Clinical trial NCT01767636
Conditions: Carcinoma of the Collecting Ducts of Bellini Chromophobe Renal Cell Carcinoma Kidney Medullary Carcinoma Kidney Oncocytoma Metastatic Renal Cell Cancer Papillary Renal Cell Carcinoma Recurrent Renal Cell Carcinoma Sarcomatoid Renal Cell Carcinoma Stage IV Renal Cell Cancer
Sponsor: Mayo Clinic
Start date: 2013-05-16; Completion date: 2021-01-20
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pazopanib hydrochloride works in treating patients with kidney cancer that has spread to other places in the body (metastatic). 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 kidney cancer by blocking blood flow to the tumor.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the efficacy of pazopanib hydrochloride (pazopanib) in non clear cell metastatic renal cell cancer patients as assessed by the overall survival rate at 12 months.

SECONDARY OBJECTIVES:

I. To determine the rates of best tumor response at the end of the first two treatment cycles of pazopanib in non clear cell metastatic renal cell cancer patients.

II. To determine the benefit of pazopanib in increasing progression free survival time.

III. To describe toxicity profile of pazopanib in non clear cell metastatic renal cell cancer patients.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.

Arms: arm 1: Patients receive pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Pazopanib Hydrochloride
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 




  
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Index 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factor  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Consent Form  
 
Appendix I  
ECOG Performance Status 
Appendix II  
Concomitant Medication 
Appendix III   Patient Medication Diary  
Appendix IV   New York Heart Association (NYHA) Class III  
Appendix V 
Blank 
Appenidx VI 
Inhibitors and Inducers of CYP3A4 
Appendix VII Adverse Events Reported 
Appendix VIII Table 78-80 – Adverse Reactions/Organ Class 
 
 
 
 


  
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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up information. 
 
1 Cycle length=28 days 
 
Generic name: Pazopanib 
Mayo abbreviation:  786034 
Availability: Novartis 
 
Treatment1  
 
Pazopanib 800 mg once daily until 
progression 
 
Event Monitoring (2 years) 
 
 
PD* at any time 
Unacceptable adverse  
Event 
events   
 
 
Monitoring 
Patient refusal 
 
 
*unless otherwise specified 
 
Registration 


  
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1.0 
Introduction   
 
1.1 
Renal Cell Carcinoma 
 
 
Renal cell carcinoma (RCC) is a non-homogenous collection of histologically distinct 
tumor types broadly classified as clear cell and non-clear cell kidney cancer as recognized 
by the Heidelberg classification system. While clear cell histology forms the bulk (75-
80%) (Cohen and McGovern 2005) of all kidney cancers several distinct non clear cell 
histological subtypes constitute 15-25% of all renal cell cancers. The approximate 
distribution among histological sub-types of kidney cancer is as follows: 
 
Clear cell (75 to 85 percent of tumors)  
 
Chromophilic (papillary) (10 to 15 percent)  
 
Chromophobic (5 to 10 percent)  
 
Oncocytic (uncommon)  
 
Collecting duct (Bellini's duct) (very rare) 
 
The genetic and molecular biology of clear cell renal cancer has been successfully targeted 
with the approval of several new drugs that inhibit the vascular endothelial growth factor 
(VEGF) and the mammalian-target of rapamycin (m-TOR) pathways since 2006 (Di 
Lorenzo, Autorino et al. 2009). These pathways  are  up regulated as a result of mutational 
inactivations in the Von Hippel-Lindau (VHL) gene that inhibition of these pathways 
using pazopanib (LaPlant and Louzon), sunitinib (Motzer, Hutson et al. 2007), sorafenib 
(Escudier, Eisen et al. 2007), everolimus (Motzer, Escudier et al. 2008), bevacizumab with 
interferon (Rini, Halabi et al. 2008) and temsirolimus (Hudes, Carducci et al. 2007) has 
resulted in slowing disease progression and prolonging longevity of life in the metastatic 
setting compared to previous cytokine based approaches for progressive stage IV disease.  
 
Most of the above trials however excluded non clear cell histological subtypes, and it 
remains unclear if patients with metastatic non clear cell histology will derive therapeutic 
benefit from the above drugs as well, since the genetic and molecular characteristics of 
non clear cell histology are distinct and the clinical behavior of these histological subtypes 
are different from clear cell histology. For example, when initially diagnosed in the 
localized stage, papillary, chromophobe and oncocytomas have a better prognosis than 
clear cell renal cancer. However, after developing metastases, in general the survival of 
patients with non clear cell RCC becomes universally poor. The exception is collecting 
duct cancers (including medullary) of the kidney, which are extremely aggressive and 
carry a poor prognosis in any stage of detection. 
 
At the molecular and genetic level the characteristics of non clear cell vary with histology. 
Papillary RCC, the second most common histological subtype is histologically categorized 
into Type I and Type II. Type I (sporadic and hereditary forms) is associated with 
activating mutations of the methyl-nitroso-nitroguanidine-induced (MET) oncogene on the 
long arm of chromosome 7 (Dharmawardana, Giubellino et al. 2004). These mutations 
result in ligand independent activation of intracytoplasmic tyrosine kinase domains, which 
constitutively activate hepatocyte growth factor (HGF)/MET pathway. Additionally in its 


  
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hereditary form families with Type I papillary RCCC have germline mutations in MET 
oncogene which are passed on to offspring with variable penetrance. Individuals with 
these mutant alleles phenotypically present with bilateral multifocal papillary Type I 
RCCs (Sudarshan and Linehan 2006). Papillary Type II RCC on the other hand can 
present in its hereditary form with leiomyomatosis (Hereditary leiomyomatosis with RCC-
HLRCC) due to mutations in the Fumarate Hydratase (FH) gene which inactivate the gene 
leading to generation of a pseudo-hypoxic state characterized by the upregulation of 
hypoxia inducible factor (HIF) similar to that seen in the VHL pathway in clear cell 
RCCC, albeit by a different mechanism (Isaacs, Jung et al. 2005).  
 
The mechanisms underlying chromophobe histology are lesser understood, although an 
autosomal dominant hereditary cancer syndrome, Birt-Hogg-Dube (BHD) syndrome 
associated with bilateral multifocal chromophobe RCC is the result of loss of folliculin 
protein is thought to interact with cellular activate mitogen protein kinase (cAMP) and m-
TOR pathways (Nickerson, Warren et al. 2002). Apart from this mechanism, other 
mechanisms such as upregulation of cellular proto-oncogenic receptor tyrosine kinase (c-
KIT) have also been observed in chromophobe RCC (Yamazaki, Sakamoto et al. 2003). 
1.2 
Clinical experience with VEGF axis inhibition in non clear cell histology 
 
The underlying differences in molecular mechanisms for developing non clear RCC has a 
potential impact in therapeutic targeting, which resulted in excluding these histologies in 
the pivotal trials that targeted the VEGF axis with clear cell histology. However, with 
limitations there is some clinical evidence available indicative of efficacy for VEGF 
targeting in non clear cell RCC. 
 
The Advanced Renal Cell Carcinoma Sorafenib Expanded Access Program, a non-
randomized open label program initiated prior to drug approval treated 158 metastatic 
papillary RCC patients with sorafenib (Stadler, Figlin et al.). Stable disease was observed 
in 87 patients of 107 evaluable patients for 8 weeks with a partial response observed in an 
additional three patients.  
 
In a multi-center, international, non-randomized open label compassionate use trial with 
sunitinib in poor prognosis populations that were excluded from other trials on the basis of 
brain metastasis, non clear cell histology, poor performance status and increased age, the 
overall survival of patients with non clear cell histology was observed to be improved 
(13.4 months compared to a historical control of 9.4 months) with an overall response rate 
of 11% for non clear histology (Gore, Szczylik et al. 2009).  
 
Other small retrospective series have reported variable efficacy with sunitinib and 
sorafenib (Choueiri, Plantade et al. 2008) in patients with metastatic non clear histology 
with response rates ranging between 5% and 17% while recently a lack of response to 
sunitinib in 23 patients with metastatic papillary RCC was observed (Plimack E. et al. 
2010 J Clin Oncol 28: 15s, 2010 (suppl; abstr 4604)) in a small phase II trial with a best 
response of 1.6 months in 8 patients demonstrating stable disease.  
1.3 
Clinical Experience with non VEGF axis inhibition strategies 
 
Experience with non-VEGF axis directed drugs in non clear RCC has also been limited. In 
the Global Advanced RCC trial comparing temsirolimus, interferon or both for advanced 


  
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RCC, (Hudes, Carducci et al. 2007) 124 subjects (20%) had non clear RCC histology. In 
an exploratory analysis hazard ratios for over all survival among non clear RCC patients 
favored treatment with temsirolimus compared to interferon or observation. A prospective 
phase II trial of everolimus in advanced papillary RCC is currently ongoing in Europe and 
results remain unknown. A new novel oral receptor tyrosine kinase inhibitor, foretinib 
(formerly known as GSK 1363089/XL880) that targets c-MET and VEGFR-2 has been 
evaluated in an efficacy trial in advanced papillary RCC with interim data on the first 60 
patients recently reported in abstract form (SrinivasinR, et al. J Clin Oncol 27:15s, 2009 
(suppl; abstr 5103)). Of the 35 evaluable pts, 4 patients had confirmed partial response and 
27 had stable disease as best response with 6 patients ≥12 months, 3 patients ≥ 9 months 
and 3 patients ≥ 6 months. Four of 5 patients with Hereditary Papillary RCC had shrinkage 
(15-53%) in all measurable tumors while twenty-three patients with sporadic Papillary 
RCC had shrinkage (2-58%) in the sum of measurable tumors.  
 
Other trials with single agent erlotinib in advanced stage papillary RCC (Gordon, Hussey 
et al. 2009) or in combination with bevacizumab are currently underway at the National 
Institute of Health.  
 
 
Cytotoxic chemotherapy has so far yielded poor efficacy results in non-clear-cell renal cell 
carcinoma (RCC). A phase II study conducted to assess the efficacy of carboplatin and 
paclitaxel in such patients observed a response rate of 0% with a median survival of 63 
weeks (Bylow, Atkins et al. 2009). In another phase II multi-center trial that tested 
gemcitabine and cisplatin in collecting duct tumors in 23 patients found a response rate of 
26% with a progression free survival of 7.1 months (compared to historical controls) and 
an overall survival of 10.5 months with considerable toxicity (Oudard, Banu et al. 2007). 
 
1.4 
Mayo Clinic Nephrectomy database experience with non clear cell renal cell cancer 
 
At the Mayo Clinic (Rochester), (Department of Urology) an active kidney tumor registry 
has been maintained since 1970. The Nephrectomy Registry is currently complete with 
clinical follow up through 2007 and provides a rich source of clinical outcomes based on 
various histological subtypes. Between 1970 and 2007, 3714 nephrectomies for RCC were 
performed that had a specific RCC histo-path subtype with a breakdown as follows: 
3051 clear cell RCC 
499 papillary RCC 
156 chromophobe RCC 
 8 collecting duct RCC 
 
 
(Sarcomatoid differentiation can arise in all of these subtypes and is not considered a 
separate subtype according to the AJCC classification) 
 
 
Among the 663 nephrectomies for non-clear cell RCC, 26 were M1 at nephrectomy and 
48 subsequently developed metastases sometime following nephrectomy.  For the 74 cases 
with distant metastases either at nephrectomy or following nephrectomy, the overall 
survival rates at 1, 3, and 5 years following distant metastases were 55.2%, 24.9%, and 
16.3%, respectively (Leibovich, Lohse et al.). Non-clear cell metastatic RCC survival 


  
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reported from another large kidney cancer database from Memorial Sloan Kettering, 
published by Motzer et al (Motzer, Bacik et al. 2002) also provides insight into the poor 
prognosis of these histological subtypes. Of the 64 patients followed between 1985 and 
2001, the median survival of metastatic non clear cell RCC was found to be 9.4 months, 
with survival longer for patients with chromophobe tumors than with collecting duct and 
papillary cancers. Patients in this review had received cytokine and or hormonal 
treatments with negligible responses highlighting an unmet need for the treatment in this 
group of patients. 
 
 
Mayo Clinic (Rochester) annually averages 4-6 metastatic non-clear cell RCCs that 
undergo nephrectomy with a similar incidence at Mayo Clinic, Florida and Arizona. In 
addition in the Medical Oncology division at Rochester between 3 and 7 metastatic non-
clear cell RCCs are treated annually. 
 
 
Since the role of active treatment agents in metastatic RCC of non-clear-cell histologies 
remains to be established and the efficacy of pazopanib in delaying disease progression in 
metastatic clear cell RCC is unknown in non clear cell histological sub types, the current 
prospective phase II trial is designed to evaluate the efficacy of pazopanib in advanced 
stage non clear RCC patients. 
 
 
1.5 
Pazopanib Information 
 
Angiogenesis, the process of new blood vessel formation, plays an important role in the 
development of malignancy as well as the growth and progression of metastatic lesions.  
The molecular pathways involved in angiogenesis have been targeted for anti-tumor 
therapy.  Numerous growth factors and cytokines are involved in the angiogenic process.  
Among these factors, vascular endothelial growth factor (VEGF) has a predominant role 
as a central mediator of tumor-related angiogenesis, and its expression has been shown to 
be an adverse prognostic factor for a number of solid tumors [Folkman, 1971; Folkman 
1997; Ferrara, 1997]. 
    
αβ 
GW786034 (pazopanib) is an orally-bioavailable, adenosine triphosphate (ATP)- 
competitive tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) 
receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor (PDGFR)- α and - 
β, and stem cell growth factor receptor (c-Kit) [Kumar, 2007]. Pazopanib administered as 
oral doses up to 800 mg daily is being developed for the treatment of a variety of cancers 
and is currently approved by the Food and Drug Administration (FDA; New Drug 
Application #022465), European Medicines Agency (EMA) and other regulatory 
authorities as a monotherapy treatment for patients with advanced renal cell carcinoma 
(RCC) and advanced soft tissue sarcoma (STS). GW786034 is hereafter referred to as 
pazopanib in this document. 
 
Nonclinical pharmacology studies conducted in vitro and in vivo have shown that 
pazopanib is a potent and selective orally bioavailable, adenosine triphosphate 
competitive, TKI of VEGFR-1, -2, and -3; PDGFR- α and - β; and c-Kit. Pazopanib was 
generally efficacious in oral dosing xenograft models and in angiogenesis and 
neovascularization models using oral and topical (skin and ocular dosing) administration. 
 
As of 09 September 2015, a total of 53 GlaxoSmithKline (GSK)-sponsored studies of 
pazopanib have been conducted in oncology indications (including 2 studies initiated by 


  
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M C 1 1 5 2 
 
 
M C C C A d de n d u m 1 1 
Pr ot oc ol Versi o n Date:  1 0J ul 2 0 1 8  
Nati o nal Ca ncer I nstit ute [ N CI] V E G 1 1 0 8 2 7/ N CI 8 0 6 3 a n d P Z P 1 1 4 4 1 1/ A D V L 0 8 1 5). 
T here is 1 o n g oi n g cli nical st u d y i n Here ditar y He m orr ha gic T ela n giectasia ( H H T). T e n 
G S K -s p o ns ore d st u dies ha ve bee n c o n d ucte d i n o p ht hal mic i n dicati o ns, a n d 1 
G S Ks p o ns ore d st u d y h as bee n c o n d ucte d i n s u bj ects wit h ps oriasis . 
 
C u m ulati vel y, as of 0 9 Se pte m ber 2 0 1 5, a p pr o xi matel y 8 5 5 7 patie nts a n d healt h y 
v ol u nteers were e nr olle d a n d treate d i n paz o pa ni b cli nical st u dies, of w h o m 5 9 0 9 
recei ve d paz o pa ni b as m o n ot hera p y or i n c o m bi nati o n wit h ot her he m ot hera pe utic 
a ge nts. Data c ollecte d t o date s h o w t hat paz o pa ni b a d mi nistrati o n at 8 0 0 m g dail y is 
ass ociate d wit h a reas o na ble safet y pr ofile a n d e nc o ura gi n g efficac y i n vari o us o nc ol o g y 
setti n gs. 
 
