to NCI Common Terminology Criteria for Adverse Events v4.0  
b. 
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure. 
 
Liver toxicity 
In the event of treatment emergent hepatotoxicity, potential contributing factors such as 
concomitant medications, viral hepatitis, choledocholithiasis, and hepatic metastases should be 
investigated. Concomitant medications known to be hepatotoxic which may be contributing to 
liver dysfunction should be discontinued or replaced with alternative medications to allow for 
recovery of liver function. As generally understood, ALT >3x ULN and concomitant bilirubin 

 
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>2.0xULN (>35% direct bilirubin), in the absence of elevated alkaline phosphatase or biliary 
injury, suggests significant liver injury. Table 3 provides guidelines for hepatotoxicity 
monitoring.  
Note: As many subjects are taking multiple concurrent medications it is critical to do a thorough 
evaluation of the subject’s concurrent medications, identify and discontinue those with known 
hepatotoxicity and replace with a non-hepatotoxic equivalent for the same indication if 
necessary. 
Table 3. Guidelines for Management of Treatment Emergent Hepatotoxicity 
AE Terms & Descriptions  
Dose Modification Algorithms 
(A). ALT of ≤3.0 x ULN  
Continue study treatment at 800mg with full panel liver function tests 
(LFTs)1 monitored as per protocol. 
(B). ALT >3.0 x ULN to  ≤8.0 x ULN 
without bilirubin elevation (defined 
as total bilirubin <2.0 x ULN or direct 
bilirubin 
≤35%) 
and 
without 
hypersensitivity 
symptoms 
(e.g., 
fever, rash)  
Continue study treatment at 800mg.  
Perform the following assessments for excluding hypersensitivity and other 
contributing factors:  
Eosinophil count 
Viral serology for hepatitis A, B and C 
Liver imaging 
Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTs weekly or more frequently if clinically indicated until ALT/AST reduced 
to Grade 1.   
If the subject is withdrawn from study treatment, follow up per protocol. 
(C). 
ALT 
>3.0 
x 
ULN 
with 
concomitant elevation in bilirubin 
(defined as total bilirubin 2.0 x 
ULN; with direct bilirubin >35%) or 
with 
hypersensitivity 
symptoms 
(e.g., fever, rash).  
 
Or 
 
(D). ALT >8.0 x ULN without 
concomitant elevation in bilirubin 
(defined as total bilirubin 2.0 x 
ULN; with direct bilirubin >35%) 
 
Or 
 
(E). Bilirubin elevation (defined as 
total bilirubin 3.0 x ULN) without 
concomitant transaminase 
elevation 
Interrupt study treatment immediately  
Consult a hepatologist and perform the following assessments to identify co-
contributing factors: 
Eosinophil count 
Viral serology for hepatitis A, B, C and E, cytomegalovirus (CMV), Epstein-
Barr virus (EBV IgM antibody, or heterophile antibody, or monospot testing) 
Anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-
mitochondrial antibody 
Serum creatinine phosphokinase (CPK) for possible muscle injury caused 
LFT elevation 
Liver imaging (ultrasound or CT scan) 
Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTs weekly or more frequently if clinically indicated until LFTs reduced to 
Grade 1.   
 
No further treatment with pazopanib will be considered. 
 
 

 
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c. 
Full panel LFTs include: AST, ALT, alkaline phosphatase, -GT and total bilirubin. If at any time the total 
bilirubin is > 1.5 x ULN, perform bilirubin fractionation for direct and indirect bilirubin 
a. 
 
For isolated total bilirubin elevation without concurrent ALT (defined as ALT <3 X ULN), 
following the guideline below:  
 Perform bilirubin fractionation at any time when total bilirubin is >1.5 X ULN.  
 If total bilirubin is 2.0 X ULN and no bilirubin fractionation can be performed: dose 
interruption, follow up weekly with LFT until total bilirubin returned to 1.5 X ULN, 
then rechallenge. 
 If total bilirubin is 2.0 X ULN and direct bilirubin is <35%, continue dosing at 800mg 
dose, perform full panel LFT weekly until total bilirubin returned to 1.5 X ULN. 
 If total bilirubin is 2.0 X ULN and direct bilirubin is 35%:  dose interruption, follow 
up weekly with LFT until total bili returned to 1.5 X ULN, discuss with before 
rechallenge. 
 If total bilirubin is 3.0 x ULN, permanently discontinue dosing.  
 
Fatigue and asthenia 
Fatigue and asthenia are commonly reported symptoms in patients with cancer. Both fatigue and 
asthenia have been reported with pazopanib and other angiogenesis inhibitors in this class. 
Although the etiology of these events is generally unknown, hypothyroidism has been reported 
with this class of agents [Fruehauf, 2008] and may be a contributing factor in some patients with 
fatigue and asthenia. 
To avoid any delay in the treatment of easily manageable conditions such as electrolyte disorders 
and to quickly recognize possible serious conditions such as cardiac dysfunction, Novartis 
recommends the following steps when caring for subjects with fatigue and asthenia.  Subjects 
complaining of grade 2, 3, or 4 fatigue and/or asthenia should be investigated as appropriate 
including at a minimum the items outlined below. 
 
Subjects with grade 3 or more fatigue and/or asthenia should be seen immediately. 
 
A workup should include a detailed history and physical examination, measurement of 
serum electrolytes, liver function tests, an electrocardiogram, chest x-ray, thyroid 
function tests, and an early morning cortisol.   
 
Electrolyte abnormalities should be corrected and adrenal insufficiency or 
hypothyroidism should be treated with replacement therapy.  
 
An ACTH stimulation test should be performed if the cortisol concentration is 
<10mcg/dL (280nmol/L).  
 
If the subject's history or physical examination point towards symptoms or signs of 
congestive heart failure, the appropriate investigations should be performed including 
an echocardiogram.  
 
Subjects should be closely monitored on a weekly basis or more frequently if clinically 
indicated for duration of severe fatigue and asthenia. 

 
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Pazopanib dose and schedule should be adjusted according to dose adjustment guidelines in the 
protocol.  Please contact the Lead Investigator or study contact if you require further guidance. 
Abdominal pain 
Abdominal pain is not an uncommon symptom with vascular endothelial growth factor (VEGF) 
receptor antagonists, of which pazopanib is one.  Bowel perforations have been reported in 
clinical trials of pazopanib and with other agents in this class.  Bowel perforations have been 
associated in some patients with tumor in the bowel wall, or diverticulitis, while in others there 
has been no clear explanation. 
Although bowel perforation is a rare event, investigators and study staff at the site are advised to 
be vigilant of this potential complication in subjects receiving pazopanib.   
 
5.3.2. 
Paclitaxel Dose Reduction 
The highest paclitaxel dose intensity possible for each subject should be maintained.  In the event 
paclitaxel toxicity requires sustained dose reduction to 65mg/m2, upon recovery, the paclitaxel 
dose may be re-escalated to 80mg/m2 weekly at the discretion of the investigator.  Subjects 
requiring frequent omissions or dose reductions for individual infusions (eg, one-half of 
administered doses during a 2-cycle period), may discontinue treatment with paclitaxel and 
resume therapy with pazopanib monotherapy per investigator discretion. 
Hematological Toxicity 
A complete blood count must be obtained prior to each paclitaxel dose.  Paclitaxel dose 
reductions should be made according to Table 4: 
Table 4.  Paclitaxel Dose Reductions for Hematological Toxicity 
 Granulocytes* 
  
Platelets 
Paclitaxel Dose 
> 1200/mm3 
and 
> 100,000/mm3 
80mg/m2 
1000-1199/mm3 
or 
75,000-99,000/mm3 
65mg/m2 single dose only 
< 1000/mm3 
or 
< 75,000/mm3 
**Hold 
*  For this purpose, the terms neutrophil and granulocyte are used interchangeably.  
 
**  Hold therapy until granulocytes > 1200/mm3 and platelets > 100,000/mm3.   
Paclitaxel infusions reduced to 65mg/m2 according to the guidance in Table 4 should be followed 
by re-escalation to 80mg/m2 unless the subject experiences one of the following: 
        Fever (> 38.5C) associated with granulocytes < 1000/mm3 
        Absolute granulocyte count < 500/mm3 for > 5 days 
        Significant bleeding associated with a platelet count < 40,000/mm3 
        Any platelet count < 20,000/mm3 

 
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In the event the above hematological toxicities are observed, the paclitaxel dose should be 
reduced to 65mg/m2 for subsequent infusions after hematological recovery. No re-escalation will 
be allowed.  If the above severe hematologic toxicities recur in subsequent cycles despite dose 
reduction, the subject should be evaluated for discontinuation of paclitaxel treatment. 
Filgramostim support is allowed. 
 
Hepatic Toxicity 
AST/ALT and total bilirubin must be obtained prior to the start of each cycle of therapy.  Liver 
functions contributing to dose modification decisions may be the worst during the previous cycle 
or those observed prior to start of the next cycle.  Paclitaxel dose should be modified according 
to Table 5 for liver function abnormalities considered to be attributable to treatment with 
paclitaxel or paclitaxel in combination with pazopanib. 
 
