The Effect of Antiangiogenic Therapy With Pazopanib Prior to Preoperative Chemotherapy for Subjects With Extremity Soft Tissue Sarcomas: A Randomized Study to Evaluate Response by Imaging
Phase: NA
Conditions: Stage IIA Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma
Sponsor: University of Washington

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FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
Previous version: 05/05/2015
Current version:  03/02/2016
Title of Protocol:  
The Effect of Antiangiogenic Therapy with Pazopanib Prior to Preoperative 
Chemotherapy for Subjects with Extremity Soft Tissue Sarcomas: A 
Randomized Study to Evaluate Response by Imaging
Investigator List:
Principal Investigator    Professional Title
Phone Number
Darin Davidson, MD
Assistant Professor of Orthopedics and Sports Medicine,
University of Washington
(206) 543-3690
Co-Principal
Investigator
Robin Jones, MD
Eve Rodler, MD
Co-Investigators
Andrew Shields, MD
Elizabeth Loggers, 
MD, PhD
Lee Cranmer, MD, 
PhD
Affiliate Professor of Medicine,  University of Washington
Affiliate Member, Fred Hutchinson Cancer Research Center
Affiliate Assistant Professor of Medicine, University of 
Washington
Affiliate Assistant Member, Fred Hutchinson Cancer 
Research Center
Clinical Assistant Professor, University of Washington
Assistant Professor of Medicine, University of Washington
Assistant Member, Fred Hutchinson Cancer Research Center
Associate Professor, University of Washington
Associate Member, Fred Hutchinson Cancer Research 
Center
(206) 288-7439
(206)-288-7438
(206) 288-6975
(206) 288-7439
Gabrielle Kane, MD
Rosa Yeh, Pharm. D.      
Seth Pollack, M.D.
Associate Professor, Radiation Oncology, University of 
Washington 
Director, Pharmacokinetics Lab SCCA
Affiliate Investigator, FHCRC
Assistant Professor, University of Washington
Assistant Member, Fred Hutchinson Cancer Research Center
(206)-598-7362
(206)288-7396
(206)-667-6629
Biostatistician:
Brenda F. Kurland
Associate Member, Fred Hutchinson Cancer Research Center      (206)-667-2804
Research Staff:
Phase I Program
(206) 288-7551
Emergency Contact: Operator at UWMC (206) 598-6190

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Table of Contents
1.0 INTRODUCTION .............................................................................................................................. 4
2.0 BACKGROUND ............................................................................................................................... 4
2.1
Soft Tissue Sarcoma Adjuvant and Neoadjuvant Chemotherapy ........................................... 4
2.2
Antiangiogenic Therapy in Sarcoma ....................................................................................... 6
2.3
Pazopanib in Sarcoma ............................................................................................................. 6
2.4
Study Agent – Pazopanib ........................................................................................................ 7
2.5
Dose Rationale ....................................................................................................................... 11
2.6
Chemotherapy ........................................................................................................................ 11
2.7
Imaging Studies to Determine Early Response to Therapy in Soft Tissue Sarcoma ............ 11
2.8
Risks/Benefits ........................................................................................................................ 12
3.0 STUDY OBJECTIVES ..................................................................................................................... 12
3.1
Primary Objectives ................................................................................................................ 12
3.2
Secondary Objectives ............................................................................................................ 13
4.0 STUDY DESIGN .............................................................................................................................. 13
4.1
Description of Study .............................................................................................................. 13
4.2
Endpoints ............................................................................................................................... 13
4.3
Study Procedures ................................................................................................................... 13
5.0 SUBJECT SELECTION ................................................................................................................... 16
5.1
Inclusion Criteria ................................................................................................................... 16
5.2
Exclusion Criteria .................................................................................................................. 17
6.0 SUBJECT REGISTRATION ............................................................................................................ 20
7.0 TREATMENT PLAN ....................................................................................................................... 20
7.1
Agent Administration ............................................................................................................ 21
7.2       Radiation Therapy ................................................................................................................. 25
7.3       Surgery .................................................................................................................................. 26
7.4
Concomitant Medication and Supportive Care Guidelines ................................................... 26
7.5
Duration of Therapy ..............................................................................................................28
7.6
Duration of Follow Up .......................................................................................................... 28
7.7
Dosing Delays/Dose Modifications ...................................................................................... 29
7.8
Criteria for Evaluability and Removal/Withdrawal from Study ........................................... 33
8.0 GUIDELINES FOR ADVERSE EVENT REPORTING ................................................................. 34
8.1
Adverse Event Reporting/Institutional Policy ....................................................................... 34
8.2
Study-Specific Adverse Event Capture ................................................................................. 37
9.0 DATA AND SAFETY MONITORING PLAN .............................................................................. 37
9.1
Data Monitoring ……………………………………………………………………………..37
9.2
Safety Monitoring …………………………………………………………………………...38
9.3
Auditing ……………………………………………………………………………………..38

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9.4
Quality Assurance Review …………………………………………………………………..38
10.0 STUDY AGENT INFORMATION .................................................................................................38
10.1
Pazopanib ................................................................................................................………..38
10.2
Ifosfamide ..............................................................................................................................43
10.3
Doxorubicin ...........................................................................................................................44
10.4
Mesna
..............................................................................................................................47
10.5
Pegfilgrastim..........................................................................................................................48
11.0 ASSESSMENT OF EFFICACY ..................................................................................................... 49
11.1
Pharmacodynamic Studies .....................................................................................................49
11.2
Pharmacokinetic Studies........................................................................................................ 50
11.3
Efficacy Variables ................................................................................................................. 51
11.4
Determining Response to Pazopanib for Continuation on Maintenance ...............................53
12.0 DATA MANAGEMENT/CONFIDENTIALITY ........................................................................... 53
13.0 CORRELATIVE STUDIES ............................................................................................................ 54
14.0 STATISTICAL CONSIDERATIONS .............................................................................................54
14.1    Analysis Plan .......................................................................................................................... 54
14.2    Sample Size Justification ........................................................................................................ 55
14.3    Protocol Enrollment and Special Considerations .................................................................... 55
15.0 RECORDS
15.1
Source Documentation ..............................................................................................................56
15.2
Access........................................................................................................................................56
16.0 TERMINATION OF STUDY ......................................................................................................... 57
REFERENCES ........................................................................................................................................ 57
APPENDICES
APPENDIX A: Study Activities and Treatment Calendar
APPENDIX B: Performance Status Criteria
APPENDIX C: Additional Eligibility Criteria for Women
APPENDIX D: Drugs Known to be Metabolized by Selected CYP450 Isoenzymes
APPENDIX E:  Drugs Associated with QTc Prolongation
APPENDIX F:  Blood Pressure - Recommendations for Data Collection and Event Management

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1.0
INTRODUCTION
This document is a clinical research protocol and the described study will be conducted in 
compliance with the IRB approved protocol, associated Federal regulations and all applicable 
IRB requirements.
This is a randomized study in patients with intermediate/high grade adult soft tissue sarcoma of
the extremity or chest wall which will utilize an oral angiogenesis inhibitor versus placebo 
followed by neoadjuvant chemotherapy. The primary objective is to use FDG-PET to evaluate 
early response to antiangiogenic therapy with pazopanib. This will be correlated with 
pharmacokinetic analysis of pazopanib. Standard RECIST response to therapy will be measured 
and compared with FDG-PET results. The study will provide preliminary data on the relative 
contributions of pazopanib and chemotherapy with doxorubicin and ifosfamide as measured by 
changes in SUV by FDG-PET.  Secondary objectives include: analyzing the safety of sequential 
pazopanib and neoadjuvant chemotherapy; measuring histologic response at the time of surgery 
as a surrogate marker of outcome; and evaluating tumor and serum biomarker response. The 
hypothesis is that the addition of pazopanib to preoperative chemotherapy with doxorubicin and 
ifosfamide will increase the overall response rate which could ultimately translate into an 
improvement in outcome for patients with resectable soft tissue sarcoma. The results of this 
study will inform the design and feasibility of a larger trial which would incorporate pazopanib 
as neoadjuvant therapy.
FDG-PET will be performed pre-treatment, after pazopanib, and after neoadjuvant chemotherapy 
to provide correlative, exploratory pharmacodynamic data on the anti-tumor effect of adding 
antiangiogenic inhibition to chemotherapy. Biomarker studies will also be performed including 
plasma measurement of VEGF and soluble VEGFR2 (sVEGFR2). Quantitative enzyme-linked 
immunosorbent assays (ELISA) for VEGF and sVEGFR2 will be performed on plasma and 
tumor extracts. Plasma will also be collected for micro RNA.
This is a pilot study to test the hypothesis that antiangiogenic therapy with pazopanib
will enhance the response rate of front line chemotherapy agents as measured by radiologic 
response and tumor necrosis. This would provide the rationale to undertake a larger Phase II 
trial, randomizing patients to neoadjuvant chemotherapy with or without pazopanib, with 
progression-free and overall survival as end points.
2.0
BACKGROUND
2.1
Soft Tissue Sarcoma Adjuvant and Neoadjuvant Chemotherapy
Soft tissue sarcomas account for less than 1% of all solid tumors in adults. They encompass a 
complex heterogeneous group of tumors likely arising from pluripotential mesenchymal stem 
cells. Although most patients present with localized disease which allows good local control 
by surgical resection and radiation, approximately 50% die from subsequent metastatic 
disease.[1,2]  There is a strong need to develop new treatments which will improve outcome 
for this group of patients.

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The role of neoadjuvant and/or adjuvant chemotherapy in adult soft tissue sarcomas is 
controversial.  A 1997 individual patient meta-analysis published in the Lancet of all 
randomized clinical trial data showed a significant 10% improvement in local and distant 
disease free survival at 9.4 years follow-up for patients who received adjuvant chemotherapy 
versus those who underwent surgery alone. The meta-analysis failed to show a significant 
benefit in terms of overall survival[3] but a subgroup analysis suggested that patients with 
extremity sarcomas had a 7% improvement in overall survival, which was significant. It is 
possible that the benefits of chemotherapy were underestimated in this meta-analysis since 
patients with low grade lesions who would not be expected to benefit from chemotherapy 
were included and less than 5% of patients received ifosfamide, which was found to be an 
active agent in soft tissue sarcoma in later studies.  A subsequent Italian Phase III study 
involving 104 patients with high grade, large (> 5 cm) resectable or recurrent extremity and 
limb girdle sarcomas evaluated adjuvant chemotherapy with epirubicin and ifosfamide versus 
observation.[4]  At 5 years follow-up there was an absolute overall survival benefit of 19% 
favoring the chemotherapy arm which was significant. When the study was updated at 90 
months, the intent-to-treat analysis no longer showed a statistically significant overall 
survival benefit.[5]  An updated meta-analysis which included the meta-analysis from 1997 
as well as 4 modern studies showed a significant improvement in overall survival benefit for 
chemotherapy, with an odds ratio of 0.56 for anthracycline-ifosfamide combination therapy. 
[6]  
The sole randomized trial conducted in the neoadjuvant setting showed no survival advantage 
in those patients treated with a doxorubicin/ifosfamide based-regimen versus no 
chemotherapy.[7] However, this trial was small and may have been underpowered to show a 
survival benefit. In addition, lower doses of doxorubicin (50 mg/m2) and ifosfamide 
(5/gm/m2) for each cycle were administered, compared to what would now be considered 
optimal dosage of these drugs. 
There are practical and theoretical advantages to offering neoadjuvant chemotherapy for 
patients with large high-risk extremity sarcomas.  Neoadjuvant chemotherapy may act in the 
early systemic treatment of micrometastases and improve outcome for subgroups of patients. 
In one retrospective study combining data from Dana Farber and Memorial Sloan Kettering, 
neoadjuvant chemotherapy with doxorubicin and ifosfamide provided a disease specific 
survival benefit for patients with tumors larger than 10 cm. [8] In some cases neoadjuvant 
chemotherapy can downsize tumors and improve resectability. Neoadjuvant chemotherapy 
allows the tumor to be used as a measure of response in-vivo, by performing imaging studies 
before and after treatment.  Finally, there is prognostic value to treatment induced pathologic 
necrosis. A study by Eilber and colleagues from UCLA utilizing neoadjuvant chemotherapy 
and radiation therapy showed that soft tissue sarcoma patients having 5% or less residual 
viable tumor (at least 95% tumor necrosis) after therapy at the time of surgery had a 
significantly lower risk for local recurrence and improved overall survival.[9]
While chemotherapy in adult soft tissue sarcoma may improve outcome for some patients 
with localized disease, there is a compelling need to develop better control of soft tissue 
sarcoma dissemination by systemic approaches. Even doxorubicin and ifosfamide, the two 
most active agents in soft tissue sarcoma, result in frequent tumor recurrence and progression 
after initial responsiveness.

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2.2 Antiangiogenic Therapy in Sarcoma
Angiogenesis, the growth of new vessels from pre-existing vasculature, is essential for tumor 
progression.  Since the time that tumor angiogenesis was initially postulated by Folkman in 
1971, several basic and clinical studies have shown that the growth, invasion and metastatic 
potential of solid tumors is dependent on angiogenesis.[10-13] In the past two decades, 
inhibitors of angiogenesis have been developed for clinical use and recently have shown 
clinical benefit in combination with chemotherapy [14,15] and as monotherapy in certain 
solid tumors [16-18].
Soft tissue sarcomas express vascular endothelial growth factor (VEGF) which is a key 
mediator of angiogenesis.[19, 20]  In one study of 115 patients with soft tissue sarcoma, the 
concentration of VEGF in the tumor tissue was found to be an independent prognostic factor 
for disease outcome.[21] Tumors associated with local recurrence or metastasis in this study 
showed a significantly higher tissue VEGF concentration than those without either. In 
addition, VEGF blood levels in patients with soft tissue sarcomas are elevated compared with 
healthy controls and correlate with outcome. [19,22-24]. Other angiogenic factors such as 
platelet-derived growth factor (PDGF) are likely involved in the pathogenesis of soft tissue 
sarcoma.[25] Thus, there is a rationale for targeting angiogenesis in soft tissue sarcoma. 
Recent clinical trials have provided preliminary evidence to support this scientific rationale. 
Sunitinib malate and sorafenib, both small molecule inhibitors whose targets include VEGF 
receptors and PDGF receptor, have shown activity in several soft tissue sarcoma subtypes as 
monotherapy in Phase II studies.[26,27]  
2.3 Pazopanib in Sarcoma
Pazopanib is an oral angiogenesis inhibitor that potently inhibits the tyrosine kinase activity 
of VEGF, platelet-derived growth factor receptor (PDGFR) and c-KIT. [28,29,30]  In 
murine studies, pazopanib inhibited VEGF-induced VEGFR2 phosphorylation, tumor 
angiogenesis and the growth of human tumor xenografts. In a Phase I study, pazopanib was 
well tolerated which prompted further studies.  Recently, pazopanib gained FDA approval 
for the treatment of patients with advanced renal cell carcinoma based on the results of a 
Phase III trial which demonstrated that the agent improved progression-free survival and 
tumor response compared with placebo in this population of patients.[31]
Promising results of a Phase II study conducted by the European Organization for the 
Research and Treatment of Cancer (EORTC) in advanced soft tissue sarcoma have been 
published.[32]  In this study 142 patients with intermediate- or high-grade disease received 
pazopanib 800 mg orally daily. The progression-free rate at 12 weeks was 44% in 
leiomyosarcoma patients, 49% in synovial sarcoma patients, and 39% in other subtypes, 
which compares favorably with historical controls treated with second-line chemotherapy.  
The median duration of response was longer than 1 year. The most common toxicities were 
hypertension, fatigue, hypopigmentation, and nausea. Mild myelosuppression and liver 
enzyme elevations were encountered. In light of the anti-tumor activity demonstrated in this 
trial, a double-blind, placebo-controlled, Phase III trial of pazopanib has been initiated in 
patients with angiogenesis-naïve, metastatic soft tissue sarcoma who had progressive disease 
after several lines of treatment. [57] Results showed a significant improvement in median 

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progression-free survival for pazopanib versus placebo, 12.6 months versus 10.7 months, 
respectively.
Given the scientific rationale for combining conventional chemotherapy with inhibitors of 
the VEGF receptor pathway [33] we are interested to evaluate further the potential benefit of 
adding pazopanib to standard front-line cytotoxic agents that have activity in sarcoma, 
doxorubicin and ifosfamide.
2.4 Study Agent - Pazopanib
Pazopanib is a potent and selective, orally bioavailable, adenosine triphosphate competitive, 
small molecule inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -
3, platelet-derived growth factor receptor (PDGFR)-Į-ȕDQGF-KIT tyrosine kinases 
(TKs).[34] In human umbilical vein endothelial cells (HUVECs), pazopanib inhibited 
VEGF-induced VEGFR-2 phosphorylation and was 3- to 400-fold selective for VEGFRs 
compared to 23 other kinases tested. Pazopanib showed significant growth inhibition of a 
variety of human tumor xenografts in mice, and also inhibited angiogenesis in several 
different models of angiogenesis.  Because angiogenesis is necessary for the growth and 
metastasis of solid tumors, and VEGF is believed to have a pivotal role in this process, 
pazopanib treatment may have broad-spectrum clinical utility.
Mechanism of Action
Pazopanib inhibits VEGFR-1, -2, and -3 with concentrations causing 50% inhibition (IC50)
values of 10, 30, and 47 nM, respectively, and inhibits PDGFR-Į-ȕDQGF-KIT with IC50
values of 71, 84, and 74 nM, respectively [34,35,36].
Preclinical Pharmacology, Toxicology , Pharmacokinetics, and Drug Metabolism
Refer to the Investigator’s Brochure 2016.
Clinical Experience
Approximately 8600 subjects with cancer have been enrolled in clinical studies of 
pazopanib as of September 2015.  In October 2009, the FDA approved pazopanib tablets for 
the treatment of subjects with advanced renal cell carcinoma (RCC) and soft tissue sarcoma 
(STS).  In addition, several clinical studies evaluating pazopanib in non-small cell lung 
cancer (NSCLC), ovarian cancer, breast cancer, cervical cancer, hepatocellular cancer 
(HCC), multiple myeloma (MM), and glioma are in progress or have been completed.  
Clinical Efficacy
In a randomized, parallel assignment, double-blind, placebo-controlled study evaluating 
safety, efficacy and PFS of subjects with soft tissue sarcomas, statistically significant 
improvements in PFS were observed in the pazopanib arm when compared with subjects 
taking placebo.  The median PFS in the placebo arm was 7.0 weeks and in the pazopanib 
arm was 20.0 weeks with corresponding HR or 0.35 as assessed by independent radiology 
review.  Soft tissue sarcoma sub-types included in this trial included synovial (48.6%), 
adipocytic (26.3%) and “other” sarcomas (39%). [34]
In a randomized, double-blind, placebo-controlled phase III study evaluating the efficacy 
and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated subjects 