 
I n V E G 1 1 0 7 2 7 (a ra n d o mize d place b o-c o ntr olle d P hase III st u d y of paz o pa ni b 
m o n ot hera p y i n s u bjects wit h S T S), t he me dia n ti me o n paz o pa ni b was 1 9. 4 wee ks, as 
c o m pare d wit h 8. 1 wee ks i n t he place b o ar m. T he m ost c o m m o n A Es ( 2 0 %) re p orte d 
i n t he paz o pa ni b ar m (as of 2 9 Mar 2 0 1 3) were fati g ue ( 6 5 %), diarr hea ( 5 9 %), na usea 
( 5 6 %), wei g ht decrease d ( 5 1 %), h y perte nsi o n ( 4 2 %), decrease d a p petite ( 4 0 %), hair 
c ol or c ha n ges ( 3 9 %), v o miti n g ( 3 4 %), t u m or pai n ( 3 0 %), d ys g uesia ( 2 8 %), 
gastr oi ntesti nal pai n ( 2 4 %), hea dac he ( 2 4 %), m usc ul os keletal pai n ( 2 3 %), m yal gia 
( 2 3 %), a n d d ys p nea ( 2 0 %). T we nt y-ei g ht perce nt of s u bj ects o n place b o a n d 6 3 % of 
s u bj ects o n paz o pa ni b e x perie nce d a n A E of ma xi m u m Gra de 3 or hi g her. T he 
pr o p orti o n of s u bjects w h o e x perie nc e d ma xi m u m Gra de 4 a n d Gra de 5 A Es was si milar  
i n b ot h treat me nt ar ms. 
I n V E G 1 1 0 6 5 5 (a ra n d o mize d, place b o-c o ntr olle d, P hase III st u d y of paz o pa ni b 
m o n ot hera p y i n s u bjects wit h o varia n, fall o pia n t u be or pri mar y perit o neal ca ncer), t he 
mea n ti me o n st u d y dr u g i n t he paz o pa ni b ar m was s h orter t ha n i n t he place b o ar m 
( 8. 9 m o nt hs vs. 1 1. 7 m o nt hs). T he m ost c o m m o n A Es ( > 2 0 %) occ urri n g i n s u bj ects i n 
t he paz o pa ni b ar m i ncl u de d h y perte nsi o n ( 5 4 %), diarr hea ( 5 3 %), na usea ( 3 7 %), hea dac he 
( 2 9 %), fati g ue ( 2 8 %), a n d ne utr o pe nia ( 2 2 %). A hi g her pr o p orti o n of s u bjects i n t he 
paz o pa ni b ar m ha d Gra de 3 or Gra de 4 A Es c o m pare d wit h t he place b o ar m ( 6 3 % vs. 
2 3 %); t he maj orit y of t hese e ve nts were Gra de 3. T he m ost c o m m o n Gra de 3 A Es ( 5 %) 
i n t he paz o pa ni b ar m i ncl u de d h y perte nsi o n ( 2 9 %), diarr hea ( 8 %), ne utr o pe nia ( 6 %) a n d 
A L T i ncrease d ( 5 %). Fatal S A Es were re p orte d i n 3 s u bj ects i n t he paz o pa ni b ar m a n d 1  
s u bj ect i n t he place b o ar m. 
 
A n a nal ysis of i nte grate d safet y data fr o m V E G 1 1 0 6 5 5 a n d V E G 1 1 4 0 1 2 (a ra n d o mize d, 
place b o-c o ntr olle d, P hase II st u d y of paz o pa ni b m o n ot hera p y i n East Asia n w o me n wit h 
o varia n, fall o pia n t u be or pri mar y perit o neal ca ncer) s h o we d a safet y pr ofile si milar t o  
t hat o bser ve d i n t he paz o pa ni b ar m of V E G 1 1 0 6 5 5 al o ne. A d verse e ve nts t hat occ urre d i n 
at least 2 0 % of paz o pa ni b-treate d s u bjects i n t he i nte grate d a nal ysis i ncl u de d: 
h y perte nsi o n ( 5 7 %), diarr hea ( 5 2 %), na usea ( 3 4 %), fati g ue ( 2 7 %), hea dac he ( 2 7 %),  
ne utr o pe nia ( 2 7 %), hair c ol or c ha n ges ( 2 3 %), a n d A L T i ncrease d ( 2 0 %). Of t he m ost  
c o m m o n A Es i n paz o pa ni b-treate d s u bjects, t he i nci de nces of diarr hea, na usea, a n d 
fati g ue i n t he o varia n st u dies were si milar or l o wer c o m pare d wit h t h ose i n t he i nte grate d 
S T S a n d R C C st u dies, as well as i n R C C St u d y V E G 1 0 8 8 4 4. H y perte nsi o n a n d 
ne utr o pe nia occ u rre d m ore fre q ue ntl y i n paz o pa ni b-treate d s u bjects i n t he o varia n 
st u dies. 
 


  
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A number of these events are known class effects of VEGF inhibitors.  Therefore, this 
protocol is designed to closely monitor and provide clear management guidelines for these 
events based on the clinical experience with pazopanib to date. 
 
 
2.0 
Goals    
 
2.1 
Primary  
 
2.11  
To determine the efficacy of pazopanib in non clear cell metastatic renal cell 
cancer patients as assessed by the overall survival rate at 12 months. 
 
2.2 
Secondary  
 
2.21 
To determine the rates of best tumor response at the end of the first two treatment 
cycles of pazopanib in non clear cell metastatic renal cell cancer patients. 
 
2.22 
To determine the benefit of pazopanib in increasing progression free survival 
time. 
 
2.23 
To describe toxicity profile of pazopanib in non clear cell metastatic renal cell 
cancer patients. 
 
 
3.0 
Patient Eligibility   
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥ 18 years  
3.12 
Histological confirmation of non-clear cell renal cancer (including Chromophilic 
(papillary), Chromophobic, Oncocytic, sarcomatoid, Collecting duct (Bellini's 
duct), translocation-type carcinoma or medullary renal cell carcinoma. 
3.13 
Up to one prior treatment for metastatic non clear cell carcinoma is allowed prior 
to registration as long as the agent used to treat was not pazopanib. 
3.14 
Measurable or non-measurable metastatic disease as defined in Section 11.0.    
 
 
3.15 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix II). 
 
3.16 
The following laboratory values obtained ≤ 14 days prior to registration. 
• 
ANC ≥1500 
• 
PLT ≥100,000 
• 
HgB >9.0 g/dL.  NOTE:  Subjects may not have had a transfusion within 
7 days of registration.) 
• 
Total Bilirubin <1.5 x ULN  
• 
Alanine amino transferase (ALT) ≤2.5 X ULN.  NOTE:  Concomitant 
elevations in bilirubin and ALT above 1.0 x ULN (upper limit of normal) 
is not permitted. 


  
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• 
Aspartate aminotransferase (AST) ≤2.5 X ULN. Note: Concomitant 
elevations in bilirubin and AST above 1.0 x ULN (upper limit of normal) 
is not permitted. 
• 
Urine Protein to Creatinine Ratio (UPC; appropriate appendix) (UPC) <1 
NOTE: 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. 
• 
Prothrombin time (PT) or international normalized ratio (INR) ≤1.2 X 
ULN NOTE: Subjects receiving anticoagulant therapy are eligible if their 
INR is stable and within the recommended range for the desired level of 
anticoagulation 
 
3.17 
A female is eligible to enter and participate in this study if she is of: 
a. Non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant), including any female who has had: 
• 
A hysterectomy 
• 
A bilateral oophorectomy (ovariectomy) 
• 
A bilateral tubal ligation 
• 
Is post-menopausal 
Subjects not using hormone replacement therapy (HRT) must have 
experienced total cessation of menses for ≥ 1 year and be greater than 45 years 
in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) 
value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).  
 
 
Subjects using HRT must have experienced total cessation of menses for >= 1 
year and be greater than 45 years of age OR have had documented evidence of 
menopause based on FSH and estradiol concentrations prior to initiation of 
HRT 
 
b. Childbearing potential, including any female who has had a negative serum 
pregnancy test, ≤7 days prior to registration. 
c. Agrees to use adequate contraception.  Acceptable contraceptive methods, 
when used consistently and in accordance with both the product label and the 
instructions of the physician, are as follow: 
• 
Complete abstinence from sexual intercourse for 14 days before 
exposure to investigational product, through the dosing period, and 
for at least 21 days after the last dose of investigational product 
• 
Oral contraceptive, either combined or progestogen alone 
• 
Intrauterine device (IUD) or intrauterine system (IUS) with a 
documented failure rate of less than 1% per year 
• 
Male partner sterilization (vasectomy with documentation of 
azoospermia) prior to the female subject's entry into the study, and 
this male is the sole partner for that subject  
• 
Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository) 
 


  
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3.18 
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. 
 
3.19 
Willing to return to Mayo Clinic enrolling institution for follow-up. 
 
 
3.2 
Exclusion Criteria  
 
3.21 
Any of the following because this study involves an investigational agent  
 
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and 
 
newborn are unknown  
• 
Nursing women 
• 
Pregnant women 
•  Men or women of childbearing potential who are unwilling to employ 
 
adequate contraception  
 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Immunocompromised patients (other than that related to the use of  
corticosteroids) including patients known to be HIV positive. 
 
3.24 
Prior history of receiving pazopanib treatments. 
 
3.25 
Uncontrolled intercurrent illness including, but not limited to:  
• 
ongoing or active infection,  
• 
symptomatic anemia, uncontrolled hypertension hypertension [defined as 
systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure 
(DBP) of ≥ 90mmHg].,  
• 
symptomatic congestive heart failure as defined by the New York Heart 
Association (NYHA) (See Appendix IV), Does not exclude Class III 
CHF. 
• 
previously treated with therapies that are known to negatively impact 
cardiac function (e.g. prior treatment with anthracyclines) 
• 
unstable angina pectoris,  
• 
cardiac arrhythmia,  
• 
evidence of active bleeding or bleeding diathesis 
• 
psychiatric illness/social situations that would limit compliance with study 
requirements,  
• 
or any other serious uncontrolled medical disorders in the opinion of the 
investigator. 
3.26 
History of cerebrovascular accident including transient ischemic attack (TIA), 
myocardial infarction, pulmonary embolism or untreated deep venous thrombosis 
(DVT), Coronary artery bypass graft surgery within 6 months prior to registration. 
Note: Subjects with recent DVT who have been treated with therapeutic anti-
coagulating agents for at least 6 weeks are eligible 


  
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3.27 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.28 
Other active malignancy ≤5 years prior to registration.  EXCEPTIONS:  Non-
melanotic skin cancer or carcinoma-in-situ of the cervix.  NOTE:  If there is a 
history or prior malignancy, they must not be receiving other specific treatment 
for their cancer.  
 
3.29a 
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. 
 
3.29b Clinically significant gastrointestinal abnormalities that may increase the  
 
risk for gastrointestinal bleeding including, but not limited to: 
• 
Active peptic ulcer disease 
• 
Known intraluminal metastatic lesion/s with risk of bleeding 
• 
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or 
other gastrointestinal conditions with increased risk of perforation  
• 
History of abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess ≤28 days prior to registration. 
• 
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. 
 
3.29c 
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula. 
 
3.29d Receiving any medications or substances with risk of torsades de pointes (see 
Appendix II).  Note: medications or substances on the list “Drugs with Risk of 
Torsades de Pointes” are prohibited.  Medications or substances on the list “Drugs 
with Possible or Conditional Risk of Torsades de Pointes” may be used while on 
study with extreme caution and careful monitoring. 
 
3.29e 
Known endobronchial lesions and/or lesions infiltrating major   
pulmonary vessels and/or hemoptysis in excess of 2.5 mL (or one half teaspoon) 
≤8 weeks of registration 
 
3.29f 
Treatment with any of the following anti-cancer therapies: radiation therapy, 
surgery or tumor embolization, chemotherapy, immunotherapy, biologic therapy, 
investigational therapy or hormonal therapy ≤ 14 days prior to registration. 
 
3.39g Prior autologous or allogeneic organ or tissue transplantation. 
 
3.39h Elective or planned major surgery to be performed during the course of 


  
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the trial. 
 
3.39i 
Receiving any medications or substances that are strong or moderate inhibitors 
of CYP3A4 (for a listing of medications or substances see Appendix VI). 
 
Use of the following strong or moderate inhibitors are prohibited < 7 days prior to 
registration. 
 
3.39j 
Receiving any medications or substances that are inducers of CYP3A4 (for a 
listing of medications or substances see Appendix VI). 
 
Use of inducers are prohibited < 7 days prior to registration. 
 
 
 
 
 


  
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4.0 Test Schedule 
Active Monitoring Phase 
 
Tests and procedures 
≤28 days prior  
to registration 
≤14 days prior 
to registration 
Day 14,  
Every cycle  
On interval 
weeks 2, 6, 10 
Every other 
cycle 
End of treatment 
 
Informed Consent 
X 
 
 
 
 
 
History and exam, Wt, PS  
 
 
X 
 
 
X 
Adverse event assessment 
 
 
X 
 
 
 
Height 
 
X 
 
 
 
 
Pregnancy test 
 
X2 
 
 
 
 
Vital Signs, including temperature 
 
X 
X 
 
 
X 
Echo (2D M-Mode) 
XR 
 
 
 
X8 
 
Hematology   CBC with diff, platelets 
 
X 
XR,6 
 
 
X 
Chemistries1 
 
X 
XR,6 
X9 
 
X 
UPC Urine 
 
X 
 
 
 
 
Thyroid Function Test (TSH) 
 
XR 
 
 
XR 
 
Coagulation Test: PT, PTT 
 
X 
X 
 
 
 
CT Head/MRI 
 
XR 
 
 
 
 
CT scan of chest, abdomen or pelvis, MRI, etc 
 
XR 
 
 
X7 
 
Bone Scan 
 
 
 
 
X5 
 
EKG 
 
XR 
X 
 
 
 
Medication Diary 
 
 
X3 
 
 
 
1. 
SGOT, SGPT, total bili, Na, K, CI, CO2, BUN, creatinine, LDH, hemoglobin, calcium, albumin, total protein, magnesium, phosphorus and alkaline phosphatase.  
2. 
For women of childbearing potential, ≤7 days prior to registration. 
3. 
The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution OR compliance must be documented in the 
medical record by any member of the care team. 
4. 
+/- 3 days 
5. 
If applicable  
6. 
Research funded, cycles 1 and 2 only 
7. 
Use the same method throughout the study. Follow-up scans to be performed every other cycle (8 weeks). Repeat measurements are required 8 weeks following an objective Response. See 
Section 11.0 for full RECIST criteria. 
8. 
Every 4 months while on study, sooner should clinical symptoms indicate.  These follow-up echocardiograms will coincide with restaging visits. 
9. 
SGOT, SGPT, total bili, only and can be done at study site or locally and faxed. 
R 
Research funded (see Section 19.0) 


  
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5.0 
Stratification / Grouping Factor: None.  
 
6.0  
Registration Procedures  
 
 6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at (507) 284-2753 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available on the MCCC 
web page 
 and detail the process for completing and 
confirming patient registration.  Prior to initiation of protocol treatment, this process must 
be completed in its entirety and a MCCC subject ID number must be available as noted in 
the instructions.  It is the responsibility of the individual registering the patient to confirm 
the process has been successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be confirmed in any of the 
following ways: 
 
• 
Contact the MCCC Registration Office 
  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from 
the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.2 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
.  If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.3 
Prior to accepting the registration, registration application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
 
6.4  
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for unspecified 
future research of renal cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 


  
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research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
• 
Patient has given permission to store and use his/her samples for the mandatory future 
banking(section 14.1) 
 
6.5 
Treatment cannot begin prior to registration and must begin ≤ 14 days after registration. 
 
6.6 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.7 
All required baseline symptoms (see Section 10.3) must be documented and graded. 
 
6.8 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo Clinic 
Arizona, or Mayo Clinic Florida under the supervision of a medical oncologist who 
confirms the patient is a suitable candidate for this study. 
 
6.9a 
Study drug is available on site. 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule  
 
Agent 
Dose Level 
Route 
Day 
Pazopanib 
800 mg 
PO 
once daily 
 
 
     
Cycle length=28 days 
 
 
 
Protocol treatment consists of four 200mg tablets (800 mg) of pazopanib by mouth once a 
day. 
 
7.13 
GW786034 
 
 
 
 
Pazopanib monohydrochloride salt is supplied as aqueous film-coated tablets 
containing 200 mg of the free base.  The 200-mg tablets are oval-shaped and gray 
in color.  Refer to the pazopanib IB for information regarding the physical and 
chemical properties of pazopanib and a list of excipients. 
 
 
Pazopanib will be provided to the sites by Novartis.  The 200-mg pazopanib 
tablets are packaged 34 to a bottle.  Bottles are made of high-density polyethylene 
and have a child-resistant closure.  Each bottle will be labeled with the protocol 
number, dosing and storage instructions, sponsor name and address, and the 
expiration date, when required.  The contents of the label will be in accordance 
with all applicable regulatory requirements. 
 
 
 
7.12 
Dosage and Administration 
 
 
 
 
Administration of pazopanib with a high-fat or low-fat meal results in an  
 
 
 
approximately 2-fold increase in area under the plasma drug concentration curve  
 
 
 
(AUC) and maximum observed plasma drug concentration (Cmax). 


  
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Pazopanib should be taken orally without food at least one hour before or two 
hours after a meal. The tablets should be swallowed whole and must not be 
crushed or broken. The time of day the tablets are taken should be relatively 
constant.  
 
If a dose is missed, the subject should take the dose as soon as possible, but only if 
there are 12 or more hours remaining before the next dose is due.  If the next dose 
is due in less than 12 hours, the subject should skip the missed dose and take the 
next dose as scheduled. 
 
If vomiting occurs after taking pazopanib, the subject should not take a 
replacement dose on that day.  The subject should resume taking pazopanib at the 
next scheduled dose on the following day.  If vomiting persists, the subject should 
be instructed to notify the investigator. 
 
