Clinical trial NCT01610206
Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: recurrent persistent
Sponsor: Linda R Duska
Start date: 2012-09-01; Completion date: 2020-12-31
Enrollment: 148 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Ovarian cancer is the leading cause of gynecologic cancer deaths, and the fifth most common cause of cancer deaths in women. While approximately 75% of patients with epithelial ovarian cancer will respond to first-line chemotherapy with platinum and paclitaxel, most patients with advanced stage epithelial ovarian cancer will experience disease recurrence. Pazopanib is a novel agent has recently been approved for the treatment of subjects with advanced renal cell carcinoma (RCC), and preclinical studies suggest it may be effective in other cancers such as ovarian cancer. Therefore, the purpose of this study is to test the efficacy and safety of a novel agent, pazopanib, as an adjunct to a standard treatment, gemcitabine, for recurrent or persistent ovarian cancer. This is an open label study in which subjects will be randomized 1:1 to receive 4 cycles of either gemcitabine, or gemcitabine with pazopanib. Gemcitabine will be administered as an IV infusion weekly on days 1 and 8 of a 21 day cycle. Subjects randomized to receive pazopanib will take 800 mg daily during the 21 day cycle. All subjects will be monitored for toxicity and other indicators of safety (labs, physical exams, vitals) at intervals throughout the treatment cycles. Subjects will be followed for up to 5 years following the conclusion of treatment to evaluate efficacy. The primary endpoints of the study are progression free survival and overall survival, which will be assessed at three years.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Gemcitabine intervention 2: pazopanib
Intervention descriptions: intervention 1: Patients will receive gemcitabine 1000 mg/m2 administered weekly on days 1 and 8 (30 minutes IV infusion) of each cycle for up to 6 cycles. Each cycle is 21 days. intervention 2: Patients will receive pazopanib 800mg PO daily on days 1-21 of treatment cycles

Protocol documents:
Prot_SAP_001.pdf: 
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A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS 
PAZOPANIB VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS 
WITH PERSISTENT OR RELAPSED EPITHELIAL OVARIAN, FALLOPIAN TUBE OR 
PRIMARY PERITONEAL CARCINOMA 
 
Sponsor: 
 
 
 
University of Virginia School of Medicine (UVA) 
 
 
 
 
 
Charlottesville, VA  22908 
 
UVa Principal Investigator:  
Linda R. Duska, M.D. 
 
 
 
 
 
University of Virginia School of Medicine (UVA) 
 
 
 
 
 
PO Box 800712 
 
 
 
 
 
Charlottesville, VA 22908 
 
 
 
 
 
Telephone:  (434) 982-1719 
 
 
 
 
 
Fax:  (434) 982-1840 
 
 
 
 
 
lduska@virginia.edu 
 
Sub-Investigators (UVA):  
Susan C. Modesitt, M.D. 
 
 
 
 
 
Leigh Cantrell, M.D. 
 
 
 
 
 
University of Virginia School of Medicine (UVA) 
 
 
 
 
 
P.O. Box 800712 
 
 
 
 
 
Charlottesville, VA 22908 
 
 
 
 
 
Telephone:  (434) 924-2221 
 
 
 
 
 
Biostatistician: 
 
 
Gina Petroni, Ph.D. 
 
 
 
 
 
University of Virginia School of Medicine (UVA) 
 
 
 
 
 
P.O. Box 800717 
 
 
 
 
 
Phone: (434) 924-8363 
 
 
 
 
 
Fax: (434) 243-5787 
 
 
 
 
 
gpetroni@virginia.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND Information: 
 
 
Exempt 
 
 
Toxicity Grading: 
 
 
CTCAE v 4.0 will be utilized for this study. 
 
 
NCT:  
 
 
 
NCT01610206 
 
 
 
 
 
 
 
 
 


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SCHEMA:  
Randomized open-label Phase II design 
 
Regimen 1:  Gemcitabine 1000 mg/m2 administered weekly on days 1 and 8 (30-60 minutes IV 
infusion)  
 
Regimen 2:  Gemcitabine 1000 mg/m2 administered weekly on days 1 and 8 (30-60 minutes IV 
infusion) with Pazopanib 800mg PO daily days 1-21 
 
Until disease progression or adverse effects prohibit further therapy  
Maximum body surface area used for dose calculations will be 2.0 mg/m2 
One cycle = 21 days 
 
 
Patients will be stratified according to their second line platinum-free interval PFI (those with a PFI 
less than or equal to 182 days versus those with PFI greater than 182 days) and number of previous 
chemotherapy regimens (one vs two or more).  PFI will be measured from the last day the platinum 
therapy was given to time of documented progression unless a subject does not achieve a Complete 
Response after first line platinum treatment then the subject is considered platinum resistant 
regardless of the PFI. 
 
No biologic therapies aimed at treating the study cancer will be allowed while the patient is on 
study. 
  
 


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TABLE OF CONTENTS 
PAGE 
1.0 
OBJECTIVES 
4 
2.0 
BACKGROUND AND RATIONALE 
4 
3.0 
PATIENT ELIGIBILITY 
14 
4.0 
STUDY MODALITIES 
20 
5.0 
TREATMENT PLAN AND ENTRY PROCEDURE 
27 
6.0 
TREATMENT MODIFICATIONS 
32 
7.0 
STUDY PARAMETERS & SERIAL OBSERVATIONS 
35 
8.0 
EVALUATION CRITERIA 
36 
9.0 
DURATION OF STUDY 
45 
10.0 
STUDY MONITORING & REPORTING PROCEDURE 
45 
11.0 
DATA SAFETY AND MONITORING PLAN 
51 
12.0 
STUDY MANAGEMENT 
51 
13.0 
STATISTICAL CONSIDERATIONS 
54 
14.0 
BIBLIOGRAPHY 
58 
 
APPENDIX I  
- 
New York Heart Association (NYHA) classification 
APPENDIX II  
- 
Medications that may cause QTc Prolongation 
APPENDIX II  
- 
Recommended Dose Modifications for pazopanib  
APPENDIX IV 
- 
GOG General Chemotherapy Guidelines 


  
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1.0 
OBJECTIVES    
1.1 
Primary Objectives: 
1.11 
To estimate the progression-free survival hazard ratio of the combination of 
weekly gemcitabine and pazopanib compared to weekly gemcitabine alone in 
patients with persistent or recurrent ovarian, fallopian tube, or primary 
peritoneal cancer 
1.2 
Secondary Objectives: 
1.21 
To determine the frequency and severity of adverse events as assessed by 
CTCAE v 4.0. 
1.22 
To obtain preliminary estimates of overall survival (OS), time to progression 
(TTP) and the duration of response in this patient population; and to estimate the 
respective hazard ratios of the combination to gemcitabine alone. 
 
2.0 
BACKGROUND AND RATIONALE    
 
2.1 
Ovarian Cancer 
Ovarian cancer is the leading cause of gynecologic cancer deaths, and the fifth most 
common cause of cancer deaths in women. An estimated 15,460 women will die of 
ovarian cancer in 2011.1 While approximately 75% of patients with epithelial ovarian 
cancer will respond to first-line chemotherapy with platinum and paclitaxel, most 
patients with advanced stage epithelial ovarian cancer will experience disease 
recurrence. While there are several active cytotoxic agents for the treatment of recurrent 
epithelial ovarian cancer, median survival after recurrence is about 2 years.2  Therefore, 
there is a need for developing and testing novel agents in this population.   
 
Novel agents are needed in both platinum sensitive and platinum resistant ovarian 
cancer, though response rates in the setting of platinum sensitive disease tend to be 
higher.  In particular, there is a need to develop new agents and combinations in patients 
with platinum resistant or refractory ovarian cancer.  The disease free interval from last 
platinum treatment is significant in predicting subsequent response to chemotherapy.  
Patients who experience recurrence greater than 6 months from last prior platinum are 
considered “platinum sensitive” and have a 50-60% response rate to second-line 
chemotherapy, while patients whose disease free interval is less than 6 months 
(platinum resistant) or who progress during primary therapy (platinum refractory) have 
a much lower response rate of 20-30% and 10% respectively.3  It is in this platinum 
resistant/refractory group that novel compounds and combinations are most needed. 
 
