Conditions: Clear Cell Renal Cell Carcinoma Recurrent Renal Cell Cancer Stage IV Renal Cell Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
RATIONALE: Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well pazopanib hydrochloride works in treating patients with stage IV kidney cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the response rate (RR) associated with pazopanib (pazopanib hydrochloride) as 3rd-line therapy in metastatic renal cell carcinoma (mRCC) patients who have failed therapy with a distinct vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI).

SECONDARY OBJECTIVES:

I. To determine if baseline hepatocyte growth factor (HGF), endothelial selectin (E-selectin) and interleukin-6 (IL-6) are associated with progression-free survival (PFS).

II. To determine if pre-metastatic niche density in regional lymph nodes (LNs) is associated with PFS.

III. To determine an association between E-selectin, IL-6 and pre-metastatic niche density.

IV. To evaluate the prognostic effect of pre-metastatic niches as an independent factor in time to first relapse.

V. To determine if phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in tumor tissue is associated with PFS.

VI. To describe the toxicity associated with pazopanib in this patient population.

VII. To evaluate PFS and overall survival (OS). VIII. To compare, within patient, time to tumor progression of 2nd-line therapy with time to tumor progression on pazopanib as 3rd-line therapy.

OUTLINE:

Patients receive oral pazopanib hydrochloride once daily 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 every 6 months.

Arms:
arm 1: Patients receive oral pazopanib hydrochloride once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: pazopanib hydrochloride intervention 2: laboratory biomarker analysis intervention 3: immunologic technique
Intervention descriptions: intervention 1: Given orally intervention 2: Correlative studies intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
IRB #10030                                                                                                                                                                   12/07/17 
Version: 07 
CITY OF HOPE 
1500 E. DUARTE RD. 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
 
TITLE: A Phase II Study of Pazopanib in VEGF-TKI Refractory Metastatic Renal Cell Carcinoma 
(MRCC)  
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB #10030 
 
VERSION: 07 
 
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
Initial Submission: 
[COH Protocol dated, July 29, 2010]    
Version 00 
 
COH Amend 01: 
[COH Protocol dated, September 15, 2010 ] 
Version 01 
 
COH Amend 02 
[COH Protocol dated, March 18, 2011] 
Version 02 
 
COH Amend 03 
[COH Protocol dated, October 10, 2011] 
Version 03 
 
COH Amend 04 
[COH Protocol dated, April 4, 2012] 
Version 04 
 
COH Amend 05 
[COH Protocol dated, October 29, 2013] 
Version 05 
                          COH Amend 06 
[COH Title Page dated, August 18, 2014] 
Version 06 
                          COH Amend 07 at Continuation 
[COH Title Page dated, 12/7/17] 
Version 07 
 
 
 
SITE: 
Renal Cell Carcinoma 
STAGE (If applicable): 
 
 
IV 
MODALITY: 
Oral medication 
TYPE: 
Phase II 
 
 
PRINCIPAL INVESTIGATOR: 
Sumanta Pal, M.D. 
 
COLLABORATING INVESTIGATORS: 
Przemyslaw Twardowski, M.D. 
 
PARTICIPATING CLINICIANS: 
Joseph Chao, M.D., Warren Chow, M.D., Vincent Chung, M.D., 
Mihaela Cristea, M.D., Arti Hurria, M.D., Marianna Koczywas, 
M.D., Stephen Koehler, M.D.,  Dean Lim, M.D., Joanne Mortimer, 
M.D., Jana Portnow, M.D., Karen Reckamp, M.D., Stephen 
Shibata, M.D., George Somlo, M.D., Christina Yeon, M.D. 
 
 
STATISTICIAN: 
Paul Frankel, PhD 
 
PARTICIPATING INSTITUTION: 
City of Hope, Duarte, CA 
 
City of Hope Medical Group, South Pasadena, CA 
 


 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 9.15.10; 03.18.11; 10-11-11, 04-04-12, 09-26-13 
A PHASE II STUDY OF PAZOPANIB IN VEGF-TKI REFRACTORY 
METASTATIC RENAL CELL CARCINOMA (MRCC) 
 
 
PRINCIPAL INVESTIGATOR: 
Sumanta Kumar Pal, MD, Asst. Professor 
 
Dept. of Medical Oncology & Experimental 
Therapeutics 
 
1500 East Duarte Road 
 
Duarte, CA 91010 
 
Phone: (626) 256-4673, x 68218 
 
Fax: 
(626) 301-8233 
 
e-mail: spal@coh.org 
 
 
STUDY STATISTICIAN: 
Paul Frankel, PhD 
 
Dept. of Information Sciences 
 
1500 East Duarte Road 
 
Duarte, CA 91010 
 
Phone: (626) 256-4673 
 
Fax: 
(626) 301-8233 
 
e-mail: pfrankel@coh.org  
 
 
COLLABORATING  INVESTIGATOR: 
 
 
Premyslaw Twardowski, MD 
 
Dept. of Medical Oncology & Experimental 
Therapeutics 
 
1500 East Duarte Road 
 
Duarte, CA 91010 
 
Phone: (626) 256-4673, x 68218 
 
Fax: 
(626) 301-8233 
 
e-mail: ptwardowski@coh.org 
 
 
AGENT NSC# AND IND#: 
Pazopanib NSC#:737754; pending 
 
COORDINATING CENTER: 
City of Hope Comprehensive Cancer Center 
 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
Experimental Design Schema 
Open-label, phase II design as represented in the following schema:  
 
* See inclusion/exclusion criteria for full details.  
mRCC*  
• ECOG PS 0-1 
• 1 prior VEGF-TKI required 
• 1 other prior systemic 
therapy allowed  
Pazopanib 800 mg  
oral daily 
Study assessment to 
proceed until next 
anticancer therapy 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
Protocol Synopsis 
Protocol Title: 
A PHASE II STUDY OF PAZOPANIB IN VEGF-TKI REFRACTORY METASTATIC RENAL 
CELL CARCINOMA (MRCC) 
Brief Protocol Title for the Lay Public (if applicable): 
A PHASE II STUDY OF PAZOPANIB IN VEGF-TKI REFRACTORY METASTATIC RENAL 
CELL CARCINOMA (MRCC) 
Study Phase: 
Phase II 
Participating Sites: 
City of Hope Comprehensive Cancer Center 
Rationale for this Study: 
At present, 3rd line therapy of mRCC remains an area of need.  Pazopanib has shown activity in 
the setting of bevacizumab- and cytokine- refractory patients.1,2    Furthermore, there may be 
preclinical rationale to challenge patients with a structurally distinct VEGF-TKI.  Molecular 
aberrations in the receptor tyrosine kinase (RTK) targeted by VEGF-TKIs may confer a relative 
resistance to specific agents – thus, re-challenging with agents such as sunitinib is presumably 
less efficacious.3,4  Ongoing studies have assessed inhibition of distinct molecular pathways; 
however, response rates using this approach (i.e., with mTOR inhibitors or perifosine) have been 
modest at best.5,6  3rd- line therapy represents an area of need in metastatic renal cell carcinoma – 
herein, we propose use of pazopanib in this setting. 
Primary Objective: 
To determine the RR associated with pazopanib as 3rd-line therapy in mRCC patients who have 
failed therapy with a distinct VEGF-TKI 
Secondary Objective(s): 
 
To evaluate progression-free survival (PFS), overall survival (OS) 
 
To describe the toxicity associated with pazopanib in this patient population 
 
To compare, within patient, time to tumor progression of 2nd-line therapy with time to 
tumor progression on pazopanib as 3rd-line therapy 
 
To determine if baseline HGF, E-selectin and IL-6 are associated with PFS  
 
To determine if pre-metastatic niche density in regional LNs is associated with PFS 
 
To determine an association between E-selectin, IL-6 and pre-metastatic niche density 
 
To evaluate the prognostic effect of pre-metastatic niches as an independent factor in PFS 
 
To determine if pSTAT3 in tumor tissue is associated with PFS 
Study Design: 
Open-label, single institution phase II study 
Primary Endpoint and Secondary Endpoints: 
Primary: 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
RR by RECIST 1.1 Criteria 
Secondary: 
 
Toxicity, PFS, OS 
Sample Size: 
28 
Estimated Duration of the Study 
12 months  
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
 
Histologically confirmed diagnosis of metastatic clear cell RCC  
 
At least one measurable lesion at baseline as per RECIST 1.1 criteria.  If skin lesions are 
reported as target lesions, they must be documented (at baseline and at every physical 
exam) using color photography and a measuring device (such as a caliper) in clear focus 
to allow the size of the lesion to be determined from the photograph 
 
1 prior VEGF-TKI required 
 
1 other prior systemic therapy allowed 
 
ECOG PS 0-1 
 
Resolution of grade ≥ 2 toxicity from prior therapy 
 
Normal hematologic labs and serum chemistries (to be specified in the protocol)  
 
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.   
 
Age ≥ 18 years or legal age of consent if greater than 18 years 
 
A female is eligible to enter and participate in this study if she is of non-child bearing 
potential (i.e., physiologically incapable of becoming pregnant), including any female 
who has had (1) a hysterectomy, (2) a bilateral oophorectomy (ovariectomy), (3) a 
bilateral tubal ligation, or (4) 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.   
 
Patients with childbearing potential, including any female who has had a negative serum 
pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as 
close to the first dose as possible, and agrees to use adequate contraception.  GSK 
acceptable contraceptive methods, when used consistently and in accordance with both 
the product label and the instructions of the physician, are as follows: (1) 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 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
investigational product, (2) oral contraceptive, either combined or progestogen alone, (3) 
injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous 
contraceptive patches, intrauterine device (IUD) or intrauterine system (IUS) with a 
documented failure rate of less than 1% per year, (4) 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, (6) double barrier method: 
condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal 
spermicidal agent (foam/gel/film/cream/suppository) Female subjects who are lactating 
should discontinue nursing prior to the first dose of study drug and should refrain from 
nursing throughout the treatment period and for 14 days following the last dose of study 
drug.  
 
Adequate organ system function as defined in Table 1 
 
Exclusion Criteria: 
 
Concurrent use of other investigational agents 
 
Known history of allergic reactions to pazopanib or other VEGF-TKIs 
 
Presence of serious or uncontrolled infection 
 
Prior malignancy. (Note: Subjects who have had another malignancy and have been 
disease-free for 3 years, or subjects with a history of completely resected non-
melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. 
 
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.  
 
Clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding including, but not limited to (1) active peptic ulcer disease, (2) 
known intraluminal metastatic lesion/s with risk of bleeding, (3) inflammatory bowel 
disease (e.g. ulcerative colitis, Crohn’s disease), (4) other gastrointestinal conditions with 
increased risk of perforation, or (5) history of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment. 
 
Clinically significant gastrointestinal abnormalities that may affect absorption of 
investigational product including, but not limited to (1) malabsorption syndrome or (2) 
major resection of the stomach or small bowel. 
 
Presence of uncontrolled infection.  
 
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula 
 
History of any one or more of the following cardiovascular conditions within the past 6 
months: (1) cardiac angioplasty or stenting, (2) myocardial infarction, (3) unstable 
angina, (4) coronary artery bypass graft surgery, (5) symptomatic peripheral vascular 
disease, or (6) Class III or IV congestive heart failure, as defined by the New York Heart 
Association (NYHA)  
 
Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg 
or diastolic blood pressure (DBP) of ≥ 90mmHg]. (Note: Note: Initiation or adjustment of 
antihypertensive medication(s) is permitted prior to study entry.  BP must be re-assessed 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
on two occasions that are separated by a minimum of 1 hour; on each of these occasions, 
the mean (of 3 readings) SBP / DBP values from each BP assessment must be <140/90 
mmHg in order for a subject to be eligible for the study. 
 
History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary 
embolism or untreated deep venous thrombosis (DVT) within the past 6 months. (Note: 
Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents 
for at least 6 weeks are eligible) 
 
Prior major surgery or trauma within 28 days prior to first dose of study drug and/or 
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter 
placement not considered to be major). 
 
Evidence of active bleeding or bleeding diathesis.  
 
Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels 
 
Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of 
study drug.  
 
Any serious and/or unstable pre-existing medical, psychiatric, or other condition that 
could interfere with subject’s safety, provision of informed consent, or compliance to 
study procedures.  
 
Unable or unwilling to discontinue use of prohibited medications list as specified in the 
full protocol for at least 14 days or five half-lives of a drug (whichever is longer) prior to 
the first dose of study drug and for the duration of the study. 
 
Treatment with any of the following anti-cancer therapies: (1) radiation therapy, surgery 
or tumor embolization within 14 days prior to the first dose of pazoapnib OR (2) 
chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal 
therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first 
dose of pazopanib 
 
Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is 
progressing in severity, except alopecia. 
 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is 
PROHIBITED beginning 14 days prior to the first dose of study drug until 
discontinuation from the study.  Strong CYP3A4 inhibitors include (but are not limited 
to): certain antibiotics (including clarithromycin, telithromycin, and troleandomycin), 
certain HIV protease inhibitors (including ritonavir, indinavir, saquinavir, nelfinavir, 
amprenavir, and lopinavir), certain ntifungals (including itraconzaole, ketoconazole, 
voriconazole, and fluconazole) and certain antidepressants (including nefazodone). 
 