 
As a general rule, if dose reduction of pazopanib is necessary, the dose should be 
reduced stepwise by 200 mg at each step, and the subject should be monitored for 
approximately 10 to 14 days at each dose level.  If toxicity does not abate during 
this monitoring time, the medication may need to be interrupted and/or the dose 
further decreased with continued monitoring for an additional 10-14 days at each 
dose level, and so on.  
 
If the toxicity has abated with reduction of the dose and dose re-escalation is 
considered safe by the investigator, the dose can then be increased step-wise back 
to the pre-event dose (in 200 mg increments, after monitoring for 10-14 days at 
each dose level to ensure that toxicity did not recur or worsen).  
 
If a subject’s treatment has been interrupted for more than 21 days, the 
Investigator must contact the Study Physician to review the subject’s condition in 
order to resume the treatment.   
 
 
7.2 
Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval. 
 
7.3 
For this protocol, the patient must return to Mayo Rochester, Florida, or Arizona for 
evaluation at least every 28 days (+/- 3 days). 
 
 
 


  
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7.4 
Criteria for Treatment Discontinuation 
• 
Patients who develop PD/recurrent disease while receiving therapy at the time of 
response assessments will be discontinued from active study treatment and go off 
protocol; 
• 
Grade 3 or 4 toxicity requiring break from treatment and inability to re-initiate 
treatments with a >28 day delay; 
• 
Completion of 12 months of therapy. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1 
Pazopanib 
 
 
  
8.11 Pazopanib Dose Reduction Levels 
 
Starting Dose 
800 mg once daily 
Dose Level -1 
600 mg once daily 
Dose Level -2 
400 mg once daily 
 
 
 
 
 
8.12 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
Investigations 
 
Platelet count decreased 
 Grade 3 or 4 
 
 
Pazopanib 
 
Omit until ≤ 2 then restart at next lower 
dose level.  If no recovery to grade 2, 
discontinue 
Investigations 
 
Electrocardiogram QT corrected 
interval prolonged ≥ 500msec 
Grade 3 
 
Pazopanib 
 
Discontinue pazopanib 
Renal and 
urinary 
disorders 
Creatinine 
≥Grade 3 
 
Pazopanib 
 
 
Omit until < 3 then restart at next lower 
dose level.  If ≥ 3 recurs,  reduce one 
dose level again until no dose can be 
given 


  
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Vascular 
disorders 
 
Thromboembolic event  
DVT/PE  
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
 
Arterial Thrombosis/Ischemia 
Any Grade 
 
Pazopanib 
 
 
Omit and initiate anticoagulant.  Restart 
at reduced dose if  
• 
Subject must have been treated 
at desired level of 
anticoagulation for at least 1 
week 
• 
No Grade 3 or 4 or clinically 
significant Grade 2, 
hemorrhagic events have 
occurred while on 
anticoagulation treatment. 
Note: When treating with warfarin, INR 
S/B monitored within 3 to 5 days after 
any change in pazopanib dosing and 
then at least weekly until INR is stable.  
The dose of warfarin may need to be 
adjusted to maintain the desired level 
of anticoagulation. 
 
Discontinue pazopanib 
 
 
Discontinue pazopanib 
Vascular 
disorders 
Hypertension 
 
Pazopanib 
 
See table 8.2  
Gastrointestinal 
disorders 
 
Any GI bleed 
Grade 2-4 
 
 
Pazopanib  
 
Discontinue pazopanib 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
Any Pulmonary bleed 
Grade 2-4 
 
Pazopanib  
 
Discontinue pazopanib 
Dermatology/ 
Skin 
Dermatitis  
Grade 2 skin changes w/pain, 
limiting ADL’s 
 
Grade3 severe skin changes w/pain 
Limiting self care ADL’s 
 
Pazopanib  
 
Omit until ≤ 1, then restart at next lower 
dose level. If recurrent, reduce by 
another dose level or discontinue 
 
Discontinue 


  
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
All Other 
Grade 2 or 3, if clinically 
significant 
Grade 4 
Pazopanib  
Omit until ≤ 1 
Discontinue Pazopanib 
* 
Located at 
http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
 
8.2 
Pazopanib-at time of retreatment 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
AT TIME OF RETREATMENT 
Investigations 
 
Platelet count decreased 
 Grade 3 or 4 
 
 
Pazopanib 
 
Hold until ≤ 2 then restart at next 
lower dose level.  If no recovery to 
grade 2, discontinue 
Investigations 
 
Electrocardiogram QT corrected 
interval prolonged ≥ 500msec 
Grade 3 
 
Pazopanib 
 
Discontinue pazopanib 
Renal and 
urinary 
disorders 
Creatinine 
> Grade 3 
 
Pazopanib 
 
 
Hold until < 3 then restart at next 
lower dose level.  If ≥ 3 recurs, 
dose reduce again until no dose 
can be given 


  
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Vascular 
disorders 
 
Thromboembolic event  
DVT/PE  
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
 
Arterial Thrombosis/Ischemia 
Any Grade 
 
Pazopanib 
 
 
Hold and initiate anticoagulant.  
Decrease 1 dose level if  
• 
Subject must have been 
treated at desired level of 
anticoagulation for at least 
1 week 
• 
No Grade 3 or 4 or 
clinically significant 
Grade 2, hemorrhagic 
events have occurred 
while on anticoagulation 
treatment. 
Note: When treating with 
warfarin, INR S/B monitored 
within 3 to 5 days after any 
change in pazopanib dosing and 
then at least weekly until INR is 
stable.  The dose of warfarin may 
need to be adjusted to maintain 
the desired level of 
anticoagulation. 
 
Discontinue pazopanib 
 
 
Discontinue pazopanib 
Vascular 
disorders 
Hypertension 
 
Pazopanib 
 
See table 8.3  
Gastrointestinal 
disorders 
 
Any GI bleed 
Grade 2-4 
 
 
Pazopanib  
 
Discontinue pazopanib 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
Any Pulmonary bleed 
Grade 2-4 
 
Pazopanib  
 
Discontinue pazopanib 
Dermatology/ 
Skin 
Dermatitis  
Grade 2 skin changes w/pain, limiting 
ADL’s 
 
Grade3 severe skin changes w/pain 
Limiting self care ADL’s 
 
Pazopanib  
 
Hold until ≤ 1, then restart at next 
lower dose level.  
If recurrent. reduce by another 
dose level or discontinue 
 
Discontinue 


  
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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise 
specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
All Other 
Grade 2 or 3, if clinically significant 
Grade 4 
Pazopanib  
Hold until ≤ 1 
Discontinue pazopanib 
* 
Located at 
http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped  
 
8.3 
Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
Scenario A) 
• 
Asymptomatic and 
persistentd SBP of ≥140 
and <160 mmHg, or DBP 
≥90 and <100 mmHg,  
or  
• 
Clinically significant 
increase in DBP of 20 
mmHg (but still below 110 
mmHg). 
• Continue pazopanib treatment at the current dose  
• Adjust current or initiate new antihypertensive 
medication 
• Titrate antihypertensive medication(s) during the 
next 2 weeks as indicated to achieve well-
controlledb BP 
• 
If BP is not well controlled within 2 weeks, 
consider referral to a specialist and go to scenario 
(B). 
(Scenario B) 
• 
Asymptomatic SBP ≥160 
mmHg, or DBP ≥100 
mmHg,  
or  
• 
Failure to achieve well-
controlled BP within 2 
weeks in Scenario A 
• Interrupt  pazopanib  treatment if clinically 
indicated 
• Adjust current or initiate new antihypertensive 
medication(s) 
• Titrate antihypertensive medication(s) during the 
next 2 weeks as indicated to achieve well-
controlled BP 
• Once BP is well controllede, restart pazopanib 
treatment reduced by one dose level 
 
 
• 
Symptomaticf hypertension  
or  
 
• 
Persistentg SBP ≥160 
mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive 
medication and dose 
reduction of study 
treatment 
• 
Interrupt pazopanib treatment 
• 
Adjust current or initiate new antihypertensive 
medication(s) 
• 
Titrate antihypertensive medication during the next 2 
weeks as indicated to achieve well-controlled BP 
• 
Referral to a specialist for further evaluation and 
follow-up is recommended 
• 
Once BP is well controlled, restart pazopanib  
treatment reduced by one dose level  


  
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Refractory hypertension 
unresponsive to above 
interventions. 
• 
Permanently discontinue pazopanib treatment  
• 
Continue follow-up per protocol. 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Asymptomatic:  Absolute decrease 
of >10% in LVEF compared to 
baseline and ejection fraction 
below the institution’s LLN 
 
 
OR 
 
LVEF drop >15% from baseline 
regardless of whether value is 
below institution’s LLN. 
• 
Interrupt pazopanib  study treatment and repeat 
ECHO within 2 weeksb  and  monitor and control 
BP. 
• 
If the LVEF recovers within 4 weeks 
(defined as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline)  
o Restart study treatmentf reduced by one 
dose level (Please consult with Novartis if 
there are any questions prior to 
restarting) 
o Repeat ECHO 2 , 4 , 8 and 12 weeks after 
re-start; monitor BP; continue in intervals 
of 12 weeks thereafter 
• 
If repeat LVEF does not recover within 4 weeks 
o Consult with cardiologist 
o Permanently discontinue pazopanib  
treatment Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until resolution 
Please Consult with Novartisif there are any questions 
Symptomaticc:  Grade 3: resting 
LVEF 39-20% or >20% absolute 
reduction from baseline 
 
• 
Permanently discontinue pazopanib treatment   
• 
Consult with cardiologist 
• 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks or 
until resolution 
Symptomaticc   Grade 4: resting 
LVEF <20% 
 
 
 
 
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to ensure 
accuracy of the reading.  The values below refer to manually-read ECGs.  REFER READER TO 
ECG SECTION IN PROTOCOL 
QTc  ≥ 480 < 500 msec 
Continue  pazopanib; monitor as clinically indicated. 
QTc ≥500 msec 
Discontinue  pazopanib  and continue follow-up per 
protocol. 
Proteinuria 
UPC <3 
Continue pazopanib at the current dose; monitor as 
clinically indicated 
UPC ≥3 or 24-h urine protein ≥3g 
Step 1. Interrupt  pazopanib. 
Step 2. Weekly UPC or 24-hr urine protein monitoring 
until UPC is <3 or 24-hr urine protein is <3 grams.  Then 
restart pazopanib dose-reduced by 200 mg. 
Step 3.  If UPC ≥3 or 24-h urine protein ≥3g recurs, repeat 
steps 1 and 2. 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the 
pazopanib dose can no longer be reduced, discontinue 
pazopanib and continue follow-up per protocol. 
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding 


  
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Grade 1 
For hemoptysis, interrupt pazopanib and contact the 
Novartis Study Physician to discuss whether further 
treatment with pazopanib is appropriate. 
For other Grade I hemorrhage/bleeding events, continue 
pazopanib at the current dose; monitor as clinically 
indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal 
bleeding), discontinue  pazopanib  and continue follow-up 
per protocol. Otherwise, interrupt  pazopanib  until the AE 
resolved to ≤ Grade 1.  
Step 2. Restart  pazopanib ; consider reducing dose and 
monitor as clinically indicated.  
Grade 3 or 4, or  
Recurrent ≥ Grade 2 event after 
dose interruption/reduction. 
Discontinue  pazopanib  and continue with follow-up per 
protocol.  
   
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue  pazopanib  at the current dose; monitor as 
clinically indicated 
Grade 3   
 
Step 1. Interrupt  pazopanib .  
Step 2. Initiate and monitor anticoagulation as clinically 
indicated.  
Step 3. Resume  pazopanib  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 treating with warfarin, international 
normalized ratio (INR) should be monitored within three 
to five days after any change in  pazopanib  dosing (eg, re-
initiating, escalating/de-escalating, or discontinuing  
pazopanib ), and then at least weekly until the INR is 
stable. The dose of warfarin (or its derivatives) may need 
to be adjusted to maintain the desired level of 
anticoagulation 
Grade 4 and/or PE 
Discontinue  pazopanib  and continue follow-up per 
protocol.  
Arterial Thrombosis/Ischemia 
 
Any Grade 
Discontinue  pazopanib  and continue follow-up per 
protocol.  
Thrombocytopenia: Investigate and document underlying cause 
Grade 1 or 2 
Continue  pazopanib  with current dose; monitor as 
clinically indicated.  
Grade 3 or 4 
Step 1. Interrupt  pazopanib  until toxicity resolves to 
≤ Grade 2. 


  
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b. If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
c. Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary 
congestion and edema. 
d. Hypertension detected in two separate readings during up to three consecutive visits 
e. Well-controlled blood pressure defined as SBP <140 mm Hg and DBP <90 mm Hg in two separate 
readings during up to three consecutive visits. 
f. Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled 
within the normal range. 
g. Persistent hypertension is defined as asymptomatic hypertension after initially successful anti-
hypertensive intervention. 
 
 
Step 2. Restart  pazopanib  dose-reduced by 200 mg and 
monitor as clinically indicated.  
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 
thrombocytopenia, discontinue IP and follow-up per 
protocol. 
Anemia:  No specific dose reduction rules are indicated for anemia unless due to hemorrhage or 
bleeding as noted above. 
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or dermatitis 
without pain 
(erythema, oedema, 
hyperkeratosis) 
1. Continue  pazopanib  at present dose 
 Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily 
living (ADLs) (peeling, blisters, 
oedema, bleed, hyperkeratosis) 
1. Hold  pazopanib   
2. Treat as clinically appropriate 
3. Upon resolution to Level 1 or better restart   
pazopanib  with a dose reduction to dose level -1 
(if it was a full dose[800mg]) or one dose lower 
than the patient was receiving prior to developing 
the skin changes. 
4. If recurrent consider a further dose reduction by 1 
dose level until dose level -2.  If patient has a 
Grade 2 toxicity on dose level -2, then consider 
stopping the drug. 
Grade 3 
Severe skin changes with pain and 
limiting self care ADLs 
1. Discontinue  pazopanib 
Other Clinically Significant Adverse Eventsa  
Grade 1 
Continue  pazopanib ; monitor as clinically indicated. 
Grade 2 or 3, if clinically 
significant  
Step 1. Interrupt  pazopanib  until toxicity resolves to 
≤ Grade 1. 
Step 2. Restart  pazopanib  dose-reduced by 200 mg(1 
dose level) and monitor as clinically indicated.  
Grade 4 
Discontinue  pazopanib  and continue follow-up per 
protocol.    
a. AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI 
CTCAE v3)  


  
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8.4 
Guidelines for Management of Treatment Emergent Hepatotoxicity 
 
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x ULN 
Continue pazopanib at current dose with full panel LFTs0 monitored as per 
protocol. 
(B). ALT >3.0 x ULN to 
≤8.0 x ULN without 
bilirubin elevation 
(defined as total bilirubin0 
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, 
rash)  
Liver Event Monitoring Criteria: 
(1) Continue pazopanib at current dose levels.  
 (2) Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTsa weekly or more frequently if clinically indicated until 
ALT/AST is reduced to 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 Criteria0: 
(1) Interrupt pazopanib until toxicity resolves to ≤Grade 1 or baseline.  
Report the event to Novartis as an SAE within 24 hours of learning of its 
occurrence  and complete the eCRF liver event forms.  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 LFTs a weekly or more frequently if clinically indicated until 
ALT/AST is reduced to Grade 1.   
(4) If the subject is benefiting from the study treatment, contact Novartis 
Study Physician for possible re-challenge.  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.  
 
Recurrence – Liver Event Stopping Criteria0: 
Discontinue pazopanib permanently and monitor subject closely for 
clinical signs and symptoms; perform full panel LFTs a weekly or more 
frequently if clinically indicated until ALT/AST is reduced to Grade 1.  At 
the time of the recurrence, complete the eCRF liver event forms.   


  
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Event 
Dose Modification Algorithms 
 (D). ALT >3.0 x ULN 
with concomitant 
elevation in bilirubin0 
(defined as total bilirubin 
≥2.0 x ULN; with direct 
bilirubin >35%) or with 
hypersensitivity 
symptoms (e.g., fever, 
rash).  
Liver Event Stopping Criteria0: 
(1) Discontinue pazopanib immediately, report the event to Novartis as an 
SAE within 24 hours of learning of its occurrence , and complete the 
eCRF liver event forms.  Make every reasonable attempt to have subjects 
return to the clinic within 24 hours for repeat liver chemistries and liver 
event follow up assessments. 
(2) Consult a gastroenterologist / hepatologist, collect PK sample  and 
perform the following assessments to identify potential co-factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, cytomegalovirus, Epstein-Barr 
virus (IgM antibody, heterophile antibody, or monospot testing)  
- Anti-nuclear antibody, anti-smooth muscle antibody, 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 
bilirubin0 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.  Pazopanib inhibits UGT1A1 and OATP1B1, which 
can cause elevation of indirect (unconjugated) bilirubin in the absence 
of liver injury.. 
(2)  If bilirubin is >1.5 x ULN in the absence of ALT 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, GGT, and total bilirubin.  Coagulation tests 
should be performed as clinically indicated. 
b.    Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a 
subject meets the criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an 
SAE. 
c.    When a liver chemistry event meets the Liver Event Interruption Criteria, or Liver Event Stopping Criteria, 
blood samples should be obtained for PK and for clinical laboratory testing by the central laboratory (Liver 
Event Kits will be provided for this purpose).    
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; eCRF electronic case report 
form; IP investigational product; LFT liver function tests; PK pharmacokinetics; SAE serious adverse event; 
ULN upper limit of normal 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology (42) Update of 
Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence-


  
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Based, Clinical Practice Guidelines.  J Clin Oncol Vol 24, No 19 (July 1), 2006: pp. 3187-
3205  
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day).  If grade 2 diarrhea consider dose reduction of pazopanib.  If 
grade 2 diarrhea persists after 48 hours total treatment with loperamide discontinue 
pazopanib.  
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring  
 
10.1 
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 website:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.5 and 
18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).   
  