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with advanced RCC, the median progression-free-survival (PFS) was significantly 
prolonged with pazopanib compared with placebo in the overall study population (9.2 vs. 
4.2 months). The objective response rate (RR) was 30% with pazopanib and only 3% with 
placebo [37].  In subjects with ovarian cancer, 31% of subjects experienced a CA-125
response to pazopanib, with a median time to response of 29 days and median duration of 
response of 113 days (Investigator’s Brochure, 2010). In a phase II trial of subjects with 
early-stage NSCLC, 86% of subjects experienced a reduction in tumor volume after short-
term, preoperative use of pazopanib (~2-6 weeks) as assessed by high-resolution CT 
scanning [38].  Interim results from a phase II study of pazopanib in subjects with recurrent 
or metastatic breast invasive breast cancer showed that the clinical benefit rate was 26% 
[39].  The median TTP was 3.7 months, and 50% of subjects with measurable target lesions 
had some decrease in size.  PFS at 3 and 6 months was 55% and 28%, respectively.  
Preliminary results from a randomized study in subjects with first-line advanced ErbB2-
positive advanced or metastatic breast cancer showed that a higher response rate (36.2% vs. 
22.2%) was observed in subjects on combination lapatinib 1000 mg once daily + pazopanib 
400 mg once daily compared to monotherapy lapatanib 1500 mg once daily [40].  In a 
randomized phase II study of pazopanib vs. lapatinib vs. the combination of 
pazopanib/lapatinib in advanced and recurrent cervical cancer, there was a 34% reduction in 
risk for progression in subjects receiving pazopanib relative to lapatinib.  The median PFS 
was 17.1 weeks in the lapatinib group and 18.1 weeks in the pazopanib group [41].  Interim 
analysis of data from 26 subjects showed that pazopanib has both a favorable toxicity profile 
and promising clinical activity in subjects with advanced and progressive differentiated 
thyroid cancers [42].  Five confirmed partial responses (PRs) (19%) were reported.  
Pazopanib has not shown efficacy in phase II studies conducted in MM or glioma.[34]
Safety 
The randomized, phase III study in STS subjects provided a key comparison of safety with 
pazopanib compared to placebo.[34] The most common AEs reported in 20% of subjects 
in the pazopanib arm were fatigue (65%), diarrhea (59%), nausea (56%), weight decreased 
(51%), hypertension (42%), anorexia (40%), hair color change (depigmentation; 39%), and 
vomiting (34%), tumor pain (30%), dysguesia (28%), gastrointestinal pain (24%), headache 
(23%), musculoskeletal pain (23%), myalgia (23%), and dyspnea (20%).  Most of the events 
were grade 1 or 2.  A higher number of grade 3 AEs were reported in the pazopanib arm 
(63%) compared with the placebo arm (28%).  The most frequent grade 3 AEs in the 
pazopanib arm were increased alanine aminotransferase (ALT), increased aspartate 
aminotransferase (AST), hypertension, and diarrhea.  The frequency of grade 4 and grade 5 
AEs was similar between the pazopanib and placebo arms:  grade 4 in 7% and 6%, 
respectively; grade 5 in 4% and 3%, respectively.
When pazopanib was compared with sunitinib in 1102 subjects (554 subjects taking 
pazopanib and 548 subjects taking sunitinib), the frequency of AEs was similar (>99% in 
both).  The safety profiles observed between the treatment arms were different, with greater 
frequency of diarrhea (63% pazopanib, 57% sunitinib) and hypertension (47% pazopanib, 
41% sunitinib).  Subjects who took pazopanib when compared with subjects taking sunitinib 
experienced lower frequency of fatigue, nausea, dysguesia and palmar-plantar 
erythrodysesthesia (PPE) syndrome.  Grade 3 and 4 reported adverse events were similar 
between treatment arms, adding no comparative risk.  However, grade 3 AEs of increased 

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ALT; increased ASP and headache occurred more frequently in the pazopanib arm when 
compared with the sunitinib arm.  [34]
A comprehensive review of all completed and ongoing pazopanib clinical trials with a cut-
off date of September 2015, lists 15 most commonly occurring serious AEs (SAEs).[34]
Vomiting and diarrhea are the most commonly reported SAEs across all the pazopanib 
studies.  As a consequence of this, dehydration is also seen with pazopanib treatment.  For 
most reports, the AEs resolved after supportive treatment such as antiemetics, antidiarrheal 
agents, and IV fluids.  GI perforation is commonly associated with VEGF pathway 
inhibitors.  This may manifest as abdominal pain which is not uncommon in cancer subjects 
for many reasons.  Of the 42 subjects in pazopanib trials with SAEs of abdominal pain, only 
three had a documented underlying intestinal perforation.  In July 2006, the DCTD, NCI, 
issued an Action Letter to investigators using pazopanib describing the occurrence of bowel 
perforations in subjects on pazopanib clinical trials.
7KHPRVWFRPPRQ$(VOHDGLQJWRSHUPDQHQWGLVFRQWLQXDWLRQRIVWXG\GUXJZHUH
increased ALT, increased AST, proteinuria, fatigue, and hepatotoxicity.  Of these AEs, 
increased ALT, increased AST and proteinuria occurred in a higher proportion of  subjects 
taking pazopanib.
Dyspnea is also frequently seen in pazopanib-treated subjects and may reflect the underlying 
disease under treatment.  Anemia is commonly seen in cancer subjects in association with 
chemotherapy, hemorrhage, or infection.  The SAEs of pyrexia were attributed to multiple 
causes:  concurrent infections, the underlying malignancy, hepatic events, other concomitant 
medications, and unknown causes.  Hepatic events are thought to be on-target tyrosine 
kinase inhibitor (TKI) class effects, as hepatic enzyme elevations have been seen with other 
agents of this class.  Careful clinical evaluation is, therefore, warranted in subjects with 
hepatic abnormalities.  Pazopanib is not recommended in subjects with severe hepatic 
impairment (defined as total bilirubin >3UULN regardless of any level of ALT) as there is 
insufficient data in these subjects. Pneumonia can be a complication of chemotherapy or 
can result from debilitation and advanced disease.  Review of the 33 SAEs showed the 
presence of an underlying cause other than pazopanib in 19 of the 30 subjects.  Fatigue and 
asthenia are commonly reported and have multiple causes.
Hypertension observed with pazopanib is a known class effect.  There have been 30 SAEs 
of hypertension and 3 SAEs of hypertensive crisis in pazopanib clinical trials.  There were 
28 subjects who were effectively treated with antihypertensive medication initiation or dose 
adjustment, while 4 had no such treatment.  Although there were 29 SAEs of pleural 
effusion, the body of data does not suggest that any of these cases were due to pazopanib.  
There have been 24 SAEs of pulmonary embolism (PE) reported in pazopanib trials.  This is 
of particular relevance since other members of this class have been associated with PE and 
other venous thromboembolic events.
In addition, there have been reports of cardiac and cerebral ischemic events, GI perforation 
or hemorrhage, pulmonary hemorrhage, cerebrovascular hemorrhage, QT prolongation, and 
Torsades de Pointes in pazopanib clinical trials.

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Laboratory abnormalities
In both treatment arms (placebo vs. pazopanib), most on-therapy hematology grade shifts 
were Grade 1 or Grade 2.  A higher proportion of subjects in the pazopanib arm had grade 
shifts for neutrophils, platelets and WBCs compared with the placebo arm. Chemistry grade 
shifts that occurred more frequently in the pazopanib arm included hyperglycemia, 
hyperkalemia, hypoglycemia and hyponatremia.  Transaminase elevations were also more 
common on pazopanib than placebo.  Thirteen subjects experienced ALT elevations of 
>8UULN, and of these, 5 subjects experienced ALT elevations of >20UULN.  
Clinical Pharmacokinetics
The oral bioavailability of pazopanib reflects absorption that is limited by solubility above 
doses of 800 mg once daily [34,43] Increases in doses above 800 mg to 2000 mg, in the 
fasted state will not result in increased systemic exposure.  Geometric mean pazopanib t½
values ranged from 18.1-52.3 hours.  The mean t½ was 30.9 hours in the 800 mg once daily 
group, in phase 2 and 3 trials.  Oral absorption is significantly enhanced when dosed with 
food; therefore, it is recommended to administer pazopanib on an empty stomach, at least 1 
hour before or 2 hours after a meal.  Age, body weight, gender, and race have no significant 
influence on pazopanib PK.
Potential Drug Interactions
Pazopanib is metabolized primarily by CYP3A4, and systemic exposure to pazopanib is 
altered by inhibitors and inducers of this enzyme.  The concomitant use of strong CYP3A4
inhibitors should be avoided.  Grapefruit may also increase plasma concentrations of 
pazopanib and should be avoided.  CYP3A4 inducers such as rifampicin may decrease 
plasma concentrations; therefore, an alternative concurrent medication with none or minimal 
enzyme induction should be used.  
Concommitant medications that have narrow therapeutic windows and are substrates of 
CYP3A4, CYP2D6 or CYP2C8 should be used with caution.  If possible, medications that 
are not substrates for these enzymes and/or do not have narrow therapeutic windows should 
be substituted. 
Pazopanib is a substrate for P-glycoprotein (P-gp) and BCRP transporters.
Dose Selection
Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg once 
daily, results in effects consistent with inhibition of the VEGF receptors and angiogenic 
factors.[34]  Concentration-effect relationships were observed between trough plasma 
pazopanib concentrations and the development of hypertension as well as the percent 
change from baseline to the nadir of soluble VEGFR2 (sVEGFR2), a marker of VEGFR 
inhibition.  Decreases in sVEGFR2 have been correlated with increased clinical benefit in 
RCC with other small molecule TKIs.[44] The trough plasma pazopanib concentrations 
associated with the EC50 in both concentration-effect relationships were similar (15.3 
mcg/mL for hypertension and 21.3 mcg/mL for sVEGFR2). Pazopanib monotherapy has 
been approved as an 800 mg once daily dose for the treatment of advanced RCC in the US.

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2.5 Dose Rationale
In this study, subjects will receive pazopanib 800 mg or placebo orally daily for 14 days (the 
“Run-in” period) followed by preoperative chemotherapy. Doses will be taken fasting (at 
least one hour before and/or 2 hours after dose).
Subjects who respond to pazopanib during the Run-in period will have the option to 
continue pazopanib 800 mg orally daily for one year following surgery and completion of 
any adjuvant chemotherapy. Refer to Section 11.3 for details.
2.6 Chemotherapy
Pre-operative chemotherapy will consist of doxorubicin and ifosfamide administered on an 
inpatient basis.  The regimen will consist of doxorubicin 75 mg/m2 administered by 
continuous intravenous infusion over 3 days with ifosfamide 2 gm/m2 administered 
intravenously over 4 hours daily for 5 days with IV fluid and Mesna, every 21 days for 2 to 
4 cycles, depending on clinical and radiologic response.  Patients may also receive 2 to 4 
cycles of post-operative chemotherapy, (up to 6 cycles total of neoadjuvant plus adjuvant 
chemotherapy).
2.7   Imaging Studies to Determine Early Response to Therapy in Soft Tissue Sarcoma
Chemotherapy may improve the chance for a cure in patients with high risk sarcomas 
(intermediate to high grade, > 5 cm), but does not benefit every patient and is associated 
with toxicities.[3,4]  Identifying sarcoma patients who are likely to benefit from 
neoadjuvant and/or adjuvant systemic treatment has been challenging.  In most current trials 
of anticancer drugs, the objective radiographic response of tumor to treatment, as defined by 
the international Response Evaluation Criteria in Solid Tumors (RECIST), is used as a 
surrogate measure for therapeutic benefit.[45]  The assessment of soft tissue sarcoma 
response to chemotherapy is difficult, however, because sarcomas are heterogeneous tumors 
and consist of varying degrees of cellularity, fibrous septa, stroma, and necrosis. The 
beneficial effects of a therapy which is successful at eradicating neoplastic cells may be 
masked by a tumor mass that does not shrink or even grows due to necrosis or intratumoral 
hemorrhage.[46]  Standard radiologic response defined by a change in the size of the tumor 
to preoperative chemotherapy has not correlated consistently with histologic results at 
surgery or with survival.[47-49]
FDG-PET: Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG), is a 
tool for evaluation of treatment response in sarcoma. In neoadjuvant therapy for high grade
localized sarcomas, serial FDG-PET is a sensitive method to assess early response to 
therapy; pretreatment standardized uptake value (SUV) and change in SUV predict 
outcome.[50,51] Eary and colleagues first used FDG-PET in sarcomas and demonstrated the 
relationship between the quantitative value of the FDG metabolic rate of tumor and the 
semi-quantitative measure of tumor uptake, the SUV.[52]  Eary and colleagues  showed that 
a higher tumor maximum SUV at diagnosis correlated with a greater risk for disease 
progression and death from disease in patients with soft tissue or bone sarcomas.[50]  In a 
later study, Schuetze and colleagues found that the pretreatment tumor maximum SUV and 
change in maximum SUV after neoadjuvant chemotherapy independently identified 

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sarcoma patients at high risk of tumor recurrence.[51]  Forty-six patients with high-grade 
localized extremity sarcomas were studied. Those with a baseline tumor maximum SUV of 
6 or greater and less than a 40% decrease in FDG uptake after chemotherapy were at high 
risk for systemic disease recurrence, estimated to be 90% at 4 years. In contrast, those 
whose tumors had a 40% or more decline in the tumor maximum SUV after chemotherapy, 
were at significantly lower risk of recurrent disease and death following surgery and 
radiation.  Interestingly, in this study the histologic response to chemotherapy did not 
correlate with patient outcome.  
In this randomized study subjects will undergo baseline staging scans including FDG-PET. 
After the 14 day Run-in period of pazopanib versus placebo, and prior to commencement of 
preoperative chemotherapy, subjects will undergo repeat FDG-PET. After 2 cycles of 
chemotherapy FDG-PET will be repeated.
If results of this trial can be confirmed in larger trials, then this could establish that changes
in tumor SUV in response to antiangiogenic therapy and to chemotherapy may distinguish 
those patients who are likely to benefit from these systemic therapies from those who will 
not.
2.8 Risks/Benefits
Subjects will have a 2:1 chance of being randomized to receive pre-operative pazopanib
during a Run-in period. The potential benefits include early assessment of response to 
antiangiogenic therapy and possible enhanced tumor cell kill. Subjects who respond to 
pazopanib during the Run-in period (defined in Section 11.3) will have the option to 
continue pazopanib for one year, following surgical resection of their tumor.   
Antiangiogenic therapy may improve outcome for patients with high risk resectable soft 
tissue sarcoma, but this remains unproven. Benefits of chemotherapy include a potential 
improvement in disease free survival and overall survival compared to no systemic therapy.  
Risks of the study include side effects associated with pazopanib and with chemotherapy as 
described in Section 10.
3.0
STUDY OBJECTIVES
3.1 Primary Objectives
x
To determine the absolute values and changes in standardized uptake values (SUV) 
by FDG PET before and after a 14 day Run-in period of pazopanib versus placebo,
and to compare this to the change in SUV following pre-operative chemotherapy. 
x
To evaluate the correlation between antiangiogenic activity and pazopanib drug 
exposure.
x
To assess the response rate by RECIST criteria after the 14 day Run-in period of 
pazopanib versus placebo and compare this to the response rate following pre-
operative chemotherapy.

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3.2  Secondary Objectives
x
To examine the activity of antiangiogenic therapy with pazopanib combined with pre-
operative chemotherapy for high risk extremity soft tissue sarcomas as measured by:        
Histological necrosis at surgery
Change in plasma and tumor biomarker assays of angiogenesis 
x
To evaluate the safety of sequential treatment with pazopanib and pre-operative 
chemotherapy with doxorubicin and ifosfamide.
4.0
STUDY DESIGN
4.1  Description of Study
This is a multi-center randomized blinded study with 2:1 randomization of pazopanib versus 
placebo prior to neoadjuvant chemotherapy with doxorubicin and ifosfamide for adult soft 
tissue extremity sarcomas.
4.2   Endpoints
4.2.1  Primary Endpoints
x
Absolute values and changes in standardized uptake values (SUV) of tumors 
measured by FDG-PET pre- and post receipt of pazopanib versus placebo, and 
post receipt of 2 cycles of preoperative chemotherapy 
x
Tumor response by RECIST criteria
x
Correlation of pazopanib trough concentration with the change in SUV from FDG 
PET and change in RECIST measurements on MRIs
4.2.2   Secondary Endpoints
x
Safety profile
x
Pathologic response at the time of surgery as measured by % tumor viability  
x
Progression free survival and overall survival 
x
Change in plasma and tumor angiogenic biomarker levels pre- and 
postneoadjuvant therapy.
4.3 Study Procedures
The study procedures outlined in Appendix A are discussed in this section, with the
exception of Treatment (Section 7).  Screening will occur within approximately 14 days prior 
(unless otherwise noted) to the first day of dosing (pazopanib versus placebo, Run-in period, 
Day 1). For procedures performed at Screening and repeated, the later procedure performed 
prior to dosing will serve as a baseline for clinical assessment.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally acceptable 
representative by the principal investigator or a co-investigator (the “Investigator”) before 
any study-specific procedures are undertaken. 

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The Investigator or his/her representative will explain the nature of the study to the subject, 
and answer all questions regarding this study. Prior to any study-related screening procedures 
being performed on the subject, the informed consent statement will be reviewed, signed, and 
dated by the subject and by the person who administered the informed consent. A copy of the 
informed consent form will be given to the subject and the original will be placed in the 
subject's research chart.
Research analysis of plasma samples and surgical tumor tissue will be performed once the 
subject has signed and dated the informed consent, approved by the IRB of record, after the 
nature of the testing has been explained and the subject has had the opportunity to ask 
questions. The informed consent must be signed before the testing is performed or tumor 
tissue and plasma samples are used for analysis.
Medical History
The following information will be collected during the Screening Visit:
Ɣ Complete medical history, including documentation of any clinically
significant medical condition
Ɣ Oncology history, including primary cancer diagnosis
o
Pathology of primary tumor
o
Stage of tumor  (location, size, grade and depth)
At each visit, the subject's medical history will be reviewed and any changes from baseline 
will be recorded. On Run-in period, Day 1 any changes observed from the screening 
assessments, prior to dosing, will be recorded in the subject's medical history. All medication 
(prescription or over-the-counter, including vitamins and/or herbal supplements) will be 
recorded beginning with the Screening Visit and continued for the duration of the study.
Physical Examination
A complete physical examination will be performed at Screening, including height. A
symptom-directed physical examination including weight will be performed at all other visits 
unless indicated otherwise. Clinically significant physical examination findings after the
administration of the first day of dosing will be recorded as adverse events.
12-lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the Screening Visit, unless performed for 
standard of care within 14 days. The investigator or a designee will sign and date the ECGs, 
determine if any findings outside normal physiological variation are clinically significant (in 
consultation with a cardiologist if necessary), and document this on the ECG report. ECGs 
will also be performed at the initiation of pazopanib maintenance therapy, Cycle 1 Day 1 and 
Cycle 2 Day 2.   
Vital Signs
Vital sign determinations of heart rate, blood pressure and body temperature will be 
measured at all visits unless indicated otherwise. 
Pregnancy Test