2.2 
Pazopanib 
Pazopanib is a potent and selective, orally bioavailable, adenosine triphosphate 
competitive, small molecule inhibitor of vascular endothelial growth factor receptor 
(VEGFR)-1, -2, and -3, platelet-derived growth factor receptor (PDGFR)-α, -β, and c-
KIT tyrosine kinases (TKs) (Investigator’s Brochure).  In human umbilical vein 
endothelial cells (HUVECs), pazopanib inhibited VEGF-induced VEGFR-2 
phosphorylation and was 3- to 400-fold selective for VEGFRs compared to 23 other 
kinases tested.  Pazopanib showed significant growth inhibition of a variety of human 
tumor xenografts in mice, and also inhibited angiogenesis in several different models of 
angiogenesis.  Because angiogenesis is necessary for the growth and metastasis of solid 


  
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tumors, and VEGF is believed to have a pivotal role in this process, pazopanib 
treatment may have broad-spectrum clinical utility. 
 
Mechanism of Action 
Pazopanib inhibits VEGFR-1, -2, and -3 with concentrations causing 50% inhibition 
(IC50) values of 10, 30, and 47 nM, respectively, and inhibits PDGFR-α, -β, and c-KIT 
with IC50 values of 71, 84, and 74 nM, respectively (Investigator’s Brochure).4,5 
 
In addition to their direct role in tumor cell growth and survival, several of the split-
kinase domain RTKs, most notably VEGFR and PDGFR-β, play prominent roles in 
tumor neoangiogenesis.6,7  Reported data suggest that combined pharmacologic 
disruption of PDGFR-β and VEGFR-2 signaling results in profound antiangiogenic 
effects in tumors.8  Hence, although the pathogenesis of solid tumors and hematologic 
malignancies is complex, there is good rationale that inhibition of split-kinase domain 
RTK targets may result in direct effects against cancer cells expressing them. 
 
Nonclinical Efficacy 
Pazopanib selectively inhibited the proliferation of HUVECs stimulated with VEGF 
(IC50=21 nM) compared to basic fibroblast growth factor (bFGF) (IC50=721 nM).  In a 
cell proliferation assay using a panel of 282 human tumor cell lines, pazopanib inhibited 
the proliferation of only 7 cell lines (IC50<1000 nM), suggesting that pazopanib is a 
weak inhibitor of proliferation in the majority of human cell lines tested in vitro.  
Pazopanib also showed weak inhibitory activity in the colony forming unit assay 
induced by granulocyte-macrophage colony stimulating factor (GM-CSF) and Flt-3 
ligand alone.  However, the inhibition by pazopanib was enhanced by the addition of 
stem cell factor (a ligand for c-KIT), consistent with its activity against c-KIT kinase. 
 
Inhibition of VEGFR-2 phosphorylation was studied in naive mice given an IV bolus 
administration of VEGF.  The lungs of VEGF-treated mice showed increased 
phosphorylation of VEGF-2 compared to untreated control mice.  Pre-treatment of mice 
with a single oral dose of pazopanib inhibited VEGF-induced VEGFR-2 
phosphorylation in lungs in a dose- and time-dependent manner.  The results from these 
studies suggest that plasma concentrations of ~40 mcM or higher are required for the 
optimal inhibition of VEGFR-2 phosphorylation in mice.  This concentration is also 
consistent with the antiangiogenic and antitumor effects seen in mouse exposure 
studies.  Pazopanib given orally at ≥30 mg/kg inhibited bFGF and VEGF-induced 
angiogenesis in a variety of animal models including the Matrigel plug and corneal 
micropocket models in Swiss nu/nu or C57B1/6 mice.  Pazopanib also showed 
generally dose-dependent inhibition of aberrant ocular angiogenesis in laser-induced 
choroidal neovascularization in C57B1/6J mice (≥8 mg/kg orally) and Brown Norway 
rats (2.25 mg/kg, eye drops) as well as corneal neovascularization in a suture-induced 
model in New Zealand white rabbits (≥0.3 mg/kg, eye drops). 
 
Pazopanib has been evaluated in human tumor xenograft models in mice as a single 
agent as well as in combination with other TK inhibitors and with various 
chemotherapeutic agents.  The combination with lapatinib (an EGFR/ErbB2 TK 
inhibitor) showed a modest increase in tumor growth inhibition of both BT474 and in 
NCI-H322 tumor xenografts in SCID mice compared to either agent alone; however, 
the differences were not statistically significant.  Pazopanib has also been evaluated in 


  
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combination with various other chemotherapeutic agents (e.g., topotecan, irinotecan, 5-
fluorouracil, oxaliplatin, or docetaxel) against HT29 tumor xenografts.  The effect of 
any of the combinations on tumor growth was not significantly different from that of 
either agent alone.   
 
The combination of pazopanib with AKT and B-Raf kinase inhibitors was evaluated in 
human colon, ovarian, and renal xenografts in mice.  There was no increase in tumor 
growth inhibition in colon and renal xenografts with the combination as compared to 
the best single agent.  However, an increased inhibition was seen in the ovarian 
carcinoma model at the highest dose of both compounds in combination compared to 
either agent alone.  Pazopanib in combination with a B-raf inhibitor, SB-590885, in 
mutant B-raf V600E xenografts showed a modest increase in tumor inhibition with the 
combination compared to either agent alone.  The combination of pazopanib and 
bevacizumab was studied in human colon tumor xenografts:  RKO, SW620, and HT29.  
A modest increase in tumor inhibition was observed with the combination compared to 
either agent alone, suggesting a potential benefit of combining the two agents.  In 
human ovarian cancer cells as well as in OVCAR-3 mice xenografts, pazopanib 
compared to paclitaxel exerted different effects on the expression and secretion of CA-
125 and was not always associated with changes in tumor burden, suggesting cautious 
use of CA-125 as an independent marker of antitumor activity of pazopanib in clinical 
studies. 
 
Nonclinical Pharmacology and Toxicology  
In safety pharmacology studies, there were no pazopanib-related central and peripheral 
nervous system, respiratory, or cardiovascular effects in rats or monkeys given single 
oral doses of up to 300 mg/kg and 500 mg/kg.  However, following a single IV dose of 
3.75 mg/kg to monkeys, a mild, reversible decrease in heart rate was observed with no 
effects on arterial pressures, body temperature, or ECG waveform changes.  At the limit 
of pazopanib solubility for in vitro assays, there was minimal (~19%) inhibition of 
hERG tail current repolarization and no treatment-related effects on isolated dog 
Purkinje fibers.  The toxicity profile of pazopanib has been defined in single-dose 
studies in rats and dogs and repeat dose studies in mice (13 weeks), rats (26 weeks), and 
monkeys (52 weeks).  The principal nonclinical toxicities are believed to be directly 
associated with VEGFR-2 inhibition and include effects on bone and bone marrow, 
incisor teeth, ovary, kidney, pancreas, nails, testes, adrenal, pituitary, trachea, 
hematologic tissues, salivary glands, and developing embryo/fetus.  The onset of these 
effects varied with dose and systemic exposure with the earliest onset seen after 4 days 
of dosing in the rat.  Neither rats nor monkeys tolerated oral doses in the range of 300-
500 mg/kg/day for >4 weeks, both experiencing severe weight loss and morbidity.  
Hepatic effects have also been noted occasionally in rodents. 
 
Nonclinical reproductive toxicology studies indicate reduced female fertility, fetal 
teratogenic effects, and reduced fetal body weight in pregnant rats and/or rabbits given 
pazopanib.  In rats, pazopanib caused a reduction in the number of stage I-V round 
spermatids at ≥300 mg/kg/day, resulted in female reproductive tract target organs 
effects at 300 mg/kg/day, and caused early embryo resorptions.  The agent was found to 
be non-mutagenic and non-clastogenic in a range of genetic toxicity tests. 
 