Table 5.  Paclitaxel Dose Reductions for Hepatic Toxicity 
 AST/ALT 
  
Bilirubin 
Paclitaxel Dose 
< 5 x ULN 
and < 2.0mg/dL 
80mg/m2 
5-10 x ULN 
or 
2.1-3.0mg/dL 
65mg/m2 
> 10 x ULN 
or 
> 3.0mg/dL 
*Hold 
  
*Hold therapy until AST < 10 x ULN and bilirubin < 3.0mg/dL.  If paclitaxel must be held for  
3 weeks to allow for resolution of hepatic toxicity, the subject should be evaluated for 
discontinuation of paclitaxel treatment.  Subjects requiring a delay in paclitaxel therapy due to 
hepatic toxicity should be evaluated for possible progressive hepatic disease.  
Anaphylaxis/Hypersensitivity 
Mild symptoms (e.g. mild flushing, rash pruritis): No treatment needed. Supervise at bedside and 
complete paclitaxel infusion. 
Moderate symptoms (moderate flushing, rash, mild dyspnea, chest discomfort):  Stop paclitaxel 
infusion.  Administer appropriate treatment.  After recovery of symptoms, resume infusion at 
half the previous rate for 15 minutes.  If no further symptoms occur, complete the infusion at the 
full dose rate.  If symptoms recur, the reaction should be reported as an adverse event and the 
subject should be evaluated for discontinuation of paclitaxel treatment. 
Severe life-threatening symptoms (e.g. hypotension requiring pressor therapy, angioedema, 
respiratory distress requiring bronchodilators, generalized urticaria):  Stop the infusion and 
administer appropriate treatment.  Add epinephrine or bronchodilators if needed.  The reaction 
should be reported as an adverse event and the subject should be discontinued from paclitaxel 
treatment. 
Peripheral Neuropathy 

 
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If grade 3 toxicity develops, paclitaxel should be held until neuropathy recovers to < grade 1.  
When treatment is resumed, the paclitaxel dose should be reduced to 65mg/m2.  If grade 3 
neuropathy persists for > 3 weeks or recurs after dose reduction, the subject should be evaluated 
for discontinuation of paclitaxel treatment. If grade 2 toxicity develops, paclitaxel dosing should 
be delayed until neuropathy recovers to < grade 1. Full dosing can be resumed unless the delay in 
therapy was > 3 weeks, in which case the paclitaxel dose should be reduced to 65mg/m2.    
Other Toxicities 
If the subject develops any other grade 3 or 4 toxicity thought to be related to paclitaxel, 
paclitaxel should be held until symptoms resolve to grade 1 or less.  When treatment is resumed, 
the paclitaxel dose should be reduced to 65mg/m2.  If grade 3 toxicity persists for > 3 weeks or 
recurs after dose reduction, the subject should be evaluated for discontinuation of paclitaxel 
treatment. 
5.4. 
Packaging and Labeling 
The contents of the label will be in accordance with all applicable regulatory requirements.   
 
Votrient commercial available supply with auxiliary label will also be provided by Novartis. 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). 
 
5.5. 
Handling and Storage 
Study medications will be dispatched to a site only after receipt of required documents in 
accordance with applicable regulatory requirements and Novartis  procedures. 
Study medications must be dispensed or administered according to procedures described herein.  
Only subjects enrolled in the study may receive study medication, in accordance with all 
applicable regulatory requirements.  Only authorized site staff may supply or administer study 
medication. All study medications must be stored in a secure area with access limited to the 
investigator and authorized site staff and under physical conditions that are consistent with the 
specific requirements for the study medications.  
Study medications should be stored at room temperature up to 25°C. Study medications in 
unopened bottles are stable until the date indicated on the package when stored at the above 
condition.  
Under normal conditions of handling and administration, investigational product is not expected 
to pose significant safety risks to site staff. A Material Safety Data Sheet (MSDS) describing the 
occupational hazards and recommended handling precautions will be provided to site staff if 
required by local laws or will otherwise be available from Novartis  upon request. 

 
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5.6. 
Product Accountability 
The lead investigator will be responsible for study medication accountability, reconciliation, and 
record maintenance. In accordance with local regulatory requirements, the investigator, 
designated site staff, or head of the medical institution (where applicable) must document the 
amount of Novartis investigational product dispensed and/or administered to study subjects, the 
amount returned by study subjects, and the amount received from and returned to Novartis, when 
applicable.  Product accountability records must be maintained throughout the course of the 
study. 
After completion of the study, a final inventory of accountability records and unused study 
medications will be performed by the study monitor and site personnel. Unused study 
medications will be destroyed and proof of destruction will be forwarded to Novartis. 
5.7. 
Treatment Compliance 
A record of the number of tablets dispensed to and taken by each subject at each visit must be 
maintained and reconciled with the study medication and compliance records in the CRF. 
The cause of any missed doses should be discussed. Any AE(s) associated with missed doses 
must be recorded in the CRF. Subjects should be instructed for the importance of compliance to 
study treatments. 
5.8. 
Concomitant Medications and Non-Drug Therapies 
5.8.1. 
Permitted Medications and Non-Drug Therapies 
All concomitant medications taken during the study will be recorded in the CRF. The minimum 
requirement is that drug name and dates of administration are to be recorded.  In addition, 
indication and dose information should also be captured on the CRF, if possible. If there are any 
questions on medications not listed below, please contact the lead investigator for further 
information and clarification. 
Subjects should receive full supportive care during the study, including transfusion of blood and 
blood products, treatment with antibiotics, anti-emetics, anti-diarrheal agents, analgesics, 
erythropoietin, or bisphosphonates, when appropriate. 
5.8.1.1. 
Hematopoietic Growth Factors 
Prophylactic use of hematopoietic growth factors to support neutrophil or platelet counts is 
permitted during this study.  Filgrastim (shorter-acting G-CSF) may be administered more than 
24 hours prior to the next administration of paclitaxel or no sooner than the day following the 
dose.   Pegfilgastrim (longer-acting G-CSF) may be administered when a paclitaxel 
administration is not anticipated for 14 days.  Treatment with pazopanib should continue during 
G-CSF treatment unless the subject is experiencing complicated neutropenia (prolonged or 
associated with fever or infection).  Subjects who enter the study on stable doses of 

 
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erythropoietin or darbepoietin may continue this treatment, and subjects may start either drug 
during the study at the discretion of the investigator for Hgb values <10 when Fe, TIBC, and 
ferritin levels are within normal limits.  Subjects with neutropenic fever or infection should be 
treated promptly and may receive therapeutic colony-stimulating factors if appropriate.  
Potential Impact of Pazopanib on Other Medications 
In vitro data indicate that pazopanib is a potential inhibitor for CYP2C9, CYP1A2, CYP2A6, 
CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.  Pregnane X receptor 
transient transfection assay data suggested some potential for human CYP3A4 induction at high 
concentrations.  However, definitive information on the metabolism and drug interaction profile 
of pazopanib in humans is not available.   
Certain medications should be used with CAUTION due to the potential for alterations in the 
pharmacologic effects or increased adverse events secondary to the inhibition of multiple CYP 
enzymes by pazopanib.  These medications include (but are not limited to): 
 
Antidepressants: amitriptyline, buproprion, fluoxetine, fluvoxamine, imipramine. 
 
3-hydroxy-3-methylglutaryl (HMG) co-reductase inhibitors: atorvastatin, fluvastatin, 
lovastatin, simvastatin. 
 
Oral hypoglycemics:  pioglitazone, rosiglitazone; see below for specific recommendations 
on other oral hypoglycemics. 
 
Benzodiazepines:  alprazolam, midazolam, triazolam, clorazepate, diazepam, flurazepam. 
 
Calcium channel blockers:  diltiazem, felodipine, nifedipine, nicardipine, nimodipine, 
nitrendipine, verapamil, amlodipine, nisoldipine, isradipine; see below for specific 
recommendations for verapamil and diltiazem. 
 
Angiotensin II blockers: losartan, irbesartan. 
 
Beta-blockers:  carvedilol, metoprolol, propranolol, timolol. 
 
Anticonvulsants: phenobarbital, phenytoin, primadone, carbamazepine, oxcarbazepine. 
 
Miscellaneous:  aprepitant, codeine, methadone, mifepristone, haloperidol, estrogens and 
progestins (including oral contraceptives). 
 
Specific recommendations regarding oral hypoglycemics: 
Co-administration of pazopanib with some oral hypoglycemics, including glipizide, glyburide 
(glibenclamide), glimepiride, nateglinide, repaglinide, gliclazide, acetohexamide, carbutamide, 
glibornuride, glymidine, metahexamide, and tolazamide, may result in an increase in plasma 
concentrations of the oral hypoglycemic agent.  This increase may result in hypoglycemia.  
Therefore, the dose of the oral hypoglycemic agent should be reduced by 50% when pazopanib 
administration starts.  The blood glucose should be monitored closely, and the subject should be 
instructed to measure their blood glucose if they experience symptoms of hypoglycemia and 
inform their physician if their blood glucose concentration is low.  After at least 14 days of 

 
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pazopanib administration, the dose of the oral hypoglycemic agent may be increased as 
necessary to maintain adequate blood glucose control. 
Specific recommendation regarding non-dihydropyridine calcium channel blockers 
(verapamil and diltiazem): 
Co-administration of pazopanib with calcium channel blockers may result in increased plasma 
concentrations of the calcium channel blocker.  Non-dihydropyridine calcium channel blockers, 
verapamil and diltiazem, have potential depressive effects on cardiac conduction and 
contractility. When pazopanib therapy is initiated, the administration of an anti-hypertensive or 
anti-anginal agent other than verapamil and diltiazem is recommended in the setting of a 
prolonged PR interval (greater than 200msec), sinus bradycardia (less than 60 beats per minute), 
or second or third degree heart block, unless the subject has a permanent pacemaker. 
Potential Impact of Other Medications 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, pazopanib has been demonstrated to interact with p-glycoprotein in vitro. 
Therefore, substances that induce or inhibit CYP3A4 may alter the pharmacologic effects of 
pazopanib and should be used with caution. These medications include (but are not limited to):  
Inhibitors of CYP3A4: 
 
Antibiotics:  clarithromycin, erythromycin, troleandomycin. 
 
HIV:  anti-retrovirals (delaviridine), protease inhibitors (ritonavir, indinavir, saquinavir, 
nelfinavir, amprenavir, lopinavir). 
 
Antifungals:  itraconzaole, ketoconazole, voriconazole, fluconazole. 
 
Antidepressants:  nefazodone, fluvoxamine. 
 
Calcium channel blockers:  diltiazem, verapamil 
 
GI:  cimetidine, aprepitant. 
 
Miscellaneous:  Grapefruit or its juice. 
Inducers of CYP3A4: 
 
Glucocorticoids:  dexamethasone. 
 
Anticonvulsants:  phenytoin, carbamazepine, phenobarbital, oxcarbazepine. 
 
HIV:  efavirenz, nevirapine. 
 
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene. 
 
Miscellaneous:  St. John’s Wort, modafinil. 