  
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• 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the 
same as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review nor mentioned in the consent form. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the drug 
and the adverse event.  
 
10.31 Special Situations for Expedited Reporting  
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious 
Adverse Events where the AE is EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard 
Expedited Adverse Event Reporting Requirements:  
 
 
 
 
 
 
 
 
 
 


  
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System Organ Class (SOC) 
 
Adverse event/Symptoms 
 
CTCAE Grade at which 
the event will not be 
expeditedly reported.1 
Gastrointestinal disorders 
Abdominal pain 
Grade 3 
Diarrhea 
Grade 3 
Nausea 
Grade 3 
Vomiting 
Grade 3 
General disorders and 
administrations site conditions 
Fatigue  
Grade 3 
Metabolism and nutrition 
disorders 
Anorexia 
Grade 3 
Nervous system disorders 
Headache 
Grade 3 
Skin and subcutaneous tissue 
disorders 
Hair color changes 
Grade 3 
Vascular disorders 
Hypertension 
Grade 3 
 
1These exceptions only apply if the adverse event does not result in 
hospitalization. If the adverse event results in hospitalization, then the standard 
expedited adverse events reporting requirements must be followed 
 
Specific protocol exceptions to expedited reporting will be reported expeditiously 
by investigators ONLY if they exceed the expected grade of the event. 
 
 
10.32 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time following 
treatment with an agent under an IND/IDE since they are considered to be a serious AE and 
must be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
10.33 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 


  
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• 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported as 
Grade 5 “Neoplasms benigh, malignant and 
unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death was 
a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
10.34 
Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.35 
Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
 




  
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Mayo Clinic Cancer Center (MCCC) Institutions:  Provide copies, along with the UPIRTSO 
cover sheet, by fax 
 the MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist who will determine and complete IRB reporting. The RAU will submit 
to the MCCC IND Coordinator to determine if FDA submission is needed, and to the MCCC 
SAE Coordinator.  
 
NOTE:  The Grade 4 or 5 Non-AER Reportable Events/Hospitalization Form is not being 
used for investigational agent(s) in this study. 
 
10.5 
Reporting requirements for Novartis 
 
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.. 
 
10.51 Serious adverse event reporting 
 
All serious adverse events must be reported by facsimile within 24 hours to 
the oncology Novartis DS&E department with the appropriate fax coversheet 
(see Appendix IX). Fax: 
 
 
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 
 
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) (For patients taking Pazopanib / Novartis drugs). 
 


  
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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 atleast 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: 
 
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. 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. 
 
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 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. 
 


  
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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. 
 
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. 
 
 
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 
2 weeks 
Pregnancy Notification 
Form 
2 weeks 
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. 
 
bLiver Event Case Report 
Form (CRF) and liver 
imaging and/or biopsy 
CRFs if applicable 
24 hours 
Updated SAE data 
collection tool.  
 
bUpdated Liver 
Event 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. 
 
Liver Event CRFb  
24 hours 
Updated SAE data 
collection tool.  
 
Updated Liver Event 
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. 
 
 
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. 
 
10.6 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 


  
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System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Gastrointestinal 
Disorders 
Baseline number of stools 
per day 
 
X 
 
Diarrhea 
 
X 
Vascular Disorders 
Hypertension 
X 
X 
General disorders 
and administration 
site conditions 
Fatigue 
 
 
X 
 
 
X 
Investigations 
Alanine aminotransferase 
increased 
 
X 
 
X 
Aspartate 
aminotransferase increased 
 
X 
 
X 
Blood bilirubin increased 
X 
X 
Lymphocytes decreased 
X 
X 
Metabolism and 
Nutrition Disorders 
 
Hypophosphatemia 
X 
X 
Hyponatremia 
X 
X 
Hypomagnesemia 
X 
X 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6. 
 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613 Grade 5 AEs (Deaths) 
 
10.6131 
Any death within 30 days of the patient’s last study treatment 
or procedure regardless of attribution to the study treatment or 
procedure. 
 
10.6132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE:  This study uses protocol RECIST v1.1 template dated 2/16/2011.  See the footnote for the 
table regarding measureable disease in Section 11.44, as it pertains to data collection and analysis. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1) Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the short axis measurements in the case of lymph nodes are used in the RECIST guideline. 
 


  
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11.1 
Schedule of Evaluations:  For the purposes of this study, patients should be reevaluated 
every 8 weeks.  In addition to a baseline scan, confirmatory scans should also be obtained 
8 weeks following initial documentation of objective response. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
 
 


  
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11.21   Measurable Disease 
 
11.211   A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT 
scan, CT component of a PET/CT, or MRI.  
 
11.212  A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 
cm in diameter as assessed using calipers (e.g. skin nodules) or imaging.  
In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
 
11.213   A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to be 
no greater than 5 mm).   
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm).  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
 
Note:  ‘Cystic lesions’ thought to represent cystic metastases can be 
 
considered as measurable lesions, if they meet the definition of 
 
measurability described above. However, if non-cystic lesions are present 
 
in the same patient, these are preferred for selection as target lesions.  In 
 
addition, lymph nodes that have a short axis <1.0 cm are considered non- 
 
pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal fractions 
of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease: 
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or 


  
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less. If CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness. 
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and 
site of disease.  The lesions should be measured on the same pulse sequence.  
Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.   
 
• 
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 
scans are preferable. 
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT at the same evaluation, additional follow-up CT scans 
(i.e., additional follow-up scans at least 4 weeks later) are needed to 
determine if there is truly progression occurring at that site. In this 
situation, the date of PD will be the date of the initial abnormal PDG-
PET scan.   
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing site 
of disease on CT that is not progressing on the basis of the anatomic 
images, it is not classified as PD. 
 
 
 


  
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11.33 Measurement at Follow-up Evaluation:   
 
• 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 8 weeks 
(see Section 11.44). 
 
• 
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. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” 
and recorded and measured at baseline.  These lesions can be non-nodal or 
nodal (as defined in 11.21), where no more than 2 lesions are from the same 
organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be 
the case that, on occasion, the largest lesion (or malignant lymph node) does 
not lend itself to reproducible measurements in which circumstance the next 
largest lesion (or malignant lymph node) which can be measured reproducibly 
should be selected.   
 
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The BSD 
will be used as reference to further characterize any objective tumor response 
in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph nodes 
will be calculated and reported as the post-baseline sum of dimensions (PBSD).  
If the radiologist is able to provide an actual measure for the target lesion (or 
target lymph node), that should be recorded, even if it is below 0.5 cm.  If the 
target lesion (or target lymph node) is believed to be present and is faintly seen 


  
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but too small to measure, a default value of 0.5 cm should be assigned.  If it is 
the opinion of the radiologist that the target lesion or target lymph node has 
likely disappeared, the measurement should be recorded as 0 cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target lesions 
or non-target lymph nodes and should also be recorded at baseline.  These lesions 
and lymph nodes should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT/Chest X-ray/physical examination must be measured on 
re-evaluation at evaluation times specified in Section 11.1.  Specifically, a 
change in objective status to either a PR or CR cannot be done without re-
measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be evaluated 
at each assessment, especially in the case of first response or confirmation 
of response.  In selected circumstances, certain non-target organs may be 
evaluated less frequently.  For example, bone scans may need to be 
repeated only when complete response is identified in target disease or 
when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.  


  
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b. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis of 
all the target lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41).  In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
c. See Section 11.32 for details in regards 
to the requirements for PD via FDG-
PET imaging. 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target lesions.  
 
b. Each non-target lymph node must have 
a reduction in short axis to <1.0 cm. 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant  lesion, 
which also includes  any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.   
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal 
progression should not normally trump 
target lesion and target lymph node 
status.  It must be representative of 
overall disease status change.)  
   
c. See Section 11.32 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
 
 




  
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11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration.  A patient is 
classified as having PD due to “symptomatic deterioration” if any of the following 
occur that are not either related to study treatment or other medical conditions: 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors  
 
12.1 
Prior treatment for metastatic non clear cell renal cell cancer: none vs. sorafenib vs. 
sunitinib vs. temsirolimus vs. interferon vs bevacizumab vs everolimus vs. other 
metastatic renal cell cancer treatments. 
 
12.2 
Non-clear cell metastatic renal cell cancer histology: chromophilic vs. chromophobic vs. 
oncocytic vs. collecting duct vs. sarcomatoid differentiation. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
 
13.4 
Patients who develop non-CNS PD at any time should go to event monitoring.   
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will go 
directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol.  
 
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point is 
questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
 


  
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13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before any 
study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  The patient will go directly to the event-monitoring 
phase of the study, and event monitoring will be required per Section 18.0 of the protocol. 


  
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14.0 
Body Fluid Biospecimens   
 
Note: As of addendum 7 all blood and urine correlatives discussed in section 14 are no longer being collected at any of the Mayo Clinic 
sites. All blood and urine specimens collected prior to the implementation of addendum 7 will be stored and utilized in the manner 
described above if and when funding becomes available. 
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol* 
 
 
Correlative Study   
Mandatory 
or 
Optional 
Specimen 
to Collect 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube  
(# of tubes 
to  collect) 
 
Prior to 
Registrati
on (≤14 
days) 
 
Cycle 3 
Day 1 
Cycle 5 
Day 1 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
Bank for Future  
Proteomics, Metabolomics, 
and Genomics Studies 
(Section  14.21) 
Mandatory 
Whole 
Blood 
EDTA (purple 
top) 
4, 6 mL 
(2) 
X 
X 
X 
No 
Frozen / 
Dry Ice 
Bank for Future  
Proteomics, Metabolomics, 
and Genomics Studies 
 (Section  14.21) 
Mandatory 
Whole 
Blood 
Sodium 
Citrate 
(blue top) 
5 mL 
(1) 
X 
X 
X 
No 
Frozen / 
Dry Ice 
Bank for Future  
Proteomics, Metabolomics, 
and Genomics Studies 
 (Section  14.22) 
Mandatory 
Whole 
Blood 
SST 
(black/red 
top) 
8.5 mL 
(1) 
X 
X 
X 
No 
Frozen / 
Dry Ice 
Bank for Future  
Proteomics, Metabolomics, 
and Genomics Studies 
 (Section  14.23) 
Mandatory 
Whole 
Blood 
Paxgene 
5 mL 
(1) 
X 
X 
X 
No 
Frozen / 
Dry Ice 
Bank for Future  
Proteomics, Metabolomics, 
and Genomics Studies 
 (Section  14.24) 
Mandatory 
Urine 
- 
10-15 mL 
X 
X 
X 
No 
Frozen / 
Dry Ice 
 
*Research Blood and Body fluid specimens are funded by Mayo


  
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14.2  
Collection and Processing  
 
 
Mayo Clinic Florida and Mayo Clinic Arizona will collect and ship all 
samples to Mayo Clinic Rochester for processing. 
 
 
 
14.21 Please include the following tissue reports with specimens:  Research  
 
 
 
Blood Submission Form and Research Urine Submission Form. 
 
14.22 EDTA and Sodium Citrate Whole Blood  
 
Collect at the following time points: 
 
Prior to Registration (≤14 days) 
Cycle 3 Day 1 (Prior to Treatment) 
Cycle 5 Day 1 (Prior to Treatment) 
 
Collect the following tubes of blood: 
Two 5mL EDTA (purple top) tube 
One Sodium Citrate (blue top) tube 
 
Process whole blood as follows: 
Centrifuge EDTA and Sodium Citrate tubes at 600g for 10 
minutes 
 
Label all cryovials with Protocol #, Patient Initials and Patient 
ID #, Type of Sample (EDTA plasma (4), Sodium Citrate plasma 
(2), EDTA buffy coat (2), Sodium Citrate buffy coat (1 )). 
 
Divide plasma from each blood tube into two cryovials, 
approximately 1.25 mL of plasma per tube (6 aliquots- 4 EDTA 
plasma and 2 Sodium Citrate aliquots).  
 
Aliquot buffy coat from each tube into separate Cryovials.  
 
Label two of each of the EDTA and one of the Sodium Citrate 
plasma aliquots PRP (Platelet Rich Plasma). Then aliquot 0.5mL 
of each of these aliquots into 2 cyrovials (labeled EDTA PRP 
plasma and Sodium Citrate PRP plasma).  In addition label the 
new aliquots with Protocol #,, Patient Initials and Patient ID #, 
Date of Birth, and U1806. 
 
Label the second set of EDTA and Sodium Citrate aliquots with 
PPP (Platelet Poor Plasma).  Add 50 uL of protease inhibitor 
cocktail / mL of plase  to each of these cryovials and 
mix.Centrifuge cryovials at 9000g  for 5 minute to separate the 
platelets. Aliquot 0.5 mL of each sample into two cryovials and 
label with sample type (2 cryovials for EDTA PPP plasma and 2 
cryovials with Sodium Citrate PPP plasma). In addition label the 
new aliquots with Protocol #, Patient Initials and Patient ID #,  
Date of Birth and U1806. 
 


  
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Snap freeze all aliquots (4 PRP EDTA aliquots, 2 PPP EDTA 
aliquots, 2 PRP Sodium Citrate aliquots, 2 PPP Sodium Citrate 
aliquots, 2 EDTA buffy coat, 1 Sodium Citrate buffy coat 
aliquot) 
 
Store at -80C until requested. 
 
14.23 SST Tubes of Whole Blood 
 
Collect at the following time points: 
 
Prior to Registration (≤14 days) 
Cycle 3 Day 1 (Prior to Treatment) 
Cycle 5 Day 1 (Prior to Treatment) 
 
Collect the following tubes of blood: 
One 8.5mL SST (black/red top) tube 
 
Process whole blood as follows: 
Centrifuge SST tube at 600g for 10 minutes. 
 
Aliquot the serum equally between two 2mL cryovials. 
 
Re-aliquot one of the serum tubes into 0.5 mL aliquots (~4 
serum aliquots).  Label the new serum aliquots with Protocol #, 
Patient Initials and Patient ID #, Date of Birth, U1806, and 
Serum w/o inhibitor. 
 
With second 2mL aliquot of serum  add 50 uL protease inhibitor 
cocktail / mL of serum and mix.  Aliquot 0.50 mL of this serum 
into cryovials (~4 serum aliquots).  Label  the new serum 
aliquots with Protocol #, Patient Initials and Patient ID #, Date of 
Birth, and U1806, and  Serum w/ inhibitor. 
 
Store at -80C until requested. 
 
14.24 PAXgene RNA 
 
Collect at the following time points: 
 
Prior to Registration (≤14 days) 
Cycle 3 Day 1 (Prior to Treatment) 
Cycle 5 Day 1 (Prior to Treatment) 
 
Collect the following tubes of blood: 
One 5mL Paxgene tube 
 
Process whole blood per manufacturer’s instructions (as follows): 
 
Incubate blood sample for at least 2 hours at room temp to 
ensure cells are lysed. 


  
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Centrifuge tube for 10 minutes at 3000-5000 x g using a swing 
out rotor NOTE: Tubes may break if tube adapters for round 
bottom tubes is not used. 
 
Pipet off  the supernatant and discard. 
 
Add 4mL RNase-free water to the pellet and close tube with a 
fresh secondary BD Hemogard closure.  
 
Vortex the pellet until visible dissolved and centrifuge at 3000-
5000 x g using a swing-out rotor. 
 
Decant or Pipet off the supernatant and discard.  NOTE: Be sure 
to remove as much supernatant as possible.  Remaining 
supernatant will inhibit lysis and dilute the lysate, thus 
affecting binding of RNA to PAXgene membrane.  
 
Add 350µL Buffer BR1, and vortex until pellet is visibly 
dissolved.  
 
Pipet sample into 1.5mL microcentrifuge tube and add 300µL 
Buffer BR2 and 40µL proteinase K.  NOTE:  Do not mix 
Buffer BR2 and proteinase K together prior to adding to 
sample. 
 
Mix by vortexing for 5 seconds, and incubate on a shaker (400-
1400 rpm) for 10 minutes at 55ºC. 
 