Nonclinical Pharmacokinetics and Drug Metabolism 


  
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Mean bioavailability ranged from 47% in dogs to 72% in rats.  There was a 4- to 5-fold 
decrease in exposure in fed compared to fasting dogs, but in monkeys the exposure did 
not change substantially on feeding.  Pazopanib is highly (>98.8%) plasma protein 
bound in mouse, rat, dog, monkey, and human plasma.  In vitro data indicate that 
pazopanib is highly permeable across membranes and is a substrate for the P-
glycoprotein (P-gp) transporter and breast cancer resistant protein (BCRP).  Following 
oral administration of radiolabeled pazopanib, excretion of drug-related material was 
rapid and essentially complete.  Circulating metabolites observed in humans were minor 
and were also noted in the nonclinical species.  Metabolism appeared to be 
predominantly mediated by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8.  
The majority of the dose was excreted via feces in humans, rats, and monkeys. 
 
Clinical Experience 
Over 6000 subjects with cancer have been enrolled in clinical studies of pazopanib as of 
September 2011.  In October 2009, the FDA approved pazopanib tablets for the 
treatment of subjects with advanced renal cell carcinoma (RCC).  In addition, several 
clinical studies evaluating pazopanib in non-small cell lung cancer (NSCLC), ovarian 
cancer, breast cancer, soft tissue sarcoma (STS), carcinosarcoma of the uterus, cervical 
cancer, hepatocellular cancer (HCC), multiple myeloma (MM), and glioma are in 
progress or have been completed.   
 
Clinical Efficacy 
In a randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy 
and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated 
subjects with advanced RCC, the median progression-free-survival (PFS) was 
significantly prolonged with pazopanib compared with placebo in the overall study 
population (9.2 vs. 4.2 months).  The objective response rate (RR) was 30% with 
pazopanib and only 3% with placebo.9  In subjects with ovarian cancer, 31% of subjects 
experienced a CA-125 response to pazopanib, with a median time to response of 29 
days and median duration of response of 113 days (Investigator’s Brochure).10  Median 
PFS was 84 days and the overall RR was 18%.  In advanced or metastatic STS, the rate 
of PFS at 12 weeks was 43.9% for leiomyosarcoma, 48.6% for synovial sarcoma, 
26.3% for adipocytic sarcoma, and 39% for other types of sarcoma.11  In a phase 2 trial 
of subjects with early-stage NSCLC, 86% of subjects experienced a reduction in tumor 
volume after short-term, preoperative use of pazopanib (~2-6 weeks) as assessed by 
high-resolution CT scanning.12  Interim results from a phase 2 study of pazopanib in 
subjects with recurrent or metastatic breast invasive breast cancer showed that the 
clinical benefit rate was 26%.13  The median TTP was 3.7 months, and 50% of subjects 
with measurable target lesions had some decrease in size.  PFS at 3 and 6 months was 
55% and 28%, respectively.  Preliminary results from a randomized study in subjects 
with first-line advanced ErbB2-positive advanced or metastatic breast cancer showed 
that a higher response rate (36.2% vs. 22.2%) was observed in subjects on combination 
lapatinib 1000 mg once daily + pazopanib 400 mg once daily compared to monotherapy 
lapatinib 1500 mg once daily.14  In a randomized phase 2 study of pazopanib vs. 
lapatinib vs. the combination of pazopanib/lapatinib in advanced and recurrent cervical 
cancer, there was a 34% reduction in risk for progression in subjects receiving 
pazopanib relative to lapatinib.  The median PFS was 17.1 weeks in the lapatinib group 
and 18.1 weeks in the pazopanib group.15 Interim analysis of data from 26 subjects 
showed that pazopanib has both a favorable toxicity profile and promising clinical 


  
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activity in subjects with advanced and progressive differentiated thyroid cancers.16  Five 
confirmed partial responses (PRs) (19%) were reported.  Pazopanib has not shown 
efficacy in phase 2 studies conducted in MM or glioma (Investigator’s Brochure) 
 
Safety  
The randomized, phase 3 study in RCC subjects provided a key comparison of safety 
with pazopanib compared to placebo.9  The overall frequency of adverse events (AEs) 
reported during the study was higher in the pazopanib arm (92%) compared with 
placebo (74%).  The most common AEs reported in >20% of subjects in the pazopanib 
arm were diarrhea (52%), hypertension (40%), hair color change (depigmentation; 
38%), nausea (26%), anorexia (22%), and vomiting (21%).  Most of the events were 
grade 1 or 2.  A higher number of grade 3 AEs were reported in the pazopanib arm 
(33%) compared with the placebo arm (14%).  The most frequent grade 3 AEs in the 
pazopanib arm were increased alanine aminotransferase (ALT), increased aspartate 
aminotransferase (AST), hypertension, and diarrhea.  The frequency of grade 4 and 
grade 5 AEs was similar between the pazopanib and placebo arms:  grade 4 in 7% and 
6%, respectively; grade 5 in 4% and 3%, respectively. 
 
A comprehensive review of all completed and ongoing pazopanib clinical trials with a 
cut-off date of September 2009, lists 15 most commonly occurring serious AEs (SAEs) 
(Investigator’s Brochure).  Vomiting and diarrhea are the most commonly reported 
SAEs across all the pazopanib studies.  As a consequence of this, dehydration is also 
seen with pazopanib treatment.  For most reports, the AEs resolved after supportive 
treatment such as antiemetics, antidiarrheal agents, and IV fluids.  GI perforation is 
commonly associated with VEGF pathway inhibitors.  This may manifest as abdominal 
pain which is not uncommon in cancer subjects for many reasons.  Of the 42 subjects in 
pazopanib trials with SAEs of abdominal pain, only three had a documented underlying 
intestinal perforation.  In July 2006, the DCTD, NCI, issued an Action Letter to 
investigators using pazopanib describing the occurrence of bowel perforations in 
subjects on pazopanib clinical trials. 
 
Dyspnea is also frequently seen in pazopanib-treated subjects and may reflect the 
underlying disease under treatment.  Anemia is commonly seen in cancer subjects in 
association with chemotherapy, hemorrhage, or infection.  The SAEs of pyrexia were 
attributed to multiple causes:  concurrent infections, the underlying malignancy, hepatic 
events, other concomitant medications, and unknown causes.  Hepatic events are 
thought to be on-target tyrosine kinase inhibitor (TKI) class effects, as hepatic enzyme 
elevations have been seen with other agents of this class.  Careful clinical evaluation is, 
therefore, warranted in subjects with hepatic abnormalities.  Pneumonia can be a 
complication of chemotherapy or can result from debilitation and advanced disease.  
Review of the 33 SAEs showed the presence of an underlying cause other than 
pazopanib in 19 of the 30 subjects.  Fatigue and asthenia are commonly reported and 
have multiple causes. 
 
Hypertension observed with pazopanib is a known class effect.  There have been 30 
SAEs of hypertension and 3 SAEs of hypertensive crisis in pazopanib clinical trials.  
There were 28 subjects who were effectively treated with antihypertensive medication 
initiation or dose adjustment, while 4 had no such treatment.  Although there were 29 
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due to pazopanib.  There have been 24 SAEs of pulmonary embolism (PE) reported in 
pazopanib trials.  This is of particular relevance since other members of this class have 
been associated with PE and other venous thromboembolic events. 
 
In addition, there have been reports of cardiac and cerebral ischemic events, GI 
perforation or hemorrhage, pulmonary hemorrhage, cerebrovascular hemorrhage, QT 
prolongation, and Torsades de Pointes in pazopanib clinical trials. 
 