 
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5.8.2. 
Prohibited Medications 
Co-administration of pazopanib and medications which are substrates for the CYP450 enzymes 
and which have the potential to cause serious and/or life-threatening adverse events is 
PROHIBITED.  Prohibited medications should not be used from 14 days (or 5 half-lives, 
whichever time is greater) prior to the first dose of study drug until discontinuation of study 
drug.  These medications include (but are not limited to): 
 
Anticoagulants: warfarin (Note: prophylactic low-dose warfarin is permitted) 
 
Oral hypoglycemics: tolbutamide, chlorpropamide 
 
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine 
 
Neuroleptic: pimozide 
 
Erectile dysfunction agents: sildenafil, tadalafil, vardenafil 
 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexilitine, amiodarone, quinidine, 
propafenone, 
 
Immune modulators:  cyclosporine, tacrolimus, sirolimus 
 
Miscellaneous:  theophylline, quetiapine, risperidone, tacrine, clozapine, atomoxetine, 
tizanidine 
5.8.3. 
Concomitant Anti-cancer Therapies 
Concomitant anti-cancer treatments for melanoma with other drugs, surgical procedures or 
radiation therapy to sites of measurable disease are not permitted. Palliative radiotherapy outside 
of fields containing measurable disease is allowed. A subject’s treatment with study medication 
should be terminated once another anti-cancer therapy has been initiated. However, the subject 
will be followed for survival. The new anti-cancer treatment and its start date must be recorded 
on the CRF. 
5.9. 
Treatment after the End of the Study 
A rollover study may be made available at the discretion of Novartis to those subjects who are 
exhibiting clinical benefit (stable disease or better) when all data needed to satisfy the study 
endpoints have been completed and collected.   
5.10. 
Treatment of Investigational Product Overdose 
No maximum tolerated dose (MTD) was reached in dose escalation studies of pazopanib 
administered as a single agent at doses of up to 2000mg/day.  Peak pazopanib exposures 
occurred at 1000mg/day; similar or lower exposures were seen at doses between 1000-
2000mg/day.   
In the event of overdose (defined as administration of more than the protocol-specified dose), the 
investigator should contact the PI: John Fruehauf MD, PhD.   

 
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6. 
STUDY ASSESSMENTS AND PROCEDURES 
A signed, written informed consent form must be obtained from the subject prior to any study-
related assessments and procedures. The study assessments schedules and visit windows are 
summarized in Table 6 Time and Events Table. 
 

 
 
 
 
 
Version 09 Aug 10 
Table 6. Time and Events Table 
Protocol Activities 
Screening 
Study Treatment [1] 
Post treatment 
 28 Days Prior to 
Enrollment 
Day 1 
(-3/+3) [2] 
Day 8 
(-3/+3) 
Day 15 
(-3/+3) 
Day 22 
(-3/+3) 
End of Tx/ 
Withdrawal [3] 
Post Tx 
[4] 
Baseline Documentation 
 
 
 
 
 
 
 
Informed Consent [5] 
X 
 
 
 
 
 
 
Medical/Oncological History [6] 
X 
 
 
 
 
 
 
Physical Examination/ ECOG PS[7] 
X 
X 
 
 
 
X 
(X) 
Vital Signs/Body Weight [7] 
X 
X 
X 
X 
 
X 
 
Baseline Signs/Symptoms 
 
X C1 
 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
 
 
Hematology [8] 
X 
X 
X 
X 
 
X 
 
Blood Chemistry including LDH [8] 
X 
X 
 
X C1-2 
 
X 
 
Thyroid function tests[8] 
X 
X (every 8 weeks) 
 
 
 
X 
 
Amylase and Lipase tests [8] 
 
X (every 8 weeks) 
 
 
 
 
 
UA- Urine Protein:Creatinine Ratio 
X 
X 
 
 
 
X 
 
Pregnancy Test (as appropriate) 
X (2 weeks prior to 
first dose) 
 
 
 
 
 
 
12-lead ECG [9] 
X 
X (Week 4, then every 4 
weeks) 
 
 
 
X 
 
MUGA scan[10] 
X 
X (if clinically indicated) 
X 
 
Study Enrollment [11] 
X 
 
 
 
 
 
 
Paclitaxel Infusion 
 
X 
X 
X 
 
 
 
Pazopanib  Capsule Dosing  
 
X 
 
 
 
 
 
Disease Assessments 
 
 
 
 
 
 
 
Whole body PET/CT scans [12] 
X 
X 8-week intervals  
 
 
 
(X) 
(X) 
Brain CT or MRI Scan [13] 
X 
X (if clinically indicated) 
(X) 
(X) 
Other Clinical Assessments 
 
 
 
 
 
 
 
Adverse Events [14] 
X 
X 
X 
X 
X 
X 
X 
Pazopanib Drug Compliance [15]  
 
X 
 
 
 
X 
 
Concomitant Medications/Treatments [16] 
X 
X 
X 
X 
X 
X 
X 
Survival Follow-up [17] 
 
 
 
 
 
 
X 
Special Laboratory Studies 
 
 
 
 
 
 
 
Pharmacokinetic Plasma Sample [18] 
 
X C1D1 (pre-dose), C2D1 and C2D28 
 
 
Soluble Proteins [19] 
 
X C1D1 (pre-dose), C2D1 and C2D28 
 
 
Archived Tumor Tissues 
X 
 
 
 
 
 
 
Fresh Tumor biopsy (when applicable) [20] 
X (2 weeks prior to 
first dose if archived 
tissue 
is 
not 
attainable) 
X C2D1 
 
 

 
 
 
 
 
Version 09 Aug 10 
 
Footnotes for Schedule of Events 
1. 
Study Treatment: All assessments should be performed prior to dosing with study medications unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headings.  Each cycle is 28 days in duration.  Subjects discontinuing treatment with paclitaxel and 
continuing to receive pazopanib may have reduced clinic visits, returning to clinic at 4-week intervals.  Subjects discontinuing all treatment prior to disease 
progression may return to clinic at 8-week intervals for disease assessments.     
2. 
Cycle 1 Day 1: Hematology, blood chemistry, and physical examination not required if acceptable screening assessment is performed within 7 days prior to 
the start of treatment with Study Medication. 
3. 
End of Treatment/Withdrawal: Obtain these assessments if not completed during the previous 4 weeks on study (during the last 8 weeks on study for 
disease assessments). 
4. 
Post Treatment Follow-up:  Subjects discontinuing both agents prior to PD will be followed for tumor assessment until PD, or until the initiation of a 
subsequent anti-cancer therapy in the absence of documented PD, or until death, whichever occurs first.  Subjects should be evaluated for safety up to 28 
days after last dose of study treatment.  Adverse events should be followed up until all serious or study drug-related toxicities have resolved or are determined 
to be “chronic” or “stable”, whichever is later.  Refer to the protocol for specific guidelines.  
5. 
Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period. 
6. 
Medical/Oncologic History and Demographics: To include information on prior regimens for melanoma (duration of administration), description of best 
response observed and treatment failure. 
7. 
Physical Examination: Examination of major body systems, ECOG performance status, body weight, height (at Screening visit only), and vital signs 
(temperature, blood pressure, heart rate, respiratory rate).  Body weight to be recorded prior to each treatment with paclitaxel.  Post-treatment physical 
examinations are for the purpose of disease assessment and safety follow-up (assessment of vital signs and body weight are not required). 
8. 
Hematology/Chemistry/Thyroid Testing/Amylase and Lipase: See Table 8 for required tests.  Subjects discontinuing treatment with paclitaxel and 
continuing to receive pazopanib may reduce hematology to 4-week intervals.  Thyroid function testing (TSH, T3 and T4), amylase and lipase testing to be 
completed at baseline and every 8 weeks while on study therapy or as clinically indicated.  Please refer to Table 10. Clinical Laboratory Parameters  for 
specific guidance. 
9. 
12-lead ECG: Three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine the mean QTc interval.  The ECGs should be 
performed at the same time of the day and time matched ( 1 hour).  A 12-lead ECG will be obtained at Screening/Baseline, Week 4 and then every 4 weeks 
during study treatment.  If the mean QTc interval is prolonged (>440 msec), then the ECGs should be re-read by a cardiologist at the site for confirmation. 
ECGs must be completed at the time of discontinuation of each study treatment  
10. MUGA:  At baseline and during treatment as clinically indicated.  A MUGA scan should be performed sooner if a subject develops signs and symptoms of CHF 
(ie, shortness of breath during mild exertion or when lying down, feeling very tired, cough (especially at night), swelling of the feet and/or ankles).  A MUGA 
scan is the preferred method for LVEF measurement. If a MUGA scan cannot be performed an echocardiogram should be done 
11. Study Enrollment: Subject number assignment will be obtained from the UCI central research office. 
12. Tumor Imaging:  Disease assessment should be performed as outlined in the assessment table, whenever disease progression is suspected, and to confirm 
a partial or complete response (at least 4 weeks after initial documentation of response).   Disease assessment will include whole body PET/CT scans and 
clinical assessment of superficial disease.  Assessments will be performed at screening and every 8 weeks (56 calendar days) from the enrollment date during 
the study.  Lesions assessed by clinical methods should be recorded in the CRF.  The schedule of assessments should be fixed according to the calendar, 
regardless of treatment delays.  The allowable window for disease assessments is +/-7 days.  Imaging assessment delay to conform to treatment delay is not 
permitted. Subjects who discontinue study treatment due to reasons other than objective RECIST-defined PD, need to be followed every 8 weeks until PD, 
initiating another anti-cancer therapy or death whichever occurs first.  
13. Brain CT or MRI Scan: Repeat brain scan required if new metastases are suspected. 
14. Adverse Events: Subjects must be followed for adverse events from the first day of study treatment until at least 28 days after the last dose of all study 
treatment, or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.  Serious adverse 
events should be monitored and reported from the time that the subject provides informed consent as described in the protocol.   

 
 
 
 
 
Version 09 Aug 10 
Footnotes for Schedule of Events 
15. Pazopanib Drug Compliance: Pazopanib bottle(s) including any unused capsules will be returned to the clinic for drug accountability.   
16. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and 
up to 28 days post the last dose of study treatment.   
17. Post-Study Survival Status: After discontinuation of study treatment, post-study survival status will be collected by telephone contact every 2 months until 
death or 2 years from first study treatment. 
18. Pharmacokinetic Plasma Samples: (7 mL blood/sample) for pazopanib will be obtained 15 minutes prior to the morning dose (taken in the clinic) and 1 to 2 
hours after that dose on the specified days.    Samples will be submitted to the Fruehauf Lab for shipping. 
19. Soluble Proteins Assessment:  One 10 mL blood sample will be collected prior to dosing on the specified days. 
20. Pre-dose Fresh Tumor Biopsy: When possible, if archived sample is not attainable, a pre-treatment sample by excisional, core or punch biopsy must be 0.5 
– 1 cm3 and collected 2 weeks prior to first dose of study therapy to allow appropriate healing time.  The post-dose sample will require a pazopanib drug 
holiday of 2 days prior and 1 week after.   

 
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6.1. 
Screening and Baseline Assessments 
6.1.1. 
Assessments within 4 Weeks of the First Dose  
 
Demography: date of birth, race and gender. 
 