Investigational Product Dosage and Administration: 
Pazopanib 200 mg 4 tablets oral daily 
Clinical Observations and Tests to be Performed: 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Assessments within 28 Days of the First Dose Medical history:  
 RCC-specific history including: date of diagnosis, primary tumor type with 
histology/cytology determination, current stage of cancer, prior systemic treatment(s) 
for RCC, ongoing toxicity related to prior treatment(s); and history of other 
malignancies 
  Prior surgery and/or radiotherapy (date, organ/anatomic region(s) of surgery and/or 
radiotherapy must be documented), other significant medical and surgical histories 
within the past 6 months.  
 
Baseline bone scan for tumor assessment 
 
Baseline disease assessments with CT of the chest, abdomen or pelvis 
 
MRI or CT of the brain within 2 weeks of first dose if clinically indicated or if the subject 
has a history of CNS metastases 
Assessments within 7 Days of the First Dose  
 
Physical examinations: height (only recorded at baseline) and body weight and current 
medical conditions. 
 
Vital signs: body temperature, blood pressure and heart rate. Note: If a subject presents with 
poorly controlled hypertension, defined as SBP 140mmHg or DBP 90mmHg, 
antihypertensive medication(s) should be initiated or adjusted with a goal to control the 
blood pressure to <140/90 mmHg.  
 
ECOG PS 
 
Clinical laboratory assessments, listed in 6.2 
 
12-lead ECG with QTc measurement 
 
Baseline IL-6 and E-selectin assessment 
 
Serum pregnancy test for women of childbearing potential.  
 
Pre-dose Assessments on Day 1 
 
Physical examination: to identify any changes in the subject’s mental and medical conditions 
since baseline assessment that would make him/her ineligible for the study.  
 
Blood pressure measurements: subjects must have a blood pressure reading of 
<140/90mmHg to be eligible. If anti-hypertensives were initiated and/or dosing has been 
adjusted during the Baseline Period, the blood pressure must be re-assessed on two 
occasions consecutively that are separated by a minimum of 1 hour. The mean SBP/DBP 
values from both blood pressure assessments must be <140/90mmHg in order for a subject 
to be eligible. These two assessments must also be the most recent ones prior to 
randomization (the blood pressure values from the later assessment will be used as the 
subject’s baseline blood pressure values). All the blood pressure readings must be recorded 
on the appropriate eCRF.  
 
ECOG PS: Any changes since baseline assessment should be recorded in the eCRF. Subjects 
having deterioration of ECOG PS to > 1 will be excluded from the study.  
 
Record all the medication(s) received within 2 weeks prior to the first dose of study 
medication and indicate if the medication is continuing. 
 
Obtain archived tumor tissue samples for biomarker assessments (if available).  
 
 
Assessments on Study 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
Physical examination: to identify any changes in the subject’s mental and medical conditions 
since baseline assessment that would make him/her ineligible for the study. This will occur 
at C1D15, C2D1 and monthly thereafter (1 cycle = 28 days). 
 
ECOG PS: Any changes since baseline assessment should be recorded in the eCRF. Subjects 
having deterioration of ECOG PS to 2 will be excluded from the study. This will occur at 
C1D15, C2D1 and monthly thereafter (1 cycle = 28 days). 
 
Obtain blood sample for IL-6 and E-selectin measurement.  This will occur monthly while 
patients are on study.  
 
Tumor assessments will be performed every 8 weeks (+/- 1 week) from randomization until 
the start of another anticancer therapy. A partial or complete response warrants confirmation 
no sooner than 4 weeks and no later than 6 weeks after its initial observation.  This 
confirmatory scan is considered outside of standard of care, and will be funded by the 
sponsor.  
 
Post-Study Assessments 
 
Any research participant who is discontinued from study treatment for any reason other than 
PD will continue to have tumor assessments every 8 weeks (+/- 1 week) until the patient 
starts another anticancer therapy. The investigator or his/her designee will continue 
collecting information on the initiation of anticancer therapies until the date of data cutoff 
for the final analysis.  All new anticancer therapy therapies after the last dose of treatment 
will be recorded on the appropriate CRF.  
 
All research participants will be followed for survival every 6 months. 
 
Clinical Laboratory Assessments 
 
All clinical laboratory assessments will be performed at City of Hope.  Laboratory tests should be 
performed at baseline, at specified visits during the study, and at the follow-up visit, all as 
indicated in the Time and Events Table(s).  Laboratory assessments may be performed within 3 
days before the actual visit to allow flexibility in scheduling.  Assessments may be performed 
more frequently if clinically indicated.   
 
All laboratory tests with values that become clinically abnormal while the subject is participating 
in the study or within 28 days after the last dose of study drug should be repeated at the PI’s 
discretion until the values return to normal or baseline.  
 
Results for all unscheduled clinical laboratory assessments (i.e., hematology, TSH/T4, 
coagulation parameters) should be recorded on an unscheduled laboratory form in the eCRF. 
 
Hematology and Clinical Chemistry 
 
Appendix A shows the hematology and clinical chemistry laboratory parameters that should be 
reported.  Assays for hematology and clinical chemistry should be performed at baseline, every 4 
weeks until 6 months, and then every 8 weeks thereafter.  Hepatic assays should be performed at 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
baseline, 2, 4, and 8 weeks, followed by every 4 weeks until 6 months, and then every 8 weeks 
thereafter. 
 
Liver Function Tests 
 
When a separate liver function test (LFT) panel is conducted, this panel should include the 
following: ALT, AST, alkaline phosphatase, GGT, and total bilirubin.  A direct bilirubin level 
should be obtained if the total bilirubin level is greater than 1.5 x upper limit of normal (ULN).  
Liver chemistry threshold stopping criteria and dose modification guidelines have been designed 
to ensure subject safety.   
 
Evaluation of Proteinuria 
 
Proteinuria will be evaluated using the urine protein to creatinine ratio (UPC; see Appendix C).  
UPC will be determined at times specified in the Time and Events Table.  If UPC  3, then the 
dose modification table guidelines should be followed.  
 
Coagulation Tests 
 
Coagulation tests should be performed as specified in the Time and Events Table and also in 
response to an AE/SAE as clinically indicated.  Coagulation tests include activated partial 
thromboplastin time (aPTT) and either prothrombin time (PT) or international normalized ratio 
(INR). 
 
Lipid Tests 
 
Lipid tests include cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), 
and triglycerides.  These tests should be performed as specified in the Time and Events Table.  
Additional testing may be performed if clinically indicated.  In such a case, the subject should be 
in a fasting state. 
 
Thyroid Function Tests 
 
Thyroid function tests to assess thyroid stimulating hormone (TSH) and thyroxine (free T4) 
should be performed as specified in the Time and Events Table.  Unscheduled thyroid function 
tests (TSH and free T4) may be performed if clinically indicated (e.g., if a subject develops signs 
and symptoms suggestive of hypothyroidism). 
 
Statistical Considerations: 
The primary endpoint is the confirmed response rate (CR+PR), as determined by the RECIST 1.1 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
criteria.  We will employ the two stage MinMax design suggested by Simon.  
 
Prior data indicates that an overall RR of 20% can be obtained with pazopanib therapy.  For 
patients with mRCC eligible for this 3rd line study, a response rate of 20% would represent a 
significant improvement over current approaches (3rd line therapy with the Akt inhibitor 
perifosine, for instance, yielded a 7% response rate) and would further indicate that the activity of 
pazopanib is maintained through multiple prior lines of therapy in selected patients.   
 
Prior studies suggest that a response rate between 5-10% would not be an improvement over 
current approaches.  As a result, we have set a discouraging response rate at 8%, and an 
encouraging response rate at 23%. Initially, we will accrue 14 patients. If there is at least 1 
responder, accrual will continue to 28 patients. If 5 or more responders (18%) are observed, 
pazopanib will be declared promising for future studies, assuming toxicity and survival endpoints 
are also within acceptable limits. This Simon’s MiniMax two-stage design has a type I error of 
10% (probability of declaring an agent with a true 8% response rate as promising), and a power of 
80% (probability of not declaring an agent promising with a true 23% response rate is 10%). All 
eligible patients treated will be included in the calculation of response rate.  Any patients with an 
unknown response rate will be included as a non-responder. 
 
This design has 31% chance of stopping at the first stage if true response rate is 8%. 
 
Toxicity will be monitored on an ongoing basis. If the number of unacceptable toxicities exceeds 
1 in the first 3, or exceeds 2 in the first 6 or more than 25% thereafter, the study will hold accrual 
for an amendment regarding treatment modifications or study termination. Toxicity will be 
graded and recorded for each patient in this population according to CTCAE 4.0.   
Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity, 
and we will also compare PFS on this study to time to progression on the previous line of therapy.  
Additional secondary endpoints relate to biological correlates, including E-Selection, IL-6, the 
pre-metastatic niche density, pSTAT3, and baseline HGF.  Because the nature of these secondary 
endpoints is exploratory, we will not consider the issue of multiple comparisons and the 
according adjustment of p-values. 
Univariate or multivariate Cox proportional hazards model will be invoked to assess the 
association of these biological correlatives and both PFS and OS.  
In addition, a t-test will be conducted to determine if there is an association between E-selectin, 
IL-6 and the pre-metastatic niche density. 
 


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Date Prepared: 4.23.10 
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Table of Contents 
 
SECTION 
PAGE 
1.0 
Goals and Objectives (Scientific Aims) ............................................................................ 17 
1.1 
Primary Objectives 
1.2 
Secondary Objectives 
2.0 
Background ....................................................................................................................... 17 
2.1 
Current Standards: 1st-Line Therapy for mRCC 
2.2 
Current Standards: 2nd-Line Therapy for mRCC 
2.3 
Beyond 2nd-Line Therapy for mRCC 
2.4 
Rationale for Pazopanib as 3rd-Line Therapy 
2.5 
Cytokine and Angiogenic Factors (CAFs): Potential Predictors of Response? 
2.6 
IL-6/STAT3: Role in RCC Tumorigenesis 
2.7 
Other Biomarkers of Pazopanib Response Identified in the Randomized Discontinuation 
Study 
2.8 
Unifying E-Selectin and IL-6: The Pre-Metastatic Niche 
3.0 
Patient Eligibility .............................................................................................................. 20 
3.1 
Inclusion Criteria 
3.2 
Exclusion Criteria 
3.3 
Inclusion of Women and Minorities 
4.0 
Screening and Registration Procedures............................................................................. 24 
4.1 
Screening Procedures 
5.0 
Informed Consent ............................................................................................................. 26 
5.1 
Registration Requirements/Process 
6.0 
Treatment Program ........................................................................................................... 27 
6.1 
Treatment Overview 
6.2 
Laboratory Studies 
6.3 
Studies Obtained During the Trial 
6.4 
Post-Study Assessments 
6.5 
Criteria for Removal from Study 
6.6 
Supportive Care and Other Concomitant Therapy 


. 
12 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
7.0 
Dose Delays/Modifications for Adverse Events ............................................................... 32 
7.1 
Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities 
7.2 
Dose Interruptions/Modifications for Hepatotoxicity 
8.0 
Data Safety and Monitoring and Adverse Event Reporting.............................................. 38 
8.1 
Data and Safety Monitoring 
C) 
Adverse Events 
8.2 
Adverse Event Monitoring and Reporting 
8.3 
Regulatory Reporting Requirements for Agent(s) under an IND 
9.0 
Agent Information ............................................................................................................. 41 
9.1 
Pazopanib (Votrient; GW786034) 
9.2 
Agent Ordering 
10.0 
Correlative/Special Studies ............................................................................................... 45 
10.1 
Laboratory Correlative Studies 
11.0 
Study Calendar .................................................................................................................. 47 
12.0 
Evaluation Criteria/Measurement of Effect ...................................................................... 49 
12.1 
12.2 
Best Response 
13.0 
Data Reporting/Protocol Deviations ................................................................................. 51 
13.1 
Data Reporting 
13.2 
Protocol Deviations 
14.0 
Statistical Considerations .................................................................................................. 52 
14.1 
Study Design 
14.2 
Sample Size Accrual Rate 
15.0 
Human Subject Issues ....................................................................................................... 54 
15.1 
Institutional Review Board 
15.2 
Recruitment of Subjects 
15.3 
Advertisements 
15.4 
Study location and Performance Sites 
15.5 
Confidentiality 
15.6 
Financial Obligations and Compensation 
15.7 
Informed Consent Processes 
16.0 
References ......................................................................................................................... 56 


. 
13 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
17.0 
Appendix I:  Urine Protein Creatinine Ratio (UPC) ......................................................... 59 
18.0 
Patient Monitoring and Management Guidelines for Certain Treatment Emergent Adverse Events 
of Interest (AEOIs) 
18.1 
Diarrhea ............................................................................................................... 64 
Appendix 1: Supportive Care Guidelines 
 


