Phase II Study Evaluating the Role of Pazopanib in Angiosarcoma
Phase: PHASE2
Conditions: Adult Angiosarcoma, Recurrent Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma
Sponsor: Fox Chase Cancer Center

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Phase II Study Evaluating the Role of Pazopanib in Angiosarcoma
Funding:
NCCN (from a research grant provided by Novartis)
Coordinating Center:
Fox Chase Cancer Center
Office of Extramural Research
Principal Investigator:
Margaret von Mehren, MD
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA-19111 
Phone: 215-728-2460
Fax: 215-728-3639
Email: Margaret.vonMehren@fccc.edu
Co-Investigators:
Andrew Kraft, MD
Medical University of South Carolina 
86 Jonathan Lucas Street,
Charleston, SC-29425 
Phone: 843-792-8284
Fax: 843-792-9456
Email: kraft@musc.edu
J. Q. Michael Yu, MD, FRCPC 
Fox Chase Cancer Center 
Phone: 215-728-3865
Email: Michael.Yu@fccc.edu
Eric D. Tetzlaff, PA-C 
Fox Chase Cancer Center
Email: Eric.Tetzlaff@fccc.edu
Vinod Ravi, MD 
Assistant Professor
Sarcoma Medical Oncology
UT MD Anderson Cancer Center 
1515 Holcombe blvd., Unit 450
Houston, TX 77030 
vravi@mdanderson.org 
Phone  : 713-792-3626
Fax
: 713-794-1934

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Mark Agulnik, MD 
Northwestern University 
676 N St. Clair
Suite 850
Chicago IL 60611
Phone: 312.695. 1222
Fax:: 312.695.6189
Scott Schuetze, MD 
University of Michigan
North Campus Research Complex
2800 Plymouth Road, Building 300 Main 
Ann Arbor, MI 48109-2800 
Phone:734.615.0654
Fax: 734.647.2066
Statistician:
Samuel Litwin, PhD 
333 Cottman Avenue 
Philadelphia, PA-19111
Email: Samuel.Litwin@fccc.edu
Quality Assurance Specialist/
Study Monitor:
Beth Adaire-Halenda, CCRP
Clinical Trial Operations 
Fox Chase Cancer Center 
333 Cottman Avenue
Philadelphia PA 19111
Phone: 215-214-3704
Fax: 215-214-1511
Email: beth.adaire@fccc.edu
IND Number:
112423
Version
Date:  18 May 2011
Amendment 1       Date:  22 June 2011
Amendment 2       Date:  28 July 2011
Amendment 3       Date:  04 Oct  2011
Amendment 4       Date:  14 Mar 2012
Amendment 5       Date:  21 Nov 2012
Amendment 6       Date: 09 May 2013
                                                                   Amendment 7        Date: 12 Dec 2018 

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Schema
Angiosarcoma patients:
•
Recurrent or metastatic and failed at least 1 prior therapy
•
Pass screen for eligibility and baseline testing 
N=30
Treatment (21 days per cycle +/-5 calendar days): 
Pazopanib 800 mg po once daily
Disease Assessment:
Evaluation after every 2 cycles (CT or MRI)
Continue treatment until:
•
Disease progression
•
Unacceptable toxicity
•
Patient preference
Follow up:
Follow every 3 months for study related
toxicities and survival
Primary objective: dual end 
points: RR and  PFS at 3 months
Secondary Objective: endpoints: 
Median OS and toxicity

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Table of Contents
Schema
iii
Table of Contents
iv
1.0 Introduction/Background
6
1.1 Angiosarcoma
6
1.2 Pazopanib
6
1.3 Study Rationale
19
1.4 Correlative Testing
19
2.0 Objectives
20
2.1 Primary Objective
20
2.2 Secondary Objective
20
3.0 Study Plan
20
3.1 Description of study, duration of study therapy
20
4.0 Selection of Patients
20
4.1 Inclusion criteria
21
4.2 Exclusion criteria
23
4.3 Women and Minorities
26
4.4 Patient Registration
26
5.0 Treatment Plan
27
5.1 Treatment Administration
27
5.2 Dosing Rationale
27
5.3 Concomitant Medication, Supportive care, and excluded therapies and 
restrictions
29
5.4 Duration of therapy
32
5.5 Duration of follow up
32
5.6 Criteria for study discontinuation
33
6.0 Dose modifications
33
6.1 General principles
33
6.2 Dose Interruptions/Modifications for Specific, Non-liver Related 
Toxicities
33
6.3 Dose Interruptions/Modifications for Hepatotoxicity
36
7.0 Study Agent Information
38
7.1 Pazopanib Formulation, product identification, package and labeling
38
7.2 Destruction of drug
39
7.3 Records to be kept at site, dispensing and accountability
39
7.4 Treatment of Investigational Product Overdose
40
8.0 Correlative/Special Studies
40

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8.1 Hypothesis
40
8.2 Preliminary Data
40
8.3 Study Design
41
9.0 Study Assessments and Procedures
44
9.1 Screening and Baseline Assessments
44
9.2 Study Calendar
48
10.0 Adverse Event
49
10.1 Definitions
49
10.2 Recording Responsibilities
50
10.3 Reporting Responsibilities
50
10.4 Pregnancy
53
11.0 Measurement of Effect
53
11.1 Definitions
54
11.2 Disease Parameters
54
11.3 Methods for Evaluation of Measurable Disease
55
11.4 Response Criteria
56
12.0 Statistical Consideration
59
12.1 Study Design/Endpoints
59
12.2 Sample Size and Accrual Rate
59
12.3 Analysis of Secondary endpoints
60
12.4 Reporting and Exclusions
60
13.0 Data and Safety Monitoring Plan
60
13.1 Monitoring plan
60
13.2 Extramural Data Safety Monitoring Committee (EDMSC)
61
14.0 Administrative
61
14.1 Data Reporting
61
14.2 Retention of Records
61
14.3 Study Agents
61
15.0 References
62
Appendices
Appendix A: Performance Status Criteria
Appendix B: Determination of Creatinine Clearance (ClCR) 
Appendix C: Urine Protein to Creatinine Ratio (UPC)
Appendix D: New York Heart Association (NYHA) Classification of Congestive Heart Failure 
Appendix E: Bazett’s formula
Appendix F: Supportive Care Guidelines for Diarrhea, Nausea, and Vomiting 
Appendix G: Pazopanib Pill Diary

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1.1 Introduction
1.2
Angiosarcoma
Soft tissue sarcomas account for ~1% of adult malignancies. Angiosarcomas 
account for a small proportion of this 1% and arise from endothelial cells [1]. 
Angiosarcomas are most commonly seen on the face and scalp of elderly males. 
They have also been described in the setting of chronic lymphedema and post- 
radiation.[2], [3]. Data from the US Surveillance, Epidemiology and End Results 
registries from 1973-1997 reported 263 subsequent cases of sarcoma in 274,572 
patients with breast cancer [4]. The cumulative incidence at 15 years post breast 
cancer diagnosis was 3.2 per 1,000 for those who received radiation therapy and
2.3 per 1,000 for those who did not receive radiation therapy (p=0.001). Overall 
5-year survival was poor at 27-35%, however there was no difference in survival 
between those who did and did not receive radiation.
Therapy is primarily surgical, however these tumors have a propensity for 
recurrence and metastasis requiring eventual systemic therapy. Few systemic 
therapy options exist and response rates to existing agents are poor. Additionally, 
given the rarity of angiosarcomas, studies in sarcomas have included only very 
small numbers of patients with the angiosarcoma subtype. Most studies have 
evaluated doxorubicin based regimens with response rates ranging from 17% to 
34%.[5-8]. The collective experience of physicians at Memorial Sloan Kettering 
Cancer Center reported a response in 8 out of 9 patients treated with paclitaxel 
either weekly or every three weeks for angiosarcomas of the scalp and face [9]. 
Given the frequent incorporation of radiation in the adjuvant treatment of breast 
cancer, the increasing incidence of breast cancer, we may see more of these 
tumors arising from blood vessels in the future. It is therefore prudent to evaluate 
newer possible therapies. Evaluation of paclitaxel in patients with metastatic 
angiosarcoma lead to a 74 and 45% PFS at 2 and 4 months respectively [10].
Preclinical studies in angiosarcoma tumor models have shown antitumor effects 
of antiangiogenic agents. Primate vascular endothelial growth factor 121 
(VEGF121) was expressed in an endothelial cell line. Expression of VEGF121 
resulted in slow growing endothelial tumor with histology similar to that seen in 
angiosarcoma. The endothelial cells were then treated with VEGFR-2 tyrosine 
kinase inhibitor SU-1498, which resulted in reduced expression of transcription 
factor ets-1, which is stimulated by VEGF [11]. Clinical studies evaluating agents 
with anti-angiogenic properties, such as sorafenib and bevacizumab have shown 
encouraging single agent activity in this disease [12], [13].
1.2
Study Drug - Pazopanib
Numerous growth factors and cytokines are involved in the angiogenic process, 
i.e., the process of new blood vessel formation, important in the development and 
progression of malignancy. Among these factors, VEGF has a predominant role

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as a central mediator of tumor-related angiogenesis, and its expression has been 
shown to be an adverse prognostic factor for a number of solid tumors [14-16].
Pazopanib, being developed by GlaxoSmithKline (GSK) for the treatment of a 
variety of cancers, is a multi-target, small molecule inhibitor.  It is an orally- 
bioavailable, ATP-competitive tyrosine kinase inhibitor of VEGF receptor 
(VEGFR) (-1, -2, and -3), platelet-derived growth factor receptor PDGFR (-α and
-β), and c-Kit [17].
Clinical data from more than 20 clinical Phase I, II, and III studies are presented 
in the current version of the Investigator’s Brochure (IB) (RR2002/00017/10). As 
of 09 September 2010, over 5000 subjects have been enrolled in pazopanib 
oncology clinical studies conducted by GSK or National Cancer Institute (NCI). 
Clinical data indicate that (a) pazopanib is absorbed after oral administration, (b) 
the 800 mg daily dosing regimen is an active monotherapy dose for subjects with 
cancer, providing optimal biologic and clinical effects associated with VEGFR 
inhibition, (c) pazopanib is generally well-tolerated at the 800 mg daily dosing 
regimen, and (d) pazopanib has encouraging efficacy in specific tumor settings 
such as Renal Cell Carcinoma (RCC), sarcoma, Non-Small Cell Lung Cancer 
(NSCLC), cervical and ovarian cancer.
The most common adverse events (AEs) reported for pazopanib monotherapy to 
date are diarrhea, fatigue, nausea, hypertension, hair color changes (hair 
depigmentation), anorexia, vomiting, dysgeusia, headache, abdominal pain, rash, 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increases, 
constipation, cough, and arthralgia. Most of these events were Grade 1 or 2 using 
the National Cancer Institute-Common Toxicity Criteria of Adverse Events, 
Version 3.0 (NCI-CTCAE v3.0). The most frequent Grade 3 or 4 events were 
hypertension, fatigue, diarrhea, and AST and ALT increases. Less common AEs 
of note include hand-foot syndrome, mucositis/stomatitis, proteinuria, venous 
thrombotic events, and bleeding. Intestinal perforations and arterial thromboses 
were uncommon.
A review of serious adverse events (SAEs) across oncology studies revealed that 
the most frequently reported SAEs (≥ 50 events), regardless of causality and 
treatment regimen, as of 09 September 2010 in decreasing order of frequency 
were ALT increased, vomiting, dyspnea, abdominal pain, diarrhea, dehydration, 
pyrexia, fatigue, pneumonia, anemia, AST increased, nausea, pleural effusion, 
hypertension, and pulmonary embolism. A number of these events are known 
class effects of VEGF inhibitors.
1.2.1
Safety in clinical studies with monotherapy pazopanib
1.2.1.1 Subjects with RCC
Completed Study VEG105192: A Randomized, Double-blind, 
Placebo-controlled, Multi-center Phase III Study to Evaluate the 
Efficacy and Safety of Pazopanib (GW786034) Compared to

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Placebo in Patients with Locally Advanced and/or Metastatic 
Renal Cell Carcinoma
A total of 435 subjects were enrolled in completed Study 
VEG105192 between 18 April 2006 and 24 April 2007. Two 
hundred and ninety subjects were randomized to the pazopanib 
arm and 145 subjects were randomized to the placebo arm [18].
As of the cut-off date of 23 May 2008, the median exposure time 
in the pazopanib arm was 7.4 months, almost twice the 3.8 months 
exposure in the placebo arm.  The overall incidence of AEs 
reported during the study was higher in the pazopanib arm (92%) 
as compared with placebo (74%) (Table 1.1)
Most AEs were of Grade 1 or 2 intensity.  More Grade 3 AEs were 
reported for the pazopanib arm (33%) compared with the placebo 
arm (14%).  Grade 4 AEs were reported in 7% of subjects in the 
pazopanib arm and 6% in the placebo arm. The most frequent 
Grade 3 AEs in the pazopanib arm were ALT increased, AST 
increased, hypertension, and diarrhea. The rates for Grade 4 and 
Grade 5 events were similar between the pazopanib and placebo 
arms: Grade 4 AEs in 7% versus 6% and Grade 5 in 4% versus 3% 
respectively.

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Table 1.1
Adverse Events Reported for at Least 10% of Subjects (Safety 
Population) in Study VEG105192
Number (% of subjects)
Preferred Term
Placebo (n=145)
Pazopanib (n=290)
Any
Grade
Grade 3
Grade 4
Any
Grade
Grade 3
Grade 4
Any AEa
107 (74)
21 (14)
8 (6)
268 (92)
96 (33)
20 (7)
Diarrhea
13 (9)
1 (<1)
0
150 (52)
9 (3)
2 (<1)
Hypertension
15 (10)
1 (<1)
0
115 (40)
13 (4)
0
Hair color
changes
4 (3)
0
0
109 (38)
1 (<1)
0
Nausea
13 (9)
0
0
74 (26)
2 (<1)
0
Anorexia
14 (10)
1 (<1)
0
65 (22)
6 (2)
0
Vomiting
11 (8)
3 (2)
0
61 (21)
6 (2)
1 (<1)
Fatigue
11 (8)
2 (1)
2 (1)
55 (19)
7 (2)
0
ALT increased
5 (3)
1 (<1)
0
53 (18)
18 (6)
3 (1)
AST increase
5 (3)
0
0
43 (15)
13 (4)
1 (<1)
Asthenia
12 (8)b
0
0
41 (14)
8 (3)
0
Abdominal pain
2 (1)
0
0
32 (11)
6 (2)
0
Headache
7 (5)
0
0
30 (10)
0
0
AEs are ranked by incidence in the pazopanib arm.  Any AE, any grade includes Grade 5
(fatal) events (12 [4%] subjects in the pazopanib arm and 4 [3%] subjects in the placebo 
arm).
One placebo subject had Grade 5 asthenia.
AEs leading to permanent discontinuation of investigational 
product (IP) were reported for 44 (15%) subjects in the pazopanib 
arm and 8 (6%) subjects in the placebo arm, respectively.  In the 
pazopanib arm, AEs associated with liver function/enzyme 
abnormalities (including increased ALT, AST, hepatotoxicity, 
increased hepatic enzyme, and hyperbilirubinemia) led to 
discontinuation of IP for 11 (3.8%) subjects while diarrhea led to 
discontinuation of IP for 6 (2%) subjects.  For 3 of the 44 subjects 
in the pazopanib arm with AEs leading to discontinuation of IP, the 
investigator indicated that the reason for discontinuation was 
“other” since the investigator considered that disease progression 
also contributed to discontinuation of IP.
1.2.1.1.2 Laboratory abnormalities
The incidences of leukopenia, neutropenia, and 
thrombocytopenia with any grade increase relative to 
baseline were 37%, 34%, and 32%, respectively in the 
pazopanib arm, which were higher than those in the 
placebo arm (6%, 6% and 5%, respectively) (Table 1.2).