Medical history: Melanoma-specific history including date of diagnosis, primary 
tumor type with histology/cytology determination, prior surgical and/or radiological 
therapies (date, organ/anatomic region(s) that have received surgical and/or 
radiological therapies must be documented), current stage of cancer, prior systemic 
treatment(s) for locally advanced/metastatic melanoma, ongoing toxicity related to 
prior treatment(s); history of other malignancies; other significant medical histories 
within the past 6 months.  
 
Physical examinations: height (only recorded at baseline) and body weight and 
current medical conditions. 
 
Vital signs: body temperature, blood pressure and heart rate. 
      Note: If a subject presents with poorly controlled hypertension, defined as SBP 
150mmHg or DBP 90mmHg, antihypertensive medication(s) should be initiated or 
adjusted with a goal to control the blood pressure to <150/90 mmHg. See Section 
6.3.2 for instruction on blood pressure measurement and obtaining mean blood 
pressure values, and Section 11.5, Appendix 5 for antihypertensive medications 
suggested for the study. 
 
ECOG PS.  
 
Clinical laboratory assessments include hematology and coagulation tests, clinical 
chemistry, LDH, calculated creatinine clearance, urinalysis by UPC ratio, amylase 
and lipase, and thyroid function tests (TSH, T3 and T4). Clinical laboratory 
parameters of these tests are listed in Section 6.3.4 Table 10. 
 Whole body PET/CT scan  [Refer to Table 7 in Section 6.2.3 for details].   
 
12-lead ECG with QTc measurement. 
 
MUGA or ECHO 
6.1.2. 
Assessments within 2 Weeks of the First Dose  
 
Serum pregnancy test for women of childbearing potential.  
 
Request previous archived tumor tissue when possible. 
 
A punch, core, or excisional biopsy should be used to obtain approximately 0.5 – 1 
cm3 of tumor tissue when possible.  The biopsied lesions may not be the only sites of 
measurable disease.  See Section 11.8, Appendix 8 for processing instructions.  
Archived specimen may be used as a substitute for this pre-treatment sample. The 
biospiable lesion may be used as the site of the post-treatment sample. 

 
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6.1.3. 
Pre-dose Assessments on Day 1 
 
Review of the inclusion/exclusion criteria. 
 
Physical examination: to identify any changes in the subject’s mental and medical 
conditions since baseline assessment that would make him/her ineligible for the 
study.  
 
Blood pressure measurements: subjects must have a blood pressure reading of 
<150/90mmHg to be eligible. If a subject has been treated with anti-hypertensive 
medications during the Baseline Period, the blood pressure must be re-assessed on 
two occasions consecutively that are separated by a minimum of 24 hours. The mean 
SBP/DBP values from both blood pressure assessments must be <150/90mmHg in 
order for a subject to be eligible. These two assessments must also be the most recent 
ones prior to enrollment (the blood pressure values from the later assessment will be 
used as the subject’s baseline blood pressure values). All the blood pressure readings 
must be recorded on the appropriate CRF. See Section 6.3.2 for instruction on blood 
pressure measurement and obtaining mean blood pressure values.  
 
ECOG PS: Any changes since baseline assessment should be recorded in the CRF. 
Subjects having deterioration of ECOG PS to 2 will be excluded from the study.  
 
Review results of all the other baseline assessments to determine the subject’s 
eligibility for the study. Any screening laboratory results result outside the normal 
range will be repeated (prior to the first dose) at the discretion of the Principal 
Investigator. All laboratory results must be within the values outlined in Section 4.2, 
Inclusion Criteria before the first dose of study drug. 
 
Record all the medication(s) received within 2 weeks prior to the first dose of study 
medication and indicate if the medication is continuing. 
 
Obtain a blood plasma sample for proteomics research.  
 
Obtain a blood plasma sample for pharmacokinetics research.  
6.2. 
Efficacy 
6.2.1. 
Primary Endpoint 
 
The primary endpoint is 6-month progression free survival (6-month PFS)  
6.2.2. 
Secondary Endpoints 
 1-and 2-year Survival 
 Objective response rate (ORR) 
 Clinical benefit response (CBR) 
 Duration of response (DR) 

 
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 Incidence, severity of adverse events (AE), serious adverse events (SAEs) and 
other safety parameters. 
Exploratory Endpoints 
 Concentrations of plasma proteins (serum VEGF, soluble VEGF receptor 2, 
serum HIF and serum TSP1) that may be associated to angiogenesis and tumor 
proliferation.  
 Tissue levels of angiogenic markers, including p53, HIF, CD31, nNOS, TSP1, 
and VEGF  
 BRAF mutation status  
 In vitro response of tumor cells grown in culture with vascular endothelial cells to 
pazopanib, paclitaxel, topotecan and resveratrol. 
6.2.3. 
Methods, Scope and Schedules of Disease Assessments 
The following methods are acceptable for disease assessments in this study. The disease 
assessment scope and schedules are summarized in Table 7. 
Whole body PET/CT scans: Dual-modality PET/CT imaging should be performed 
using a biograph (Siemens Medical Solutions, Hoffman Estates, Ill) or equivalent which  
provides separate CT and PET data sets, which can be accurately fused on a computer 
workstation. 
Note: chest X-ray is not acceptable for assessing measurable lesions.  

 
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Table 7.  Disease Assessment Scope and Schedules 
Anatomic 
Region 
& 
Assessment 
Modality
1, 2 
Baseline
3 
Following First Dose
4  
Whole body PET- 
CT scans 
To be performed on all 
subjects. 
To be performed on all subjects every 8 
weeks from date of first dose (+/- 7 
days). 
Head CT or MRI 
To be performed on all 
subjects. Note: subjects 
with a positive scan must be 
excluded from the study5 
To be performed only on subjects if 
clinically indicated. 
d. 
The following information must be documented: date of assessment, diagnostic technology used for each 
anatomic region, description of the type and site of a lesion (e.g. liver mass). 
e. 
The same method, technique should be used to characterize each identified lesion at baseline and 
subsequent disease assessments.  
f. 
All the baseline disease assessments should be completed within 28 days prior to enrollment.  
g. 
Disease assessments should be performed at the indicated frequency following the first dose until 
documented disease progression, death or upon initiating another anti-cancer treatment, whichever 
occurs first.  
h. Subjects who have previously-treated CNS metastases (surgery radiotherapy, radiosurgery, or gamma 
knife) and meet all 3 of the following criteria are eligible: 1) are asymptomatic, 2) have had no 
evidence of active CNS metastases for 28 days prior to enrollment, and 3) have no requirement for 
steroids or EIACs 
 
6.2.3.1. 
Measurability of Tumor Lesions at Baseline 
All measurements should be recorded in metric notation, using a ruler or calipers. All 
identified tumor lesions are to be classified as measurable or non-measurable per 
RECIST criteria.  
Measurable lesions: lesions that can be accurately measured in at least one dimension 
with the longest diameter 20mm using conventional techniques, or 10mm with spiral 
CT scan. 
Non-measurable lesions: all other lesions, including lesions too small to be considered 
measurable (longest diameter 20mm using conventional techniques or 10mm with 
spiral CT scan), and the following lesions and disease sites: bone lesions, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, and cystic lesions.  
Measurable disease: subjects presenting with at least one measurable lesion at baseline 
are identified as having measurable disease. Only subjects with baseline measurable 
disease are eligible for the study. If the measurable disease is restricted to a solitary 
lesion, its neoplastic nature must be confirmed by cytology/histology evaluation. 
Subjects presenting with the following baseline conditions must be excluded from the 
study: 1) positive head CT or MRI scan for CNS metastasis (except as noted in Table 7); 
2) all measurable lesions are within previously irradiated areas.  

 
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6.2.3.2. 
Determination of Target and non-Target Lesions 
At baseline, all the lesions must also be categorized as “Target” or “non-Target” lesions 
using the following RECIST guideline. 
Target lesions: all measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, representative of all involved organs should be identified as target 
lesions, and measured and recorded at baseline.   
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). Lesions that are present within a previously irradiated area 
cannot be selected as target lesions.  
Non-target lesions: all other lesions (or sites of disease) should be identified as non-
target lesions, and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout subsequent 
assessments. 
6.2.3.3. 
Response Evaluation of Measurable Disease 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. During Treatment Assessments, any new 
lesion(s) must be recorded in the CRF.  If the lesion(s) noted at baseline is not evaluated 
at the subsequent Treatment Assessment, this will be noted as 'not done' (ND) in the 
CRF. 
Response criteria for target and non-target lesion(s) are presented in Table 8. 

 
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Table 8.  Response Criteria for Target and non-Target Lesions 
Evaluation of Target Lesions 
Complete response (CR) 
Disappearance of all target lesions 
Partial response (PR) 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as a reference the baseline sum LD 
Progressive disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, 
taking as a reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
Not evaluable (NE) 
Any subject who cannot be classified by one of the four 
preceding definitions 
Evaluation of non-Target Lesions 
Complete response (CR) 
The disappearance of all non-target lesions  
Incomplete response/Stable 
Disease (SD) 
The persistence of one or more non-target lesion(s)  
Progressive disease (PD) 
The appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Note: New bone scan lesions that are equivocal may be confirmed using X-ray, CT or 
MRI.  
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started).   
Table 9 shows the overall response for all possible combinations of tumor responses in 
target and non-target lesions, with or without the appearance of new lesions. 
Table 9. Evaluation of Best Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 

 
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In some circumstances it may be difficult to distinguish residual disease from normal 
tissue on radiographic evaluation. When the evaluation of CR depends on this 
determination, it is recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the CR status. 
6.2.3.4. 
Evaluation of Disease Progression  
During the course of the study, the investigator will assess a subject’s disease status 
based on the radiological assessment (as below) and clinical assessment, and will make 
clinical decisions on the subject’s care based on medical judgment. Disease assessments 
by the investigator at baseline and subsequent visits must be documented in the source 
records and case report forms. 
The primary method for assessing disease progression will be based on radiologic 
assessments using the methods described in Section 6.2.3. The primary method for 
assessing disease progression will be based on radiologic assessments using the methods 
described in Section 6.2.3.1. Every effort should be made to have a radiological 
assessment to objectively confirm progression in subjects who experience progression 
based only on the subject’s overall deterioration of health status. However it is 
anticipated that some subjects will have symptomatic progression that cannot be 
confirmed by radiologic assessment. If a subject experiences symptomatic progression at 
a certain time point that meets all of the following three criteria with proper 
documentation, the subject is considered to have progressive disease. Thus, symptomatic 
progression is defined as meeting all three criteria: (1) ECOG performance status of at 
least 3, (2) subject is unable to have follow-up radiologic assessment due to performance 
status decline, and (3) symptomatic decline deemed to be related to metastatic disease 
(not toxicity from therapy or concurrent illness.)   
6.2.3.5. 
Survival Assessment 
All subjects should be followed up to two years from date of enrollment or until death 
whichever occurs first, if possible. The date of death and cause of death should be 
evaluated and documented in the appropriate CRF.  
6.3. 
Safety 
A secondary objective of this study is to evaluate and compare the incidence and severity 
of adverse events (AE), serious adverse events (SAEs) and other safety parameters. 
6.3.1. 
Physical Examination  
Physical examination is assessed at Screening/Baseline, pre-dose on Day 1, and every 4 
weeks thereafter until discontinuation of study treatment. Physical examination includes 
height (baseline only), body weight and evaluation of the subject’s medical conditions. 
Any new or worsening of medical conditions from the baseline condition (pre-dose on 
Day 1) should be recorded in the AE or SAE CRF.  

