Conditions: Adult Alveolar Soft Part Sarcoma Adult Angiosarcoma Adult Desmoplastic Small Round Cell Tumor Adult Epithelioid Hemangioendothelioma Adult Epithelioid Sarcoma Adult Extraskeletal Myxoid Chondrosarcoma Adult Extraskeletal Osteosarcoma Adult Fibrosarcoma Adult Leiomyosarcoma Adult Liposarcoma Adult Malignant Peripheral Nerve Sheath Tumor Adult Rhabdomyosarcoma Adult Synovial Sarcoma Adult Undifferentiated Pleomorphic Sarcoma Malignant Adult Hemangiopericytoma Recurrent Adult Soft Tissue Sarcoma Sarcoma Stage III Adult Soft Tissue Sarcoma AJCC v7 Stage IV Adult Soft Tissue Sarcoma AJCC v7
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 54
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Pazopanib hydrochloride may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether gemcitabine hydrochloride is more effective with or without pazopanib hydrochloride in treating patients with soft tissue sarcoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To investigate whether treatment with gemcitabine (gemcitabine hydrochloride) plus pazopanib (pazopanib hydrochloride) improves the median progression-free survival (PFS) of patients with metastatic soft tissue sarcoma when compared to gemcitabine plus placebo.

SECONDARY OBJECTIVES:

I. To assess overall response in this population to gemcitabine plus pazopanib compared to gemcitabine plus placebo.

II. To assess overall survival (OS) in this population to gemcitabine plus pazopanib compared to gemcitabine plus placebo.

III. To investigate differences in treatment response in different histologic subgroups (liposarcoma vs. all other eligible soft tissue sarcoma subtypes).

IV. To evaluate the safety and tolerability of the combination of gemcitabine plus pazopanib.

V. To assess the progression-free survival and overall response in patients treated with single agent pazopanib following administration of gemcitabine in the cross-over portion of this study.

VI. To collect specimens for an exploratory analysis of potential biomarkers that predict response in patients receiving combination therapy with gemcitabine plus pazopanib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and pazopanib hydrochloride orally (PO) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive single-agent pazopanib hydrochloride PO daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed up every 3 months.

Arms:
arm 1: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and pazopanib hydrochloride PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and placebo PO on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive single-agent pazopanib hydrochloride PO daily. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Gemcitabine intervention 2: Gemcitabine Hydrochloride intervention 3: Laboratory Biomarker Analysis intervention 4: Pazopanib intervention 5: Pazopanib Hydrochloride intervention 6: Placebo Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given PO intervention 5: Given PO intervention 6: Given PO

Protocol document:
Prot_SAP_000.pdf: 
Version 3: 10/18/2016 
 
i
Oregon Health & Science University 
OHSU Knight Cancer Institute 
IRB Protocol #: 7943 
 
TITLE:  A Randomized, Double-Blind Phase II, Study of Gemcitabine Alone or in     
   Combination with Pazopanib for Refractory Soft Tissue Sarcoma 
 
Coordinating Center: 
 
Oregon Health & Science University Knight Cancer Institute 
 
Principal Investigator: 
Christopher W. Ryan, M.D.  
Hematology/Oncology  
Oregon Health & Science University Knight Cancer Institute 
3303 SW Bond Ave., CH14R  
Portland, OR 97239  
(503) 494-8487 
 
Co-Investigators: 
 
Lara Davis, M.D. 
 
 
 
 
Hematology/Oncology, OHSU 
 
Suman Malempati, M.D.  
Pediatric Oncology, OHSU  
 
Atiya Mansoor, M.D.  
Pathology, OHSU  
 
Yiyi Chen, Ph.D  
Biostatistics, OHSU 
 
Data Manager / 
            Phil Norr 
Study Coordinator:             Oregon Health & Science University Knight Cancer Institute  
 
            503-494-0825 
 
 
Final Protocol Date:  
10/12/2011 
Protocol Revision Dates: 
3/26/2013   
 
 
08/20/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 


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iii
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PAGE 
SCHEMA ................................................................................................................................................................ ii 
TABLE OF CONTENTS ....................................................................................................................................... iii 
1. OBJECTIVES .............................................................................................................................................. 5 
1.1. 
Primary Objective ............................................................................................................................. 5 
1.2. 
Secondary Objectives ....................................................................................................................... 5 
2. BACKGROUND ......................................................................................................................................... 5 
2.1 
 Soft Tissue Sarcomas ....................................................................................................................... 5 
2.2     Angiogenesis and VEGF....................................................................................................................... 5 
2.3     VEGF and Soft Tissue Sarcoma ........................................................................................................... 6 
2.4  
Pazopanib .......................................................................................................................................... 6 
2.5  
Pazopanib and Soft Tissue Sarcoma ................................................................................................. 7 
2.6  
Gemcitabine and Soft Tissue Sarcoma ............................................................................................. 8 
2.7  
Combination of Gemcitabine and Pazopanib ................................................................................... 8 
2.8 
 Study Rationale ................................................................................................................................ 9 
3. PATIENT SELECTION ............................................................................................................................ 10 
3.1 
 Eligibility Criteria .......................................................................................................................... 10 
3.2. 
Exclusion Criteria ........................................................................................................................... 12 
4. TREATMENT PLAN ................................................................................................................................ 14 
4.1. 
Agent Administration ..................................................................................................................... 14 
4.2 
 Supportive Care Guidelines ........................................................................................................... 18 
4.3. 
Duration of Therapy ........................................................................................................................ 20 
5. DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................ 21 
5.1. 
Study Drug (Pazopanib/Placebo) .................................................................................................... 21 
5.2. 
Gemcitabine .................................................................................................................................... 31 
6. AGENT FORMULATION AND PROCUREMENT ................................................................................ 32 
6.1. 
Agent Accountability ...................................................................................................................... 32 
6.2.      Pazopanib (Votrient) ......................................................................................................................... 32 
6.3. 
 Gemcitabine (Gemzar) ................................................................................................................... 35 
7. CORRELATIVE/SPECIAL STUDIES ..................................................................................................... 37 
7.1.  
Angiogenic Biomarkers .................................................................................................................. 37 
7.2.      Genetic mutation screen .................................................................................................................... 38 
8.  
 STUDY PROCEDURES AND SCHEDULE OF EVENTS ................................................................. 38 
8.1 
 Subject Registration ....................................................................................................................... 38 
8.2.      Randomization process ..................................................................................................................... 38 
8.3. 
Standard Laboratory Assessments .................................................................................................. 39 
8.4. 
Baseline Screening .......................................................................................................................... 40 
8.5. 
Study Visits ..................................................................................................................................... 42 
8.6.    Pathology Sample Submission ............................................................................................................ 42 
8.7.     Follow-up ........................................................................................................................................... 42 
8.8. 
Early Termination ........................................................................................................................... 42 
8.9.     Schedule of Events for Randomized Portion of the Protocol ............................................................ 43 
8.10.    Schedule of Events for Cross-over Portion of the Protocol .............................................................. 45 
9. MEASUREMENT OF EFFECT ................................................................................................................ 46 
9.1. 
Definitions ...................................................................................................................................... 46 
9.2. 
Guidelines for Evaluation of Measurable Disease .......................................................................... 47 
9.3. 
 Response Criteria ........................................................................................................................... 48 


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9.4. 
Confirmatory Measurement/Duration of Response ........................................................................ 49 
9.5. 
Progression-Free Survival ............................................................................................................... 50 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................................................... 50 
10.1 
Protocol Review .............................................................................................................................. 50 
10.2 
Informed Consent ............................................................................................................................ 50 
10.3 
Changes to Protocol ........................................................................................................................ 50 
10.4     Maintenance of Records ................................................................................................................... 51 
10.5      OHSU IRB Reporting of Unanticipated Problems and Adverse Events ......................................... 51 
10.6     Central Reporting of Adverse Events for Multicenter Studies ......................................................... 51 
10.7      MedWatch Reporting ....................................................................................................................... 52 
10.8     Adverse Events Reporting Guidelines .............................................................................................. 52 
10.9     OHSU Knight Cancer Institute Data and Safety Monitoring Plan ................................................... 57 
10.10      Inclusion of Women, Minorities and Children .............................................................................. 57 
11. 
STATISTICAL CONSIDERATIONS ................................................................................................... 60 
11.1   Study Endpoints and Objectives ......................................................................................................... 60 
11.2 
Methods to assess study objectives ................................................................................................. 61 
11.3 
Safety Monitoring ........................................................................................................................... 62 
11.4 
Sample Size and Power ................................................................................................................... 62 
11.5 
Interim Analysis and Stopping Rules ............................................................................................. 62 
APPENDIX A ......................................................................................................................................................... B 
APPENDIX B ......................................................................................................................................................... B 
APPENDIX C ......................................................................................................................................................... C 
APPENDIX D ........................................................................................................................................................ D 
APPENDIX E ........................................................................................................................................................ D 
REFERENCES ....................................................................................................................................................... E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5 
 
1. OBJECTIVES 
 
1.1. Primary Objective 
 
1.1.1. To investigate whether treatment with gemcitabine plus pazopanib improves the median  
progression-free survival (PFS) of patients with metastatic soft tissue sarcoma when compared to 
gemcitabine plus placebo. 
 
1.2. Secondary Objectives 
 
1.2.1. To assess overall response in this population to gemcitabine plus pazopanib compared to  
gemcitabine plus placebo. 
1.2.2. To assess overall survival (OS) in this population to gemcitabine plus pazopanib compared to  
gemcitabine plus placebo. 
1.2.3. To investigate differences in treatment response in different histologic subgroups (liposarcoma 
vs. all other eligible soft tissue sarcoma subtypes). 
1.2.4. To evaluate the safety and tolerability of the combination of gemcitabine plus pazopanib. 
1.2.5 To assess the progression-free survival and overall response in patients treated with single agent 
pazopanib following administration of gemcitabine in the cross-over portion of this study. 
1.2.6 To collect specimens for an exploratory analysis of potential biomarkers that predict response in 
patients receiving combination therapy with gemcitabine plus pazopanib. 
 
2. BACKGROUND 
 
2.1 
Soft Tissue Sarcomas 
 
Soft tissue sarcomas are a rare and heterogeneous group of malignant tumors of mesenchymal origin 
that comprise approximately 1% of all adult malignancies and 12% of pediatric cancers1,2. This group 
includes more than 50 different histologic subtypes of soft tissue sarcoma1. Surgery with or without 
radiotherapy is the cornerstone of therapy for patients with early stage localized soft tissue sarcomas. 
However, many of these patients develop advanced disease for which the prognosis is poor3.  
 
Chemotherapy is used for the treatment of advanced and/or metastatic soft tissue sarcomas, but few 
cytotoxic drugs have demonstrated activity in this disease. Doxorubicin and ifosfamide remain the most 
active agents for treating these tumors, with overall response rates of less than 25%4 and survival benefit 
never having been demonstrated in randomized trials.   
 
2.2     Angiogenesis and VEGF 
 
Angiogenesis, the process of new blood vessel formation, plays an important role in the development of 
malignancy as well as the growth and progression of metastatic lesions.  The molecular pathways 
involved in angiogenesis have been targeted for anti-tumor therapy. Numerous growth factors and 
cytokines are involved in the angiogenic process. Among these factors, vascular endothelial growth 
factor (VEGF) has a predominant role as a central mediator of tumor-related angiogenesis, and its 
expression has been shown to be an adverse prognostic factor for a number of solid tumors5-7. 
 
The VEGF family consists of several glycoproteins including VEGF-A, -B,-C, -D, -E, and placental 


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6 
growth factor8. Cellular signaling is initiated when members of the VEGF family bind to cell surface 
receptors including VEGFR-1 (Flt-1), VEGFR-2 (KDR or Flk-1), and VEGFR-3 (Flt-4). Given the key 
role of VEGF and its family of receptors in regulating angiogenesis, inhibitors of both VEGF and its 
receptors are actively being developed as anti-cancer therapies. 
 
2.3     VEGF and Soft Tissue Sarcoma 
 
Overexpression of PDGFR, VEGF, and VEGFR have been seen in soft tissue sarcomas9-11, but it is not 
clear whether VEGF and VEGFR expression correlate with clinical outcome12,13. Certain histologic 
subtypes of soft tissue sarcoma are more likely to express PDGFR, VEGF, and VEGFR including 
angiosarcomas and solitary fibrous tumors (previously termed hemangiopericytomas)10,14-16. 
 
Several VEGF inhibitors have been studied in patients with refractory soft tissue sarcoma including 
bevacizumab, sunitinib, sorafenib, and pazopanib. A Phase II study of doxorubicin and bevacizumab 
showed a response rate of only 12% but 65% of patients had stable disease through 4 cycles of 
treatment17. Two Phase II studies have been performed using the VEGF tyrosine kinase inhibitor (TKI), 
sunitinib. The study by George, et al demonstrated durable disease control in patients with DSRCT and 
solitary fibrous tumor18. Another study of sunitinib in patients with refractory soft tissue sarcoma by 
Mahmood, et al showed a progression-free rate of >40% in patients with liposarcoma and 
leiomyosarcoma19. Two Phase II studies have also been performed using another VEGF TKI, sorafenib. 
A study by Maki, et al showed a response rate of 14% in patients with angiosarcoma and minimal 
activity in other soft tissue sarcomas with a median progression-free survival (PFS) in all subtypes of 
3.2 months20. Another study using sorafenib by von Mehren, et al showed an overall median PFS of 3 
months but a median PFS of 5 months in patients with vascular sarcoma subtypes21. Studies of the 
VEGF TKI, pazopanib are discussed in section 2.5. 
 
2.4  
Pazopanib 
 
2.4.1    Introduction 
 
Pazopanib is an orally-bioavailable, ATP-competitive tyrosine kinase inhibitor of VEGFR (-1, -2, 
and -3), PDGFR (-α and -β), and c-Kit22.  Pazopanib has been approved by the FDA for treatment of 
renal cell carcinoma and soft tissue sarcoma. In nonclinical experiments, pazopanib has 
demonstrated encouraging potency and selectivity for VEGF receptors: for example, pazopanib 
demonstrated significant inhibition of VEGF-induced VEGFR-2 phosphorylation in human 
umbilical vein endothelial cells and was 3- to 400-fold selective for VEGF receptors compared to 23 
other kinases tested. Pazopanib showed significant growth inhibition of a variety of human tumor 
xenografts in mice, and also inhibited angiogenesis in several different models of angiogenesis (e.g., 
the Matrigel plug assay, the cornea micropocket, and the laser-induced choroidal neovascularization 
models). Further physico-chemical characteristics of pazopanib as well as more detailed results of 
nonclinical studies are described in the Investigator Brochure (IB)23.  
 