Clinical Pharmacokinetics 
The oral bioavailability of pazopanib reflects absorption that is limited by solubility 
above doses of 800 mg once daily (Investigator’s Brochure).17  Increases in doses above 
800 mg to 2000 mg in the fasted state will not result in increased systemic exposure.  
Geometric mean pazopanib t½ values ranged from 18.1-52.3 hours.  The mean t½ was 
30.9 hours in the 800 mg once daily group, in phase 2 and 3 trials.  Oral absorption is 
significantly enhanced when dosed with food; therefore, it is recommended to 
administer pazopanib on an empty stomach, at least 1-2 hours after a meal.   
 
Preliminary information on the pharmacokinetics (PK) of pazopanib administered in 
combination with lapatinib has been reported.18  Thirty-three subjects received doses of 
lapatinib ranging from 750-1500 mg once daily along with pazopanib at doses of 200-
500 mg daily.  Preliminary mean plasma concentrations 24 hours after administration 
(C24) on day 22 were ~19 mcg/mL and 23 mcg/mL after pazopanib doses of 250 mg and 
500 mg, respectively.  These values are similar to the mean C24 values observed after 
administration of 800 mg pazopanib alone (23.1 mcg/mL).  Plasma lapatinib 
concentrations at 750-1500 mg daily were similar to those observed after monotherapy.  
Concurrent administration of pazopanib and lapatinib was generally well tolerated; 
coadministration of lapatinib may alter the PK of pazopanib.18  
 
Preliminary PK information on the combination of pazopanib and paclitaxel 
administered to subjects with advanced cancer has been reported.19 Twelve subjects 
received paclitaxel (15-80 mg/m2 on days 1, 8, and 15 every 28 days) and pazopanib at 
400 or 800 mg/day starting on day 2 of the first cycle.  Coadministration of pazopanib 
increased paclitaxel mean Cmax and AUC0-8 approximately 20-35%.19 
 
Age, body weight, gender, and race had no significant influence on pazopanib PK. 
 
Potential Drug Interactions 
Pazopanib is metabolized primarily by CYP3A4, and systemic exposure to pazopanib is 
altered by inhibitors and inducers of this enzyme.  The concomitant use of strong 
CYP3A4 inhibitors should be avoided.  If co-administration of a strong CYP3A4 
inhibitor is warranted, a dose reduction to 400 mg is recommended.  Grapefruit may 
also increase plasma concentrations of pazopanib and should be avoided.  CYP3A4 
inducers such as rifampicin may decrease plasma concentrations; therefore, an 
alternative concurrent medication with none or minimal enzyme induction should be 
used.  Concomitant use of medications that have narrow therapeutic windows and that 
are substrates of CYP3A4, CYP2D6 or CYP2C8 should occur only with caution. 
 
Concomitant medications that have narrow therapeutic windows and are substrates of 
CYP3A4, CYP2D6 or CYP2C8 should be used with caution.  If possible, medications 


  
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that are not substrates for these enzymes and/or do not have narrow therapeutic 
windows should be substituted.  
 
Dose Selection 
Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg once 
daily, results in effects consistent with inhibition of the VEGF receptors and angiogenic 
factors (Investigator’s Brochure).  Concentration-effect relationships were observed 
between trough plasma pazopanib concentrations and the development of hypertension 
as well as the percent change from baseline to the nadir of soluble VEGFR2 
(sVEGFR2), a marker of VEGFR inhibition.  Decreases in sVEGFR2 have been 
correlated with increased clinical benefit in RCC with other small molecule TKIs.20   
The trough plasma pazopanib concentrations associated with the EC50 in both 
concentration-effect relationships were similar (15.3 mcg/mL for hypertension and 21.3 
mcg/mL for sVEGFR2).    Pazopanib monotherapy has been approved as an 800 mg 
once daily dose for the treatment of advanced RCC in the US.  In a phase 1 dose-finding 
study in subjects with HCC, the maximum tolerated dose (MTD) for single-agent 
pazopanib in subjects was determined to be 600 mg once daily (Investigator’s 
Brochure).  The 800 mg once daily dose was not well tolerated resulting in 40% of 
subjects experiencing dose-limiting toxicities (DLTs).  No DLTs were observed at 600 
mg once daily among the six subjects enrolled in the dose-escalation phase.  However, 
in the cohort expansion phase at 600 mg, one subject had a grade 4 GI hemorrhage and 
grade 4 transaminase increases. 
 
2.3 
Rationale for the use of pazopanib in ovarian, peritoneal and tubal cancers 
Angiogenesis targeting and Pericyte targeting  
Currently, the GOG (in concert with CTEP and/or the pharmaceutical companies) is 
running several single arm phase II biologic agent trials in the 170-queue.  To date, 
clinical activity has been reported in seven. One of these agents has demonstrated 
clinical activity considered significant for further clinical development, bevacizumab 
(GOG-0170D).21  It is not a surprise that agents targeting the processes of angiogenesis 
would be of some importance in this disease, which has been documented both pre-
clinically and clinically to be vulnerable to inhibition of VEGF and/or its receptors and 
be associated prognostically with fluctuating levels of pVEGF.  Multiple reports have 
shown that angiogenesis, as measured by microvessel density, is associated with worse 
survival for ovarian cancer patients.22-26  Bevacizumab is already in front-line and 
recurrent phase III investigation, and has been shown to increase the progression-free 
survival by 3.8 months in the upfront setting.  Burger et al. demonstrated a 21% 
response rate with a median response duration of 10 months for patients with recurrent 
epithelial ovarian cancer treated with single agent bevacizumab.21  Nevertheless, new 
agents are vitally necessary, specifically those that may offer clinical response in 
women previously exposed to VEGF targeted therapy by targeting other factors in the 
tumor microenvironment, such as pericytes and stromal growth factors.   
 
Pericyte homeostasis has been demonstrated to be an important factor in maintaining 
normal and maturing vasculature.27 This homeostasis is controlled by a ligand-receptor 
system, which is amplified in many human tumor cells and pericytes and leads to 
bizarre morphology and dysfunction of these supporting vascular cells.  Pericytes have 
also been implicated in protecting endothelial cells from the effects of anti-VEGF 
therapy.28 Unfortunately, targeting just the pericyte with PDGF inhibitors has led to 


  
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little or no effect on tumor growth, and in some clinical trials has led to undesirable 
toxicities, such as fluid accumulation – largely explained by the reversion of a more 
immature vascular phenotype devoid of pericytes.29 Nevertheless, it has been 
hypothesized that dual targeting of VEGF and PDGF would lead to enhanced anti-
angiogenesis therapy.  Preclinical models using specific agents (fusion proteins against 
VEGF and PDGF) or multi-targeted (SU6668) agents have supported this effect in 
various tumor models.27,28  Another study reported efficacy in controlling malignant 
ascites from ovarian cancers in a murine model.30 Clinically, trials are ongoing in 
ovarian cancer with agents targeting VEGFR and PDGFR.  Recently, a phase II trial of 
sunitinib demonstrated a response rate of 13%- 1 partial response and 3 CA125 
responses.31  In addition, a phase II study of sorafenib, a multi-targeted receptor kinase 
inhibitor, including VEGFR and PDGFR in combination with gemcitabine 
demonstrated an objective response rate of 4%, and a CA125 response of 28%.  23% of 
patients were progression free for at least 6 months.32  Sorafenib also demonstrated 
modest single-agent activity, with substantial toxicity, in GOG 170F where 69 patients 
were enrolled.33  PRs were observed in 3% of measurable patients and nearly 24% were 
non-progressive at 6 months.   
 