 
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6.3.2. 
Vital Signs and Blood Pressure Monitoring 
Vital signs, including heart rate, temperature, and blood pressure should be obtained at 
Screening/Baseline, pre-dose on Day 1, Day 8 and Day 15 of every combination cycle 
until discontinuation of study treatment.  
As hypertension is a common drug-related AE observed from other pazopanib studies, 
blood pressure monitoring is mandatory. The following instructions should 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 each visit, blood pressure should be measured three times at approximately 2-minute 
intervals. All three blood pressure values should be recorded on the CRF. 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. Refer to Section 5.3.1 for the algorithm of dose 
modification of study medication in event hypertension occurs; refer to Section 11.5, 
Appendix 5 for recommendations for management of hypertension during the study 
treatment.  
6.3.3. 
ECOG PS  
ECOG PS is assessed at Screening/Baseline, pre-dose on Day 1 and every 4 weeks 
thereafter until discontinuation of study treatment. If subjects discontinue study treatment 
without disease progression (e.g., withdrawal study treatment due to unacceptable 
toxicity), continue the assessments of ECOG PS every 8 weeks in accordance with the 
disease assessments until subjects experience disease progression.  
6.3.4. 
Clinical Laboratory Assessments 
Hematology should be performed at Screening/Baseline and prior to each paclitaxel 
infusion on Day(s) 1, 8, 15 of each cycle.  If subjects discontinue paclitaxel study 
treatment and continue on pazopanib monotherapy, hematology should be performed 
every 4 weeks. 
Clinical chemistry, liver function tests (ALT and AST) and coagulation should be 
performed at Screening/Baseline and every 2 weeks for the first 2 cycles, then every 4 
thereafter until discontinuation of study treatment. 
Coagulation tests should be performed at Screening/Baseline and every 4 weeks 
thereafter until discontinuation of study treatment.  

 
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Amylase and lipase tests should be performed at Screening/Baseline and every 8 weeks 
following the first dose until discontinuation of study treatment. 
Urinalysis by urine protein:creatinine ratio should be performed at Screening/Baseline 
and every 4 weeks thereafter until discontinuation of study treatment.  Refer to Section 
11.6, Appendix 6 for reference for UPC calculation. 
The thyroid function tests should be performed at Screening/Baseline and every 8 weeks 
following the first dose until discontinuation of study treatment. Serum thyroid-
stimulating hormone (TSH), total serum T4, and triiodothyronine (T3) resin uptake will 
be assessed. 
Table 10. Clinical Laboratory Parameters 
Clinical Chemistry 
Alkaline phosphatase, Bilirubin (total)1, Blood Urea Nitrogen (BUN), 
Creatinine2, 
Calcium, 
Potassium, 
Sodium, 
Glucose, 
Lactate 
Dehydrogenase (LDH), Protein (total), Magnesium and Inorganic 
phosphate 
Liver Function Tests (LFTs) 
Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) 
Pancreatic Function Tests 
Amylase and Lipase 
Hematology 
Hematocrit (HCT), Hemoglobin (HGB), Platelet count, White Blood Cell 
(WBC) count, Neutrophil count (ANC), Eosinophil count, and Lymphocyte 
count 
Coagulation Tests 
International Normalization Ratio (INR) and Partial thromboplastin time 
(PTT) 
Urinalysis
 
Urine protein creatinine ratio (UPC) 
Thyroid Function Test 
TSH, free T4, free T3 
i. 
If total bilirubin 1.5 ULN, direct and indirect bilirubin will be measured 
j. 
Estimated Creatinine Clearance (CrCl) is calculated at Baseline using Cockcroft and Gault formula  
 
6.3.5. 
12-Lead Electrocardiogram 
There is no preclinical or clinical evidence of an effect on QTc with either pazopanib or 
lapatinib. However, 12-lead ECG will be obtained at Screening/Baseline, Week 4 and 
every 4 weeks during the Treatment Period for QTc monitoring. Prior to each ECG 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 for all subsequent 
ECG tests.   
All ECGs must include QTc measurements either manually or machine calculated using 
Bazett’s formula, and recorded in the CRF. The Bazett’s formula is: 
QTcB = QT / RR1/2  
At Screening/Baseline, if QTc interval is > 480 msecs, subject will be excluded from the 
study.  
If a QTc ≥ 440 msec is noted on a scheduled or unscheduled ECG, then 2 additional 
ECGs should be obtained within 5 minutes to confirm the abnormality.  The average QTc 

 
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will be determined from the 3 ECG tracings by manual evaluation and will be used to 
determine continued eligibility.  If the average QTc is less < 430 msec, the subject may 
continue therapy.  If the average QTc is ≥ 430 msec, the study treatment should be 
discontinued immediately.  
The subject should be treated appropriately for QTc prolongation and monitored until 
resolution is documented by a repeat ECG with QTc intervals returning to < 430 msec.  
No further therapy will be allowed. 
6.3.6. 
Pregnancy Test 
A screening serum -HCG pregnancy test is mandatory for all women of child-bearing 
potential and should be done within 2 weeks prior to the first dose of study medication. 
Thereafter, the serum pregnancy test only needs to be repeated if clinically indicated or as 
required by local regulation. 
6.3.7. 
Safety Assessments upon Discontinuation of Study Treatment  
Subjects should have the following safety assessments upon discontinuation of study 
treatment: physical examination and vital signs, ECOG PS, LFTs, clinical chemistry and, 
hematology and coagulation tests, urinalysis, thyroid function tests (the above 
assessments can be omitted if the last assessments are performed within 6 weeks of the 
previous assessments), and ECG (this assessment can be omitted if the last assessments 
are performed within 12 weeks of the previous assessments). The date and reason for 
discontinuation of study treatment must be recorded clearly in the Study Treatment 
Discontinuation CRF.   
6.3.8. 
Adverse Events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
6.3.8.1. 
Definition of an AE 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.   
Examples of an AE include: 
 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 

 
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 
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 concurrent medication (overdose per se should not 
be reported as an AE/SAE). 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will 
not be reported as an AE or SAE.  However the signs and symptoms and/or 
clinical sequelae resulting from lack of efficacy will be reported if they fulfill 
the definition of an AE or SAE. 
Examples of an AE does not include a/an: 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy). Note, 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. 
 
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. 
For Novartis clinical studies, AEs may include pre- or post-treatment events that occur as 
a result of protocol-mandated procedures (i.e., invasive procedures, modification of 
subject’s previous therapeutic regimen). 
6.3.8.2. 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-subject setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 

 
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the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
g. All grade 4 laboratory abnormalities 
6.3.9. 
Clinical 
Laboratory 
Abnormalities 
and 
Other 
Abnormal 
Assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other 
abnormal assessments (e.g., ECGs) that are judged by the investigator as clinically 
significant will be recorded as AEs or SAEs if they meet the definition of an AE or SAE.  
Clinically significant abnormal laboratory findings or other abnormal assessments that 
are detected during the study or are present at baseline and significantly worsen following 
the start of the study will be reported as AEs or SAEs.  However, clinically significant 
abnormal laboratory findings or other abnormal assessments that are associated with the 
disease being studied, unless judged by the investigator as more severe than expected for 
the subject’s condition, or that are present or detected at the start of the study and do not 
worsen, will not be reported as AEs or SAEs.  
The investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 

 
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6.3.10. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
An event which is part of the natural course of the disease under study (e.g., disease 
progression) does not need to be reported as an SAE.  Progression of the subject's 
neoplasia will be recorded in the clinical assessments in the CRF.  Death due to 
progressive disease is to be recorded on the 'Record of Death' CRF page and not 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 study treatment (pazopanib) or protocol design/procedures 
and the disease progression, then this must be reported as an SAE.  Any new primary 
cancer must be reported as an SAE. 
6.3.11. 
Time Period, and Frequency of Detecting AEs and SAEs 
All SAEs that are identified from the time a subject consents to participate in the study 
until he or she has completed the study and that are assessed as related to study 
participation (e.g., protocol-mandated procedures, invasive tests, or change in existing 
therapy) or as related to a Novartis concomitant medication must be reported promptly to 
Novartis.  Refer to Section 6.3.13, Prompt Reporting of Serious Adverse Events and 
Other Events to Novartis, for guidance on reporting of SAEs.   
In addition, all AEs and SAEs will be collected and recorded from receipt of first dose of 
study drug until 28 days have elapsed following cessation of study drug, regardless of 
initiation of a new cancer therapy or transfer to hospice. 
The investigator will monitor all AEs/SAEs that are ongoing after discontinuation of 
study drug until resolution, until the condition stabilizes, or until the subject is lost to 
follow-up 
6.3.12. 
Pregnancy 
6.3.12.1. 
Time period for collecting pregnancy information 
The time period for collecting pregnancy information is identical to the time period for 
collecting AEs, as stated in Section 6.3.11 “Time Period, Frequency, and Method of 
Detecting AEs and SAEs”, from first dose of study treatment to 28 days after last dose. 
6.3.12.2. 
Action to be taken if pregnancy occurs 
If a female subject becomes pregnant while participating in the study, the study treatment 
must be immediately terminated. The investigator will collect pregnancy information 
record on the appropriate form and submit it to Novartis within 2 weeks of learning of a 
subject's pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to 
Novartis.  Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date.  Any premature termination of the pregnancy will be reported. 