2.4.2 Summary of Pharmacokinetic and Pharmacodynamic Data 
 
Results of pharmacokinetic and pharmacodynamic analyses demonstrate that pazopanib is absorbed  
 after oral administration; a plateau is reached in steady-state systemic exposure at a dose of 800 mg 
daily; a maximum tolerated dose has not been reached at pazopanib doses up to 2000 mg daily; and 
doses of pazopanib that maintain plasma pazopanib concentrations above 15 μg/mL - 20 μg/mL (i.e., 
800 mg daily and 300 mg twice daily [BID]) are associated with pharmacodynamic and clinical 


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7 
effects23. 
 
2.4.3 Drug-Drug Interactions 
 
In vitro data indicate that pazopanib is a potential inhibitor for CYP2C9, CYP1A2, CYP2A6, 
CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Pregnane X receptor transient 
transfection assay suggested some potential for human CYP3A4 induction at high concentrations.  
Due to the early phase of development, human experience with pazopanib is limited and definitive 
information on the metabolism and drug interaction profile of pazopanib is not available. However, 
coadministration of pazopanib and medications which are substrates for the CYP450 enzymes and 
which have the potential to cause serious and/or life-threatening adverse events is PROHIBITED23. 
 
2.4.4 Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 
The most common AEs reported to date include diarrhea, fatigue, nausea, hypertension, hair color 
changes (hair depigmentation), anorexia, vomiting, dysgeusia, headache, abdominal pain, rash, 
aspartate aminotransferase (AST), and alanine aminotransferase (ALT) increase, constipation, 
cough, and arthralgia. Most of these events were Grade 1 or 2 using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. 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. 
The most common SAEs occurring in patients enrolled in pazopanib studies regardless of treatment 
assignment include vomiting, diarrhea, abdominal pain, hypertension / hypertensive crisis, dyspnea, 
pleural effusion, pyrexia, anemia, dehydration, and pulmonary embolism23. 
 
2.4.5 Summary of Laboratory Abnormalities 
 
Treatment-emergent laboratory abnormalities are available for two Phase II studies (VEG20002 and 
VEG102616). A review of the data from these 2 studies suggest that laboratory abnormalities of all 
grades occurring commonly in patients receiving pazopanib include AST and ALT elevations, 
hyperbilirubinemia, alkaline phosphatasemia, amylase and lipase elevations, elevations in creatinine, 
hyponatremia, hyperkalemia, lymphopenia, leukopenia, thrombocytopenia, neutropenia and anemia, 
hyperglycemia, and increased thyroid-stimulating hormone (TSH). Concomitant elevations in 
transaminases and bilirubin have been rare; for example, in Study VEG102616 they were observed 
in 2 (<1%) patients. Elevations in amylase and lipase have been primarily Grade 1 or 2. Most have 
been asymptomatic; clinical signs and symptoms of pancreatitis have been uncommon. 
Hyponatremia and hyperkalemia have not been reported concomitantly in the same patients in a 
manner that would suggest adrenal insufficiency23. 
 
2.5  
Pazopanib and Soft Tissue Sarcoma  
 
A Phase II single arm EORTC study of pazopanib in relapsed and refractory STS was performed24. This 
study was stratified by histology (liposarcoma vs leiomyosarcoma vs synovial sarcoma vs other soft 
tissue sarcoma subtypes). The drug was well tolerated. Amongst 142 patients, grade 3-4 neutropenia, 
and thrombocytopenia were seen in 6 and 2 pts, respectively. Grade 3-4 bilirubin, AST, ALT, and 
creatinine elevations in 9, 6, 6, and 5 pts, respectively. The main other toxicities (all grades; grade 3-4) 
were fatigue (36.6%; 7.7%), hypertension (40.1%; 7.7%), nausea (35.9%, 0.7%), diarrhea (28.9%; 
3.5%), and hypopigmentation (35.2%, 0%). The majority of other reported adverse events (all grades; 


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8 
grade 3-4) were fatigue (70.4%; 14.1%), hypertension (43.7%; 7.7%), nausea (44.4, 1.4), diarrhea 
(30.3%; 3.5%), and hypopigmentation (36.6%, 0%). 
 
Pazopanib 800 mg once daily showed encouraging efficacy in patients with advanced or metastatic soft 
tissue sarcoma in the EORTC Phase II study. The progression-free rate at 12 weeks was 18 of 41 
patients (44%) for leiomyosarcoma; 18 of 37 patients (49%) for synovial sarcoma; 5 of 19 patients 
(26%) for liposarcoma, and 16 of 41 patients (39%) for other types of sarcoma. Progression-free 
survival was 91 days for leiomyosarcoma, 161 days for synovial sarcoma, 80 days for liposarcoma, and 
91 days for other types of sarcoma.24. 
 
A subsequent Phase III study of pazopanib vs. placebo in refractory soft tissue sarcomas excluding 
liposarcoma reported a median progression-free survival of 4.6 months for pazopanib compared with 1.6 
months for placebo (HR 0.31, 95% CI 0.24-0.40; p<0.0001) .  This study led to FDA approval of 
pazopanib for the treatment of patients with advanced soft tissue sarcoma who have received prior 
chemotherapy.  Because liposarcoma was excluded from this trial, the FDA indication includes a 
limitation of use stating that the efficacy of pazopanib for the treatment of adipocytic soft tissue sarcoma 
has not been demonstrated 25. 
 
2.6  
Gemcitabine and Soft Tissue Sarcoma 
 
Single agent gemcitabine has been assessed in a number of Phase II trials in the second line setting in 
patients with refractory STS and is well tolerated. A study by Hartmann, et al in 2006 using gemcitabine 
1000 mg/m2 over 30 min on days 1, 8, and 15 every 4 weeks showed moderate efficacy with a 
progression-free rate at 3 and 6 months of 46.7% and 13.3% respectively26. The median progression-free 
survival was 3 months. Patel, et al found a median time to progression of 3 months in patients treated 
with single agent gemcitabine27. A study of gemcitabine in patients with refractory uterine 
leiomyosarcoma by Look, et al showed an overall response rate of 20.5%28. Ferraresi, et al investigated 
fixed dose-rate gemcitabine (10 mg/m2/min over 100 min) in patients with refractory STS and found a 
median time to progression of 3.1 months29. Fixed-dose rate gemcitabine infusion has not been shown to 
be superior to standard administration. 
 
The combination of gemcitabine and docetaxel is a frequently used regimen, especially in the treatment 
of leiomyosarcoma, the histology in which the highest response rates have been reported. A Bayesian 
design, randomized Phase II trial of gemcitabine vs. gemcitabine plus docetaxel suggested a survival 
benefit of the combination30. This trial randomized patients receiving 1st to 4th line therapy. The median 
progression-free survival in this study was 6.2 months for gemcitabine-docetaxel and 3.0 months for 
gemcitabine alone. The median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 
months for gemcitabine. The French TaxoGem trial randomized patients to receive gemcitabine or 
gemcitabine and docetaxel as second line therapy for metastatic leiomyosarcoma. A pooled analysis of 
the Bayesian Phase II trial and the French trial have recently been presented31. Primary data from 121 
patients with leiomyosarcoma were analyzed. For the subgroup of patients with uterine leiomyosarcoma, 
the response rate was 18% for those treated with gemcitabine and 23% for the combination, and 
progression-free survival was 4.9 and 6 months respectively. For patients with extra uterine 
leiomyosarcoma, the response rate was 13% for those treated with gemcitabine and 10% for those 
treated with the combination, and progression-free survival was 5.5 and 7 months respectively. There 
was no significant difference in response or progression-free survival between the gemcitabine and 
gemcitabine and docetaxel arms.  Patients treated with gemcitabine had moderate toxicity, whereas 17% 
of cycles were complicated by grade 3/ 4 thrombocytopenia in patients treated with the combination.   
2.7  
Combination of Gemcitabine and Pazopanib 


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9 
 
To our knowledge, there is no published preclinical data regarding potential synergy of the combination 
of gemcitabine and pazopanib. However, there is preclinical data reporting synergy of pazopanib with 
other cytotoxic chemotherapies including the combination of pazopanib with docetaxel in docetaxel-
resistant bladder cancer cells32. There is another study reporting increased effect of the combination of 
pazopanib with metronomic topotecan therapy in preclinical ovarian cancer models compared to either 
agent alone33. Clinically, a survival benefit has been seen with the combination of other antiangiogenic 
therapies in combination with cytotoxic chemotherapy in lung cancer and colon cancer with the addition 
of bevacizumab to standard cytotoxic chemotherapy regimens. Several mechanisms have been proposed 
that may account for the additive or synergistic activity of antiangiogenic agents and cytotoxic 
chemotherapy, including the possibility that anti-VEGF therapy may transiently normalize leaky tumor 
vasculature, which could facilitate more effective drug delivery to the tumor34. 
 
A Phase I, open-label, study of the safety, tolerability, and pharmacokinetics of pazopanib in 
combination with gemcitabine for advanced solid tumors was conducted from April 2008 through 
March 201035. This study used a standard cohort 3 + 3 design (dose level 0 – pazopanib 400 mg PO 
daily and gemcitabine 1000 mg/m2 by 30 minute infusion on days 1 and 8 of a 21 day treatment cycle; 
dose level 1 – pazopanib 800 mg PO daily and gemcitabine 1000 mg/m2 by 30 minute infusion on days 
1 and 8 of a 21 day treatment cycle; and dose level 2 – pazopanib 800 mg PO daily and gemcitabine 
1250 mg/m2 by 30 minute infusion on days 1 and 8 of a 21 day treatment cycle).  
 
There were 6 patients treated at dose level 0, 3 patients at dose level 1, and dose level 2 was expanded 
with a total of 13 patients treated at that dose level. One death occurred in a subject assigned to dose 
level 0, which was considered by the investigator to be related to study treatment. The subject withdrew 
from the study due to pneumonia and died 5 days after the last dose of study treatment. Two dose-
limiting toxicities (DLTs) were reported in 2 subjects during cycle 1: Grade 4 thrombocytopenia (dose 
level 0) and grade 3 fatigue (dose level 2). Although dose level 2 was expanded, upon analysis of 
tolerability based on dose intensity, it was determined that dose level 1 (pazopanib 800 mg PO daily and 
gemcitabine 1000 mg/m2 by 30 minute infusion on days 1 and 8 of a 21 day treatment cycle) would be 
carried forward to Phase II studies (internal GSK communication).  
 
One PR was reported in a patient with melanoma and stable disease was observed in 14 subjects with 
various tumor types including cholangiocarcinoma, melanoma, and colorectal cancer. 
 
2.8 
Study Rationale 
 
Gemcitabine is an agent with activity in soft tissue sarcomas. The combination of gemcitabine and 
docetaxel is a frequently used regimen, especially in the treatment of leiomyosarcoma, the histology in 
which the highest response rates have been reported. A Bayesian design, randomized Phase II trial of 
gemcitabine vs. gemcitabine plus docetaxel suggested a survival benefit of the combination30. However, 
the combination of gemcitabine with docetaxel is a relatively poorly-tolerated regimen associated with 
significant fatigue with 40% of patients discontinuing treatment due to non-hematologic toxicity within 
6 months of therapy, despite dose reductions. Furthermore, the additional benefit of docetaxel to 
gemcitabine is without clear rationale, as single-agent taxanes have minimal benefit in the treatment of 
most soft tissue sarcomas. 
 
There is a need for development of new treatments for soft tissue sarcomas, which has been difficult 
given the biologic heterogeneity of this group of tumors. Recently, interesting data have emerged 
regarding the potential role of VEGF-directed therapies for soft tissue sarcomas. The VEGF tyrosine 


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10
kinase inhibitor pazopanib has shown some activity in the second line setting24, and a placebo controlled 
Phase III trial of pazopanib in refractory soft tissue sarcomas has recently reported an increase in median 
progression-free survival of 13 weeks25. We hypothesize that the combination of gemcitabine plus 
pazopanib will result in improved PFS compared to single agent therapy with gemcitabine. 
 
3. PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
3.1.1 Subjects must provide written informed consent prior to performance of study-specific 
procedures or assessments, and must be willing to comply with treatment and follow-up. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, 
imaging study) and obtained prior to signing of informed consent may be utilized for screening 
or baseline purposes provided these procedures are conducted as specified in the protocol.   
 
3.1.2 Age ≥ 18 years  
 
3.1.3 Histologically confirmed diagnosis of metastatic or unresectable soft tissue sarcoma, excluding 
gastrointestinal stromal tumors, Kaposi’s sarcoma, Ewing’s family of tumors, and embroynal or 
alveolar rhabdomyosarcoma   
 
3.1.4 Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See Appendix A for 
description) 
 
3.1.5 Measurable disease per RECIST 1.1 
 
3.1.6 Patients must have received at least one, but not more than three, systemic regimens for 
treatment of metastatic soft tissue sarcoma. Patients must have had a prior anthracycline in the 
neoadjuvant, adjuvant or metastatic setting unless medically inappropriate for the patient.  
 
3.1.7 Neoadjuvant or adjuvant therapy will not count towards prior treatment for metastatic disease, 
unless the patient relapsed within 2 years of completing such therapy.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1.8 Adequate organ system function as defined in Table 1 
 


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11
                    Table 1: Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematology 
Absolute neutrophil count (ANC) 
≥1.5 X 109/L 
Hemoglobina 
≥8 g/dL  
Platelets 
≥100 X 109/L 
Prothrombin time (PT) or international 
normalized ratio (INR)b  
≤1.2 X ULN 
Activated partial thromboplastin time 
(aPTT) 
≤1.2 X ULN 
Hepatic 
Total bilirubin 
≤1.5 X ULN  
Alanine amino transferase (ALT) and 
Aspartate aminotransferase (AST)c  
≤2.5 X ULN 
Renal 
Serum creatinine 
≤1.5 mg/dL (133 
µmol/L) 
Or, if >1.5 mg/dL: Calculated creatinine 
clearance (ClCR) (Appendix B) 
≥30 mL/min  
Urine Protein to Creatinine Ratio (UPC; 
Appendix C)d  
<1 
Or 24-hour urine protein 
<1 g 
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 1.0 x 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. Use of urine dipstick 
for renal function assessment is not acceptable. 
 
3.1.9 A female is eligible to enter and participate in this study if she is of: 
 
• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any 
female who has had: 
o A hysterectomy 
o A bilateral oophorectomy (ovariectomy) 
o A bilateral tubal ligation 
o Is post-menopausal 
 
Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of 
menses for ≥ 1 year and be greater than 45 years in age, OR, in questionable cases, have a 
follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 
pmol/L).  
 
Subjects using HRT must have experienced total cessation of menses for >= 1 year and be 


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12
greater than 45 years of age OR have had documented evidence of menopause based on FSH and 
estradiol concentrations prior to initiation of HRT. 
 
• Childbearing potential, including any female who has had a negative serum pregnancy test 
within 7 days prior to the first dose of study treatment, preferably as close to the first dose as 
possible, and agrees to use adequate contraception.  Defined as follows: 
o 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 
o Oral contraceptive, either combined or progestogen alone 
o Injectable progestogen 
o Implants of levonorgestrel 
o Estrogenic vaginal ring  
o Percutaneous contraceptive patches  
o Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of 
less than 1% per year 
o 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   
o Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) 
with a vaginal spermicidal agent (foam/gel/film/cream/suppository) 
 
Female subjects who are lactating should discontinue nursing prior to the first dose of study drug 
and should refrain from nursing throughout the treatment period and for 14 days following the 
last dose of study drug. 
 