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The incidences of grade increases in other hematologic 
parameters (i.e., lymphocytopenia, anemia, increased PTT, 
INR) were similar in the pazopanib and placebo arms.
Post-baseline increases to Grade 3 or Grade 4 in any 
hematologic parameter were uncommon in both treatment 
arms, occurring between <1% to 4%.
Table 1.2
Summary of Worst-case Hematologic Toxicity Grade Shift from 
Baseline (Safety Population) in Study VEG105192
Hematologic
Number (%) of subjects
Toxicity
Placebo 
(n=145)
Pazopanib 
(n=290)
N
Any 
gradea
Grade 
3
Grade 
4
N
Any 
gradea
Grade 3
Grade 
4
Leukopenia
144
9 (6)
0
0
280
103 (37)
0
0
Neutropenia
144
9 (6)
0
0
280
94 (34)
3 (1)
1 (<1)
Thrombocytopenia 144
7 (5)
0
1 (<1)
280
89 (32)
2 (<1)
1 (<1)
Lymphocytopenia
144
34 (24)
2 (1)
0
280
86 (31)
11 (4)
1 (<1)
Increased PTT
140
34 (24)
1 (<1)
0
271
72 (27)
4 (1)
0
Anemia
144
44 (31)
2 (1)
1 (<1)
280
62 (22)
5 (2)
2 (<1)
INR
128
25 (20)
2 (2)
0
246
42 (17)
4 (2)
0
PTT= Partial thromboplastin time; INR= International Normalized ratio.
a. Any grade increase from baseline. Subjects with missing baseline grade were assumed to have baseline 
grade of 0.
The most common increases relative to baseline in any 
toxicity grade for clinical chemistry parameters in the 
pazopanib arm were elevations in ALT, AST, and total 
bilirubin, which occurred in 53%, 53% and 36% subjects, 
respectively, compared with lower incidences in the 
placebo arm (22%, 19%, and 10% respectively) (Table 
1.3).  Other clinical chemistry parameters with a higher 
incidence in any grade increase in the pazopanib arm 
compared with the placebo arm included 
hypophosphatemia (34% versus 11%), hypoglycemia (17%
versus 3%), hypokalemia (9% versus 2%), and
hypomagnesemia (26% versus 14%). Although 17% of 
subjects in the pazopanib arm had any grade increase in 
hypoglycemia, only 1 subject had an increase above Grade 
2.
ALT and AST elevation and hypophosphatemia were the 
most common clinical chemistry parameters with increases 
to Grade 3 (10%, 7% and 4%, respectively) in the 
pazopanib arm compared with lower rates in the placebo 
arm (1%, <1% and 0%, respectively). A toxicity grade
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increase of clinical chemistry parameters to Grade 4 was 
uncommon (2% or less for any individual laboratory test) 
for both pazopanib and placebo arms.
Table 1.3
Summary of Worst-Case Toxicity Grade Shift from Baseline for 
Clinical Chemistry Parameters (Safety Population) in Study 
VEG105192
Clinical
Chemistry
Placebo
Number (%) of subjects
Pazopanib
Parameter
(n=145)
(n=290)
N
Any 
gradea
Grade 
3
Grade 
4
N
Any 
gradea
Grade 
3
Grade 
4
ALT increase
144
32 (22)
2 (1)
0
289
152 (53)
30 (10)
5 (2)
AST increase
144
27 (19)
1 (<1)
0
288
152 (53)
21 (7)
2 (<1)
Hyperglycemia
144
47 (33)
2 (1)
0
280
115 (41)
2 (<1)
0
Total Bilirubin
increase
144
15 (10)
2 (1)
1 (<1)
280
102 (36)
7 (3)
2 (<1)
Hyponatremia
144
35 (24)
6 (4)
0
280
86 (31)
11 (4)
4 (1)
Hypophosphatemia
141
16 (11)
0
0
276
95 (34)
11 (4)
0
Hypocalcemia
137
35 (26)
2 (1)
1 (<1)
272
91 (33)
4 (1)
4 (1)
Hyperkalemia
144
33 (23)
7 (5)
0
280
76 (27)
12 (4)
1 (<1)
Alkaline
phosphatase
144
50 (35)
3 (2)
0
280
75 (27)
4 (1)
1 (<1)
Creatinine
increase
144
36 (25)
1 (<1)
0
280
73 (26)
0
2 (<1)
Hypomagnesemia
141
20 (14)
0
0
276
72 (26)
2 (<1)
4 (1)
Hypoglycemia
144
4 (3)
0
0
280
47 (17)
0
1 (<1)
Hypermagnesemia
141
13 (9)
3 (2)
0
276
31 (11)
9 (3)
0
Hypernatremia
144
11 (8)
0
0
280
30 (11)
2 (<1)
0
Hypercalcemia
137
25 (18)
2 (1)
0
272
29 (11)
0
4 (1)
Hypokalemia
144
3 (2)
0
0
280
24 (9)
3 (1)
2 (<1)
a: Any grade increase from baseline.
There was an apparent increase from baseline in the urine 
protein level (based on dipstick testing) in the pazopanib 
arm compared with the placebo arm.
1.2.1.1.3 Overall safety summary -Integrated data from 
Studies VEG105192, VEG102616, and VEG107769
The safety profile of pazopanib used in the treatment of 
RCC has been further defined in an integrated analysis of 
data from 593 subjects who received pazopanib across 3 
RCC studies as of 09 January 2009.  The database 
supporting the safety profile of pazopanib in subjects with 
RCC includes the completed placebo-controlled Phase III 
study VEG105192, with 290 subjects treated with 
pazopanib, a completed supportive Phase II study
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(VEG102616) in which 225 subjects were treated with 
pazopanib, and the ongoing open-label extension study 
VEG107769 (n=78).
For the RCC studies described, the AE profile and 
hematology and laboratory chemistry abnormalities were 
similar to those seen for VEG105192 alone.  As of
09 January 2009, the most common AEs reported in 
subjects receiving pazopanib included diarrhea (55%), 
hypertension (41%), hair color changes (40%), nausea 
(32%), fatigue (29%), anorexia (24%), vomiting (21%), 
and ALT increased (17%). Most of these events were 
Grade 1 or 2 using the NCI CTCAE Version 3.0. 
Commonly reported AEs with the most frequent Grade 3 
classification were hypertension (6%), ALT increased 
(5%), and AST increased (4%).  Grade 4 and Grade 5 
events were infrequently reported (9% and 4%, 
respectively).
The most common chemistry abnormalities included ALT, 
AST, and bilirubin elevations, hyperglycemia and 
hypophosphatemia.  Hyperglycemia was not significantly 
different in the pazopanib (41%) versus placebo (33%) arm 
of VEG105192 study, as of 23 May 2008, suggesting that 
hyperglycemia was unlikely to be drug induced.  Most of 
these chemistry abnormalities were Grade 1/2. The most 
common Grade 3/4 laboratory abnormalities were ALT and 
AST elevations.  Although leukopenia, neutropenia, and 
thrombocytopenia were not uncommon, Grade 3/4 
cytopenias were generally uncommon as demonstrated in 
VEG105192 as of 23 May 2008.
The only significant urinalysis abnormality reported across 
the 3 RCC studies as of 23 May 2008 was proteinuria: 44 
subjects (8%) reported an AE of proteinuria.  Of those 
cases, most were Grades 1 or 2, but 5 subjects (<1%) had 
Grade 3 proteinuria and 1 subject had Grade 4 proteinuria.
Rare but severe AEs previously described for VEGFR 
inhibitors, such as cardiac/cerebral ischemia, hemorrhage, 
and bowel perforation, were observed with pazopanib 
treatment.
Across RCC studies as of 09 January 2009, 92 (16%) 
pazopanib-treated subjects experienced AEs leading to 
discontinuation or withdrawal from study.  The most 
common AE leading to discontinuation from IP was an
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increase in ALT (11 subjects, 2%). The next most common 
AEs leading to discontinuation were diarrhea, AST 
increased, and proteinuria (all 1% incidence).
In summary, pazopanib treatment in subjects with RCC 
was generally well tolerated with an AE profile similar to 
other VEGFR inhibitors. Most AEs were mild to moderate 
in severity and were reversible upon interruption or 
discontinuation of pazopanib.
1.2.1.1.4 Hepatotoxicity
Liver enzyme abnormalities were noted early in pazopanib 
clinical development and have been extensively evaluated. 
Close monitoring of liver markers (ALT, AST, bilirubin, 
and alkaline phosphatase) with strict stopping criteria was 
implemented in pazopanib protocols.  While approximately 
half of all subjects who receive pazopanib experience some 
elevations in transaminases, few subjects (4%) had 
increases to ≥ 10xULN as of 09 January 2009.  In addition, 
1% subjects had concurrent ALT and bilirubin elevations, 
without significant alkaline phosphatase elevations, that 
might be predictive of possible development of hepatic 
functional impairment.  Elevations in transaminases 
typically occurred in the first 18 weeks of treatment. 
Hepatobiliary adverse events that were not laboratory 
abnormalities were less common and liver failure and fatal 
hepatic events were rare.  Three fatal hepatic events 
occurred:  one in a subject for which an independent 
pathology review demonstrated massive hepatic 
replacement by tumor, a second in a subject with rapid 
disease progression in the liver (adjudicated as unrelated to 
study drug by an independent hepatologist), and a third in a 
subject with underlying cirrhosis who developed a fatal 
esophageal hemorrhage (independent hepatologist could 
not rule out contribution of study drug in the setting of 
underlying cirrhosis).
Across the RCC database (N=593), 107 (18%) subjects had 
an elevation in ALT ≥ 3xULN as of 09 January 2009. ALT 
is a more specific indicator of hepatocellular injury than 
AST and was therefore used as a single criterion for 
evaluating outcomes.  Liver enzyme elevations were 
reversible upon cessation of the drug and in some cases 
while continuing on pazopanib.  In an analysis performed 
across the RCC database, 96/106 (91%) subjects had full 
recovery.  Recovery was defined as any ALT < 2.5xULN

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after the first elevation including post-therapy tests.  Seven 
of the remaining 10 subjects had limited or no follow-up to 
determine recovery and 3 died of cancer progression with 
no follow-up ALT data.  It was noted early in development 
that some of the subjects with elevated hepatic enzymes 
remained on study drug despite these elevations and had 
normalization of their transaminases while remaining on 
pazopanib (“adaptation”). Most subjects with transaminase 
elevations in whom dosing was interrupted could be 
successfully re-challenged.
For purposes of this analysis, adaptation was defined as an 
ALT ≥ 3xULN while exposed to study drug followed by a 
return to grade 0 or baseline grade without any interruption 
of study drug. Subjects were considered to have been re- 
challenged if they developed ALT ≥ 3xULN during 
exposure to study drug which recovered to Grade 1 or 
below following interruption and subsequently received 
study drug at either the same or reduced dose. These 
subjects were evaluated for recurrence of ALT 
abnormalities following the re-challenge.
Adaptation:
•
32 subjects remained on study drug despite elevations 
of ALT ≥ 3xULN and experienced adaptation;
•
29 (91%) without dose reduction
•
3 (9%) after a dose reduction
•
Median time to adaptation was 57 days (range 19-188 
days)
Re-challenge:
•
31 subjects who had a dose interruption following an 
ALT elevation to ≥ 3xULN were re-challenged; 4 
(13%) at the same dose and 27 (87%) at a lower dose. 
The dose was reduced from 800 mg to 400 mg in 24 
subjects and from 400 mg to 200 mg in 3 subjects.
•
Median duration of interruption prior to re-challenge 
was 19 days (range 5-139 days).
•
The median duration of re-treatment among all re- 
challenge subjects was 194 days (range 2-681 days). 
The maximum ALT before re-challenge and the latest 
ALT prior to interruption did not appear to correlate 
with the likelihood of recurrent elevations.

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•
20 (65%) subjects did not experience an ALT ≥ 3x 
ULN following a resumption of study drug;
•
10 (32%) subjects had recurrent elevations
•
2/10 (20%) subjects with recurrent elevations were 
continued on study drug and subsequently met the 
criteria for adaptation as defined above.  Thus, these 2 
subjects are counted both as re-challenges and as 
adaptations.
•
6/10 (60%) positive re-challenges recovered;
•
2/10 (20%) had inadequate follow-up to assess 
recovery.
•
1 (3%) subject had no follow-up data on the outcome of 
the re-challenge.
The remaining 45 subjects with increases in ALT ≥ 3xULN 
included 10 subjects with inadequate or absent follow-up 
data to assess recovery as well as those whose 
transaminases did recover either while remaining on 
pazopanib (but who did not meet criteria for adaptation 
and/or re-challenge) or after discontinuation of pazopanib.
1.2.1.1.5 Hypertension
The cumulative incidence of hypertension across the 3 
primary RCC studies was similar to that of the pazopanib- 
treated subjects in the VEG105192 study.  Two hundred 
and seventy-two (47%) out of 586 subjects experienced an 
on-study episode of hypertension (defined as systolic blood 
pressure of ≥ 150 mmHg and/or diastolic blood pressure of
≥ 100 mmHg). These subjects did not have hypertension at 
baseline.  By Week 18, it was noted that 239 of these 272 
subjects had at least 1 episode of hypertension, which was 
87.9% of all occurrences of hypertension.  By Week 24, it 
was noted that 249 of 272 subjects had at least 1 occurrence 
of hypertension, which was 91.5% of all episodes of 
hypertension that occurred on pazopanib during the RCC 
trials.
Only 6% of the RCC pazopanib-treated subjects reported 
Grade 3 hypertension.  Most subjects had a maximum 
grade of 1-2 for these events.  No Grade 4 or 5 
hypertension event was reported in the RCC studies, with 
the exception of the Grade 4 SAE of hypertensive crisis.

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1.2.1.1.6 Cardiac and vascular events
Cardiac and vascular events were categorized as follows: 
non-vascular cardiac events included arrhythmias and 
cardiac dysfunction while vascular events included arterial 
thrombotic events (myocardial infarction/ischemia, cerebral 
vascular accident and transient ischemic attack [TIA]) and 
venous thrombotic events (deep vein thrombosis, 
pulmonary embolus).
In VEG105192, the overall incidence rate of cardiac and 
vascular events was higher in the pazopanib arm compared 
with placebo (10% versus 6%).  A comprehensive analysis 
of exposure-adjusted incidence rates of cardiac and 
vascular events (a rate of ‘10 per 100 patient-years’ 
indicates that in a cohort of 100 patients each treated for 1 
year, 10 patients would be expected to experience the event 
of interest) demonstrates a similar incidence across placebo 
and pazopanib in VEG105192 and in the integrated RCC.
While the exposure-adjusted incidence rates for all cardiac 
and vascular events were similar between the 2 arms (11.99 
[CI 7.55, 16.43] per 100 patient-years in the pazopanib arm 
compared with 10.22 [CI, 3.14, 17.30] in the placebo arm), 
the exposure-adjusted incidence rate for Grade 5 events 
was higher on placebo (1.28 versus 2.55 per 100 patient- 
years).  Analysis of exposure adjusted incidence rates of 
arrhythmia, cardiac dysfunction (cardiomyopathy), and 
venous thrombotic events demonstrate were similar 
between the placebo and pazopanib arm of study 
VEG105192 and the integrated the RCC population. The 
exposure adjusted incidence rate of arterial thrombotic 
events was higher in the pazopanib arm of VEG105192 
compared with placebo (3.85 [CI 1.33, 6.37] versus 0 [CI 
could not be estimated] per 100 patient years). Subjects 
who experienced these events had underlying risk factors 
for arterial thrombotic events including male gender, age > 
65, hypertension, tobacco use, diabetes and peripheral 
vascular disease (PVD).
Overall for the RCC program, QT prolongation (> 500 
msec) occurred in 10/558 (1.8%) subjects treated with 
pazopanib. Two Torsades de Pointes cases have been 
identified. [Section  5.2.8.3 of the IB [RR2002/00017/10]].

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1.2.1.1.7 Hemorrhagic events
Exposure-adjusted hemorrhagic event rates were higher on 
the pazopanib arm of VEG105192 compared with placebo, 
but similar to those seen in the integrated RCC population. 
The exposure-adjusted incidence rate was 15.95 (CI 10.74, 
20.96) per 100 patient-years in the pazopanib arm 
compared to 8.94 (CI 2.32, 15.56) in the placebo arm. 
Hemoptysis/pulmonary hemorrhages and GI tract 
hemorrhages were the most common SAEs reported. 
Association to known metastases was noted for 4 of the 5 
hemoptysis/pulmonary hemorrhagic SAEs and 3 of the 7 
GI tract hemorrhagic SAEs.  The most common 
hemorrhagic event was epistaxis. Life-threatening and fatal 
hemorrhagic events were uncommon across both the RCC 
and monotherapy populations.
1.2.1.1.8 Thyroid function abnormalities
Increases in thyroid stimulating hormone (TSH) are 
commonly noted in RCC subjects receiving pazopanib 
(29%).  Most of these subjects do not appear to develop 
clinically overt hypothyroidism.  Clinical hypothyroidism 
manifested as elevated T4 was noted in 6% of subjects. 
The hypothyroidism AE incidence rate was also low (4- 
7%) and similar between VEG105192 and across the RCC 
studies for pazopanib-treated subjects.
Hyperthyroidism occurs infrequently (1%) and the 
incidence was not significantly different in subjects 
receiving pazopanib compared to those receiving placebo 
on study VEG105192.
1.2.1.1.9 Bowel Perforations and Enteral Fistulae
In the RCC population, 5 subjects (0.9%) suffered SAEs 
related to GI perforations or fistulae. The 5 events were 
described as follows: ileal perforation (n=1), large intestine 
perforation (n=2), peritonitis secondary to intestinal 
perforation (n=1), and enterocutaneous fistula (n=1).  Two 
of these events, large intestine perforation and peritonitis 
secondary to intestinal perforation were fatal. One event of 
large intestinal perforation was associated with 
diverticulitis.  Three events of perforation were related to 
underlying tumor.