 
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While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE [see Section 6.3.8, of the protocol for definitions of AEs/SAEs and a 
description of follow-up]. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the investigational product by the investigator, will be reported to 
Novartis as described in Section 6.3.13. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
6.3.12.3. 
Action to be taken if pregnancy occurs in a female partner of a male 
study subject 
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study and record the 
pregnancy information on the appropriate form and submit it to Novartis within 2 weeks 
of learning of the partner’s pregnancy.  The partner will also be followed for the outcome 
of the pregnancy.  Information on the status of the mother and child will be forwarded to 
Novartis.  Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date.  Any premature termination of the pregnancy will be reported. 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  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 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. 
6.3.13. 
Prompt Reporting of SAEs to Novartis 
SAEs will be reported promptly to Novartis as described in the following table once the 
investigator determines that the event meets the protocol definition for that event. 
6.3.13.1. 
Timeframes for Submitting SAE Reports to Novartis 
Any serious adverse events which occur during the clinical study or within 5 days of 
receiving the last dose of study medication, whether or not related to the study drug, must 
be reported by the investigator. In addition, any SAEs which occur as a result of protocol 
specific diagnostic procedures or interventions must also be reported. 
All Events must be reported to Novartis within 24 hours of learning of its occurrence  
Information about all SAEs is collected and recorded on a Serious Adverse Event Report 

 
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Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of 
each SAE to each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form in English, and send the completed, signed form by fax 
to (fax: 877-778-9739) within 24 hours to the oncology Novartis DS&E department 
with the provided FAX cover sheets.  
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question. Where applicable, information from relevant hospital case 
records and autopsy reports should be included. Follow-up information should be 
forwarded to Novartis within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of pazopanib 
and considered by the investigator to be related or possibly related to pazopanib must be 
reported to Novartis if and when they occur. Additionally, in order to fulfill international 
reporting obligations, SAEs that are related to study participation (e.g., procedures, 
invasive tests, change from existing therapy) or are related to a concurrent medication 
will be collected and recorded from the time the subject consents to participate in the 
study until he/she is discharged. 
6.3.13.2. 
AE and SAE Documentation and Follow-up Procedures 
The investigator will review and adhere to the following procedures: 
 
Method of Detecting AEs and SAEs 
 
Recording of AEs and SAEs 
 
Evaluating of AEs and SAEs 
 
Completion and Transmission of SAE Reports to Novartis 
 
Follow-up of AEs and SAEs 
 
Post-study AEs and SAEs  
 
Regulatory Reporting Requirements for SAEs 
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to Novartis are provided in the 
SPM. Procedures for post-study AEs/SAEs are provided in the SPM. 
6.4. 
Biomarker(s) 
6.5. 
Biomarker Research  
Plasma/Serum Biomarkers 
Approximately 10ml of blood will be taken from subjects for preparation of plasma for 
biomarker research at the timepoints specified in Table 6.  Examination of pre-dose 
protein profiles may uncover novel blood-borne protein candidate biomarkers profiles 

 
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which could be used to predict drug response. In particular, circulating levels of 
solubleVEGF ligand, soluble VEGF receptor 2, serum HIF and serum TSP1 will be 
investigated. Analyses will be carried out at the UCI Fruehauf laboratory. 
The plasma samples will be “coded” with a study specific number that can only be traced 
or linked back to the subject by the investigator or site staff.  Coded samples do not carry 
personal identifiers (such as name or social security number) therefore the true identify of 
the subject will remain unknown to anyone outside of the study investigator or site staff. 
Samples will be retained for a maximum of 15 years after the last subject completes the 
trial. 
Instructions on sample preparation, storage are provided in Section 11.7, Appendix 7. 
Archived Tumor Biomarkers 
Archived formalin-fixed paraffin embedded tumor tissue from the time of original 
diagnosis (or from second surgery for metastatic disease) will be tested to determine 
intra-tumoral expression levels of relevant biomarkers (encoded in RNA or protein) in the 
angiogenesis pathway (e.g. VEGFR, c-kit) and potentially other biomarkers that are 
downstream or related to these pathways.  In addition, analyses of underlying genetic 
aberrations (mutations, amplifications, and deletions) will be performed in DNA isolated 
from the tumor tissue. Biomarkers will be analyzed using appropriate technologies such 
as immunohistochemistry and transcriptional profiling. 
Preferably a tumor block or a minimum of fifteen (20) slides of paraffin-embedded tissue 
from the tumor obtained at the initial diagnosis or recent biopsy or surgery (archived 
tumor tissue) should be sent for testing. Biomarker analyses will be carried out at the UCI 
Fruehauf laboratory. BRAF mutation status will be tested at an outside laboratory on 
tissue sections. 
Fresh Tumor Biomarkers 
To test the hypothesis that tissue levels of angiogenic markers are modulated by the drug 
combination, IHC assays for HIF, p53, TSP1, VEGF and vessel counts (CD31) on pre-
treatment tissue sections and on post-treatment biopsies from consented subjects with 
subcutaneous lesions when possible will be  performed. Archived formalin-fixed paraffin 
embedded tumor tissue from the time of original diagnosis (or from second surgery for 
metastatic disease) may also be used to substitute the pre-treatment tissue samples.  
Analyses will be carried out at the UCI Fruehauf laboratory. Tumor biopsy specimens 
will be grown in co-culture with vascular endothelial cells and exposed to pazopanib 
alone and in combination with paclitaxel, topotecan and resveratrol to determine the 
effects of different tumor samples on endothelial cell response. Gene arrays will be 
performed on the tumor and endothelial cells to determine if a gene signature is 
associated with sensitivity or resistance to pazopanib. 

 
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7. 
DATA MANAGEMENT 
For this study, subject data will be collected in the subject’s source documents and 
entered onto UCI generated case report forms (CRFs).  The UCI central research office 
will be responsible for data management. 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Hypotheses 
The goal of this single arm, open label, phase II study is to determine if paclitaxel and 
pazopanib demonstrate clinically significant activity as reflected by the proportion of 
subjects alive without progression six months after the start of treatment, or alternatively, 
if the level of activity is clinically irrelevant.   Based on data from a meta-analysis of 
trials in stage IV melanoma [Korn, 2008], the sample size for this study is determined on 
the assumptions that the 6 month PFS of 30% or greater for subjects receiving 
pazopanib/paclitaxel in the first-line treatment setting will be of significant interest for 
further evaluation.  If the 6-month PFS probability is less than 15%, further evaluation of 
this combination in this patient population will not be of interest.  If 13 or more subjects 
survive and are free of disease progression beyond six months, this combination therapy 
will warrant further evaluation in this patient population.  This design has a significance 
level of 6% (probability of falsely declaring an agent with a 15% six-month PFS rate to 
warrant further study) and a power of 88% (correctly declaring an agent with a 30% six-
month PFS rate as warranting further study).   
8.2. 
Study Design Considerations 
8.2.1. 
Sample Size Assumptions 
A total of 60 subjects will be enrolled to obtain a minimum of 55 fully evaluable subjects 
for a sufficient estimate of the 6-month PFS probability, the 6-month overall survival 
probability and toxicity rates to within +/-13% (95% confidence interval).  Assuming that 
at least 80% of 55 eligible subjects have measurable disease, this would be sufficient to 
estimate the response probability to within +/- 15% (95% confidence interval).  Any 
toxicity occurring with at least 5% probability is likely to be seen at least once (94% 
probability).   
8.2.2. 
Analysis Populations 
The Intent-to-Treat (ITT) population will comprise all randomized subjects and will be 
used for the analysis of efficacy data. 
The Safety population will comprise all randomized subjects who receive at least one 
dose of investigational product, and will be based on the actual treatment received if this 
differs from that to which the subject was randomized.  The safety population will be 
used for the analysis of safety data. 

 
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8.2.3. 
Analysis Data Sets 
The primary data set for assessing efficacy will comprise the intent-to-treat population.  
The primary data set for assessing safety will comprise the safety population defined in 
Section 8.2.2 Analysis Populations. 
8.2.4. 
Early Stopping Rule 
The purpose of implementing a Simon 2-stage Minimax design is to minimize the 
number of subjects exposed to pazopanib when unfavorable results occur [Simon, 1989].  
For the Simon two-stage design, and with a Type I error rate (alpha) of 0.05, power of 
90%, a null proportion of 0.10 and an alternative proportion of 0.25, the total sample size 
is 66.  The first stage is n1=21 with a decision rule to stop for futility if there are 2 or 
fewer responses.    
8.2.5. 
Key Elements of Analysis Plan 
Withdrawal 
Subjects will be treated until disease progression or withdrawal from study due to 
unacceptable toxicity. Subjects may also withdraw from the study for other reasons prior 
to disease progression or unacceptable toxicity. All subjects who withdraw from the 
study will be included in analyses up to the time of withdrawal, regardless of the duration 
of treatment. 
Missing Data 
As the period of treatment for any subject will be dependent on its efficacy and toxicity, 
the duration of follow-up will vary between subjects. Consequently, there will be no 
imputation for missing data. Where appropriate, available data will be summarized over 
specified intervals (e.g. from enrollment until withdrawal from the study) using suitable 
summary statistics.  
For the PFS endpoint, the date associated with the last visit with adequate assessment will 
be used for those subjects who are alive and have not progressed at the time of analysis; 
such subjects will be considered censored in the analysis.  If a progression event occurs 
after an extensive lost-to-follow-up time (12 weeks or greater) the primary analysis will 
censor those subjects at the date of their last visit with an adequate assessment.   
Derived and Transformed Data 
Details of the determination of overall tumor response (complete response, partial 
response, stable disease, or progressive disease) are given in Section 6.2.3.3 “Response 
Evaluation of Measurable Disease”.  
Table 11 represents how progression and censoring dates are assigned in the primary 
analysis. The primary method for assessing progression will be based on radiologic 

 
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assessment. However it is anticipated that some subjects will have evidence of clinical 
progression prior to radiological progression.  
Table 11. Assignments for Progression and Censoring Dates  
Situation 
Date 
of 
Progression 
or 
Censoring 
Outcome 
No baseline assessment 
Enrollment 
Censored 
Progression documented at or 
between scheduled visits (during 
adequate follow-up)1 
Date of scan 
Progressed 
No Progression 
Date of last visit with adequate 
assessment 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last visit with adequate 
assessment 
Censored 
Study withdrawal for toxicity or 
other 
reason(prior 
to 
documentation of progression or 
death) 
Date of last visit with adequate 
assessment 
Censored 
New anticancer treatment started 
with no claim of progression 
Date of last visit with adequate 
assessment 
Censored 
Death 
before 
first 
PD 
assessment 
Date of Death 
Progressed 
Death prior to progression during 
adequate follow-up 
Date of Death 
Progressed 
Death or progression after an 
extended lost-to-follow-up time 
(greater than 12 weeks) 
Date of last visit with adequate 
assessment 
Censored 
b. 
The subject need not be on IP at the time of the scan. In this situation, it is possible that the subject has 
discontinued IP. 
k. 
 