As mentioned previously, pazopanib is a potent angiogenic small molecular inhibitor of 
the tyrosine kinases VEGRF-1, -2, -3, PDGFR, and c-kit which has been evidenced by 
inhibition VEGFR-2 phosphorylation and endothelial cell migration.34-36   Friedlander et 
al. studied pazopanib in 36 patients with recurrent platinum sensitive and resistant 
epithelial ovarian, fallopian tube and primary peritoneal cancers.10  Patients with 
elevated CA125 with or without non-bulky (no mass > 4cm) measurable disease were 
eligible.  The CA125 response rate was 31%, median time to response was 29 days and 
median response duration was 113 days.  The most common adverse events included 
fatigue, gastrointestinal issues (nausea, vomiting, diarrhea) and headache.  Only 1 
patient had a grade 4 toxicity- peripheral edema.10 
 
2.4 
Weekly Gemcitabine and Safety of Combination Weekly Gemcitabine/Pazopanib 
Gemcitabine (2’,2’ – difluorodeoxycytidine, dFdC) is a nucleoside analog of cytidine 
with a wide-range activity in solid tumors.  Gemcitabine has undergone investigation in 
a series of phase I and phase II trials as single agent for second line therapy.  
Gemcitabine was approved for use in recurrent ovarian cancer by the FDA in 2006.  
Response rates have ranged from 11-60%.37-54  Very few and well tolerated side effects 
were observed. 
 
The earliest 3 trials were reported between 1995 and 1998.  Lund et al treated 51 
women with recurrent ovarian cancer.45  Gemcitabine dose was 800 mg/m2 and 
treatment was given weekly for 3 weeks followed by 1 week off.  In this study a 19% 
PR rate was reported (no CR).  In 1996 Shapiro et al reported 38 women with recurrent 
ovarian cancer treated on the same schedule with a dose of 1000 mg/m2.52  In this study 
the RR was 13%.  Friedlander et al reported 38 patients with recurrent ovarian cancer 
treated with a dose of 1200 mg/m2.40  Two patients had CR, 3 had PR for overall RR of 
13.9%.  Notably, there was stable disease in 50% of patients.  The most common 
toxicities seen in this study were neutropenia and leukopenia.   
 
Subsequent studies were more rigorous about defining platinum sensitivity status and 
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The retrospective review published by Safra et al highlights the different response rates 
between platinum resistant and platinum sensitive patients.51  In this series, most 
women were heavily pretreated, with a mean of 3 prior regimens (range 2-8).  Single 
agent gemcitabine was given at 1000 mg/m2 for 3 weeks with 1 week off.  Forty three 
total patients were treated: 22 platinum sensitive and 21 platinum resistant.  In the 
platinum sensitive group, there were 45% PR and 45% SD.  Median time to progression 
(TTP) was 5 months and median survival was 16.5 months.  In the platinum resistant 
group, the PR rate was only 5% but there were 43% of patients with SD.  Median TTP 
was 2.8 months and median survival 6.3 months. 
 
Other prospective studies suggest a higher response rate for single agent gemcitabine in 
the platinum resistant population.  The phase II study reported by Markman et al had 
very stringent criteria for establishing platinum resistance and included only patients 
that were both platinum and paclitaxel resistant.48  In that study 51 patients were treated 
in a 3 out of 4 week schedule. These patients had been treated with a median of 3 prior 
therapies (range 1-6).  The gemcitabine dose started at 1250 mg/m2 but after the first 10 
patients was decreased to 1000 mg/m2 due to toxicity. Even at 1000 mg/m2 dose 
modifications were required in 50% of patients.  In this very highly platinum resistant 
population, there were 4 PR’s by RECIST and 4 patients with greater than 75% drop in 
CA 125 for an ORR of 16%.  There were no CR’s.  The median duration of response 
was 4 months and overall survival 7 months. 
 
Overall, when all studies of single agent gemcitabine are combined, the response rate is 
19%.42,43    In the majority, but not all of these studies, the participants were likely to 
have platinum-resistant disease and were heavily pretreated.  Doses higher than 1000 
mg/m2 in heavily pretreated patients are not advised because of the risk of severe 
myelosuppression42,43   It is notable that an additional 30% of patients experienced 
stable disease, for an overall clinical benefit rate of approximately 50%. 
 
Gemcitabine toxicity is mild, transient, and noncumulative.55  It includes 
myelosuprresion (dose-limiting), flu-like symptoms, fatigue, fever, peripheral edema, 
proteinuria, cutaneous reactions, and respiratory and GI effects. There have been rare 
reports of HUS and cardiac dysfunction, including MI, CHF, and atrial fibrillation.  
Overall, gemcitabine toxicity is rarely severe or a cause for discontinuing drug. The 
myelosuppression is easily managed by lowering the dosage. 
 
The combination of pazopanib and gemcitabine has been studied in a phase I trial and 
the results reported in the most updated pazopanib IB (Version 9.0, January 25, 2012).  
The primary goal of the phase I study was to determine the OTR (defined as the highest 
dosing regimen that resulted in a DLT in no more than 1 of 6 subjects) of oral 
pazopanib administered once daily plus gemcitabine on days 1 and 8 of a 21 day 
treatment cycle.  A total of 22 subjects with advanced solid tumors were enrolled in 3 
consecutive dose cohorts. 
 
For cohort Paz800/gem 1000 there were no DLTs observed in any subject during cycle 
1.  Paz800/Gem1250 was identified as the OTR. 
 


  
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The most commonly reported Aes (>50%) in enrolled subjects, regardless of causality, 
were: fatigeu (82%), nausea (68%), decreased appetite (59%), neutropenia (59%), and 
diarrhea (55%).  
 
 
A phase II trial (NCT01080248) is currently open at Washington University evaluating 
gemcitabine and pazopanib in pancreatic cancer.  The doses in this study are 
gemcitabine 1000 mg/m2 IV over 30 minutes on Days 1, 8 and 15 (of a 28 day cycle) 
and pazopanib 800 mg po daily every 28 days. 
 
The OTR has not yet been defined. 
 
2.5 
Translational Research 
There are no planned translational endpoints for this study. 
 
2.6 
Rationale for Clinical Trial Design 
This is an open label, randomized phase II trial. All patients will receive IV gemcitabine 
on days 1 and 8, every 21 days in combination with either oral pazopanib or no oral 
treatment.   
 
2.7 
Inclusion of Women and Minorities 
The University of Virginia will not exclude potential subjects from participating in this 
or any study solely on the basis of ethnic origin or socioeconomic status.  Every attempt 
will be made to enter all eligible patients into this protocol and therefore address the 
study objectives in a patient population representative of the entire ovarian, fallopian 
tube and primary peritoneal cancer population treated. 


  
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3.0 
PATIENT ELIGIBILITY   
 
3.1 
Inclusion Criteria 
3.11 
Patients must have recurrent or persistent epithelial ovarian, fallopian tube or 
primary peritoneal carcinoma.  Histologic documentation of the original primary 
tumor is required via the pathology report. 
3.12 
Patients must have measurable disease or detectable (non-measurable) disease: 
3.121 Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded).  
Each lesion must be greater than or equal to 10 mm when measured by 
CT, MRI or caliper measurement by clinical exam; or greater than or 
equal to 20 mm when measured by chest x-ray.  Lymph nodes must be 
greater than or equal to 15 mm in short axis when measured by CT or 
MRI. 
3.122 Detectable disease in a patient is defined as one who does not have 
measurable disease but has baseline value of CA-125 at least 2 x ULN 
3.13 
Patients who have measurable disease must have at least one “target lesion” to 
be used to assess response on this protocol as defined by RECIST 1.1.  Tumors 
within a previously irradiated field will be designated as “non-target” lesions 
unless progression is documented or a biopsy is obtained to confirm persistence 
at least 90 days following completion of radiation therapy. 
3.15 
Patients who have received one prior regimen must have an ECOG Performance 
Status of 0, 1, or 2. 
 
Patients who have received two or three prior regimens must have an ECOG 
Performance Status of 0 or 1. 
3.16 
Recovery from effects of recent surgery, radiotherapy, or chemotherapy: 
3.161 Patients should be free of active infection requiring antibiotics (with the 
exception of uncomplicated UTI). 
3.162 Any hormonal therapy directed at the malignant tumor must be 
discontinued at least one week prior to registration.   
3.163 Any other prior therapy directed at the malignant tumor, including 
chemotherapy, biological/targeted and immunologic agents (including 
small molecules and murine monoclonal antibodies), must be 
discontinued at least three weeks prior to registration.  Chimeric or 
human or humanized monoclonal antibodies (including bevacizumab) or 
VEGF receptor fusion proteins (including VEGF TRAP/aflibercept) 
must be discontinued for at least 8 weeks prior to registration. 
3.164 At least 4 weeks must have elapsed since the patient underwent any 
major surgery (e.g., major: laparotomy, laparoscopy, thoracotomy, video 
assisted thorascopic surgery (VATS); minor: central venous access 
catheter placement, ureteral stent placement or exchange, paracentesis, 
thoracentesis). 