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1.2.1.10 Amylase and Lipase elevations
In VEG102616, amylase and lipase elevations were 
reported in 24% and 29% respectively. Clinical 
manifestation of pancreatitis was reported in < 1% of 
subjects across all pazopanib monotherapy studies 
(N=977).
1.2.1.2 Subjects with soft tissue sarcoma (STS)
1.2.1.2.1 Concluded Study VEG20002: Phase II Study of 
GW786034 in Patients with Relapsed or Refractory Soft 
Tissue Sarcoma (European Organization for Research and 
Treatment of Cancer [EORTC] Study)
As of 09 September 2008, enrollment was completed with 
142 adult subjects enrolled. Safety and efficacy analyses 
were completed by the European Organization for Research 
and Treatment of Cancer (EORTC) and described in a 
synoptic clinical pharmacology study report, with effective 
date of 24 September 2008, and published by Sleijfer et al 
[19].
1.2.1.2.2 Adverse events
All 142 subjects received pazopanib 800 mg once daily. AE 
data were available for all 142 subjects. The most frequent 
clinical adverse events (AEs) (≥ 30%), regardless of 
causality, were fatigue (70%), nausea (46%), diarrhea 
(46%), hypertension (45%), decreased appetite (39%), skin
hypopigmentation (37%), vomiting (36%), weight
decreased (31%), dyspnea (31%), cough (30%), and
constipation (30%).
1.2.1.2.3 Subjects withdrawn due to adverse events 
There were 9 subjects (6.3%) who had the IP withdrawn
due to an AE. Four of the 9 subjects had IP withdrawn for 
elevation in transaminase. Elevation in transaminase was 
the single most common cause of IP discontinuation. Other 
events that lead to discontinuation of IP were disseminated 
intravascular coagulation (DIC), pulmonary embolism, 
hypertension, hemoptysis and severe back pain, and bowel 
perforation with peritonitis.
1.2.2
Pazopanib Efficacy in Sarcoma
Final efficacy data for the phase II study (VEG20002) of GW786034 in 
patients with relapsed or refractory soft tissue sarcoma study were

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published in 2009 [19]. Treatment response data are available for 138 
subjects who received pazopanib 800 mg once daily. Ninety-nine percent 
of subjects had received prior chemotherapy: 35 subjects (25%) had 
received therapy in a (neo)-adjuvant setting, 83 (59%) had received 
therapy in an advanced setting, and 22 (16%) had received both.
The primary endpoint was the progression-free rate, using Response 
Evaluation Criteria in Solid Tumors (RECIST) at 12 weeks after start of 
treatment. Patients with leiomyosarcoma, synovial sarcoma and “the other 
types of sarcoma” strata receiving pazopanib in VEG20002 experienced a 
12 week progression free rate of ≥ 40%, the pre-defined threshold 
indicating anti-tumor activity. The liposarcoma stratum did not meet its 
prespecified endpoint at the end of stage 1 and did not progress to stage 2. 
Based on the results of the VEG20002, a Phase III randomized, double 
blind, placebo controlled study (VEG110727) of pazopanib versus placebo 
in subjects with soft tissue sarcoma (study excluded patients with GIST or 
liposarcoma) was initiated in 2008. VEG110727 has completed patient 
enrollment and data are expected in 2011.
1.3 Study Rationale
Pazopanib has shown encouraging activity in a previous phase II trial in certain 
sarcoma subtypes. In the phase II trial of pazopanib as described above,  
conducted by the EORTC, the progression free rate at 12 weeks exceeded 40% for 
patients with leiomyosarcomas, synovial cell sarcomas, and other eligible 
sarcomas, but not liposarcomas. In the group of other sarcomas, five were 
described as vascular sarcomas.
We hypothesize that pazopanib will have therapeutic activity in angiosarcoma 
because they are derived from endothelial cells[1], and pazopanib is an anti- 
angiogenic agent. In addition, agents with anti-angiogenic properties have shown 
single agent activity in this disease. Sorafenib has been shown to have a 14% 
response rate in angiosarcomas in previously treated patients in the phase II 
setting[12]. Bevacizumab has demonstrated a 12% response rate [13]. Given the 
limited data on the activity of pazopanib in angiosarcomas, we propose to 
evaluate its activity in patients with angiosarcoma.
1.4 Correlative Testing
Pazopanib is believed to function as an anti-angiogenic agent given its activity 
against the VEGFR 1-3 as well as PDGFRA and B kinases. We hypothesize that 
the agent will be effective in tumors that are undergoing angiogenesis. 
Angiosarcoma is derived from endothelial cells and its growth has been shown to 
be inhibited by anti-angiogenic agents, and thus the tumor itself appears to mimic 
angiogenesis. However, it would be clinically useful to be able to predict whether 
a tumor will or will not respond to angiogenic inhibitors, as well as have an early 
read out on efficacy of such an agent prior to evidence of response from size

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based imaging techniques such as CT or MRI. Reliable means of potentially 
predicting this are in development, but have not been studied systematically. We 
therefore propose to explore the ability of PET imaging with [F-18] FDG PET/CT 
to assess angiosarcomas prior to and following ongoing therapy with pazopanib to 
determine changes in metabolic response as an early marker of response to 
pazopanib.
2.1 Objectives
2.2 Primary
To determine the Progression Free Survival (PFS) at 3 months and response rate
defined as Complete Response (CR) and Partial Response (PR) in angiosarcoma 
patients treated with pazopanib.
2.3 Secondary
1) To assess overall survival of patients treated with pazopanib.
2) To gather more safety data for pazopanib in this patient population.
3) To explore the ability of [F-18] FDG PET/CT imaging to assess response
3.1 Study Plan
3.2 Description of study design, population and duration of study therapy
This is a phase II single arm study of pazopanib in patients with angiosarcoma. 
The dual primary endpoints are response rate and PFS at 3 months. Success of 
either end-point at interim analysis will allow the study to move forward. 
Approximately 30 patients will be enrolled in this study at about 5 institutions. 
Patients will continue on treatment until progression, intolerable toxicity or 
withdrawal of consent.
4.1 Selection of Patients
Deviations from inclusion and exclusion criteria are not allowed because deviations can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.
4.2 Inclusion Criteria

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4.2.1. Subjects must provide written informed consent and HIPAA consent 
prior to performance of study-specific procedures or assessments and must 
be willing to comply with treatment and follow-up.
Note:  Informed consent must be obtained prior to start of the specified 
screening window.
Note:  Procedures conducted as part of the subject’s routine clinical 
management (e.g., blood count, imaging study such as bone scan) and 
obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided these procedures are conducted as 
specified in the protocol.
4.2.2. Age ≥ 18 years.
4.2.3. Histologically or cytologically proven diagnosis of advanced stage 
angiosarcoma that is not amenable to treatment with curative intent. 
Specify site of origin as cutaneous vs. non-cutaneous.
4.2.4. Eastern Cooperative Oncology Group (ECOG) performance status 
of < 2.
4.2.5. Must have measurable disease per RECIST v.1.1 or cutaneous 
disease amenable to serial measurements. A measurable lesion is defined 
as a lesion that can be accurately measured in at least one dimension with 
the longest diameter ≥ 10 mm with CT scan. Lesions that have been 
treated with therapeutic intent will be considered measurable if they have 
increased in size by more than 20%.

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System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
≥1.5 X 109/L
Hemoglobina
≥9 g/dL (5.6 mmol/L)
Platelets
≥100 X 109/L
International normalized ratio (INR)b
≤1.2 X ULN
Activated partial thromboplastin time
(aPTT)
≤1.2 X ULN
Hepatic
Total bilirubinc
≤1.5 X ULN
(May not have abnormalities in both bilirubin and 
transaminases)
Alanine amino transferase (ALT) and 
Aspartate aminotransferase (AST)c
≤2.5 X ULN
May not have abnormalities in both bilirubin and 
transaminases)
Renal
Serum creatinine
≤1.5 mg/dL (133 µmol/L)
Or, if serum creatinine >1.5 mg/dL:
Calculated creatinine clearance (ClCR)
(Appendix B)
≥50 mL/min
Urine Protein to Creatinine Ratio 
(UPC; Appendix C)d
<1
4.2.6. Adequate organ system function as defined in Table 4.1 below. 
Table 4.1
Definitions for Adequate Organ Function
a. Subjects may not have had a transfusion within 7 days of screening assessment.
b Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range 
for the desired level of anticoagulation.
c Concomitant elevations in bilirubin and AST/ALT above ULN (upper limit of normal) are not permitted.
d If UPC ≥ 1, then a 24-hour urine protein must be assessed.  Subjects must have a 24-hour urine protein value
<1 g to be eligible.
4.1.7 Able to swallow pills whole and retain oral medication
4.1.8 A female is eligible to enter and participate in this study if the 
following apply:
Non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant), including any female who has had:
•
A hysterectomy
•
A bilateral oophorectomy (ovariectomy)
•
A bilateral tubal ligation
•
Is post-menopausal
Subjects not using hormone replacement therapy (HRT) must have 
experienced total cessation of menses for ≥ 1 year and be greater than 45 
years in age, OR, in questionable cases, have a follicle stimulating 
hormone (FSH) value > 40 mIU/mL and an estradiol value < 40pg/mL (< 
140 pmol/L).

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Subjects using HRT must have experienced total cessation of menses for > 
1 year and be greater than 45 years of age OR have had documented 
evidence of menopause based on FSH and estradiol concentrations prior to 
initiation of HRT
Childbearing potential, including any female who has had a negative 
serum pregnancy test within 2 weeks prior to the first dose of study 
treatment and for 3 months after the completion of treatment, preferably as 
close to the first dose as possible, and agrees to use adequate 
contraception. Acceptable contraceptive methods, when used consistently 
and in accordance with both the product label and the instructions of the 
physician, are as follow:
•
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
•
Oral contraceptive, either combined or progestogen alone
•
Injectable progestogen
•
Implants of levonorgestrel.
•
Estrogenic vaginal ring
•
Percutaneous contraceptive patches
•
Intrauterine device (IUD) or intrauterine system (IUS) with a 
documented failure rate of less than 1% per year.
•
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.
•
Double barrier method: condom and an occlusive cap (diaphragm 
or cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository)
Female subjects who are lactating must discontinue nursing prior to the 
first dose of study drug and refrain from nursing throughout the treatment 
period and for 14 days following the last dose of study drug
4.1.10 A male is eligible to enter and participate in this study if he and his 
female sexual partner in the reproductive age group agree to use effective 
methods of contraception.
4.2
Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the
study:
4.2.1. Prior malignancy:
Subjects with a history of a prior malignancy other than angiosarcoma who have 
been disease-free for at least 2 years prior to the first dose of study drug and/or 
subjects with a history of completely resected non-melanomatous skin 
carcinoma or successfully treated in situ carcinoma are eligible.

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4.2.2. History or clinical evidence of central nervous system (CNS) 
metastases or leptomeningeal carcinomatosis, except for individuals who 
have previously-treated CNS metastases, are asymptomatic, and have had 
no requirement for steroids or anti-seizure medications for 3 months prior 
to first dose of study drug. Screening with CNS imaging studies 
(computed tomography [CT] or magnetic resonance imaging [MRI]) is 
required only if clinically indicated or if the subject has a history of CNS 
metastases.
4.2.3. Clinically significant gastrointestinal (GI) abnormalities that may 
increase the risk for GI bleeding including, but not limited to:
•
Active peptic ulcer disease
•
Known intraluminal metastatic lesion/s with risk of bleeding
•
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s 
disease), or other GI conditions with increased risk of perforation
•
History of abdominal fistula, GI perforation, or intra-abdominal 
abscess within 28 days prior to beginning study treatment.
•
Clinically significant (> ½ teaspoon) hemoptysis or gastrointestinal 
hemorrhage in the past 6 months
4.2.4
Evidence of active bleeding or bleeding diathesis.  Recent 
hemoptysis (≥½ teaspoon of red blood within 8 weeks before first 
dose of study drug).
4.2.5
Clinically significant GI abnormalities that may affect absorption 
of investigational product including, but not limited to:
•
Malabsorption syndrome
•
Major resection of the stomach or small bowel
4.2.6
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula 
(Appendix E)
4.2.7
LVEF < 50%
4.2.8
History of any one or more of the following cardiovascular 
conditions within the past 6 months:
•
Cardiac angioplasty or stenting
•
Myocardial infarction
•
Unstable angina
•
Coronary artery bypass graft surgery
•
Symptomatic peripheral vascular disease
•
Class III or IV congestive heart failure, as defined by the New 
York Heart Association (NYHA; Appendix D)

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4.2.9. Poorly controlled hypertension [defined as systolic blood pressure 
(SBP) of ≥ 140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. 
Note:  Initiation or adjustment of antihypertensive medication(s) is 
permitted prior to study entry.  Following antihypertensive medication 
initiation or adjustment, blood pressure (BP) must be re-assessed three 
times at approximately 2-minute intervals. At least 24 hours must have 
elapsed between anti-hypertensive medication initiation or adjustment and 
BP measurement. These three values will be averaged to obtain the mean 
diastolic blood pressure and the mean systolic blood pressure. The mean 
SBP / DBP ratio must be < 140/90 mmHg in order for a subject to be 
eligible for the study. Triplicate BP measurements must be performed at 
screening and on Cycle 1 Day 1 prior to starting treatment. (see Table 6.1 
for details on BP control and re-assessment).
4.2.10. Cerebrovascular accident including transient ischemic attack 
(TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) 
within the past 6 months.
Note:  Subjects with recent DVT who have been therapeutically 
coagulated for at least 6 weeks are eligible.
4.2.11. Major surgery or trauma within 28 days prior to first dose of 
investigational product and/or presence of any non-healing wound, 
fracture, or ulcer (procedures such as catheter placement not considered to 
be major surgery).
4.2.12. Known endobronchial lesions and/or lesions infiltrating major 
pulmonary vessels (Note: tumor abutting the vessel is acceptable, but 
contiguous tumor and vessel is not; CT with contrast is strongly 
recommended to evaluate such lesions).
4.2.13  Abnormal serum calcium, magnesium, or potassium levels .
4.2.14. Any serious and/or unstable pre-existing medical, psychiatric, or 
other condition that could interfere with subject’s safety, provision of 
informed consent, or compliance to study procedures.
4.2.15. Use of any prohibited medication within the timeframes as listed in 
Section 5.3.3.
4.2.16. Treatment with any of the following therapies:
•
Radiation therapy, surgery or tumor embolization within 14 days 
prior to the first dose of pazopanib OR
•
Chemotherapy, immunotherapy, biologic therapy, investigational 
therapy or hormonal therapy within 14 days or five half-lives of a 
drug (whichever is longer) prior to the first dose of pazopanib