3.2. 
Exclusion Criteria 
 
3.2.1 Prior malignancy 
 
Note: Subjects who have had another malignancy and have been disease-free for >3 years, or 
subjects with a history of completely resected non-melanomatous skin carcinoma, successfully 
treated in situ carcinoma, or successfully treated superficial bladder cancer are eligible.  
 
3.2.2 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 medication for 6 months 
prior to first dose of study drug.  Screening with CNS imaging studies (computed tomography 
[CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the 
subject has a history of CNS metastases.  
 
 
 
 
 
 
3.2.3 Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal 
bleeding including, but not limited to: 
• Active peptic ulcer disease 
• Known intraluminal metastatic lesion/s with risk of bleeding 


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13
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other gastrointestinal 
conditions with increased risk of perforation  
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 
days prior to beginning study treatment 
 
3.2.4 Clinically significant gastrointestinal abnormalities that may affect absorption of investigational 
product including, but not limited to: 
• Malabsorption syndrome  
• Major resection of the stomach or small bowel 
 
3.2.5 Presence of uncontrolled infection 
 
3.2.6 Corrected QT interval (QTc) > 480 msecs using Bazett’s formula 
 
3.2.7 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 
 
3.2.8 Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) 
(See Appendix D for description) 
 
3.2.9 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 should be averaged to obtain the mean diastolic blood pressure and the mean 
systolic blood pressure.  The mean SBP / DBP ratio must be <140/90 mmHg. 
 
3.2.10 History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary 
embolism or untreated deep venous thrombosis (DVT) within the past 6 months. 
 
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents 
for at least 6 weeks are eligible. 
 
3.2.11 Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of 
any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered 
to be major) 
 
3.2.12 Evidence of active bleeding or bleeding diathesis 
 
3.2.13 Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase 
the risk of pulmonary hemorrhage 
 


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14
3.2.14 Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug 
 
3.2.15 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 
 
3.2.16 Unable or unwilling to discontinue use of prohibited medications listed in Section 5.1.4.6 for at 
least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study 
drug and for the duration of the study. Administration of any non-oncologic investigational drug 
within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study 
treatment. 
 
3.2.17 Treatment with any of the following anti-cancer 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 28 days in the case of monoclonal antibody therapy) prior to the first dose of 
PazopanibAny prior treatment with pazopanib 
• Prior treatment with a VEGF or VEGFR-targeting agents other than pazopanib (eg. sorafenib, 
sunitinib, and bevacizumab) in the metastatic setting.  Prior use of such agents in the 
neoadjuvant or adjuvant setting is permitted. 
• Any prior treatment with gemcitabine for metastatic disease.  Prior use of gemcitabine in the 
neoadjuvant or adjuvant setting is permitted. 
 
3.2.18 Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing 
in severity, except alopecia 
 
4. TREATMENT PLAN 
 
4.1. 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Patients will be randomized to either the experimental arm or the placebo arm prior to starting treatment 
(See Section 8.2 for details regarding randomization.) 
 
Study drug (pazopanib/placebo) should be taken orally without food at least one hour before or two 
hours after a meal. 
 
The time of day for administration of study drug should be relatively constant. 
 
If a patient misses a dose of study drug, the patient 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 patient should skip the missed dose and take the next 
dose as scheduled. 
 
A diary will be kept by all subjects indicating that the study drug was taken as per protocol. 


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15
 
4.1.1 Experimental Arm 
 
• Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1 and 8 every 21 days  
• Pazopanib 800 mg (4x200mg) PO daily  
 
4.1.2 Placebo Arm 
 
• Gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1 and 8 every 21 days  
• Placebo 4 tablets PO daily  
 
Placebo tablets matching the 200 mg pazopanib tablets will be used for the study. 
 
Patients who progress on gemcitabine + placebo will be offered cross-over treatment with single-
agent, open-label pazopanib. 
 
4.1.3    Cross-over treatment eligibility criteria 
 
Subjects who discontinue treatment on the placebo arm of the randomized portion of the protocol 
due to disease progression are eligible for treatment with open-label pazopanib 
alone (800 mg PO daily). Subjects who develop disease progression on the Experimental arm 
(pazopanib arm) will NOT be eligible for treatment with open-label pazopanib alone. 
 
Subjects have 4 weeks after documented disease progression on the randomized portion of the 
protocol to begin treatment with open-label pazopanib. If more than 4 weeks elapse, subjects will 
not be eligible for cross-over treatment with pazopanib. 
 
The subject must meet the following eligibility criteria to be eligible for the cross-over portion of the 
protocol: 
 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See Appendix A 
for description) 
• Adequate contraceptive method for subjects with reproductive potential (See section 3.1.9 
for details) 
• Must have adequate organ function: 
 
 
 
 
 
 
 
                                             Table 1: Definitions for Adequate Organ Function 


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16
System 
Laboratory Values 
Hematology 
Absolute neutrophil count (ANC) 
≥1.5 X 109/L 
Hemoglobina  
≥8 g/dL  
Platelets 
≥100 X 109/L 
Prothrombin time (PT) or international 
normalized ratio (INR)b  
≤1.2 X ULN 
Activated partial thromboplastin time 
(aPTT) 
≤1.2 X ULN 
Hepatic 
Total bilirubin 
≤1.5 X ULN  
Alanine amino transferase (ALT) and 
Aspartate aminotransferase (AST)c  
≤2.5 X ULN 
Renal 
Serum creatinine 
≤1.5 mg/dL (133 
µmol/L) 
Or, if >1.5 mg/dL: Calculated creatinine 
clearance (ClCR) (Appendix B) 
≥30 mL/min  
Urine Protein to Creatinine Ratio (UPC; 
Appendix C)d  
<1 
Or 24-hour urine protein 
<1 g 
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 1.0 x 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. Use of urine 
dipstick for renal function assessment is not acceptable. 
 
• No uncontrolled infection 
• Corrected QT interval (QTc) ≤ 480 msecs using Bazett’s formula 
• Adequately controlled hypertension (see section 3.2.9 for details) 
• No prior major surgery or trauma within 28 days prior to first dose of study drug and/or 
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement 
not considered to be major) 
• No radiation therapy or tumor embolization within 14 days prior to the first dose of 
pazopanib 
• No evidence of active bleeding or bleeding diathesis 
• No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels 
• No hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of 
study drug 
• No history of cerebrovascular accident including transient ischemic attack (TIA), pulmonary 
embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects 


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17
with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 
6 weeks are eligible. 
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days prior to beginning study treatment 
• No known intraluminal metastatic lesion/s with risk of bleeding 
• No history or clinical evidence of central nervous system (CNS) metastases or 
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS 
metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure 
medication for 6 months prior to first dose of study drug. 
• No history of any one or more of the following cardiovascular conditions within the past 6 
months: 
o 
Cardiac angioplasty or stenting 
o 
Myocardial infarction 
o 
Unstable angina 
o 
Coronary artery bypass graft surgery 
o 
Symptomatic peripheral vascular disease 
• No class III or IV congestive heart failure, as defined by the New York Heart Association 
(NYHA) (See Appendix D for description) 
• Must be able and willing to discontinue use of prohibited medications listed in Section 
5.1.4.6 for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first 
dose of study drug and for the duration of the study. 
 
4.1.4     Procedure for entering the cross-over portion of the study 
 
As described in Section 8.2.2, subjects may be unblinded after progression if the investigator and 
subject want to proceed with open-label pazopanib. In order to do this, documentation of progression 
and documentation of the investigator’s intent to treat the patient with open label pazopanib if the 
patient is found to be on the placebo arm will be provided to the coordinating center. Once 
progression has been confirmed by the coordinating center, the blind will be broken by the OHSU 
Research Pharmacy and if subject was on the placebo arm of the randomized portion of the trial, the 
patient may proceed with screening for the open-label pazopanib study arm.  Once an eligibility 
checklist documenting the subject’s eligibility for open-label pazopanib treatment has been 
submitted and approved by the coordinating center, open label pazopanib can be dispensed for the 
subject per the study schedule.  The patient must start taking open label pazopanib within 4 weeks of 
documentation of progression on the randomized portion of the protocol.   
 
 4.1.5     Cross-over treatment 
 
Treatment on the cross-over portion of the study is with pazopanib 800 mg PO daily. A cycle will be 
considered 21 days. No chemotherapy, radiation therapy or investigational agents are permitted. 
Dose modifications and management of toxicity is the same as for the pazopanib/placebo portion of 
the randomized part of the study (see Section 5.1). 
 
Treatment on the cross-over portion of the study should continue until: 
• Unacceptable toxicity, as per section 5.1 
• Disease progression using the disease burden at the time of cross-over as baseline (per 
RECIST 1.1) 
 
4.1.6     Schedule of events for cross-over treatment 


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18
 
Please see section 8.10. 
 
4.2 
Supportive Care Guidelines 
 
4.2.1    General guidelines 
 
Appropriate anti-emetics per institutional standard and at the investigator’s discretion should be used 
prior to gemcitabine administration. 
 
Normal saline IV piggyback may be run with gemcitabine to decrease vein discomfort. 
 
Use of erythroid growth factors to support hemoglobin levels are permitted, at the discretion of the 
investigator.  
 
Use of myeloid growth factors for neutropenia are permitted, at the discretion of the investigator. 
 
Prophylactic antibiotics for prevention of neutropenic fever may be used at the discretion of the 
investigator. Use of prophylactic antibiotics must be recorded in the case report forms. 
 
4.2.2    Supportive care guidelines for diarrhea, nausea, and vomiting associated with the     
 
 
 study drug (pazopanib or placebo) 
 
 
 
4.2.2.1   Diarrhea 
 
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 diarrhea36. 
 
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 should 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 in Table 2 below: 
 
 
       
 
 
 
 
 
 
 
Table 2. NCI CTCAE Version 4.0 criteria for diarrhea.      
 


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19
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 
 
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. 
 
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 holding study drug.  Consider dose reduction for recurrent 
toxicity (see section 5.1.1). 
• 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: 


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20
 
• 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. 
- Hold study drug and refer to dose modification guidelines in section 5.1.1. 
• 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 be 
medically 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.  
• Before initiation of antimicrobial therapy, stool cultures should be obtained. When bacterial 
etiology for diarrhea is suspected, study-treatment and anti-motility agents (loperamide or 
others) should be held. 
• Intervention should be continued until diarrhea free for 24 hours. 
 
Alternative Pharmacologic Intervention for Uncomplicated and Complicated Diarrhea 
 
• Lomotil (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 should be attempted. 
• The synthetic octapeptide, octreotide, has been shown to be effective in the control of 
diarrhea induced by flouropyrimidine-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. 
 
4.2.2.2  Nausea and Vomiting 
 
Every attempt should be made to control nausea and vomiting in subjects who have emesis and 
are unable to retain the study drug. 
 
As necessary, symptomatic subjects should be treated with anti-nausea/anti-emetic therapy per 
institutional standards. 
 
If a subject vomits after taking study drug, the subject should be instructed not to take a 
replacement dose on that same day.  The subject should resume taking study drug at the next 
scheduled dose on the following day.  If vomiting persists, then the subject should contact their 
physician. 
 
4.3. 
Duration of Therapy 


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21
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
 
 Disease progression, 
 
 Intercurrent illness that prevents further administration of treatment, 
 
 Unacceptable adverse events(s), 
 
 Patient decides to withdraw from the study, or 
 
 General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1. 
Study Drug (Pazopanib/Placebo) 
 
5.1.1   Dose Modification for Potential Treatment-Related Adverse Events 
 
Dose modification algorithms for specific toxicities (hypertension, proteinuria, hemorrhage, 
thrombosis, thrombocytopenia, neutropenia, palmar-plantar erythrodysesthesia, QTc interval 
prolongation, and liver dysfunction) are detailed below in Tables 3 and 4. For all other Grade 3 or 4 
non-hematologic toxicities (except alopecia, nausea, or vomiting) that are at least in part attributable 
to the study drug, the dose should be held until the toxicity resolves to ≤ Grade 1. Treatment should 
then be resumed at a reduction of one dose level. For recurrent grade 3 or 4 toxicity, the study drug 
should again be held until the toxicity resolves to ≤ Grade 1 and then reintroduced at another dose 
level reduction.  Up to 3 dose reductions are allowed, after which patient will be removed from 
protocol treatment if the grade 3-4 toxicity recurs. If the toxicity has abated with reduction of the 
dose and dose re-escalation is considered safe by the investigator, the study drug dose can then be 
increased step-wise back to the pre-event dose (in 200 mg increments, after monitoring for 14 days 
at each dose level to ensure that toxicity did not recur or worsen).  Patients who require a reduction 
of dose below Dose Level -3 will be removed from study treatment. 
 
Dose Level 
Study Drug Dose 
0 
800 mg PO daily 
-1 
600 mg PO daily 
-2 
400 mg PO daily 
-3 
200 mg PO daily 
 
 
 
 
 
 
 
 
   Table 3. Dose Modification Algorithms for Specific Study Drug-Related Adverse Events 
 


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22
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
(A). Asymptomatic and persistent SBP 
of ≥140 and <170 mmHg, or DBP ≥90 
and <110 mmHg, or a clinically 
significant increase in DBP of 20 
mmHg (but still below 110 mmHg). 
Step 1. Continue the study drug at the current dose.  
Step 2. Adjust current or initiate new antihypertensive               
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2               
weeks as indicated to achieve well-controlleda blood pressure (BP). If 
BP is not well-controlled within 2 weeks, consider referral to a       
specialist and go to scenario (B). 
(B). Asymptomatic SBP ≥170 mmHg, 
or DBP ≥110 mmHg, or failure to 
achieve well-controlled BP within 2 
weeks in scenario (A).  
Step 1.Consider reducing or interrupting the study drug, as clinically   
    indicated. 
Step 2. Adjust current or initiate new antihypertensive medication.       
  
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlled BP.  
Step 4. Once BP is well-controlled, restart the study drug dose-
reduced by one dose level if the study drug was interrupted. 
(C). Symptomatic hypertension or 
recurring SBP ≥170 mmHg, or DBP 
≥110 mmHg, despite modification of 
antihypertensive medication(s) 
Step 1. Interrupt the study drug.  
Step 2. Adjust current or initiate new antihypertensive medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2                 
 weeks as indicated to achieve well-controlled BP.  Referral to a        
specialist for further evaluation and follow-up is also recommended. 
Step 4. Once BP is well-controlled, restart the study drug dose-
reduced by one dose level. 
(D). Refractory hypertension 
unresponsive to above interventions. 
Discontinue the study drug and continue follow-up per protocol. 
Proteinuria 
UPC <3 
Continue the study drug at the current dose; monitor as clinically         
 indicated 
UPC ≥3 or 24-h urine protein ≥3g 
Step 1. Interrupt the study drug. 
Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is 
<3 or 24-hr urine protein is <3 grams.  Then restart the study drug 
dose-reduced by one dose level. 