Pipet lysate into PAXgene Shredder spin Column (lilac) and 
place in a 2mL processing tube.  Centrifuge for 3 minutes at 
maximum speed (but not greater than 20,000 x g)   
NOTE:  Be sure that the all the lysate is transferred to the 
spin column. 
NOTE:  Some samples may flow through spin column 
without being centrifuged. 
 
Transfer the supernatant that flowed through column into a fresh 
1.5mL microcentrifuge tube without disturbing the pellet in the 
processing tube. 
 
Add 350uL ethanol (96-100%) and mix by vortexing. Centrifuge 
briefly (1-2 seconds at 500-1000- x g) to remove drops from the 
sides of the tube.   NOTE: Do not centrifuge longer or RNA 
yield will be compromised. 
 
Pipet 700µL sample into PAXgene RNA spin column (red) and 
place in a 2mL processing tube.  Centrifuge for 1 minute at 
8000-20,000 x g.   
 


  
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Place the spin column in a new 2mL processing tube and discard 
the old processing containing flow-through. 
 
Pipet remaining sample into the PAXgene RNA spin column, 
and centrifuge for 1 minute at 8000-20,000 x g.  Place the spin 
column in a new 2mL processing tube and discard the old 
processing tube containing the flow-through.  
NOTE:  Carefully pipet the sample into the spin column and 
visually check that the sample is completely transferred to the 
spin column.  
 
Pipet 350µL Buffer BR3 into the PAXgene RNA spin column, 
and centrifuge for 1 minute at 8000-20,000 x g.   Place the spin 
column in a new 2 mL processing tube and discard the old 
processing tube containing the flow-through. 
 
Add 10µL DNase I stock solution to 70uL Buffer RDD in a 
1.5mL microcentrifuge tube, and mix by gently flicking the tube, 
and centrifuge to collect liquid at the bottom of tube.  
NOTE:  DNase I is especially sensitive to denaturation. Mix 
ONLY by gently flicking the tube.  DO NOT VORTEX. 
 
Pipet the DNase I incubation mix (80µ) directly onto the 
PAXgene RNA spin column membrane, and let sit at room 
temperature for 15 minutes. NOTE:  Be sure DNase I incubation 
mix is placed directly onto the membrane (not on walls or the O-
ring of the spin column). 
 
Pipet 350µL Buffer BR3 into the PAXgene RNA spin column, 
and centrifuge for 1 minute at 8000-20,000 x g.  Place the spin 
column in a new 2 mL processing tube and discard the old 
processing tube containing flow-through. 
 
Pipet 500µL diluted BR4 Buffer to the PAXgene RNA spin 
column, and centrifuge for 1 minute 8000-20,000 x g.  Place the 
spin column in a new 2 mL processingtube, and discard the old 
processing tube and flow-through. NOTE:  Buffer BR4 is 
supplied as a concentrate and must be diluted with ethanol 
(96-100%) prior to use.  For 500µL for diluted BR4 buffer 
use 100µL BR4 concentrate and 400 µL ethanol.). 
 
Add another 500µL diluted BR4 Buffer to the PAXgene spin 
column, and centrifuge for 3 minutes at 8000-20,000 x g. 
 
Discard the tube containing the flow-through, and place the 
PAXgene RNA spin column in a new 2mL processing tube, and 
centrifuge for 1 minute at 8000-20,000 x g. 
 
Discard the tube containing the flow-through, and place the 
PAXgene RNA spin column in a 1.5mL microcentrifuge tube 
and pipet 40µL Buffer BR5 directly onto the PAXgene RNA 


  
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spin column membrane, and centrifuge for 1 minute at 8000-
20,000 x g to elute the RNA.  NOTE:  It is important to wet 
the entire membrane with Buffer BR5 to achieve maximum 
elution efficiency. 
 
Repeat the elution step using the same microcentrifuge tube – 
Pipet 40µL Buffer BR5 directly onto the PAXgene RNA spin 
column membrane, and centrifuge for 1 minute at 8000-20,000 x 
g to elute the RNA.   
 
Incubate for 5 minutes at 65º.  NOTE:  This step denatures the 
RNA.  Do not exceed the incubation time. 
 
Chill on ice.  
 
Store at -80C until requested.   
 
14.25 Urine 
 
 
Mayo Clinic Florida and Mayo Clinic Arizona will collect and ship 
all samples to Mayo Clinic Rochester for processing. 
 
Collect at the following time points: 
 
Prior to Registration (≤14 days) 
Cycle 3 Day 1 (Prior to Treatment) 
Cycle 5 Day 1 (Prior to Treatment) 
 
Collect the following: 
10-15 mL Urine 
 
Process urine as follows: 
 
 
Centrifuge 3mL urine at 600g for 10 minutes. 
 
Aliquot 1 mL into two cryovials without disturbing pellet.  Label 
cryovials with Protocol #, Patient Initials, and Date of Birth.  
 
On the first urine cryovial label Urine w/o Inhibitor, and set a 
side. 
 
For the second urine aliquot, add 50 uL / mL and label Urine w/ 
Inhibitor. 
 
Store urine aliquots at -80C until requested.  
 
14.3 
Specimen Shipping and Handling 
 
14.31 Collection Supplies 
 
Collection supplies should be provided at each site. 




  
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15.14 Administration:  The medication is taken orally.  Pazopanib should be 
taken without food, at least 1 hour before or 2 hours after a meal.  
Pazopanib should be taken whole with water and must not be broken or 
crushed.  If a dose is missed, it should not be taken if it is less than 12 
hours until the next dose. 
 
 
15.15 Pharmacokinetic information: 
a)  Absorption – Pazopanib is absorbed orally with an absolute 
oral bioavailability range of 13.5 to 38.9% after an 800 mg dose, 
with a median absolute bioavailability of 21%.  Plasma 
concentrations of pazopanib peak from 2 to 4 hours following 
single dose administration. Systemic exposure to pazopanib is 
increased when administered with food.  Administration with a 
high-fat or low-fat meal results in an approximately 2-fold 
increase in AUC and Cmax.  Pazopanib should be administered at 
least one hour before or 2 hours after a meal. Administration of 
pazopanib as a crushed tablet increases the rate and extent of oral 
absorption relative to administration of the whole tablet.  The 
crushing of the tablet increases AUC by 46% and Cmax  by 
approximately 2-fold, but decreases tmax by approximately 2 hours 
relative to administration of the whole tablet.  Consequently, it is 
recommended not to crush pazopanib tablets. 
b)  Distribution – Binding of pazopanib to human plasma protein 
in vivo was greater than 99% with no concentration dependence.  
Pazopanib is associated with a small volume of distribution (9.2 to 
131L). 
c)  Metabolism – In vitro studies demonstrate pazopanib is 
metabolized by CYP3A4 with a minor contribution from CYP1A2 
and CYP2C8.  Patients who have AST/ALT >3 X ULN and 
concurrent bilirubin >2 X ULN must permanently discontinue 
pazopanib.  Use of pazopanib is not recommended in patients with 
total biblirubin >3 X ULN (regardless of any ALT) due to 
insufficient data with this severe impairment. 
d)  Elimination – Pazopanib has a mean half-life of 30.9 hours 
after administration of an 800mg dose.  Elimination is primarily 
via feces with renal elimination accounting for < 4% of the 
administered dose. 
 
 
15.16 Potential Drug Interactions:  CYP3A4 Inhibitors and Inducers:  
Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., 
itraconazole, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, 
telithromycin, voriconazole, ketoconazole, ritonavir, clarithromycin) 
increases pazopanib concentrations and should be avoided.  Grapefruit 
juice should be avoided as it inhibits CYP3A4 activity and may also 
increase plasma concentrations of pazopanib. CYP3A4 inducers such as 
rifampin may decrease plasma pazopanib concentrations. Pazopanib 
should not be used if chronic use of strong CYP3A4 inducers cannot be 
avoided.  Please see Appendix VI for a list of strong inhibitors and 
inducers of CYP3A4. 


  
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CYP Substrates:  Results from drug-drug interaction trials conducted in 
cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, 
CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, 
or CYP2C19.   Concomitant use of pazopanib with agents with narrow 
therapeutic windows that are metabolized by CYP3A4, CYP2D6, or 
CYP2C8 is not recommended. Coadministration may result in inhibition 
of the metabolism of these products and create the potential for serious 
adverse events. 
 
Concomitant use of pazopanib and simvastatin increases the 
incidence of ALT elevations.  If a patient receiving concomitant 
simvastatin develops ALT elevations, follow dosing guidelines for 
pazopanib or consider discontinuing simvastatin.  Insufficient data 
are available to assess the risk of concomitant administration of 
alternative statins and pazopanib. 
 
If the concomitant use of a PPI is medically necessary, the dose of 
pazopanib should be taken without food once daily in the evening 
concomitantly with the PPI. If the concomitant administration of 
an H2-receptor antagonist is medically necessary, pazopanib 
should be taken without food at least 2 hours before or at least 10 
hours after a dose of an H2- receptor antagonist. Pazopanib should 
be administered at least 1 hour before or 2 hours after 
administration of short-acting antacids. 
 
With concomitant use of pazopanib with lapatinib (an inhibitor of 
P-gp, BCRP and a weak inhibitor of CYP3A4), patients should be 
observed for adverse reactions and the pazopanib dose should be 
reduced as needed. 
 
In vitro studies also showed that pazopanib inhibits UGT1A1 and 
OATP1B1.   Pazopanib may increase concentrations of drugs 
eliminated by UGT1A1 and OATP1B1. Coadministration of 
pazopanib 400 mg once daily with cetuximab 250 mg/m2 and 
irinotecan 150 mg/m2 resulted in a 20% increase in systemic 
exposure to SN-38 (a substrate for UGT1A1 and OATP1B1). 
 
15.17 Known potential toxicities: 
Summary of adverse reactions in patients with renal cell 
carcinoma (RCC): 
Very common: ≥ 1/10 (≥ 10%) 
Metabolism and nutrition:  Anorexia 
Nervous system:  Headache 
Cardiac:  Bradycardia 
Vascular:  Hypertension 
Gastrointestinal:  Abdominal pain, diarrhea, nausea, 
vomiting 
Hepatobiliary:  Increased ALT and AST 
Skin and subcutaneous tissue:  Hair depigmentation 
General:  Asthenia, fatigue 


  
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Common: ≥1/100 and <1/10 (≥ 1% and <10%) 
Blood and lymphatic:  Neutropenia, thrombocytopenia 
Endocrine:  Hypothyroidism 
Metabolism and nutrition:  Weight decreased 
Nervous system:  Dysgeusia, transient ischemic attack 
Cardiac:  Myocardial ischemia, QT prolongation 
Vascular:  Epistaxis, gastrointestinal hemorrhage, hematuria,  
venous thromboembolic events 
Respiratory, thoracic and mediastinal:  Dysphonia 
Gastrointestinal:  Dyspepsia, lipase elevations 
Hepatobiliary:  Hepatic function abnormal, hyperbilirubinemia 
Skin and subcutaneous tissue:  Alopecia, palmar-plantar  
erythrodysesthesia, rash, skin depigmentation 
Renal and urinary:  Proteinuria 
General:  Chest pain 
Uncommon: ≥1/1,000 and <1/100 (≥0.1% and <1%) 
Nervous system:  Ischemic stroke 
Cardiac:  Cardiac dysfunction (such as a decrease in ejection 
fraction and congestive heart failure), myocardial infarction, 
Torsade de Pointes 
Vascular:  Cerebral hemorrhage, pulmonary hemorrhage 
Gastrointestinal:  Gastrointestinal perforation, 
gastrointestinal fistula 
Laboratory Abnormalities:  ≥15% 
Leukopenia, neutropenia, thrombocytopenia, 
lymphocytopenia, ALT increased, AST increased, glucose 
increased, total bilirubin increased, phosphorus decreased, 
calcium decreased, sodium decreased, potassium increased, 
creatinine increased, magnesium decreased, glucose 
decreased. 
 
Summary of adverse reactions in patients with soft tissue 
sarcoma (STS): 
Very common: ≥ 1/10 (≥ 10%) 
Metabolism and nutrition:  Anorexia, weight decreased 
Nervous system:  Dizziness, dysgeusia, headache 
Cardiac:  Bradycardia 
Vascular:  Hypertension 
Respiratory, thoracic and mediastinal:  Cough, dyspnea 
Gastrointestinal:  Abdominal pain, diarrhea, nausea, 
stomatitis, vomiting 
Skin and subcutaneous tissue:  Alopecia, exfoliative rash, hair 
depigmentation, palmar-plantar erythrodysesthesia, skin 
depigmentation 


  
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Musculoskeletal and connective tissue:  Musculoskeletal pain, 
myalgia 
General:  Chest pain, fatigue, peripheral edema 
Common: ≥1/100 and <1/10 (≥ 1% and <10%) 
Endocrine:  Hypothyroidism 
Cardiac:  Cardiac dysfunction, myocardial infarction, QT  
prolongation 
Vascular:  Epistaxis, gastrointestinal hemorrhage, pulmonary 
hemorrhage, venous thromboembolic events  
Respiratory, thoracic and mediastinal:  Dysphonia,  
pneumothorax 
Gastrointestinal:  Dyspepsia 
Hepatobiliary:  Increased ALT and AST  
Skin and subcutaneous tissue:  Dry skin, nail disorder 
General:  Chills, blurred vision 
Uncommon: ≥1/1,000 and <1/100 (≥0.1% and <1%) 
Nervous system:  Ischemic stroke 
Vascular:  Cerebral hemorrhage, hematuria 
Gastrointestinal:  Gastrointestinal fistula 
Hepatobiliary:  Hyperbilirubinemia 
Skin and subcutaneous tissue:  Rash 
Renal and urinary:  Proteinuria 
General:  Asthenia 
Laboratory Abnormalities:  ≥15%:   
Leukopenia, neutropenia, thrombocytopenia, 
lymphocytopenia, anemia, ALKP increased, ALT increased, 
AST increased, albumin decreased, glucose increased, total 
bilirubin increased, sodium decreased, potassium increased. 
 
Post Marketing Adverse Drug Reactions 
Very common: ≥ 1/10 (≥ 10%) 
Musculoskeletal and connective tissue:  Arthralgia 
Common: ≥1/100 and <1/10 (≥ 1% and <10%) 
Infections and infestations (with or without neutropenia 
Gastrointestinal:  Flatulence 
Hepatobiliary:  Gamma-glutamyl transpeptidase increased 
Musculoskeletal and connective tissue:  Muscle spasms 
Uncommon: ≥1/1,000 and <1/100 (≥0.1% and <1%) 
Blood and lymphatic system:  Thrombotic microangiopathy 
(including thrombotic thrombocytopenic purpura and 
hemolytic uremic syndrome), polycythemia 
Eye:  Retinal detachment/tear 
Gastrointestinal:  Pancreatitis 
Rare: ≥1/10,000 and <1/1,000 (≥0.01% and <0.1%) 
Nervous system:  Posterior reversible encephalopathy 
syndrome 


  
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Respiratory, thoracic and mediastinal:  Interstitial lung 
disease/pneumonitis 
 
15.18 Drug procurement:  Pazopanib HCl (GW786034) is an investigational 
agent that will be supplied by Novartis.  See Appendix V for detailed 
drug ordering instructions/form. 
 
15.2 
Nursing Guidelines for pazopanib 
 
15.21 Pazopanib should be taken without food (1 hour before or 2 hours after a 
meal). Should be taken whole with water and not broken or crushed. If a 
dose is missed, do not take if it is less than 12 hours until the next dose. 
 
15.22 There are numerous drug to drug interactions between pazopanib and 
other agents metabolized through the P450 system.  Assess patient’s 
concomitant medications, including OTC and herbal products.  Refer to 
appendix for medications that should be avoided or used concomitantly 
with caution. 
 
15.23 Hypertension is the most commonly reported side effect. Monitor blood 
pressure closely per study guidelines. Administer antihypertensives as 
ordered by MD. 
 
15.24 Inform patient of possible changes in hair color. 
 
15.25 Gastrointestinal side effects are common (diarrhea, nausea, vomiting, 
loss of appetite). Treat symptomatically and assess for effectiveness. 
 
15.26 Due to the similarity in nature of this agent to other VEGF inhibitors 
(bevacizumab, VEGF-trap, etc.) monitor for signs of bleeding, 
thrombosis and PE. Instruct patient to report any calf tenderness, 
shortness of breath, chest pain or bleeding immediately. 
 
15.27 Cytopenias are common. Monitor CBC w/diff and instruct patient to 
report any unusual bruising or bleeding and/or signs of infection to study 
team. 
 
15.28 Monitor LFT’s. Patients who have AST/ALT levels > 3x ULN and 
concurrent bilirubin >2X ULN should permanently discontinue 
pazopanib. Patients with AST/ALT levels as above and mild 
hyperbilirubinemia (with suspected or known Gibert’s syndrome) should 
be monitored weekly while continuing pazopanib. 
 
15.29 Cardiac side effects (CHF, MI, chest pain, etc).  while rare can be serious 
and life threatening. Instruct patient to report any cardiac symptoms to 
study team immediately. 
 
15.29a RPLS, CVA, and TIA are uncommon, but are life threatening. Instruct 
patient to report any neurological symptoms to the study team 
immediately.  
 