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•
Patients who require chronic use of strong CYP3A4 inhibitors or 
inducers including but not limited to grapefruit juice. Please see 
section 5.3 for additional detail.
4.2.17. Any ongoing toxicity from prior anti-cancer therapy that is > 
Grade 1 (except hemoglobin value; see Table 4.1) and/or that is 
progressing in severity, except alopecia.
4.2.18. Previous exposure to pazopanib or a VEGFR targeted kinase 
therapy, except for bevacizumab or VEGFR-Trap (Aflibercept).
4.2.19. Known immediate or delayed hypersensitivity reaction or 
idiosyncrasy to drugs chemically related to pazopanib.
4.3 Inclusion of Women and Minorities
Both men and women and members of all races, sexual orientation and ethnic 
groups are eligible for this study.
4.4 Patient Registration
Eligible patients will be entered on study centrally by the Fox Chase Cancer 
Center Office Quality Assurance (QA) Coordinator or their designee. Following 
registration, patients will begin protocol treatment within 7 days of registration. 
Issues that would cause treatment delays must be discussed with the Principal 
Investigator.  If a patient does not receive protocol therapy following registration, 
the patient’s registration on the study will be cancelled and the subject will be 
replaced. The QA Coordinator will be notified of cancellations as soon as 
possible.
Subjects may be registered from 9:00 am to 5:00 pm by calling the QA 
Coordinator at 215-728-4770.  The investigator or designee will then fax the 
completed registration form, informed consent and HIPAA signature pages, and 
eligibility checklist to 215-214-1511.  The QA Coordinator will notify the site by 
phone and fax when registration is confirmed and the sequence number has been 
assigned. Subjects must be registered and have received a sequence number 
assigned by the QA Coordinator prior to the initiation of treatment. The 
following forms must be completed at the time of registration:
•
Signed and dated informed consent form
•
Signed and dated HIPAA consent form
•
Registration form
•
Signed eligibility checklist
Exceptions to the current registration policies will not be permitted as well as:
•
Late registrations (after initiation of treatment)

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•
Exceptions to eligibility requirements
•
Participation by an institution/member not identified as eligible
•
Non-Compliance with regulatory paperwork
5.1 Treatment Plan
Treatment will be administered on an out-patient basis. Treatment will be administered as 
described below.  Dose delays and modifications will only be done following protocol 
guidelines described in section 6.0.  If treatment delays are > 28 days study therapy will 
be discontinued. Each treatment cycle after cycle 1 is 21 days +/- 5 calendar days for 
holidays, inclement weather and/or other scheduling conflict. Treatment should continue 
during the 5 day window for cycle evaluation should a particular cycle need to be 
extended due to a scheduling conflict.
5.2 Treatment Administration
Table 5.1
Agent
Precautions
Dose
Route
Schedule
Cycle Length
Pazopanib
Orally without 
food at least one 
hour before or two 
hours after a meal.
200 mg x 4
(or 400 mg x 2) 
total dose 800 mg
PO
(time of day the 
tablets are taken 
should be relatively 
constant)
Daily
21 days (3 
weeks)
+/- 5 Calendar 
Days
Administration of pazopanib with a high-fat or low-fat meal results in an 
approximately 2-fold increase in area under the plasma drug concentration curve 
(AUC) and maximum observed plasma drug concentration (Cmax).
Pazopanib should be taken orally without food at least one hour before or two
hours after a meal. The tablets should be swallowed whole and must not be 
crushed or broken. The time of day the tablets are taken should be relatively 
constant.
If a subject misses a dose, the subject should take the dose as soon as possible, but 
not less than 12 hours before the next dose is due.  If the next dose is due in less 
than 12 hours, the subject should skip the missed dose and take the next dose as 
scheduled.
If a subject vomits after taking pazopanib, the subject will be instructed not to 
take another dose that day.  The subject will resume taking pazopanib at the next 
scheduled dose.  If vomiting persists, the subject will be instructed to notify the 
investigator.

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5.3 Dosing Rationale
Pazopanib 800 mg once daily is the recommended monotherapy dose based on 
clinical and preclinical results.  Once daily doses of 50 mg to 2000 mg pazopanib 
were investigated in the “First Time in Human”, Phase I Study VEG10003.(IB 
RR2002/00017/10)  Increases in the pazopanib dose above 800 mg once daily 
when administered in the fasted state did not result in a consistent increase in 
systemic exposure at steady-state.  Therefore, no further benefit is expected at 
pazopanib doses above 800 mg once daily.
Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg 
once daily, results in effects consistent with inhibition of the VEGF receptors it 
was designed to target.  Concentration-effect relationships were observed between 
trough plasma pazopanib concentrations and the development of hypertension in 
Study VEG10003 and the percent change from baseline in sVEGFR2 nadir in 
Study VEG102616.  The trough plasma pazopanib concentrations associated with 
one-half the maximal effect (EC50) in both concentration-effect relationships were 
similar (21.3 µg/mL and 15.3 µg/mL) and demonstrate that there is a consistent 
inhibition of VEGF receptor(s) in subjects with cancer when plasma pazopanib 
concentrations are maintained above 15 µg/mL.  The plasma pazopanib EC50 
values for biologic effects observed in the clinical studies are similar to the 
plasma concentration of 40 µM (17.5 µg/mL) required for optimal inhibition of 
VEGFR-2 phosphorylation in mice [GSK Report RH2003/00005/00].
Progression Free Survival (PFS) in subjects with renal cell cancer in Study 
VEG102616 was compared between subjects whose trough plasma pazopanib 
concentrations (Cmin) at Week 4 were above or below selected threshold values. 
The deciles of the observed Cmin values were selected as threshold values so that 
approximately equal numbers of subjects were included in each Cmin interval. 
Subjects with a Cmin at Week 4 above the threshold values had significantly better 
PFS, compared to the remaining subjects, when the threshold concentrations were
12.6 µg/mL, 17.4 µg/mL, and 20.6 µg/mL.  Use of thresholds higher than
21 µg/mL did not result in a significant improvement in PFS between patients 
with Cmin values above and below the threshold.  Patients with Cmin concentrations 
above 20.6 µg/mL also had a significantly better response rate and tumor 
shrinkage than the remaining patients.
Pazopanib C24 at steady-state was greater than 15 µg/mL in 93% of subjects who 
received 800 mg once daily in Study VEG10003.  Individual subjects receiving 
pazopanib doses below 800 mg once daily can achieve plasma concentrations 
over 15 µg/mL, albeit at a lower frequency compared with what is observed at 
800 mg once daily.  Therefore, the pharmacokinetic and pharmacodynamic results 
across clinical studies demonstrate that pazopanib 800 mg once daily results in 
plasma concentrations that provide optimal biologic effects associated with 
VEGFR inhibition in the greatest proportion of subjects.

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5.3 Concomitant Medications, supportive care and excluded therapies and 
restrictions
5.3.1 Permitted Medications
All subjects will be asked to provide a complete list of prescription and 
over-the-counter medications that have been taken within the 2 weeks 
prior to Screening.  The investigator must be informed as soon as possible 
about any new medication(s) taken from the time of Screening until the 
completion of the post-treatment follow-up visit.
All concomitant medications taken during the study will be recorded in the 
case report form (CRF) with indication, dose information, and dates of 
administration.
Subjects should receive full supportive care during the study, including 
transfusion of blood and blood products, and treatment with antibiotics, 
analgesics, erythropoietin (per ASCO guidelines), or bisphosphonates, 
when appropriate.
Antiemetics (such as prochlorperazine, lorazepam, ondansetron or other 5- 
HT antagonists) may be administered prophylactically in the event of 
nausea. Anti-diarrheals, such as loperamide, may be administered as 
needed in the event of diarrhea. (See Appendix F for Supportive care 
guidelines for nausea/vomiting and diarrhea)  Although acetaminophen at 
doses of ≤ 2 g/day is permitted, it should be used with caution in subjects 
with impaired liver function. Glucocorticosteroids may be used as 
antiemetics and megestrol acetate may be used for appetite.
5.3.2 Permitted Medications – Use with Caution 
Specific recommendations regarding anticoagulants:
Results from drug-drug interaction studies conducted in subjects with 
cancer suggest that pazopanib has no effect on the metabolism of S- 
warfarin.  Hemorrhagic events, however, have been reported in clinical 
studies with pazopanib; therefore, pazopanib should be used with caution 
in subjects with increased risk of severe bleeding or who are receiving 
concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low 
molecular weight heparin, unfractionated heparin).  Subjects taking 
concomitant anticoagulant therapy should be monitored regularly for 
changes in relevant coagulation parameters as clinically indicated, as well 
as for any clinical bleeding episodes.

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Specific recommendations regarding hypoglycemic therapy including 
insulin:
Results from drug-drug interaction studies conducted in subjects with 
cancer suggest that there will be no clinically relevant pharmacokinetic 
interaction between pazopanib and hypoglycemic agents.  Transient 
decreases in serum glucose (mainly Grade 1 and 2, rarely Grade 3) have 
been observed in clinical studies with pazopanib. In addition, decreases in 
blood sugar have been recently reported in subjects treated with another 
small molecule tyrosine kinase inhibitor, sunitinib [20]. Such changes may 
require an adjustment in the dose of hypoglycemic and/or insulin therapy. 
Subjects will be advised to report symptoms of hypoglycemia (e.g., 
confusion, visual disturbances, palpitations, sweating).  Serum glucose 
will be tested during treatment with pazopanib as outlined in section 9.2 
study calendar and as clinically indicated.
5.3.2.1 The Effects of Pazopanib on Other Drugs
In vitro data indicate that pazopanib is a potential inhibitor for 
CYP3A4, CYP2C8, CYP2D6, CYP1A2, CYP2C9, CYP2C19,
CYP2A6, CYP2B6, and CYP2E1.  Pregnane X receptor transient 
transfection assay suggested some potential for human CYP3A4 
induction at high concentrations. Results from drug-drug 
interaction studies conducted in subjects with cancer suggest that 
pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 
in vivo, but had no clinically relevant effect on CYP1A2, CYP2C9 
or CYP2C19 metabolism. Therefore, concomitant use of 
pazopanib with certain medications (substrates of CYP3A4, 
CYP2C8, and CYP2D6) with a narrow therapeutic window will be 
undertaken with CAUTION due to the potential for alterations in 
the pharmacologic effects of these medications or an increased risk 
for serious or life threatening adverse events associated with such 
medications (see below) secondary to the inhibition of specific 
CYP enzymes by pazopanib.  In addition, the potential for drug 
interaction with such medications, although diminished, may 
persist after the last dose of pazopanib due to its long half-life (i.e., 
mean 30.9 hours); therefore, continue to exercise CAUTION for at 
least 7 days and up to 15 days after the last dose of pazopanib 
when administering these medications. These medications include 
(but are not limited to):
•
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, 
methylergonovine (potential increased risk for developing  
ergot toxicity that includes severe vasospasm leading to 
peripheral as well as cerebral ischemia)

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•
Neuroleptics: pimozide (potential increased risk for QT 
interval prolongation, ventricular arrhythmia, and sudden 
death)
•
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, 
amiodarone, quinidine, propafenone (potential increased risk 
for QT interval prolongation and Torsades de Pointes)
•
Immune modulators: cyclosporine, tacrolimus, sirolimus 
(potential increased risk for nephrotoxicity and neurotoxicity)
•
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine.
5.3.2.2 The Effects of Other Food and Drugs on Pazopanib
Results from in vitro studies suggest that the oxidative metabolism 
of pazopanib in human liver microsomes is mediated primarily by 
CYP3A4, with minor contributions from CYP1A2 and CYP2C8. 
Furthermore, in vitro data suggest that pazopanib is a substrate for 
p-glycoprotein.  Substances that induce or inhibit CYP3A4 may 
alter the pharmacologic effects of pazopanib and will be used with 
CAUTION.
Foods and medications that inhibit CYP3A4 may result in 
increased plasma pazopanib concentrations.  Co-administration 
of strong CYP3A4 inhibitors is prohibited (see Section on 
Prohibited Medications); therefore selection of an alternate 
concomitant medication with no or minimal potential to inhibit 
CYP3A4 is recommended.
CYP3A4 inducers may decrease plasma pazopanib concentrations. 
Selection of an alternate concomitant medication with no or 
minimal enzyme induction potential is recommended.  Drugs that 
induce CYP3A4 and may decrease pazopanib plasma 
concentrations include (but are not limited to):
•
Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 
mg), prednisone (>10 mg), methylprednisolone (>8 mg), 
dexamethasone (>1.5 mg)
•
Anticonvulsants:  phenytoin, carbamazepine, 
phenobarbital, oxcarbazepine
•
HIV antivirals:  efavirenz, nevirapine
•
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentine
•
Miscellaneous:  St. John’s Wort, modafinil, pioglitazone

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5.3.3 Prohibited Foods and Medications
Subjects must not receive other anti-cancer therapy [cytotoxic, biologic, 
radiation, or hormonal (other than leuprolide or other GnRH agonists)] 
while on treatment in this study.
Foods and medications that inhibit CYP3A4 may result in increased 
plasma pazopanib concentrations; therefore, co-administration of strong 
CYP3A4 inhibitors is PROHIBITED beginning 14 days prior to the first 
dose of study drug until discontinuation from the drug. Strong CYP3A4 
inhibitors include (but are not limited to):
•
Antibiotics: clarithromycin, telithromycin, troleandomycin
•
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, 
nelfinavir, lopinavir)
•
Antifungals:  itraconazole, ketoconazole, voriconazole
•
Antidepressants: nefazodone
•
Grapefruits and grapefruit juice
Foods and medications that induce CYP3A4 are PROHIBITED 
beginning 14 days prior to the first dose of study drug until 
discontinuation from the drug.
Subjects must not receive any other investigational drug within 15 days of 
the last dose of pazopanib.
5.4 Duration of Therapy
Subjects will receive study treatment until one of the following criteria applies:
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse events (including meeting stopping criteria for liver 
chemistry or for hematologic and other non-hematologic toxicity defined 
in Section 6.0)
•
Treatment held > 28 days
•
Patient required > 2 dose modifications
•
Patient becomes pregnant
•
Patient decides to withdraw from the study
•
Study is closed or terminated

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•
General or specific changes in the patient’s condition that render the 
patient unacceptable for further treatment in the judgment of the 
investigator.
5.5 Duration of Follow up
After discontinuation of the study treatment, subjects will remain on the study for 
follow-up assessments of disease status and updates on anti-cancer treatments 
until death or for a maximum of two years from the date of the last subject 
enrolled. Patients removed from study for unacceptable study related adverse 
events requiring discontinuation of the study treatment will be followed until 
resolution or stabilization of the adverse event.
5.6 Criteria for discontinuation
Patients will be removed from study when any of the criteria listed in Section 5.4 
applies or if they are lost to follow-up. In addition deviation(s) from the protocol 
may be a cause for discontinuation. The primary reason for study removal and the 
date the patient was removed must be documented in the medical record and case 
report form. If treatment is discontinued for a scheduled surgery, pazopanib must 
be held at least 7 days prior to the scheduled surgery.
6.1 Dose modifications
6.2 General principles
At each visit during the Treatment Period, subjects will first be evaluated for the 
occurrence of AEs and laboratory abnormalities.  The potential causes of the AEs 
will be thoroughly investigated and confounding factors identified and eliminated 
whenever possible.  Some AEs, although rare, can result in significant clinical 
consequence such as arterial/venal thrombosis, severe hemorrhage, bowel 
perforation and severe fatigue/asthenia, therefore will be promptly identified and 
managed.
Should a patient require scheduled surgery while on study, pazopanib must be 
discontinued for at least 7 days prior to surgery. Following the surgery, adequate 
would healing must be determined by the treating physician, in order for the 
patient to resume pazopanib treatment in this trial.
The National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.0 (NCI-CTCAE, v.4) must be used to Grade the severity of AEs except 
for hypertension and palmar-plantar Erythrodysesthesia Syndrome: grading for 
these events is described in the table below. Specific recommendations for 
management of these possible AEs along with guidelines for dose interruption, 
modification, or discontinuation are provided in Table 6.1 for pazopanib.  In the 
event of treatment emergent hepatotoxicity, the guidelines for management of