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23
AE Terms & Descriptions 
Dose Modification Algorithms 
Step 3.  If UPC ≥3 or 24-h urine protein ≥3g recurs, repeat steps 1 and 
2. 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the study drug 
dose can no longer be reduced, discontinue the study drug and 
continue follow-up per protocol. 
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding 
Grade 1 
For hemoptysis, interrupt the study drug and consider whether further 
treatment with the study drug is appropriate. 
For other Grade 1 hemorrhage/bleeding events, continue the study 
drug at the current dose; monitor as clinically indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding), 
discontinue the study drug and continue follow-up per protocol. 
Otherwise, interrupt the study drug until the AE resolved to ≤ Grade 1.  
Step 2. Restart the study drug; consider reducing dose and monitor as 
clinically indicated.  
Grade 3 or 4, or  
Recurrent ≥ Grade 2 event after dose 
interruption/reduction. 
Discontinue the study drug and continue with follow-up per protocol.  
   
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue the study drug at the current dose; monitor as clinically 
indicated 
Grade 3   
 
Step 1. Interrupt the study drug.  
Step 2. Initiate and monitor anticoagulation as clinically indicated.  
Step 3. Resume the study drug at reduced 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 should be monitored as clinically indicated during 
anticoagulation treatment and after resuming study treatment. When 


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24
AE Terms & Descriptions 
Dose Modification Algorithms 
treating with warfarin, international normalized ratio (INR) should be 
monitored within three to five days after any change in the study drug 
dosing (eg, re initiating, escalating/de-escalating, or discontinuing the 
study drug), 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 the study drug and continue follow-up per protocol.  
Arterial Thrombosis/Ischemia 
 
Any Grade 
Discontinue the study drug and continue follow-up per protocol.  
Thrombocytopenia/Neutropenia - Study drug dosing will be modified only for persistent grade 3-4 
thrombocytopenia or neutropenia despite gemcitabine modification. 
Grade 1 or 2 
Continue the study drug with current dose; monitor as clinically 
indicated.  
Grade 3 or 4 
Step 1. Interrupt the study drug until toxicity resolves to ≤ Grade 2. 
Step 2. Restart the study drug dose-reduced by one dose level and 
monitor as clinically indicated.  
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 
thrombocytopenia despite maximum dose reduction of gemcitabine, 
discontinue the study drug and follow-up per protocol 
Anemia:  No specific dose reduction rules are indicated for anemia unless due to hemorrhage or bleeding          
        as noted above. 
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or dermatitis 
without pain 
(erythema, edema, hyperkeratosis) 
1. Continue the study drug at present dose 
 Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily living 
(ADLs) (peeling, blisters, edema, 
bleed, hyperkeratosis) 
1. Hold the study drug  
2. Treat as clinically appropriate 
3. Upon resolution to Grade 1 or better restart the study drug with 
a dose reduction to 400 mg (dose level -2) 
4. If recurrent consider a further dose reduction to 200mg (dose 
level -3) or discontinuation 
Grade 3 
Severe skin changes with pain and 
limiting self care ADLs 
1. Discontinue the study drug 
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to ensure                  


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25
AE Terms & Descriptions 
Dose Modification Algorithms 
 accuracy of the reading.  The values below refer to manually-read ECGs. 
QTc  ≥ 480 < 500 msec 
Continue the study drug; monitor as clinically indicated. 
QTc ≥500 msec 
Discontinue the study drug and continue follow-up per protocol. 
a.  Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. 
b.  AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4)  
Abbreviations: BP, blood pressure. 
 
5.1.2   Dose Modifications and Management of Liver Toxicity 
 
Recommendations for study drug dose interruptions/modifications in case of liver-related treatment-
emergent AEs are provided in Table 4. As a general rule, since many subjects are taking multiple 
concurrent medications, it is critical to (a) do a thorough evaluation of the subject’s concurrent 
medications, and (b) identify and discontinue those with known hepatotoxicity and replace with a 
non-hepatotoxic equivalent for the same indication if necessary. Liver dysfunction must be fully 
evaluated even if clinical signs and symptoms indicate progression of liver tumor lesions. Imaging 
studies must be obtained to document potential progression of malignancy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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26
Table 4. Dose Modification Algorithms for Liver Dysfunction 
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x ULN 
Continue the study drug at current dose with full panel LFTsa monitored 
as per protocol. 
(B). ALT >3.0 x ULN to 
≤8.0 x ULN without 
bilirubin elevation (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 the study drug 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 Grade 1. 
(C). ALT >8.0 x ULN 
without bilirubin elevation 
(defined as total bilirubinb 
<2.0 x ULN or direct 
bilirubin ≤35%) and without 
hypersensitivity symptoms 
(e.g., fever, rash) 
1st occurrence – Liver Event Interruption Criteria: 
(1) Interrupt the study drug until toxicity resolves to ≤Grade 1 or 
baseline.  Report the event to Novartis as an SAE within 24 hours of 
learning of its occurrence (refer to section 10.7.7 for details regarding 
SAE reporting).  Make every reasonable attempt to have subjects 
return to the clinic within 24 to 72 hours for repeat liver chemistries 
and liver event follow up assessments. 
(2)  Liver imaging and other laboratory investigations should be 
considered as clinically appropriate. 
(3) Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTsa weekly or more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1.   
(4)   Re-treatment may be considered if ALL following criteria are met:  
- ALT/AST reduced to Grade 1 
- Total bilirubin <1.5 x ULN or direct bilirubin ≤35% 
- No hypersensitivity signs or symptoms 
- Subject is benefiting from therapy.  
 If criteria are met, reintroduce pazopanib at a -2 dose level (400 mg once 
daily) and measure serum LFTs weekly for 8 weeks. 
Recurrence – Liver Event Stopping Criteria: 
Following reintroduction of pazopanib, if ALT/AST elevations >3 X 
ULN recur, then pazopanib should be permanently discontinued.   
Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTsa weekly or more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1.   


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27
Table 4. Dose Modification Algorithms for Liver Dysfunction 
Event 
Dose Modification Algorithms 
 (D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubinb (defined as total 
bilirubin ≥2.0 x ULN; with 
direct bilirubin >35%) or 
with hypersensitivity 
symptoms (e.g., fever, rash).  
Liver Event Stopping Criteria: 
(1) Discontinue the study drug permanently immediately, report the 
event to Novartis as an SAE within 24 hours of learning of its 
occurrence (refer to section 10.7.7 for details regarding SAE 
reporting).  Make every reasonable attempt to have subjects return to 
the clinic within 24 hours for repeat liver chemistries and liver event 
follow up assessments. 
(2) Consider consulting a gastroenterologist / hepatologist. Consider 
performing the following assessments to identify potential co-factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, cytomegalovirus, Epstein-
Barr virus (IgM antibody, heterophile antibody, or monospot testing)  
- Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-
liver kidney microsomal antibodies. 
- Serum creatinine phosphokinase for possible muscle injury caused 
LFT elevation 
- Liver imaging 
- Consider toxicological blood screen for possible contributing 
chemical/medical entities  
(3) Monitor subject closely for clinical signs and symptoms; record the 
appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever rash or eosinophilia as relevant on 
the AE report form.  Perform full panel LFTs a weekly or more 
frequently if clinically indicated until LFTs are reduced to Grade 1.   
For isolated total bilirubinb 
elevation without concurrent 
ALT increases (defined as 
ALT <3 X ULN). 
 
(1) 
Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT 
or other signs/symptoms of liver injury) does not require dose 
modification.  The study drug 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 elevation, 
fractionation of bilirubin elevation should be performed.  If bilirubin 
is >35% direct (conjugated), further evaluation for underlying cause 
of cholestasis should be performed. 
a. Full panel LFTs include: AST, ALT, alkaline phosphatase, and total bilirubin.  Coagulation tests 
should be performed as clinically indicated. 
b. Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and 
a subject meets the criterion of total bilirubin >1.5 x ULN, then the event should be promptly 
reported as an SAE. 
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; LFT liver function tests; 
PK pharmacokinetics; SAE serious adverse event; ULN upper limit of normal 
 
 
 
 
 
 


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28
5.1.3  Treatment of Study Drug (Pazopanib/Placebo) 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 should contact the Novartis Study Physician.  Decisions regarding pazopanib 
dose modifications or interruptions will be made by the investigator in consultation with the 
Novartis Study Physician based on the clinical evaluation of the subject.    
 
Following an overdose, additional monitoring of the subject for AEs/SAEs and laboratory 
abnormalities should be considered.  A plasma sample for pharmacokinetic analysis for pazopanib 
may be requested by the Novartis Study Physician on a case-by-case basis.  This plasma sample 
should 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, should 
be documented in the CRF. 
 
5.1.4  Concomitant Medications 
 
5.1.4.1 
    Concomitant Medications and Non-Drug Therapies 
 
If future changes are made to the list of permitted/prohibited medications, formal documentation 
will be provided by  Novartis and stored in the study file.  Any such changes will be 
communicated to the investigative sites in the form of a letter. 
 
5.1.4.2 
    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 4 weeks prior to Screening.  The investigator must 
be informed as soon as possible about any new medication(s) taken from the time of Screening 
until the completion of the post-treatment follow-up visit.   
 
All concomitant medications taken during the study will be recorded in the case report form 
(CRF) with indication, dose information, and dates of administration. 
 
Patients should receive full supportive care during the study, including transfusion of blood and 
blood products, and treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, 
when appropriate.  Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-
HT antagonists) may be administered prophylactically in the event of nausea.  Anti-diarrheals, 
such as loperamide, may be administered as needed in the event of diarrhea.  Although 
acetaminophen at doses of ≤2 g/day is permitted, it should be used with caution in subjects with 
impaired liver function.  
 
 


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29
5.1.4.3 
     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. 
 
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, 
sunitinib37.  Such changes may require an adjustment in the dose of hypoglycemic and/or insulin 
therapy.  Subjects should be advised to report symptoms of hypoglycemia (e.g., confusion, visual 
disturbances, palpitations, sweating).  Serum glucose should be tested during treatment with 
pazopanib as outlined in the protocol and as clinically indicated. 
 
5.1.4.4 
    The Effects of Pazopanib on Other Drugs 
 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CYP2C8, CYP2D6, 
CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.  Pregnane X receptor 
transient transfection assay suggested some potential for human CYP3A4 induction at high 
concentrations.  Results from drug-drug interaction studies conducted in subjects with cancer 
suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had 
no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19 metabolism.  Therefore, 
concomitant use of Pazopanib with certain medications (substrates of CYP3A4, CYP2C8, and 
CYP2D6) with a narrow therapeutic window should be undertaken with CAUTION due to the 
potential for alterations in the pharmacologic effects of these medications or an increased risk for 
serious or life threatening adverse events associated with such medications (see below) 
secondary to the inhibition of specific CYP enzymes by Pazopanib.  In addition, the potential for 
drug interaction with such medications, although diminished, may persist after the last dose of 
Pazopanib due to its long half-life (i.e., mean 30.9 hours); therefore, continue to exercise 
CAUTION for at least 7 days and up to 15 days after the last dose of Pazopanib when 
administering these medications.  These medications include (but are not limited to): 
• 
Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, methylergonovine 
(potential increased risk for developing ergot toxicity that includes severe vasospasm 
leading to peripheral as well as cerebral ischemia) 
• 
Neuroleptics: pimozide (potential increased risk for QT interval prolongation, 
ventricular arrhythmia, and sudden death) 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, 
propafenone (potential increased risk for QT interval prolongation and Torsade de 
Pointes) 


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30
• 
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for 
nephrotoxicity and neurotoxicity) 
• Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine 
 
5.1.4.5 
    The Effects of Other Drugs on Pazopanib 
 
Results from in vitro studies suggest that the oxidative metabolism of pazopanib in human liver 
microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and 
CYP2C8.  Furthermore, in vitro data suggest that pazopanib is a substrate for p-glycoprotein. 
Substances that induce or inhibit CYP3A4 may alter the pharmacologic effects of Pazopanib and 
should be used with CAUTION.  
  
Medications that inhibit CYP3A4 may result in increased plasma Pazopanib concentrations.  Co-
administration of strong CYP3A4 inhibitors is prohibited (see Section on Prohibited 
Medications); therefore selection of an alternate concomitant medication with no or minimal 
potential to inhibit CYP3A4 is recommended.  
 
CYP3A4 inducers may decrease plasma Pazopanib concentrations.  Selection of  
an alternate concomitant medication with no or minimal enzyme induction potential is 
recommended.   
 
Drugs that induce CYP3A4 and may decrease Pazopanib plasma concentrations include (but are 
not limited to): 
• 
Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10  
      mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
• 
Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
• 
HIV  antivirals:  efavirenz, nevirapine 
• 
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene 
• 
Miscellaneous:  St. John’s Wort, modafinil, pioglitazone, troglitazone 
 
5.1.4.6 
    Prohibited medications 
 
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation, or hormonal 
(other than leuprolide or other GnRH agonists)] while on treatment in this study.   
 
Medications that inhibit CYP3A4 may result in increased plasma Pazopanib concentrations; 
therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED beginning 14 days 
prior to the first dose of study drug until discontinuation from the study.   
 
Strong CYP3A4 inhibitors include (but are not limited to): 
• 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
• 
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir,       
   lopinavir) 
• 
Antifungals:  itraconzaole, ketoconazole, voriconazole, fluconazole 
• 
Antidepressants:  nefazodone 
 
 
 


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31
5.2. 
Gemcitabine 
 
Dose modifications for gemcitabine-related toxicity will be based on the following dose level schema. 
All patients will start treatment at dose level 0. Patients who require a reduction of dose below Dose 
Level –2 will be removed from study treatment. 
 
Dose Level 
Gemcitabine Dose (mg/m2 
days 1 and 8) 
0 
1000 
-1 
750 
-2 
500 
 
 
 
5.2.1   Hematologic Toxicity 
 
5.2.1.1 
ANC and Platelets 
 
Day 1: A treatment cycle may not begin unless the patient's absolute neutrophil count (ANC) is 
1500/L and platelet count is 100,000/L (without transfusion).  
 
Day 8:  
If ANC is 1000 to 1499/L or platelet count is 75,000 to 99,000/L (without transfusion), reduce 
by one dose level for day 8 of current cycle only.  If the patient is already at dose level -2, further 
dose reduction for D8 is at investigators discretion.  If ANC is <1000/L or platelet count is 
<75,000/L, hold day 8 gemcitabine dose of current cycle; if treatment parameters are met by day 
15, gemcitabine may be administered and the next cycle should begin 2 weeks later.  If the 
patient does not meet treatment parameters by day 15, gemcitabine should be held until the next 
cycle. 
  