  
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3.17 
Prior therapy 
3.171 Patients must have had one prior platinum-based chemotherapeutic 
regimen for management of primary disease containing carboplatin, 
cisplatin, or another organoplatinum compound.  This initial treatment 
may have included intraperitoneal therapy, consolidation, non-cytotoxic 
agents (biologic/targeted agents, such as bevacizumab) or extended 
therapy administered after surgical or non-surgical assessment.  If 
patients were treated with paclitaxel for their primary disease, this can 
have been given weekly or every 3 weeks. 
3.172 Patients are allowed to receive, but are not required to receive, two 
additional cytotoxic regimens for management of recurrent or persistent 
disease. 
3.173 Patients are allowed to receive, but are not required to receive, non-
cytotoxic (biologic/targeted agents, such as bevacizumab) therapy as part 
of their primary treatment regimen.  Patients are allowed to receive, but 
are not required to receive, PARP inhibitors for management of primary 
or recurrent/persistent disease (either alone or in combination with 
cytotoxic chemotherapy).  PARP inhibitors or non-cytotoxic therapies do 
NOT count as a prior regimen when given alone. 
3.18 
Patients must have adequate: 
3.181 Bone marrow function:  
 Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl. 
 Platelets greater than or equal to 100,000/mcl. 
 Hemoglobin greater than or equal to 9 g/dL.  Patients may not have 
had a transfusion within 7 days of screening assessment. 
3.182 Blood coagulation parameters: PT such that international normalized 
ratio (INR) is less than or equal to 1.2 x ULN (or an in-range INR, 
usually between 2 and 3, if a patient is on a stable dose of therapeutic 
warfarin) and a PTT less than or equal to 1.2 x ULN.   
 Note: Subjects receiving anticoagulant therapy are eligible if their 
INR is stable and within the recommended range for the desired level 
of anticoagulation. 
3.183 Renal function:  Creatinine less than or equal to 1.5 mg/dL, or if >1.5 
mg/dL, creatinine clearance must be at least 50 ml/min 
3.184 Urine Protein:  Urine Protein to urine creatinine ratio (UPC) should be 
less than 1. If greater than 1, then 24 hour urine protein must be less than 
1g for patient to be eligible. 
3.185 Hepatic function:  
 Bilirubin less than or equal to 1.5 x ULN. 
 AST (SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN  


  
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 Subjects who have BOTH bilirubin greater than ULN and AST/ALT 
greater than 1.0 x ULN are not eligible 
3.186 Thyroid function: Patients should have normal baseline TSH. Patients 
with elevated TSH level (between 4.5-10 mU/L in the absence of 
symptoms of hypothyroidism) must have a normal free thyroxine (T4). 
TSH that is 10 mU/L or higher is exclusionary.  
 A history of hypothyroidism and/or hyperthyroidism is allowed, as 
long as the patient has stable well-controlled thyroid function for a 
minimum of 2 months. 
3.19 
Patients of childbearing potential must have a negative pregnancy test prior to 
the study entry and be practicing an effective form of contraception.  Pregnant 
women are excluded from this study because of the potential for teratogenic or 
abortifacient effects. 
3.110 Patients must have signed an approved informed consent and 
authorization permitting the release of personal health information.   
3.111 Patients must meet pre-entry requirements as specified in section 7.0. 
3.112 Patients must be greater than or equal to 18 years of age.  
3.113 Patients must be capable of taking and absorbing oral medications.  A 
patient must be clear of the following: 
 any lesion, whether induced by tumor, radiation or other conditions, 
which makes it difficult to swallow tablets 
 prior surgical procedures affecting absorption including, but not 
limited to major resection of stomach or small bowel 
 active peptic ulcer disease 
 malabsorption syndrome 
3.114 Any concomitant medications that are associated with a risk of QTc 
prolongation and/or Torsades de Pointes should be discontinued or 
replaced with drugs that do not carry these risks, if possible.  Patients 
who must take medication with a  risk of possible risk of Torsades de 
Pointes should be watched carefully for symptoms of QTc prolongation, 
such as syncope.  See Appendix II for a list of medications that may 
cause QTc prolongation.  
 
Patients with personal or family history of congenital long QTc 
syndrome are NOT eligible. 
3.115 CYP3A4 Inhibitors: Strong inhibitors of CYP3A4 are prohibited.  
Grapefruit juice is an inhibitor of CYP450 and should not be taken with 
pazopanib. 
CYP3A4 Inducers: Strong inducers of CYP3A4 are prohibited. 


  
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CYP Substrates:  Concomitant use of agents with narrow therapeutic 
windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not 
recommended.   
3.116 A female is eligible to enter and participate in this study if she is of:  
a.   Non-childbearing potential (i.e., physiologically incapable of 
becoming pregnant), including any female who has had: 
 a hysterectomy 
 a bilateral oophorectomy 
 a bilateral tubal ligation 
 is post-menopausal 
 
b.  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: 
 complete abstinence from sexual intercourse for 14 days before 
exposure to investigational product, through the dosing period, 
and for at least 21 days after the last dose of investigational 
product 
 oral contraceptive, either combined or progestogen alone 
 injectable progestogen 
 estrogenic vaginal ring 
 percutaneous contraceptive patches 
 Intrauterine device (IUD) or intrauterine system (ISU) with a 
documented failure rate of less than 1% per year 
 male partner sterilization (vasectomy with documentation of 
azzospermia) prior to the female subject’s entry into the study, 
and this male is the sole partner for that subject 
 double barrier method: condom and an occlusive cap (diaphragm 
or cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository)  
3.2 
Exclusion Criteria 
3.21 
Patient who have had previous treatment with pazopanib or with weekly 
gemcitabine for recurrent or persistent disease. 
3.22 
Patients with a history of other invasive malignancies, with the exception of 
non-melanoma skin cancer and other specific malignancies as noted in Section 
3.23 and 3.24, are excluded if there is any evidence of other malignancy being 
present within the last two years.  Patients are also excluded if their previous 
cancer treatment contraindicates this protocol therapy. 


  
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3.23 
Patients who have received prior radiotherapy to any portion of the abdominal 
cavity or pelvis within the last three years are excluded. Prior vaginal 
brachytherapy is allowed. Prior radiation for localized cancer of the breast, head 
and neck, or skin is permitted, provided that it was completed more than two 
years prior to registration, and the patient remains free of recurrent or metastatic 
disease.  
3.24 
Patients who have received prior chemotherapy for any abdominal or pelvic 
tumor OTHER THAN for the treatment of ovarian, fallopian tube, or primary 
peritoneal cancer within the last three years are excluded. Patients may have 
received prior adjuvant chemotherapy for localized breast cancer, provided that 
it was completed more than three years prior to registration, and the patient 
remains free of recurrent or metastatic disease. 
3.25 
Patients with clinically significant cardiovascular disease. This includes: 
3.251 Uncontrolled hypertension, defined as systolic greater than 150 mm Hg 
or diastolic greater than 90 mm Hg  
Note: Initiation or adjustment of antihypertensive medication(s) is 
 
permitted prior to study entry.   
3.252 Congenital long QT syndrome or baseline QTc greater than 480 
milliseconds. 
3.253 Myocardial infarction or unstable angina within 6 months prior to 
registration. 
3.254 New York Heart Association (NYHA) Class III or greater congestive 
heart failure. (see Appendix I ) 
3.255 History of serious ventricular arrhythmia (i.e., ventricular tachycardia or 
ventricular fibrillation) or serious cardiac arrhythmia requiring 
medication. This does not include asymptomatic, atrial fibrillation with 
controlled ventricular rate. 
3.256 Patients who have received prior treatment with an anthracycline 
(including doxorubicin, excluding liposomal doxorubicin) must have an 
echocardiogram or MUGA assessment and are excluded if they have an 
ejection fraction less than 50%. 
3.257 CTCAE v.4.0 Grade 2 or greater peripheral vascular disease (at least 
brief less than 24 hrs) episodes of ischemia managed non-surgically and 
without permanent deficit. 
3.258 History of cardiac angioplasty or stenting within 6 months prior to 
registration.  History of coronary artery bypass graft surgery within 6 
months prior to registration. 
3.259 Arterial thrombosis within 6 months prior to registration. 
3.26 
Patients with serious non-healing wound, ulcer, or bone fracture. This includes 
history of abdominal fistula, gastrointestinal perforation or intra-abdominal 
abscess within 28 days prior to the first date of study treatment.  
Note: Deliberate surgically created abdominal fistula is acceptable.  