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hepatotoxicity provided in Table 6.2 will be followed. Dose reductions are 
permanent; there are no dose re-escalations. Patients requiring > 2 dose 
reductions must discontinue protocol treatment. Patients requiring treatment to be 
held > 28 days must discontinue protocol treatment. Treatment will be held for
> grade 3 toxicity except alopecia. Hold until < grade 1 then dose reduce 1 level.
6.3 Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities
If dose reduction is necessary, two dose reductions will be permitted (unless 
otherwise noted in Tables 6.1 and 6.2) in a stepwise fashion (initially to 600 mg po 
daily and subsequently to 400 mg po daily if necessary; 400 mg po daily will be the 
minimum dose level) according to Table 6.1.
Table 6.1
Dose Modification Algorithms for Potential Treatment-Related Adverse 
Events
AE Terms & Descriptions
Dose Modification Algorithms
Hypertension
(A). Asymptomatic and persistent SBP of
≥140 and <160 mmHg, or DBP ≥90 and
<100 mmHg, or a clinically significant 
increase in DBP of 20 mmHg (but still 
below 110 mmHg). (Grade 2)
(1) Continue pazopanib at the current dose.
(2) Adjust current or initiate new antihypertensive medication(s).
(3) Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled BP.  Well-controlled BP defined as
SBP <140 mmHg and mean DBP <90 mmHg. If BP is not well- 
controlled within 2 weeks, consider referral to a specialist and go to 
scenario (B).
(B). Asymptomatic SBP ≥160 mmHg, or 
DBP ≥100 mmHg, or failure to achieve 
well-controlled BP within 2 weeks in 
scenario (A). (Grade 3)
(1) Consider reducing or interrupting pazopanib as clinically indicated.
(2) Adjust current or initiate new antihypertensive medication(s).
(3) Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled BP.
(4) Once BP is well-controlled (< 140/90), restart pazopanib dose-
reduced by 200 mg if pazopanib was interrupted.
(C). Symptomatic hypertension or 
recurring SBP ≥160 mmHg, or DBP
≥100 mmHg, despite modification of 
antihypertensive medication(s) (Grade 3)
(1) nterrupt pazopanib.
(2) Adjust current or initiate new antihypertensive medication(s).
(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.
(4) Once BP is well-controlled, restart pazopanib dose-reduced by
200 mg.
(D). Refractory hypertension unresponsive 
to above interventions
Discontinue pazopanib and continue follow-up per protocol.
Prolongation of QTc Interval:
QTc  ≥ 480 < 500 msec
Continue pazopanib at the current dose; monitor as clinically indicated.
QTc ≥ 500 msec
Discontinue pazopanib and continue follow-up per protocol.
Proteinuria
UPC < 3
Continue pazopanib at the current dose; monitor as clinically indicated
UPC ≥ 3 or 24-h urine protein ≥ 3g
(1) nterrupt pazopanib.
(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

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AE Terms & Descriptions
Dose Modification Algorithms
by 200 mg.
(3) f UPC > 3 or 24-h urine protein ≥ 3g recurs, repeat steps 1 and 2
(4) f UPC ≥ 3 or 24-hr urine protein ≥ 3g recurs and the pazopanib dose 
can no longer be reduced, discontinue pazopanib and continue 
follow-up per protocol.
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding
Grade 1
For hemoptysis, interrupt pazopanib and contact the Principal
Investigator to discuss whether further treatment with pazopanib is 
appropriate.
For other Grade I hemorrhage/bleeding events, continue pazopanib at the 
current dose; monitor as clinically indicated.
Grade 2
(1) f pulmonary or GI bleed (other than hemorrhoidal bleeding),
discontinue pazopanib and continue follow-up per protocol.  Otherwise, 
interrupt pazopanib until the AE resolves to ≤ Grade 1.
(2) Restart pazopanib; consider reducing dose and monitor as indicated.
Grade 3 or 4, or recurrent ≥ Grade 2 event 
after dose interruption/reduction.
Discontinue pazopanib and continue with follow-up per protocol.
Venous Thrombosis (DVT, PE)
Grade 2
Continue pazopanib at the current dose; monitor as clinically indicated
Grade 3
(1) nterrupt pazopanib treatment.
(2) nitiate and monitor anticoagulation as clinically indicated.
(3) Resume pazopanib treatment at the same dose only if all of the 
following criteria are met:
- The subject must have been treated with anticoagulant at the desired 
level of anticoagulation for at least one week.
- No Grade 3 or 4 or clinically significant Grade 2, hemorrhagic events 
have occurred while on anticoagulation treatment.
Subject will be monitored as clinically indicated during anticoagulation
treatment and after resuming study treatment.  When treating with 
warfarin, INR will be monitored within three to five days after any
change in pazopanib dosing (e.g., re-initiating, escalating/de-escalating,
or discontinuing pazopanib), and then at least weekly until the INR is 
stable.  The dose of warfarin (or its derivatives) may need to be adjusted
to maintain the desired level of anticoagulation.
Grade 4 and/or PE
Discontinue pazopanib and continue follow-up per protocol.
Arterial Thrombosis/Ischemia
Any Grade
Discontinue pazopanib and continue follow-up per protocol.
Thrombocytopenia: Investigate and document underlying cause
Grade 1 or 2
Continue pazopanib with current dose; monitor as clinically indicated.
Grade 3 or 4
(1) nterrupt pazopanib until toxicity resolves to ≤ Grade 2.
(2) estart pazopanib dose-reduced by 200 mg and monitor as clinically 
indicated. If recurrent, further dose reduce to 400 mg po daily.
If no recovery to ≤ Grade 2 or in the event of recurrent Grade 3 or 4 
thrombocytopenia, discontinue pazopanib and follow-up per protocol.

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AE Terms & Descriptions
Dose Modification Algorithms
Anemia:
No specific dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding as noted above.
Palmar-plantar Erythrodysesthesia Syndrome
Grade 1
Minimal skin changes or dermatitis without 
pain
(erythema, edema, hyperkeratosis)
(1) Continue pazopanib at present dose
(2) nitiate supportive care with emollient lotions
Grade 2
Skin changes with pain; limiting 
instrumental activities of daily living
(ADLs) (peeling, blisters, edema, bleed, 
hyperkeratosis)
(1)Hold pazopanib
(2)Treat as clinically appropriate: emollient lotions, limiting tight shoes 
and heels
(3)Upon resolution to Grade 1 or better, restart pazopanib with a dose 
reduction to 600 mg
(4)f recurrent consider a further dose reduction to 400mg or 
discontinuation
Grade 3
Severe skin changes with pain and limiting 
self care ADLs
(1) Discontinue pazopanib
Other Clinically Significant Adverse Events
Grade 1
Continue pazopanib; monitor as clinically indicated.
Grade 2 or 3, if clinically significant
(1) nterrupt pazopanib until toxicity resolves to ≤ Grade 1.
(2) Restart pazopanib dose-reduced by 200 mg and monitor as clinically 
indicated. If recurrent, further dose reduce to 400 mg po daily.
Grade 4
Discontinue pazopanib and continue follow-up per protocol.
6.4 Dose Interruptions/Modifications for Hepatotoxicity
Recommendations for pazopanib dose interruptions/modifications in case of liver- 
related treatment-emergent AEs are provided in Table 6.2. As a general rule, 
since many subjects are taking multiple concurrent medications, it is critical to (a) 
do a thorough evaluation of the subject’s concurrent medications (ensuring all are 
recorded in the CRF), and (b) identify and discontinue those with known 
hepatotoxicity and replace with a non-hepatotoxic equivalent for the same 
indication if necessary.  Record alcohol use is recorded on the history and 
physical form in the CRF binder.  Liver dysfunction must be fully evaluated even 
if clinical signs and symptoms indicate progression of liver tumor lesions. 
Imaging studies must be obtained to document potential progression of 
malignancy.

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Table 6.2
Guidelines for Management of Treatment Emergent Hepatotoxicity
Event
Dose Modification Algorithms
(A). Grade 1:
ALT/AST
> ULN - 3.0 x ULN
Continue pazopanib at current dose with full panel liver function tests (LFTs)a
monitored as per protocol. Study calendar (section 9.2)
(B). Grade 2:
asymptomatic with 
ALT/AST
> 3.0 – 5.0 x ULN;
symptomatic
> 3.0 without bilirubin 
elevation (defined as 
total bilirubinb <2.0 x
ULN or direct bilirubin
≤ 35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash)
Liver Event Monitoring Criteria:
(1) Continue pazopanib at current dose levels.
(2) Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTsa weekly or more frequently if clinically indicated until ALT/AST is 
reduced to < 3.0 x ULN.
C). Grade 3: ALT/AST
> 5.0 – 20.0 x ULN; >
5.0 x ULN for > 2 
weeks without 
bilirubin elevation 
(defined as total
bilirubinb <2.0 x ULN
or direct bilirubin ≤ 
35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash)
1st occurrence – Liver Event Interruption Criteriac:
(1) Interrupt pazopanib until toxicity resolves to ≤ ULN - 3.0 x ULN or baseline.
Report the event to the QA Specialist/ Study Monitor and Novartis as an SAE 
within 24 hours of learning of its occurrence and complete the CRF and SAE 
report. Make every reasonable attempt to have subjects return to the clinic 
within 24 to 72 hours for repeat liver chemistries and LFTs.
(2) Liver imaging and other laboratory investigations will be considered as 
clinically appropriate.
(3) Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTs a weekly or more frequently if clinically indicated until ALT/AST is 
reduced to < 3.0 x ULN.
(4) If the potential benefit for reinitiating pazopanib treatment is considered to 
outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced
dose and measure serum liver tests weekly for 8 weeks.* Re-challenge may
be considered if ALL following criteria are met:
- ALT/AST reduced to < 3.0 x ULN
- Total bilirubin <1.5 x ULN or direct bilirubin ≤ 35%
- No hypersensitivity signs or symptoms
- Subject is benefiting from therapy.
Recurrence – Liver Event Stopping Criteriac:
Discontinue pazopanib permanently and monitor subject closely for clinical signs 
and symptoms; perform full panel LFTs a weekly or more frequently if clinically 
indicated until ALT/AST is reduced to < 3.0 x ULN.
(D). ALT/AST > ULN
- 3.0 x ULN with 
concomitant elevation 
in bilirubinb (defined
as total bilirubin ≥1.5 x 
ULN; with direct 
bilirubin >35%) or 
with hypersensitivity 
symptoms (e.g., fever, 
rash).
Liver Event Stopping Criteriac:
(1) Discontinue pazopanib immediately, report the event to the QA Specialist/ 
Study Monitor and Novartis as an SAE within 24 hours of learning of its 
occurrence (section 10.3). Make every reasonable attempt to have subjects 
return to the clinic for repeat liver chemistries and repeat LFTs
(2) Monitor subject closely for clinical signs and symptoms; record the 
appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever rash or eosinophilia as relevant on the AE report form. Perform full 
panel LFTs a weekly or more frequently if clinically indicated until LFTs are 
reduced to ALT/AST < 3.0 x ULN and Bilirubin < 1.5 x ULN.

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Event
Dose Modification Algorithms
(E). For isolated total 
bilirubinb elevation 
without concurrent
ALT/AST increases.
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT/AST or
other signs/symptoms of liver injury) does not require dose modification. 
Pazopanib inhibits UGT1A1 and OATP1B1, which can cause elevation of 
indirect (unconjugated) bilirubin in the absence of liver injury..
(2)
If bilirubin is >1.5 x ULN in the absence of ALT/AST elevation,
fractionation of bilirubin elevation will be performed. If bilirubin is >35% 
direct (conjugated), further evaluation for underlying cause of cholestasis 
will be performed.
(3) If bilirubin elevation concurrent with ALT/AST increases following 
treatment guidelines above based on ALT/AST value.
a.
Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin. Coagulation tests will be
performed as clinically indicated.
b.
Serum bilirubin fractionation will be performed if testing is available.  If testing is unavailable and a subject meets 
the criterion of total bilirubin >1.5 x ULN, then the event will be promptly reported as an SAE.
c.
When a liver chemistry event meets the Liver Event Interruption Criteria, or Liver Event Stopping Criteria, blood
samples will be obtained for clinical laboratory testing 
ULN = upper limit of normal
7.1 Study Agent Information
7.2 Pazopanib Formulation, product identification, package and labeling
7.2.1 Product description
Pazopanib monohydrochloride salt is supplied as aqueous film-coated 
tablets containing either 200 mg or 400 mg of the free base.  Both the 200- 
mg and the 400-mg tablets are oval-shaped and white in color. Refer to 
the pazopanib IB for information regarding the physical and chemical 
properties of pazopanib and a list of excipients.
7.2.2 Route of administration
Pazopanib will be taken orally without food at least one hour before or 
two hours after a meal. The tablets should be swallowed whole and must 
not be crushed or broken. The time of day the tablets are taken should be 
relatively constant.
7.2.3 Availability
Pazopanib will be provided to the sites by Novartis.  The 200-mg 
pazopanib tablets are packaged 34 to a bottle.  The 400-mg tablets are 
packaged 68 to a bottle. All bottles are made of high-density polyethylene 
and have a child-resistant closure.  Each bottle will be labeled with the 
protocol number, dosing and storage instructions, sponsor name and 
address, and the expiration date, when required. The contents of the label 
will be in accordance with all applicable regulatory requirements.
Pazopanib will be dispatched to the site only after receipt of required 
documents in accordance with applicable regulatory requirements and 
Novartis’ procedures.

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7.2.4 Storage requirements
Pazopanib must be stored in a secure, limited-access area at the study site, 
under the appropriate physical conditions for the product. The 
recommended storage conditions, and expiration date where required, are 
stated on the product label.
Under normal conditions of handling and administration, pazopanib is not 
expected to pose significant safety risks to site staff. A Material Safety 
Data Sheet (MSDS) describing the occupational hazards and 
recommended handling precautions will be provided to site staff if 
required by local laws or will otherwise be available from Novartis upon 
request.
7.3 Destruction of drug
At the time of study closure, the unused, used and expired study drug will be 
destroyed at the site per Institutional SOPs unless otherwise specified.
7.4 Records to be kept at site, dispensing and accountability
Pazopanib must be dispensed or administered according to procedures described 
herein.  Only subjects enrolled in the study may receive pazopanib, in accordance 
with all applicable regulatory requirements.  Only the site pharmacist, 
Investigator, or other authorized site personnel may have access to and supply or 
administer pazopanib.  Pazopanib will be dispensed to the subject after it has been 
confirmed that the subject meets all eligibility criteria and all screening 
assessments have been completed and the results reviewed. Subjects are to return 
to the site approximately every 3 weeks for re-supply of pazopanib, according to 
the study visit schedule (section 9.2).
It is the responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed.  Records or logs must comply 
with applicable regulations and guidelines, and will include:
•
Amount received and placed in storage area.
•
Amount currently in storage area.
•
Label ID number or batch number.
•
Dates and initials of person responsible for each investigational 
product inventory entry/movement.
•
Amount dispensed to and returned by each patient, including unique 
patient identifiers.
•
Amount transferred to another area for dispensing or storage.
•
Non-study disposition (e.g., lost, wasted, broken).

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It is recommended that the NCI Drug Accountability Record Form be utilized for 
drug tracking.
7.5 Treatment of Investigational Product Overdose
No maximum tolerated dose (MTD) was reached in the dose escalation study of 
pazopanib administered as a single agent at repeated doses of up to 2000mg/day 
(Study VEG10003). Systemic exposure to pazopanib at steady-state appeared to 
plateau at doses greater than 800 mg once daily.  Increases in the daily pazopanib 
dose above 800 mg in the fasted state resulted in a small or no increase in mean 
systemic exposure to pazopanib.
In the event of pazopanib overdose (defined as administration of more than the 
protocol-specified dose), the investigator will contact the Principal Investigator. 
Decisions regarding pazopanib dose modifications or interruptions will be made 
by the investigator in consultation with the Principal Investigator based on the 
clinical evaluation of the subject.
Following an overdose, additional monitoring of the subject for AEs/SAEs and 
laboratory abnormalities will be considered. A plasma sample for 
pharmacokinetic analysis for pazopanib may be requested by the Principal 
Investigator on a case-by-case basis. This plasma sample will be collected as 
soon as possible, but within 7 days from the date of the last dose of study drug. 
Information regarding the quantity of the excess dose, as well as the duration of 
overdosing, will be documented in the CRF.
8.0 Correlative /Special Studies
8.1. Hypothesis
Pazopanib is believed to function as an anti-angiogenic agent given its activity 
against the VEGFR 1-3 as well as PDGFRA and B kinases. We hypothesize that 
the agent will be effective in tumors that are undergoing angiogenesis. 
Angiosarcoma is derived from endothelial cells and its growth has been shown to 
be inhibited by anti-angiogenic agents, and thus the tumor itself appears to mimic 
angiogenesis. However, it would be clinically useful to be able to predict whether 
a tumor will or will not respond to angiogenic inhibitors, as well as have an early 
read out on efficacy of such an agent prior to evidence of response from size 
based imaging techniques such as CT or MRI. Reliable means of potentially 
predicting this are in development, but have not been studied systematically. We 
therefore propose to explore the ability of PET imaging with [F-18]RDG-K5 to 
assess angiosarcomas prior to and following ongoing therapy with pazopanib to 
determine changes in angiogenesis as an early marker of response to pazopanib as 
compared with [F-18] FDG PET/CT and CT imaging.
8.2. Preliminary Data