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For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening Visit and a urine pregnancy test will be done at the Run-in period Day 1 visit prior 
to the first dose of pazopanib versus placebo. Subjects considered not of childbearing
potential must be documented as being surgically sterile or post-menopausal (for at least 1
year). The test results must be reviewed and determined to be negative prior to dosing. If the
urine pregnancy test is positive at Cycle 1 Day 1, it should be confirmed by a serum
pregnancy test. The test may be repeated at the discretion of the Investigator at any time
during the study. Should the subject become pregnant or suspect she is pregnant while 
participating in this study, she should inform the Investigator immediately. The Principal 
Investigator should be notified and will be responsible for contacting the representative at 
Novartis.
Clinical Laboratory Tests
All subjects will undergo the laboratory assessments outlined in Appendix A. After Cycle 1 
Day 1, clinical laboratory tests should be performed within 72 hours surrounding the 
scheduled study visit date. Any laboratory value outside the reference range that is 
considered clinically significant by the investigator will be followed as appropriate. 
Clinically significant laboratory values will be recorded as adverse events if they meet the 
criteria as specified in Section 7.7.
Tumor Assessments (Radiologic)
Baseline staging scans including a positron emission tomograph with a built-in CT 
component (FDG-PET), MRI of the primary tumor, and diagnostic CT chest are required at 
Screening (within approximately 14 days of the Run-in Period, Day 1). After the 14-day 
Run-in period of pazopanib versus placebo, and prior to commencement of preoperative 
chemotherapy, subjects will undergo repeat FDG-PET and MRI of the primary tumor. After 
2 cycles of chemotherapy, FDG-PET and MRI of the primary tumor will be repeated.
CT of the chest without contrast will be performed approximately every 3 months for the first 
year following surgery and MRI (or CT) of the primary site of the tumor will be performed 
every 6 months. 
ECOG Performance Status
The ECOG performance status will be assessed at Screening, Run-in Period Day 1 and Day 1 
of each subsequent cycle, Final Visit, and at the 30-day Follow-up Visit.  See Appendix B
for ECOG criteria. 
Pharmacokinetic Studies
Trough level (22-24 hrs after pazopanib dosing): A blood sample (4 mL K2EDTA purple top 
blood collection tube) will be drawn to assess the trough plasma pazopanib concentration 
during the 14 day Run-in period of pazopanib monotherapy, after completion of adjuvant 
chemotherapy, and every 3 months thereafter until completion of pazopanib maintenance 
therapy. During the Run-in period, the trough level will be drawn twice during Days 10 
through 14: 1) one trough on any of Days 10-14 and 2) on the day of the FDG PET after the 
Run-in period, 22-24 hours after the patient’s last dose of pazopanib versus placebo.  After 
completion of surgery/adjuvant chemotherapy, the trough will be drawn once during each of 
the following periods: 1) Week 2 (Days 10-15 after restarting pazopanib), Weeks 3-4 after 

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restarting pazopanib, and then every 3 months for 1 year).  If all trough levels are drawn, a 
total of 8 samples are possible in a single subject.
An optional full intensive pharmacokinetic visit will be performed in consenting patients 
during Weeks 2-4 in subjects following surgery/adjuvant chemotherapy. Blood (4 mL 
K2EDTA purple top blood collection tube) will be obtained at the following timepoints: 
immediately before pazopanib dosing (within 5 minutes before giving pazopanib on the day 
of PK dosing) and 1, 2, 3, 4, 6, 8 hour timepoints (+/- 10 minutes) , and 24 hrs (range 22 to 
24 hours) after dosing (a total of 8 samples/subject).
Biomarker Studies
Plasma will be collected for measurement of VEGF and soluble VEGFR2 (sVEGFR2) at 
baseline, after the 14 day Run-in period of pazopanib, after completion of neoadjuvant 
chemotherapy and approximately every 3 months thereafter until completion of pazopanib 
maintenance therapy, when indicated.   Quantitative enzyme-linked immunosorbent assays 
(ELISA) for VEGF and sVEGFR2 will be performed on plasma and tumor extracts.
Plasma will also be collected for micro RNA at baseline, after the 14 day Run-in period of 
pazopanib, following neoadjuvant chemotherapy and every 3 months thereafter until 
completion of pazopanib maintenance therapy, when indicated.
5.0
SUBJECT SELECTION 
5.1
Inclusion Criteria
5.1.a  
Histologically or cytologically confirmed soft-tissue sarcoma, excluding alveolar 
and embryonal rhabdomyosarcoma, well- and dedifferentiated adipocytic 
sarcomas, Ewing’s, osteosarcoma, or gastrointestinal stromal tumor. AJCC (6th
Edition) Stage III or T2a Stage II or Stage IV-treatment naive patients planned for 
resection of the primary tumor, with resectable metastatic disease.
5.1.b
Measurable disease greater than 5 centimeters in greatest dimension.  Measurable 
lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter for non-nodal lesions and short axis for nodal lesions 
to be recorded) by chest x-ray, CT scan, MRI or with calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).  
5.1.c
Intermediate or high grade lesions: 2 or 3 on a scale of 1-3 or grades 2 to 4 on a 
scale of 1-4.
5.1.d
Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities 
or on the body wall.
5.1.e
Life expectancy of greater than 6 months.
5.1.f
(&2*SHUIRUPDQFHVWDWXV.DUQRIVN\0%; see Appendix B).

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5.1.g
No prior chemotherapy, radiotherapy, or antiangiogenic therapy.
5.1.h
Age > 18 years
5.1.i
No significant organ dysfunction with initial labs:
ANC
t 1500 /PL
Hgb
JG/
Platelets
t 100,000 /PL
Creatinine
d 1.5 x ULN
Bilirubin
d 1.5 mg/dL
AST/ALT
d 1.5 x ULN
PT/INR/PTT within 1.2 X the upper limit of normal unless a subject is receiving 
Coumadin and has stable INR which is in range for the desired level of 
anticoagulation
5.1.j
Normal cardiac function: LVEF t 50%
5.1.k
Blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg 
(diastolic) for eligibility.  Initiation or adjustment of BP medication is permitted 
prior to study entry provided that the average of three BP readings on baseline 
assessment prior to enrollment is less than 140/90 mmHg.
5.1.l
Eligibility of subjects receiving any medications or substances known to affect or 
with the potential to affect the activity or pharmacokinetics of pazopanib will be 
determined following review of their cases by the Principal Investigator (see 
Section 7.4 for further information).
5.1.m
Women of child-bearing potential and men must agree to use adequate 
contraception.
5.1.n
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) or if 
she is of childbearing potential, if she fits the criteria in Appendix C.
5.1.o
Ability to understand and the willingness to sign a written informed consent 
document.
5.2.
Exclusion Criteria
5.2.a
Subjects with known brain metastases and/or unresectable sarcoma.
5.2.b
Uncontrolled intercurrent illness including, active serious infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac ventricular arrhythmia 
requiring anti-arrhythmic therapy, serious hepatic impairment, or psychiatric 
illness/social situations that would limit compliance with study.
5.2.c
Pregnant or lactating women.
5.2.d
Subjects with no additional active malignancy within the last 3 years.

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5.2.e
Subjects receiving other investigational agents.
5.2.f
Subjects with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to pazopanib or other agents used in the study.
5.2.g
Subjects who have both bilirubin >ULN and AST/ALT >ULN
5.2.h
Subjects with a urine protein/creatinine ratio greater than 1.
5.2.i
Subjects with a baseline QTc of equal to or greater than 480 msecs or other 
significant ECG abnormalities.
5.2.k
Certain medications that act through the CYP450 system are specifically 
prohibited in subjects receiving pazopanib and others should be avoided or 
administered with extreme caution and require PI approval.
x
Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinivir, ritonavir, 
saquinavir, telithromycin, voriconazole may increase pazopanib 
concentrations and are prohibited. Grapefruit juice is also an inhibitor of 
CYP450 and should not be taken with pazopanib.
x
Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib 
concentrations, are prohibited.  (See Section 7.2)
x
Medications which have narrow therapeutic windows and are substrates of 
CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, 
administered with caution.  (See Section 7.2)
A list of medications that are specifically prohibited or those that should be used 
with caution during this trial of pazopanib can be found in Section 7.2.
Comprehensive lists of agents that could affect pazopanib through the cytochrome 
P450 system can be found in Appendix D.
Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2, or CYP2C19 
in vivo but does in vitro.  Therefore, therapeutic doses of warfarin, a substrate of 
CYP2C9, and omeprazole, a substrate of CYP2C19 are permitted.  Caffeine, a 
substrate of CYP1A2, is also permitted.   
5.2.l
Certain medications that are associated with a risk for QTc prolongation and/or 
Torsades de Pointes, although not prohibited, should be avoided or replaced with 
medications that do not carry these risks, if possible.  Comprehensive lists of 
agents that that are associated with a risk for QTc prolongation and/or Torsades 
de Pointes can be found in Appendix E.
5.2.m
Subjects who require heparin other than low-molecular weight heparin

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5.2.n
Subjects with any condition that may impair the ability to swallow or absorb oral 
medications/investigational product including:
x
any lesion, whether induced by tumor, radiation or other conditions, which 
makes it difficult to swallow capsules or pills 
x
prior surgical procedures affecting absorption including, but not limited to 
major resection of stomach or small bowel
x
active peptic ulcer disease, not on a proton pump inhibitor
x
malabsorption syndrome
5.2.o
Subjects with any condition that may increase the risk of gastrointestinal bleeding 
or gastrointestinal perforation, including
x
active peptic ulcer disease, not on a proton pump inhibitor
x
known intraluminal metastatic lesions
x
inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) or 
x
other gastrointestinal conditions which increase the risk of perforation
x
history of abdominal fistula, gastrointestinal perforation or intra-
abdominal abscess within 28 days prior to beginning study treatment
5.2.p
Subjects with any of the following cardiovascular conditions within the past 6 
months
x
cerebrovascular accident (CVA) or transient ischemic attack (TIA) 
x
cardiac arrhythmia
x
admission for unstable angina
x
cardiac angioplasty or stenting 
x
coronary artery bypass graft surgery 
x
pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT 
which has been treated with therapeutic anticoagulation for less than 6
weeks
x
arterial thrombosis 
x
symptomatic peripheral vascular disease.
x
Class III or IV heart failure as defined by the NYHA functional
classification system. A subject who has a history of Class II heart failure
and is asymptomatic on treatment may be considered eligible.
5.2.q
History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to 
first dose of study drug 
5.2.r
History of serious or non-healing wound, ulcer, or bone fracture.
5.2.s
HIV-positive subjects on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with pazopanib.
5.2.t
Subjects with severe hepatic impairment
x
Bilirubin >3UULN, regardless of any level of ALT
6.0
SUBJECT REGISTRATION AND RANDOMIZATION

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All subjects will be registered by the coordinating center (University of Washington) and entered 
into the Protocol Accrual Tracking System (PATS). Information regarding the PATS system is 
available at http://www.cancerconsortium.org/rto/protocol_office/pats/.  A complete, signed 
study consent and HIPAA consent are required for registration.  An Investigator must review 
and sign the eligibility list for patients enrolled on the trial.
This is a double-blinded study.  Patients will be randomized 2:1 to receive pazopanib versus 
placebo by the SCCA Investigator Drug Supply (IDS) Pharmacy according to a computer 
program from randomization.com.  Physicians, research study staff, and patients will be blinded 
from the time of enrollment until the time of the patient's surgery, when unblinding will occur. 
7.0
TREATMENT PLAN
TREATMENT
PAZOPANIB 
RUN-IN A
CYCLES    
1 AND 2B
CYCLES 
3 AND 4C
PRE-
OP RT
D
SURGERY
E
CYCLES 5
AND 6B
POST-OP RTF
DOXORUBICIN
75 MG/M2
CIVI
OVER 3
DAYS,
EACH 
CYCLE
WEEKS  
3-8
75 MG/M2
CIVI
OVER 3
DAYS,
EACH 
CYCLE
WEEKS   
9-14
WEEKS 
16-21
2-4 WEEKS 
AFTER 
COMPLE-
TION OF 
PRE-
OPERATIVE 
THERAPY
75 MG/M2
CIVI OVER 3
DAYS, EACH 
CYCLE
2-4 WEEKS 
AFTER 
SURGERY
2-4 WEEKS AFTER 
COMPLETION OF 
CHEMO-THERAPY
IFOSFAMIDE
2 GM/M2
IV, DAYS 
1-5, EACH 
CYCLE
WEEKS  
3-8
(6-DAY
WASHOUT 
AFTER 
PAZOPAN
-IB
2 GM/M2
IV, DAYS 
1-5, EACH 
CYCLE
WEEKS  
9-14
2 GM/M2 IV,
DAYS 1-5,
EACH CYCLE
2-4 WEEKS 
AFTER 
SURGERY

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TREATMENT
PAZOPANIB 
RUN-IN A
CYCLES    
1 AND 2B
CYCLES 
3 AND 4C
PRE-
OP RT
D
SURGERY
E
CYCLES 
5
AND 6B
POST-OP RTF
MESNAI
AFTER 
EACH 
DOSE OF 
IFOS
AFTER 
EACH 
DOSE OF 
IFOS
AFTER EACH 
DOSE OF IFOS
PAZOPANIB
OR PLACEBO
800 MG PO
DAILY,
WEEKS 1-2
PAZOPANIB  
MAINTEN-
ANCEG
1 WEEK AFTER 
COMPLETION OF 
CHEMO/RT
(DURATION 52
WEEKS)
A
Pazopanib versus placebo run-in 14 days
B
Chemotherapy cycles every 21 days. Cycle 1 may not commence until a 6 day washout period of pazopanib has occurred.
C
Cycles 3 and 4 will only be given if there is a response to chemotherapy identified on imaging 
after cycles 1 and 2.
D
Pre-operative radiation administration, when given, will consist of external beam 50 Gy in 25 
fractions of 2 Gy/fraction 
over 5 weeks. If the target volume encompasses sensitive structures such as bowel or lung, the dose can be reduced to 45 Gy in 
25 fractions of 1.8 Gy without 
protocol violation.
E
Surgery should be planned for 2-4 weeks after completion of pre-operative therapy.  Any planned post surgical adjuvant 
chemotherapy should be initiated only after adequate wound healing has 
been achieved.   Patients who require a delay of 
greater than 10 weeks from the initial surgery 
due to inadequate wound healing will be removed from further protocol 
therapy.
F
Post-operative radiation administration, when given, will consist of external beam 50 Gy in 25 fractions of 2 Gy/fraction over 5 
weeks, followed by 10 Gy boost (in 5 fractions) to a reduced, or 
boost, volume. For contaminated or close margins, the 
boost dose will be 10 - 16 Gy; for 
microscopically positive margins, 16 - 20 Gy, and for grossly positive margins, 20 – 26 
Gy. 
For patients who received pre-operative radiation, but have positive surgical margins, 16 – 20 Gy (2Gy x 8 - 10 fractions) will be 
given by external beam following any planned adjuvant 
chemotherapy.  
G
Pazopanib may be resumed 1 week after completion of post-operative therapy (chemotherapy +/- radiation) for those randomized 
to the treatment who had a response by imaging, to be continued for 1 year.  Unblinding occurs during the first post-op visit after 
surgery.
H
PEG-Filgrastim should be administered approximately 24-48 hours after completing chemotherapy.  10 days of filgrastim may be 
substituted.
I
Mesna will be given at 400 mg/m2.  Post IFOS doses will be at 4 hours and 8 hours (+/- standard clinical dosing windows)
7.1
Agent Administration
7.1.1
Pazopanib Administration
Subjects will be randomized to receive either pazopanib 800 mg orally daily or 
placebo for 14 days as a Run-in period, prior to beginning neoadjuvant chemotherapy 
with doxorubicin and ifosfamide. Doses of pazopanib/placebo will be taken fasting 
(at least 1 hour prior and/or 2 hours after).

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Subjects deemed to be responders to pazopanib preoperative therapy (defined in 
Section 11.3), will have the option to receive one year of therapy with pazopanib 800 
mg orally daily following completion of surgery and post-operative adjuvant 
treatments. 
Treatment Regimen
Treatment will be administered on an outpatient basis.  Subjects receive pazopanib 
versus placebo at a dose of 800 mg/day (four 200-mg tablets or two 400 mg tablets;
dose modification will be accomplished by combining 200-mg tablets as necessary).  
Subjects are instructed to swallow tablets once a day (preferably in the morning) on 
an empty stomach, either 1 hour before or 2 hours after food with about 1 cup (240 
mL) water. Tablets should be swallowed whole; they must not be chewed, broken, or 
crushed.  Treatment continues until one of the criteria in Section 7.3 applies.
For the subjects who will have intensive pharmacokinetic analyses performed during 
pazopanib maintenance, subjects should wait to take the pazopanib on-site (observed 
dose by study personnel).  Subjects should either wait to eat on-site (1 hour after 
pazopanib dosing) or make sure to eat at least 2 hours before the planned time of 
pazopanib dosing for that day.
Subjects will be provided with a Medication Diary for pazopanib, instructed in its 
use, and asked to bring the diary with them to each appointment.  A new copy of the 
Medication Diary will be given to subjects whose dose is reduced due to AEs. Prior 
to the scheduled study visit, subjects will be reminded to document the exact time of 
pazopanib dosing the day before blood is drawn for measurement of trough 
concentrations.  Subjects will also be reminded not to take their morning pazopanib 
dose until after the blood draw for trough concentrations has been completed.
All prescription and over-the-counter medications as well as alternative medicines 
that have been taken within 4 weeks prior to the first dose of pazopanib must be fully 
documented in the Case Report Form (CRF; indication, dose information and dates of 
administration).  The Investigator or a designee must be informed as soon as possible 
about any new medication taken from the time of screening until the end the study;
these new medications will be fully documented in the CRF (indication, dose 
information, and dates of administration).  
All concomitant medications taken during the study will be recorded in the CRF with 
indication, dose information, and dates of administration.
Precautions/Warnings
Certain drugs which induce or inhibit cytochrome P450 enzymes are prohibited.
Medical personnel must refer to the list of prohibited agents in Section 7.4 prior 
to administering treatment.

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Certain drugs which are listed as “use with caution” should be avoided if possible, but 
if necessary, subjects who receive these medications should be closely monitored for 
AEs.  Medical personnel must refer to the list of “use with caution” agents in 
Section 7.4_ prior to administering treatment.
Hypertension is an important AE associated with pazopanib.  Frequent blood 
pressure (BP) monitoring is important in subjects receiving pazopanib versus 
placebo starting on day 8 and continuing until the subject is off study.  Experience to 
date suggests that increases in BP may occur following dosing with pazopanib for a 
number of weeks and that these increases may occur relatively quickly. Section 7.7
includes specific guidelines on the management of treatment-emergent hypertension.  
Recommendations for hypertension monitoring and management are presented in 
Appendix F.
QTc prolongation and Torsades de Pointes is a rare but serious adverse event 
associated with pazopanib.  Therefore, the following is required:
x
Intensive QTc monitoring.  A baseline ECG is required prior to study
registration, and subjects with QTc480 msec are excluded. Repeat 
ECG must be performed during the week 2.  After surgery, for those 
subjects continuing on maintenance pazopanib, if the QTc interval at 4 
weeks is 500 msec, the ECG should be repeated within 7 days and, if the 
QTc interval remains 500 msec, the subject should be removed from the 
study.  Additionally, if the QTc interval is increased by 60 msec or more 
from baseline but the QTc interval remains at <500 msec, an ECG should 
EHUHSHDWHGZLWKLQGD\V,IWKHUHSHDW(&*DJDLQVKRZVDPVHF
increase in the QTc interval from baseline, consideration should be given 
to removing the subject from the study or increasing monitoring, after 
discussion with the Principal Investigator.
x
Subjects must be questioned about family history of prolonged QTc, 
personal history of prolonged QTc, relevant cardiac disease, and 
concomitant medications which are associated with a high risk of 
causing QTc prolongation prior to study registration.
x
Concomitant treatment with drugs that are associated with a high risk 
of causing QTc prolongation should be changed to similar agents that 
do not pose such a risk, if possible, prior to a subject receiving the first 
dose of pazopanib. A comprehensive list of agents that are associated 
with a risk of prolonging the QTc interval is provided in Appendix E.  
x
Potassium, calcium, phosphate, and magnesium levels must be 
obtained before administration of the first dose of pazopanib and 
frequently thereafter (as described in the Study Calendar, Appendix 
A).  