. 
14 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
 


(26.4 mos 
—; however, 
. 
15 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
1.0 
Goals and Objectives (Scientific Aims) 
1.1 
Primary Objectives 
1.1.1 
To determine the RR associated with pazopanib as 3rd-line therapy in mRCC patients who 
have failed therapy with a distinct VEGF-TKI 
1.2 
Secondary Objectives 
1.2.1 
To determine if baseline HGF, E-selectin and IL-6 are associated with PFS 
1.2.2 
To determine if pre-metastatic niche density in regional LNs is associated with PFS 
1.2.3 
To determine an association between E-selectin, IL-6 and pre-metastatic niche density 
1.2.4 
To evaluate the prognostic effect of pre-metastatic niches as an independent factor in 
time to first relapse 
1.2.5 
To determine if pSTAT3 in tumor tissue is associated with PFS 
1.2.6 
To describe the toxicity associated with pazopanib in this patient population 
1.2.7 
To evaluate PFS and OS  
1.2.8 
To compare, within patient, time to tumor progression of 2nd-line therapy with time to 
tumor progression on pazopanib as 3rd-line therapy 
2.0 
Background 
2.1 
Current Standards: 1st-Line Therapy for mRCC 
Today, the oncologist is armed with a multitude of active agents for the therapy of metastatic renal cell 
carcinoma (mRCC).  An enhanced understanding of pathways related to RCC tumorigenesis has led to the 
development of clinically validated targeted therapies.  At present, these agents can be broadly divided 
into two classes, inhibitors of vascular-endothelial growth factor (VEGF)-mediated signaling and 
inhibitors of the mammalian target of rapamycin (mTOR).  Substantial evidence exists to support use of 
the former class of agents as 1st-line therapy for mRCC.  VEGF-mediated signaling may be abrogated by 
inhibition of the intracellular tyrosine kinase domain of the VEGF-receptor with agents such as sunitinib, 
or by neutralization of circulating VEGF with agents such as bevacizumab.  In a randomized, phase III 
trial including 750 previously untreated patients with metastatic clear cell RCC, sunitinib was shown to 
improve overall survival (OS) as compared to IFN-
vs 21.8 mos, P=0.051).7  With censoring 
of patients who crossed over to sunitinib therapy, this difference was even more pronounced (26.4 mos vs 
20.0 months, P=0.036).  Data for bevacizumab derived from two phase III trials (AVOREN and CALGB 
90206) suggests substantial activity as first-line therapy for mRCC in combination with IFN-
 
survival data with bevacizumab fails to surpass the “highwater mark” achieved with sunitinib.8-10   
Within the past several months, a distinct VEGF-TKI has gained FDA approval for the treatment of 
mRCC.  The novel TKI pazopanib demonstrates strong affinity for VEGFR-2 (inhibiting the moiety at 
serum concentrations of 17.5 mcg/mL), and was recently examined in a pivotal phase III trial.11  In this 
study, 400 patients with clear cell mRCC and either no prior therapy or 1 prior cytokine-based therapy 
were randomized in a 2:1 fashion to receive pazopanib at 800 mg oral daily or placebo.  The study met its 
prior endpoint of improved PFS (9.2 vs 4.2 mos, P<0.0000001), and showed an even more impressive 
difference in PFS amongst treatment-naïve patients enrolled (11.1 vs 2.8 mos, P<0.0000001).  The agent 


. 
16 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
was well tolerated, with diarrhea, hypertension and hair color change representing the most frequent 
treatment-related adverse events.  Already, the agent has been allotted a category 1 recommendation 
(along with bevacizumab/IFN and sunitinib) in the National Comprehensive Cancer Network (NCCN) 
Clinical Practice Guidelines.12 
2.2 
Current Standards: 2nd-Line Therapy for mRCC 
Subsequent to failure of a VEGF-TKI, there is a role for therapy with the mTOR inhibitor everolimus.  A 
phase III experience with this agent has been reported, randomizing 416 patients who had previously 
progressed on VEGFR-tyrosine kinase inhibitor (TKI) therapy to either everolimus or placebo.5  Results 
from a second interim analysis of this trial demonstrate a substantial increase in PFS with everolimus 
therapy (4.9 mos v 1.9 mos, P<0.001). OS associated with everolimus therapy was 14.8 months; taken 
together with data from the phase III experience with sunitinib, OS for patients with advanced RCC can 
now be projected at upwards of 41 mos with initial sunitinib therapy followed by everolimus.   
2.3 
Beyond 2nd-Line Therapy for mRCC 
Trials are currently ongoing to determine the optimal sequencing of therapy in mRCC.  As one example, 
RECORD-3 will compare 1st-line therapy with either sunitinib or everolimus, followed by crossover to 
the other agent at the time of progression.13  Though such efforts will optimize 1st- and 2nd-line therapy, 
there is currently a need for trials exploring approaches beyond failure of antiangiogenesis and mTOR 
inhibitors in mRCC.  At present, observational studies suggest that oncologists frequently re-challenge 
patients with a VEGF-TKI after initial failure.14 Although somewhat counter-intuitive, data from these 
series suggest that (in the 2nd line setting) patients may have a higher response rate to re-challenge with a 
VEGF-TKI as compared to an initial challenge with an mTOR inhibitor.  A retrospective analysis of 
patients given consecutive treatment with sorafenib followed by sunitinib demonstrated response rates of 
up to 17% with sunitinib therapy.15  Impressively, in a similar analysis of patients receiving a reversed 
schedule of these agents, one patient treated with sunitinib followed by sorafenib exhibited a complete 
response.   
2.4 
Rationale for Pazopanib as 3rd-Line Therapy 
Though the approach of re-challenging mRCC patients with VEGF-TKI therapy appears to be reasonably 
efficacious in retrospective series, clearly this strategy warrants further prospective validation (the 
ongoing AXIS and SWITCH studies may define the feasibility of this approach).16-18 Pazopanib has 
shown activity in the setting of bevacizumab- and cytokine- refractory patients.1,2    Furthermore, there 
may be preclinical rationale to challenge patients with a structurally distinct VEGF-TKI.  Molecular 
aberrations in the receptor tyrosine kinase (RTK) targeted by VEGF-TKIs may confer a relative resistance 
to specific agents – thus, re-challenging with agents such as sunitinib is presumably less efficacious.3,4  
Ongoing studies have assessed inhibition of distinct molecular pathways; however, response rates using 
this approach (i.e., with mTOR inhibitors or perifosine) have been modest at best.5,6  3rd- line therapy 
represents an area of need in metastatic renal cell carcinoma – herein, we propose use of pazopanib in this 
setting.   
2.5 
Cytokine and Angiogenic Factors (CAFs): Potential Predictors of Response? 
Responses observed with pazopanib therapy may be augmented by appropriate selection of patients with 
sensitivity to the agent.  Data from a randomized discontinuation trial of pazopanib have recently been 
reported.19  In this study, 225 patients with mRCC (both treatment-naïve and refractory) were treated with 
12 weeks of pazopanib at the approved dose of 800 mg oral daily.  Patients were continued on therapy 
thereafter if a CR or PR was obtained, and discontinued if PD was observed.  Initially, patients with SD 


. 
17 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
were randomized to either pazopanib or placebo; however, in light of robust clinical activity, this 
randomization was ultimately halted. On independent review, pazopanib was associated with a clinical 
benefit rate (CBR; CBR = CR + PR) of 34.7%, and a median OS of 11.9 mos.    
Correlative analyses to accompany this study included comprehensive assessment of CAFs obtained at 
baseline and during therapy.20  Elevated levels of HGF, IL-6 and IL-8 were significantly correlated with 
less tumor shrinkage in patients treated with pazopanib.  Lower IL-6 baseline levels of IL-6 were 
associated with a profound improvement in PFS (77.7 v 28.6 wks).  Notably, other studies have suggested 
the predictive and prognostic relevance of IL-6 in the setting of distinct therapies.21,22 While the data 
presented herein is encouraging, prospective validation is necessary to determine the true clinical utility 
of IL-6 as a predictive marker with pazopanib therapy.   
2.6 
IL-6/STAT3: Role in RCC Tumorigenesis 
IL-6 may play a role in RCC tumorigenesis through activation of STAT3-related pathways.23  Seminal 
observations by Yu and Figlin indicate that inhibition of STAT3 activation by VEGF-TKIs correlates 
with their apoptotic effect.24  This may occur through a multitude of mechanisms, including immune 
modulation.  In vivo experiments suggest that VEGF-TKI therapy leads to decreased STAT3 activation in 
tumor-associated myeloid-derived suppressor cells (MDSCs), and further decreases the quantity of tumor 
MDSCs and tumor T-regulatory cells. 
In the current proposal, the role of IL-6 as a predictive marker is examined in the context of 3rd-line 
therapy with pazopanib.  Given that 3rd-line therapy for mRCC represents an area of need and that the 
majority of patients will have already encountered previous treatment with a VEGF-TKI, use of relevant 
biomarkers to select appropriate patients is paramount.  Correlative studies assessing the role of STAT3 
may validate the purported role of IL-6 in RCC tumorgenesis.   
2.7 
Other Biomarkers of Pazopanib Response Identified in the Randomized 
Discontinuation Study 
Outside of IL-6 level, data from the randomized discontinuation study of pazopanib previously cited 
provided hypothesis-generating data regarding the prognostic role of E-selectin. Specifically, using a two-
factor signature with E-selectin and IL-6, selected groups with significantly different PFS could be 
identified.  Patients with low IL-6 and high E-selectin had superior PFS (median: 100 wks) in comparison 
to those patients with high IL-6 and low E-selectin (median: 28.3 wks).  An intermediate group of patients 
comprised of patients with high or low levels of both IL-6 and E-selectin had a median PFS of 53.0 wks.  
2.8 
Unifying E-Selectin and IL-6: The Pre-Metastatic Niche 
A “seed-and-soil” hypothesis has been en vogue as an explanation for metastatic progression in multiple 
malignancies.25  Recently, strong preclinical rationale has emerged for this hypothesis, suggesting that 
bone marrow derived cells (BMDCs) are stimulated to migrate to ‘pre-metastatic’ sites by various 
inflammatory cytokines, including IL-6.26,27  As outline on the following page, the pre-metastatic niche is 
cultivated into an area conducive to tumor migration through various molecular mediators which modify 
the extracellular matrix.  Strong evidence implicates the role of E-selectin, VEGFA and LOX, amongst 
other moieties, in this process.28,29   
Given the role of both IL-6 and E-selectin in this model, the currently proposed study offers a prime 
opportunity to explore whether the pre-metastatic niche can explain their prognostic role.   In the setting 
of mRCC, the nice can be assessed in regional lymph nodes (LNs) harvested at the time of nephrectomy.  


. 
18 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Pre-metastatic niche density (characterized as the number of clusters of VEGFR1+VLA-4+ cells per x 100 
objective field) can be used as a quantitative assessment. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. 
3.0 
Patient Eligibility 
3.1 
Inclusion Criteria  
3.1.1 
Histologically confirmed diagnosis of metastatic clear cell RCC  
3.1.2 
At least one measurable lesion at baseline as per RECIST 1.1 criteria.  If skin lesions are 
reported as target lesions, they must be documented (at baseline and at every physical 
exam) using color photography and a measuring device (such as a caliper) in clear focus 
to allow the size of the lesion to be determined from the photograph 
3.1.3 
1 prior VEGF-TKI required 
3.1.4 
1 other prior systemic therapy allowed 
3.1.5 
ECOG PS 0-1 
3.1.6 
Resolution of grade ≥ 2 toxicity from prior therapy 
3.1.7 
Normal hematologic labs and serum chemistries (see table 1, under 3.1.12 for definition 
of normal)  
3.1.8 
Subjects must provide written informed consent prior to performance of study-specific 
procedures or assessments, and must be willing to comply with treatment and follow-up. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided these procedures are conducted as specified 
in the protocol.  
3.1.9 
Age ≥ 18 years or legal age of consent if greater than 18 years 
3.1.10 A female is eligible to enter and participate in this study if she is of non-child bearing 
potential (i.e., physiologically incapable of becoming pregnant), including any female 
who has had (1) a hysterectomy, (2) a bilateral oophorectomy (ovariectomy), (3) a 
bilateral tubal ligation, or (4) 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.   
3.1.11 Patients with childbearing potential, including any female who has had a negative serum 
pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as 
close to the first dose as possible, and agrees to use adequate contraception.  GSK 
acceptable contraceptive methods, when used consistently and in accordance with both 
the product label and the instructions of the physician, are as follows: (1) complete 


> 
> 
> 
< 
< 
< 
< 
< 
> 
≥ 
. 
19 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
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, (2) oral contraceptive, either combined or progestogen alone, (3) 
injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous 
contraceptive patches, intrauterine device (IUD) or intrauterine system (IUS) with a 
documented failure rate of less than 1% per year, (4) 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, (6) double barrier method: 
condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal 
spermicidal agent (foam/gel/film/cream/suppository) Female subjects who are lactating 
should discontinue nursing prior to the first dose of study drug and should refrain from 
nursing throughout the treatment period and for 14 days following the last dose of study 
drug. 
3.1.12 Adequate organ system function as defined in Table 1 
Table 1. Definitions for Adequate Organ Function 
 
System 
Laboratory Values 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobin 
9 g/dL (5.6 mmol/L) 
 
Platelets 
100 X 109/L 
Prothrombin time (PT) or 
international normalized ratio 
(INR)a 
1.2 X ULN 
Activated partial thromboplastin 
time (aPTT) 
1.2 X ULN 
Total bilirubin 
1.5 X ULN 
Alanine amino transferase (ALT) 
and Aspartate aminotransferase 
(AST)b 
2.5 X ULN 
Serum creatinine 
2.0 mg/dL (133 µmol/L) 
Or, if >2.0 mg/dL: Calculated 
creatinine clearance (ClCR) by 
Cockroft-Gault formula 
30 mL/min 
Urine Protein to Creatinine Ratio 
(UPC; appropriate appendix)c 
<1 
  
a. 
Subjects receiving anticoagulant therapy are eligible if their 
INR is stable and within the recommended range for the desired 
level of anticoagulation. 
b. 
Concomitant elevations in bilirubin and AST/ALT above 1.0 x 
ULN (upper limit of normal) are not permitted. 
c. 
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. 