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[F-18]RDG-K5 is a promising radiolabeled diagnostic agent for imaging of alpha 
v Beta 3 integrin expression, a family of integrin glycoproteins, found on newly 
formed blood vessels in tumors. The agent was studied in 21 normal and cancer 
subjects and found to have no safety concerns; Dr. Yu at Fox Chase was one of 
the Principal Investigators for that study. In addition, studies in patients with 
breast, lung, sarcoma and melanoma found good signal/background ratios. In 
addition, in two patients biopsies were performed from tumor samples 
demonstrating the presence of alpha v Beta 3 integrin expression by immune 
histochemistry. The agent is being studied at Fox Chase in patients treated with 
Bevacizumab; three patients have been accrued and are undergoing initial 
baseline studies.
8.3. Correlative Study Design
All patients at treated at Fox Chase Cancer Center will participate in these 
correlative studies. Patients will have [F-18] FDG PET/ CT imaging acquired at 
baseline and then following therapy with pazopanib for approximately 3 weeks. 
Imaging will be compared to baseline imaging with CT/MRI or physical exam 
measurements determined at baseline and at 12 weeks.
8.3.1. Study Population
All patients treated at Fox Chase Cancer Center on the phase II trial of 
Pazopanib
8.3.2 Methodology
[F-18] Fluorodeoxyglucose injection is a radiopharmaceutical containing 
no-carrier added radioactive 2-deoxy-2-[F-18]fluoro-D-g1ucose, which is 
used for diagnostic purposes in conjunction with PET imaging. It is 
administered by intravenous injection. Currently, it is the 
radiopharmaceutical used the majority of the time with PET imaging. It 
has an uptake phase of approximately 60 to 90 minutes.
Information from the baseline and 3 weeks of treatment of [F-18] 
Fluorodeoxyglucose PET/CT scans will be reviewed, evaluated and 
recorded for:
• location of the lesion(s), specific diagnosis, and confidence in diagnosis
• tumor uptake or non-tumor uptake
• standard uptake values (SUV)
• tumor to background ratio
Tumor size from baseline and at 12 weeks diagnostic CT will be recorded 
and change in tumor response determined by routine computer processing 
techniques. If a contrast agent was used during the diagnostic CT, the 
Hounsfield units will be recorded and evaluated for change in tumor 
density. Documentation and follow up of cutaneous lesion(s) response(s)

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will be evaluated by the medical oncologist at baseline and at 12 weeks of 
treatment.
8.3.3 Analytic plan
The objective of the study is to examine how [F-18] FDG PET/CT as an 
imaging agent may be able to predict efficacy or early response as 
compared with CT imaging. Analyses will be made by Dr. Yu at Fox 
Chase Cancer Center utilizing individual lesions with a minimum of one 
lesion per patient up to a maximum of five lesions per patient. Given the 
patient population with metastatic disease, it is anticipated we will be 
analyzing up to 50 lesions. PET images will be scored using the following 
criteria:
Score = 0 Disease progression (< - 20%); Defined as the percentage 
change in SUV values in each paired image assessment to be less than a 
negative 20%, when baseline images are compared to week 4 images 
Score = 1 No response ( 20% to > - 20%); Defined as the percentage 
change in SUV values in each paired image assessment to be less than 
20% up to greater than or equal to a negative 20%, when baseline images 
are compared to week 4 images
Score = 2 Partial response (> 20% to < 50%); Defined as the percentage 
change in SUV values in each paired image assessment to be between > 
20% and < 50%, when baseline images are compared to week 4 images 
Score = 3 Successful response (> 50% to <90%); Defined as the 
percentage change in SUV values in each paired image assessment to be 
between > 50% and < 90%, when baseline images are compared to week 4 
images
Score = 4 Complete response (> 90%); Defined as the percentage 
change in SUV values in each paired image assessment to be >90%, when 
baseline images are compared to week 4 images CT imaging will utilize 
RESIST criteria and will also document changes in Hounsfield units 
utilizing the baseline and the week 12 studies; if a patient progresses at the 
week 6 imaging time point, the week six study will be used.
If a lesion is not detected on the pre treatment [F-18] FDG PET image
/CT or diagnostic CT image), the score for the paired image sets will be 
defined as not interpretable.
The descriptive statistics will include mean, SD, median, minimum, and 
maximum for continuous variables and the numbers and percentages for 
categorical variables. The statistical test will be two sided at the 0.05 level 
of significance with 95% confidence limit. The score of each variable will 
be calculated as an average of the lesion level score for each patient. 
Imaging data for SUVs, tumor to background ratios, lesion size, score will 
be analyzed and presented individually.
Summary statistics for changes in SUVs, tumor to background ratios,

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lesion size, and comparison scores will be analyzed and presented. A 
paired t-test will be used to evaluate the mean changes among pre- 
treatment, the subsequent imaging test, and 95% confidence internal for 
the changes in primary endpoints will be presented.
The change in images (i.e., [ [F-18]FDG PET SUV or Diagnostic CT 
tumor size changes) will be computed as the baseline value (pre-treatment) 
minus the appropriate post baseline (after mid-treatment) value. Changes 
from pre-treatment values in SUVs and target-to-background ratios, and 
qualitative scores for change in lesion uptake at each of the time-points 
will be explored for their ability to predict patient response to therapy.
The change in images (i.e.,  [F-18]FDG PET SUV or Diagnostic CT tumor 
size changes) will be computed as the baseline value (pre-treatment) minus 
the on treatment value. Changes from pre-treatment values in SUVs and 
target-to-background ratios, and qualitative scores for change in lesion 
uptake will be explored for their ability to predict patient response to 
treatment.
The statistic for determining the correlation between the [F-18] FDG 
PET/CT and other imaging modalities is the Pearson's correlation 
coefficient. If the assumption of normality does not hold, then Spearman's 
rank correlation coefficient will be computed. Pearson's correlation 
coefficients and the corresponding 2-sided 90% confidence intervals will 
be computed for the change in [F-18] FDG PET/CT and the change in 
Diagnostic CT from baseline to on treatment imaging (4 week/ 12 week 
for FDG PET and CT respectively). If the lower bound of the confidence 
interval is >0.4, then it will be concluded that the given pair of SUVs are 
correlated. In addition to Pearson's correlation coefficient, graphical 
displays of the data will be provided. All other secondary and exploratory 
correlations will be analyzed in the same manner as the primary 
correlations
FDG-PET While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow- 
up is a sign of PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the

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date of the initial abnormal FDG-PET scan).  If the positive FDG- 
PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is 
not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance will be prospectively described in the 
protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid 
with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image.
9.1 Study Assessments and Procedures
A signed, written informed consent and HIPAA consent form must be obtained from the 
subject prior to any study-specific procedures or assessments. Procedures conducted as 
part of the subject’s routine clinical management (e.g., blood count, imaging study) and 
obtained prior to signing of informed consent may be utilized for screening or baseline 
purposes provided these procedures are conducted as specified in the protocol. The study 
assessments schedules and visit windows are summarized below. Refer to Section 9.2, 
the Study Calendar for a complete list and schedule.
9.2 Screening and Baseline Assessments
9.1.1
Assessments within 4 Weeks of the First Dose
•
Baseline radiologic evaluation scan (CT/ MRI) for tumor 
assessment (Refer to Section 11.3)
•
Correlative PET/CT (for Fox Chase Cancer Center patients only)
•
Echo/MUGA
9.1.2
Assessments within 2 Weeks of the First Dose
•
Demography: date of birth, race and gender.
•
Medical history including:
o
Angiosarcoma specific history including: date of diagnosis, 
primary tumor type with histology/cytology determination, 
current stage of cancer, prior systemic treatment(s) for 
angiosarcoma, ongoing toxicity related to prior 
treatment(s); and history of other malignancies

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o
Prior surgery and/or radiotherapy (date, organ/anatomic 
region(s) of surgery and/or radiotherapy must be 
documented), other significant medical and surgical 
histories within the past 6 months.
•
Physical examinations: height (only recorded at baseline), body 
weight and current medical conditions.
•
Record all the medication(s) received within 2 weeks prior to the 
first dose of study medication and indicate if the medication is 
continuing.
•
Vital signs: body temperature, respiratory rate, blood pressure and 
heart rate.  At the baseline visit, blood pressure will be measured 
three times at approximately 2-minute intervals.  All three blood 
pressure values will be recorded on the CRF. These three values 
will be averaged to obtain the mean diastolic blood pressure and 
the mean systolic blood pressure. The mean diastolic and the mean 
systolic blood pressures are to be used to determine if the subject’s 
blood pressure is within the well-controlled range (<140/90 mm 
Hg).
If a subject presents with poorly controlled hypertension, defined 
as SBP ≥140 mmHg or DBP ≥90 mmHg, antihypertensive 
medication(s) will be initiated or adjusted with a goal to control the 
blood pressure to <140/90 mmHg.
•
ECOG PS, height and weight
•
Clinical laboratory assessments. Laboratory assessments will be 
performed as indicated in the Study Calendar in section 9.2. These 
assessments may be carried out within 3 days before the actual 
visit to allow flexibility in scheduling.  Assessments may be 
performed more frequently if clinically indicated.  Correction of 
electrolytes (most importantly, potassium, magnesium and 
calcium) to within normal ranges will take place prior to study 
entry and during study conduct as clinically indicated.
•
12-lead ECG with QTc measurement  (Appendix E)
•
Serum pregnancy test for women of childbearing potential. 
(Section 4.1.9)
9.1.3 Pre-first dose Eligibility Assessments
•
Physical examination: to identify any changes in the subject’s 
mental and medical conditions since baseline assessment that 
would make him/her ineligible for the study.
•
Vital Signs including: Temperature, Pulse, Respirations and Blood 
pressure measurements: subjects must have a blood pressure 
reading of <140/90mmHg to be eligible.  At the Day 1 visit, blood

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pressure will be measured three times, with each measurement 
separated from the prior measurement by at least 2 minutes. All 
three blood pressure values will be recorded on the CRF. These 
three values will be averaged to obtain the mean diastolic blood 
pressure and the mean systolic blood pressure.  The mean diastolic 
and the mean systolic blood pressures are to be used to determine 
if the subject’s blood pressure is within the well-controlled range.
It is particularly important to check the blood pressure of any 
subject for whom anti-hypertensive medication has been initiated 
and/or dosing has been adjusted during the Baseline Period. At 
least 24 hours must have elapsed between anti-hypertensive 
medication initiation or adjustment and BP measurement.  If, after 
treatment with anti-hypertensive medication, a subject’s mean 
diastolic and/or mean systolic blood pressure is not
<140/90mmHg, then further modifications of these medication(s) 
may be made while the subject is still in the Baseline Period. After 
further anti-hypertensive treatment, the subject’s blood pressure 
must then be rechecked to determine eligibility for the trial.
See Table 6.1 for instruction on blood pressure measurement and 
determination of mean blood pressure values.
•
ECOG PS: Any changes since baseline assessment will be 
recorded in the CRF. Subjects having deterioration of ECOG PS to
>2 will be excluded from the study.
•
Weight
•
Clinical Laboratory Assessments: Review results of all the other 
baseline assessments to re-confirm the subject’s eligibility for the 
study. Any screening laboratory result outside the normal range 
will be repeated prior to the first dose. All laboratory results must 
remain within the values outlined in the Inclusion Criteria (Section 
4.1), otherwise the subject is no longer eligible to participate in the 
study.

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9.2 Study 
Calendar
Screeningb
Prior to Every 
Cycle
Daily
Weeks 3,5,7
and 9
Even 
Numbered 
cycles
End of Therapy
Follow upl
Informed consent & HIPAAa
X
Medical history
X
Physical exam
X
X
X
X
Concurrent Meds
X
X
X
X
Vital signs (T, P, R, BPh)
Xh
Xh
X
X
Height
X
Weight
X
X
X
X
Performance status
X
X
X
X
PT/INR, APTT
X
X
X
X
CBC w/diff
X
X
X
X
GGT, Serum chemistryc
X
Xc
Xc
Xc
GGT, LFT’sd
Xd
MagnesiumC
X
β-HCG
Xe
TSH, free T4
X
X
X
UPC ratio
X
X
X
Echo/MUGAf
X
X
EKGg
Xg
Xg
Xg
Xg
Adverse Events
X
X
Xb
X
X
Radiologic Evaluation: 
CT or MRIi, j
X
X
Xk
Tumor Measurementsij,k
X
X
Xk
Correlative PET/CT
Xm
Xm
Pazopanibn
X
X
a:
Informed consent must be signed within 30 days of registration. If signature is outside that window the patient must initial and date their
original consent or sign a new consent.
b:
Pre-study H&P and all labs must be < 2 weeks before registration. Tumor measurements and radiologic evaluations must be < 4 weeks before
study drug initiation. EKG < 2 weeks before study drug initiation, ECHO/MUGA < 6 weeks before study drug initiation. Pre-study assessments 
may be used for C1D1 assessments if completed < 2 weeks before study drug initiation. AEs are to be recorded daily as they occur by the 
patient on their pill diary and collected after each cycle is complete. Daily AEs does not imply that the site should contact the patient daily for 
this assessment.
c:
Albumin, alkaline phosphatase, total bilirubin, direct bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus,
potassium, sodium, total protein, SGOT [AST], SGPT [ALT] and GGT. All laboratory tests with values that become clinically significant while 
subject is participating in study or < 28 days after last dose of study drug will be repeated until values return to baseline. Magnesium must be 
within normal limits. Please see footnote d for cycles 2 and 3.
d:
during weeks 3-9 only, obtain GGT, AST, ALT, T. Bili every other week ; liver function tests do not need to be included in the serum chemistry 
evaluation performed prior to cycles 2 and 3; all others chemistries as still required to be performed as per footnote c..
e:
Serum pregnancy test (women of childbearing potential) must be completed < 2 weeks before beginning treatment.
f:
Echo/MUGA will be repeated every 12 weeks in patients who received prior anthracycline.
g:
A 12-lead ECG will be obtained at Screening/Baseline, every 6 weeks during the first 6 months of the study and every 12 weeks in the next 6 
months. After 1 year on study, ECGs will be performed every 6 months.
h:
BP assessment are to be performed in triplicate, 2 minutes apart at both screening and on Cycle 1 Day 1, prior to treatment. BP assessments 
need only be performed 1 time on Day 1 for Cycles 2 and beyond. (section 9.1.2).
i:
Pre-study imaging for CNS metastases only as clinically indicated (see Section 4.2.2) 
j
Response to treatment will be measured using RECIST 1.1 criteria.
k:
Off-therapy evaluation. If PD documented during scheduled on-study assessment, tumor measurements and radiologic staging do not need to
be repeated.
l: Subjects will be followed for clinical assessments of disease status and updates on anti-cancer treatments. The first visit should be within 3 – 4 weeks 
then every 3 months for a maximum of two years from the date of the last subject enrolled or until death. Patients removed from study for 
unacceptable adverse events related to the study treatment will be followed until resolution/ stabilization of the adverse event. Any labs or scans 
relating to a toxicity or disease measurement will be conducted at an interval determined by the treating physician and results will be
recorded on the long term follow up case report forms.

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m:
PET FDG will be done only in FCCC patients at baseline < 2 weeks prior to initiation of drug therapy and  once after 3 weeks of 
drug therapy
n:       Pazopanib 800 mg p.o. once daily
10.1 Adverse Event
10.2 Definitions
10.2.1 Adverse Events (AE)
An Adverse event (AE) is any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medicinal (investigational) product, treatment 
or procedure regardless of whether it is considered related to the medical 
treatment or procedure (NCI CTEP Guidelines March 28, 2011)
10.2.2 Serious Adverse Event (SAE)
Serious Adverse Event (SAE) is an AE that is fatal or life threatening, 
requires inpatient hospitalization or prolongation of existing 
hospitalization (for > 24 hours), persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or is a 
congenital anomaly/ birth defect, or results in any important medical event 
that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent any of the above outcomes. A “life-threatening” 
adverse event places the patient at immediate risk of death in the judgment 
of the investigator or sponsor.
10.2.3 Severity Rating
The investigator will evaluate the severity of each adverse event. NCI 
Common Terminology Criteria for Adverse Events (CTCAE v.4.0) or 
study specific toxicity tables provided in the protocol define severity.  If 
not included in CTCAE v.4.0, severity is expressed in numerical grade 
using the following definitions:
•
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
•
Grade 2: Moderate-minimal, local or noninvasive intervention 
indicated; limiting age appropriate instrumental ADL.
•
Grade 3: Severe-severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care ADL.

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•
Grade 4: Life-threatening consequences; urgent intervention indicated.