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x
Abnormalities that occur after enrollment in potassium, calcium, 
phosphate, and magnesium levels should be managed as follows: 
Pazopanib should be held and an ECG must be performed for 
K\SRNDOHPLDRUK\SHUNDOHPLDJUDGHK\SRFDOFHPLDRUK\SHUFDOFHPLD
JUDGHK\SRSKRVSKDWHPLDJUDGHK\SRPDJQHVHPLa or 
K\SHUPDJQHVHPLDJUDGHGrading is according to CTCAE v4.  These 
laboratory values should be corrected as soon as possible in a manner 
consistent with good medical judgment.  Pazopanib may be re-
administered when hypokalemia or hyperkalemia is grade 1 or within 
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K\SRSKRVSKDWHPLDLVJUDGHDQGK\SRPDJQHVHPLDRU
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allowed at these lower grades, every effort should be made to correct the 
abnormal lab values to normal if possible.  
If an ECG, obtained because of these lab values, reveals an increase in the 
QTc to >500 msec or an increase in the QTc by at least 60 msec from 
baseline, the ECG should be repeated before re-administration of 
pazopanib.  If the QTc interval, on the repeat ECG, is still >500 msec, the 
subject should be removed from the study.  If the QTc, on the repeat ECG, 
remains increased in the QTc by at least 60 msec from baseline but is less 
than 500 msec, consideration should be given to removing the subject 
from the study.
Renal function (creatinine and urinary protein) should be frequently monitored as 
suggested by the pathologic changes noted in animal studies and evidence from 
studies of other antiangiogenic agents.  Specific guidelines for management of 
proteinuria and elevated creatinine are presented in Section 7.7.
Hepatic Function monitoring include ALT, AST, GGT, alkaline phosphotase and 
total bilirubin at the following visits:
x
at screening; 
x
before initiation of pazopanib treatment;
x
end of week 2;
x
prior to Day 1 of each cycle;
x
at post-treatment visit;
x
final visit;
x
30-day follow-up
Periodic monitoring should continue monthly if pazopanib monotherapy is continued. 
Pazopanib is not recommended for subjects with severe hepatic impairment (defined 
as >3UULN, regardless of any level of ALT).
7.1.2
Chemotherapy Administration

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Pre-operative chemotherapy will consist of doxorubicin and ifosfamide administered 
on an inpatient basis. Subjects may also receive 2 to 4 cycles of post-operative 
chemotherapy, (up to 6 cycles total of neoadjuvant plus adjuvant chemotherapy).  
Doxorubicin: 75 mg/m2 by continuous IV infusion days 1 through 3 of each cycle. 
Ifosfamide: 2.0 g/m2  over 4 hours IV, days 1 through 5 of each cycle.
Mesna: 400 mg/m2 IV pre, 4 hours post, and 8 hours post each dose of ifosfamide.
Hydration:   D5W with 100 meq/L sodium acetate, 20 meq/L potassium acetate, 4 
meq/L magnesium sulfate continuous IV infusion at a rate of 83 mL/hour, begun 
approximately 2 hours prior to chemotherapy and discontinued after completion of 
chemotherapy and Mesna. 
Cycle 1 of chemotherapy may only commence after a minimum 6-day washout 
period of pazopanib.
7.2
Radiation Therapy
Radiation treatment (XRT) will be administered using standard of care delivery and 
quality assurance techniques, using mega-voltage photons. Electrons may be used if 
dosimetrically appropriate, but no other particle therapy such as neutrons or protons may
be used.  Brachytherapy and IORT may be used for boost volumes to sites of residual 
disease, when appropriate. Simulation must be CT-based, using contrast if possible, and 
appropriate immobilization devices. Target delineation for preoperative XRT must 
include the GTV, CTV, PTV and organs at risk, with identified dose constraints, and for 
postoperative XRT, delineation must include the pre-operative GTV, CTV (i.e., surgical 
bed), PTV and organs at risk, also with identified dose constraints. Treatment planning 
must generate dosimetry with no more than plus or minus 5% heterogeneity, while 
sparing an adequate strip of circumferential tissue to allow ongoing lymphatic drainage, 
and utilizing external beam delivery techniques, such as IMRT and 3-D conformal 
approaches when necessary, to achieve this aim. The use of bolus is at the discretion of 
the radiation oncologist, but is rarely indicated in the preoperative setting. 
For preoperative XRT, the prescribed dose to the PTV should be 50 Gy in 25 fractions of 
2 Gy/fraction over 5 weeks. If the target volume encompasses sensitive structures such as 
bowel or lung, the dose can be reduced to 45 Gy in 25 fractions of 1.8 Gy without 
protocol violation.
For postoperative XRT, the prescribed dose to the PTV should be 50 Gy in 25 fractions 
of 2 Gy/fraction over 5 weeks, followed by 10 Gy boost (in 5 fractions) to a reduced 
volume.   For contaminated or close margins, the boost dose will be 10 - 16 Gy; for 
microscopically positive margins, 16 - 20 Gy, and for grossly positive margins, 20– 26
Gy. 
Verification must include initial and weekly isocenter imaging checks with image 
guidance with cone beam CT as appropriate to the technique, as well as weekly on-
treatment patient review visits. Diode checks and physics review must be completed as 
standard procedure.  

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Maintenance pazopanib for those who respond to therapy during the Run-in period, may 
not commence until one week following completion of radiation. 
7.3
Surgery
The goal of surgical treatment is to resect the tumor with negative margins.  All lesions of 
the trunk and extremities will be treated with conservative resection (minimal wide 
excision) after pre-operative therapy.  Surgical resection should remove as wide a margin 
of tissue around the tumor as possible without compromising function.  If postoperative 
pathology evaluation reveals positive soft-tissue margins other than bone, nerve, or large 
blood vessels, this margin should be re-resected if possible.  If bone, major blood vessel 
or nerve is microscopically positive additional radiation should be given as noted in the 
protocol.  Resectability will depend upon the judgment of the operating surgeon.  For the
extremities, limb salvage procedure is standard of care if achievable.  For other anatomic 
areas, it must be the judgment of the operating surgeon that he/she may reasonably expect 
to obtain negative margins. Extremity patients who are not resectable without amputation 
may be amputated, and should complete chemotherapy per protocol.
7.4
Concomitant Medication and Supportive Care Guidelines
7.4.1
Potential Drug Interactions
Pazopanib is primarily metabolized by the human CYP3A4 isoenzyme.  Potent CYP3A4 
inhibitors and inducers are prohibited on the trial.
Medications prohibited during pazopanib therapy that strongly inhibit CYP3A4 
include (but are not limited to):
x Antibiotics:  clarithromycin, telithromycin, troleandomycin, erythromycin
x HIV:  protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir,
lopinavir)
x Antifungals:  itraconzaole, ketoconazole, voriconazole
x Antidepressants:  nefazodone
x Antiarrythmics: ditiazem, felodipine, nicardipine, quinidine, verapamil
Medications prohibited during pazopanib therapy that strongly induce CYP3A4 
include (but are not limited to):
x Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 mg), 
methylprednisolone (>8 mg), dexamethasone (>1.5 mg)
x Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, oxcarbazepine
x HIV antivirals: efavirenz, nevirapine
x Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene
x Miscellaneous:  St. John’s Wort, modafinil, pioglitazone, troglitazone, canertinib, 
erlotinib, lapatinib
Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6.  Drugs that have narrow 
therapeutic windows and are substrates for these enzymes should be administered with 

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extreme caution.  Because of pazopanib’s long half-life, caution should continue to be
exercised for at least 14 days after the last dose of pazopanib when administering these 
medications.
Medications to use with caution that are substrates for these enzymes and have narrow 
therapeutic windows medications include (but are not limited to):
x Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, methylergonovine 
(potential increased risk for developing ergot toxicity that includes severe vasospasm 
leading to peripheral as well as cerebral ischemia)
x Neuroleptics: pimozide (potential increased risk for QT interval prolongation, ventricular 
arrhythmia, and sudden death)
x Antiarrhythmics:  bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, 
propafenone (potential increased risk for QT interval prolongation and Torsade de 
Pointes)
x Immune modulators:  cyclosporine, tacrolimus, sirolimus (potential increased risk for 
nephrotoxicity and neurotoxicity)
x Miscellaneous:  quetiapine, risperidone, clozapine, atomoxetine, simvastatin, 
bevacizumab, topotecan, short-acting antacids and PPIs.
Pazopanib can prolong the QTc interval.  Drugs that are generally accepted to have a risk of 
causing Torsades de Pointes (see Appendix E) should be discontinued or replaced with drugs 
that do not carry this risk, if at all possible.  Subjects who receive potential QTc-prolonging 
medications (see Appendix E) should be monitored closely. 
Pazopanib may increase bleeding.  Subjects, receiving pazopanib and anticoagulation, should 
be monitored for bleeding.
Pazopanib may cause decreased glucose.  Subjects, receiving pazopanib and hypoglycemia 
agents, should be monitored for hypoglycemia.
7.4.2
Supportive Care 
Anti-Emetics
Routine use of anti-emetics is recommended for subjects due to the highly emetogenic nature
of the chemotherapy regimen.  Selection of anti-emetics is based on the institution’s standard 
and is at the Investigator’s discretion.  
Prophylactic Antibiotics
Prophylactic antibiotics for prevention of neutropenic fever may be used at the discretion of
the Investigator.  Use of prophylactic antibiotics must be recorded in the case report forms.
Growth Factors
Administration of growth factor is required after all chemotherapy cycles:
PEG-filgrastim 6 mg administered as a subcutaneous injection starting 24-48 hours after 
completion of chemotherapy (may substitute filgrastim 5 mcg/kg/day (rounded to nearest vial 

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size) administered as a subcutaneous injection starting 24-48 hours after completion of 
chemotherapy for 10 days, or until white blood count has recovered after nadir (ANC > 
10,000)
Transfusion of Blood Products
Depending on the particular setting, red blood cell and platelet transfusions may be 
appropriate, at the Investigator’s discretion and with the subject’s consent.
7.5
Duration of Therapy
Treatment should continue until the end of protocol therapy, defined as the completion of all 
adjuvant treatments following surgical resection of the primary tumor, or until one of the 
following criteria applies:
x
Disease progression,
x
Intercurrent illness that prevents further administration of treatment,
x
Unacceptable adverse events(s),
x
Greater than 3-week delay in therapy due to adverse event
x
The subject or legal representative requests to withdraw from the study, or
x
Changes in the subject's condition render the subject unacceptable for further 
treatment in the judgment of the Investigator.
7.6
Duration of Follow-Up
When a subject discontinues the study, a Final Visit will be conducted. All subjects will 
have one Follow-up Visit approximately 30 days after the Final Visit. This Follow-up Visit 
does not need to be performed for subjects who have had a Final Visit conducted 30 days 
after discontinuation of maintenance pazopanib therapy.
Study visits and evaluations will be performed in clinic at Screening and within 
approximately 72 hours prior to hospital admission for each chemotherapy cycle 
(neoadjuvant as well as adjuvant). Assessments will include interval history, physical 
examination, blood counts and chemistries. Radiological assessments including FDG-PET
CT, MRI of the primary tumor, and diagnostic CT chest will be performed prior to the 14 day 
Run-in period of pazopanib versus placebo. After the Run-in period, and prior to 
commencement of preoperative chemotherapy, subjects will undergo repeat FDG-PET CT 
and MRI of the primary tumor. After 2 cycles of chemotherapy, FDG-PET CT and MRI of 
the primary tumor will be repeated. (Refer to Section 4.3 and Appendix A). Study 
procedures may be performed up to approximately 72 hours before or after the scheduled 
visit date.
Subjects will be evaluated daily during radiation therapy.  Following surgery, subjects who 
remain on pazopanib monotherapy will have study visits and evaluations monthly for the one 
year duration of therapy, and follow-up visits will be every 3 months for those not on 
pazopanib.  CT of the chest without contrast will be performed every 3 months for the first 

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year following surgery and MRI (or CT) of the primary site of the tumor will be performed 
every 6 months.
Following the Final Visit and/or 30-day Follow-up Visit, follow-up will proceed as described 
in the study calendar (Appendix A) until recurrence or progression.  Patients experiencing 
recurrence or progression will be contacted every 4 months for overall survival, unless the 
patient has withdrawn consent for the study has ended.
7.7
Dosing Delays/Dose Modifications
Recommendations for pazopanib dose interruptions/modifications in case of specific 
treatment-emergent AEs are provided in the following sections. 
As a general rule, if dose reduction of pazopanib is necessary, the dose should be reduced 
stepwise by 200 mg at each step, and the subject should be monitored for approximately 10 
to 14 days at each dose level.  If toxicity does not abate during this monitoring time, the IP 
may need to be interrupted and/or the dose further decreased with continued monitoring for 
an additional 10-14 days at each dose level, and so on. 
If the toxicity has abated with reduction of the dose and dose re-escalation is considered safe 
by the Investigator, the pazopanib dose can then be increased step-wise back to the pre-event 
dose (in 200 mg increments, after monitoring for 10-14 days at each dose level to ensure that 
toxicity did not recur or worsen). 
General: Pazopanib dosing will be modified for adverse events according to the following 
sections.  Reference the following Dose Level table:
*Patients will be removed from protocol treatment if dose reduction below this level is 
indicated.
7.7.1
Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities
Recommendations for pazopanib (investigational product, IP) dose 
interruptions/modifications in case of specific treatment-emergent AEs are provided 
in Table 1.
Table 1
Dose Modification Algorithms for Potential Treatment-Related Adverse Events
AE Terms & Descriptions
Dose Modification Algorithms
Dose Level
Pazopanib
-2*
400 mg daily
-1
600 mg daily
1
800 mg daily

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AE Terms & Descriptions
Dose Modification Algorithms
Hypertension
(A). Asymptomatic and persistent SBP of t140 and 
<170 mmHg, or DBP t90 and <110 mmHg, or a clinically 
significant increase in DBP of 20 mmHg (but still below 110 
mmHg).
Step 1. Continue investigational product (IP) at the current dose. 
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-controlleda blood pressure (BP). If BP is not well-
controlled within 2 weeks, consider referral to a specialist and go to 
scenario (B).
(B). Asymptomatic SBP t170 mmHg, or DBP t110 mmHg, 
or failure to achieve well-controlled BP within 2 weeks in 
scenario (A).
Step 1. Consider reducing or interrupting IP, as clinically indicated.
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. Once BP is well-controlled, restart IP dose-reduced by 200 mg if 
IP was interrupted.
(C). Symptomatic hypertension or recurring SBP t170
mmHg, or DBP t110 mmHg, despite modification of 
antihypertensive medication(s)
Step 1. Interrupt IP 
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.  Referral to a specialist for further 
evaluation and follow-up is also recommended.
Step 4. Once BP is well-controlled, restart IP dose-reduced by 200 mg.
(D). Refractory hypertension unresponsive to above 
interventions.
Discontinue IP and continue follow-up per protocol.
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to ensure accuracy of the reading.  The values 
below refer to manually-read ECGs. Refer to Section 7.1.1 for ECG monitoring
QTc  t 480 < 500 msec
Continue IP; monitor as clinically indicated.
QTc t 500 msec
Discontinue IP and continue follow-up per protocol.
Proteinuria
UPC <3
Continue pazopanib at the current dose; monitor as clinically indicated
UPC ≥3 or 24-h urine protein t3g
Step 1. Interrupt IP.
Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is <3 or 
24-hr urine protein is <3 grams.  Then restart pazopanib dose-reduced 
by 200 mg.
Step 3.  If UPC ≥3 or 24-h urine protein t3g recurs, repeat steps 1 and 2.
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the pazopanib 
dose can no longer be reduced, discontinue pazopanib and continue 
follow-up per protocol.
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding
Grade 1
For hemoptysis, interrupt pazopanib and contact the Novartis Study Physician to discuss 
whether further treatment with pazopanib is appropriate.

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For other Grade I hemorrhage/bleeding events, continue pazopanib at the current dose; 
monitor as clinically indicated.
Grade 2
Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding), discontinue IP and 
continue follow-up per protocol. Otherwise, interrupt IP until the AE resolved to d Grade 1. 
Step 2. Restart IP; consider reducing dose and monitor as clinically indicated. 
Grade 3 or 4, or 
Recurrent t Grade 2 event after dose 
interruption/reduction.
Discontinue IP and continue with follow-up per protocol. 
Venous Thrombosis (DVT, PE)
Grade 2
Continue IP at the current dose; monitor as clinically indicated
Grade 3 
Step 1. Interrupt IP. 
Step 2. Initiate and monitor anticoagulation as clinically indicated. 
Step 3. Resume IP at same dose only if all of the following criteria are met: 
x
The subject must have been treated with anticoagulant at the desired level of 
anticoagulation for at least one week.
x
No Grade 3 or 4 or clinically significant Grade 2, hemorrhagic events have occurred 
while on anticoagulation treatment.
Subject should be monitored as clinically indicated during anticoagulation treatment and after 
resuming study treatment. When treating with warfarin, international normalized ratio (INR) 
should be monitored within three to five days after any change in IP dosing (eg, re-initiating, 
escalating/de-escalating, or discontinuing IP), and then at least weekly until the INR is stable. 
The dose of warfarin (or its derivatives) may need to be adjusted to maintain the desired level 
of anticoagulation
Grade 4 and/or PE
Discontinue IP and continue follow-up per protocol. 
Arterial Thrombosis/Ischemia
Any Grade
Discontinue IP and continue follow-up per protocol. 
Thrombocytopenia: Investigate and document underlying cause
Grade 1 or 2
Continue IP with current dose; monitor as clinically indicated. 
Grade 3 or 4
Step 1. Interrupt IP until toxicity resolves to ≤Grade 2.
Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically indicated. 
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 thrombocytopenia, discontinue IP and 
follow-up per protocol.
Anemia: No specific dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding as noted above.
Palmar-plantar Erythrodysesthesia Syndrome

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Grade 1
Minimal skin changes or dermatitis 
without pain
(erythema, oedema, hyperkeratosis)
1.
Continue IP at present dose
Grade 2
Skin changes with pain; limiting 
instrumental activities of daily living 
(ADLs) (peeling, blisters, oedema, 
bleed, hyperkeratosis)
1.
Hold IP 
2.
Treat as clinically appropriate
3.
Upon resolution to Level 1 or better restart  IP with a dose reduction to 400 mg
4.
If recurrent consider a further dose reduction to 200mg or discontinuation
Grade 3
Severe skin changes with pain and 
limiting self care ADLs
1.
Discontinue IP
Other Clinically Significant Adverse Eventsb
Grade 1
Continue IP; monitor as clinically indicated.
Grade 2 or 3, if clinically significant 
Step 1. Interrupt IP until toxicity resolves to d Grade 1.
Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically indicated. 
Grade 4
Discontinue IP and continue follow-up per protocol.   
a.
Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg.
b.
AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4)
Abbreviations: BP, blood pressure; IP, investigational product.
7.7.2
Dose Interruptions/Modifications for Hepatoxicity
AST, ALT and/or Bilirubin
Isolated AST/ALT elevations between 3X ULN 
and 8X ULN
Reduce pazopanib dose to 200 mg QD, and
monitor weekly until AST/ALT returns to < 2.5
or baseline
AST/ALT >8 X ULN
Hold pazopanib until AST/ALT returns to < 2.5
X ULN or baseline.  
If the potential benefit of reinitiating pazopanib
treatment is considered to outweigh the risk for 
hepatotoxicity, then consider reintroducing  
pazopanib at a reduced dose of 400 mg once 
daily and measure serum liver tests weekly for 8 
weeks only after discussion with the PI.
If AST/ALT elevations >3 X ULN recur, then 
pazopanib should be permanently discontinued.
AST/ALT >3 X ULN and concurrent bilirubin
elevations >2 X ULN
Permanently discontinue pazopanib.
Mild indirect hyperbilirubinemia, known or 
suspected Gilbert’s syndrome, and elevation in 
AST/ALT >3 X ULN
Continue pazopanib, but monitor weekly until 
AST/ALT returns from >3 X ULN to grade 1 
(NCI CTCAE) or baseline.