. 
20 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
 
 
3.2 
Exclusion Criteria 
3.2.1 
Concurrent use of other investigational agents 
3.2.2 
Known history of allergic reactions to pazopanib or other VEGF-TKIs 
3.2.3 
Presence of serious or uncontrolled infection 
3.2.4 
Prior malignancy. (Note: Subjects who have had another malignancy and have been 
disease-free for 3 years, or subjects with a history of completely resected non-
melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. 
3.2.5 
History or clinical evidence of central nervous system (CNS) metastases or 
leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS 
metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure 
medication for 6 months prior to first dose of study drug.  Screening with CNS imaging 
studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required 
only if clinically indicated or if the subject has a history of CNS metastases.  
3.2.6 
Clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding including, but not limited to (1) active peptic ulcer disease, (2) 
known intraluminal metastatic lesion/s with risk of bleeding, (3) inflammatory bowel 
disease (e.g. ulcerative colitis, Crohn’s disease), (4) other gastrointestinal conditions with 
increased risk of perforation, or (5) history of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment. 
3.2.7 
Clinically significant gastrointestinal abnormalities that may affect absorption of 
investigational product including, but not limited to (1) malabsorption syndrome or (2) 
major resection of the stomach or small bowel. 
3.2.8 
Corrected QT interval (QTc) > 480 msecs using Bazett’s formula 
3.2.9 
History of any one or more of the following cardiovascular conditions within the past 6 
months: (1) cardiac angioplasty or stenting, (2) myocardial infarction, (3) unstable 
angina, (4) coronary artery bypass graft surgery, (5) symptomatic peripheral vascular 
disease, or (6) Class III or IV congestive heart failure, as defined by the New York Heart 
Association (NYHA)  
3.2.10 Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg 
or diastolic blood pressure (DBP) of ≥ 90mmHg]. (Note: Note: Initiation or adjustment of 
antihypertensive medication(s) is permitted prior to study entry.  BP must be re-assessed 
on two occasions that are separated by a minimum of 1 hour; on each of these occasions, 
the mean (of 3 readings) SBP / DBP values from each BP assessment must be <140/90 
mmHg in order for a subject to be eligible for the study. 
3.2.11 History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary 
embolism or untreated deep venous thrombosis (DVT) within the past 6 months. (Note: 


. 
21 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents 
for at least 6 weeks are eligible) 
3.2.12 Prior major surgery or trauma within 28 days prior to first dose of study drug and/or 
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter 
placement not considered to be major). 
3.2.13 Evidence of active bleeding or bleeding diathesis.  
3.2.14 Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels 
3.2.15 Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks prior to the first 
dose of study drug.  
3.2.16 Any serious and/or unstable pre-existing medical, psychiatric, or other condition that 
could interfere with subject’s safety, provision of informed consent, or compliance to 
study procedures.  
3.2.17 Unable or unwilling to discontinue use of prohibited medications list as specified in the 
full protocol for at least 14 days of a drug prior to the first dose of study drug and for the 
duration of the study. 
3.2.18 Treatment with any of the following anti-cancer therapies: (1) radiation therapy, surgery 
or tumor embolization within 14 days prior to the first dose of pazoapnib OR (2) 
chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal 
therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first 
dose of pazopanib 
3.2.19 Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is 
progressing in severity, except alopecia. 
3.2.20 Non-Compliance: Patients, who in the opinion of the investigator, may not be able to 
comply with the safety monitoring requirements of the study. 
3.2.21 Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is 
PROHIBITED beginning 14 days prior to the first dose of study drug until 
discontinuation from the study.  Strong CYP3A4 inhibitors include (but are not limited 
to): certain antibiotics (including clarithromycin, telithromycin, and troleandomycin), 
certain HIV protease inhibitors (including ritonavir, indinavir, saquinavir, nelfinavir, 
amprenavir, and lopinavir), certain ntifungals (including itraconzaole, ketoconazole, 
voriconazole, and fluconazole) and certain antidepressants (including nefazodone). 
3.3 
Inclusion of Women and Minorities 
The study is open to all participants regardless of gender or ethnicity.  Efforts will be made to extend the 
accrual to a representative population, but in this trial which will accrue approximately 28 patients, a 
balance must be struck between patient safety considerations and limitations on the number of individuals 
exposed to potentially toxic or ineffective treatments on the one hand and the need to explore gender, 
racial, and ethnic aspects of clinical research on the other.  If differences in outcome that correlate to 
gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 


> 
> 
. 
22 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
4.0 
Screening and Registration Procedures 
4.1 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Documentation of the informed consent for screening will 
be maintained in the patient’s research chart and medical record. Studies or procedures that were 
performed for clinical indications (not exclusively to determine study eligibility) and within the screening 
window,  may be used for baseline values even if the studies were done before informed consent was 
obtained. 
4.1.1 
Assessments within 28 days of the first dose 
4.1.1.1 
Medical history:  
4.1.1.2 
Renal cell carcinoma specific history including: date of diagnosis, primary tumor 
type with histology/cytology determination, current stage of cancer, prior systemic 
treatment(s) for RCC, ongoing toxicity related to prior treatment(s); and history of 
other malignancies 
4.1.1.3 
Prior surgery and/or radiotherapy (date, organ/anatomic region(s) of surgery and/or 
radiotherapy must be documented), other significant medical and surgical histories 
within the past 6 months. 
4.1.1.4 
Baseline bone scan for tumor assessment 
4.1.1.5 
Baseline disease assessments of chest, abdomen and pelvis using CT or MRI 
4.1.1.6 
 MRI or CT of the brain within 2 weeks of first dose if clinically indicated or if the 
subject has a history of CNS metastases 
 
4.1.2 
Assessments within 7 days of the first dose 
4.1.2.1 
Physical examinations: height (only recorded at baseline) and body weight and 
current medical conditions. 
4.1.2.2 
Vital signs: body temperature, blood pressure and heart rate. 
Note: If a subject presents with poorly controlled hypertension, defined as SBP 140mmHg or DBP 
90mmHg, antihypertensive medication(s) should be initiated or adjusted with a goal to control the blood 
pressure to <140/90 mmHg.  
4.1.2.3 
ECOG PS 
4.1.2.4 
Clinical laboratory assessments.  
4.1.2.5 
12-lead ECG with QTc measurement 
4.1.2.6 
Baseline IL-6 and E-selectin assessment 
4.1.2.7 
Serum pregnancy test for women of childbearing potential.  
 
 


> 
• 
• 
• 
. 
23 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
4.1.3 
Pre-dose Assessments on Day 1 
4.1.3.1 
Physical examination: to identify any changes in the subject’s mental and medical 
conditions since baseline assessment that would make him/her ineligible for the 
study.  
4.1.3.2 
Blood pressure measurements: subjects must have a blood pressure reading of 
<140/90mmHg to be eligible.  
4.1.3.3 
ECOG PS: Any changes since baseline assessment should be recorded in the eCRF. 
Subjects having deterioration of ECOG PS to 2 will be excluded from the study 
4.1.3.4 
Review results of all the other baseline assessments to determine the subject’s 
eligibility for the study. Any screening laboratory results outside the normal range 
will be repeated (prior to the first dose) at the discretion of the Investigator. All 
laboratory results must be within the values outlined in the Inclusion Criteria 
before the first dose of study drug. 
4.1.3.5 
Record all the medication(s) received within 2 weeks prior to the first dose of study 
medication and indicate if the medication is continuing. 
4.1.3.6 
Obtain archived tumor tissue samples for biomarker assessments (if available).  
4.1.3.7 
Obtain a blood sample for biomarker research. It is preferable to collect the sample 
on the first day of dosing but the sample may be collected at any time after first 
dose of investigational product. Note: a signed written informed consent for 
participating biomarker research must be obtained before collecting the blood 
sample for biomarker analysis. 
5.0 
Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
patient and a signed informed consent will be obtained. 
5.1 
Registration Requirements/Process 
Once the signed informed consent has been obtained, all pretreatment evaluations have been performed, 
and patient’s eligibility has been confirmed by the PI or collaborating investigator, a patient will be 
entered on study.   
To register a patient, the research nurse or data manager must complete the eligibility/registration form 
and contact the PI, FAX a copy of the completed eligibility checklist, required pre-study tests (laboratory 
and pathology report), signed Informed Consent, signed Patients' Bill of Rights and HIPAA authorization 
form.  
The nurse or data manager must log into the Electronic Data Capture (EDC) system and enter the 
eligibility/registration data for their reserved patient.  The research nurse or data manager at the 
participating site will then: 
 
Verify eligibility 
 
Register the patient on study 
 
Assign a patient accession number 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
Confirm the patient study number and dose level in the EDC system 
6.0 
Treatment Program 
6.1 
Treatment Overview 
Treatment will be administered in an outpatient setting. 
6.1.1 
Schedule 
Pazopanib should be taken at a dose of 800 mg oral daily, with 28 days of therapy constituting 1 cycle.   
6.1.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days (+/- 3 days) if the patient has at least stable disease and continue 
to meet laboratory parameters as defined in the eligibility section. 
6.2 
Laboratory Studies 
A local laboratory is to be used to perform all clinical laboratory assessments.  Laboratory tests should be 
performed at baseline, at specified visits during the study, and at the follow-up visit, all as indicated in the 
Time and Events Table(s).  Laboratory assessments may be performed within 3 days before the actual 
visit to allow flexibility in scheduling.  Assessments may be performed more frequently if clinically 
indicated.   
All laboratory tests with values that become clinically abnormal while the subject is participating in the 
study or within 28 days after the last dose of study drug should be repeated until the values return to 
normal or baseline.  
Results for all unscheduled clinical laboratory assessments (i.e., haematology, TSH/T4, coagulation 
parameters) should be recorded on an unscheduled laboratory form in the eCRF. 
Hematology and Clinical Chemistry 
Appendix A shows the hematology and clinical chemistry laboratory parameters that should be reported.  
Assays for hematology and clinical chemistry should be performed at baseline, every 4 weeks until 6 
months, and then every 8 weeks thereafter.  Hepatic assays should be performed at baseline, 2, 4, and 8 
weeks, followed by every 4 weeks until 6 months, and then every 8 weeks thereafter. 
Estimated creatinine clearance should be calculated using the Cockroft and Gault method.   
Liver Function Tests 
When a separate liver function test (LFT) panel is conducted, this panel should include the following: 
ALT, AST, alkaline phosphatase, GGT, and total bilirubin.  A direct bilirubin level should be obtained if 
the total bilirubin level is greater than 1.5 x upper limit of normal (ULN).  Liver chemistry threshold 
stopping criteria and dose modification guidelines have been designed to ensure subject safety.   


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Evaluation of Proteinuria 
Proteinuria will be evaluated using the urine protein to creatinine ratio (UPC; see Appendix C).  UPC will 
be determined at times specified in the Time and Events Table.  If UPC  3, then the dose modification 
table guidelines should be followed.  
Coagulation Tests 
Coagulation tests should be performed as specified in the Time and Events Table and also in response to 
an AE/SAE as clinically indicated.  Coagulation tests include activated partial thromboplastin time 
(aPTT) and either prothrombin time (PT) or international normalized ratio (INR). 
Lipid Tests 
Lipid tests include cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 
triglycerides.  These tests should be performed as specified in the Time and Events Table.  Additional 
testing may be performed if clinically indicated.  In such a case, the subject should be in a fasting state. 
Thyroid Function Tests 
Thyroid function tests to assess thyroid stimulating hormone (TSH) and thyroxine (free T4) should be 
performed as specified in the Time and Events Table.  Unscheduled thyroid function tests (TSH and free 
T4) may be performed if clinically indicated (e.g., if a subject develops signs and symptoms suggestive of 
hypothyroidism). 
6.3 
Studies Obtained During the Trial 
Physical examination: to identify any changes in the subject’s mental and medical conditions since 
baseline assessment that would make him/her ineligible for the study. This will occur at C1D15, C2D1 
and monthly thereafter (1 cycle = 28 days). 
ECOG PS: Any changes since baseline assessment should be recorded in the eCRF. Subjects having 
deterioration of ECOG PS to 2 will be excluded from the study. This will occur at C1D15, C2D1 and 
monthly thereafter (1 cycle = 28 days). 
Obtain blood sample for IL-6 and E-selectin measurement.  This will occur monthly while patients are on 
study.  
Tumor assessments will be performed every 8 weeks (+/- 1 week) from randomization until the start of 
another anticancer therapy. A partial or complete response warrants confirmation no sooner than 4 weeks 
and no later than 6 weeks after its initial observation. 
6.4 
Post-Study Assessments 
Any patient who is discontinued from study treatment for any reason will continue to have tumor 
assessments every 12 weeks (+/- 1 week) until the patient starts another anticancer therapy. The 
investigator or his/her designee will continue collecting information on the initiation of anticancer 
therapies until the date of data cutoff for the final analysis.  All new anticancer therapy therapies after the 
last dose of treatment will be recorded on the appropriate CRF. 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
6.5 
Criteria for Removal from Study 
Treatment may continue until one of the following criteria applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw from the study,  
 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator, or 
 
Treatment delays of > 2 weeks due to adverse events. 
 