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•
Grade 5: Death related to AE
10.2.4 Attribution/Relationship to study drug
•
Definite – clearly related
•
Probable – likely related
•
Possible – may be related
•
Unlikely – doubtfully related
•
Unrelated – clearly not related
10.2.5 Expectedness
An Expected Adverse Event is one where the specificity or severity is 
consistent with the current information available from the resources.
An Unexpected Adverse Event is one where the nature, severity, or 
frequency of the event is related to participation in the research is not 
consistent with either:
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the 
protocol-related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the current IRB- 
approved informed consent document, and (b) other relevant sources 
of information, such as product labeling and package inserts: or
2. The expected natural progression of any underlying disease, 
disorder, or condition of the subject (s) experiencing the adverse 
event and the subjects(s) predisposing risk factor profile for the 
adverse event.
(OHRP Guidance on reviewing unanticipated problems 2007)
10.3 Recording Responsibilities
10.3.1 Investigative site recording responsibilities:
Upon identification of an AE or SAE, the site investigator will utilize the 
above definitions to properly classify the event.  Each category listed 
above must be recorded for each event.
All AEs and SAEs will be recorded in the “AE case report forms” (CRF) 
and in progress reports with details about the grade and attribution of each 
episode, action taken with respect to the study drug, and the patient’s 
outcome will be recorded in the CRF. All events will be recorded on case 
report forms for the duration of the study until they resolve.
All SAEs will be recorded on the FDA MedWatch form 3500a or other 
sponsor-designated SAE reporting form After submitting the initial report

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it may be necessary to submit follow up reports to the QA Specialist/ 
Study Monitor should the event require further investigation.
10.4 Reporting Responsibilities
10.4.1 Investigative site reporting responsibilities:
•
The investigator/ site is responsible to report all SAEs to the the 
QA Specialist/ Study Monitor within 24 hours of becoming aware 
of the event.  A written report must follow within 48 hours.
•
Each investigator is responsible to report all AEs/SAEs to their 
local IRB following guidelines set by that IRB.  Fox Chase Cancer 
Center reserves the right to request an event be reported to the IRB 
at their discretion.  Copies of events reviewed by the IRB must be 
sent to Extramural Research Program (ERP) Regulatory 
Coordinator.
•
If the investigator or IRB feels the event warrants a revision to the 
informed consent that was not already initiated by the ERP, draft 
revisions will be made in track changes and submitted to  for 
consideration.  Any consent revisions must receive ERP approval 
prior to submission to the IRB.
•
Any investigator who is in doubt of whether a particular AE needs 
to be reported is directed to call the QA Specialist / Study Monitor 
who will review and verify the particular AE’s reporting 
requirements with the Principal Investigator.
•
If the results of an investigator or ERP investigation show an 
adverse event not initially determined to be reportable is so 
reportable, the investigator will report the event following the 
above guidelines based on the date the determination is made.
•
Copies of all related correspondence and reporting documents must 
be submitted to the ERP Regulatory Coordinator and will be 
maintained in a regulatory file.
The participating site should report events to: 
Quality Assurance Specialist / Study Monitor 
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia PA 19111
Phone: 215-214-3704
Fax: 215-214-1511
10.4.2 Extramural Research Program (ERP) Reporting Responsibilities: 
Adverse events which meet all of the following criteria must be
reported to all participating institutions for IRB submission within 2 
weeks of notification of the event.

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i.
Unexpected (in terms of nature, severity, or frequency) given
(a) the research procedures that are described in the protocol- 
related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of 
the subject population being studied;
ii. Possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the 
procedures involved in the research); and
iii. Serious (refer to above definition) or otherwise one that 
suggests that the research places subjects or others at a greater 
risk of physical or psychological harm than was previously 
known or recognized.
If the adverse event requires modification of the study protocol and 
informed consent, these changes will be provided to all participating 
institutions in the form of an amendment from ERP for each site’s 
IRB of record along with the report of the adverse event.
SAEs that related, unexpected, fatal, or life-threatening are 
reportable through the Food and Drug Administration (FDA) 
MedWatch program by telephone or fax no later than 7 calendar 
days after initial receipt of the information. Further information on 
the timing of submissions are as directed by FDA guidelines 
(http://www.fda.gov/medwatch/index.html).  Serious, unexpected 
events that suggest significant clinical risk will be submitted to 
within 15 calendar days after initial receipt of this information.
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-800-FDA-0178
http://www.fda.gov/medwatch/report.htm
Mandatory Drug Reporting: 
Central Document Room
Center for Drug Evaluation and Research 
Food and Drug Administration
12229 Wilkins Avenue
Rockville, MD 20852
Office of Post-Marketing Drug Risk Assessment (HFD 730) 
Center for Drug Evaluation and Research
Food and Drug Administration 
5600 Fishers Lane
Rockville, MD 20857
(301) 827-3169 for any further questions regarding where to 
send drug mandatory reporting forms

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Reporting to Novartis and NCCN:
Any serious adverse events which occur during the clinical study or 
within 30 days of receiving the last dose of study medication, 
whether or not related to the study drug, will be reported by the 
investigator. In addition, any SAEs which occur as a result of 
protocol specific diagnostic procedures or interventions must also be 
reported. Follow-up information will be forwarded to Novartis 
within 24 hours.
All serious adverse events will be reported by the QA Specialist / 
Study Monitor by facsimile within 24 hours to Novartis. 
Novartis Patient Safety Fax: (877) 778-9739
And
NCCN via fax at 215-358-7699 or e-mailed to
ORPReports@nccn.org
SAEs brought to the attention of the Quality Assurance Specialist / 
Study Monitor at any time after cessation of pazopanib and 
considered by the investigator to be related or possibly related to 
pazopanib will be reported to Novartis if and when they occur. 
Additionally, in order to fulfill international reporting obligations, 
SAEs that are related to study participation (e.g., procedures, 
invasive tests, change from existing therapy) or are related to a 
concurrent medication will be collected and recorded from the time 
the subject consents to participate in the study until the follow up 
period is ended.
In addition, the Investigator will adhere to the safety reporting 
requirements and timelines described in the Clinical Trial Agreement 
with National Comprehensive Cancer Network (NCCN).
10.5 Pregnancy
All WOCBP will be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation.

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In the event of a confirmed pregnancy in a patient participating in the study, the 
Investigator must immediately notify the QA Specialist / Study Monitor who will 
either notify or have their designee notify Dr. von Mehren, the Principal 
Investigator and Novartis.
11.1 Measures of Effect
Response Evaluation Criteria in Solid Tumors (RECIST)
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used for 
objective tumor response assessment. Assessments will be performed after every two 
cycles of treatments. Once protocol treatment has been completed subjects will be assessed 
every three months or sooner as indicated and judged by treating physicians.
11.2 Definitions.
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response. Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.
11.3 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as
>20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable.  Sarcomas arising in a previously irradiated 
site will be considered measurable. Sarcoma lesions that have been treated with 
therapeutic intent will be considered measurable if they have increased in size by 
more than 20%.
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed.

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Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts will not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, will be identified as 
target lesions and recorded and measured at baseline.  Target lesions will be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
will be selected.  A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions will be identified as non- 
target lesions and will also be recorded at baseline. Measurements of these 
lesions are not required, but the presence, absence, or in rare cases unequivocal 
progression of each will be noted throughout follow-up.
11.4 Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations will be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique will be used to 
characterize each identified and reported lesion at baseline and during follow-up.
54

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Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam.
Clinical lesions  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.
CT and MRI This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion will 
be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans).
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used will be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up will be the 
same as was used at baseline and the lesions will be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner will be used and the image 
acquisition protocol will be followed as closely as possible to prior scans.  Body 
scans will be performed with breath-hold scanning techniques, if possible.
11.5 Response Criteria 
Evaluation of Target Lesions
Complete Response (CR):Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to
<10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters
Progressive Disease (PD):At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note:  the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study

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Evaluation of Non-Target Lesions
Complete Response (CR):Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological 
in size (<10 mm short axis)
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits
Progressive Disease (PD):Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician will prevail in such circumstances, and the 
progression status will be confirmed at a later time by the review panel (or 
Principal Investigator).
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.

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Amendment 7 Version Date 12/12/2018
For Patients with Measurable Disease (i.e., Target Disease)
Table 11.1
Target
Lesions
Non-Target
Lesions
New
Lesions
Overall
Response
Best Overall Response
when Confirmation is 
Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
CR
Not
evaluated
No
PR
PR
Non-
CR/Non- 
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-
CR/Non- 
PD/not 
evaluated
No
SD
documented at least
once >4 wks. from 
baseline**
PD
Any
Yes or
No
PD
Any
PD***
Yes or
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**    Only for non-randomized trials with response as primary endpoint.
*** In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression.
Note:
Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time  
will be reported as “symptomatic deterioration.”  Every effort should be made 
to document the objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Table 11.2
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised
11.6 Duration of Response
Duration of overall response:  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).

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The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.
Duration of stable disease:  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, including the baseline 
measurements.
11.6.1 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of
progression or death, whichever occurs first.
11.6.2 Response Review
Patients that have a CR or PR by RECIST 1.1 may have the imaging 
studies documenting that response centrally reviewed by the department of 
radiology in coordination with the study PI Dr. Margaret von Mehren.   If 
requested, baseline, the initial response image and the confirming scan 
must be forwarded in DICOM format to the QA Specialist / Study Monitor 
for review.
12.1 Statistical Considerations
12.2 Study Design/Endpoints
This study’s primary objective is to estimate the chance of Progression Free
Survival at 3 months and test the hypothesis that it exceeds 5% in angiosarcoma 
patients treated with pazopanib. The secondary objectives are to estimate the 
response rate (RR) defined as Complete Response (CR) and Partial Response 
(PR) in angiosarcoma patients treated with pazopanib, to assess overall survival of 
patients treated with pazopanib and to gather more safety data for pazopanib in 
this patient population. Additionally, Fox Chase Cancer Center, alone; will 
explore the ability of PET with RGD-5 and FDG imaging to assess response.
Using a Simon design with n1=15, n2=30, we will submit 15 patients initially and 
evaluate them for response and any time up to 3 months. If at least 1/15 patient 
responds, then another 15 patients will be recruited. If at least 4/30 patients 
respond we will reject the null of 5% response and accept the 20% alternative. 
Otherwise, the study will be terminated after the initial 15 patients are evaluated 
and the null hypothesis accepted. The study has 46% chance of early stopping 
under the null, 3.5% under the alternative.  It has overall 86% power and 5.8% 
type I error.
12.3 Early stopping for excessive toxicity

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We will test the hypothesis that grade 4 toxicity (despite maximum supportive 
care) is at most 5% versus the alternative that it is a least 25% .The design will 
have a 54% chance of early stopping if the true toxicity is at least 25% and 0.6% 
chance of early stopping in error. It will declare the treatment too toxic with 82% 
power if the true toxicity is at least 25%. The study will be terminated early if 
ever 4 of the initial 15 patients have grade 4 or higher toxicity despite maximum 
supportive care. Similarly, if at any point 6 patients have grade 4 or higher 
toxicity the study will also be terminated and declared too toxic. Properties of the 
stopping rule and final decision rule are tabulated below.
Table entries as percents
True toxicity
10
15
20
25
30
35
40
p(early stop)
6
18
35
54
70
82
91
p(decision)
10
33
61
82
93
98
99
p(early stop): chance that trial is terminated for excess toxicity at or before 15 
patients are evaluated.
p(decision): chance that treatment is declared too toxic either early or at the latest 
after patient 30 has been evaluated.
12.2.1 Methods of data analysis
At completion PFS and OS will be estimated using the method of Kaplan and 
Meier. Patients lost to follow up or followed until the end of the study will be 
censored at the time and conditions of their last visit. Standard estimates of the 
binomial proportion will be used to estimate and place confidence bounds on the 
several response rates.
12.3 Sample Size/Accrual Rate
The planned sample size is 30 patients. We estimate the accrual will be complete 
in 2 years, with 1-2 patients per month across the multiple sites.
12.4 Analysis of Secondary Endpoints
Overall survival, RR and toxicity data will be collected and summarized in a 
descriptive fashion.  The analysis of the imaging correlative studies to be 
performed at FCCC are outlined in section 8.3.3 of the protocol.
12.5 Reporting and Exclusions
12.4.1 Evaluation of toxicity: All patients will be evaluable for toxicity 
from the time of their first treatment with pazopanib.
12.4.2 Evaluation of response:  All patients included in the study must be 
assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible. Each patient will be assigned

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one of the following categories: 1) complete response, 2) partial response,
3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, 
or 9) unknown (not assessable, insufficient data).
All of the patients who met the eligibility criteria (with the possible 
exception of those who received no study medication) should be included 
in the main analysis of the response rate.  Patients in response categories 
4-9 should be considered to have a treatment failure (disease progression). 
Thus, an incorrect treatment schedule or drug administration does not 
result in exclusion from the analysis of the response rate.
13.1 Data and Safety Monitoring Plan
13.2 Monitoring plan
The QA Specialist / Study Monitor will monitor the medical and study records of
each participant accrued at each site throughout the course of the study.  In 
addition, the QA Specialist / Study Monitor will collect and report data to the 
study Principal Investigator who will review these data on a regular basis at a rate 
dependent on subject accrual. All serious adverse events (SAEs) will be reviewed 
on a real time basis first by the study site PI and subsequently by the ERP and 
study PI as applicable.
13.3 Extramural Data Safety Monitoring Committee
Interim analysis of toxicity, outcome and ongoing scientific investigations may be
performed every 6 months by the Extramural Data Safety Monitoring Committee 
(EDSMC).  In this capacity the EDSMC will serve as an advisory committee to 
The ERP. The EDSMC will review those aspects of this trial that are outlined in 
the responsibilities section of the Extramural Data and Safety Monitoring Plan 
(DSMP).  If the committee decides that changes should be made to this trial, it 
will make recommendations in writing to the Study PI, the Extramural Research 
Committee and Division Medical Director, which, in turn, have the authority to 
approve or disapprove these recommendations. These changes will be discussed 
with the Study Principal Investigator before they are implemented. These 
changes may include early termination of accrual.  Other changes might include 
altering the accrual goals or changing the eligibility criteria for the trial.
14.1 Administrative
This study will be conducted in accordance will local, state and Federal regulations
and according to accepted good clinical practice guidelines.
14.2 Data Reporting
The QA Specialist / Study Monitor will request case report form submission upon
resolution of outstanding queries.  Participating sites are responsible to respond to 
queries prior to the next scheduled monitoring visit.  Participating sites are

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responsible for submitting case report forms to the the QA Specialist / Study 
Monitor within two weeks of request.
The QA Coordinator is responsible for compiling and submitting data to the study 
PI and statistician on an ongoing basis for monitoring as described in the data 
safety monitoring plan and reporting to the Extramural Data and Safety 
Monitoring Committee.
The ERP Regulatory Coordinator is responsible for distributing and tracking 
review of all IND Action Letters, Safety Reports, study specific Serious Adverse 
Events
14.3 Retention of Records
Time points for the retention of records are described in detail in the contract
between the grantor and ERP and passed on to the participating site.  Please refer 
to the study specific terms for specific time points.  In all cases the QA Specialist
/ Study Monitor must be notified of any plans to move records to an offsite 
location prior to doing so. The QA Specialist / Study Monitor will notify the ERP 
Regulatory Coordinator.
14.4 Study Agents
Any study agent supplied through the ERP from the manufacturer or a third party
distributor may not be used for any purpose outside the scope of this protocol. 
The agent may not be transferred to any party not participating in the clinical trial.