  
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3.27 
Patients with active bleeding or pathologic conditions that carry high risk of 
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving 
major vessels  
3.28 
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. 
3.29  History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pazopanib. 
3.210 Known HIV-positive subjects on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with 
pazopanib. 
3.211 Patients with any condition that may increase the risk of gastrointestinal 
bleeding or gastrointestinal perforation, including:  
 active peptic ulcer disease 
 known gastrointestinal intraluminal metastatic lesions 
(gastrointestinal serosa metastatic lesions are permitted) 
 inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s 
disease) or other gastrointestinal conditions with increased risk 
of perforation 
 patients with clinical symptoms or signs of gastrointestinal 
obstruction and patients who require parenteral hydration and/or 
nutrition. 
 
3.212 Clinically significant gastrointestinal abnormalities that may affect 
absorption of investigational product, including but not limited to.   
 malabsorption syndrome 
 major resection of the stomach or small bowel 
3.213 Patients who are pregnant or nursing.   
3.214  History of hemoptysis in excess of 2.5 mL (1/2 teaspoon) within 8 weeks 
prior to first dose of pazopanib. 
3.215  Uncontrolled intercurrent illness including, but not limited to, psychiatric 
illness/social situations that would limit compliance with study 
requirements. 
3.216 Any ongoing toxicity from prior anti-cancer therapy that is greater than 
grade 1 and/or that is progressing in severity, except alopecia. 
 
 


  
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3.217 Unable or unwilling to discontinue use of prohibited medications listed 
in Section 4.211 for at least 14 days or five half-lives of a drug (whichever is 
longer) prior to the first dose of study drug and for the duration of the study.  
 
4.0 
STUDY MODALITIES    
 
4.1 
Gemcitabine, Gemzar ® (NSC #613327) 
4.11 
Formulation:  Gemcitabine HCl is a nucleoside analog that exhibits anti-tumor 
activity. 
 
4.12  Supplier/How Supplied: Gemcitabine HCl is commercially available from Eli 
Lilly and Co. Gemcitabine is supplied as a white lyophilized powder in sterile 
single use vials containing 200mg (10 ml) or 1000 mg (50 ml) of gemcitabine as 
the hydrochloride salt. 
 
4.13  Stability/Storage:  Unopened vials of gemcitabine are stable until the expiration 
date indicated on the package when stored at controlled room temperature 
between 20 to 25ºC (68 to 77°F). 
 
4.14 
Preparation:   To reconstitute, add 5 ml of 0.9% Sodium Chloride Injection to 
the 200 mg vials or 25 ml to the 1000 mg vial. Shake to dissolve. These 
dilutions each yield a gemcitabine concentration of 38 mg/ml which includes 
accounting for the displacement volume of the lyophilized powder. The total 
volume upon reconstitution will be 5.26 ml or 26.3 ml, respectively. Complete 
withdrawal of the contents will provide 200 mg or 1 g of gemcitabine, 
respectively. The appropriate amount of drug may be administered as prepared 
or further diluted with 0.9% Sodium Chloride Injection to concentrations as low 
as 0.1 mg/ml. The solution should be clear, colorless to slightly straw colored. 
Do not administer if discoloration or particulate matter is found. Once the drug 
has been reconstituted, it should be stored at controlled room temperature and 
used within 24 hours. 
 
4.15 
Administration:  The mixed solution will be continuously infused over 30-60 
minutes minutes (see Section 5.2).  
 
4.16 
Adverse effects:   
 
Hematologic: The following Grade 3 and 4 toxicities can be expected after 
single agent therapy with doses between 800 and 1250 mg/m2: neutropenia 25%, 
leukopenia 9%, anemia 8%, and thrombocytopenia 5%. Infection occurred in 
16% of patients; sepsis occurred in less than 1%. 17% of patients experienced 
hemorrhage of Grade 2 or less. 
Gastrointestinal: Nausea and vomiting is frequent, up to 69%, but usually mild 
to moderate. Grade 3 and 4 nausea and vomiting were noted in 14%. Diarrhea 
was seen in 19%, stomatitis in 11%, and constipation in 23%. 
Pulmonary: Dyspnea was seen in 23%, severe in 3%. Rarely parenchymal 
toxicity including pneumonitis has been reported. Treatment should be 
discontinued immediately, if suspicious symptoms occur. 


  
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Hepatic: Transient elevation of hepatic enzymes was seen in 70%, however, this 
was not dose dependent and no increase was noted during prolonged therapy. 
Serious hepatotoxicity, including liver failure and death, has been reported very 
rarely. 
Fever: This is seen in up to 41%, but usually of a mild degree. Fever may be 
accompanied by flu-like symptoms in 19%. 
Renal: Reversible proteinuria, hematuria are frequent; increased BUN and 
creatinine in 16% and 8% of patients, respectively. However, renal insufficiency 
or hemolytic uremic syndrome is very rare. If suspicious symptoms are noted 
therapy should be discontinued immediately. 
Dermatologic/Skin: Alopecia is seen in 15%; a reversible macular or 
macularpapular rash is seen in 30%; pruritus occurs in 13%. Peripheral edema is 
seen in up to 20% of the patients treated. Infusion site reactions occurred in 4% 
of patients. 
Neurologic: There was a 10% incidence of mild paresthesias; somnolence 
occurred in 11% of patients. 
Pain at the site of injection: Seen in 48% of patients; Grade 3 in 9%. 
Other: Cardiovascular or allergic reactions are seen very rarely. 
 
*See FDA-approved gemcitabine package insert for a comprehensive list of 
adverse events associated with gemcitabine. 
 
 
4.2 
Pazopanib (CTEP IND#75648, NSC#737754)  
All investigators who receive a copy of the protocol will also receive a copy of the 
Investigator’s Brochure (IB). 
 
4.21 
Other Names:  Pazopanib HCl, GW786034B (the suffix B denotes the 
monohydrochloride salt). 
 
4.22 
Classification:  VEGFR tyrosine kinase inhibitor 
 
4.23 
Mechanism of Action:   Pazopanib is a highly potent inhibitor of vascular 
endothelial growth factor (VEGF) receptor tyrosine kinases (VEGFR1, VEGFR2, 
and VEGFR3). Vascular endothelial growth factor receptor inhibition may block 
VEGF driven angiogenesis and, as a consequence, constrain tumor growth.  
 
4.24 
Molecular Formula and Weight: C21H23N7O2S-HCl M.W.: 474.0 
(monohydrochloride salt); 437.5 (free base) 
 
4.25 
Chemical Name:     5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-
pyrimidinyl]amino]-2 methylbenzenesulfonamide monohydrochloride 
 
4.26 
Approximate Solubility:   The monohydrochloride salt is very slightly soluble in 
0.1 M HCl (0.65 mg/mL), and is practically insoluble in pH 7.0 phosphate buffer 
(0.00005 mg/mL), and in pH 11 piperidine buffer (0.0002 mg/mL).  
 