Treatment may be interrupted within a cycle for up to 2 weeks and missed doses should be omitted.  
However, patients will be replaced if they do not receive at least 80% of the planned treatment in the first 
cycle of therapy. 
6.6 
Supportive Care and Other Concomitant Therapy 
6.6.1 
Investigational Therapy 
No other investigational treatment may be given while the patient is on study. 
6.6.2 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to 
be used as necessary. 
6.6.3 
Concomitant Medications 
Permitted Medications 
All subjects will be asked to provide a complete list of prescription and over-the-counter medications that 
have been taken within the previous 4 weeks prior to Screening.  The investigator must be informed as 
soon as possible about any new medication(s) taken from the time of Screening until the completion of 
the post-treatment follow-up visit.   
All concomitant medications taken during the study will be recorded in the case report form (CRF) with 
indication, dose information, and dates of administration. 
Subjects should receive full supportive care during the study, including transfusion of blood and blood 
products, treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, when appropriate.   
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT antagonists) may be 
administered prophylactically in the event of nausea.  Anti-diarrheals, such as loperamide, may be 
administered as needed in the event of diarrhea.  Although acetaminophen at doses of 2 g/day is 
permitted, it should be used with caution in subjects with impaired liver function.   
Permitted Medications – Use with Caution 
Specific recommendations regarding anticoagulants: 


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27 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that pazopanib has 
no effect on the metabolism of S-warfarin.  Hemorrhagic events, however, have been reported in clinical 
studies with pazopanib; therefore, pazopanib should be used with caution in subjects with increased risk 
of severe bleeding or who are receiving concomitant anticoagulant therapy (e.g., warfarin or its 
derivatives, low molecular weight heparin, unfractionated heparin).  Subjects taking concomitant 
anticoagulant therapy should be monitored regularly for changes in relevant coagulation parameters as 
clinically indicated, as well as for any clinical bleeding episodes. 
Specific recommendations regarding hypoglycemic therapy including insulin: 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that there will be no 
clinically relevant pharmacokinetic interaction between pazopanib and hypoglycemic agents.  Transient 
decreases in serum glucose (mainly Grade 1 and 2, rarely Grade 3) have been observed in clinical studies 
with pazopanib.  In addition, decreases in blood sugar have been recently reported in subjects treated with 
another small molecule tyrosine kinase inhibitor, sunitinib (British Journal of Cancer 2008: 99, 1380).  
Such changes may require an adjustment in the dose of hypoglycemic and/or insulin therapy.  Subjects 
should be advised to report symptoms of hypoglycemia (e.g., confusion, visual disturbances, palpitations, 
sweating).  Serum glucose should be tested during treatment with pazopanib as outlined in the protocol 
and as clinically indicated. 
The Effects of Pazopanib on Other Drugs 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CYP2C8, CYP2D6, CYP1A2, 
CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.  Pregnane X receptor transient transfection assay 
suggested some potential for human CYP3A4 induction at high concentrations.  Results from drug-drug 
interaction studies conducted in subjects with cancer suggest that pazopanib is an inhibitor of CYP3A4, 
CYP2C8, and CYP2D6 in vivo, but had no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19 
metabolism.  Therefore, concomitant use of pazopanib with 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.  In 
addition, the potential for drug interaction with such medications, although diminished, may persist after 
the last dose of pazopanib due to its long half-life (i.e., mean 30.9 hours); therefore, continue to exercise 
CAUTION for at least 7 days and up to 15 days after the last dose of pazopanib when administering these 
medications.  These medications include (but are not limited to): 
• 
Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, methylergonovine (potential 
increased risk for developing ergot toxicity that includes severe vasospasm leading to peripheral as 
well as cerebral ischemia) 
• 
Neuroleptics: pimozide (potential increased risk for QT interval prolongation, ventricular arrhythmia, 
and sudden death) 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, propafenone 
(potential increased risk for QT interval prolongation and Torsade de Pointes) 


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28 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
• 
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for nephrotoxicity 
and neurotoxicity) 
• 
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
The Effects of Other Drugs on Pazopanib 
Results from in vitro studies suggest that the oxidative metabolism of pazopanib in human liver 
microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.  
Furthermore, in vitro data suggest that pazopanib is a substrate for p-glycoprotein.  Substances that induce 
or inhibit CYP3A4 may alter the pharmacologic effects of pazopanib and should be used with 
CAUTION.   
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations.  Co-
administration of strong CYP3A4 inhibitors is prohibited (see Section on Prohibited Medications); 
therefore selection of an alternate concomitant medication with no or minimal potential to inhibit 
CYP3A4 is recommended.   
CYP3A4 inducers may decrease plasma pazopanib concentrations.  Selection of an alternate concomitant 
medication with no or minimal enzyme induction potential is recommended.  Drugs that induce 
CYP3A4 and may decrease pazopanib plasma concentrations include (but are not limited to): 
• 
Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 mg), 
methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
• 
Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
• 
HIV  antivirals:  efavirenz, nevirapine 
• 
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene 
• 
Miscellaneous:  St. John’s Wort, modafinil, pioglitazone, troglitazone 
Prohibited Medications 
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation, or hormonal (other 
than leuprolide or other GnRH agonists)] while on treatment in this study.   
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations; therefore, co-
administration of strong CYP3A4 inhibitors is PROHIBITED beginning 14 days prior to the first dose of 
study drug until discontinuation from the study.  Strong CYP3A4 inhibitors include (but are not 
limited to): 
• 
Antibiotics: clarithromycin, telithromycin, troleandomycin 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
• 
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir) 
• 
Antifungals:  itraconzaole, ketoconazole, voriconazole, fluconazole 
• 
Antidepressants:  nefazodone 
6.6.4 
Other Treatments Allowed on Study  
Surgery and radiation therapy are not permitted while the patient is on the current study.   
7.0 
Dose Delays/Modifications for Adverse Events 
Recommendations for investigational product (IP) dose interruptions/modifications in case of specific 
treatment-emergent AEs are provided in the following sections. 
As a general rule, if dose reduction of IP is necessary, the dose should be reduced stepwise by 200 mg at 
each step, and the subject should be monitored for 10 to 14 days at each dose level.  If toxicity does not 
abate during this monitoring time, the IP may need to be interrupted and/or the dose further decreased 
with continued monitoring for an additional 10-14 days at each dose level, and so on.  
If the toxicity has abated with reduction of the dose and dose re-escalation is considered safe by the 
investigator, the IP 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 GSK 
Study Physician to review the subject’s condition in order to resume the treatment. 
7.1 
Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities 
Recommendations for investigational product dose interruptions/modifications in case of specific 
treatment-emergent AEs are provided in Table 1  
Table 1 
Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
(A). Asymptomatic and 
persistent SBP of 140 and 
<170 mmHg, or DBP 90 and 
<110 mmHg, or a clinically 
significant increase in DBP of 
Step 1. Continue investigational product (IP) at the current 
dose.  
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
20 mmHg. 
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlleda blood pressure 
(BP). If BP is not well-controlled within 2 weeks, consider 
referral to a cardiologist and go to scenario (B). 
(B). Asymptomatic SBP 170 
mmHg, or DBP 110 mmHg, or 
failure to achieve well-
controlled BP within 2 weeks in 
scenario (A).  
Step 1.Consider reducing or interrupting IP, as clinically 
indicated. 
Step 2. Adjust current or initiate new antihypertensive 
medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP. Referral to 
a cardiologist for further evaluation and follow-up is also 
recommended. 
Step 4. Once BP is well-controlled, restart IP dose-reduced by 
200 mg if IP was interrupted. 
(C). Symptomatic hypertension 
or recurring SBP 170 mmHg, 
or DBP 110 mmHg, despite 
modification of antihypertensive 
medication(s) 
Step 1. Interrupt IP  
Step 2. Adjust current or initiate new antihypertensive 
medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP.  Referral to 
a cardiologist for further evaluation and follow-up is also 
recommended. 
Step 4. Once BP is well-controlled, restart IP dose-reduced by 
200 mg. 
(D). Refractory hypertension 
unresponsive to above 
interventions. 
Discontinue IP and continue follow-up per protocol. 
Proteinuria 
UPC  > 3 grams 
Step 1. Interrupt IP. 
Step 2. Test weekly the UPC until the level is < 3 grams.  


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Then, restart IP dose reduced by 200 mg. 
Step 3. If UPC ≥ 3 grams recurs, repeat Steps 1 and 2. 
Step 4.  If UPC ≥ 3 grams recurs and the IP dose can no 
longer be reduced, discontinue IP and continue follow up per 
protocol. 
Haemorrhage /Bleeding 
Grade 1 
Continue IP with current dose; monitor as clinically indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal 
bleeding), discontinue IP and continue follow-up per protocol. 
Otherwise, interrupt IP until the AE resolved to  Grade 1.  
Step 2. Restart IP; consider reducing dose and monitor as 
clinically indicated.  
Grade 3 or 4, or  
Recurrent  Grade 2 event after 
dose interruption/reduction. 
Discontinue IP and continue with follow-up per protocol.  
   
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue IP with same dose; initiate and monitor 
anticoagulation as clinically indicated. 
Grade 3   
 
Step 1. Interrupt IP.  
Step 2. Initiate and monitor anticoagulation as clinically 
indicated.  
Step 3. Resume IP 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 


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32 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
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 IP dosing (eg, re-initiating, escalating/de-escalating, 
or discontinuing IP), and then at least weekly until the INR is 
stable. The dose of warfarin (or its derivatives) may need to be 
adjusted to maintain the desired level of anticoagulation 
Grade 4 and/or PE 
Discontinue IP and continue follow-up per protocol.  
Arterial Thrombosis/Ischemia 
 
Any Grade 
Discontinue IP and continue follow-up per protocol.  
Thrombocytopenia: Investigate and document underlying cause 
Grade 1 or 2 
Continue IP with current dose; monitor as clinically indicated.  
Grade 3 or 4 
Step 1. Interrupt IP until toxicity resolves to ≤ Grade 2. 
Step 2. Restart IP dose-reduced by 200 mg and monitor as 
clinically indicated.  
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 
thrombocytopenia, discontinue IP and follow-up per protocol 
Anaemia:  No specific dose reduction rules are indicated for anaemia unless due to haemorrhage 
or bleeding as noted above. 
Other Clinically Significant Adverse Eventsb  
Grade 1 
Continue IP; monitor as clinically indicated. 


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IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Grade 2 or 3, if clinically 
significant  
Step 1. Interrupt IP until toxicity resolves to  Grade 1. 
Step 2. Restart IP dose-reduced by 200 mg and monitor as 
clinically indicated.  
Grade 4 
Discontinue IP and continue follow-up per protocol.    
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. 
QTc   480 < 500 msec 
Continue IP; monitor as clinically indicated. 
QTc 500 msec 
Discontinue IP and continue follow-up per protocol. 
a. Well-controlled BP defined as mean SBP <140 mmHg and mean DBP <90 mmHg. 
b. AEs are graded according to NCI Common Terminology Criteria for Adverse Events 4.0 
(NCI CTCAE 4.0).  
Abbreviations: BP, blood pressure; IP, investigational product. 
7.2 
Dose Interruptions/Modifications for Hepatotoxicity 
Recommendations for investigational product dose interruptions/modifications in case of liver-related 
treatment-emergent AEs are provided in Table 3.  As a general rule, since many subjects are taking 
multiple concurrent medications, it is critical to (a) do a thorough evaluation of the subject’s concurrent 
medications, and (b) identify and discontinue those with known hepatotoxicity and replace with a non-
hepatotoxic equivalent for the same indication if necessary. 
Table 3. Dose modifications for hepatotoxicity.  
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x upper 
limit of normal (ULN)  
Continue IP at current dose with full panel liver function tests (LFTs)a 
monitored as per protocol. 
(B). ALT >3.0 x ULN to  
≤8.0 x ULN without bilirubin 
elevation (defined as total 
bilirubin <2.0 x ULN or direct 
bilirubin ≤35%) and without 
hypersensitivity symptoms 
(e.g., fever, rash)  
1. Continue IP at current dose.  
2. Perform the following assessments for excluding hypersensitivity and 
other contributing factors:  
 
Eosinophil count 
 
Viral serology for hepatitis A, B and C 
 
Liver imaging 
3. Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTs weekly or more frequently if clinically indicated until alanine 


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34 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Event 
Dose Modification Algorithms 
aminotransferase (ALT)/aspartate aminotransferase (AST) reduced to 
Grade 1.   
(C). ALT >8.0 x ULN without 
bilirubin elevation (defined as 
total bilirubin <2.0 x ULN or 
direct bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, rash) 
1st occurrence 
1. Interrupt IP until toxicity resolves to  Grade 1 or baseline 
2. Perform the following assessments for excluding hypersensitivity and 
other contributing factors:  
 