  
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16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  This protocol will assess the efficacy of pazopanib in patients with 
non-clear cell metastatic renal cancer using a one-stage phase II study design.   
 
 
16.11  Primary Endpoint:  The primary endpoint of this trial is the 12-month 
overall survival rate.  A “12-month overall survivor” will be considered 
synonymous with “success”, unless otherwise specified. A patient is 
considered to be a 12-month survivor if the patient lives 12 months from 
registration (note, all deaths prior to 12 months, regardless of cause, will 
be considered a failure). All patients meeting the eligibility criteria who 
have signed a consent form and have begun treatment will be evaluable 
for the primary endpoint. All eligible patients will be followed until 
death or a minimum of 2 years. 
 
16.2  
Statistical Design:  
 
16.21  Decision Rule:  The largest success proportion where the proposed 
treatment regimen would be considered ineffective in this population is 
55%, and the smallest success proportion that would warrant subsequent 
studies with the proposed regimen in this patient population is 75%. The 
one-stage design based on properties of the binomial distribution uses 39 
patients to test the null hypothesis that the true success proportion in a 
given patient population is at most 55%.   
 
16.22  Sample Size:  There will be 35 evaluable patients accrued onto this study 
unless undue toxicity is encountered. We anticipate accruing an 
additional 4 patients to account for ineligibility, cancellation, major 
treatment violation, or other reasons.   
 
16.23  Accrual Time and Study Duration:  The anticipated accrual rate is 
approximately 1-2 patients per month, based on the incidence of tumor 
type and the potential to accrue at Mayo Clinic sites (Mayo Clinic 
Rochester, Mayo Clinic Florida and Mayo Clinic Arizona).  Therefore, 
the accrual period for this phase II study is expected to be 24 months.  
The final analysis can begin approximately 36 months after the trial 
begins, i.e. as soon as the last patient has been observed for 12 months. 
 
16.24  Power and Significance Level:  The null 12-month overall survival rate 
of 55% is based on the Kaplan-Meier estimate of 12-month survival from 
the Mayo Clinic Nephrectomy database (Leibovich, Lohse et al.).  
Assuming that the number of successes is binomially distributed and the 
significance level is ≤0.10, we are required to accrue evaluable 35 
patients to achieve an 80% power under the alternative hypothesis of a 
75% success proportion. 
 
16.3  
Analysis Plan:  The analysis for this trial will commence at the time all patients 
have become evaluable for the primary endpoint. Such a decision will be made 
by the Statistician and Study Chair, in accord with standard operating procedures, 
availability of data for secondary endpoints, and the level of data maturity. 
 


  
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16.31  Primary Endpoint 
 
16.311 
The primary endpoint of this trial is the 12-month overall 
survival rate. This endpoint has been described as a binomial 
endpoint of success and failure, therefore patients lost to 
follow-up (eg, progressed/recurred, refusing further study 
participation, etc) prior to the time necessary for the binomial 
endpoint (eg, 12 months) will be defined as failure.  All 
patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be considered 
evaluable for the primary endpoint. All eligible patients will be 
followed until death or a minimum of 2 years. 
 
16.312  
Estimation: The proportion of successes will be estimated by 
the number of successes divided by the total number of 
evaluable patients. Confidence intervals for the true success 
proportion will be calculated.   
 
16.313  
Over Accrual: If more than the target number of patients are 
accrued, the additional patients will not be used to evaluate the 
stopping rule or used in any decision making processes; 
however, they will be included in final point estimates and 
confidence intervals. 
 
16.32  Definitions and Analyses of Secondary Endpoints 
 
16.321  
A tumor response is defined to be a CR or PR noted as the 
objective status on 2 consecutive evaluations at least 8 weeks 
apart. Tumor response will be evaluated. All patients meeting 
the eligibility criteria who have signed a consent form and 
have begun treatment will be evaluable for response. 
 
16.322  
Progression-free survival is defined as the time from 
registration to the earliest date documentation of disease 
progression or death.  Kaplan-Meier curve will be used to 
estimate progression-free survival time. 
 
16.323 
Adverse events: All eligible patients that have initiated 
treatment will be considered evaluable for assessing adverse 
event rate(s). The maximum grade for each type of adverse 
event will be recorded for each patient, and frequency tables 
will be reviewed to determine patterns. Additionally, the 
relationship of the adverse event(s) to the study treatment will 
be taken into consideration. 
 
16.324 
Observation Phase: Retreatment of patients who have relapsed 
will be left to the discretion of the treating physician. 
Statistical analysis of the observational phase data for these 
patients will be of a descriptive nature. 
 


  
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16.4 
Data & Safety Monitoring: 
 
16.41 The study chair(s) and the study statistician will review the study at least 
twice a year to identify accrual, adverse event, and any endpoint 
problems that might be developing. The Mayo Clinic Cancer Center 
(MCCC) Data Safety Monitoring Board (DSMB) is responsible for 
reviewing accrual and safety data for this trial at least twice a year, based 
on reports provided by the MCCC Statistical Office. 
 
16.42 Adverse Event Stopping Rules: The stopping rules specified below are 
based on the knowledge available at study development. We note that the 
Adverse Event Stopping Rule may be adjusted in the event of either (1) 
the study re-opening to accrual or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the 
adverse event profile of the treatment(s) under investigation. The study 
team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as “possible”, “probable”, or 
“definite”) that satisfy the following: 
 
If 4 or more patients in the first 15 treated patients or anytime 
thereafter more than 25% of patients experience a ≥grade 4 or 
higher adverse event, except for hypertension, diarrhea, and 
abnormal liver function tests, accrual will be temporarily 
suspended. 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
16.5  
Results Reporting on ClinicalTrials.gov: At study activation, this study will have 
been registered within the “ClincialTrails.gov” website. The primary and 
secondary endpoints (ie, “Outcome Measures”) along with other required 
information for this study will be reported on ClinicalTrials.gov. For purposes of 
timing of the Results Reporting, the initial estimated completion date for the 
Primary Endpoint of this study is 36 months after the study opens to accrual. The 
definition of “Primary Endpoint Completion Date” (PECD) for this study is at the 
time the last patient registered has been followed for at least 12 months overall 
survival status. 
 
16.6  
Inclusion of Women and Minorities 
 
16.61  This study will be available to all eligible patients, regardless of race, 
gender, or ethnic origin. 
 


  
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16.62  There is no information currently available regarding differential effects 
of this regimen in subsets defined by race, gender, or ethnicity, and there 
is no reason to expect such differences to exist. Therefore, although the 
planned analysis will, as always, look for differences in treatment effect 
based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
 
 
16.63  The geographical region served by Mayo Clinic sites, has a population 
which includes approximately 10 % minorities. Based on prior Mayo 
Clinic sites only studies involving similar disease sites, we expect about 
10 % of patients will be classified as minorities by race and about 50 % 
of patients will be women. Expected sizes of racial by gender subsets for 
patients registered to this study are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 1 
 1 
 2 
Not Hispanic or Latino 
 18 
 19 
 37 
Ethnic Category: Total of all subjects 
 19 
 20 
 39 
Racial Category 
American Indian or Alaskan Native 
 1 
 0 
 1 
Asian 
 0 
 1 
 1 
Black or African American 
 1 
 1 
 2 
Native Hawaiian or other Pacific Islander 
 0 
 0 
 0 
White 
 17 
 18 
 35 
Racial Category: Total of all subjects 
 19 
 20 
 39 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


  
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17.0 
Pathology Considerations/Tissue Biospecimens   
 
None 
 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s) -  
CRF 
 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study Form1 
 
 
 
 
≤2 weeks after registration 
Adverse Events: Baseline 
RECIST Measurements: Baseline 
Specimen Submission: Blood (see Section 
14.0) 
Specimen Submission: Urine (see Section 
14.0) 
Laboratory Tests and Results 
 
Concomitant Medication Form 
Patient Status: Baseline 
 
Off Treatment2 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1. On-Study: Prior Surgery, On-Study Prior Radiation, and On-Study Prior Systemic Therapy will be 
added as needed. 
2. Added if needed based on the responses on the Patient Status: Baseline form 
 
 
 


  
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Central Pathology Review Material(s) -  
CRF 
 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Pathology Materials (this is for central 
review, eligibility, etc.) 
Submit ≤30 days after registration  
 
Test Schedule Material(s) -  
CRF 
 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation 
during treatment 
At end of treatment 
 
Treatment (Intervention)  
X1 
X 
Adverse Events: Solicited  
X 
X 
RECIST Measurement2 s 
X 
X 
Specimen Submission: Blood  
X (see Section 14.0) 
 
Specimen Submission: Urine 
X (see Section 14.0) 
 
Laboratory Tests and Results 
X 
 X 
Concomitant Medications 
X 
X 
Patient Status: Treatment 
X 
 
Off Treatment2 
 
X 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
1. 
Complete at each evaluation during Active Treatment (see Section 4.0).  
2. 
Added if needed based on the responses on the Patient Status: Treatment form 
 
 
Follow-up Material(s) -  
CRF 
Survival Follow-up Phase1 
 
 
q. __3__ 
months 
until PD 
 
 
 
At PD1 
After 
PD q. 
__6__ 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Patient Status: Survival Follow-up1 
X2 
X2 
X 
X 
At each occurrence 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the MCCC Operations Office, 
Attention: QAS for MC1152 
 


  
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18.2 
Patient identification labels will be produced for each patient entry.  The 
labels are produced for use on the data forms and will be mailed to the 
co-sponsors/participants twice.  Additional labels may be obtained by 
directly calling the Mayo Clinic Cancer Center (MCCC) Registration 
Office 
. 
 
18.3 
Each co-sponsor/participant will be responsible for insuring that all 
materials contain the patient’s initials, MCCC registration number, and 
MCCC protocol number.  Patient’s name must be removed. 
 
18.4 
Any materials deemed incomplete by the MCCC Operations Office will 
be considered “not received” and will not be edited or otherwise 
processed until the missing information is received.  A list of the missing 
documents will be made available to the appropriate co-
sponsor/participant. 
 
18.5 
Overdue lists:  A list of overdue materials and forms for study patients 
will be generated monthly.  The listings will be sorted by location and 
will include the patient study registration number.  The appropriate co-
sponsor/participant will be responsible to obtain the overdue material. 
 
18.6 
Corrections forms:  If a correction is necessary the QAS will query the 
co-sponsor/participant.  The query will be sent to the appropriate co-
sponsor/participant who will make the correction and return the query 
and documentation of correction back to the QAS.  
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
19.2 
Tests to be research funded: Echocardiogram, screening EKG, CT Head/MRI at 
baseline, urinalysis cycle 3 and 5, metabolic panel/ CBC  Cycle 1 and 2 only, 
TSH, correlative analysis on blood. 
 
 
19.3 
Other budget concerns: 
 
20.0 
References 
 
Bylow, K. A., M. B. Atkins, et al. (2009). "Phase II trial of carboplatin and paclitaxel in papillary 
renal cell carcinoma." Clin Genitourin Cancer 7(1): 39-42. 
Choueiri, T. K., A. Plantade, et al. (2008). "Efficacy of sunitinib and sorafenib in metastatic 
papillary and chromophobe renal cell carcinoma." J Clin Oncol 26(1): 127-31. 
Cohen, H. T. and F. J. McGovern (2005). "Renal-cell carcinoma." N Engl J Med 353(23): 2477-
90. 
Dharmawardana, P. G., A. Giubellino, et al. (2004). "Hereditary papillary renal carcinoma type 
I." Curr Mol Med 4(8): 855-68. 
Di Lorenzo, G., R. Autorino, et al. (2009). "Metastatic renal cell carcinoma: recent advances in 
the targeted therapy era." Eur Urol 56(6): 959-71. 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 


  
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Verweij J.  New response evaluation criteria in solid tumors:  revised RECIST guideline 
(version 1.1).  Eur J Cancer 45(2):  228-247, 2009. 
Escudier, B., T. Eisen, et al. (2007). "Sorafenib in advanced clear-cell renal-cell carcinoma." N 
Engl J Med 356(2): 125-34. 
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 
1997;18:4-25. 
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186. 
Folkman J. Antiangiogenic therapy, in DeVita VTJ, Hellman S, Rosenberg SA (eds): Cancer: 
Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997;3075-
3085. 
Gordon, M. S., M. Hussey, et al. (2009). "Phase II study of erlotinib in patients with locally 
advanced or metastatic papillary histology renal cell cancer: SWOG S0317." J Clin Oncol 
27(34): 5788-93. 
Gore, M. E., C. Szczylik, et al. (2009). "Safety and efficacy of sunitinib for metastatic renal-cell 
carcinoma: an expanded-access trial." Lancet Oncol 10(8): 757-63. 
Hudes, G., M. Carducci, et al. (2007). "Temsirolimus, interferon alfa, or both for advanced renal-
cell carcinoma." N Engl J Med 356(22): 2271-81. 
Isaacs, J. S., Y. J. Jung, et al. (2005). "HIF overexpression correlates with biallelic loss of 
fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability." 
Cancer Cell 8(2): 143-53. 
Kumar R, Knick VB, Rudolph SK, et al.  PK-PD correlation from mouse to human with 
pazopanib, a multi-kinase angiogenesis inhibitor with potent anitumor and antiangiogenic 
activity.  Mol Cancer Therapy 2007; 6 2012-2021. 
LaPlant, K. D. and P. D. Louzon "Pazopanib: an oral multitargeted tyrosine kinase inhibitor for 
use in renal cell carcinoma." Ann Pharmacother 44(6): 1054-60. 
Leibovich, B. C., C. M. Lohse, et al. "Histological subtype is an independent predictor of 
outcome for patients with renal cell carcinoma." J Urol 183(4): 1309-15. 
Motzer, R. J., J. Bacik, et al. (2002). "Treatment outcome and survival associated with metastatic 
renal cell carcinoma of non-clear-cell histology." J Clin Oncol 20(9): 2376-81. 
Motzer, R. J., B. Escudier, et al. (2008). "Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial." Lancet 
372(9637): 449-56. 
Motzer, R. J., T. E. Hutson, et al. (2007). "Sunitinib versus interferon alfa in metastatic renal-cell 
carcinoma." N Engl J Med 356(2): 115-24. 
Nickerson, M. L., M. B. Warren, et al. (2002). "Mutations in a novel gene lead to kidney tumors, 
lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-
Dube syndrome." Cancer Cell 2(2): 157-64. 
Oudard, S., E. Banu, et al. (2007). "Prospective multicenter phase II study of gemcitabine plus 
platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe 
d'Etudes des Tumeurs Uro-Genitales) study." J Urol 177(5): 1698-702. 
Rini, B. I., S. Halabi, et al. (2008). "Bevacizumab plus interferon alfa compared with interferon 
alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206." J 
Clin Oncol 26(33): 5422-8. 
Stadler, W. M., R. A. Figlin, et al. "Safety and efficacy results of the advanced renal cell 
carcinoma sorafenib expanded access program in North America." Cancer 116(5): 1272-
80. 
Sudarshan, S. and W. M. Linehan (2006). "Genetic basis of cancer of the kidney." Semin Oncol 
33(5): 544-51. 
Yamazaki, K., M. Sakamoto, et al. (2003). "Overexpression of KIT in chromophobe renal cell 
carcinoma." Oncogene 22(6): 847-52. 
 


  
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APPENDIX 1 
 
ECOG PERFORMANCE STATUS 
 
 
Grade 
 
0  
Fully active, able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100). 
 
1  
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 (Karnofsky 
70-80). 
 
2  
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50 percent of waking hours   (Karnofsky 50-
60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50 percent or more of 
waking hours (Karnofsky 30-40). 
 
4  
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair (Karnofsky 10-20). 
 
5  
Dead 
 
 
 
 
 
 


  
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APPENDIX II  
 
Drugs with Risk of Torsades de Pointes 
 
This list contains medications that are generally accepted (and documented in published data) as 
having an increased risk of QT prolongation and/or torsades de pointes.  Concomitant 
administration of pazopanib and a medication on this list is prohibited.  
 
 
Generic Name 
Brand Name 
Comments 
Amiodarone 
Cordarone®, Pacerone® 
Low risk torsades de pointes 
Arsenic trioxide 
Trisenox® 
Torsades de pointes 
Bepridil 
Vasocor® 
 
Chloroquine 
Aralen® 
 
Chlorpromazine 
Thorazine® 
 
Cisapride 
Propulsid® 
Restricted availability in U.S. 
Clarithromycin 
Biaxin® 
 
Disopyramide 
Norpace® 
Torsades de pointes 
Dofetilide 
Tikosyn® 
Torsades de pointes 
Dolasetron 
Anzemet® 
 
Droperidol 
Inapsine® 
Torsades de pointes 
Erythromycin 
Erythrocin®, E.E.S. ® 
IV > PO 
Halofantrine 
Halfan® 
 
Haloperidol 
Haldol® 
IV > PO, high doses increase QT 
prolongation and torsades de pointes 
Ibutilide 
Corvert® 
Torsades de pointes, female > male, 
non-Caucasian > Caucasian 
Levomethadyl 
Orlaam® 
 
Mesoridazine 
Serentil® 
 
Methadone 
Dolophine®, Methadose® 
 
Pentamidine 
Pentam®, Nebupent® 
 
Pimozide 
Orap® 
 
Procainamide 
Pronestyl®, Procan®, 
Procanbid® 
N-acetylprocainamide causes torsade 
de pointes, not parent compound 
Quinidine 
Cardioquin®, Quinaglute® 
Torsades de pointes 
Sotalol 
Betapace® 
Torsade de pointes female > male 
Sparfloxacin 
Zagam® 
 
Thioridazine 
Mellaril® 
 
Note:  the above list is not all-inclusive.   
 