5.2.1.2   Neutropenic fever or grade 4 neutropenia for >5 days:  
 
Reduce by one dose level for next and all subsequent cycles  
 
5.2.1.3 
Grade 3-4 thrombocytopenia with clinically significant bleeding or grade 4  
thrombocytopenia lasting >5 days:  
 
Reduce by one dose level for next and all subsequent cycles 
 
5.2.1.4   Anemia:  
 
Supportive care at physician's discretion  
 
 
5.2.2   Non-hematologic Toxicity 
 
Patients who experience Grade 3 or 4 toxicity (except alopecia, nausea, or vomiting) that is 
attributable to gemcitabine and not to the underlying disease or exclusively to the study drug 
(pazopanib/placebo) should have chemotherapy held until the toxicity resolves to ≤ Grade 1. 
Treatment should then be resumed at a reduction of one dose level for the next and all subsequent 
cycles. Patients who are delayed greater than 3 weeks due to non-resolution of such toxicity will be 
removed from study treatment. In the case of grade 3 or 4 hypertension or proteinuria, study drug 


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32
should be dose reduced first. Gemcitabine will only be modified for grade 3 or 4 hypertension or 
proteinuria that is persistent despite study drug dose modification. 
 
6. AGENT FORMULATION AND PROCUREMENT 
 
6.1. 
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of the study agent. 
 
6.2.      Pazopanib (Votrient) 
 
Availability:   Pazopanib is supplied to investigators by Novartis. 
 
Product description: Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble 
at pH 1 and practically insoluble above pH 4 in aqueous media. 200 mg tablets of pazopanib are modified 
capsule-shaped, gray, film-coated with GS JT debossed on one side in bottles of 120 tablets. Each 200 mg 
tablet of pazopanib contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free 
base.  
 
The inactive ingredients of pazopanib are: Tablet Core: Magnesium stearate, microcrystalline cellulose, 
povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, 
macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.    
 
Solution preparation:  Not applicable 
 
Storage requirements:  Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). 
 
Stability:  The current shelf life is 36 months. 
 
Route of administration: Orally once daily without food (at least 1 hour before or 2 hours after a meal.  
Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. 
If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Expected adverse events:   


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33
Table 5. Adverse Reactions Occurring in ≥10% of Patients who Received Pazopanib 
 
Pazopanib 
Placebo 
(N = 290) 
(N = 145)  
All 
Gradesa 
Grade 3 
Grade 4  
All 
Gradesa  
Grade 3  
Grade 4  
Adverse Reactions  
%  
%  
%  
%  
%  
%  
Diarrhea  
52  
3  
<1  
9  
<1  
0  
Hypertension  
40  
4  
0  
10  
<1  
0  
Hair color changes  
38  
<1  
0  
3  
0  
0  
Nausea  
26  
<1  
0  
9  
0  
0  
Anorexia  
22  
2  
0  
10  
<1  
0  
Vomiting  
21  
2  
<1  
8  
2  
0  
Fatigue  
19  
2  
0  
8  
1  
1  
Asthenia  
14  
3  
0  
8  
0  
0  
Abdominal pain  
11  
2  
0  
1  
0  
0  
Headache  
10  
0  
0  
5  
0  
0  
a  National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
 
Table 6. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received 
Pazopanib and More Commonly (≥5%) in Patients who Received Pazopanib Versus Placebo 
 
 
 
Parameters  
Pazopanib 
(N = 290)  
Placebo  
(N = 145)  
All 
Gradesa 
Grade 3  
Grade 4  
All 
Gradesa  
Grade 3  
Grade 4 
%  
%  
%  
%  
%  
%  
Hematologic  
Leukopenia  
37  
0  
0  
6  
0  
0  
Neutropenia  
34  
1  
<1  
6  
0  
0  
Thrombocytop
enia  
32  
<1  
<1  
5  
0  
<1  
Lymphocytope
nia  
31  
4  
<1  
24  
1  
0  
Chemistry  
ALT increased  
53  
10  
2  
22  
1  
0  
AST increased  
53  
7  
<1  
19  
<1  
0  
Glucose 
increased  
41  
<1  
0  
33  
1  
0  
Total bilirubin 
increased  
36  
3  
<1  
10  
1  
<1  
Phosphorus 
decreased  
34  
4  
0  
11  
0  
0  
Sodium 
decreased  
31  
4  
1  
24  
4  
0  
Magnesium 
decreased  
26  
<1  
1  
14  
0  
0  
Glucose 
decreased  
17  
0  
<1  
3  
0  
0  
a  National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 
 


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34
Other adverse reactions observed more commonly in patients treated with pazopanib than placebo and 
that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), 
dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), 
palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), 
rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). 
 
Hepatic Toxicity — In a controlled clinical study with pazopanib for the treatment of RCC, ALT >3 X 
ULN was reported in 18% and 3% of the pazopanib and placebo groups, respectively. ALT >10 X ULN 
was reported in 4% of patients who received pazopanib and in <1% of patients who received placebo. 
Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline 
phosphatase >3 X ULN occurred in 5/290 (2%) of patients on pazopanib and 2/145 (1%) on placebo.  
 
Hypertension — In a controlled clinical study with pazopanib for the treatment of RCC, 115/290 
patients (40%) receiving pazopanib compared with 15/145 patients (10%) on placebo experienced 
hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving pazopanib compared 
with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with 
anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing 
treatment with pazopanib because of hypertension. In the overall safety population for RCC (N = 586), 
one patient had hypertensive crisis on pazopanib.  
 
QT Prolongation and Torsades de Pointes — In a controlled clinical study with pazopanib, QT 
prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of 
patients treated with pazopanib compared with no patients on placebo. Torsades de pointes was reported 
in 2/586 (<1%) patients treated with pazopanib in the RCC studies.  
 
Arterial Thrombotic Events — In a controlled clinical study with pazopanib, the incidences of arterial 
thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident 
[1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with 
pazopanib compared to the placebo arm (0/145 for each event).  
 
Hemorrhagic Events — In a controlled clinical study with pazopanib, 37/290 patients (13%) treated 
with pazopanib and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most 
common hemorrhagic events in the patients treated with pazopanib were hematuria (4%), epistaxis 
(2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with pazopanib who 
had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and 
genitourinary hemorrhage. Four (4/290) (1%) patients treated with pazopanib died from hemorrhage 
compared with no (0/145) (0%) patients on placebo. In the overall safety population in RCC (N = 586), 
cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with pazopanib. 
 
Hypothyroidism — In a controlled clinical study with pazopanib, more patients had a shift from thyroid 
stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-
baseline visit in pazopanib compared with the placebo arm (27% compared with 5%, respectively). 
Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with pazopanib and no 
patients (0%) in the placebo arm.  
 
Diarrhea — Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients 
should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to 
severe diarrhea occurs so appropriate management can be implemented to minimize its impact.  
 


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35
Proteinuria — In the controlled clinical study with pazopanib, proteinuria has been reported as an 
adverse reaction in 27 patients (9%) treated with pazopanib. In 2 patients, proteinuria led to 
discontinuation of treatment with pazopanib.  
 
Lipase Elevations — In a single-arm clinical study, increases in lipase values were observed for 48/181 
patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were 
Grade 3 for 6 patients and Grade 4 for 1 patient. In the studies of pazopanib in RCC studies, clinical 
pancreatitis was observed in 4/586 patients (<1%).  
 
Cardiac Dysfunction — Pazopanib has been associated with cardiac dysfunction (such as a decrease in 
ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In 
the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients 
(<1%). 
6.3. 
 
Gemcitabine (Gemzar) 
 
Product description:  Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly 
soluble in methanol, and practically insoluble in ethanol and polar organic solvents. The clinical 
formulation is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg 
or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, 
respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. 
Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. This agent is 
commercially available. 
 
Solution preparation:   The recommended diluent for reconstitution of Gemzar is 0.9% Sodium 
Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration 
for Gemzar upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL 
may result in incomplete dissolution, and should be avoided.  
 
To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg vial or 25 mL of 0.9% 
Sodium Chloride Injection to the 1-g vial. Shake to dissolve. These dilutions each yield a gemcitabine 
concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized 
powder (0.26 mL for the 200-mg vial or 1.3 mL for the 1-g vial). The total volume upon reconstitution 
will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg 
or 1 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be 
diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.  
 
Reconstituted Gemzar is a clear, colorless to light straw-colored solution. After reconstitution with 0.9% 
Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution 
should be inspected visually for particulate matter and discoloration prior to administration, whenever 
solution or container permit. If particulate matter or discoloration is found, do not administer.  
 
When prepared as directed, Gemzar solutions are stable for 24 hours at controlled room temperature 20° 
to 25°C (68° to 77°F). Discard unused portion. Solutions of reconstituted Gemzar should not be 
refrigerated, as crystallization may occur.  
 
The compatibility of Gemzar with other drugs has not been studied. No incompatibilities have been 
observed with infusion bottles or polyvinyl chloride bags and administration sets. 
 
Route of administration: Intravenous infusion should be performed over 30 minutes. Prolongation of 


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36
the infusion time >60 minutes has been shown to increase toxicity. 
 
Expected adverse events:   
 
Hematologic — In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with 
Gemzar, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. 
Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. 
Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 
1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during 
Gemzar therapy and dosage modified or suspended according to the degree of hematologic toxicity.  
 
Gastrointestinal — Nausea and vomiting were commonly reported (69%) but were usually of mild to 
moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. 
Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.  
 
Hepatic — In clinical trials, Gemzar was associated with transient elevations of one or both serum 
transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic 
toxicity with either longer duration of exposure to Gemzar or with greater total cumulative dose. Serious 
hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving 
Gemzar alone or in combination with other potentially hepatotoxic drugs.  
 
Renal — In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings 
consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) 
receiving Gemzar in clinical trials. Four patients developed HUS on Gemzar therapy, 2 immediately 
post therapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence 
of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, 
and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemzar therapy should be 
discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and 
dialysis may be required. 
 
Fever — The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) 
and indicates that Gemzar may cause fever in the absence of clinical infection. Fever was frequently 
associated with other flu-like symptoms and was usually mild and clinically manageable.  
 
Rash — Rash was reported in 30% of patients. The rash was typically a macular or finely granular 
maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. 
Pruritus was reported for 13% of patients.  
 
Pulmonary — In clinical trials, dyspnea, unrelated to underlying disease, has been reported in 
association with Gemzar therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary 
toxicity has been reported with the use of Gemzar. The etiology of these effects is unknown. If such 
effects develop, Gemzar should be discontinued. Early use of supportive care measures may help 
ameliorate these conditions. 
 
Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less 
than 1% of patients discontinued due to edema.  
 
Flu-like Symptoms — “Flu syndrome” was reported for 19% of patients. Individual symptoms of fever, 
asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia 


Version 3: 10/18/2016 
 
37
were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were 
reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms.  
 
Infection — Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).  
 
Alopecia — Hair loss, usually minimal, was reported by 15% of patients. 
 
Neurotoxicity — There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.  
 
Extravasation — Injection-site related events were reported for 4% of patients. There were no reports of 
injection site necrosis. Gemzar is not a vesicant.  
 
Allergic — Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been 
reported rarely. Gemzar should not be administered to patients with a known hypersensitivity to this 
drug.  
 
Cardiovascular — During clinical trials, 2% of patients discontinued therapy with Gemzar due to 
cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and 
hypertension. Many of these patients had a prior history of cardiovascular disease. 
 
7. CORRELATIVE/SPECIAL STUDIES 
 
7.1.  Angiogenic Biomarkers 
 
Specimens will be collected for the following potential correlative studies.  
 
 
7.1.1 Tumor Tissue 
 
 
 
In an effort to explore tumor biomarkers that may correlate with response, archived formalin-fixed 
paraffin embedded tumor tissue will be collected for potential testing to examine expression levels 
of biomarkers (encoded in RNA or protein) in pathways relevant to angiogenesis (e.g. VEGF, 
PDGF) and related pathways. A tumor block of sufficient size must be sent to OHSU for testing. In 
the event a tumor block is not available, efforts will be made to obtain 20 slides of paraffin-
embedded tissue. 
 
Representative areas from each whole-mount paraffin block chosen as the best composite 
representation of tumor based on H&E morphology will be placed in standard-sized tissue cassettes. 
These will be re-embedded, sectioned at 4 μm, and mounted on poly-L-lysine–coated slides for 
immunohistochemistry. Sections of paraffin embedded tissue will be deparaffinized and rehydrated. 
After appropriate antigen retrieval methods, potential IHC staining with commercial antibodies 
including but not limited to VEGF-A, VEGF-R2, phospho-VEGF-R2, PDGFR, and phospho-
PDGFR will be performed using an automated Dako immunostainer. Staining will be visualized by 
incubating the slides with 3,3'-diaminobenzidine solution, after which they will be rinsed, 
counterstained with hematoxylin, dehydrated in a Leica Autostainer XL, coverslipped, and reviewed 
by a single experienced pathologist who will score the percentage of positively staining cells. 
 
 
 
7.1.2 Serum 
 


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38
Serum (10 mL blood sample) will be collected at baseline and at week 6. Serum samples will be 
collected for potential tumorigenic and angiogenic markers including but not limited to VEGF, 
VEGF-A, sVEGFR2, and bFGF at baseline to correlate with response, and to identify any changes in 
circulating markers levels in response to treatment. Blood samples (10 mL) will be drawn using 
venipuncture into a Vacutainer containing potassium EDTA and inverted gently several times to mix 
with anticoagulant. Within 10-15 minutes after collecting, blood samples will be centrifuged in a 
refrigerated (4C) centrifuge for 10 minutes to separate the plasma. If a refrigerated centrifuge is not 
available, the tubes should be chilled in an ice bath for 5-15 minutes and then placed in a standard 
centrifuge for 10 minutes to separate the plasma. The plasma will be transferred to polypropylene 
tubes and frozen at -70C or lower. The tubes will be labeled with the investigator’s name, study 
number, and subject’s study number, and time and date of the sample acquisition. 
 
Quantitative enzyme-linked immunosorbent assays (ELISA) for angiogenic markers including but 
not limited to VEGF, VEGF-A, sVEGFR2, and bFGF may be performed on plasma using 
commercial kits. Manufacturers' protocols will be followed and samples are to be measured in 
duplicate. 
 
7.2.      Genetic mutation screen 
 
Tumor specimens may be used to screen for genetic alterations in a number of genes. DNA will be 
extracted and purified from available tumor material. Mutations will be detected using multiplex PCR 
amplification of gene exons of interest, followed by primer extension reactions, and readout of primer 
extension products by mass spectrometry. Confirmation of mutations by mass spectrometry will be 
confirmed by sequencing. 
 
       
8.   
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
 
8.1 
Subject Registration  
 
Written informed consent must be obtained before any study specific medical procedures are performed.  
 
All patients must be registered through the Oregon Health & Science University Knight Cancer Center. 
 
8.2.      Randomization process 
 
 
8.2.1 Method of blinding 
 
The OHSU Knight Cancer Institute will serve as the data coordinating center for this multicenter 
study. The OHSU statistician will generate a list of randomization codes for each sarcoma subtype 
(liposarcoma vs. other sarcoma subtypes) for each study site. Each site pharmacy will have a list of 
randomization codes and the corresponding assignment to drug vs. placebo. The OHSU pharmacy 
will have a master list of the assigned randomization codes and corresponding drug assignments for 
all study sites.  
 