Eosinophil count 
 
Viral serology for hepatitis A, B, C and E, cytomegalovirus, 
Epstein-Barr virus IgM antibody, or heterophile antibody, or 
monospot testing) 
 
Liver imaging 
3. Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTs weekly or more frequently if clinically indicated until alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) reduced to 
Grade 1.   
4. If the subject is benefiting from the study treatment, contact GSK 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.  
If approval for retreatment is granted, the subject must be reconsented 
(with new informed consent specific to hepatotoxicity). 
Recurrence 
Discontinue IP permanently and monitor subject closely for clinical signs and 
symptoms; perform full panel LFTs weekly or more frequently if clinically 
indicated.  
(D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubin (defined as total 
bilirubin 2.0 x ULN; with 
direct bilirubin >35%) or with 
hypersensitivity symptoms 
(e.g., fever, rash).  
1. Discontinue IP immediately  
2. Consult a gastroenterologist / hepatologist 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, or heterophile antibody, or 
monospot testing) 
 
Anti-nuclear antibody, anti-smooth muscle antibody, anti-
mitochondrial antibody 
 
Serum creatinine phosphokinase for possible muscle injury caused 
LFT elevation 
 
Liver imaging (ultrasound or CT scan) 
3. Monitor subject closely for clinical signs and symptoms; perform full 
panel LFTs weekly or more frequently if clinically indicated until LFTs 
reduced to Grade 1.   
For isolated total bilirubin 
elevation without concurrent 
ALT increases (defined as 
ALT < 3 X ULN) 
 
1. Isolated hyperbilirubinemia (ie 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 > 2 x ULN in the absence of ALT elevation, fractionation 
of bilirubin elevation should be performed.  If the bilirubin is 


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35 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Event 
Dose Modification Algorithms 
predominantly indirect (unconjugated), continue pazopanib at the same 
dose.  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. 
8.0 
Data Safety and Monitoring   
 
8.1    Definition of Risk Level  
 
This is a Risk Level 4 study, as defined in the “City of Hope Data 
and Safety Monitoring Plan”, http://www.coh.org/dsmc/Pages/forms-
and-procedures.aspx involving COH as IND holder in a Phase II Trial. 
 
8.2 Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, collaborating 
investigator, CRA/protocol nurse, and statistician is responsible for 
monitoring the data and safety of this study, including implementation of 
the stopping rules for safety and efficacy. 
 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 


• 
. 
36 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
 
Data and safety will be reported to the COH DSMC using the PMT report 
and submitted quarterly from the anniversary date of activation.  Protocol 
specific data collection will include the following items: Adverse event 
reporting and quarterly safety assessment of pazopanib.   
 
8.3 Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change 
of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it 
is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the 
adverse event 
 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected 
or unexpected adverse event that results in any of the following outcomes: 
 Death 
 Is life-threatening experiences (places the subject at immediate risk of death 
from the event as it occurred) 
 Unplanned hospitalization equal or greater than 24 hours)) or prolongation of 
existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary Malignancy 


• 
• 
. 
37 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
8.4 Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs 
during the study conduct will be reported to the DSMC and IRB by submitting 
electronically in iRIS (http://iris.coh.org). 
 
 
Serious Adverse Events - All SAEs occurring during this study, whether 
observed by the physician, nurse, or reported by the patient, will be reported 
according to definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-
policies.aspx and Table 2 below.  Those SAEs that require expedited reporting will be 
submitted electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the continuation reports and PMT reports (see Table 2 below). 
 


. 
38 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 


. 
39 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations Director. 
The DSMC will review the case and make a determination as to whether the study will be 
suspended, terminated, amended, or allowed to continue without amendment. 
 
 
 


. 
40 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
ADDITIONAL REPORTING REQUIREMENTS  
  
SAEs meeting the requirements for expedited reporting to the FDA, as defined in 21 CFR 312.32, will be 
reported as an IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting which 
can found at: http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
  
The PI or designee will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA will assist the 
PI with the preparation of the report and submit the report to the FDA in accordance with the following: 
 
any unexpected fatal or life threatening adverse experience associated with use of the drug must 
be reported to the FDA no later than 7 calendar days after initial receipt of the information [21 
CFR 312.32(c)(2)]; 
 
any adverse experience associated with use of the drug that is both serious and unexpected must 
be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
 
any follow-up information to a study report shall be reported as soon as the relevant information 
becomes available. [21 CFR 312.32(d)(3)] 
  


. 
41 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
All serious adverse events must be reported by facsimile within 24 hours to the study’s PI 
(Sumanta Kumar Pal, MD) and GlaxoSmithKline. MDC - Oncology Fax: (610) 675-2632 
For medical emergencies contact: 
Julie Maltzman, MD: (610) 917-4079 
Toll Free Number: (800) 877-7074, ext. 4079 
After Hours or Weekends: (800) 366-8900, ask for physician on call 
GlaxoSmithKline UP4420 
1250 S. Collegeville Road, 
P.O. Box 5089 
Collegeville, PA 19426-0989 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question. Where applicable, information from relevant hospital case records 
and autopsy reports should be included. Follow-up information should be forwarded to the study 
PI (Sumanta Kumar Pal, MD) and GSK within 24 hours.  Fax number for reporting of SAE: 
(610) 675 2632 
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 
GSK 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. 
 
8.1 
Regulatory Reporting Requirements for Agent(s) under an IND 
Serious adverse events that are unexpected and relationship to the study investigational agent cannot be 
ruled out, must be conveyed to the study PI (Sumanta Kumar Pal, M.D.) within 24 hours of receipt of 
notification of event.  A Mandatory MedWatch Reporting Form (Form FDA 3500A) for recording 
information related to such an event must be included in the iRIS report. 
9.0 
Agent Information 
9.1 
Pazopanib (Votrient; GW786034)  
NSC#:   737754 


. 
42 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
9.1.1 
Structure and Molecular Weight: 
C21H23N7O2S-HCl, MW 474.0 (monohydrate salt) 
9.1.2 
Supplier 
Glaxo-Smith-Kline 
9.1.3 
Formulation 
Pazopanib monohydrochloride is supplied as a series of aqueous film-coated tablets 
containing 200mg and 400mg of the freebase: 
 
• 200mg, oval-shaped, white, packaged in bottles containing 34 tablets each 
 
 
Refer to the pazopanib IB for information regarding the physical and chemical properties of pazopanib 
and a list of excipients. 
9.1.4 
Storage 
The intact bottles should be stored at controlled room temperature [20oC-25oC (68oF-77oF)]. Excursions 
are permitted between 15oC and 30oC.  
9.1.5 
Stability 
Stability studies are ongoing.  
9.1.6 
Administration 
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 not if there are less than 12 hours before the next 
dose is due.  If the next dose is due in less than 12 hours, the subject should skip the missed dose and take 
the next dose as scheduled. 
If vomiting occurs after taking pazopanib another dose is not permitted on that day.  The subject should 
resume taking pazopanib at the next scheduled dose.  If vomiting persists, the subject should be instructed 
to notify the investigator. 
9.1.7 
Human Toxicities 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single, complete list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of 
events by body system. In addition to the comprehensive list, a subset, the Agent Specific Adverse Event 
List (ASAEL), appears in a separate column and is identified with bold and italicized text. This subset of 
AEs (ASAEL) contains events that are considered 'expected' for expedited reporting purposes only. Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers for further clarification. 
Frequency is provided based on 1019  patients. Below is the CAEPR for pazopanib (GW786034). 
 
Version 2.1, April 13, 2009 


. 
43 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 1019] 
 
 
EXPECTED AEs FOR 
ADEERS REPORTING 
Agent Specific Adverse 
Event List 
(ASAEL) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
BLOOD/BONE MARROW 
 
Expected 
 
Leukocytes (total WBC) 
 
Leukocytes (total WBC) 
 
Lymphopenia 
 
Lymphopenia 
 
Neutrophils/granulocytes 
(ANC/AGC) 
 
Neutrophils/granulocytes 
(ANC/AGC) 
 
Platelets 
 
Platelets 
CARDIAC ARRHYTHMIA 
 
 
 
Prolonged QTc interval 
(accompanied by 
Torsades de pointes) 
 
CARDIAC GENERAL 
 
 
 
Cardiac 
ischemia/infarction 
 
Hypertension 
 
 
Hypertension 
 
 
Left ventricular systolic 
dysfunction 
 
CONSTITUTIONAL SYMPTOMS 
 
Fatigue 
(asthenia, 
lethargy, 
malaise) 
 
 
Fatigue (asthenia, 
lethargy, malaise) 
 
Weight Loss  
 
 
DERMATOLOGY/SKIN 
 
 
Hair loss/alopecia (scalp 
or body) 
 
Hair loss/alopecia (scalp 
or body) 
Hypopigmentati
on 
 
 
Hypopigmentation 
 
Rash/desquamation 
 
Rash/desquamation 
 
 
Rash: hand-foot skin 
reaction 
 
ENDOCRINE 
 
 
Thyroid function, low 
(hypothyroidism) 
 
 
GASTROINTESTINAL 
 
Anorexia 
 
 
Anorexia 
 
Constipation 
 
 
 
Dehydration 
 
Dehydration 
Diarrhea 
 
 
Diarrhea 
 
 
Fistula, GI – Select 
Fistula, GI - Select 


. 
44 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Nausea 
 
 
Nausea 
 
 
Perforation, GI - Select 
Perforation, GI - Select 
 
Taste alteration 
(dysgeusia) 
 
 
Vomiting 
 
 
Vomiting 
HEMORRHAGE/BLEEDING 
 
 
 
Hemorrhage, GI - Select 
 
 
Hemorrhage, pulmonary/ 
upper respiratory - Select 
 
Hemorrhage, 
pulmonary/upper 
respiratory - Select 
METABOLIC/LABORATORY 
 
 
ALT, SGPT (serum 
glutamic pyruvic 
transaminase) 
 
ALT, SGPT (serum 
glutamic pyruvic 
transaminase) 
 
AST, SGOT(serum 
glutamic oxaloacetic 
transaminase) 
 
AST, SGOT(serum 
glutamic oxaloacetic 
transaminase) 
 
Amylase 
 
 
 
Bilirubin 
(hyperbilirubinemia) 
 
Bilirubin 
(hyperbilirubinemia) 
 
Glucose, serum-high 
(hyperglycemia) 
 
Glucose, serum-high 
(hyperglycemia) 
 
Glucose, serum-low 
(hypoglycemia) 
 
Glucose, serum-low 
(hypoglycemia) 
 
Lipase 
 
 
 
Magnesium, serum-high 
(hypermagnesemia) 
 
 
 
Magnesium, serum-low 
(hypomagnesemia) 
 
 
 
Phosphate, serum-low 
(hypophosphatemia) 
 
Phosphate, serum-low 
(hypophosphatemia) 
 
Proteinuria 
 
Proteinuria 
NEUROLOGY 
 
 
Dizziness 
 
Dizziness 
 
Extrapyramidal/involuntar
y movement/restlessness 
 
 
PAIN 
 
 
Pain - Abdomen NOS 
 
Pain - Abdomen NOS 
 
Pain - Head/headache 
 
Pain - Head/headache 
 
Pain - Joint 
 
Pain - Joint 
 
Pain - Muscle 
 
 
 
Pain - Tumor pain 
 
 
PULMONARY/UPPER RESPIRATORY 
 
 
Cough 
 
 
 
Dyspnea 
 
 
RENAL/GENITOURINARY 
 
 
 
Fistula, GU – Select 
Fistula, GU - Select 


. 
45 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Also reported on pazopanib (GW786034) trials but with the relationship to pazopanib (GW786034) still 
undetermined: 
BLOOD/BONE MARROW - Hemoglobin 
CARDIAC ARRHYTHMIA - Supraventricular and nodal arrhythmia - Atrial fibrillation; 
Supraventricular and nodal arrhythmia - Sinus bradycardia 
COAGULATION - INR (International Normalized Ratio of prothrombin time); PTT (Partial 
Thromboplastin Time) 
CONSTITUTIONAL SYMPTOMS - Fever  
DERMATOLOGY/SKIN - Pruritus/itching 
GASTROINTESTINAL - Dysphagia (difficulty swallowing); Flatulence; Heartburn/dyspepsia; 
Obstruction, GI - Small bowel NOS 
HEMORRHAGE/BLEEDING - Hemorrhage, CNS; Hemorrhage, GU - Urinary NOS 
HEPATOBILIARY - Pancreatitis 
METABOLIC/LABORATORY - Alkaline phosphatase; Calcium, serum-low (Hypocalcemia); 
Creatinine; Potassium, serum-high (Hyperkalemia); Potassium, serum-low (Hyperkalemia); Sodium, 
serum-high (Hypernatremia); Sodium, serum-low (Hyponatremia) 
MUSCULOSKELETAL/SOFT TISSUE - Muscle weakness, generalized or specific area (not due to 
neuropathy) - Whole body/generalized 
NEUROLOGY - Confusion 
OCULAR/VISUAL - Vision, blurred vision 
PAIN - Pain - Back; Pain - Chest/thorax NOS; Pain - Pleura; Pain - Throat/pharynx/larynx 
PULMONARY/UPPER RESPIRATORY - Voice changes/dysarthria (e.g., hoarseness, loss or alteration 
in voice, laryngitis 
VASCULAR - Thrombosis/thrombus/embolism 
Note: Pazopanib (GW786034) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent 