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Severe hepatic impairment, defined as bilirubin >3 
X ULN, regardless of any level ALT
Permanently discontinue pazopanib.
7.7.3
Chemotherapy Dose Modifications
A treatment cycle may not begin unless the patient's absolute neutrophil count (ANC) 
is t1500/PL and platelet count is t100,000/PL (without transfusion).
Patients who experience Grade 3 or 4 hematologic or non-hematologic toxicity that is 
attributable to chemotherapy and not to the underlying disease should have 
chemotherapy held until the toxicity UHVROYHVWR*UDGH. Dose modifications for 
doxorubicin and ifosfamide-related toxicity will be based on the Investigator’s 
discretion.
Patients who are delayed greater than 3 weeks due to non-resolution of such toxicity 
will be taken off study. 
7.8
Criteria for Evaluability and Removal/Withdrawal from Treatment
Criteria for evaluability of the Trial
x Patients must have received a total of at least 80% of the intended dose of 
doxorubicin, ifosfamide, and pazopanib to be evaluable for the trial. If less
than this amount is received, the patient may remain on the study, but will 
not be evaluated for primary endpoints.
Criteria for stopping therapy:
x
Substantial non-compliance with the requirements of the study.
x
Any adverse event which, in the Investigator’s opinion, requires termination of 
the study medication.
x
Disease progression, unless at the discretion of the Investigator (in 
collaboration with
Novartis) continued treatment
with study drug is 
appropriate.
x
The patient would benefit from additional radiation therapy beyond that 
specified in the protocol.
x
Request by the patient or a legal representative/relative to stop the treatment.
x
The patient presents with a beta-HCG test consistent with pregnancy.  
Pregnancy will be reported along the same timelines as a serious adverse event.
x
The patient uses illicit drugs or other substances that may, in the opinion of the
x
Investigator, have a reasonable chance of contributing to toxicity or otherwise 
interfering with results.
x
The development of a second malignancy that requires treatment, which would 
interfere with this study.
x
The patient is lost to follow-up.
x
Interruption in administration of pazopanib or chemotherapy for greater than 3-
week delay.
x
Development of an intercurrent illness or situation which would, in the 
judgment of the Investigator, affect assessments of clinical status and study 
endpoints to a significant degree.

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Criteria for study withdrawal:
x
Study closure.
x Patient decision to withdraw from both study therapy and follow-up.
The Investigator will make every reasonable effort to keep each patient in the study unless it is 
in the patient’s best interest to discontinue participation.  If a patient is removed from the study 
or declines further participation, all End of Treatment evaluations should be performed if the 
patient is willing and able to be assessed.  A description of the reason(s) for withdrawal from 
the study will be recorded on the case report form (CRF).  The Investigator should also ensure 
that all patients are followed up for survival and recurrence after the Final Visit.
Relevant visit data should be entered on the CRF and any unused study medication will be 
accounted for and returned for all patients participating in the study, even for a brief period of 
time.  Patients who discontinue following entry will have relevant information completed and 
recorded on the CRF.  All patients who discontinue because of adverse events or clinically 
significant laboratory abnormalities should be followed up until they recover or stabilize, and 
the subsequent outcome will be recorded.  If any patient should die during the trial or within 30 
days of stopping study treatment, the Investigator will inform the IRB and the Novartis 
representative.  The cause of death should be recorded in detail, within 24 hours, on a serious 
adverse event (SAE) form and reported to the IRB and Novartis.
Subjects who are withdrawn from the study prior to surgery will be replaced and randomized to 
treatment with pazopanib versus placebo according to the 2:1 design.
8.0
GUIDELINES FOR ADVERSE EVENT REPORTING
8.1
Adverse Event Reporting/ Institutional Policy
In accordance with institutional policy, all adverse events which in the opinion of the Principal
Investigator are unexpected and related or possibly related to the research and serious or suggest 
that the research places research participants or others at greater risk of physical or psychological 
harm than was previously known or recognized be reported to the IRB within 10 calendar days 
of learning of the problem.
Definitions:
Adverse Event: - Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, medical treatment or procedure and which does not 
necessarily have to have a causal relationship with this treatment.  An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
medical treatment or procedure whether or not considered related to the medicinal product. 
Life-threatening Adverse Event: – Any adverse event that places the patient or subject, in view 
of the Investigator, at immediate risk of death from the reaction.  

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Unexpected Adverse Event: – An adverse event is “unexpected” when its nature (specificity), 
severity, or frequency are not consistent with (a) the known or foreseeable risk of adverse events 
associated with the research procedures described in the Protocol-related documents, such as the 
IRB-approved research protocol, informed consent document and other relevant sources of 
information such as product labeling and package inserts; and are also not consistent with (b) the 
characteristics of the subject population being studied including the expected natural progression 
of any underlying disease, disorder or condition any predisposing risk factor profile for the 
adverse event.
Serious Adverse Event (SAE): – Any adverse event occurring that results in any of the 
following outcomes:  
¾
death; 
¾
a life-threatening adverse event (real risk of dying);
¾
inpatient hospitalization or prolongation of existing hospitalization (for 
reasons other than planned chemotherapy or post-surgical care)
¾
a persistent or significant disability/incapacity;
¾
a congenital anomaly;
¾
requires intervention to prevent permanent impairment of damage.
Attribution: - The following are definitions for determining whether an adverse event is related 
to a medical product, treatment or procedure:
An adverse event is “related or possibly related to the research procedures” if in the 
opinion of the Principal Investigator, it was more likely than not caused by the research 
procedures.
Adverse events that are solely caused by an underlying disease, disorder or condition of the 
subject or by other circumstances unrelated to either the research or any underlying disease, 
disorder or condition of the subject are not “related or possibly related.”
If there is any question whether or not an adverse event is related or possibly related, the 
adverse event should be reported.
The Cancer Consortium Expedited Reporting Form should be completed for all adverse events 
that meet the expedited reporting requirements.  The AE form should be faxed to the IRO at 
(206) 667-6831.  All available information should be submitted.
It is the responsibility of the Principal Investigator and/or a designated staff member to notify 
Novartis, NIH, and the FDA of adverse events that meet expedited reporting (such as Serious 
Adverse Events) as required in the protocol.
Also considered serious for the purposes of this study:
x
ALT >3.0 x ULN with concomitant elevation in bilirubin (defined as total bilirubin <2.0 
x ULN or direct bilirubin 35%) or with hypersensitivity symptoms (e.g., fever, rash) –
bilirubin fractionation should be performed in testing available.
x
ALT >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) – bilirubin 

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fractionation should be performed if testing available.
Serious Adverse Events
For Open Label Portion of Study:
All SAEs arising during the study in subjects exposed to pazopanib will be reported to Novartis 
using copies of the original Case Report Form pages and within 24 hours of first becoming aware 
of the event, regardless of causality assessments.
For Blinded Portion of Study:
Study conduct procedures will be ensured and in place to allow for the expedited reporting of 
relevant SAEs to the appropriate regulatory authorities, IEC(s) or IRB(s) as required, during the 
course of the study.
SAEs will be sent to Novartis as they arise in subjects exposed to pazobanib using copies of the 
original Case Report Form pages and within 24 hours of first becoming aware of the event, 
regardless of causality assessments.
Pregnancy Reports
Reports of pregnancy information on any female subjects who becomes pregnant while 
participating in the study and following exposure to the study product will be sent to Novartis
using copies of the original Case Report Form pages and within two weeks of the pregnancy 
(including premature termination of the pregnancy).  
Information on the status of the mother and child will be reported to the coordinating center.  
Generally, follow-up will be requested by Novartis no longer than 8 weeks following the 
estimated delivery date.
8.2
Study-Specific Adverse Event Capture
8.2.1
Duration and Grade of Adverse Event Capture
All grade 3 and 4 adverse events occurring after the subject has taken the first 
dose of study drug until the end of study will be recorded in the subject’s case 
record form.
Documentation must be supported by an entry in the subject’s file.  A laboratory 
test abnormality considered clinically relevant, e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the Investigator, should be reported as an 
adverse event.  Each grade 3 or 4 event should be described in detail along with 
start and stop dates, severity, relationship to investigational product, action taken 
and outcome.

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8.2.2
Adverse Event Grading 
Toxicities will be graded using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) (the most current version available.  The scale in its 
entirety can be found at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
9.0
DATA AND SAFETY MONITORING PLAN
9.1
Data Monitoring
Data and safety monitoring for the study will be performed by the Clinical Research Support 
Office of the Fred Hutchinson/University of Washington Cancer Consortium (the 
“Consortium”). The purpose of the monitoring is to verify the accuracy of the study data, assess 
compliance with the protocol and with Good Clinical Practice (GCP) regulations, and assure the 
timely and complete reporting of safety (adverse event) data. To facilitate the monitoring, 
medical records for subjects enrolled by the University of Washington/Seattle Cancer Care 
Alliance (the coordinating center) and Oregon Health & Science University will be reviewed by
the Clinical Research Support Office. The records will be made available for monitoring by 
study staff.
Monitoring for this study will be scheduled in accordance with the Cancer Consortium Data and 
Safety Monitoring Plan. The intervals and scope are detailed in the monitoring plan.
9.2
Safety Monitoring
Investigators will conduct continuous review of data and patient safety.  Bi-monthly review 
meetings will include Principal Investigators and study coordinators.  Other study staff may be 
included per the PI’s discretion.  A summary of the following will be presented at each meeting:
x
Total subject accrual
x
Significant toxicities experienced by enrolled subjects
x
Dose modifications and responses
The Principal Investigators and co-Investigators will provide study oversight and will review 
adverse events for trends that indicate a change in the known risks to the study participant. The
Principal Investigator will meet with these individuals on a regular basis to review recently 
acquired data, and adverse events. If it is the opinion of any investigator that the risks or benefits 
to a patient warrant suspension or termination of study activity, the recommendation must be 
submitted in writing to the Principal Investigator for safety committee review.  The safety 
committee will include John Thompson, MD, and Bojana Askovich, Ph.D in addition to the 
Principal Investigators and primary study staff.  Suspension or termination of study activities 
may also be initiated based on the bi-monthly review.
9.3
Auditing
All trials conducted or coordinated by UW/SCCA are subject to audit.  Internal audit reports will 
be reviewed at bi-monthly meetings.
9.4
Quality Assurance Review (QAR)
All trials conducted or coordinated by UW/SCCA are subject to quality assurance review (QAR).  
Quality assurance review reports will be reviewed at bi-monthly meetings.

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10.0
STUDY AGENT INFORMATION
10.1
Pazopanib (GW786034) (NSC 737754)
Other Names:
Pazopanib HCl, GW786034B (the suffix B denotes the
monohydrochloride salt), Votrient.
Classification:
VEGFR tyrosine kinase inhibitor
Mechanism of Action:
Pazopanib is a highly potent inhibitor of vascular endothelial
growth factor (VEGF) receptor tyrosine 
kinases (VEGFR1,
VEGFR2, and VEGFR3).  Vascular 
endothelial growth factor
receptor inhibition may block VEGF driven 
angiogenesis and, as 
a consequence, constrain tumor growth. 
Molecular Formula:               C21H23N7O2S-HCl       
M.W.:     
474.       
Chemical Name:                        5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-
2-pyrimidinyl]amino]-2-methylbenzenesulfonamide 
monohydrochloride
Approximate Solubility:
The monohydrochloride salt is very slightly soluble in 
0.1 M HCl (0.65 mg/mL), and is practically insoluble in pH 
7.0 phosphate buffer (0.00005 mg/mL), and in pH 11 
piperidine buffer (0.0002 mg/mL). 
How Supplied:
GW786034 monohydrochloride is supplied as a series of 
aqueous film-coated tablets containing 100 mg, 200 mg,
                                                     400 mg, and 500 mg of the free base:
x
100 mg, round, white to off white, packaged in bottles 
containing 100 tablets each
x
200 mg, oval-shaped, white, packaged in bottles 
containing 34 tablets each
x
400 mg, oval-shaped, white, packaged in bottles 
containing 68 tablets each
x
500 mg, capsule shaped, white to off white, packaged in 
bottles containing 68 tablets each
Tablet excipients in all tablet sizes include microcrystalline

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cellulose, povidone, sodium starch glycolate, and 
magnesium stearate.  The film-coat consists of titanium
dioxide, hypromellose, polyethylene glycol, and 
polysorbate 80. 
Storage:
The intact bottles should be stored at controlled room
temperature.
Stability:
Stability studies are ongoing.
Route of Administration:
Oral pazopanib should be taken on an empty stomach
either 1 hour before or 2 hours after meals.  The tablets
should be swallowed whole and cannot be crushed or 
broken.
Method of Administration:
Subjects should fast for 2 hours before and 1 hour after each 
pazopanib dose. 
Availability:
Pazopanib is a commercial product provided to the SCCA for 
the study by Novartis.
Expected Adverse Events:
The CTEP Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with pazopanib. A subset, the 
Agent Specific Adverse Event List (ASAEL), appears in a separate column and is identified with
bold and italicized text. This subset of AEs (ASAEL) contains events that are considered 
'expected' for expedited reporting purposes only. 
Version 2.2, March 18, 20101
Adverse Events with Possible
Relationship to Pazopanib (GW786034)
(CTCAE 4 Term)
[n= 1019]
EXPECTED AEs FOR 
ADEERS REPORTING
Agent Specific Adverse 
Event List
(ASAEL)
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
Expected
CARDIAC DISORDERS
Chest pain
Angina
Bradycardia
Bradycardia
QT-prolongation
Cardiac dysfunction
Left ventricular systolic 
dysfunction
Myocardial infarction
ENDOCRINE DISORDERS

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Hypothyroidism
Liver Failure
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain
Constipation
Flatulence
Diarrhea
Diarrhea
Gastrointestinal fistula2
Gastrointestinal fistula2
Gastrointestinal hemorrhage3
Gastrointestinal perforation4
Gastrointestinal 
perforation4
Nausea
Nausea
Vomiting
Vomiting
Dyspepsia
Pancreatitis
Pancreatitis
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
Fatigue
Chills/Rigors
Vital organ hemorrhages
Infection
INVESTIGATIONS
Alanine aminotransferase 
increased
Alanine aminotransferase 
increased
Aspartate 
aminotransferase increased
Aspartate aminotransferase 
increased
Blood bilirubin increased
Blood bilirubin increased
Gamma-glutamyl 
transpeptidase increased
GGT Increased
Electrocardiogram QTc 
interval prolonged 
(accompanied by Torsades de 
pointes)
Lipase increased
Lymphocyte count decreased
Leukopenia
Neutrophil count 
decreased
Neutropenia
Platelet count decreased
Thrombocytopenia
Serum amylase increased
Weight loss
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia
Dehydration
Dehydration
Hyperglycemia
Hyperglycemia
Hypermagnesemia

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Hypoglycemia
Hypoglycemia
Hypomagnesemia
Hypophosphatemia
Hypophosphatemia
Weight Loss
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia
Arthralgia
Myalgia
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS)
Tumor pain
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness
Dysgeusia
Extrapyramidal disorder
Headache
Headache
Stroke
Aneurysm
Reversible posterior
leukoencephalopathy 
syndrome
RENAL AND URINARY DISORDERS
Hematuria
Proteinuria
Proteinuria
Urinary fistula
Urinary fistula
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
Female genital tract fistula
Female genital tract fistula
Uterine fistula
Uterine fistula
Vaginal fistula
Vaginal fistula
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Cough
Dyspnea
Respiratory hemorrhage5
Respiratory hemorrhage5
Oral stomatitis
Mouth sores
Dysphonia
Hoarseness
Pneumothorax
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Alopecia
Edema in face, hands, ankles, 
feet and/or eyelids
Desquamation
Hemoptysis
Blurred vision
Ametropia
Palmar-plantar 
erythrodysesthesia 
syndrome
Rash maculo-papular
Rash maculo-papular
Skin hypopigmentation
Skin hypopigmentation
VASCULAR DISORDERS

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Hypertension
Hypertension
Thromboembolic event 
(venous)6
Thrombotic microangiopathy 
(including thrombotic 
thrombocytopenic purpura 
and hemolytic uremic 
syndrome)
Vital organ hemorrhage
Vascular disorders – other 
(arterial thromboembolic 
event)6
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal Investigators at the 
time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric fistula, Gastrointestinal fistula, 
Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the
GASTROINTESTINAL DISORDERS SOC.
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal 
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage,
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal 
perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.
5Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, Mediastinal hemorrhage, Pharyngeal 
hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.
6These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications.
10.2
Ifosfamide (Isophosphamide, Iphosphamide, Z4942, Ifex®) NSC #109724 (122004)
Source and Pharmacology: Ifosfamide is a structural analogue of cyclophosphamide. 
Ifosfamide requires hepatic microsomal activation (P-450 3A isoenzymes) for the production of 
the reactive 4-hydroxyoxazaphorine intermediate which serves as a carrier molecule for the 
ultimate intracellular liberation of acrolein and phosphoramide mustard which is an active 
bifunctional alkylating species. Acrolein is thought to be the cause of the hemorrhagic cystitis as 
seen with cyclophosphamide. Ifosfamide demonstrates dose-dependent pharmacokinetics 
whereby the terminal half-life ranges from 7 to 16 hours at doses of 1.6-2.4g/m² to 3.8-5 g/m², 
respectively. At 1.6-2.4g/m²/d, 12 to 18% of the dose was excreted as unchanged drug in the 
urine, whereas at a 5g/m² single-dose, 61% was excreted in the urine as the parent drug. 
Evidence also exists to suggest that ifosfamide metabolism is inducible, with more rapid 
clearance occurring in the second and later doses when a course of therapy is given as
fractionated doses over 3 to 5 days. There is more chloroethyl side chain oxidation of ifosfamide 
(up to 50%) than of cyclophosphamide (<10%), and the degree of such metabolism is more 
variable than with cyclophosphamide. Oxidation of the chloroethyl groups produces 
chloroacetaldehyde, which is thought to be responsible for the neurotoxicity and renal toxicity 
that have been seen with ifosfamide therapy.