When other coordinating sites have an eligible patient, they will contact the OHSU study 
coordinator who will review and approve patient eligibility. If eligible, the OHSU study site 
coordinator will assign the patient a unique ID# (randomization#) from the pre-generated list of 
randomization codes. The OHSU study site coordinator will then notify the OHSU research 
pharmacy and the study site pharmacy (if the patient is enrolled at another site) of the assigned 


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39
randomization code via a secure email. The unblinded research pharmacist will assign the patient to 
drug vs. placebo based on the corresponding drug assignment list. Double signature confirmation 
should be employed in the study specific enrollment record kept in the research pharmacy study 
binder.  
 
The randomization procedure will use the Biostatistics Shared Resources (BSR) at Knight Cancer 
Institute (KCI), which will serve as the randomization center. The BSR center will be using Stata 
module called Ralloc to create a sequence of randomization assignment in blocks of varying sizes. 
The randomization sequence is stratified by both the sarcoma subtype (liposarcoma vs. other 
sarcoma subtypes) and the study site. The size and the order of the blocks are also randomized to 
lessen the chance of predicting future assignments.  
 
 
8.2.2 Unblinding procedure 
 
Treatment assignment will remain blinded throughout the Study Treatment Period. Upon 
documented disease progression, a request to unblind the treatment assignment may be made by the 
investigator as per section 4.1.4. Unblinding will be performed by the OHSU Research Pharmacy. 
 
In the case of an emergency, when knowledge of the investigational product is essential for the 
clinical management or welfare of the patient, a patient’s treatment assignment may be unblinded. 
The principal investigator should be contacted to authorize the unblinding after review of the 
circumstances.  In the unlikely case that the principal investigator is not available, the OHSU 
Research Pharmacy is authorized to unblind the subject’s treatment assignment upon provision of 
supporting documentation by the investigator or managing healthcare professional. 
 
  8.3. Standard Laboratory Assessments 
 
Laboratory assessments should be performed as indicated in the Schedule and Events Tables (Sections 
8.9 and 8.10). These assessments may be carried out within 3 days before the actual visit to allow 
flexibility in scheduling.  Assessments may be performed more frequently if clinically indicated.  
Correction of electrolytes (most importantly, potassium, magnesium and calcium) to within normal 
ranges should take place prior to study entry and during study conduct as clinically indicated. 
 
All laboratory tests with values that become abnormal and clinically significant while the subject is 
participating in the study or within 28 days after the last dose of study drug should be repeated until the 
values return to normal or baseline.   
 
Table 7 shows the clinical laboratory assessments that should be reported. 
 


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40
 
 
Table 7. 
Clinical Laboratory Assessments 
Clinical Chemistry 
 
Renal function 
 Urea, Creatininea 
Liver function test 
(LFT) Panel  
Albumin, Alkaline phosphatase,  Alanine 
aminotransferase (ALT), Aspartate aminotransferase 
(AST), and Bilirubin (total)b 
Electrolytes and others 
Calcium, Potassium, Sodium, and Glucose 
Hematology 
Hematocrit, Hemoglobin, White Blood Cell Count, 
Red Blood Cell Count, Neutrophils, and Platelets 
Coagulation Tests 
Activated partial thromboplastin (aPTT) and 
International Normalization Ratio (INR)c 
Urinalysis for 
Proteinuria 
UPCd 
Thyroid Function Test 
TSH and thyroxine (free T4)e 
 
a) Estimated creatinine clearance should be calculated using the Cockcroft and Gault method 
(Appendix B).  Alternatively, creatinine clearance can be measured directly by 24-hour urine 
collection.  
b) A direct bilirubin level should be obtained if the total bilirubin level is greater than 1.5 X 
upper limit of normal (ULN).  See Section 5.1.2 for stopping criteria and dose modification 
guidelines for treatment-emergent liver function abnormality. 
c) Coagulation tests may also be performed in response to an AE/SAE of bleeding and as 
clinically indicated.   
d) UPC should be evaluated as described in Appendix C or by 24-hour urine protein.  If UPC ≥ 
3 or if urine protein is ≥3g, then the dose modification table guidelines should be followed 
(Section 5.1.1).   
e) Unscheduled thyroid function tests [TSH and thyroxine (free T4)] should be performed if 
clinically indicated (e.g., if a subject develops signs and symptoms suggestive of 
hypothyroidism). 
 
   8.4. Baseline Screening 
 
The following assessment will be completed prior to randomization: 
 
• Medical history (information on prior lines of therapies given for soft tissue sarcoma are  
important) 
 
• Physical examinations and demographics (age, gender, race, ethnicity, ECOG performance 
status, blood pressure, pulse rate and body weight) 
 
• Blood pressure (BP): for patients presenting with hypertension, their BP must be adequately 
controlled to ≤140/90 mmHg prior to the first dose of study medication. 
 
o 
Note:  Initiation or adjustment of antihypertensive medication(s) is permitted prior to 
study entry.  Following antihypertensive medication initiation or adjustment, blood 
pressure (BP) must be re-assessed three times at approximately 2-minute intervals.  At 
least 24 hours must have elapsed between anti-hypertensive medication initiation or 
adjustment and BP measurement.  These three values should be averaged to obtain the 
mean diastolic blood pressure and the mean systolic blood pressure.  The mean SBP / 
DBP ratio must be <140/90 mmHg in order for a subject to be eligible for the study. 


Version 3: 10/18/2016 
 
41
 
• Adverse events 
 
• Cancer signs and symptoms 
 
• Complete blood counts (including hemoglobin, hematocrit, white blood cell count, red blood cell 
count, neutrophils, and platelets) and serum chemistry (including calcium, sodium, potassium,  
urea, creatinine, total bilirubin, alkaline phosphatase, AST, ALT, glucose and albumin), PT/INR, 
PTT 
 
o 
Note: In case of co-administration of pazopanib with the anticoagulant warfarin (or its  
derivatives): International normalized ratio (INR) should be monitored within three to 
five days after initiating, escalating/de-escalating or discontinuing pazopanib therapy, 
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. 
 
• Thyroid function: TSH and free T4 
 
• UPC (Urine protein Creatinine ratio mg/dl, Appendix C) must be ≤1. If UPC > 1, urine protein 
excretion over 24h must be performed. Any patient with protein > 1 g over 24 hours would not 
be eligible. 
 
• Pregnancy test (serum β-HCG) for women of childbearing potential. Serum or urine pregnancy 
testing is required within 7 days of enrollment. 
 
• Cardiac function: 12-lead ECG and QTc measurement will be recorded. 
 
• Disease assessment within 4 weeks prior to start of treatment: 
 
o 
Radiological assessment to include CT (with contrast) of chest, abdomen, pelvis ( 
abdomen MRI with gadolinium and/or a non-contrast chest CT can be substituted for 
patients with renal insufficiency or if otherwise clinically indicated). 
 
o 
In case of suspicion of brain metastases perform CT or MRI brain (enhanced contrast). 
 
 
The above assessments should be completed within the following timeframes: 
Within 4 weeks of randomization: 
•   Medical history & Physical 
•   12-lead ECG and QTc measurement 
•   Informed consent 
 
Within 1 week of randomization: 
Labs, including: 
•   CBC 
•   Chemistries 
•   LFTs 
•   Pregnancy test 
•   UPC 
•   TSH 


Version 3: 10/18/2016 
 
42
•   Free T4 
•   PT/INR 
•   aPTT 
Prior to randomization and within 4 weeks of treatment start: 
•   CT (with contrast) of chest, abdomen, pelvis (abdomen MRI with gadolinium and/or non- 
contrast chest CT also acceptable with PI approval) 
 
C1D1 of treatment must be within 7 days of randomization.  
 
 8.5. Study Visits 
 
 See section 8.9. 
  
Toxicities and adverse experiences will be assessed at each visit using the NCI Common Toxicity 
Criteria for Adverse Events v4.0 (CTCAE, see appendix E).  
 
 8.6.    Pathology Sample Submission 
 
All pathology slides from the diagnostic biopsy must be submitted for central review at OHSU by a 
pathologist experienced in sarcoma. 
 
 8.7.     Follow-up 
 
After disease progression, the patient should be followed every 3 months for survival.  
 
 8.8. Early Termination 
 
            8.8.1 Criteria for stopping therapy:  
 
• Substantial non-compliance with the requirements of the study.  
• Any adverse event which, in the Investigator’s opinion, requires termination of the study  
medication.  
• Disease progression 
• Need for radiation therapy 
• Request by the patient or a legal representative/relative to stop the treatment.  
• The patient presents with a beta-HCG test consistent with pregnancy.  
• The patient uses illicit drugs or other substances that may, in the opinion of the Investigator, 
have a reasonable chance of contributing to toxicity or otherwise interfering with results.  
• The development of a second malignancy that requires treatment, which would interfere  
 
with this study.  
• The patient is lost to follow-up.  
• Interruption in study drug’s administration for greater than 3-weeks.  
• Development of an intercurrent illness or situation which would, in the judgment of the  
 
investigator, affect assessments of clinical status and study endpoints to a significant degree.  
 
If study treatment is stopped for any reason other than disease progression or patient death, every 


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43
effort should be made to continue to assess for disease progression according the study schedule 
until the patient progresses, starts a new therapy, or meets criteria for study withdrawal. The time of 
progressive disease will be recorded in the CRF.  
 
            8.8.2 Criteria for study withdrawal: 
 
• Substantial non-compliance with the requirements of the study.  
• Study closure 
• Patient decision to withdraw from the study 
 
The Investigator will make every reasonable effort to keep each patient in the study unless it is in the 
patient’s best interest to discontinue participation. If a patient is removed from the study or declines 
further participation, all End of Treatment evaluations should be performed if the patient is willing 
and able to be assessed. A description of the reason(s) for withdrawal from the study will be 
recorded on the case report form (CRF). The Investigator should also ensure that all patients are 
followed up for survival and recurrence after the Final Visit.  Relevant visit data should be entered 
on the CRF and any unused study medication will be accounted for and returned for all patients 
participating in the study, even for a brief period of time. Patients who discontinue following entry 
will have relevant information completed and recorded on the CRF. All patients who discontinue 
because of adverse events or clinically significant laboratory abnormalities should be followed up 
until they recover or stabilize, and the subsequent outcome will be recorded. If any patient should 
die during the trial or within 30 days of stopping study treatment, the Investigator will inform the 
OHSU IRB and the Novartis representative. The cause of death should be recorded in detail, within 
24 hours, on a serious adverse event (SAE) form and reported to the sponsor Drug Safety Unit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.9.     Schedule of Events for Randomized Portion of the Protocol 


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44
 
Screeninga 
Day 1 of each 
21 day cycle 
(+/- 3 days) 
Day 8 of each 21 
day cycle (+/- 1 
day) 
End of 
Treatment 
Informed Consent 
X 
 
 
 
History/Progress Notes 
X 
X 
 
X 
Physical Exam 
X 
X 
 
X 
Vitals signs 
X 
Xb 
X 
X 
Performance Status 
X 
X 
 
X 
Treatment Toxicity  
 
X 
 
X 
Chemistriesc 
X 
X 
 
X 
LFTsd 
 
Xd 
Xd 
 
CBCe 
X 
X 
X 
X 
Pregnancy testf 
X 
X 
 
X 
UPC 
X 
X 
 
 
Thyroid function test 
X 
Xg 
 
 
Coagulation test 
Xh 
 
 
 
Correlative study labs 
X 
Xi 
 
 
ECG with QTc 
measurement 
X 
Xj 
 
 
Gemcitabine 
administration 
 
X 
X 
 
Study drug 
administration 
 
Xk 
Xk 
 
Disease assessmentl 
X 
X 
 
X 
Submission of 
Pathology Slides 
X 
 
 
 
aScreening History, physical exam, and performance status assessment may be substituted for cycle 1 day 1 if 
performed within 2 weeks.  Laboratory exams (CBC, chemistries, LFTs, pregnancy test, UPC) may be substituted for 
cycle 1 day 1 if performed within 1 week. Cycle 1 Day 1 must occur within 7 days of randomization. 
bMonitoring of BP only:  A measurement of BP should be taken weekly during cycle 1, and then at the beginning of 
each cycle starting with cycle 2.  BP can be assessed by any method (i.e., at home or by another physician) as long as 
the study physician is informed of the measurement, verifies any measurement that is not normal and takes 
appropriate action. 
cChemistries should include calcium, sodium, potassium,  glucose, urea, and creatinine 
dMonitoring of LFTs (total bilirubin, alkaline phosphatase,  AST, ALT, and albumin):   LFTs at day 8 cycle 1, then at 
day 1 for each subsequent cycle. 
eCBC should include hemoglobin, hematocrit, white blood cell count, red blood cell count, neutrophils, and platelets 
fSerum or urine pregnancy testing within 7 days of enrollment and with each cycle thereafter until study treatment 
end. 
gBeginning with cycle 5, thyroid function tests (free T4 and TSH) are to be monitored every 4 cycles.   
hScreening coagulation tests included PT/INR and PTT. If the patient is on warfarin, will repeat PT/INR 3-5 days after 
starting treatment and weekly thereafter until stable. 
iCorrelative study labs: At baseline and after 2 cycles. 
jECG: At baseline, cycle 2, and then every 3 cycles until end of treatment 
kStudy drug (pazopanib/placebo) administered daily (Days 1-21 of each 21 day cycle) 


Version 3: 10/18/2016 
 
45
lDisease assessment recommendations: CT (with contrast) of chest, abdomen, pelvis (or abdomen and pelvis MRI 
with gadolinium and  non-contrast chest CT) within 4 weeks of enrollment, then every 6 weeks (± 1 week) for the first 
6 months of treatment, and then every 12 weeks (± 1 week) after the first 6 months of treatment until disease 
progression. If study treatment is stopped for any reason other than disease progression or patient death, disease 
assessment should continue according to the study schedule until progression, the patient starts a new therapy or 
otherwise meets criteria for study withdrawal. 
 