. 
46 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
9.2 
Agent Ordering 
A drug supply request form is included in Appendix A.   
10.0 Correlative/Special Studies 
10.1 
Laboratory Correlative StudiesMeasurement of HGF, E-selectin and IL-6 
Patients will have a baseline assessment of IL-6 and E-selectin using previously described techniques.20 
Serum samples (within 2 weeks of collection) will be inserted into the Cyto-8 MAX BIOCHIP and serum 
IL-6 and E-selectin will be measured using SearchLight, an automated, multiplex immunoassay 
workstation from Aushon Biosystem. A total of 7.5 mL of blood will be collected in CPT tubes along 
with baseline laboratories.  Plasma will be separated and stored at -80oC in the laboratory of Dr. Hua Yu.  
10.1.2 Measurement of pre-metastatic niche density and pSTAT3 
If patient consent is obtained, a total of 12 unstained slides derived from tumor and 12 unstained slides 
derived from normal lymph node tissue will be requested.  Normal lymph node tissue will be assessed for 
pre-metastatic niche density, characterized as the number of clusters of VEGFR1+VLA-4+ cells per x 100 
objective field.29  This assessment will be performed through previously defined techniques.   
pSTAT3 will be measured in paraffin-embedded sections.  The authors of the protocol understand that 
collection procedures for specimens in this retrospective analysis are not standardized, and this may lead 
to inherent variability in pSTAT3 levels.  Acknowledging this potential caveat, we would like to measure 
pSTAT3 and determine the relationship of this activated moiety to PFS.  pSTAT3 will be determine 
through previously reported techniques.24 
 


. 
47 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
11.0 Study Calendar   
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk  
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12c 
Off 
Studyd 
Pazopanib 800 mg oral dailya 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-----------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Serum chemistryb 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 8 weeks, ± 1 week.  Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. 
Xd 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 8weeks. 
Xd 
B-HCG (women of child-bearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of IL-6, E-selectin 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
UPC 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xd 
Collection of tumor specimens 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: Excepting adjustments for toxicity. b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. c: After week 12, on study, continue daily oral pazopanib therapy as previous 
and repeat assessments noted at weeks 1, 3, 5 and 9 every 28 days. d: Off-study evaluation. Follow up will be every 6 months for survival. 


 
48 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
12.0 Evaluation Criteria/Measurement of Effect 
Response Criteria (Primary endpoint is confirmed response rate). To take place >28 days 
following a response. Otherwise events will be lost). 
12.1 
   
12.1.1 Evaluation of Target Lesions 
 
Complete Response (CR):  
Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as 
reference the baseline sum LD 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest 
sum LD recorded since the treatment started or 
the appearance of one or more new lesions 
 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD since the 
treatment started 
 
12.1.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 


 
49 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 


-
 
 
50 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
12.2 
Best Response 
12.2.1 The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also 
Requires: 
CR 
CR 
No 
CR 
 
CR 
Non-
CR/Non-PD 
No 
PR 
 
 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once 
>4 wks. from baseline 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”.  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
13.0 Data Reporting/Protocol Deviations 
13.1 
Data Reporting 
13.1.1 Confidentiality of Records 
The original data collection forms will be stored at the originating institution in a secure location.  When 
results of this study are reported in medical journals or at meetings, identification of those taking part will 
be withheld.  Medical records of patients will be maintained in strictest confidence, according to current 
legal requirements.  They will be made available for review, as required by the FDA or other authorized 
users such as the NCI, under the guidelines established by the Federal Privacy Act. 


 
51 
IRB#10030 
 
 
 
 
 
 
 
 
Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
13.1.2 Patient Consent Form 
At the time of registration, the original signed and dated patient’s Informed Consent with the 
Experimental Subject’s Bill of Rights (for the medical record).  All Institutional, NCI, Federal, and State 
of California regulations concerning the Informed Consent form will be fulfilled.  } 
13.1.3 Data Collection Forms and Submission Schedule  
All data will be collected in a timely manner protocol defined case report forms. Data will be sent to the 
City of Hope Department of Biostatistics  and stored in a secure location.   
13.1.3.1 Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research associate and signed 
by a participating investigator prior to registering the patient.  See Section 4.3 for the registration 
procedure. 
13.1.3.2 Prior Therapy and On-Study Forms 
Within two weeks of registration, the clinical research associate will submit pre-study data collection 
forms.  
13.2 
Protocol Deviations 
Protocol deviations must be submitted to the Data Coordinating Center.  The clinical research associate at 
COH will also submit copies to the Protocol Management Team and the COH Data and Safety 
Management Board. 
13.2.1 Deviation Policy 
In accordance with the COH Policy on Clinical Research Protocol Deviation, there will be a “no 
deviations” rule for this protocol.  However, for subject safety or unforeseen scheduling problems, 
planned deviations from this protocol will be permitted in accordance with COH IRB policies and if 
applicable, FDA approval.  
13.2.2 Reporting of Unplanned Deviations 
All unplanned deviations will be reported to the COH DSMB. 
13.2.3 Resolving Disputes 
If there is a dispute among the persons involved in the provision of research treatment, in regard to 
whether a treatment deviates from the protocol, the facts of the case will be reported to the DSMB which 
will be serve as the arbiter of whether a deviation exists. 
 
14.0 Statistical Considerations 
14.1 
Study Design 
The study is an open label, phase II assessment of pazopanib as 3rd-line therapy for mRCC.   
14.1.1 Primary Endpoints 
The primary endpoint is the confirmed response rate (CR+PR), as determined by the RECIST 1.1 criteria.  
We will employ the two stage MinMax design suggested by Simon.  


 
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Prior data indicates that an overall RR of 20% can be obtained with pazopanib therapy.  For patients with 
mRCC eligible for this 3rd line study, a response rate of 20% would represent a significant improvement 
over current approaches (3rd line therapy with the Akt inhibitor perifosine, for instance, yielded a 7% 
response rate) and would further indicate that the activity of pazopanib is maintained through multiple 
prior lines of therapy in selected patients.   
Prior studies suggest that a response rate between 5-10% would not be an improvement over current 
approaches.  As a result, we have set a discouraging response rate at 8%, and an encouraging response 
rate at 23%. Initially, we will accrue 14 patients. If there is at least 1 responder, accrual will continue to 
28 patients. If 5 or more responders (~18%) are observed, pazopanib will be declared promising for future 
studies, assuming toxicity and survival endpoints are also within acceptable limits. This Simon’s MinMax 
two-stage design has a type I error of 10% (probability of declaring an agent with a true 8% response rate 
as promising), and a power of 80% (probability of not declaring an agent promising with a true 23% 
response rate is 20%). All eligible patients treated will be included in the calculation of response rate.  
Any patients with an unknown response rate will be included as a non-responder. 
This design has 31% chance of stopping at the first stage if true response rate is 8%. 
Toxicity will be monitored on an ongoing basis. If the number of unacceptable toxicities exceeds 1 in the 
first 3, or exceeds 2 in the first 6 or more than 25% thereafter, the study will hold accrual for an 
amendment regarding treatment modifications or study termination. 
14.1.2 Secondary Endpoints 
Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity.  
Toxicity will use the CTCAE 4.0 and will summarize the worst grade per toxicity, per patient.  
Additional secondary endpoints relate to biological correlates, including E-Selection, IL-6, the pre-
metastatic niche density, pSTAT3, and baseline HGF.  Because the nature of these secondary endpoints is 
exploratory, we will not consider the issue of multiple comparisons and the according adjustment of p-
values. 
To determine an association between E-selectin, IL-6 and pre-metastatic niche density, we will conduct a 
a pairwise correlation test (linear regression). When the sample size is 28, the linear regression test of 
rho=0 (alpha = 0.050 one-sided) for one normally distributed covariate will have 80% power to detect a 
correlation coefficient of 0.435.  
 
To determine if the biological correlates (e.g, IL-6, E-selectin, pSTAT3, and HGF), are associated with 
progression-free survival (PFS), we will fit univariate or multivariate Cox proportional hazards model and 
report the corresponding p-values. The same method will be employed to evaluate the prognostic effect of 
pre-metastatic niches. 
14.2 
Sample Size Accrual Rate 
The previously noted sample size of 28 patients is anticipated to accrue over the course of 12 months.   


 
53 
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Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
15.0 Human Subject Issues 
15.1 
Institutional Review Board 
In accordance with federal regulations, an Institutional Review Board (IRB) that complies with 
regulations at 45 CFR 46 and 21 CFR 50, 56 must review and approve this protocol and the informed 
consent form prior to initiation of the study.  All institutional, NCI, Federal, and State of California 
regulations must be fulfilled. 
15.2 
Recruitment of Subjects 
Patients with mRCC will be recruited from patients undergoing evaluation and treatment at City of Hope 
Cancer Center for this diagnosis.  
15.3 
Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, etc., will be 
reviewed and approved by the IRB prior to their use to recruit potential study subjects.   
15.4 
 Study location and Performance Sites 
This study will be performed at COH.   
15.5 
Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating 
to protected health information (PHI).   
15.6 
Financial Obligations and Compensation 
If there is a serious medical complication of the research, treatment will be available at City of Hope, but 
there will be no compensation to the subject for this injury.   
15.7 
Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will advise the research subjects about their rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without jeopardizing, include as applicable, their future care or their 
employment at City of Hope or any relationship they have with City of Hope.   
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  Following this 
procedure, the research team will review the results of eligibility testing and determine if the research 
subject is a candidate for study enrollment.  


 
54 
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Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
16.0 References 
 
 
1. 
Hurwitz HI, Dowlati A, Saini S, et al: Phase I Trial of Pazopanib in Patients with 
Advanced Cancer. Clin Cancer Res 15:4220-4227, 2009 
 
2. 
Motzer RJ, Hutson TE, Tomczak P, et al: Overall Survival and Updated Results for 
Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 
27:3584-3590, 2009 
 
3. 
Gajiwala KS, Wu JC, Christensen J, et al: KIT kinase mutants show unique mechanisms 
of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proceedings of the 
National Academy of Sciences 106:1542-1547, 2009 
 
4. 
Nishida T, Takahashi T, Nishitani A, et al: Sunitinib-resistant gastrointestinal stromal 
tumors harbor cis-mutations in the activation loop of the KIT gene. International Journal of Clinical 
Oncology 14:143-149, 2009 
 
5. 
Kay A, Motzer R, Figlin R, et al: Updated data from a phase III randomized trial of 
everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC). Presented at the 2009 
Genitourinary Cancers Symposium (Abstr 278)  
 
6. 
Vogelzang NJ, Hutson TE, Samlowski W, et al: Phase II study of perifosine in metastatic 
renal cell carcinoma (RCC) progressing after prior therapy (Rx) with a VEGF receptor inhibitor. J Clin 
Oncol 27:15s, 2009 (suppl; abstr 5034)  
 
7. 
Figlin RA, Hutson TE, Tomczak P, et al: Overall survival with sunitinib versus interferon 
(IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC). J Clin Oncol 26: 2008 (May 
20 suppl; abstr 5024)  
 
8. 
Escudier B, Pluzanska A, Koralewski P, et al: Bevacizumab plus interferon alfa-2a for 
treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103-
11, 2007 
 
9. 
Escudier BJ, Bellmunt J, Negrier S, et al: Final results of the phase III, randomized, 
double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-α2a (IFN) in metastatic renal 
cell carcinoma (mRCC). J Clin Oncol 27:15s, 2009 (suppl; abstr 5020)  
 
10. 
Rini BI, Halabi S, Rosenberg J, et al: Bevacizumab plus interferon-alpha versus 
interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: Results of overall survival 
for CALGB 90206. J Clin Oncol 27:18s, 2009 (suppl; abstr LBA5019)  
 
11. 
Sternberg CN, Szczylik C, Lee E, et al: A randomized, double-blind phase III study of 
pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). 
J Clin Oncol (Meeting Abstracts) 27:5021-, 2009 
 
12. 
Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical Features and Outcome of Patients 
With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009 
 
13. 
Sandler A, Gray R, Perry MC, et al: Paclitaxel-Carboplatin Alone or with Bevacizumab 
for Non-Small-Cell Lung Cancer. N Engl J Med 355:2542-2550, 2006 
 
14. 
Vickers MM, Choueiri TK, Zama I, et al: Failure of initial VEGF-targeted therapy in 
metastatic renal cell carcinoma (mRCC): What next? J Clin Oncol 27:15s, 2009 (suppl; abstr 5098)  


 
55 
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Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
15. 
Dham A, Dudek AZ: Sequential therapy with sorafenib and sunitinib in renal cell 
carcinoma. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 
18S (June 20 Supplement), 2007: 5106  
 
16. 
Patel JD, Hensing TA, Rademaker A, et al: Phase II Study of Pemetrexed and 
Carboplatin Plus Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy 
for Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol:JCO.2008.20.8181, 2009 
 
17. 
Spanknebel K, Cheung KY, Stoutenburg J, et al: Initial Clinical Response Predicts 
Outcome and Is Associated With Dose Schedule in Metastatic Melanoma and Renal Cell Carcinoma 
Patients Treated With High-Dose Interleukin 2. Annals of Surgical Oncology 12:381-390, 2005 
 
18. 
Dham A, Dudek AZ: Sequential therapy with sorafenib and sunitinib in renal cell 
carcinoma. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 
18S (June 20 Supplement), 2007: 5106  
 
19. 
Hutson TE, Davis ID, Machiels JH, et al: Biomarker analysis and final efficacy and 
safety results of a phase II renal cell carcinoma trial with pazopanib (GW786034), a multi-kinase 
angiogenesis inhibitor. J Clin Oncol 26: 2008 (May 20 suppl; abstr 5046)  
 
20. 
Heymach J, Tran HT, Fritsche HA, et al: Lower baseline levels of plasma hepatocyte 
growth factor (HGF), IL-6 and IL-8 are correlated with tumor shrinkage in renal cell carcinoma patients 
treated with pazopanib. To be presented at the 2010 American Association of Cancer Research Annual 
Meeting (Data confidential until presented).  
 