References:   
 
Al-Khatib SM, Allen LaPointe NM, Kramer JM, Califf RM.  What Clinicians Should Know About 
the QT Interval.  Journal of the American Medical Association 2003;289:2120-2127. 
 
Crouch MA, Limon L, Cassano AT. Clinical Relevance and Management of Drug-Related QT 
Interval Prolongation.  Pharmacotherapy 2003;23:887-908. 
 
Kies SJ, Pabelick CM et al.  Anesthesia for Patients with Congenital Long QT Syndrome. 
Anesthesiology 2005;102:204-210 
 
Li EC, Esterly JS, Pohl S, Scott SC, McBride BF.  Drug-Incuded QT-Interval Prolongation:  
Considerations for Clinicans.  Pharmacotherapy 2010;30:684-701. 
 


  
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Roden DM. Drug-Induced Prolongation of the QT Interval.  The New England Journal of Medicine 
2004;350:1013-1022. 
 
http://www.azcert.org/medical-pros/druginteractions.cfm   Accessed 5/13/11 
 
 
 
Drugs with Possible or Conditional Risk of Torsades de Pointes 
 
This list contains medications that, in some reports, have been associated or weakly associated 
with causing torsades de pointes and/or QT prolongation.  There is insufficient data that these 
medications alone may cause torsades de pointes and/or QT prolongation, however when 
pazopanib is given concomitantly with a medication on this list (or other risk factors are present 
such as bradycardia, electrolyte disturbances, congenital long QT syndrome, or concomitant 
drugs that inhibit metabolism), there may be possible or conditional risk of torsades de pointes 
and/or QT prolongation.  Extreme caution and careful monitoring should be instituted with 
concomitant administration of pazopanib and a medication on this list. 
 
Generic Name 
Brand Name 
Comments 
Alfuzosin 
Uroxatral® 
 
Amantadine 
Symmetrel® 
Low 
Amitriptyline 
Elavil® 
Nonspecific ECG changes reported. 
Atazanavir 
Reyataz® 
 
Azithromycin 
Zithromax® 
 
Chloral hydrate 
Noctec® 
 
Ciprofloxacin 
Cipro® 
 
Citalopram 
Celexa® 
 
Clomipramine 
Anafranil® 
 
Desipramine 
Pertofrane® 
QT prolongation, VF/sudden death 
reported 
Diphenhydramine 
Benadryl®, Nytol® 
 
Dolasetron 
Anzemet® 
Granisetron < Ondansetron < 
Dolasetron 
Doxepin 
Sinequan® 
 
Dronedarone 
Multaq® 
 
Escitalopram 
Lexapro®, Cipralex® 
 
Felbamate 
Felbatrol® 
 
Flecainide 
Tambocor® 
 
Foscarnet 
Foscavir® 
 
Fosphenytoin 
Cerebyx® 
 
Fluconazole 
Diflucan® 
IV > PO 
Fluoxetine 
Prozac®, Sarafem® 
1 in 10,000 ventricular arrhythmias 
reported 
Galantamine 
Reminyl® 
 
Gatifloxacin 
Tequin® 
 
Gemifloxacin 
Factive® 
 
Granisetron 
Kytril® 
Granisetron < Ondansetron < 
Dolasetron 
Imipramine 
Norfranil® 
Nonspecific arrhythmias reported 
Indapamide 
Lozol® 
 
Isradipine 
Dynacirc® 
 
Itraconazole 
Sporanox® 
 
Ketoconazole 
Nizoral® 
 
Lapatinib 
Tykerb® 
 
Levofloxacin 
Levaquin® 
Lower risk than that of similar agents 
Lithium 
Lithobid®, Eskalith® 
 


  
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Moexipril/HCTZ 
Uniretic® 
 
Moxifloxacin 
Avelox® 
 
Nicardipine 
Cardene® 
 
Nilotinib 
Tasigna® 
 
Nortriptyline 
Pamelor® 
Nonspecific arrhythmias reported  
Octreotide 
Sandostatin® 
 
Ofloxacin 
Floxin® 
 
Ondansetron 
Zofran® 
Granisetron<Ondansetron< Dolasetron 
Oxytocin 
Pitocin® 
 
Paliperidone 
Invega® 
 
Paroxetine 
Paxel® 
Lower risk than TCA’s 
Perflutren lipid 
microspheres 
Definity® 
 
Protriptyline 
Vivactil® 
 
Quetiapine 
Seroquel® 
QT prolongation 
Ranolazine 
Ranexa® 
 
Risperidone 
Risperdal® 
QT 
prolongation, 
sudden 
death 
reported 
Ritonavir 
Norvir® 
 
Sertraline 
Zoloft® 
Lower risk than TCA’s 
Solifenacin 
VESIcare® 
 
Sunitinib 
Sutent® 
 
Tacrolimus 
Prograf® 
 
Tamoxifen 
Nolvadex® 
 
Telithromycin 
Ketek® 
 
Tizanidine 
Zanaflex® 
 
Trazodone 
Desyrel® 
 
Trimethoprim-Sulfa 
Sulfa®, Bactrim®, Bactrim 
DS® 
Low 
Trimipramine 
Surmontil® 
 
Vardenafil 
Levitra® 
 
Venlafaxine 
Effexor® 
1 :1000 risk of arrhythmia reported 
Voriconazole 
VFend® 
 
Ziprasidone 
Geodon® 
QT prolongation, 1:1000 risk of 
arrhythmia 
Note:  the above list is not all-inclusive. 
 
References:   
 
Al-Khatib SM, Allen LaPointe NM, Kramer JM, Califf RM.  What Clinicians Should Know About 
the QT Interval.  Journal of the American Medical Association 2003;289:2120-2127. 
 
Crouch MA, Limon L, Cassano AT. Clinical Relevance and Management of Drug-Related QT 
Interval Prolongation.  Pharmacotherapy 2003;23:887-908. 
 
Kies SJ, Pabelick CM et al.  Anesthesia for Patients with Congenital Long QT Syndrome. 
Anesthesiology 2005;102:204-210 
 
Li EC, Esterly JS, Pohl S, Scott SC, McBride BF.  Drug-Incuded QT-Interval Prolongation:  
Considerations for Clinicans.  Pharmacotherapy 2010;30:684-701. 
 
Roden DM. Drug-Induced Prolongation of the QT Interval.  The New England Journal of Medicine 
2004;350:1013-1022. 
 
http://www.azcert.org/medical-pros/druginteractions.cfm   Accessed 5/13/11


  
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Appendix III 
Patient Medication Diary 
 
 
NAME: __________________________________________ I.D. # _________    
CYCLE#____ 
 
This calendar is for you to indicate that you took the study drugs according to the 
instructions.  Please put a check mark or your initials after each dose and record how 
many tablets you took. 
 
Please bring the calendar back to your next clinic visit. 
 
 
Pazopanib Pill Diary 
Day 
Dose 
Number of tablets 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4. 
 
 
 
5. 
 
 
 
6. 
 
 
 
7. 
 
 
 
8. 
 
 
 
9. 
 
 
 
10. 
 
 
 
11. 
 
 
 
12. 
 
 
 
13. 
 
 
 
14. 
 
 
 
15. 
 
 
 
16. 
 
 
 
17. 
 
 
 
18. 
 
 
 
19. 
 
 
 
20. 
 
 
 
21. 
 
 
 
22. 
 
 
 
23. 
 
 
 
24. 
 
 
 
25. 
 
 
 
26. 
 
 
 
27. 
 
 
 
28. 
 
 
 
Signature:__________________________________ 
Date:______________________________________


  
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Appendix IV 
 
The Stages of Heart Failure – NYHA Classification 
In order to determine the best course of of therapy, physicians often assess the stage of 
heart failure according to the New York Heart Association (NYHA) functional 
classification system. This system relates symptoms to everyday activities and the 
patient's quality of life. 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 
 


  
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Appendix V 
 
  




  
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Appendix VII 
 
 
 
Table 14  
Adverse Events Reported for at Least 10% of Subjects (Safety 
Population) in Study VEG105192  
Preferred 
Term  
Number (% of subjects)  
Placebo (n=145)  
 
Pazopanib (n=290)  
 
Any 
Grade  
Grade 3   
Grade 
4  
Any 
Grade  
Grade 3  Grade 
4  
Any AEa  
107 (74)  
21 (14)  
 
8 (6)  
268 (92)  
96 (33)  
20 (7)  
Diarrhea  
13 (9)  
1 (<1)  
 
0  
150 (52)  
9 (3)  
2 (<1)  
Hypertension  
15 (10)  
1 (<1)  
 
0  
115 (40)  
13 (4)  
0  
Hair color 
changes  
4 (3)  
0  
 
0  
109 (38)  
1 (<1)  
0  
Nausea  
13 (9)  
0  
 
0  
74 (26)  
2 (<1)  
0  
Anorexia  
14 (10)  
1 (<1)  
 
0  
65 (22)  
6 (2)  
0  
Vomiting  
11 (8)  
3 (2)  
 
0  
61 (21)  
6 (2)  
1 (<1)  
Fatigue  
11 (8)  
2 (1)  
 
2 (1)  
55 (19)  
7 (2)  
0  
ALT increased  
5 (3)  
1 (<1)  
 
0  
53 (18)  
18 (6)  
3 (1)  
AST increase  
5 (3)  
0  
 
0  
43 (15)  
13 (4)  
1 (<1)  
Asthenia 
 12 (8)b  
0  
 
0  
41 (14)  
8 (3)  
0  
Abdominal pain  
2 (1)  
0  
 
0  
32 (11)  
6 (2)  
0  
Headache  
7 (5)  
0  
 
0  
30 (10)  
0  
0  
a. AEs are ranked by incidence in the pazopanib arm. Any AE, any grade includes Grade 5 
(fatal) events (12 [4%]  
subjects in the pazopanib arm and 4 [3%] subjects in the placebo arm).  
b. One placebo subject had Grade 5 asthenia.  
ALT= alanine aminotransferase; AST= aspartate aminotransferase  
 
 
 
 


  
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ICF_001.pdf: 
 
 
 
 
 
 
 
MC1152 
 
A Phase II Efficacy Trial of Pazopanib in Non-Clear Cell 
Metastatic Renal Cell Cancer (mRCC) PINC 
 
NCT01767636 
 
 
Document Date: 08/01/2018 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 1 of 16 
Version 8/9/2012 
Name and Clinic Number 
 
 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
 
Study Title: MC1152, A Phase II Efficacy Trial of Pazopanib in Non-Clear Cell Metastatic Renal Cell 
Cancer (mRCC) (PINCR)  
 
IRB#:  
11-003340  
 
Principal Investigator: Dr. B. Costello and Colleagues 
 
Please read this information carefully. It tells you important things about this research study. A member 
of our research team will talk to you about taking part in this research study. If you have questions at 
any time, please ask us. 
 
Take your time to decide. Feel free to discuss the study with your family, friends, and healthcare 
provider before you make your decision.   
 
To help you decide if you want to take part in this study, you should know: 
• Taking part in this study is completely voluntary.  
• You can choose not to participate.  
• You are free to change your mind at any time if you choose to participate.   
• Your decision won’t cause any penalties or loss of benefits to which you’re otherwise entitled. 
• Your decision won’t change the access to medical care you get at Mayo Clinic now or in the 
future if you choose not to participate or discontinue your participation.   
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and Rochester, 
Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, hospitals, and entities. 
 
If you decide to take part in this research study, you will sign this consent form to show that you want to 
take part. We will give you a copy of this form to keep. 
 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 2 of 16 
Version 8/9/2012 
Name and Clinic Number 
 
CONTACT INFORMATION 
 
 
You can contact … 
At … 
If you have questions about … 
Principal Investigators: 
Dr. Brian Costello 
(Rochester) 
 
Other Study Contacts: 
Dr. Thai H. Ho 
(Arizona)  
 
Dr. Winston Tan  
(Florida) 
Phone: 
(507) 284-2511 
 
 
 
(480) 301-8000 
 
 
(904) 953-7290 
 
Address: 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 Study tests and procedures 
 Research-related injuries or 
emergencies 
 Any research-related concerns or 
complaints 
 Withdrawing from the research study 
 Materials you receive 
 Research-related appointments 
Mayo Clinic Institutional 
Review Board (IRB) 
Phone: 
(507) 266-4000 
 
Toll-Free: 
(866) 273-4681 
 Rights of a research participant 
 
Research Subject 
Advocate 
(The RSA is independent 
of the Study Team) 
Phone: 
(507) 266-9372 
 
Toll-Free: 
(866) 273-4681 
 
E-mail: 
researchsubjectadvocate@mayo.edu 
 Rights of a research participant 
 Any research-related concerns or 
complaints 
 Use of your Protected Health 
Information 
 Stopping your authorization to use 
your Protected Health Information 
Research Billing 
 
 
Rochester, MN:  
(507) 266-5670 
 
Florida:  
(904) 953-7058 
 
Arizona:  
(800) 603-0558 
 Billing or insurance related to this 
research study 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 3 of 16 
Version 8/9/2012 
Name and Clinic Number 
Other Information:  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Website will not include information that can identify you. At most, the Website will include 
a summary of the results. You can search this Website at any time. 
 
 
1. 
Why are you being asked to take part in this research study? 
 
 
You are being asked to take part in this research study because you have been diagnosed with metastatic 
non-clear renal cell cancer. 
 
 
2. 
Why is this research study being done? 
 
 
The purpose of this study is to determine how the study drug pazopanib works in the treatment of 
metastatic non-clear cell renal cell cancer and disease progression. The use of pazopanib for this 
indication in the study is considered investigational, which means it has either not been approved by the 
Food and Drug Administration (FDA) for routine clinical use or for the use described in this study. 
However, the FDA has allowed the use of this drug in this research study. 
 
 
3. 
Information you should know 
 
 
Who is Funding the Study? 
 
Novartis is funding the study and will pay the institution to cover costs related to running the study.  
 
Information Regarding Conflict of Interest: 
 
One or more of the investigators associated with this project have a financial interest in one of the 
companies sponsoring this trial and/or providing a product for this trial and that the investigator may 
stand to gain financially from the successful outcome of the research. 
 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 4 of 16 
Version 8/9/2012 
Name and Clinic Number 
Both the Mayo Clinic Conflict of Interest Review Board and the Institutional Review Board have 
reviewed the financial interest for one or more of the investigators and/or Mayo Clinic related to this 
research and they have determined that this financial interest poses no additional significant risk to the 
welfare of participants in this research project or to the integrity of the research. 
 
Additional information is available to any interested study participant regarding the details of this 
financial interest and how it is being managed by contacting the study coordinator or the Office of 
Conflict of Interest Review at 507-284-0075. 
 
 
4. 
How long will you be in this research study? 
 
 
You will be in the study for 3 years or until your disease gets worse. 
 
 
5. 
What will happen to you while you are in this research study? 
 
 
If you agree to be in the study, you will be asked to participate in the following: 
 
On your first visit, you will have tests done to evaluate your condition and ability to participate in the 
study. These include blood tests, 24 hour urine sample, echocardiogram (a test which looks at your heart 
and surrounding tissue), thyroid function test, CT (x-ray) or MRI of the head, electrocardiogram (EKG – 
a test to measure your heart function), and CT (x-ray) or MRI scan of chest, abdomen or pelvis. Your 
doctor will ask you questions about your medical history and examine you. If you are a woman who can 
have children, you will be required to have a negative pregnancy test within 7 days prior to starting the 
study. The pregnancy tests must be negative for you to start treatment. 
 
We will collect tissue samples from a previous biopsy you have had for testing. 
 
For the bone scan, a small amount of radioactive material will be injected in your vein and a special 
camera will be used to image the material inside of your body. 
 
If you are eligible and agree to participate, you will begin treatment. You will receive pazopanib tablets 
once a day, every day that you are on the study.  
 
Pazopanib should be taken orally without food at least one hour before or two hours after a meal. The 
tablets should be swallowed whole and must not be crushed or broken. The time of day the tablets are 
taken should be relatively constant. 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 5 of 16 
Version 8/9/2012 
Name and Clinic Number 
 
You will also be asked to keep a diary to record your medications taken. This should take no more than 
a couple of minutes a day to complete. 
 
If your disease gets worse, you will be taken off  treatment with the study drug and your physician may 
start you on another treatment. We will continue to collect information about how you and your disease 
are doing for up to 3 years after you stop treatment. 
 