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Formulation and Stability: Available in 1 g and 3 g single dose vials of lyophilized white 
powder without preservatives. Reconstitute with sterile water for injection or bacteriostatic water 
for injection, 20ml for the 1gm vial or with 60mL for the 3gm vial to produce a final 
concentration of 50mg/ml ifosfamide. Although the reconstituted product is stable for 7 days at 
room temperature and up to 6 weeks under refrigeration, the manufacturer recommends 
refrigeration and use within 24 hours to reduce the possibility of microbial contamination. Store 
unreconstituted vials at room temperature 20°-25°C (68°-77° F). Protect from temperatures 
above 30°C (86° F). Ifosfamide may liquefy at temperatures > 35°C.
Guidelines for Administration: Solutions of ifosfamide may be diluted further to 
concentrations of 0.6 to 20 mg/ml in dextrose or saline containing solutions. Such admixtures, 
when stored in large volume parenteral glass bottles, Viaflex bags or PAB bags, are physically 
and chemically stable for 1 week at 30°C (86°F) or 6 weeks at 5°C (41°F). The manufacturer 
recommends refrigeration and use within 24 hours to reduce the possibility of microbial 
contamination.
Supplier: Commercially available from various manufacturers. 
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding should 
be discontinued during therapy.
Expected adverse events:
Central nervous system: Somnolence, confusion, hallucinations in 12% and coma (rare) 
have occurred and are usually reversible; usually occur with higher doses or in patients with 
reduced renal function; depressive psychoses, polyneuropathy. Note: CNS depression can 
be reversed with methylene blue (50 mg intravenously) and methylene blue is recommended 
for prophylaxis for subsequent doses if the patient has CNS manifestations with the first 
dose. 
Dermatologic: Alopecia occurs in 50% to 83% of patients 2-4 weeks after initiation of 
therapy; may be as high as 100% in combination therapy. Phlebitis, dermatitis, nail ridging, 
skin hyperpigmentation, impaired wound healing.
Gastrointestinal: Nausea and vomiting in 58% of patients is dose and schedule related (more 
common with higher doses and after bolus regimens); nausea and vomiting can persist up to 
3 days after therapy; also anorexia, diarrhea, constipation, transient increase in LFTs and 
stomatitis noted. 
Genitourinary: Hemorrhagic cystitis has been frequently associated with the use of 
ifosfamide; a urinalysis prior to each dose should be obtained; ifosfamide should never be 
administered without a uroprotective agent (MESNA); hematuria has been reported in 
6% to 92% of patients; renal toxicity occurs in 6% of patients and is manifested as an 
increase in BUN or serum creatinine and is most likely related to tubular damage; renal 
toxicity, including ARF, may occur more frequently with high-dose ifosfamide; metabolic 
acidosis may occur in up to 31% of patients.
Endocrine & metabolic: SIADH 

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Hematologic: Myelosuppression: Leukopenia is mild to moderate, thrombocytopenia and 
anemia are rare. However, myelosuppression can be severe when used with other 
chemotherapeutic agents or with high-dose therapy; be cautious with patients with 
compromised bone marrow reserve 
Respiratory: Nasal stuffiness, pulmonary fibrosis
Cardiovascular: Cardiotoxicity 
Miscellaneous: Immunosuppression, sterility, possible secondary malignancy, allergic
reactions
10.3
Doxorubicin (Adriamycin®) NSC #123127 (042006)
Source and Pharmacology: An anthracycline antibiotic isolated from cultures of Streptomyces
peucetius. The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various 
organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding 
activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and 
RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of doxorubicin cytocidal activity. Doxorubicin 
cellular membrane binding may affect a variety of cellular functions. Enzymatic electron 
reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generate 
highly reactive species including the hydroxyl free radical OH•. Free radical formation has been 
implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular 
level. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic 
changes associated with apoptosis or programmed cell death. Doxorubicin induced apoptosis 
may be an integral component of the cellular mechanism of action relating to therapeutic effects, 
toxicities, or both. Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is 
approximately 5 minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 
48 hours reflects a slow elimination from tissues. Steady-state distribution volumes exceed 20 to 
30 L/kg and are indicative of extensive drug uptake into tissues. Plasma clearance is in the range 
of 8 to 20 ml/min/kg and is predominately by metabolism and biliary excretion. The P450 
Cytochromes which appear to be involved with doxorubicin metabolism are CYP2D6 and
CYP3A4. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of 
the drug and its metabolites appear in the urine during the same time period. Binding of
doxorubicin and its major metabolite, doxorubicinol to plasma proteins is about 74 to 76% and is 
independent of plasma concentration of doxorubicin.
Formulation and Stability: Doxorubicin is available as red-orange lyophilized powder for 
injection in 10mg, 20mg, 50mg, 150mg vials and a preservative free 2mg/ml solution in 10mg, 
20mg, 50mg, 75mg, 200mg vials. Aqueous Solution: Store refrigerated 2° to 8°C, (36° to 46°F). 
Protect from light. Retain in carton until contents are used. Powder for injection: Store 
unreconstituted vial at room temperature 15° to 30°C (59° to 86°F). Retain in carton until 
contents are used. Reconstitute with preservative free normal saline to a final concentration of 
2mg/ml. After adding the diluent, the vial should be shaken and the contents allowed to dissolve.  
The reconstituted solution is stable for 7 days at room temperature under normal room light and 
15 days under refrigeration 2° to 8°C (36° to 46°F). Protect from exposure to sunlight.

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Guidelines for Administration: Administer by IV push; by IV side arm into a running infusion; 
or doxorubicin may be further diluted in saline or dextrose containing solutions and administered 
by infusion. Protect final preparation from light. Avoid extravasation.
Supplier: Commercially available from various manufacturers.
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding should 
be discontinued during therapy.
Expected adverse events:
Hematologic: Hematologic side effects have been reported in 60% to 80% of patients and 
they may be profound (depending entirely on dose). While myelosuppression can affect all 
cell lines, leukopenia is most common, appearing in 60% to 75% of all treated patients. 
Absolute white blood cell counts of less than 1,000/mm3 are not uncommon after 
recommended therapeutic doses. Severe thrombocytopenia and anemia may also occur.
Gastrointestinal: Gastrointestinal side effects have included acute nausea and vomiting in 
20% to 85% of patients. Stomatitis has been reported in up to 80% of patients, and is dose 
and schedule-related. Ulceration of the esophagus and the colon (particularly the cecum) 
have also been reported. Anorexia and diarrhea have been reported in approximately 15% of 
patients. Rare cases of tongue hyperpigmentation have also been associated with the use of 
doxorubicin.
Dermatologic: Alopecia, flushes, skin and nail hyperpigmentation, oncholysis (nail loss),
photosensitivity, hypersensitivity to irradiated skin.
Extravasation: Infiltration can cause severe inflammation, tissue necrosis, and ulceration.   If 
the drug is infiltrated, consult institutional policy, apply ice to area, and elevate the limb.  
May require debridement.
Hypersensitivity:  Hypersensitivity reactions have occasionally been reported, and may 
include fever, chills, urticaria, angioneurotic edema or anaphylaxis.  Local IV site "flares" 
can be confused with extravasation, but are probably due to allergy to this drug. Flare 
reactions were reported in 3% to 18% of patients, but are now rare since the vehicle in 
which doxorubicin is carried has changed. Flare reactions are characterized by erythema, 
appear proximally along the affected vein, and typically resolve within 45 minutes. Pain, 
burning and adverse sequelae are infrequent or absent. Extravasation, on the other hand, 
appears at the injection site and resolves slowly over days to weeks. As opposed to flare 
reactions, pain, burning, and edema are common, and adverse sequelae are variable and may
be serious.  Allergic reactions have also been reported after the intravesical administration 
of doxorubicin.
Renal: Renal insufficiency has been associated with doxorubicin-induced hyperuricemia 
(secondary to cell lysis). Animal data suggest that doxorubicin may cause glomerular 
basement membrane injury via production of reactive oxygen species. Renal side effects 
have included rare cases of new or worsened renal insufficiency. A single case of rapidly 
progressive glomerulonephritis without evidence of a secondary cause or immunologic 
mechanism has been reported.

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Ocular: Ocular side effects have included rare cases of conjunctivitis, periorbital edema, 
lacrimation, blepharospasm, keratitis, and decreased visual acuity.
Genitourinary: Genitourinary side effects including rare cases of bladder contracture have 
been reported.
Musculoskeletal: Musculoskeletal side effects have been extremely rare. In one case, 
administration of doxorubicin was associated with a clinically significant flare of ankylosing 
spondylitis.
Cardiac: Anthracycline-induced cardiac toxicity may be manifested by early or late events.
Early cardiac toxicity consists mainly of sinus tachycardia and/or ECG abnormalities such 
as non-specific ST-T wave changes, but tachyarrhythmias, bradycardia, as well as 
atrioventricular and bundle-branch block have also been reported.  Although rhythm 
disturbances are common after acute administration they are rarely of clinical importance. 
Early effects of anthracyclines also include extremely rare cases of pericarditis-myocarditis 
(which can affect patients with no prior history of cardiac disease and which carries a high 
mortality rate of about 20%),  and left ventricular dysfunction (which may lead to clinically 
significant heart failure in patients with limited cardiac reserve). Isolated cases of 
symptomatic supraventricular tachycardia, heart block, and ventricular arrhythmias (some 
sudden and fatal) have also been reported.  Cardiovascular side effects have included 
congestive heart failure due to the development of left ventricular (LV) systolic dysfunction 
in 1% to 2% of patients. Retrospective data have shown that the incidence of clinical heart 
failure in patients with preexisting LV systolic dysfunction (ejection fraction [LVEF] <
50%), who experienced a decline of 10% or more in absolute LVEF, and who received at 
least 450 mg/m2 cumulative dose, is approximately 16%. (Data have shown right 
ventricular septal wall motion may also be affected and that LV diastolic dysfunction may 
precede the development of doxorubicin-induced LV systolic dysfunction.).
Secondary Leukemia:  The occurrence of secondary acute myelogenous leukemia has been 
reported in patients treated with anthracyclines. 
Other: Radiation pneumonitis or esophagitis may be more likely with the combination of 
doxorubicin and XRT than with XRT alone. Prior cardiac or mediastinal XRT appears to 
portend a higher risk of doxorubicin-induced cardiomyopathy. Other side effects of 
doxorubicin have included the predisposition of patients who have previously received 
radiation therapy (XRT) to demonstrate the so-called "recall" phenomenon
10.4
Mesna (sodium 2-mercaptoethane sulfonate,UCB 3983, Mesnex®) NSC #113891 
(012006)
Source and Pharmacology: Mesna was developed as a prophylactic agent to reduce the risk of
hemorrhagic cystitis induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, 
mesna disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and is 
rapidly eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol 
compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites (acrolein 
and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the detoxification 
process is the binding of mesna to 4-hydroxyifosfamide forming a nonurotoxic 4-

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sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic 
metabolites. In multiple human xenograft or rodent tumor model studies, mesna in combination 
with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to 
demonstrate interference with antitumor efficacy.  After an 800mg dose the half lives for Mesna 
and DiMesna are 0.36 hours and 1.17 hours, respectively. Approximately 32% and 33% of the 
administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. 
The majority of the dose recovered was eliminated within 4 hours. Mesna tablets have an oral 
bioavailability of 45-79% and a urinary bioavailability which ranged from 45-79% of
intravenously administered mesna. The oral bioavailability is unaffected by food. When 
compared to intravenously administered mesna, the intravenous plus oral dosing regimen 
increases systemic exposures (150%) and provides more sustained excretion of mesna in the 
urine over a 24-hour period.
Unknown Frequency and Timing: **Fetal toxicities and teratogenic effects of mesna have not 
been noted in animals fed 10 times the recommended human doses. There are however no 
adequate and well controlled studies in pregnant women. It is not known if mesna or dimesna is 
excreted into human milk.
Guidelines for Administration: For IV administration, dilute to 20 mg/mL with dextrose or 
saline containing solutions. Mesna may be mixed with ifosfamide or cyclophosphamide. After 
dilution for administration, mesna is physically and chemically stable for 24 hours at 25ºC 
(77ºF).  Carefully expel air in syringes prepacked for use to avoid oxidation to dimesna. Mesna
may cause false positive test for urinary ketones.
Supplier: Commercially available from various manufacturers.
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding should 
be discontinued during therapy.
Expected adverse events: 
Cardiovascular: Hypotension 
Central nervous system: Malaise, headache 
Gastrointestinal: Diarrhea, nausea, vomiting, bad taste in mouth, soft stools 
Neuromuscular & skeletal: Limb pain 
Dermatologic: Skin rash, itching
10.5
Pegfilgrastim (pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®) (072006)
Source and Pharmacology: Pegfilgrastim is the pegylated form of recombinant methionyl 
human G-CSF (filgrastim). Pegfilgrastim is produced by covalently binding a 20-kilodalton (kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of filgrastim. 
The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage specific colony-stimulating 
factor which regulates the production of neutrophils within the bone marrow and affects 
neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation 
(including enhanced phagocytic ability, priming of the cellular metabolism associated with 

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respiratory burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). After subcutaneous injection the elimination half-life of 
pegfilgrastim ranges from 15 to 80 hours and the time to peak concentration ranges from 24 to 
72 hours. Serum levels are sustained in most patients during the neutropenic period 
postchemotherapy, and begin to decline after the start of neutrophil recovery, consistent with 
neutrophil-dependent elimination.
Formulation and Stability: Supplied as a preservative-free solution containing 6 mg (0.6ml) of
pegfilgrastim (10mg/ml) in a single-dose syringe with 27 g, ½ inch needle with an UltraSafe® 
Needle Guard. Store refrigerated at 2-8º C (36-46ºF) and in the carton to protect from light. Prior 
to injection, pegfilgrastim may be allowed to reach room temperature protected from light for a 
maximum of 48 hours. Avoid freezing.
Guidelines for Administration: Pegfilgrastim should not be administered in the period 
between 2 weeks before and 24 hours after chemotherapy. Do not shake.
Supplier: Commercially available from various manufacturers
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding should 
be discontinued during therapy.
Expected Adverse Events:
Bone pain was the most frequent adverse event attributable to pegfilgrastim in clinical trials.  
Hypoxia was observed in one patient. Toxicities associated with the parent compound, filgrastim 
include:
Central nervous system: Neutropenic fever, fever.
Dermatologic: Alopecia.
Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, splenomegaly (this occurs more 
commonly in patients with cyclic neutropenia/congenital agranulocytosis who received S.C. 
injections for a prolonged (>14 days) period of time; ~33% of these patients experience 
subclinical splenomegaly; ~3% of these patients experience clinical splenomegaly).
Neuromuscular & skeletal: Medullary bone pain (24% incidence--this occurs most 
commonly in lower back pain, posterior iliac crest, and sternum and is controlled with non-
narcotic analgesics), weakness.
Cardiovascular:
Chest pain, fluid retention, transient supraventricular arrhythmia, 
pericarditis.
Central nervous system: Headache.
Dermatologic: Skin rash.
Gastrointestinal: Anorexia, stomatitis, constipation.
Hematologic: Leukocytosis.
Local: Pain at injection site, thrombophlebitis.
Respiratory: Dyspnea, cough, sore throat.
Miscellaneous: Anaphylactic reaction.

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11.0
ASSESSMENT OF EFFICACY
Evaluability: In order for a patient to be evaluable, 80% of the intended dose of all three 
drugs must be delivered in the first 2 cycles of chemotherapy.
11.1
Pharmacodynamic Studies
The primary endpoint of the study is to evaluate the absolute values and changes in maximum 
standardized uptake values of tumors measured by FDG-PET pre- and post receipt of pazopanib
versus placebo, and post receipt of 2 cycles of preoperative chemotherapy. This will be 
compared to tumor response by RECIST criteria.
FDG PET
PET imaging will be performed at baseline, after the 14 day Run-in Period with pazopanib 
versus placebo and after 2 cycles of neoadjuvant chemotherapy.  Imaging studies will be 
performed on the SCCA GE discovery LS PET/CT imaging device operating in a two-
dimensional high-sensitivity mode with 35 imaging planes per axial field of view of 15 cm 
(plane thickness 4.25 mm) and an in-plane resolution of 4 to 5 mm.
The UW/SCCA will follow FDG-PET protocol consensus recommendations[53] and PET 
Response Criteria in Solid Tumors (PERCIST), version 1.0.[54]
Key elements of PERCIST include performance of PET scans in a method consistent with the
National Cancer Institute recommendations. Patients will fast for at least 4–6 h before 
undergoing scanning, and the measured serum glucose level (no correction) must be less than 
200 mg/dL. The patients may be on oral hypoglycemics but not on insulin. A baseline PET scan 
will be obtained at 50–70 min after tracer injection. The follow-up scan should be obtained 
within 15 min (but always 50 min or later) of the baseline scan. All scans will be performed on 
the same PET scanner with the same injected dose +/- 20% of radioactivity. 
Appropriate attenuation correction along with evaluation for proper PET and CT registration of 
the quantitated areas will be performed. SUV will be corrected for lean body 
mass (SUL) and should not be corrected for serum glucose levels (glucose corrections have been 
variably useful, and errors in glucometer measurements are well known and may add 
errors). The SUL will be determined for up to 5 tumors (up to 2 per organ) with the most 
intense 18F-FDG uptake.  The SUV peak (this is a sphere with a diameter of approximately 1.2 
cm—to produce a 1-cm3-volume spheric ROI) centering around the hottest point in the tumor 
foci will be determined, and the image planes and coordinates will be noted (SUL peak). This 
SUL peak ROI will typically include the maximal SUL pixel (which should also be recorded) but 
is not necessarily centered on the maximal SUL pixel. Automated methods for searching for this 
peak region will be used. Tumor sizes will be noted and should be 2 cm or larger in diameter for 
accurate measurement, though smaller lesions of sufficient 18F-FDG uptake, including those not 
well seen anatomically, can be assessed. Each baseline (pretreatment) tumor SUL peak must be 
1.5 x mean liver SUL + 2 SDs of mean SUL. If the liver is diseased, 2.0 x blood-pool 18F-FDG 
activity + 2 SDs in the mediastinum will be used as minimal metabolically measurable tumor 
activity.[54]

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Serial PET will measure the SUV (SUV lean or SUL) peak for up to 5 target lesions in order to 
assess FDG uptake pre-therapy, after a 14 day Run-in period of pazopanib versus placebo, and 
after 2 cycles of chemotherapy. Analysis of changes in SUV from baseline and after treatment 
with pazopanib versus placebo and then again after chemotherapy will test whether 
antiangiogenic therapy has anti-tumor efficacy as monotherapy and if so, what is its relative 
contribution to a decline in tumor metabolism compared to chemotherapy.
RECIST
The radiographic response of the primary tumor to preoperative therapy will be evaluated.  For 
subjects with stage II (T2a) or III disease, the primary lesion will serve as the sole target lesion 
and will be recorded and measured at baseline.  RECIST measurements will be performed on 
serial MRIs to evaluate the correlation with FDG-PET.
For patients with stage IV disease, target lesions will be chosen according to RECIST 
procedure. The longest diameter (LD) of the target lesions will be measured and reported as the 
baseline LD. The baseline LD will be used as reference to further characterize the objective 
tumor response of the measurable dimension of the disease. This will be compared to changes in 
SUV on FDG PET.  Response and progression will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee.[55]
Changes in only the largest diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST 1.1 criteria.
11.2
Pharmacokinetic Studies
Trough level (22-24 hrs after pazopanib dosing): A blood sample will be drawn to assess the 
trough plasma pazopanib concentration during the 14 day Run-in period of pazopanib 
monotherapy (2 samples), after completion of adjuvant chemotherapy (2 samples), and every 3 
months thereafter until completion of pazopanib maintenance therapy (4 samples).  If all trough 
levels are drawn, a total of 8 samples are possible in a single subject. The trough levels will be 
compared for any differences over time and will be correlated with the change in SUV from 
FDG PET and with the change in RECIST measurements on MRIs. 
In subjects consenting to the optional full intensive pharmacokinetic visit during Weeks 2-4
following surgery/adjuvant chemotherapy, blood will be obtained at the following timepoints: 
immediately before pazopanib dosing (within 5 minutes before giving pazopanib on the day of 
PK dosing) and 1, 2, 3, 4, 6, 8 hour timepoints (+/- 10 minutes) , and 24 hrs (range 22 to 24 
hours) after dosing (a total of 8 samples/subject).
Pazopanib pharmacokinetic parameters of maximum observed plasma concentration (Cmax), 
the time to Cmax (peak time, Tmax), the area under the plasma concentration-time curve 
(AUC0-24hr), concentration at the end of the dosing interval (Ctr), oral clearance (CL/F), 
volume of distribution (Vd/F), and half-life (t1/2) will be determined using noncompartmental 
methods. The correlation between trough concentrations and AUC will also be evaluated.
11.3 Efficacy Variables
11.3.1 FDG Criteria for Tumor Response

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Determination of SUV (SUV lean or SUL) of the primary tumor and metastases will be 
performed, for up up to 5 target lesions, and for non-target lesions.  FDG changes of 
more than 25% from baseline cannot be attributed to the imprecision of the technique and 
are therefore regarded as true changes in tumor glucose metabolism.[54] FDG criteria for 
tumor response will be as per the PET Response Criteria in Solid Tumors (PERCIST) 
criteria.[54] PERCIST includes a specific percentage reduction in the SUV (SUV lean, 
or SUL) from baseline.  Response to therapy is assessed as a continuous variable and 
expressed as percentage change in SUL peak (or sum of lesion SULs) between the pre-
and post treatment scans.  A complete metabolic response is defined as visual 
disappearance of all metabolically active tumor. A partial response is considered more 
than a 30% and a 0.8-unit decline in SUL peak between the most intense lesion before 
treatment and the most intense lesion  after treatment, although not necessarily the same 
lesion.  More than a 30% and 0.8-unit increase is SUL peak or new lesions is classified as 
progressive disease.
11.3.2 RECIST Criteria for Tumor Response
Response criteria will be assessed using RECIST (version 1.1).[55]
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 longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target 
lesions, taking as 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
Evaluation of best overall response:
The best overall response is the best response achieved prior to surgical resection of the 
target lesion.
Target Lesions
New Lesions
Overall Response
CR
No
CR
PR
No
PR
SD
No
SD
PD
Yes or No
PD
Any
Yes
PD

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Note:
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends upon this determination, 
this will be determined at the time of surgical resection.
11.3.3 Pathologic Response at Surgery
All specimens of primary tumor will be examined for pathologic response at the time of 
surgery.  The study pathologist will estimate the amount of viable tumor, and report the 
percentage of necrosis.  For purpose of analysis, tumors will be classified as either 
t95% necrosis or <95% necrosis.
11.3.4 Duration of Response/Stable Disease
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
11.3.5 Definition of Disease Progression
Disease progression will be defined as:
x
Radiologic progression of disease by FDG PET PERCIST 1.0 criteria
x
Radiologic progression of disease by RECIST (version 1.1) criteria.
11.3.6 Time-to-Event Measures
Time to Local Recurrence- Defined as the duration of time from surgical resection of 
the primary tumor until local recurrence (amputated patients excluded).
Local Disease-Free Survival- Defined as the duration of time from surgical resection of 
the primary tumor until local recurrence or death, whichever occurs first.
Distant Disease-Free Survival - Defined as the duration of time from randomization
until development of distant metastatic disease or death, whichever occurs first.  
Subjects with stage IV disease will be censored from this analysis.
Disease-Free Survival - Defined as the duration of time from surgical resection to local 
recurrence, distant metastatic disease, or death, whichever occurs first.  Subjects with 
stage IV disease will be censored from this analysis.