21. 
Harrison ML, Obermueller E, Maisey NR, et al: Tumor Necrosis Factor {alpha} As a 
New Target for Renal Cell Carcinoma: Two Sequential Phase II Trials of Infliximab at Standard and High 
Dose. J Clin Oncol 25:4542-4549, 2007 
 
22. 
Berntsen A, Trepiakas R, Wenandy L, et al: Therapeutic Dendritic Cell Vaccination of 
Patients With Metastatic Renal Cell Carcinoma: A Clinical Phase 1/2 trial. Journal of Immunotherapy 
31:771-780 10.1097/CJI.0b013e3181833818, 2008 
 
23. 
Yu H, Jove R: The STATs of cancer [mdash] new molecular targets come of age. Nat 
Rev Cancer 4:97-105, 2004 
 
24. 
Xin H, Zhang C, Herrmann A, et al: Sunitinib Inhibition of Stat3 Induces Renal Cell 
Carcinoma Tumor Cell Apoptosis and Reduces Immunosuppressive Cells. Cancer Res 69:2506-2513, 
2009 
 
25. 
Bedard PL, Body J-J, Piccart-Gebhart MJ: Sowing the Soil for Cure? Results of the 
ABCSG-12 Trial Open a New Chapter in the Evolving Adjuvant Bisphosphonate Story in Early Breast 
Cancer. J Clin Oncol 27:4043-4046, 2009 
 
26. 
Mantovani A, Allavena P, Sica A, et al: Cancer-related inflammation. Nature 454:436-
444, 2008 
 
27. 
Psaila B, Lyden D: The metastatic niche: adapting the foreign soil. Nat Rev Cancer 
9:285-293, 2009 
 
28. 
Erler JT, Bennewith KL, Cox TR, et al: Hypoxia-Induced Lysyl Oxidase Is a Critical 
Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche. Cancer Cell 15:35-44, 2009 
 
29. 
Kaplan RN, Riba RD, Zacharoulis S, et al: VEGFR1-positive haematopoietic bone 
marrow progenitors initiate the pre-metastatic niche. Nature 438:820-827, 2005 
 
 


 
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Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
  
17.0 Appendix I:  Urine Protein Creatinine Ratio (UPC) 
Clinical meaning of UPC 
There is a good correlation between the ratio of protein concentration to creatinine concentration in a 
random urine sample and the amount of protein excreted over 24 hours.  Creatinine excretion is fairly 
constant throughout the day regardless of changes in urine flow rate. 
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day. 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day. 
Normal protein excretion is <100 mg to 150 mg/24 hours and is similar for men and women. 
 
Calculating UPC 
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL).  
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs.  
Example:  Patient has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL.   
UPC ratio= (90 mg/dL) / (30 mg/dL) =  3   
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a 24-hour 
period. 
 
Units for UPC ratio 
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the same units 
(mg/dL, g/L, or μmol/L).  If, for example, protein concentration is expressed in mg/dL and creatinine 
concentration is expressed in µmol/L, conversion of one of the concentration values is required.  
Conversion factors are:  
From  
To  
Conversion Factor  
Conventional Units: mg/dL 
SI Units: µmol/L 
Multiply by 88.4 
SI Units: µmol/L 
Conventional Units: mg/dL Divide 88.4  
References: 
Xin G, Wang M, Jian L, Xu F, Wang H.  Protein-to-creatinine ratio in spot urine samples as a predictor of 
quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39.  
NKF: NKF KDOQI Guidelines [Internet].  National Kidney Foundation; nd.  KDOQI Clinical Practice 
Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification.  Available from 
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm 


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


 
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Date Prepared: 4.23.10 
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Appendix III: 
New York Heart Association (NYHA) Classifications 
 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitations of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be present 
event at rest.  If any physical activity is undertaken, discomfort is increased. 
This table is an excerpt from the Oxford Textbook of Medicine, 2nd ed. Oxford; New York: Oxford University Press, 1987, p. 
2228. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Date Prepared: 4.23.10 
Revised: 07.29.10; 09.15.10; 03.18.11; 10-11-11, 04-04-12, 10-29-13 
 
 
 
 
 
Appendix V: 
ECOG Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 


> 
> 
 
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18.0 
Patient Monitoring and Management Guidelines for Certain 
Treatment Emergent Adverse Events of Interest (AEOIs) 
18.1 
 Diarrhea 
In cancer patients, diarrhea can be debilitating and potentially life threatening, with dehydration, renal 
insufficiency, and electrolyte imbalances. Pazopanib as a monotherapy has been associated with an 
increased incidence of diarrhea, which is grade 1 or 2 in the majority with grade 3/4 diarrhea occurring in 
approximately 4% of subjects.  The incidence and severity may increase when administered with other 
agents known to cause diarrhea. 
Early identification and intervention is critical for the optimal management of diarrhea.  Please refer to 
Supportive Care Guidelines for Diarrhea in Appendix I, Section 19.1 for detailed management guidelines.  
A subject’s baseline bowel pattern should be established so that changes in that pattern can be identified.  
In addition, subjects should be educated on signs and symptoms of diarrhea with instructions to report any 
changes in bowel pattern to the physician.   
 
Appendix 1: Supportive Care Guidelines 
Diarrhea 
The NCI CTCAE Version 4.0 criteria for defining diarrhea are provided below. 
Toxicity 
Grade 
Diarrhea  
(includes diarrhea of small bowel or colonic origin and/or ostomy diarrhea) 
1 
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline 
2 
Increase of 4-6 stools/day over baseline; IV fluids indicated < 24 h; moderate increase in 
ostomy output compared to baseline; not interfering with daily living 
3 
Increase of 7 stools/day over baseline; incontinence; IV fluids  24 h; hospitalization; 
severe increase in ostomy output compared to baseline; interfering with activities of daily 
living 
4 
Life threatening consequences (e.g., hemodynamic collapse) 
5 
Death 
 
Uncomplicated diarrhea is considered mild to moderate and defined as CTCAE Grade 1 to 2 with no 
complicating signs or symptoms. 
Complicated diarrhea is severe and defined as CTCAE Grade 3 or 4 or Grade 1 or 2 with 1 or more of the 
following signs or symptoms; cramping, nausea/vomiting, ≥ Grade2, decreased performance status, fever, 
sepsis, neutropenia, frank bleeding, and/or dehydration.  If complicated diarrhea goes unrecognized or 
untreated, it may lead to death. 
Experience thus far suggests that, when pazopanib is used as monotherapy, uncomplicated CTCAE Grade 
1 or 2 diarrhea may ensue.  In rare cases, subjects treated with monotherapy pazopanib may develop 


• 
• 
• 
• 
• 
µ 
 
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debilitating and potentially life-threatening diarrhea with dehydration, renal insufficiency, and electrolyte 
imbalances.  The pathophysiologic mechanism of diarrhea with pazopanib is not known. 
The following broad general management principles are recommended as means by which a subject with 
diarrhea may avoid more serious complications. Guidelines such as these should never replace sound 
clinical judgment.  Standardized and universal guidelines have been developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea [Benson, 2004].  The 
guidance provided here is a modification of the ASCO guidelines.. 
Early identification and intervention is critical for the optimal management of diarrhea.  
 
A subject’s baseline bowel pattern should be established so that changes in that pattern can be 
identified.   
 
Subjects should be educated on the signs and symptoms of diarrhea with instructions to report 
any changes in bowel pattern to the physician. 
 
At the initiation of diarrhea, an assessment of frequency, consistency, duration and other 
symptoms such as fever, cramping pain, nausea, vomiting, dizziness and thirst should be taken to 
identify subjects at high risk of complications. 
Several treatments have demonstrated efficacy in diarrhea management: 
 
Loperamide, administered as an initial 4-mg dose, followed by 2-mg doses after every unformed 
stool with a maximum of 16mg per day.  This dose and regimen are moderately effective.  
Continuation of loperamide is suggested until the subject is diarrhea-free for 12 hours.  Dose should 
not exceed a maximum of 8 tablets (16 mg) per day. 
 
The synthetic octapeptide, octreotide, has been shown to be effective in the control of diarrhea 
induced by fluoropyrimidine-based chemotherapy regimens when administered as an escalating dose 
by continuous infusion or subcutaneous injection.  In the treatment of chemotherapy-induced 
diarrhea, octreotide can be administered at doses ranging from 100 g twice daily to 500 g 3 times 
daily, with a maximum-tolerated dose of 2000 g 3 times daily in a 5-day regimen.  However, the 
effect of octreotide on diarrhea associated with use of pazopanib is unknown.  
 
 
 
 
 
 
 
 
 


 
62 
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Date Prepared: 4.23.10 
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Figure 1.  Generic flow chart for suggested management of Diarrhea 


• 
•
4 
V
4 
 
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 EVALUATE 
• Obtain history of onset and duration of diarrhea 
• Describe number of stools and stool composition 
• Assess patient for fever, dizziness, abdominal pain/cramping or weakness 
• Medications and dietary profile 
UNCOMPLICATED 
grade 1-2
ADDED RISK 
FACTORS 
COMPLICATED 
grade 3 or 4 diarrhea or grade 1 or 2 with 
≥ 1 of these signs or symptoms: 
• Cramping 
• Nausea/vomiting (≥ grade 2) 
• Decreased performance status 
• Fever 
• Sepsis 
• Neutropenia 
• Frank bleeding 
• Dehydration 
 MANAGEMENT 
• Discontinue lactose products and alcohol 
• Drink 8-10 large glasses of clear liquids per day 
• Eat frequent small meals (e.g., bananas, rice, applesauce, and toast) 
• Grade 2 diarrhea: Consider holding cytotoxic chemotherapy (if applicable) and consider 
pazopanib dose reduction until symptoms resolve 
 
SUGGESTED TREATMENT 
Ad i i
d d
i di
h
l (
l
id )
Reassess 12-24 hours later
Diarrhea resolving 
• Continue instructions for dietary 
modification 
• Gradually add solid food to diet 
• Discontinue standard anti-
diarrheal after 12-hour diarrhea-
free interval 
Diarrhea unresolved 
 
Continue standard anti-
diarrhea treatment (e.g. 
loperamide) 
 
Evaluate for  possible 
infection 
 
Administer oral 
antibiotics if warranted
Reassess 24 hours later
Diarrhea unresolved 
 
Start Second line anti-
diarrheal (e.g. octreotide, 
or opiates) 
SYMPTOMS 
PERSIST 
 MANAGEMENT 
• Patient must call physician immediately 
• Interrupt  pazopanib and cytotoxic 
chemotherapy (if applicable) 
• Evaluate for possible infection  
• Consider hospitalization   
 
SUGGESTED TREATMENT 
• Administer standard anti-diarrheal 
immediately, (e.g. loperamide)  
• Hydration (i.v. fluids as needed) 
•
Consider need for antibiotics and consider
Diarrhea Free for 24 hours 
 
Discontinue diarrhea intervention 
 
Consider reintroducing pazopanib 
at either full dose or reduced dose  
depending on clinical interpretation 
of risk-benefit ratio and cytotoxic 
chemotherapy (if applicable) 


 
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Date Prepared: 4.23.10 
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Nausea and Vomiting 
Every attempt should be made to control nausea and vomiting in subjects who have emesis and are unable 
to retain pazopanib. 
Routine pre-medication for nausea is not necessary, but symptomatic subjects should be treated with 
standard anti-nausea/anti-emetic therapy as necessary. 
If a subject vomits after taking study medication, the subject should be instructed not to take a 
replacement dose on that same day.  The subject should resume taking pazopanib at the next scheduled 
dose on the following day.  .  If vomiting persists then the subject should contact their physician. 
To prevent or treat nausea and vomiting standard medications are recommended.  Depending upon 
approved medications in your region, these may include: 5-HT3 receptor antagonist (granisetron, 
ondansetron, dolasetron mesylate); NK-1 receptor antagonists such as aprepitant,  metoclopramide,  
phenothiazines (prochlorperazine); corticosteroids, (dexamethasones, prednisone); and cannibinoids 
(dronabinol).  
References: 
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et al.  Recommended 
Guidelines for the Treatment of Cancer Treatment-Inducted Diarrhea.  J Clin Oncol. 2004, 22; 2918-26.