If your disease gets better, you will continue on the study for up to 12 more cycles (months). After this 
you will go to event monitoring and we will continue to collect information about how you and your 
disease are doing for an additional 2 years. 
 
You will be watched for side effects and the dose will be adjusted if necessary. If your dose is reduced, 
you will continue on with the same treatment schedule as before.  
 
These are the procedures and study visits:  
 
Before study enrollment 
 
• Sign informed consent 
• History and exam 
• Vital signs including temperature 
• Routine blood test (including complete blood count) 
• Pregnancy test at least 7 days prior to registration (only for females 
who may still become pregnant) 
• Urinalysis 
• Thyroid function test 
• Blood coagulation test 
• CT/MRI scan of the head 
• Echocardiogram 
• EKG 
• CT/MRI scan of chest, abdomen or pelvis 
Prior to each new cycle 
• History and exam 
• Vital signs including temperature 
• Check for side effects 
• Routine blood tests (including complete blood count). Can be 
drawn at outside institution 
• Blood coagulation test 
• EKG 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 6 of 16 
Version 8/9/2012 
Name and Clinic Number 
 
Weeks 2, 6 and 10 
• Routine Blood tests 
Every other cycle  
• Thyroid function test 
• CT/MRI scan of chest, abdomen, or pelvis  
• Bone scan (if applicable) 
• Echocardiogram (every four months) 
End of Treatment 
 
• History and exam 
• Vital signs including temperature 
• Routine blood tests (including complete blood count)  
 
The schedule of blood specimen tests is listed above. Approximately 2 tablespoons of blood will be 
drawn at each time. 
 
For the time you are enrolled in this study, you may not donate blood, or participate in other cancer 
research trials or other trials with new medications. 
 
 
6. 
What are the possible risks or discomforts from being in this research study? 
 
 
GW786034 (Pazopanib) 
 
Likely risks of GW786034 (events occurring greater than 20% of the time) 
• Feeling tired (Fatigue) 
• Loss of appetite, not feeling hungry (Anorexia) 
• Loose stools (Diarrhea) 
• Feeling sick to your stomach (Nausea) 
• Throwing up (Vomiting) 
• High blood pressure (Hypertension) 
• Decreased function of the thyroid gland and/or thyroid hormone, which can result in feeling tired 
and weight gain, that may first show up as an increased levels of thyroid stimulating hormone 
(Hypothyroidism)  
• Loss of pigment in the skin causing it to look lighter (Skin de-pigmentation)  
• Loss of hair color 
• Abnormal liver function tests which may indicate that your liver is not functioning properly or 
injured 
• Abdominal pain 
• Headache 
• Tumor pain 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 7 of 16 
Version 8/9/2012 
Name and Clinic Number 
Less likely risks of GW786034 (events occurring less than or equal to 20% of the time)  
• Hair thinning or loss (Alopecia)  
• Loss of the protein in the urine (Proteinuria)  
• Decrease in red blood cells, which are the oxygen carrying cells, which could make you feel tired 
(Anemia)  
• Opening or hole in the bowel that can lead to infection, may require surgery to repair and/or lead 
to death (Bowel perforation) 
• Fever (Pyrexia) 
• Flare of diverticulitis (inflammation of the bowel associated with diverticulosis of the colon) 
• Inflammation of the colon (Colitis) 
• Rash/flaking or shedding of outer layer of skin  
• Nose bleed (Epistaxis) 
• Bleeding from the lungs or respiratory tract (Pulmonary hemorrhage) 
• Sensation of lightheadedness or vertigo (Dizziness) 
• Joint pain (Arthralgia) 
• Decrease in the number of white blood cells, which are the infection fighting cells and important 
to the immune system, which could put you at risk for infection (Neutropenia, Lymphopenia, 
Leukopenia) 
• Decreased number of blood cells (platelets) that help to clot the blood (which could put you at 
increased risk of bleeding) (Thrombocytopenia) 
• Difficulty passing stool (Constipation) 
• Intestinal gas (Flatulence) 
• Change in taste sensation (Dysgeusia) 
• Restless movements caused by abnormalities in the part of the brain that coordinates movement 
• Coughing up blood or blood tinged sputum (Hemoptysis) 
• Anxiety, agitation, confusion  
• Feeling sad or blue (Depression ) 
• Abnormal blood level of fat-digesting enzyme (lipase) and/or abnormal digestive enzyme level 
(amylase) potentially indicating inflammation or injury to the pancreas  
• Cough  
• Low levels of magnesium in the blood (Hypomagnesmia)  
• Decreased level of phosphorus in the blood (Hypophosphatemia)  
• Excessive or abnormal loss of body fluids (Dehydration) 
• Elevation of a liver pigment (bilirubin) in the blood indicating liver dysfunction 
(Hyperbilirubinemia) 
• High blood sugar (Hyperglycemia) 
• Increased magnesium in the blood (Hypermagnesemia)  
• Low blood sugar (Hypoglycemia)  
• Muscle pain (Myalgia) 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
Page 8 of 16 
Version 8/9/2012 
Name and Clinic Number 
• Shortness of breath or difficulty breathing (Dyspnea) 
• Weight loss 
• Pain, redness or tissue breakdown at the sites where there has been exposure to radiation therapy 
(Radiation recall) 
• An increase in the amount of time it takes to “recharge” heart cells after they have been 
stimulated to beat. This increase in time can cause an abnormal heartbeat that can cause you to 
“pass-out or faint” and/or be life threatening (QT prolongation) 
• Indigestion or heartburn (Dyspepsia) 
• Infections, including lung infection (pneumonia) 
• Insomnia (difficulty sleeping) 
 
Rare but serious risks of GW786034 (events occurring less than 2-3% of the time) 
• Collection of fluid in the space around the lung (Pleural effusion) 
• Decrease in the ability of the heart to pump blood, because of weakening of the heart muscle 
(Congestive heart failure)  
• Development of fluid in the area around the heart  (Pericardial effusion)   
• Abnormal heartbeat (Arrhythmia)  
 
• Bleeding in the brain (Cerebral hemorrhage)  
• Blood clot in a vein (Deep vein thrombosis) 
• Blood clots in the lungs which could be life threatening or cause death (Pulmonary embolism)   
• Lack of oxygen to the heart muscle which can cause damage to the heart (Heart attack)  
• Kidney injury (Kidney failure) 
• Elevated liver enzymes 
• Cough and/or a sudden spasm of the vocal cords which may result in the closing of the airway 
(Laryngospasm) 
• Abnormal connection between different parts of the body (fistula)- This can occur in the between 
structures of the urinary tract (i.e. bladder) and the genital or reproductive system (i.e. vagina) 
OR between different organs of the digestive tract  
• Bleeding from the stomach, large intestine and/or small intestine (Gastrointestinal bleeding )  
• Redness or sores of the palms of the hands or soles of the feet (Palmar-plantar erysdysthesia-
“hand-foot syndrome”) 
• Lack of oxygen to the brain caused by either bleeding in the brain or blood clot. Also called a 
stroke. (Cerebral vascular accident) 
• Leakage of air into the chest cavity surrounding the lung and associated breathing difficulties 
(Pneumothorax) 
• Inflammation of the lungs (Pneumonitis) 
• Separation of the retina from its connection at the back of the eye (Retinal tear/retinal 
detachment) 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
IRB#: 11-003340 00 
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• Swelling or scarring of the lungs which may cause shortness of breath 
• Blood clots in small blood vessels 
• Elevated platelets 
 
The company that makes pazopanib has identified a chemical that is present in pazopanib tablets in very 
small amounts. In laboratory tests, this chemical by itself caused changes to genes (DNA) that indicate 
that is has the potential to cause cancer or tumors. Exactly what these results mean about your taking 
pazopanib is not known; however, the risk of harm to you is thought to be low for the following reasons:  
1) When pazopanib (which contains a small amount of this impurity) was tested in these same laboratory 
tests, it did not cause damage to genes; 2) Many cancer drugs have the potential to damage genes, but 
the benefits of these drugs are believed to be greater than their risks in patients with cancer.  
 
As with any medication, allergic reactions are a possibility. 
 
The risks of drawing blood for a study sample include pain, bruising, or rarely, infection at the site of the needle 
stick. 
 
You will be exposed to radiation in this research study. The amount of radiation you will receive has a low risk 
of harmful effects.   
 
There may also be a risk of death. 
 
Your doctor will discuss the risks of tests and procedures that are part of your standard clinical care. 
 
Pregnancy and Birth Control:  
 
1) Will women of child-bearing-potential be allowed to participate in this study? 
 
Yes: Women of child-bearing-potential will be able to participate in this study if they have a 
negative pregnancy test and agree to use acceptable birth control (see #5) since the risks to an 
unborn child are either unknown or potentially serious. 
 
2) Will pregnant and/or nursing women be allowed to participate in this study?  
 
No:  There is not enough medical information to know what the risks might be to an unborn child 
carried by a woman who takes part in this study. 
   


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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3) Do you need to have a pregnancy test done to be part of the study? 
 
Yes: As part of this study a pregnancy test is required for all women who are able to become 
pregnant. 
 
A blood pregnancy test will be done by taking blood from your arm. 
 
You will be told the results of the pregnancy test. If the pregnancy test is positive, you will not 
be able to take part in the study. 
 
4) Will men who are able to father a child be allowed to participate in this study? 
 
Yes:  Men who are able to father a child will be able to participate in this study if they agree to 
use acceptable birth control (see #5) since the risks to an unborn child are either unknown or 
potentially serious. 
 
5) What types of birth control are acceptable (for 21 days after last dose of investigational product)?  
 
Surgical sterilization 
Approved hormonal contraceptives (such as birth control pills, Depo-Provera) 
Barrier methods (such as a condom or diaphragm) used with a spermicide 
An intrauterine device (IUD) 
Complete abstinence for 14 days prior to investigational product 
 
 
7. 
Are there reasons you might leave this research study early? 
 
 
Taking part in this research study is voluntary. You may decide to stop at any time. You should tell the 
researcher if you decide to stop and you will be advised whether any additional tests may need to be 
done for your safety.  
 
In addition, the researchers, Novartis, or Mayo may stop you from taking part in this study at any time: 
• if it is in your best clinical interest,  
• if you do not follow the study procedures,  
• if the study is stopped. 
 
We will tell you about any new information that may affect your willingness to stay in the research 
study. 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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8. 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. Mayo Clinic will offer care 
for research-related injuries, including first aid, emergency treatment, and follow-up care as needed. 
 
Who will pay for the treatment of research related injuries: 
 
Care for such research-related injuries will be billed in the ordinary manner, to you or your insurance. 
You will be responsible for all treatment costs not covered by your insurance, including deductibles, co-
payments and coinsurance.   
 
Signing this consent form does not change any legal rights you may have. 
 
 
9. 
What are the possible benefits from being in this research study? 
 
 
This study may not make your health better. However, if your cancer responds to the study drug, it may 
slow the growth of your cancer. 
 
 
10. 
What alternative do you have if you choose not to participate in this research 
study? 
 
 
You do not have to be in this study to receive treatment for your condition. Your other choices may 
include:  
• Chemotherapy 
• Targeted therapy 
• Another research study 
• You may also choose not to have any treatment except medications to make you feel better. 
 
You should talk to the researcher and your regular physician about each of your choices before you 
decide if you will take part in this study. 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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11. 
What tests or procedures will you need to pay for if you take part in this research 
study?  
 
 
You will not need to pay for tests and procedures which are done just for this research study. These tests 
and procedures are: 
• Thyroid function test at screening 
• Echocardiogram at screening 
• Mandatory tumor tissue biopsy 
• Electrocardiogram at screening 
 
However, you and/or your health plan will need to pay for all other tests and procedures that you would 
normally have as part of your regular medical care.  These tests and procedures are: 
• Standard of care physical examinations 
• Standard of care blood and urine tests 
• Standard of care thyroid tests after screening 
• Standard of care CT/MRI scans 
• Bone scan (if applicable) 
• Pregnancy test (if applicable) 
• Standard of care electrocardiograms after screening 
• Standard of care echocardiograms after screening 
 
If you have billing or insurance questions, call Research Billing at the telephone number provided in the 
Contact Information section of this form. 
 
Novartis (the study sponsor), is providing the study drug free of charge to all patients. 
 
If you have billing or insurance questions call Research Billing at the telephone number provided 
in the Contact Information section of this form. 
 
 
12. 
Will you be paid for taking part in this research study? 
 
 
You will not be paid for taking part in this study. 
 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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13. 
What will happen to your samples? 
 
 
We would like to keep your sample for future research. If you agree to give your sample, it will be the 
property of Mayo Clinic. 
 
Other researchers at Mayo Clinic who aren’t involved with this study may ask to use your sample for 
future research. Researchers at other institutions may also ask for a part of your sample for future 
studies. Your sample will be sent to researchers in a coded format, which protects your identity. 
 
Some future studies may examine your DNA, which is the genetic information you inherited from your 
parents (genetic testing). The Principal Investigator may contact you if there are findings which may be 
useful for your health care. You would be given general information on the potential risks, benefits, and 
costs of choosing to learn about the findings. 
 
Please read the following statements and mark your choices: 
 
1. I permit my sample to be stored and used in future research of renal cancer at Mayo Clinic: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
2. I permit my sample to be stored and used in future research at Mayo Clinic to learn about, 
prevent, or treat any other health problems: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
3. I permit Mayo Clinic to give my sample to researchers at other institutions: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
There is a very small chance that some commercial value may result from the use of your donated 
sample. If that happens, you won’t be offered a share in any profits. 
 
You may request to have your sample destroyed by writing to the Principal Investigator. The address is 
found in the Contact Information section of this consent form. 
 
Because we cannot predict how your sample will be used in the future, we cannot promise that samples 
can be retrieved and destroyed. 
 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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14. 
How will your privacy and the confidentiality of your records be protected? 
 
 
Mayo Clinic is committed to protecting the confidentiality of information obtained about you in 
connection with this research study. The confidentiality of subjects’ data will be safeguarded by coding 
data or samples with numbers, storing research materials in locked cabinets, and password-protecting 
data stored on a computer.  
 
During this research, information about your health will be collected. Under Federal law called the 
Privacy Rule, health information is private. However, there are exceptions to this rule, and you should 
know who may be able to see, use and share your health information for research and why they may 
need to do so. Information about you and your health cannot be used in this research study without your 
written permission. If you sign this form, it will provide that permission. 
 
Health information may be collected about you from: 
• Past, present and future medical records. 
• Research procedures, including research office visits, tests, interviews and questionnaires. 
 
Why will this information be used and/or given to others? 
• To do the research. 
• To report the results. 
• To see if the research was done correctly. 
 
If the results of this study are made public, information that identifies you will not be used. 
 
Who may use or share your health information? 
• Mayo Clinic research staff involved in this study.  
• Novartis. 
 
With whom may your health information be shared?  
• The Mayo Clinic Institutional Review Board that oversees the research.  
• Other Mayo Clinic physicians involved in your clinical care. 
• Researchers involved in this study at other institutions. 
• Federal and State agencies (such as the Food and Drug Administration, the Department of Health 
and Human Services, the National Institutes of Health and other United States agencies) or 
government agencies in other countries that oversee or review research. 
• Novartis, and the people or groups it hires to help perform this research. 
• A group that oversees the data (study information) and safety of this research. 
 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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Is your health information protected after it has been shared with others? 
Mayo Clinic asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside Mayo Clinic, we cannot promise that it will remain 
private and it may no longer be protected by the Privacy Rule. 
 
Your Privacy Rights 
You do not have to sign this form, but if you do not, you cannot take part in this research study. 
 
If you cancel your permission to use or share your health information, your participation in this study 
will end and no more information about you will be collected; however, information already collected 
about you in the study may continue to be used. 
 
If you choose not to take part or if you withdraw from this study, it will not harm your relationship with 
your own doctors or with Mayo Clinic. 
 
You can cancel your permission to use or share your health information at any time by sending a letter 
to the address below: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN:  Notice of Revocation of Authorization 
200 1st Street SW 
Rochester, MN  55905 
 
Alternatively, you may cancel your permission by emailing the Mayo Clinic Research Subject Advocate 
at: researchsubjectadvocate@mayo.edu. 
 
Please be sure to include in your letter or email: 
• The name of the Principal Investigator, 
• The study IRB number and /or study name, and 
• Your contact information. 
 
Your permission lasts forever, unless you cancel it.   
 


 
 
Approval Date:  
August 1, 2018 
Not to be used after: February 21, 2019 
 
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ENROLLMENT AND PERMISSION SIGNATURES 
 
 
Your signature documents your permission to take part in this research.  
 
 
 
  
 
 
 
/        /  
 
 
   : 
       AM/PM   
Printed Name  
 
 
 
Date 
 
 
 
Time   
 
 
 
 
_______________________________ 
Signature 
 
 
Person Obtaining Consent  
• I have explained the research study to the participant. 
• I have answered all questions about this research study to the best of my ability. 
 
 
 
  
 
 
 
/        /  
 
 
   : 
       AM/PM   
Printed Name  
 
 
 
Date 
 
 
 
Time           
 
 
_______________________________ 
Signature