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Progression-Free Survival - Defined as the duration of time from randomization to 
progressive disease (per RECIST), local recurrence, distant metastatic disease 
(exclusive of stage IV subjects), or death, whichever occurs first.
Overall Survival - Defined as the interval of time from randomization until death from 
any cause.
11.4
Determining Response to Pazopanib for Continuing on Maintenance
Subjects who have a partial response by either RECIST 1.1 criteria on CT or MRI, 
and/or PERCIST 1.0 criteria by FDG PET after the 14 day Run-in period on pazopanib 
will have the option to remain on pazopanib for one year of therapy following surgery 
and adjuvant chemotherapy/radiation.
12.0
DATA MANAGEMENT/CONFIDENTIALITY
The Investigator will ensure that data collected conform to all established guidelines.  Each subject is 
assigned a unique patient number to assure subject confidentiality.  Subjects will not be referred to by 
this number, by name, or by any other individual identifier in any publication or external presentation.
The licensed medical records department, affiliated with the institution where the subject receives 
medical care, maintains all original inpatient and outpatient chart documents.  
Subject research files including paper and electronic case report forms, diagnostic pathology reports, and 
lab tests will be stored in a secure location that protects confidential information.
13.0
CORRELATIVE STUDIES
Plasma will be collected for measurement of VEGF and soluble VEGFR2 (sVEGFR2) at baseline, after 
the 14 day Run-in period of pazopanib, after completion of neoadjuvant chemotherapy and every 3 
months thereafter until completion of pazopanib maintenance therapy, when indicated.  
Quantitative enzyme-linked immunosorbent assays (ELISA) for VEGF and sVEGFR2 will be
performed on plasma and tumor extracts.
MicroRNAs have been shown to be promising blood and tissue-based markers for cancer detection.[56]
An extension of this is that such markers may also be excellent candidates for measuring response to 
therapy.  There are currently no validated biomarkers to predict response to antiangiogenic therapy.
Consequently, the ability to test candidate microRNA biomarkers before, during and after neoadjuavnt 
systemic therapy offers an ideal setting to assess potential biomarkers. Blood samples will be collected 
for micro RNA at baseline, after the 14 day Run-in period of pazopanib, following neoadjuvant 
chemotherapy and every 3 months thereafter until completion of pazopanib maintenance therapy, when 
indicated.
Samples to be tested will be an additional 3 tablespoons of whole blood (23cc) at each time of clinical 
lab draw, collected as 10cc into EDTA tubes (plasma), 10cc into serum separator tubes, and 3cc into 
Tempus tubes (containing an RNA stabilizer).

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There may also be evaluation of other potential predictive and prognostic markers using analysis of 
protein, DNA and RNA from surgical tumor tissue.
14.0
STATISTICAL CONSIDERATIONS
14.1
Analysis plan
The primary objective is to compare FDG SUV (SUV lean, SUL) measures for patients receiving 
pazopanib and placebo.  The primary endpoint is the percent change in SUV between baseline 
and the end of the 14-day Run-in period of pazopanib or placebo.  The comparison will likely be 
conducted using a two-sided Wilcoxon rank sum test, often used as a nonparametric alternative 
to the two-sample t-test for studies with a small sample size.  Additional endpoints will include 
SUV percentage change between baseline and the end of preoperative therapy, absolute post-
treatment SUV (at 14 days and following preoperative chemotherapy), and absolute difference in 
SUV.  
The analysis sample for the primary pharmacodynamic analysis is expected to exclude patients 
who have incomplete data due to missed PET scans or due to study withdrawal for toxicity.   
However, reasons for missing data will be examined, and multiple imputation will be considered 
if patients with incomplete data would be considered as part of the target population for future 
development of pazopanib in sarcoma.  However, insofar as sarcoma is heterogeneous, the 
sample size is small, and covariates are limited – multiple imputation may not be applicable.
These pharmacodynamic response measures will be compared to tumor response by RECIST 
criteria, using graphical displays.  Continuous measures of pharmacodynamic response 
(percentage change in SUL; response assessed using MRI) will also be compared to the trough 
plasma pazopanib, using graphical displays and correlation coefficients to investigate dose-
response relationships related to patients’ differing metabolism of pazopanib.
Descriptive displays of preliminary clinical endpoints (pathologic response, progression-free 
survival, overall survival) will compare response for the pazopanib and placebo groups, and will 
investigate the relationship between early pharmacodynamic response (by PET) and clinical 
endpoints.  Response of high-risk soft tissue sarcoma to neoadjuvant chemoradiation therapy was 
estimated as 52% (38% no residual tumor, 14% >=95 pathologic necrosis) in a series of 496 
patients.[9] A smaller series found only 13/46 (28%) with <10% viable tumor in surgical 
specimens following a variety of neoadjuvant regimens.[51] To direct planning of future studies,
we will measure the rate of complete pathological response defined as greater than 95% necrosis 
in the surgical excision specimen. A 90% Wilson (score) binomial confidence interval will be 
computed for the rate of complete pathological response.
There are no stopping rules planned for toxicity, but safety will be monitored continuously. All 
subjects who are registered and receive at least one dose of study drug will be included in the 
safety analysis.

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All reported adverse events will be coded using the Cancer Therapy Evaluation Program (CTEP) 
Common Toxicity Criteria version 4.0.  The number and percent of subjects reporting adverse 
events (all, severe or worse, serious and related) will be quantified.  Listings will be provided for 
all on-study deaths and adverse events that lead to withdrawal from study.  Narratives of all 
serious adverse events and deaths on-study will be provided.  
Correlative study assays will be analyzed using descriptive statistics, generally comparing 
pazopanib and placebo groups. Correlation will also be evaluated between pazopanib trough 
concentrations and drug exposure over the dosing interval (area-under-the-concentration-curve, 
AUC) in subjects consenting to the full intensive pharmacokinetic visits.
14.2
Sample size justification
If the standard deviation for percent change in is 20% and the average change is 0% for placebo 
and a 30% decrease for pazopanib, there will be approximately 90% power to detect a difference 
between the placebo and pazopanib group in average percent change for n=21 and a 2:1 
randomization.
14.3
Protocol Enrollment and Special Considerations
The ethnic and gender distribution chart below reflects estimates of race and gender of the 
population to be included in this study. 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects
Ethnic Category
Sex / Gender
Females
Males
Total
Hispanic or Latino
0
0
0
Not Hispanic or Latino
10
11
21
Ethnic Category Total of All Subjects*
10
11
21
a)
Racial Categories
American Indian / Alaska Native
0
0
0
Asian
0
0
0
Native Hawaiian or Other Pacific Islander
0
0
0
Black or African American
0
0
0
White
10
11
21
Racial Categories:  Total of All Subjects*
10
11
21
15.0
RECORDS
15.1
Source Documents
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected.  Source documents are filed at the investigator’s site.  The collaborating site 

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will send signed consents and eligibility forms to the coordinating center with source documents 
demonstrating subject eligibility within 10 business days of enrollment.
Data entered in the CRF transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained.  The investigator may need to request 
previous medical records or transfer records.  Current medical records must be available.
All data entered in to the CRF must be derived from source documents.  CRF data will be 
submitted to the coordinating center by entry into REDCapTM.  Data entered into the CRF will be 
reviewed for accuracy against source documentation per section 9.0.  
15.2
Access
The investigator and/or institution will permit study-related monitoring, audits, EC review and 
regulatory inspection, providing direct access to all related source data and documents.  The 
study is monitored per section 9.0, which details the full scope and extent of monitoring and 
provides for immediate action in the event of the discovery of major violations.  CRFs and all 
source documents, including progress notes and copies of laboratory and medical test results 
must be available at all times for review by the clinical study monitor, auditor and inspection by 
health authorities.  The Clinical Research Associate (CRA) or auditor my review all CRFs and 
written informed consents.  The accuracy of the data will be verified per section 9.0.
16.0
TERMINATION OF STUDY
The PI/IND sponsor may terminate the study at any time.  The IRB and FDA also have the 
authority to terminate the study should it be deemed necessary.
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Therapy 2003; Abstr. C42
[36]
Kumar, R., L.E. Harrington, T.M. Hopper, et al. Correlation of anti-tumor and anti-angiogenic 
activity of VEGFR inhibitors with inhibition of VEGFR2 phosphorylation in mice.  J Clin Oncol 
2005; 23 (suppl):A9537.
[37]
Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell 
carcinoma: results of a randomized phase III trial. J Clin Oncol 2010. In press.
[38]
Altorki N, Guarino M, Lee P, et al. Preoperative treatment with pazopanib (GW786034)
a multikinase angiogenesis inhibitor in early stage non-small cell lung cancer (NSCLC): a
proof-of-concept phase II study.  J Clin Oncol 2008; 26 (suppl):A7557.
[39]
Taylor, S.K., S. Chia, S. Dent, et al. A phase II study of Pazopanib (GW786034) in subjects with 
recurrent or metastatic invasive breast carcinoma: Results after completion of stage I: A trial of
the Princess Margaret Hospital Phase II Consortium. J Clin Oncol. 2009; 27 (suppl):A1133.
[40]
Slamon D, Gomez HL, Amit O, et al. Pazopanib + Lapatinib is more active than Laptinib alone: 
Updated results from a randomized study in subjects with first-line ErbB2-positive advanced or 
metastatic breast cancer [ESMO abstract 139P].  Ann Oncol.2008;19 (supp 8):viii 64-65.
[41]
Monk, B., L. Mas, J.J. Zarba, et al. A randomized phase II study: Pazopanib (P) versus lapatinib 
(L) versus combination of pazopanib/lapatinib (L+P) in advanced and recurrent cervical cancer 
(CC).  J Clin Oncol.2009; 27 (suppl):A5520.
[42]
Bible, K.C., R.C. Smallridge, W.J. Maples, et al. Phase II trial of pazopanib in progressive, 
metastatic, iodine-insensitive differentiated thyroid cancers. J Clin Oncol. 2009; 27 
(suppl):A3521.
[43]
Hurwitz, H.I., A. Dowlati, S. Saini, et al. Phase I trial of pazopanib in subjects with 
advanced cancer. Clin Cancer Res. 2009; 15:4220-4227.
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DePrimo, S.E., C.L. Bello, J. Smeraglia, et al. Circulating biomarkers of pharmacodynamic 
activity of sunitinib in subjects with metastatic renal cell carcinoma: modulation of VEGF and 
VEGF-related proteins. J Trans Med. 2007; 5:32-43.
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Therasse P, Arbuck SG, Eisenhauer EA. New guidelines to evaluate the response 
to treatment in solid tumors. European Organization for Research and Treatment

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Panicek DM, Casper ES, Brennan MF. Hemorrhage simulating tumor growth in malignant 
fibrous histiocytoma at MR imaging. Radiology 1991;181:398-400.
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Pisters PWT, Patel SR, Varma DGK, et al. Preoperative chemotherapy for stage IIIB extremity 
soft tissue sarcoma: long term results from a single institution. J Clin Oncol 1997;15:3481-87.
[48]
Meric F, Hess KR, Varma DGK, et al. Radiographic response to neoadjuvant chemotherapy is a 
predictor of local control and survival in soft tissue sarcomas. Cancer 2002;95:1120-1126.
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Delaney TF, Spiro IJ, Suit HD, et al. Neoadjuvant chemotherapy and radiotherapy for large 
extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2003;56:1117-27.
[50]
Eary JF, O’Sullivan F, Powitan Y. Sarcoma tumor FDG uptake measured by PET and patient 
outcome: a retrospective analysis. Eur J Nucl Med Mol Imaging 2002;29;1149-54.
[51]
Schuetze SM, Rubin BP, Vernon C. Use of positron emission tomography in localized extremity 
soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer 2005;103:339-348.
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Eary JF, Mankoff DA. Tumor metabolic rates in sarcoma using FDG PET. J Nucl Med 
1998;39:25-54.
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Shankar LK, Hoffman JM, Bacharach S, et al. Consensus recommendations for the use of 18F-
FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J 
Nucl Med 2006;47:1059-1066.
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Wahl RL, Jacene H, Kasamon Y, et al. From RECIST to PERCIST: Evolving considerations for 
PET response criteria in solid tumors. J Nuc Med 2009;50:122S-150S.
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
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Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers 
for cancer detection. Proc Natl Acad Sci USA 2008;105(30):10513-8.
[57]     van der Graaf WT, Blay JY, Chawla SP et al. Pazopanib for metastatic  soft-tissue sarcoma  
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APPENDIX A: Study Activities and Treatment Calendar
 
Screening 
End of Week 
Two 
Prior to Day 1 
of each cycle 
After 2 cycles 
of preop 
chemo 
At time of 
surgery 
Post-
treatment 
follow-up 
every 4 
weeks if 
receiving 
pazopanib, 
else  every 
3 months 
Informed 
Consent 
X 
 
 
 
 
 
History/Progress 
Notes 
X 
X 
X 
 
 
X 
Physical Exam 
X 
X 
X 
 
 
X 
Vitals signs 
X 
X 
X 
 
 
X 
Performance 
Status 
X 
X 
X 
 
 
X 
Treatment 
Toxicity  
 
X 
X 
 
 
X 
Pathology 
Review 
X 
 
 
 
X 
 
CBC, chemistries, 
Ca++, phos, Mg+ , 
hepatic panel 
X 
X 
X 
 
 
X 
UA 
X 
 
X 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
INR 
X 
 
 
 
 
 
ECG 
X 
X 
 
 
 
X  
(every 3 
months) 
ECHO 
X 
 
 
 
 
 
Tissue/blood for 
correlative 
studies 
X 
X 
 
X 
X 
X   
(every 3 
months) 
FDG-PET 
X 
X 
 
X 
 
 
MRI 
X 
X 
 
X 
 
 
Plasma 
pazopanib 
trough level 
 
X (2 visits) 
 
 
 
X  
(every 3 
months) 
Full plasma 
pazopanib PK 
(optional) 
 
 
 
 
 
X (once 
during 
Weeks 2-4) 
CT-chest 
X 
 
 
 
 
X  
(every 3 
months) 

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APPENDIX B
Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction.
100
Normal, no complaints, no evidence of 
disease.
90
Able to carry on normal activity; minor 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work).
80
Normal activity with effort; some signs or 
symptoms of disease.
70
Cares for self, unable to carry on normal 
activity or to do active work.
2
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities.  Up and 
about more than 50% of waking hours.
60
Requires occasional assistance, but is able 
to care for most of his/her needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization indicated.  
Death not imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
20
Very sick, hospitalization indicated. Death 
not imminent.
10
Moribund, fatal processes progressing 
rapidly.
5
Dead.
0
Dead.

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APPENDIX C
Additional Eligibility Criteria for Women
Criteria for women of non-childbearing potential (physiologically incapable of becoming 
pregnant):
x
A hysterectomy or 
x
A bilateral oophorectomy (ovariectomy) or a bilateral tubal ligation or 
x
Is post-menopausal - Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of 
PHQVHVIRU\HDUDQGEHJUHDWHUWKDQ\HDUVLQDJH25LQTXHVWLRQDEOHFDVHVKDYHDIROOLFOHVWLPXODWLQJKRUPRQH
(FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L) or
Subjects using HRT must have experienced total cessation of menses for 1 year and be greater 
than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol 
concentrations prior to initiation of HRT
Criteria for women of 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 methods of contraception 
are: 
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 
x
Oral contraceptive, either combined or progestogen alone 
x
Injectable progestogen 
x
Implants of levonorgestrel 
x
Estrogenic vaginal ring 
x
Percutaneous contraceptive patches 
x
Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 
1% per year
x
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
x
Double barrier method:  condom and an occlusive cap (diaphragm or cervical/vault caps) with a 
vaginal spermicidal agent (foam/gel/film/cream/suppository)

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APPENDIX D
Drugs Known to be Metabolized by Selected CYP450 Isoenzymes
CYP2C8/9
SUBSTRATES
INHIBITORS
INDUCERS
Generic Name
Trade Name
Generic Name
Trade Name
Generic Name
Trade Name
Antibiotics: e.g.
Rifampin
Sulfadiazine
Rifadin
--
Antifungals: e.g.
Fluconazole
Ketoconazole
Miconazole
Tioconazole
Diflucan
Nizoral
Lotramin 
Monistat
Sedatives: e.g.
Phenobarbiatl
Primidone
Luminal
Mysoline
Misc. CV agents: e.g.
Amiodarone
Carvedilol
Cordarone
Coreg
Antimalarials: e.g.
Pyrimethamine
Quinine    
Daraprim
Legatrin
Anticonvulsants: e.g.
Carbamazapine
Phenobarbital
Phenytoin
Tegretol
Luminal
Dilantin
Anti-asthmatics: e.g.
Montelukast
Zafirlukast
Singulair
Accolate
Anti-hyperlipidemics: e.g.
     Fluvastatin
Gemfibrozil
Lescol
Lopid
Antibiotics: e.g.
Rifapentine
Rifampin
Priftin
Rifadin
Antidepressants: e.g.
Fluoxetine
Sertraline
Prozac
Zoloft
Antibiotics: e.g.
Isoniazid
Sulfadiazine
Sulfamethoxazole
Trimethoprim
INH, Nydrazid
--
Bactrim, Septra
Primsol
Anticonvulsants: e.g.
Fosphenytoin
Phenytoin
Cerebyx
Dilantin
Analgesics: e.g.
Flurbiprofen
Ibuprofen
Indomethacin
Mefenamic acid
Ansaid
Advil, Motrin
Indocin
Ponstel
Anesthetics: e.g.
Ketamine
Propofol
Ketalar
Diprivan
Anti-ulceratives: e.g.
Omeprazole
Pantoprazole
Prilosec
Pantoloc
Anti-diabetics: e.g.
     Glimepiride
     Rosiglitazone
Amaryl
Avandia
Antihypertensives: e.g.
Irbesartan
Losartan
Nicardipine
Avapro
Cozaar
Cardene
Antihypertensives: e.g.
Losartan
Bosentan
Cozaar
Tracleer
Paclitaxel
Taxol
Anti-diabetics: e.g.
Pioglitazone
Rosiglitazone
Actos
Avandia
Alosetron
Lotronex
Amiodarone
Cordarone
Torsemide
Demadex
Delavirdine
Rescriptor
Piroxicam
Feldene
Warfarin
Coumadin
Zafirlukast
Accolate
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher concentrations of the ‘substrate’. When  (Study 
Agent) is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of  (Study Agent) is the potential outcome. The 
coadministration of ‘inducers’ would potentially lower plasma   (Study Agent) concentrations.