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15.0 References
1.
Orchard, G.E., et al., An immunocytochemical assessment of 19 cases of 
cutaneous angiosarcoma. Histopathology, 1996. 28(3): p. 235-40.
2.
Stewart, F.W. and N. Treves, Lymphangiosarcoma in postmastectomy 
lymphedema; a report of six cases in elephantiasis chirurgica. Cancer, 1948. 1(1): 
p. 64-81.
3.
Stewart, F.W. and N. Treves, Classics in oncology: lymphangiosarcoma in 
postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. 
CA: a cancer journal for clinicians, 1981. 31(5): p. 284-99.
4.
Yap, J., et al., Sarcoma as a second malignancy after treatment for breast cancer.
International journal of radiation oncology, biology, physics, 2002. 52(5): p. 1231-
7.
5.
Antman, K., et al., An intergroup phase III randomized study of doxorubicin and 
dacarbazine with or without ifosfamide and mesna in advanced soft tissue and 
bone sarcomas. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology, 1993. 11(7): p. 1276-85.
6.
Borden, E.C., et al., Randomized comparison of three adriamycin regimens for 
metastatic soft tissue sarcomas. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology, 1987. 5(6): p. 840-50.
7.
Edmonson, J.H., et al., Randomized comparison of doxorubicin alone versus 
ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against 
advanced soft tissue sarcomas. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology, 1993. 11(7): p. 1269-75.
8.
Verweij, J., et al., Randomized phase II study of docetaxel versus doxorubicin in 
first- and second-line chemotherapy for locally advanced or metastatic soft tissue 
sarcomas in adults: a study of the european organization for research and 
treatment of cancer soft tissue and bone sarcoma group. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology, 2000. 
18(10): p. 2081-6.
9.
Fata, F., et al., Paclitaxel in the treatment of patients with angiosarcoma of the 
scalp or face. Cancer, 1999. 86(10): p. 2034-7.
10.
Penel, N., et al., Phase II trial of weekly paclitaxel for Unresectable 
Angiosaroma: the ANGIOTAX Trial. Journal of Clinical Oncology, 2008 
26:5269-5274.
11.
Arbiser, J.L., et al., Overexpression of VEGF 121 in immortalized endothelial 
cells causes conversion to slowly growing angiosarcoma and high level 
expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo. The 
American Journal of Pathology, 2000. 156(4): p. 1469-76.
12.
Maki, R.G., et al., Phase II study of sorafenib in patients with metastatic or 
recurrent sarcomas. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology, 2009. 27(19): p. 3133-40.
13.
M. Agulnik, S.H.O., M. von Mehren, B. Jovanovic, B. Brockstein, R. S. 
Benjamin, A. M. Evens, An open-label multicenter phase II study of bevacizumab 
for the treatment of angiosarcoma. J Clin Oncol, 2009 27:15s (suppl; abstr 
10522)
14.
Folkman, J., Tumor angiogenesis: therapeutic implications. The New England 
journal of medicine, 1971. 285(21): p. 1182-6.

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15.
Folkman, J., Angiogenesis and angiogenesis inhibition: an overview. EXS, 1997.
79: p. 1-8.
16.
Ferrara, F., M. Falchi, and S. Puricelli, [Angiogenesis and antitumor therapy].
Annali italiani di medicina interna : organo ufficiale della Societa italiana di 
medicina interna, 1997. 12(1): p. 26-30.
17.
Kumar, R., et al., Pharmacokinetic-pharmacodynamic correlation from mouse to 
human with pazopanib, a multikinase angiogenesis inhibitor with potent 
antitumor and antiangiogenic activity. Molecular cancer therapeutics, 2007. 6(7): 
p. 2012-21.
18.
Sternberg, C.N., et al., Pazopanib in locally advanced or metastatic renal cell 
carcinoma: results of a randomized phase III trial. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 2010. 28(6): p. 
1061-8.
19.
Sleijfer, S., et al., Pazopanib, a multikinase angiogenesis inhibitor, in patients 
with relapsed or refractory advanced soft tissue sarcoma: a phase II study from 
the European organisation for research and treatment of cancer-soft tissue and 
bone sarcoma group (EORTC study 62043). Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology, 2009. 27(19): p. 3126-32.
20.
Billemont, B., et al., Blood glucose levels in patients with metastatic renal cell 
carcinoma treated with sunitinib. British journal of cancer, 2008. 99(9): p. 1380- 
2.

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

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APPENDIX B
Determination of Creatinine Clearance (ClCR)
Estimation of creatinine clearance using Cockroft and Gault method:
ClCR for males (mL/min) =
[140 - age (years)] X [weight (kg)]
(72) X [Serum creatinine (mg/dL)]
ClCR for females (mL/min) =
(0.85) X [140 - age (years)] X [weight (kg)]
(72) X [Serum creatinine (mg/dL)]
For SI units:
ClCR for males (mL/min) =
[140 - age (years)] X [weight(kg)] X (1.23)
[Serum creatinine (µmol/L)]
ClCR for females (mL/min) =
[140 - age(years)] X [weight(kg)] X (1.05)
[Serum creatinine (µmol/L)]
Calculation of creatinine clearance based on 24-hour urinary creatinine excretion and 
concurrent serum creatinine levels:
ClCR = CU·V
CCR
Here, CU is the concentration of creatinine in the urine (mg/dL or µmol/L, for SI units), V
is the urine volume (in mL per minute of urine produced during the collection period),
CCR is the serum creatinine concentration (mg/dL or µmol/L, for SI units), and ClCR is the 
creatinine clearance in mL per minute.

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APPENDIX C
Urine Protein Creatinine Ratio (UPC)
Clinical meaning of UPC
There is a good correlation between the ratio of protein concentration to creatinine 
concentration in a random urine sample and the amount of protein excreted over 24 
hours. Creatinine excretion is fairly constant throughout the day regardless of changes in 
urine flow rate.
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day. 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day.
Normal protein excretion is <100 mg to 150 mg/24 hours and is similar for men and 
women.
Calculating UPC
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL).
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs.
Example: Subject has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL. 
UPC ratio= (90 mg/dL) / (30 mg/dL) = 3
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a 
24-hour period.
Units for UPC ratio
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the 
same units (mg/dL, g/L, or μmol/L). If, for example, protein concentration is expressed in 
mg/dL and creatinine concentration is expressed in μmol/L, conversion of one of the 
concentration values is required. Conversion factors are:
From
To
Conversion Factor
Conventional Units: mg/dL
SI Units: μmol/L
Multiply by 88.4
SI Units: μmol/L
Conventional Units: mg/dL
Divide 88.4
References:
Xin G, Wang M, Jian L, Xu F, Wang H. Protein-to-creatinine ratio in spot urine samples 
as a predictor of quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39. 
NKF: NKF KDOQI Guidelines [Internet]. National Kidney Foundation; and. KDOQI 
Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and 
Stratification. Available from 
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm

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

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Bazett’s Formula
APPENDIX E
Corrected QT (QTC) = Bazett's Formula = QT Interval / √ (RR interval)
RR is the interval from the onset of one QRS complex to the onset of the next QRS 
complex, measured in seconds often derived from heart rate (HR)
RR Interval = 60/HR
Here QT is measured in milliseconds

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Toxicity 
Grade
Diarrhea
(includes diarrhea of small bowel or colonic origin and/or ostomy 
diarrhea)
1
Increase of <4 stools/day over baseline; mild increase in ostomy output
compared to baseline
2
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output
compared to baseline
3
Increase of ≥7 stools/day over baseline; incontinence; hospitalization
indicated; severe increase in ostomy output compared to baseline; limiting 
self care activities of daily living
4
Life threatening consequences, urgent intervention indicated
5
Death
APPENDIX F:
Supportive Care Guidelines for Diarrhea, Nausea, and Vomiting
These general guidelines are provided to facilitate subject care in the event of diarrhea, 
thereby avoiding serious complications. Guidelines such as these should never replace 
sound clinical judgment.  Experience thus far suggests that use of monotherapy 
pazopanib is associated with an increased incidence of diarrhea, primarily of Grade 1 or
2.  In rare cases, diarrhea can be debilitating and potentially life threatening, with 
dehydration, renal insufficiency, and electrolyte imbalances.
Standardized and universal guidelines have been developed by an American Society of 
Clinical Oncology panel for treating chemotherapy-induced diarrhea [Benson, 2004].
Early identification and intervention is critical for the optimal management of 
diarrhea.  A subject’s baseline bowel patterns should be established so that changes in 
patterns while on treatment can be identified. An assessment of frequency, consistency, 
and duration of diarrhea, as well as knowledge of other symptoms such as fever, 
cramping, abdominal pain, nausea, vomiting, dizziness and thirst should be taken at 
baseline, permitting identification of patients at high risk of diarrhea. Patients will be 
educated on signs and symptoms of diarrhea with instructions to report any changes in 
bowel patterns to the study site physician.
The NCI CTCAE Version 4.0 criteria for defining diarrhea are provided below.
Uncomplicated diarrhea is considered mild to moderate and is defined as CTCAE Grade 
1 to 2 with no complicating signs or symptoms.
Complicated diarrhea is severe and defined as CTCAE Grade 3 or 4 or Grade 1 or 2 with 
one or more of the following signs or symptoms: severe cramping, ≥Grade 2 
nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, 
obvious bleeding, dehydration.

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Management Guidelines
Uncomplicated diarrhea of CTCAE Grade 1 or 2:
•
Hydration:  have subject drink 8 to 10 large glasses (approximately 2 liters) of clear 
non-caffeinated liquids a day (e.g., broth or electrolyte-containing sports drinks).
•
If Grade 2 diarrhea, consider dose reduction of investigational products.
•
Dietary modifications: have subject stop all lactose-containing products and eat 
frequent, small meals
•
Pharmacologic intervention using loperamide:
•
Begin loperamide at initial dose of 4 mg followed by 2 mg every 4 hours or after 
every unformed stool. The recommended maximum daily dose of loperamide is 
16 mg/day.
•
Continuation of loperamide is suggested until diarrhea-free for 12 hours.
•
If mild to moderate diarrhea persists for more than 24 hours, administer 
loperamide 2 mg every 2 hours and pursue evaluation for other treatable causes.
•
If mild to moderate diarrhea persists after 48 hours total treatment with 
loperamide, discontinue study drug(s) and consider initiation of second-line 
agents (lomotil, octreotide).
Complicated diarrhea of CTCAE Grade 3 or 4 diarrhea or Grade 1 or 2 with 
complicating features requires aggressive management:
•
Subject must call study site physician immediately in response to any event of 
severe diarrhea with or without complications as listed above.
•
Hospitalization may be required for subjects most at risk for life-threatening 
complications.
•
Interrupt investigational products until symptoms resolve; consider 
reintroducing at a reduced dose (discuss with Novartis Medical 
Monitor or designee).
•
If loperamide has not been initiated, begin loperamide usage immediately at an 
initial dose of 4 mg followed by 2 mg every 2 hours or after every unformed 
stool. The recommended maximum daily dose of loperamide is 16 mg/day.
•
If no improvement in severity after 24-hours of maximal loperamide dosing, 
subject must visit study site and be evaluated:
•
For dehydration, use intravenous fluids as appropriate.
•
Antibiotic therapy should be considered in patients, who present with signs and 
symptoms of bacterial diarrhea such as fever, bloody diarrhea, and presence of 
fecal leukocytes. Investigators should have a low threshold to start such 
treatment in patients with Grade 3 or Grade 4 neutropenia.

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•
Before initiation of antimicrobial therapy, stool cultures should be obtained.
When bacterial etiology for diarrhea is suspected, study-treatment and anti- 
motility agents (loperamide or others) should be held.
•
Intervention will be continued until diarrhea free for 24 hours.
Alternative Pharmacologic Intervention for Uncomplicated and Complicated 
Diarrhea
•
Lomotil (dephenoxylate 2.5 mg + atropine 0.025 mg) can be used. The 
recommended dose is 2 tablets 4 times daily. When diarrhea is under control, a 
dose reduction will be attempted.
•
The synthetic octapeptide, octreotide, has been shown to be effective in the 
control of diarrhea induced by fluoropyrimidine-based chemotherapy regimens 
when administered as an escalating dose by continuous infusion or 
subcutaneous injection. Octreotide can be administered at doses ranging from 
100 µg twice daily to 500 µg 3 times daily, with a maximum-tolerated dose of 
2000 µg 3 times daily in a 5-day regimen.
Nausea and Vomiting
Every attempt will be made to control nausea and vomiting in subjects who have emesis 
and are unable to retain pazopanib.
Routine pre-medication for nausea is not necessary, but symptomatic subjects should be 
treated with standard anti-nausea/anti-emetic therapy as necessary.
If a subject vomits after taking study medication, the subject will be instructed not to take 
a replacement dose on that same day. The subject will resume taking pazopanib at the 
next scheduled dose on the following day.  If vomiting persists, then the subject should 
contact their physician.
To prevent or treat nausea and vomiting standard medications are recommended. 
Depending upon approved medications in your region, these may include: 5-HT3 receptor 
antagonist (granisetron, ondansetron, dolasetron mesylate); NK-1 receptor antagonists 
such as aprepitant,  metoclopramide,  phenothiazines (prochlorperazine); corticosteroids, 
(dexamethasones, prednisone); and cannibinoids (dronabinol).
WARNING: Ondansetron  Safety.
Ondansetron (Zofran) IV: Drug Safety Communication - QT prolongation 
AUDIENCE: Oncology, Surgery, Gastroenterology
ISSUE: The U.S. Food and Drug Administration (FDA) is informing healthcare 
professionals and the public that preliminary results from a recently completed clinical 
study suggest that a 32 mg single intravenous dose of ondansetron (Zofran, ondansetron 
hydrochloride, and generics) may affect the electrical activity of the heart (QT interval

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prolongation), which could pre-dispose patients to develop an abnormal and potentially 
fatal heart rhythm known as Torsades de Pointes.
There were changes to the Zofran drug label to remove the 32 mg single intravenous 
dose. The updated label will state that ondansetron can continue to be used in adults and 
children with chemotherapy-induced nausea and vomiting at the lower intravenous dose 
recommended in the drug label, a dose of 0.15 mg/kg administered every 4 hours for 
three doses; however, no single intravenous dose should exceed 16 mg. Information from 
the new clinical study will be included in the updated drug label.
BACKGROUND: Zofran (ondansetron) is in a class of medications called 5-HT3 
receptor antagonists. It is used to prevent nausea and vomiting caused by cancer 
chemotherapy, radiation therapy and surgery. FDA will evaluate the final study results 
when available, and will work with Novartis to explore an alternative single dose 
regimen that is both safe and effective for the prevention of chemotherapy-induced 
nausea and vomiting in adults.
RECOMMENDATION: The new information on QT prolongation does not change any 
of the recommended oral dosing regimens for ondansetron.  It also does not change the 
recommended lower dose intravenous dosing of ondansetron to prevent post-operative 
nausea and vomiting.
•
The use of a single 32 mg intravenous dose of ondansetron should be avoided.
New information indicates that QT prolongation occurs in a dose-dependent 
manner, and specifically at a single intravenous dose of 32 mg.
•
Patients who may be at particular risk for QT prolongation with ondansentron are 
those with congenital long QT syndrome, congestive heart failure, 
bradyarrhythmias, or patients taking concomitant medications that prolong the QT 
interval
•
Electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia) should be 
corrected prior to the infusion of ondansetron.
•
The lower dose intravenous regimen of 0.15 mg/kg every 4 hours for three doses 
may be used in adults with chemotherapy-induced nausea and vomiting. 
However, no single intravenous dose of ondansetron should exceed 16 mg due to 
the risk of QT prolongation.
•
The new information does not change any of the recommended oral dosing 
regimens for ondansetron, including the single oral dose of 24 mg for 
chemotherapy induced nausea and vomiting.
Healthcare professionals and patients are encouraged to report adverse events or side 
effects related to the use of this product to the FDA's MedWatch Safety Information and 
Adverse Event Reporting Program:
•
Complete and submit the report Online: www.fda.gov/MedWatch/report.htm

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•
Download form or call 1-800-332-1088 to request a reporting form, then complete 
and return to the address on the pre-addressed form, or submit by fax to 1-800- 
FDA-0178
Read the MedWatch safety alert, including a link to the Drug Safety Communication, at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedical 
Products/ucm310219.htm
References:
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et al.,
Recommended Guidelines for the Treatment of Cancer-Inducted Diarrhea.  J Clin Oncol. 
2004, 22; 2918-26.
U.S. Food and Drug Adminstration (FDA), GlaxoSmithKline (GSK); (6/2012) 
http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm

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APPENDIX G
Pazopanib Pill Diary

OER-SAR-043
Pazopanib Pill Diary
OER-SAR-043- 
Initials 
Weeks 
Page 1
OER-SAR-043 Phase II Study Evaluating the role of Pazopanib in Angiosarcoma
Instructions: The study coordinator will write in the dose you are supposed to take in the 
top row.  In each row write the time you took that day’s dose. Pazopanib should be taken 
once every day without food.   Pills should be taken at least 1 hour before or 2 hours after 
eating.  Pills should be swallowed whole.  They cannot be crushed or broken. You should try 
to take the pills at about the same time every day.  If you vomit after taking the tablet(s), you 
must not take another dose that day. You should take your next dose 1 day later at about the 
same time.
When the form is complete please initial it at the bottom and return the form to your study coordinator.
Pazopanib 
Dose
mg
Number of pills
for each
Comments
Date
Time
Write any reason you had to miss a dose. Write any side
effects here. Write down any medications you take for side 
effects.  And write down any thing else you think may be
Patient Initials 
Date Reviewed by Coordinator & Initials 
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