An adequate disease assessment comprises imaging assessment of the target tumor 
lesion(s) and non-target tumor lesion(s)/site(s) using CT and/or MRI of the chest, 
abdomen and pelvis with a schedule of every 8 weeks. A subject may have a bone scan to 
confirm a CR/PR. Subsequent bone scans will be performed as clinically indicated. 
New bone scan lesions that are equivocal will be considered as new malignant lesions if a 
confirmatory assessment using X-ray, CT or MRI is not available, and the subject will be 
determined as having progressive disease. 
If a bone assessment is missing at baseline, any new bone lesions identified after the first 
dose that is either consistent with or equivocal for tumor metastasis will be considered as 
new bone (malignant) lesions and the subject will be considered as having progressive 
disease.  
Other Issues 
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A summary and listing of protocol violations will be provided. 
Demographic and baseline characteristics will be summarized. 
Any deviations from, or additions to, the original analysis plan described in this protocol 
will be documented. 
8.2.5.1. 
Efficacy Analyses  
8.2.5.1.1. Primary Analysis 
6-month Progression-free Survival (PFS) 
This is defined as the percentage of subjects who are free of RECIST-defined objective 
disease progression at 6 months after study treatment start. 
Subjects in the ITT population who discontinue the study prior to 6 months will be 
included in the denominator when calculating the percentage. 
8.2.5.1.2. Secondary Analyses 
Objective Tumor Response Rate 
This is defined as the percentage of subjects achieving either a complete or partial tumor 
response per RECIST criteria. The response rate will be calculated from the review of 
best response which records confirmed cases of PR and CR only.  Confirmation will 
occur at least 4 weeks after the initial response.  Stable disease (SD) will also be defined 
by 8 weeks or greater and will be summarized by less than 6 months vs. equal or greater 
than 6 months.    
Subjects in the ITT population with unknown or missing response will be treated as non-
responders, i.e. they will be included in the denominator when calculating the percentage. 
Clinical Benefit Response 
This is defined as the percentage of subjects achieving either a complete, partial tumor or 
stable disease response per RECIST criteria. Confirmation will occur at least 4 weeks 
after the initial response for partial and complete responders.  Stable disease (SD) will 
also be defined by 8 weeks or greater.    
Subjects in the ITT population with unknown or missing response will be treated as non-
responders, i.e. they will be included in the denominator when calculating the percentage. 
Duration of Response 
Duration of response analyses will be restricted to the subgroup of the population who 
experience a response during the study. Duration of response will be defined as the time 
from first documented evidence of response (CR/PR) until the first documented sign of 
disease progression or death, if sooner.   

 
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For subjects who do not progress or die, duration of response will be censored on the date 
of last assessment.  
Duration of response will be summarized using a Kaplan-Meier methods and displayed 
graphically where appropriate. 
One and 2- year Survival 
This is defined as the percentage of subjects who are alive at 1 year and 2 years after 
enrollment. For subjects who do not die, time to death will be censored at the time of last 
contact.   
8.2.5.2. 
Safety Analyses 
The safety population will be used for the analysis of safety data. 
Extent of Exposure 
The number of subjects who receive investigational product will be summarized 
according to the duration of therapy. 
Adverse Events 
AE rates and changes in laboratory results will be summarized in tabular form. 
AEs and toxicities will be graded according to the National Cancer Institute-common 
toxicity criteria (NCI-CTC), Version 4.0. Summaries of the number of toxicity grades for 
both laboratory and non-laboratory data will be presented. If the AE is listed in the NCI-
CTC, the maximum grade will be summarized. Otherwise, the maximum intensity will be 
summarized. 
AEs will be coded using the standard dictionary (MedDRA), and grouped by system 
organ class. They will be summarized by frequency and proportion of total subjects, by 
system organ class and preferred term.  Separate summaries will be given for all AEs, for 
drug-related AEs, for SAEs, and for AEs leading to withdrawal from the study treatment. 
The incidence of deaths will also be reported. 
Clinical Laboratory Evaluations 
Hematology, coagulation parameters, clinical chemistry, and urinalysis data will be 
summarized at each scheduled assessment. Hematology, coagulation parameters and 
clinical chemistry will be summarized by NCI-CTC version 4.0 and by data outside the 
reference range for each scheduled assessment. 
Other Safety Measures 
Vital signs (blood pressure, heart rate, temperature, and weight) will be listed for each 
subject and change from baseline will be included for blood pressure and heart rate. A 

 
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descriptive summary including change from baseline pre-dose will also be presented.  
Individual profiles of blood pressure will be plotted by time. 
All ECG parameters including the corrected QT interval (QTc) will be listed for each 
subject and summarized at each scheduled assessment time. Change from baseline will be 
summarized and an analysis of central tendency (means, medians) will be presented. A 
categorical analysis for each QTc parameter will be performed to determine the number 
of subjects at each time point for the following categories: 
 
QTc. <400, 400 to <440, 440 to 450, and >450 msec. 
 
QTc change from baseline. 30 to <60 msec. and ≥60 msec., 
 
8.2.5.3. 
Biomarker(s) Analyses 
The results of biomarker investigations will be reported separately from the main clinical 
study report.  All endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  Relationships between baseline 
patient characteristics, biomarkers and outcome variables will be explored with 
appropriate techniques. 
A preplanned analysis of hypertension (HTN) as a PD marker will also be carried out to 
determine if this is a surrogate of efficacy. BP will be determined at each clinic visit and 
any diastolic reading of >/= 90 or systolic reading >/= 150 will be considered positive if 
still elevated after being repeated X3 20  minutes apart and the average of the readings is 
still positive for HTN. All subjects noted to have HTN will be treated with 
antihypertensive medications. 
Categorical statistical analysis will be performed to determine the relationship between 
PD and PK markers and outcomes. Univariate summary statistics will be calculated, such 
as the sample median, standard deviation, minimum, and maximum observations.  The 
dichotomized variables were tabulated as high and low levels or positive and negative 
expression.  Changes over time in continuously distributed biomarker levels will be 
investigated with the sign’s test because of the heavy degree of skewness observed in 
some of the marginal distributions. Associations between interval quality data with 
ordinal data will be examined with Spearman’s correlation coefficient. Associations 
between dichotomized biomarkers among themselves and with ordinal subject 
characteristics such as tumor grade or performance status will be characterized with 
Kendall’s tau-b correlation. 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
Safety Data Review 
A UCI independent data safety committee will review safety data consisting of the 
reported adverse events, discontinuations and mortality that occur during the course of 
the protocol.  The charter of the committee is to evaluate the safety of the program using 

 
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available data from the clinical and SAE databases on a quarterly basis, or more 
frequently if a safety issue arises.  Based on the data review, the committee will make 
recommendations as to whether any modifications of the trial are warranted. 
9.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the guiding principles of the declaration of 
Helsinki, including, but not limited to: 
 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval of study protocol and any subsequent amendments. 
 
Subject informed consent. 
 
Investigator reporting requirements. 
Written informed consent must be obtained from each subject prior to participation in the 
study. 

 
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10. 
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Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose 
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Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 
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Atkins MB. Cytokine-based therapy and biochemotherapy for advanced melanoma. Clin 
Cancer Res 2006;12(7 Pt 2):2353s–8s.   
 
Brick A, Kirkin AF, Zeuthen J, Hou-Jensen K. Expression of basic fibroblast growth 
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the same patients. Melanoma Res 1999;9(4):375–81. 
 
Danson S, Lorigan P. Improving outcomes in advanced malignant melanoma: update on 
systemic therapy. Drugs 2005;65(6):733–43. 
 
Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic 
melanoma: what have we learned in 30 years?. Eur J Cancer 2004;40(12):1825–36.     
 
Flaherty KT. Chemotherapy and targeted therapy combinations in advanced 
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Gorski DH, Leal AD, Goydos JS. Differential expression of vascular endothelial 
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paclitaxel and carboplatin for malignant melanoma. Am JClin Oncol 
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Perez DG, Suman VJ, Fitch TR, Amatruda T 3rd, Morton RF, Jilani SZ, Constantinou 
CL, Egner JR, Kottschade LA, Markovic SN: Phase 2 trial of carboplatin, weekly 
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patients with metastatic melanoma. Cancer 2006;106(2):375–82. 
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Immunohistochemical expression of vascular endothelial growth factor, 
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Tan AR, et al. Phase I study of the safety, tolerability, and pharmacokinetics (PK) of 
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Ugurel S, Rappl G, Tilgen W, Reinhold U. Increased serum concentration of 
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11. 
APPENDICES 
 
11.1. 
Appendix 1: American Joint Committee on Cancer (AJCC) 
Tumor Node Metastasis (TNM) Classification of Melanoma 
The existence of an accurate staging system that groups patients of similar risk of disease 
progression/natural history is a necessary tool for the appropriate selection of optimal 
treatments. An accurate staging system is also required to appropriately test new 
therapies in more homogenous patient populations allowing greater clinical relevance to 
results of clinical trials. Based on data dealing with the natural history of melanoma 
generated over the past 3-4 years, the AJCC proposed the following revised TNM staging 
system for melanoma:  
Proposed TNM Classification for Clinical Staging of Malignant Melanoma  
 
Mets: metastases 
 
a - Micrometastases are diagnosed after elective or sentinel lymphadencectomy.  
b - Macrometastases are defined as clinically detectable lymph node metastases 
confirmed by therapeutic lymphadenectomy or when any lymph node metastasis exhibits 
gross extracapsular extension.  