8.10.    Schedule of Events for Cross-over Portion of the Protocol 
 
Screening 
Day 1 of each 21 day cycle 
(+/- 3 days) 
End of Treatment 
Documentation of cross-
over eligibility 
X 
 
 
History/Progress Notes 
 
X 
X 
Physical Exam 
 
X 
X 
Vitals signs 
 
Xa 
X 
Performance Status 
 
X 
X 
Treatment Toxicity  
 
X 
X 
CBCb, chemistriesc, LFTs 
 
Xd 
X 
Pregnancy teste 
 
X 
X 
UPC 
 
X 
 
Thyroid function test 
 
Xf 
 
Coagulation test 
 
Xg 
 
ECG with QTc 
measurement 
 
Xh 
 
Scans for disease 
assessmenti 
 
X 
X 
aMonitoring of BP only:  A measurement of BP should be taken weekly during cycle 1, and then at the beginning of 
each cycle starting with cycle 2.  BP can be assessed by any method (i.e., at home or by another physician) as long as 
the study physician is informed of the measurement, verifies any measurement that is not normal and takes appropriate 
action. 
bCBC should include hemoglobin, hematocrit, white blood cell count, red blood cell count, neutrophils, and platelets 
cChemistries should include calcium, sodium, potassium,  glucose, urea, and creatinine 
dMonitoring of LFTs (total bilirubin, alkaline phosphatase,  AST, ALT, and albumin):  Day 1 of each cycle and 
additionally  between days 5 and 15 of cycles 2 and 3 only. 
eSerum or urine pregnancy testing with each cycle until study treatment end. 
f Beginning with cycle 5, thyroid function tests (free T4 and TSH) are to be monitored every 4 cycles. gIf the patient is 
on warfarin, will repeat PT/INR 3-5 days after starting treatment and weekly thereafter until stable. 
hECG:  At baseline, cycle 2, and then every 3 cycles until end of treatment 
iDisease assessment recommendations: CT (with contrast) of chest, abdomen, pelvis (or abdomen and pelvis MRI with 
gadolinium and  non-contrast chest CT) within 4 weeks of enrollment, then every 6 weeks (± 1 week) for the first 6 
months of treatment, and then every 12 weeks (± 1 week) after the first 6 months of treatment until disease progression. 
If study treatment is stopped for any reason other than disease progression or patient death, disease assessment should 
continue according to the study schedule until progression, the patient starts a new therapy or otherwise meets criteria 
for study withdrawal. 
 


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46
9. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response every 6 weeks ±1 week for the 
first 6 months and every 12 weeks ±1 week thereafter.  In addition to a baseline scan, confirmatory scans 
should also be obtained no sooner than 4 weeks following initial documentation of objective response. 
 
9.1. 
Definitions 
 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee version 1.138. Changes in 
only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST 
criteria. Note:  Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide additional 
meaning or accuracy. 
 
9.1.1 
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 with conventional techniques (CT, MRI, x-ray) or as 
>10 mm with spiral CT scan.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15mm 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. 
 
9.1.2 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable disease.  
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and 
cystic lesions are all non-measurable. 
 
9.1.3 
Target lesions 
All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the baseline sum LD.  The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
9.1.4 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions.  Measurements 


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47
of these lesions are not required but the presence or absence of each should be noted throughout 
follow-up.  
9.2. 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. 
 
Note: Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  
 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used to assess the antitumor effect of a 
treatment. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those 
of extremities usually require specific protocols. 
 
Ultrasound (US).  When the primary endpoint of the study is objective response evaluation, US should 
not be used to measure tumor lesions.  It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US might also be useful 
to confirm the complete disappearance of superficial lesions usually assessed by clinical examination. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation has not yet 
been fully and widely validated.  Their uses in this specific context require sophisticated equipment and 
a high level of expertise that may only be available in some centers.  Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in reference centers. 
However, such techniques can be useful to confirm complete pathological response when biopsies are 
obtained. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clinical response. 
 Specific additional criteria for standardized usage of prostate-specific antigen (PSA) and CA-125 
response in support of clinical trials are being developed. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 


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48
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
9.3. 
 
Response Criteria 
 
9.3.1 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 longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD 
 
Progressive Disease (PD): 
 
   At least a 20% increase in the sum of 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 progression). 
 
Stable Disease (SD):  
 
 
            Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
9.3.2 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 (<10mm short axis). 
 
Incomplete Response/  
Stable Disease (SD):  
 
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 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances the 
opinion of the treating physician should prevail, and the progression status should be confirmed at a 
later time by the review panel (or study chair).  Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response. 


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49
9.3.3 Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria (see Section 9.3.1). 
 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.”  Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When 
the evaluation of complete response depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response 
status. 
 
9.4. 
Confirmatory Measurement/Duration of Response 
 
9.4.1 Confirmation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed after the criteria for response are first met.  In the case of SD, 
follow-up measurements must have met the SD criteria at least once after study entry at a minimum 
interval of 6 (see section 9.3.3). 
 
9.4.2 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 


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50
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
 
9.4.3 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.  
 
9.5. 
Progression-Free Survival 
 
Progression free survival will be computed from the date of randomization to the first documented date 
of progression or the date of death, whatever the cause.  If a patient’s study treatment is unblinded for 
any reason prior to disease progression, progression free survival will be censored as of the date of 
unblinding for that patient.  If a patient begins another treatment for sarcoma, progression free survival 
will be censored as of the date of starting the new treatment. 
 
10. ETHICAL AND REGULATORY REQUIREMENTS 
 
10.1 Protocol Review 
 
The protocol and informed consent form for this study must be reviewed and approved in writing by 
the OHSU Knight Cancer Institute (CI) Clinical Research Review Committee (CRRC) and 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study.   
 
10.2 Informed Consent 
 
Written informed consent will be obtained from all patients, or the legally authorized representative 
of the patient, participating in this trial, as stated in the Informed Consent section of the case of 
Federal Regulations, Title 21, Part 50.  If a patients signature cannot be obtained, and for all patients 
under the age of 18, the investigator must ensure that the informed consent is signed by the patients 
legally authorized representative.  Documentation of the consent process and a copy of the signed 
consent shall be maintained in the patient’s medical record.  
 
10.3 Changes to Protocol  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment signed by the principal investigator and approved by the CRRC and IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment may 
be initiated without regulatory approval is for a change necessary to eliminate an apparent and 
immediate hazard to the patient.  In that event, the investigator must notify the CRRC and IRB in 
writing within 10 working days after the implementation. Investigators holding the IND must notify 
FDA of substantive changes to the protocol. 
 
 
 


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51
 
10.4     Maintenance of Records 
 
If the investigator relocates or for any reason withdraws from the study, the study records must be 
transferred to an agreed upon designee, such as another institution, another investigator, or to OHSU 
Knight Cancer Institute Clinical Research Management.  Records must be maintained according to 
sponsor or FDA requirements. 
 
10.5      OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
 Unanticipated Problems (UP) and Adverse Events (AE) will be reported to IRB according to the 
policies, procedures and guidelines posted on the OHSU IRB web site 
http://www.ohsu.edu/research/rda/irb/policies.shtml. 
 
Fatal and life-threatening events must be reported to OHSU IRB within 7 calendar days after the PI 
learns of the event. If any of these require a change (as determined by the PI or the IRB) to the 
protocol or consent form, the PI will make those changes promptly and submit the revised 
documents to the OHSU IRB. 
All other UP reports will be submitted to OHSU IRB no later than 15 calendar days of notification 
of the event.  If the event requires changes as determined by the PI or the IRB) to the protocol or 
consent form, the PI will make the changes promptly and submit the revised documents to the IRB.  
UP and AE reports are submitted through OHSU e-IRB and will be reviewed by OHSU IRB.   
 
10.6     Central Reporting of Adverse Events for Multicenter Studies      
 
The SAE/UP reporting for multicenter investigator initiated clinical trials will follow the guidelines 
outlined in the OHSU Knight Cancer Institute Multi-Center Investigator Initiated Trials Coordinating 
Center Operations Manual.  
A participating site must report an SAE to the to the institution’s local IRB for action as required, as  
well as to the OHSU coordinating center study team by phone, fax, or email within 24 hours of          
learning of the event. In addition, they will forward UP data no later than 10 days of occurrence or 
notification of the events to OHSU for relation assessment and evaluation. The participating center will 
send the coordinating center materials regarding the SAE including a completed Medwatch form and 
any de-identified medical records supporting the incident. If medical records are not available, then the 
Medwatch form should be sent with intent to follow up in the future with the records. 
 
SAE and UP reports and supporting documents will be faxed to: 
 
Clinical Research Management     
  
 
Attn: Phil Norr 
  
 
Fax: 503-346-6868 
  
 
OHSU Knight Cancer Institute 
  
 
3030 SW Moody Ave, Ste 235, MDYKCT  
  
 
 
  
 
Portland, OR  97201 
 
The OHSU coordinating center study team will review and submit SAEs to the FDA, OHSU IRB, and 
any other required contacts as required by the Knight Data Safety Monitoring Plan. The principal 
investigator at the Coordinating Center is responsible for distributing IND and/or IDE Action Letters or 


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52
Safety Reports, as applicable, to participating institutions for review and submission to their institution’s 
local IRB. 
 
10.7      MedWatch Reporting 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E)  
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form). Instructions are available at www.fda.gov/medwatch.  MedWatch reports can be 
submitted online at https://www.accessdata.fda.gov/scripts/medwatch/   
 
When the serious adverse event is reported to the FDA, copies of the MedWatch 3500 form and 
supporting materials will be submitted to the OHSU IRB and the OHSU Drug Information Service.  A 
copy of the MedWatch 3500 form and supporting materials will be kept on file in the study regulatory 
binder. 
 
10.8     Adverse Events Reporting Guidelines 
 
10.8.1      Definition of an adverse event 
 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
 
10.8.2    Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
AE reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site   
 
 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
   
Attribution of the AE: 
- Definite – the AE is clearly related to the study treatment. 
- Possible – the AE may be related to the study treatment. 
- Unrelated – the AE is clearly NOT related to the study treatment. 
 
 
 
10.8.3    Events meeting the definition of an adverse event (AE) include: 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline. Exacerbation of a chronic or intermittent pre-existing condition 
including either an increase in frequency and/or intensity of the condition 
• New conditions detected or diagnosed after investigational product administration even though it 
may have been present prior to the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 


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53
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication (overdose per se will not be reported as an AE/SAE) 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of 
efficacy will be reported if they fulfill the definition of an AE or SAE. 
 
 
 
10.8.4      Events that do not meet the definition of an AE include: 
 
• Any clinically significant abnormal laboratory finding or other abnormal safety assessments that 
is associated with the underlying disease, unless judged by the investigator to be more severe 
than expected for the subject’s condition.  
• The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the 
procedure is an AE 
• Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen 
• B cell depletion and hypogammaglobulinemia due to ofatumumab treatment 
 
 
 
10.8.5     Definition of a serious adverse event (SAE) 
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
- routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
- elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
- treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
- social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
• is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
 
 
10.8.6       Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline.   


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54
 
• All events meeting liver stopping criteria must be recorded as an SAE.  
 
• However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs. 
 
• B cell depletion, IgG below LLN, low CD19+ count, and hypogammaglobulinemia due to 
treatment with ofatumumab are not to be reported as AEs or SAEs. 
 
• Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the hospital due to 
slow infusion rate is not to be reported as a SAE. 
 
 
 
10.8.7       Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
 
An event which is part of the natural course of the disease under study (i.e., disease progression) 
does not need to be reported as an SAE.  However, if the progression of the underlying disease is 
greater than that which would normally be expected for the subject, or if the investigator considers 
that there was a causal relationship between treatment with investigational product or protocol 
design/procedures and the disease progression, then this must be reported as an SAE. 
 
 
 
 
10.8.8       Time Period and Frequency of Detecting and SAEs 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E)  
 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form). 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
• after the patient has provided informed consent and until at least 30 days after the patient has 
stopped study treatment/participation 
• after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and 30 days after the patient has stopped study treatment 
• after the start of any period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g., treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication) and until 30 days after the patient has 
stopped study treatment 
 
All events must be reported to Novartis within 24 hours of learning of its occurrence   
 
Information about all SAEs is collected and recorded on a Serious Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough report. 
The investigator must assess and record the relationship of each SAE to each specific study 
treatment (if there is more than one study treatment), complete the SAE Report Form in English, and 
send the completed, signed form by fax to (fax: 877-778-9739) within 24 hours to the oncology 
Novartis DS&E department with the provided FAX cover sheets. This includes serious, related, 
labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences.  


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55
 
All deaths during treatment or within 30 days following completion of active protocol therapy must 
be reported within 5 working days. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.  
 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up 
to the original episode within 24 hours of the investigator receiving the follow-up information. A 
SAE occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.  The end date of the first event 
must be provided. 
 
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be reported 
promptly to Novartis as described in the following table once the investigator determines that the 
event meets the protocol definition for that event. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 8. Reporting adverse events to the sponsor. 


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56
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time 
Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours SAE data collection 
tool 
24 hours 
Updated SAE data 
collection tool  
Pregnancy 
24 hours 
Pregnancy 
Notification Form 
24 hours 
Pregnancy Follow 
up Form 
Liver chemistry 
abnormalities: 
 
 
 
 
ALT: >3.0 x ULN  
with concomitant elevation in 
bilirubina (defined as  
total bilirubin ≥2.0 x ULN;  
with direct bilirubin >35%)  
or with hypersensitivity 
symptoms (e.g., fever, rash). 
24 hours SAE data collection 
tool. 
 
bCase Report Form 
(CRF) and liver 
imaging and/or 
biopsy if applicable 
24 hours 
Updated SAE data 
collection tool.  
 
bUpdated CRF 
ALT >8.0 x ULN  
without bilirubin elevation 
(defined as total bilirubina 
<2.0 x ULN or direct bilirubin 
≤35%) and without 
hypersensitivity symptoms 
(e.g., fever, rash) 
24 hours SAE data collection 
tool. 
 
CRFb  
24 hours 
Updated SAE data 
collection tool.  
 
Updated CRFb 
a. Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a 
subject meets the criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported 
as an SAE. 
b. Liver event documents should be completed as soon as possible. 
 
All serious adverse events must be reported by facsimile within 24 hours to Local Novartis 
Drug Safety and Epidemiology Safety Desk 1-877-778-9739 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the adverse 
events in question. Where applicable, information from relevant hospital case records and autopsy 
reports should be included. Follow-up information should be forwarded to Novartis within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of pazopanib and 
considered by the investigator to be related or possibly related to pazopanib must be reported to 
Novartis if and when they occur. Additionally, in order to fulfill international reporting obligations, 
SAEs that are related to study participation (e.g., procedures, invasive tests, change from existing 
therapy) or are related to a concurrent medication will be collected and recorded from the time the 
subject consents to participate in the study until he/she is discharged. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the Trial 
Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form was sent, 
using a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and 


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57
giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, whether the blind was broken or not (if applicable), and whether the patient continued 
or withdrew from study participation. 
 
If the SAE is not previously documented in the Pazopanib Investigator Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study drug, a DS&E associate may 
urgently require further information from the investigator for Health Authority reporting. Novartis 
may need to issue an Investigator Notification (IN), to inform all investigators involved in any study 
with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
 
 
 
 
10.8.9 
Pregnancy 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence 
 
 
 
10.9     OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
 
In addition to complete study and pharmacy files, complete records must be maintained on each patient 
treated on this protocol.  OHSU Knight Cancer Institute (CI), CRM shared resource is responsible for 
ensuring that all member investigators and affiliate investigators conduct clinical research studies in 
compliance with local IRB standards, FDA regulations and NIH policies.  The Data and Safety 
Monitoring Committee (DSMC) is responsible for conducting Quality Assurance audits on CI approved 
protocols according to the Data and Safety Monitoring Plan policies and procedures 
http://ohsucancer.com/crm  
 
Affiliate sites with their own DSMP will be responsible for forwarding the plan to OHSU CC upon 
study initiation, and must follow their DSMP by monitoring and auditing the trial at their site. Audit 
findings/letters should be sent to the CC as soon as possible following audit completion. 
 