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Comprehensive list of drugs that may have potential interactions
CYP2C8/9
SUBSTRATES
Alosetron
Amiodarone
Bosentan
Carvedilol
Fluoxetine
Fosphenytoin
Glimepiride
Glipizide
Ketamine
Losartan
Mephenytoin
Mestranol
Montelukast
Nateglinide
Paclitaxel
Phenytoin
Pioglitazone
Propofol
Rifampin
Rosiglitazone
Selegiline
Sertraline
Sulfadiazine
Sulfamethoxazole
Sulfinpyrazone
Sulfisoxazole
Tamoxifen
Tolbutamide
Torsemide
Trimethoprim
Voriconazole
Warfarin
Zafirlukast
Zopiclone
INHIBITORS
Amiodarone
Amitryptiline
Amlodipine
Anastrozole
Aprepitant
Atazanavir
Azelastine
Bortezomib
Candesartan
Chloramphenicol
Cholecalciferol (Vitamin D3)
Cimetidine
Clopidogrel
Clotrimazole
Clozapine
Cyclosporine
Delavirdine
Dexmedetomidine
Diclofenac
Diltiazem
Dimethyl sulfoxide
Disulfiram
Drospirenone
Efavirenz
Entacapone
Eprosartan
Etoposide
Felodipine
Fluconazole
Fluoxetine
Fluphenazine
Flurbiprofen
Fluvastatin
Fluvoxamine
Gemfibrozil
Ibuprofen
Imatinib
Indinavir
Indomethacin
Irbesartan
Isoniazid
Ketoconazole
Ketoprofen
Lansoprazole
Leflunomide
Losartan
Lovastatin
Mefenamic acid
Meloxicam
Methimazole
Methoxsalen
Metronidazole
Miconazole
Midazolam
Modafinil
Montelukast
Nateglinide
Nelfinavir
Nicardipine
Nifedipine
Olanzapine
Omeprazole
Ondansetron
Orphenadrine
Pantoprazole
Paroxetine
Pentamidine
Pioglitizone
Piroxicam
Pravastatin
Progesterone
Propafenone
Propofol
Propoxyphene
Pyrimethamine
Quinidine
Quinine
Ritonavir
Rosiglitazone
Saquinavir
Selegiline
Sertraline
Sildenafil
Simvastatin
Sulconazole
Sulfadiazine
Sulfamethoxazole
Sulfinpyrazone
Sulfisoxazole
Tamoxifen
Teniposide
Thioridazine
Ticlopidine
Tioconazole
Tolbutamide
Tolcapone
Tranylcypromine
Tretinoin
Triazolam
Trimethoprim
Valdecoxib
Valproic acid
Valsartan
Verapamil
Voriconazole
Warfarin
Zafirlukast
INDUCERS
Carbamazepine
Fosphenytoin
Phenobarbital
Phenytoin
Primidone
Rifampin
Rifapentine
Secobarbital
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism.  In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 
12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.)

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Selected Potential Cytochrome P450 (CYP) Drug Interactions
CYP3A4
SUBSTRATES
INHIBITORS
INDUCERS
Generic Name
Trade Name
Generic Name
Trade Name
Generic Name
Trade Name
Anti-neoplastics: e.g.
Docetaxel
Gefitinib
Irinotecan
Taxotere
Iressa
Camptosar
Anti-arrhythmics: e.g.
Amiodarone
Diltiazem
Quinidine
Cordarone, Pacerone
Cardizem, Dilacor XR
Cardioquin
Aminoglutethimide
Cytadren
Anti-virals: e.g.
Amprenivir
Rifampin
Agenerase
Rifadin
Anti-virals: e.g.
Amprenavir
Indinavir
Nelfinavir
Ritonavir
Agenerase
Crixivan
Viracept
Norvir
Antibiotics: e.g.
Rifabutin
Rifampin
Rifadin
Mycobutin
Anxiolytics: e.g.
Diazepam
Sertraline
Valium
Zoloft
Cimetadine
Tagamet
Anticonvulsants: e.g.
Carbamazapine
Phenytoin
Pentobarbital
Phenobarbital
Tegretol
Dilantin
Nembutal
Luminal
Cyclosporine
Sandimmune
Cyclosporine
Sandimmune
Hypericum perforatum (2)
St. John’s Wort
Anti-infectives: e.g.
Erythromycin
Tetracycline
Erythrocin
Sumycin
Antibiotics: e.g.
Ciprofloxacin
Clarithromycin
Doxycycline
Enoxacin
Isoniazid
Telithromycin
Cipro, Ciloxan
Biaxin
Adoxa, Periostat
Penetrex
Nydrazid, INH
Ketek
Steroids: e.g.
Estrogens, conjugated
Estradiol
Progesterone
Premarin
Climara
Crinone
Imatinib
Gleevec
Haloperidol
Haldol
Haloperidol
Haldol
Cardiovascular agents: e.g.
Digitoxin
Quinidine
Crystodigin
Cardioquin
Diclofenac
Cataflam, Voltaren
Anti-hypertensives: e.g.
Nicardipine
Verapamil
Cardene
Calan, Chronovera
Vasodilators: e.g.
Nicardipine
Verapamil
Cardene
Calan, Chronovera
Anesthetics: e.g.
Ketamine
Lidocaine
Xylocaine
Diprivan
Anesthetics: e.g.
Lidocaine
Propofol
Xylocaine
Diprivan
Nefazodone
Serzone
Anti-depressants: e.g.
Nefazodone
Sertraline
Serzone
Zoloft
Cocaine
Anti-fungals: e.g.
Itraconazole
Ketoconazole
Miconazole
Sporanox
Nizoral
Lotrimin, Monistat
Ketoconazole
Nizoral
Caffeine
Sildenafil
Viagra
Grapefruit juice (1)
Albuterol
Ventolin
Carbamazapine
Tegretol
Lovastatin
Mevacor
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher concentrations of the ‘substrate’.  When  (Study 
Agent) is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of  (Study Agent) is the potential outcome.  The 
coadministration of ‘inducers’ would potentially lower plasma   (Study Agent) concentrations.

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Comprehensive List of Drugs That May Have Potential Interactions
CYP3A4
SUBSTRATES
Albuterol
Alfentanil
Alprazolam
Amlodipine
Amprenavir
Aprepitant
Aripiprazole
Atazanavir
Atorvastatin
Benzphetamine
Bisoprolol
Bortezomib
Bosentan
Bromazepam
Bromocriptine
Buprenorphine
Buspirone
Busulfan
Carbamazapine
Cerivastatin
Chlordiazepoxide
Chloroquine
Chlorpheniramine
Cisapride
Citalopram
Clarithromycin
Clobazam
Clonazepam
Clorazepate
Cocaine
Colchicine
Cyclophosphamide
Cyclosporine
Dantrolene
Dapsone
Delavirdine
Diazepam
Digitoxin
Dihydroergotamine
Diltiazem
Disopyramide
Docetaxel
Doxepin
Doxorubicin
Doxycycline
Efavirenz
Eletriptan
Enalapril
Eplerenone
Ergoloid mesylates
Ergonovine
Ergotamine
Erythromycin
Escitalopram
Esomeprazol
Estradiol
Estrogens, conj., synthetic
Estrogens, conj., equine
Estrogens, conj., esterified
Estrone
Estropipate
Ethinyl estradiol
Ethosuximide
Etoposide
Felbamate
Felodipine
Fentanyl
Flurazepam
Flutamide
Fosamprenavir
Fulvestrant
Gefitinib
Halofantrine
Haloperidol
Ifosfamide
Imatinib
Indinavir
Irinotecan
Isosorbide dinitrate
Isosorbide mononitrate
Isradipine
Itraconazole
Ketamine
Ketoconazole
Lansoprazole
Letrozole
Levomethadyl acetate
hydrochloride
Levonorgestrel
Lidocaine
Losartan
Lovastatin
Medroxyprogesterone 
Mefloquine
Mestranol
Methadone
Methylergonovine
Methysergide
Miconazole
Midazolam
Miglustat
Mirtazapine
Modafinil
Montelukast
Moricizine
Nateglinide
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Nitrendipine
Norethindrone
Norgestrel
Ondansetron
Paclitaxel
Pergolide
Phencyclidine
Pimozide
Pioglitazone
Primaquine
Progesterone
Quetiapine
Quinidine
Rabeprazole
Repaglinide
Rifabutin
Rifampin
Ritonavir
Saquinavir
Sertraline
Sibutramine
Sildenafil
Simvastatin
Sirolimus
Sufentanil
Tacrolimus
Tamoxifen
Tamsulosin
Telithromycin
Teniposide
Terbinafine
Tetracycline
Theophylline
Tiagabine
Ticlopidine
Tolterodine
Toremifene
Trazodone
Triazolam
Trimethoprim
Trimipramine
Troleandomycin
Vardenafil
Venlafaxine
Verapamil
Vinblastine
Vincristine
Vinorelbine
Zolpidem
Zonisamide
Zopiclone

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CYP3A4
INHIBITORS
Acetominophen
Acetazolamide
Amioderone
Amlodipine
Amprenavir
Anastrozole
Aprepitant
Atazanavir
Atorvastatin
Azelastine
Azithromycin
Betamethasone
Bortezomib
Bromocriptine
Caffiene
Cerivastatin
Chloramphenicol
Chlorzoxazone
Cimetadine
Ciprofloxacin
Cisapride
Clarithromycin
Clemastine
Clofazimine
Clotrimazole
Clozapine
Cocaine
Cyclophosphamide
Cyclosporine
Danazol
Delavirdine
Desipramine
Dexmedetomidine
Diazepam
Diclofenac
Dihydroergotamine
Diltiazem
Disulfiram
Docetaxel
Doxorubicin
Doxycycline
Drospirenone
Efavirenz
Enoxacin
Entacapone
Ergotamine
Erythromycin
Ethinyl estradiol
Etoposide
Felodipine
Fentanyl
Fluconazole
Fluoxetine
Fluvastatin
Fluvoxamine
Fosamprenavir
Glyburide
Grapefruit juice
Haloperidol
Hydralazine
Ifosfamide
Imatinib
Indinavir
Irbesartan
Isoniazid
Isradapine
Itraconazole
Ketoconazole
Lansoprazole
Lidocaine
Lomustine
Losartan
Lovastatin
Mefloquine
Mestranol
Methadone
Methimazole
Methoxsalen
Methylprednisolone
Metronidazole
Miconazole
Midazolam
Mifepristone
Mirtazapine
Mitoxantrone
Modafinil
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nisoldipine
Nitrendipine
Nizatidine
Norfloxacin
Olanzapine
Omeprazole
Orphenadrine
Oxybutynin
Paroxetine
Pentamidine
Pergolide
Phencyclidine
Pilocarpine
Pimozide
Pravastatin
Prednisolone
Primaquine
Progesterone
Propofol
Propoxyphene
Quinidine
Quinine
Quinupristin
Rabeprazole
Risperidone
Ritonavir
Saquinavir
Selegiline
Sertraline
Sildenafil
Sirolimus
Sulconazole
Tacrolimus
Tamoxifen
Telithromycin
Teniposide
Testosterone
Tetracycline
Ticlopidine
Tranylcypromine
Trazodone
Troleandomycin
Valproic acid
Venlafaxine
Verapimil
Vinblastine
Vincristine
Vinorelbine
Zafirlukast
Ziprasidone
INDUCERS
Aminoglutethimide
Carbamazapine
Fosphenytoin
St. John’s wort
Nevirapine
Oxcarbazepine
Pentobarbital
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin
Rifapentine
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug 
Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.)
(1)  Malhorta et al. (2000). Clin Pharmacol Ther. 69:14-23
(2)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329

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APPENDIX E
Drugs Associated with QTc Prolongation
The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the QTc.  This list 
is frequently updated.  For the most current list of medications, refer to the following website: 
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this time 
lack substantial evidence for causing 
Torsades de Pointes
Drugs that, in some reports, have 
been weakly associated with 
Torsades de Pointes and/or QTc 
prolongation but that are unlikely to 
be a risk for Torsades de Pointes 
when used in usual recommended 
dosages and in subjects without 
other risk factors (e.g., concomitant 
QTc prolonging drugs, bradycardia, 
electrolyte disturbances, congenital 
long QTc syndrome, concomitant 
drugs that inhibit metabolism).
Generic/Brand Name
Generic/Brand Name
Generic/Brand Name
Amiodarone /Cordarone®
Alfuzosin /Uroxatral®
Amitriptyline /Elavil®
Amiodarone /Pacerone®
Amantadine /Symmetrel®
Ciprofloxacin /Cipro®
Arsenic trioxide /Trisenox®
Atazanavir /Reyataz®
Citalopram /Celexa®
Astemizole /Hismanal®
Azithromycin /Zithromax®
Clomipramine /Anafranil®
Bepridil /Vascor®
Chloral hydrate /Noctec®
Desipramine /Pertofrane®
Chloroquine /Aralen®
Clozapine /Clozaril®
Diphenhydramine /Benadryl®
Chlorpromazine /Thorazine®
Dolasetron /Anzemet®
Diphenhydramine /Nytol®
Cisapride /Propulsid®
Dronedarone /Multaq®
Doxepin /Sinequan®
Clarithromycin /Biaxin®
Felbamate /Felbatrol®
Fluconazole /Diflucan®
Disopyramide /Norpace®
Flecainide /Tambocor®
Fluoxetine /Sarafem®
Dofetilide /Tikosyn®
Foscarnet /Foscavir®
Fluoxetine /Prozac®
Domperidone /Motilium®
Fosphenytoin /Cerebyx®
Galantamine /Reminyl®
Droperidol /Inapsine®
Gatifloxacin /Tequin®
Imipramine /Norfranil®
Erythromycin /Erythrocin®
Gemifloxacin /Factive®
Itraconazole /Sporanox®
Erythromycin /E.E.S.®
Granisetron /Kytril®
Ketoconazole /Nizoral®
Halofantrine /Halfan®
Indapamide /Lozol®
Mexiletine /Mexitil®
Haloperidol /Haldol®
Isradipine /Dynacirc®
Nortriptyline /Pamelor®
Ibutilide /Corvert®
Lapatinib /Tykerb®
Paroxetine /Paxil®
Levomethadyl /Orlaam®
Lapatinib /Tyverb®
Protriptyline /Vivactil®
Mesoridazine /Serentil®
Levofloxacin /Levaquin®
Sertraline /Zoloft®

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Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this time 
lack substantial evidence for causing 
Torsades de Pointes
Drugs that, in some reports, have
been weakly associated with 
Torsades de Pointes and/or QTc 
prolongation but that are unlikely to 
be a risk for Torsades de Pointes 
when used in usual recommended 
dosages and in subjects without 
other risk factors (e.g., concomitant 
QTc prolonging drugs, bradycardia, 
electrolyte disturbances, congenital 
long QTc syndrome, concomitant 
drugs that inhibit metabolism).
Generic/Brand Name
Generic/Brand Name
Generic/Brand Name
Methadone /Dolophine®
Lithium /Lithobid®
Solifenacin /VESIcare®
Methadone /Methadose®
Lithium /Eskalith®
Trimethoprim-Sulfa /Sulfa®
Pentamidine /Pentam®
Moexipril/HCTZ /Uniretic®
Trimethoprim-Sulfa /Bactrim®
Pentamidine /NebuPent®
Moxifloxacin /Avelox®
Trimipramine /Surmontil®
Pimozide /Orap®
Nicardipine /Cardene®
Probucol /Lorelco®
Nilotinib /Tasigna®
Procainamide /Pronestyl®
Octreotide /Sandostatin®
Procainamide /Procan®
Ofloxacin /Floxin®
Quinidine /Cardioquin®
Ondansetron /Zofran®
Quinidine /Quinaglute®
Oxytocin /Pitocin®
Sotalol /Betapace®
Paliperidone /Invega®
Sparfloxacin /Zagam®
Perflutren lipid microspheres /Definity®
Terfenadine /Seldane®
Quetiapine /Seroquel®
Thioridazine /Mellaril®
Ranolazine /Ranexa®
Risperidone /Risperdal®
Roxithromycin* /Rulide®
Sertindole /Serlect®
Sertindole /Serdolect®
Sunitinib /Sutent®
Tacrolimus /Prograf®
Tamoxifen /Nolvadex®
Telithromycin /Ketek®
Tizanidine /Zanaflex®
Vardenafil /Levitra®
Venlafaxine /Effexor®
Voriconazole /VFend®
Ziprasidone /Geodon®

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APPENDIX F
Blood Pressure – Recommendations
for Data Collection/Recording and Event Management
Collection/Recording of Blood Pressure Information
1.0
General Guidelines
1.1          Frequency of monitoring. Blood pressure (BP) should be monitored at least every 2 weeks for the duration of 
treatment.  More frequent monitoring should be considered on a study by study basis, particularly during the 
first two cycles of pazopanib therapy.
1.2          Data recording. All required data should be recorded in the appropriate CRF or on the subject’s blood pressure 
monitoring diary, as appropriate.  The following data are required at baseline and at each subsequent 
assessment:
x
Assessment date and time
x
Pulse
x
Systolic and diastolic BP (2 readings/assessment taken 5 minutes apart while subject sitting)
1.3          Risk factors for hypertension (assess and record data in baseline history/physical CRF)
x
Diabetes (type 1 or type 2)
x
Renal disease (specify on CRF)
x
Endocrine condition associated with HTN (specify on CRF)
x
Use of steroids or NSAIDs (specify all concomitant meds)
x
Underlying cardiovascular condition – specify (i.e., ischemic heart disease)
2.0         Baseline data collection (at study entry)
2.1
All subjects
x
Current BP
x
Proteinuria, if present
2.2
Subjects with preexisting hypertension (i.e., those for whom “hypertension” is entered as a concomitant 
condition at study entry, or those who are currently receiving therapy with antihypertensive medication) – also 
record:
x
Date of HTN diagnosis (original)
x
Type HTN (essential or secondary)
x
CTCAE grade of HTN (at time of study entry)
x
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following:

Antihypertensive agents taken at study entry

Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy)
3.0         Follow up BP data collection (during study)
3.1
All subjects (at each clinic visit)
x
Current BP
x
Proteinuria, if present
3.2
Subjects with treatment-emergent hypertension [defined as BP increase of >20 mmHg (diastolic) OR BP 
>150/100 (if previously within normal limits)] – record at time of hypertension diagnosis and at all subsequent 
clinic visits:
x
BP changes from baseline (or from previous assessment) (specify CTCAE grade changes)
x
Hypertension-related symptoms as reported by subject (e.g., headache)
x
Other relevant changes associated with development of hypertension (e.g., ECG abnormalities)
x
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently prescribed 
antihypertensive agents

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3.3
Subjects with preexisting hypertension at study entry – record at each clinic visit
x
BP changes from previous clinic visit (specify CTCAE grade changes)
x
Hypertension-related symptoms reported by subject (e.g., headache)
x
Other relevant changes associated with development of hypertension (e.g., ECG abnormalities)
x
Changes in antihypertensive medications since last assessment (e.g., dose change, add/discontinue 
drug)
Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, diuretics, 
and angiotension II receptor antagonists.