 
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(Table was reproduced from "A New American Joint Committee on Cancer Staging 
System for Cutaneous Melanoma", Cancer 88:1484, 2000. Grade B) 
Clinical Staging for Cutaneous Melanoma  
 
a - Clinical staging includes microstaging of the primary melanoma and 
clinical/radiologic evaluation for metastases; by convention, it should be used after 
complete excision of the primary melanoma with clinical assessment for regional and 
distant metastases.  
b - Pathologic staging includes microstaging of the primary melanoma and pathologic 
information about the regional lymph nodes after partial or complete lymphadenectomy, 
except for pathologic Stage 0 or Stage 1A patients, who do not need pathologic 
evaluation of their lymph nodes (Table was reproduced from "A New American Joint 
Committee on Cancer Staging System for Cutaneous Melanoma", Cancer 88:1484, 2000, 
grade B). 
 

 
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11.2. 
Appendix 2: The Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) Scales 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 

 
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11.3. 
Appendix 3: Cockcroft and Gault Formula for Estimated 
Creatinine Clearance (CrCl) 
CrCl for males (mL/min) = 
 
[140 - age (years)] X [weight (pounds)a] 
 
 
 
      (72) X [Serum creatinine (mg/dL)] 
 
CrCl for females (mL/min) = (0.85) X [140 - age (years)] X [weight (pounds) a] 
 
 
    (72) X [Serum creatinine (mg/dL)] 
For SI units: 
CrCl for males (mL/min) =   
[140 - age(years)] X [weight(kg) 1] X (1.23) 
 
 
 
 
    [serum creatinine (µmol/L)] 
 
CrCl for females (mL/min) =  
[140 - age(years)] X [weight(kg) 1] X (1.05) 
 
 
 
 
    [serum creatinine (µmol/L)] 
1. If the subject is obese (> 30% over ideal body weight), use ideal body weight in 
calculation of estimate CrCl. 

 
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11.4. 
Appendix 4: New York Heart Association (NYHA) 
Classification of Congestive Heart Failure 
Class I 
Subjects with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
Class II 
Subjects with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion. 
Class III 
Subjects with marked limitation of activity; they are comfortable only at rest. 
Class IV 
Subjects who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 
 

 
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11.5. 
Appendix 5: Recommendations for Management of 
Hypertension 
The pathogenesis of hypertension induced by angiogenesis inhibitors is likely to be multi-
factorial. VEGF and VEGFR-2 are involved in the proper maintenance, differentiation, 
and function of endothelial cells.   Arterial hypertension is characterized by reduced nitric 
oxide (NO) biosynthesis, activation of the renin-angiotensin-aldosterone system (RAAS), 
increased vasoconstriction, and microvascular rarefaction of arterioles and capillaries.  
Microvasular rarefaction in hypertension is partly due to impaired angiogenesis. 
Hypertension observed with anti-angiogenic agents is thought to be due to decreased 
bioavailability of endothelium-derived NO, which is a potent vasodilator, as a result of 
reduced endothelium function by anti-angiogenesis.  
Control of Hypertension Prior to Study Entry  
For subjects presenting with hypertension, their BP must be adequately controlled to < 
150/90 mmHg prior to the first dose of study medication. This can be achieved by 
adjusting the existing anti-hypertensive medications or adding new one [See below for 
permitted anti-hypertensive medications and Section 6.3.2 for baseline BP assessment].  
Control of Hypertension during Study Treatment 
In event hypertension is worsened or emerged during study treatment; the management of 
hypertension should include two parts: 1. Dose modification of study medication, 
including interruption, reduction, re-challenge, or discontinuation of study medication 
[See Section 5.3.1 for guidelines and algorithm]. 2. Management of hypertension with 
anti-hypertensive medications.  
The following antihypertensive medications are permitted by the protocol but should be 
used with caution: 
 
Dihydropyridine calcium channel blockers:  felodipine, nifedipine, nicardipine, 
nimodipine, nitrendipine, amolodipine, nisoldipine, and isradipine. 
 
Angiotensin II blockers: losartan and irbesartan. 
 
Beta-blockers:  carvedilol, metoprolol, propafenone, propranolol, and timolol. 
 
Calcium channel blocker: diltiazem and verapamil. 
Based on consultation with experts in the field, we recommend the use of 
dihydropyridine calcium channel blocker and ACE inhibitors as the first line and second 
line of therapy, respectively, for treatment-related hypertension. The use of non-
dihydropyridine calcium channel blockers diltiazem and verapamil are not encouraged.  
The lead investigator should be contacted if there is any concern or need for clarification.  

 
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11.6. 
Appendix 6: Procedures for Obtaining Urine 
Protein/Creatinine Ratio 
 
1. Obtain at least 4 mL of a random urine sample (does not have to be a 24-hour 
urine) 
2. Determine protein concentration (mg/dL) 
3. Determine creatinine concentration (mg/dL) 
4. Divide the value from Step 2 by the value from Step 3 above: urine 
protein/creatinine ratio = protein concentration (mg/dL)/creatinine concentration 
(mg/dL) 
 
The urine protein/creatinine ratio directly correlates with the amount of protein excreted 
in the urine per 24 hours (i.e., a urine protein/creatinine ratio of 1 should be equivalent to 
1 g of protein in a 24-hour urine collection). 
 
Protein and creatinine concentrations should be available on standard reports of 
urinalyses, not dipsticks. If protein and creatinine concentrations are not routinely 
reported at an institution, their measurements and reports may need to be requested. 

 
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11.7. 
Appendix 7:  Blood Samples for Soluble protein 
assessments: Procedures for Sampling, Handling, Storage, 
and Shipment 
Plasma samples for analysis of soluble proteins will be obtained at the time points 
designated in the protocol Table 6. Time and Events Table.  
1. An indelible marker should be used to record the patient initials, ID number, 
collection date, and cycle day on the collection tube prior to collection. 
2. Collect 10.0 mL of blood into a sodium heparin tube (green top) at the designated 
times. 
3. After collection, gently invert the tube (15 times) to completely mix blood and 
anticoagulant. 
4. Once the sample has been mixed, it should be placed immediately into an ice bath 
ensuring that the tube is immersed so that the temperature is kept at 2° C to 8°C 
during all processing steps. 
5. Centrifuge at 3500 rpm at 4C for 10 minutes. 
6. Transfer upper layer using a pipette into 4 Nalgene (2 brown capped, and 2 orange 
capped) cryovials; split approximately a quarter of the sample into each of the vials. 
7. Store tubes at –70°C to –80°C. 
8. One brown and one orange capped cryovial (primary sample, larger 3.6 mL tubes) 
should be shipped on the day of collection and one tube each (back-up sample, 
smaller 1.8 mL tubes) should be retained at the site in a –70°C or –80°C freezer. 
Refer to the study reference binder for sample shipping instructions. 

 
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11.8. 
Appendix 8:  Fresh Tissue Samples: Procedures for 
Sampling, Handling, Storage, and Shipment 
After the patient grants informed consent for the biopsy, at least a 0.5-3 cm cube of tumor 
tissue from a superficial lesion should be obtained by a punch, core, or excisional biopsy.  
The 4 mm cube should be snap frozen in liquid nitrogen within one hour and stored at 
-70C to -80C.  The sample analysis will not be anonymized and will be carried out 
specifically for the purposes of evaluating correlation of DNA and RNA patterns with 
clinical response.  The samples will not be made available to anyone not associated with 
this study or external investigators.  All materials (DNA and RNA) will be destroyed 
immediately after analysis.  No genetic material will be stored.   

 
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11.9. 
Appendix 9:  Biomarker Analysis 
ELISA.  VEGF and TSP1 production are measured using a human Quantikine ELISA 
kits (R&D system, Minneapolis MN) per manufacturer’s instructions. HIF1α and p53 
production are measured using DuoSet IC ELISA kits (R&D system, Minneapolis MN) 
per manufacturer’s instructions.  
IHC. All sections are deparaffinized in xylene (Richard Allen, Kalamazoo MI) and 
rehydrated with increasing concentrations of water in Dehydrant (Richard Allen, 
Kalamazoo MI) and undergo target retrieval prior to staining.  CD31, CD105, and p53 
required a standard target retrieval solution (TRS) diluted from 10x (DAKO, Carpinteria 
CA).  TSP1 and VEGF antigen retrieval is performed in a home-brew target retrieval 
solution, consisting of 1mM EDTA (Sigma, St. Louis MO) in double distilled water 
titrated to pH 8.0.  Melan-A required a high pH target retrieval solution (diluted from 
10x, DAKO, Carpinteria CA).  The appropriate target retrieval solution is preheated to 
95oC in a steamer and slides were incubated in 95oC TRS for 10-20 minutes.  Slides are 
removed from the steamer to cool in the target retrieval solution for an equal amount of 
time.  Slides are rinsed twice in double distilled water and incubated in wash buffer 
(diluted from 10X, DAKO, Carpinteria CA) for a minimum of 5 minutes prior to 
staining.  All IHC is performed using a DAKO Autostainer (Carpenteria CA).  
All other staining is performed using the two-step EnVision+ system (DAKO, 
Carpinteria CA).  In this system, slides are blocked with hydrogen peroxide for 10 
minutes to block endogenous peroxidase activity and incubated with primary mouse 
antibody for an hour.  Primary antibody clones and dilutions are as follows: CD31 JC70a 
1:50 (DAKO, Carpinteria CA), p53 DO-1 1:2000 (DAKO, Carpinteria CA), TSP1 8A6B 
1:200 
(Novocastra/Leica, 
Bannockburn 
IL), 
VEGF 
Ab-7 
VG1 
1:100 
(Neomarkers/Labvision, Fremont CA), HIF1α clone 56 1:50 (BD, San Jose CA), Melan-
A A103 1:50 (DAKO, Carpinteria CA).  The secondary reagent is an HRP labeled 
polymer conjugated with goat anti-mouse and anti-rabbit antibodies.  This labeled 
polymer-HRP is incubated for 30 minutes followed by ten minutes of incubation with 
DAB.  Results are compared to appropriate isotype (DAKO, Carpinteria CA) or 
counterstain only controls.  Positive and negative cell line controls are used for each 
antibody.  Slides are counterstained with either methyl green (DAKO, Carpinteria CA) or 
hematoxylin (DAKO, Carpinteria CA).  Slides are dehydrated in increasing 
concentrations of Dehydrant, cleared in ClearRite (Richard Allen, Kalamazoo MI), and 
mounted with coverslips (Fisher, Houston TX) using Mounting Media (Richard Allen, 
Kalamazoo MI). 
 
 
 

 
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11.10. 
Appendix 10:  Phamacokinetic Samples: Procedures for 
Sampling, Handling, Storage, and Shipment. 
PK samples will be submitted to the Fruehauf lab for shipping to the reference lab 
carrying our the pazopanib PK analysis.