Locally initiated studies will be audited by an OHSU Knight CI DSMC audit team. Newly approved 
studies may be audited any time after enrollment.  Each OHSU Knight CI approved treatment protocol 
will be audited on an annual basis.   
 
 
10.10      Inclusion of Women, Minorities and Children 
 
       
           10.10.1 Inclusion of Women and Minorities 
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic subset. 
No subject will be excluded from the study on the basis of gender, racial or ethnic origin. Male, 
female and minority volunteers will be recruited for this study from the general population and 
approximately 50% men and 50% women will be studied.  


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58
 
The projected gender, racial, and ethnic composition of the study will represent that of the state of 
Oregon.  
 
                             Table 9: Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 
 
8.0 
Not Hispanic or Latino 
 
 
92.0 
Ethnic Category: Total of all subjects* 
 
 
100* 
Racial Category 
 
American Indian or Alaskan Native 
 
 
1.3 
Asian 
 
 
3.0 
Black or African American 
 
 
1.6 
Native Hawaiian or other Pacific Islander 
 
 
0.2 
White 
 
 
86.6 
More than one race 
 
 
3.1 
Unknown/Other 
 
 
4.2 
Racial Category: Total of all subjects* 
 
 
100* 
TOTALS 
50.4 
49.6 
100* 
 
                Source:   Adapted from U.S. Census Bureau, 2000    *Totals may not equal 100 due to rounding. 
 
 
               Table 10: Projected Accrual for the Present Study  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
3-4 
3-4 
0 
6-7 
Not Hispanic or Latino 
36-37 
36-37 
0 
73-74 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all 
subjects* 
40 
40 
0 
80* 
Racial Category 
 
American Indian or Alaskan 
Native 
0-1 
0-1 
0 
1-2 
Asian 
1-2 
1-2 
0 
2-3 
Black or African American 
0-1 
0-1 
0 
1-2 
Native Hawaiian or other Pacific 
Islander 
0-1 
0-1 
0 
0-1 
White 
34-35 
34-35 
0 
69-70 
More than one race 
1-2 
1-2 
0 
2-3 
Unknown 
1-2 
1-2 
0 
3-4 


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59
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Racial Category: Total of all 
subjects* 
40 
40 
0 
80* 
 
 
                   Source: Adapted from U.S. Census Bureau, 2000.  *Totals must agree.    
                  
 
10.10.2  
Inclusion of Children 
 
In accordance with NIH guidelines on the inclusion of children as participants in research involving 
human subjects, children under the age of 18 years must be included in all human subjects research, 
conducted or supported by the NIH, unless there are clear and compelling reasons not to include 
them. Therefore, proposals for research involving human subjects must include a description of 
plans for the inclusion of children 
 
This study will only include children adults. The safety of pazopanib in children is unknown and 
currently being investigated. Gemcitabine has been studied and been found to be safe in children. This 
protocol does not include children <18 years of age for the following reason: no dosing or adverse event 
data are currently available on the use of pazopanib in children, therefore, children <18 years of age are 
excluded from this study but will be eligible for future pediatric phase 2 combination trials. 
 
 
10.11     DATA COLLECTION AND STORAGE 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  Standard institutional practices will be followed as described in the 
OHSU’s Information Security Directives to maintain the confidentiality and security of data 
collected in this study. Study staff will be trained with regard to these procedures. 
Loss of participant confidentiality is a risk of participation. Efforts will be made to keep study 
participant identities confidential except as required by law. Participants’ samples will be identified 
by code only. Specifically, each consenting participant will be assigned a unique coded identifier 
consisting of numbers. This identifier will be associated with the participant throughout the duration 
of their participation in the trial. The coded identifier will also be used to identify any participant 
specific samples. 
 
Basic accrual tracking information (subject demographics, consent type and date, visit information) 
will be captured in OHSU’s electronic clinical information research system (eCRIS), hosted on 
OHSU servers and managed by OHSU’s information technology group at their data center in 
downtown Portland, Oregon. Any additional printed documents containing participant identifiers, 
such as those from the medical record to confirm eligibility, will be filed in binders and kept in a 
locked, secure location.  
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic data 
capture (EDC) system on OHSU secure servers, which facilitates information being stored in a 
unified format and location. To further preserve confidentiality, PHI in the EDC system will be 
limited to just birth date and visit dates. The web-accessible EDC system is password protected and 
encrypted with role-based security, and administered by designated informatics staff within OHSU 
or Knight Cancer Institute. All users of the database are assigned a unique ID, username, and 


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password and must complete training appropriate to their role before they are authorized to enter, 
access, and store data in the database. 
 
Data from correlative studies will be entered into the EDC system by study personnel at OHSU. All 
other electronic data extracts will be stored only on OHSU computers and restricted drives, limited 
only to study investigators and staff with authorization to access the data. Quality assurance will be 
conducted as outlined in Section 10.9 
 
 
11. STATISTICAL CONSIDERATIONS 
 
This is a double-blinded 1:1 randomized Phase II clinical trial that randomly assigns patients to either the 
gemcitabine plus pazopanib arm or the gemcitabine plus placebo arm. Randomization will be stratified by 
subtypes of sarcoma (liposarcoma vs. all other eligible soft tissue sarcoma subtypes) and the study sites. A 
total of 80 patients will be enrolled on the study. We expect 25% of the patients will have liposarcoma, 
while 75% of them will have other types of sarcoma such as pleomorphic sarcoma, leiomyosarcoma, 
synovial sarcoma, vascular sarcoma etc.   
 
11.1   Study Endpoints and Objectives 
 
11.1.1 Primary Endpoint and Primary Objective:  
 
The primary endpoint for the study is progression-free survival (PFS), calculated as the time from 
randomization to the first documented progression or death whichever occurs first, or until time of 
last contact if no progression or death occurred.  
 
The primary objective of the study is to evaluate the PFS of patients with metastatic soft tissue 
sarcoma treated with gemcitabine plus pazopanib, and compare that with the PFS of patients 
receiving gemcitabine plus placebo.  
 
 
 
 
11.1.2 Secondary Endpoints and secondary objectives:  
 
The secondary endpoints include: 
 
Progression-free survival (PFS): (for a sub-group of patients treated with single agent pazopanib 
following administration of gemcitabine in the cross-over portion of this study) 
 
The PFS for this sub-group of patients is defined somewhat differently from the PFS defined in the 
primary objective ---- it is calculated as the time from the crossover enrollment date to the next  
documented progression or death whichever occurs first.    
 
Overall response and best overall response:  
 
The response of patients is categorized into complete response (CR), partial response (PR), 
progressive disease (PD), and stable disease (SD) following RECIST version 1.1. Please see Section 
9.3.1 and 9.3.2 for more details on the criteria to be used for response evaluation.  


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61
 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence. Please see Section 9.3.3 for a detailed definition of best overall response. 
 
 
Overall Survival (OS): 
 
The overall survival is defined as the time from randomization to death due to any cause, or until last 
patient contact if the patient did not die, i.e., censored.   
 
Adverse Events (AE) and Serious Adverse Events (SAE): 
 
Adverse events of the study are defined using the Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.0.  
 
Serious adverse events are defined in great detail in Section 10.7.4.  
 
 
The secondary objectives are: 
• To assess overall response and best overall response in this population to gemcitabine  
plus pazopanib compared to gemcitabine plus placebo. 
• To assess OS in this population to gemcitabine plus pazopanib compared to gemcitabine         
plus placebo. This will be an exploratory endpoint due to cross-over effects. 
• To investigate differences in treatment response in different histologic subgroups        
      (liposarcoma vs. all other eligible soft tissue sarcoma subtypes). 
• To evaluate the safety and tolerability of the combination of gemcitabine plus pazopanib. 
• To assess the progression-free survival and overall response in patients treated  
      with single agent pazopanib following administration of gemcitabine in the cross-over  
      portion of this study. 
 
11.1.3 Correlative/Exploratory Endpoint:  
 
Perform an exploratory analysis of potential biomarkers that predict response in patients receiving 
combination therapy with gemcitabine plus pazopanib. 
 
11.2 Methods to assess study objectives 
 
To address primary objective 1.1.1, the two treatment arms will be compared for PFS using a one-sided 
log-rank test stratified by the same factors used for the randomization. The study population for the 
efficacy analysis is the intent to treat (ITT) population of all randomized patients. Kaplan-Meier 
estimates and the survival curves for each treatment arm will be presented with the estimated hazard 
ratios and their associated confidence interval. 
 
To address secondary objectives 1.2.1 and 1.2.3, the estimated odds ratio of treatment response will be 
reported with 95% confidence interval for the two histologic sarcoma subgroups (liposarcoma vs. all 
other eligible soft tissue sarcoma subtypes). Exact one-sided Cochran-Mantel-Haenszel (CMH) test will 
be used to determine whether the overall response differs for the subgroups in general. An overall odds 
ratio for overall response and best overall response will be reported with 95% confidence interval if the 
CMH test suggests the overall responses do not differ among sarcoma subgroups.   
 
To address secondary objective 1.2.2, the two treatment arms will be compared for OS using a one-sided 


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log-rank test stratified by the same factors used for the randomization. The study population for the 
efficacy analysis is the intent to treat (ITT) population of all randomized patients. Kaplan-Meier 
estimates and the survival curves for each treatment arm will be presented with the estimated hazard 
ratios and their associated confidence interval. 
 
To address secondary objective 1.2.4., toxicities will be descriptively tabulated.  The study population 
for safety analysis will be comprised of all subjects who received at least one dose of assigned 
treatment, i.e., evaluable for toxicity. Frequency and severity of adverse events will be tabulated for 
each treatment arm based on the actual treatment the patient receives. Toxicity and adverse events will 
be summarized according to each major organ group and grade outlined in the CTCAE v4.0 criteria. In 
addition, the stopping rules for transaminase and bilirubin will inform the safety of the combination in 
terms of liver toxicity. 
 
To address secondary objective 1.2.5., the patient population will be limited to the sub-group of patients 
who was originally randomized into the placebo group, had progression, and was then offered open-
label treatment of pazopanib. Notice that because the baseline time point for the sub-group of patients is 
the start of open-label treatment of pazopanib, patients may not be followed-up long enough. Also, as 
the number of patients in this sub-group is limited, the statistical analysis is exploratory --- Kaplan-
Meier estimate and the survival curve will be presented with the estimated hazard ratio and its 
associated 95% confidence interval.   
 
To address secondary objective 1.2.6, a Wilcoxon test will be performed to test for biomarker level 
(continuous) with response (responder versus non-responder).  Since these tests are exploratory, the 
results will not be considered definitive, but will be used to generate hypotheses to be validated in a 
future study. 
 
All tests will be conducted at 0.05 significance level using SAS 9.3. 
 
 
11.3 Safety Monitoring 
 
The study population for safety analysis will be comprised of all subjects who received at least one dose 
of assigned treatment, i.e., evaluable for toxicity. Toxicity and adverse events will be summarized 
according to each major organ group and grade outlined in the CTCAE v4.0 criteria.  
 
11.4 Sample Size and Power 
 
The study will be powered to address the primary objective.  The sample size is computed from a 
comparison of PFS between subjects randomized to gemcitabine placebo arm and subjects randomized 
to gemcitabine + pazopanib arm. The median PFS for the gemcitabine + placebo arm is estimated to be 
3 months. With an overall one-sided alpha of 5%, a total of 73 patients (36 in the gemcitabine + placebo 
arm, and 37 in the gemcitabine + pazopanib arm) are required to achieve 80% power to detect a 2.5 
month increase in median PFS (a hazard ratio of 0.55) between the two treatment arms. We expect to 
accrual 4-5 patients per month, and plan to accrue 80 patients to allow ~ 10% drop-out or loss to follow-
up. The power analysis is conducted using PASS 2008 version 08.0.6 for log-rank test (Lakatos). 
 
11.5 Interim Analysis and Stopping Rules 
 


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63
            No interim analysis is planned for the study. However, the OHSU Knight Data Safety Monitoring 
Committee (DSMC) will monitor for safety as per the OHSU Knight Cancer Institute data and safety 
monitoring plan (see section 10.8). 
 
 
 
 
 


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


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


 
APPENDIX C 
 
Urine Protein Creatinine Ratio (UPC) 
 
Clinical meaning of UPC 
 
There is a good correlation between the ratio of urine protein to creatinine concentrations (UPC) in a random 
urine sample and the amount of protein excreted in a 24-hour urine collection period. Thus, the UPC allows 
estimation of the 24-hour urine protein excretion from a random sample. The 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. 
The UPC ratio is roughly equal to the 24 hour urine protein excretion in g/day 
 
Calculating Urine Protein to Creatinine ratio (UPC) 
 
UPC ratio = (Urine protein mg/dl) / (urine creatinine mg/dl) = numerically equivalent to gm protein excreted in 
urine over 24 hrs. 
 
Example: Patient has a urine protein = 90 mg/dl and urine creatinine = 30 mg/dl. 
UPC ratio= (90 mg/dl) / (30 mg/dl) = 3 
Result UPC is 3 (correlates to roughly 3gm protein excretion in a 24 hour period) 
 
Units for UPC ratio 
 
Note: UPC is a calculated ratio. The guidelines in the protocol are based on having urine protein and urine 
creatinine measured in the same units (e.g., mg/dl). The SI units for urine protein and urine creatinine are not 
the same, so these must be converted to mg/dl before calculating the ratio. 
 
For reference, the conversion factor for commonly used units for protein and creatinine is provided 
in the table below. 
 
Starting units 
Conversion to mg/dl 
Protein (g/l) 
Multiply by 100 
Protein (mg/l) 
Divide by 10 
Creatinine (µmol/l) 
Divide by 88.4 
Creatinine (mmol/l) 
Multiple by 11.3 
 
 
 
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. 
 
 
 
 
 


 
APPENDIX D 
 
New York Heart Association (NYHA) classification of heart failure 
 
Class I  
 
Patients with cardiac disease but without resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
 
Class II  
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or angina 
pain. 
 
Class III  
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
 
Class IV  
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 
 
(The Criteria Committee of the New York Heart Association: Diseases of the Heart and Blood 
Vessels; Nomenclature and Criteria for Diagnosis, 6th ed Boston, Little, Brown 1964). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E 


 
 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
 
Toxicities and adverse events will be assessed using the NCI Common Toxicity Criteria for Adverse Events 
v4.0 (CTCAE).  Since CTEP has standardized the CTCAE, the NCI does not require the inclusion of the 
CTCAE within the protocol document.  A copy can be downloaded from the CTEP home page 
http://ctep.cancer.gov/reporting/ctc.html 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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