4.27 
How Supplied:  pazopanib is supplied as aqueous film-coated tablets containing 
the equivalent of 200 mg.  Each bottle will contain 34 oval-shaped, white, tablets.  


  
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Tablet excipients include microcrystalline cellulose, povidone, sodium starch 
glycolate, and magnesium stearate.   The film-coat consists of titanium dioxide, 
hypromellose, polyethylene glycol, and polysorbate 80.  
 
4.28 
Storage: The intact bottles should be stored at controlled room temperature. 
4.29 
Stability: Stability studies are ongoing.  
 
4.210 Administration: Oral Administration will be performed on an outpatient 
basis. Pazopanib will be dispensed as tablets at the beginning of each 
treatment cycle (Day 1, every 21 days).  Pazopanib should be taken on an 
empty stomach either 1 hour before or 2 hours after meals.  The tablets 
should be swallowed whole and cannot be crushed or broken.  If a dose is 
missed by > 12 hours, then the patient should skip that dose. If a dose is 
missed by ≤ 12 hours then the patient can take the missed dose when 
remembered.    
 
4.211 Potential Drug Interactions:  Additional information for drug interactions 
with cytochrome P450 isoenzymes may be found at:  
http://medicine.iupui.edu/flockhart/ 
 
Pazopanib is primarily metabolized by the human CYP3A4 isoenzyme.  Strong 
CYP3A4 inducers and inhibitors are prohibited on pazopanib trials.   
 
Medications that strongly inhibit CYP3A4 include (but are not limited to): 
 Antibiotics: clarithromycin, telithromycin, troleandomycin 
 HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, 
amprenavir, lopinavir) 
 Antifungals: itraconazole, ketoconazole, voriconazole 
 Antidepressants: nefazodone 
 
Medications that strongly induce CYP3A4 include (but are not limited to): 
 Glucocorticoids: cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone (>10 mg), methylprednisolone (>8 mg), dexamethasone 
(>1.5 mg).  Dexamethasone pre-medication for gemcitabine is allowed.   
 Anticonvulsants: phenytoin, carbamazepine, phenobarbital, 
oxcarbazepine HIV antivirals: efavirenz, nevirapine 
 Antibiotics: rifampin (rifampicin), rifabutin, rifapentine 
 Miscellaneous: St. John’s Wort, modafinil, pioglitazone, troglitazone 
 
Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6. Drugs that 
have narrow therapeutic windows and are substrates for these enzymes should 
be administered with extreme caution. Because of pazopanib’s long half-life, 
caution should continue to be exercised for at least 7 days and up to 15 days 
after the last dose of pazopanib when administering these medications. 
 
Medications that are substrates for these enzymes and have narrow 
therapeutic windows include (but are not limited to): 


  
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 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) 
 Immune modulators: cyclosporine, tacrolimus, sirolimus (potential 
increased risk for nephrotoxicity and neurotoxicity) 
 Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
 
Note: Zofran (ondansetron) is a CYP3A4 substrate but does not have a narrow 
therapeutic window and so can be given to patients for treatment of emesis.  
 
Pazopanib can prolong the QTc interval. See Appendix II. Drugs that are 
generally accepted to have a risk of causing Torsades de Pointes should be 
discontinued or replaced with drugs that do not carry this risk, if at all possible. 
Patients who receive potential QTc-prolonging medications should be monitored 
closely. 
 
Pazopanib may increase bleeding. All patients receiving pazopanib will be 
monitored for signs of bleeding with CBC and vital sign assesments performed 
on days 1 and 8 of every cycle. 
 
Pazopanib may cause decrease glucose. Patients receiving pazopanib and 
hypoglycemia agents should be monitored for hypoglycemia. 
 
Pregnant women are excluded from this study because pazopanib is an 
antiangiogenic agent which has produced teratogenic effects and reduced fetal 
body weight in pregnant rats and/or rabbits, and therefore has the potential for 
teratogenic or abortifacient effects in humans. Because there is an unknown but 
potential risk for AEs in nursing infants secondary to treatment of the mother 
with pazopanib, breastfeeding should be discontinued if the mother is treated 
with pazopanib. These potential risks may also apply to other agents used in this 
study. 
 
4.212   Availability:  
Pazopanib is an investigational agent supplied by Novartis.  
 
4.213 Clinical Supplies / Drug Ordering 
Clinical Supplies:  pazopanib (NSC 737754) will be provided by 
Novartis and distributed to the University of Virginia Investigational 
Drug Pharmacy.  UVA Investigational Drug Pharmacy will supply each 
site with full bottles for distribution by their pharmacy according to each 
pharmacy/state’s regulations. 
 


  
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Drug Ordering: 
Once a site has been activated, the site will receive a 2-cycle/8-week 
supply as an initial shipment.    Sites may reorder additional drug as 
needed by completing the provided Drug Request form and faxing it to 
UVA.  All drug orders will be shipped directly to the individual site’s 
investigational pharmacy. 
 
4.214 Drug Accountability:   
 
Sites must use an NCI DARF or an accountability form approved by the 
NCI.  UVA will review the site’s DARF (if not an NCI DARF) prior to 
dispensing drug. 
 
4.215 Drug Returns:  Only undispensed clinical supplies should be returned to 
the UVA investigational pharmacy. 
 
Drug Transfers:  Bottles MAY NOT be transferred from one patient to 
another patient or from one protocol to another protocol.  All other 
transfers must be approved in advance by the UVA investigational 
pharmacy and the UVA PI.   
4.216 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Pazopanib (GW786034, NSC 737754) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single 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_event
s_adeers for further clarification. Frequency is provided based on 1019 
patients. Below is the CAEPR for pazopanib (GW786034). 
 
 


  
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Version 2.2, March 18, 20101 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 1019] 
 
 
 
 EXPECTED AEs FOR 
OnCore REPORTING  
Agent Specific Adverse 
Event List 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Expected (up to grade 3) 
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain 
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea 
 
 
Gastrointestinal fistula2 
 Gastrointestinal fistula2 
 
 
Gastrointestinal hemorrhage3 
  
 
 
Gastrointestinal perforation4 
 Gastrointestinal perforation4 
Nausea 
 
 
 Nausea 
Vomiting 
 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased 
 
Blood bilirubin increased 
 
 Blood bilirubin increased 
 
 
Electrocardiogram QTc interval 
prolonged (accompanied by 
Torsades de pointes) 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased 
 
Neutrophil count decreased  
 Neutrophil count decreased 
 
Platelet count decreased 
 
 Platelet count decreased 
 
Serum amylase increased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia 
 
Dehydration 
 
 Dehydration 
 
Hyperglycemia 
 
 Hyperglycemia 
 
Hypermagnesemia 
 
  
 
Hypoglycemia 
 
 Hypoglycemia 
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
 Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia 
 
Myalgia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  


  
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Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness 
 
Dysgeusia 
 
  
 
Extrapyramidal disorder 
 
  
 
Headache 
 
 Headache 
 
 
  Reversible posterior 
  leukoencephalopathy syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria 
 
 Proteinuria 
 
 
  Urinary fistula 
 Urinary fistula 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
 
Female genital tract fistula 
 Female genital tract fistula 
 
 
Uterine fistula 
 Uterine fistula 
 
 
Vaginal fistula 
 Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Respiratory hemorrhage5 
 
 Respiratory hemorrhage5 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Rash maculo-papular 
 
 Rash maculo-papular 
Skin hypopigmentation 
 
 
 Skin hypopigmentation 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension 
 
 
 Thromboembolic event 
(venous)6 
  
 
 
 Vascular disorders – other 
(arterial thromboembolic 
event)6 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 
 


  
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6These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications. 
 
Also reported on pazopanib (GW786034) trials but with the relationship to pazopanib 
(GW786034) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia 
CARDIAC DISORDERS - Atrial fibrillation; Sinus bradycardia 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Dyspepsia; Dysphagia; Flatulence; Pancreatitis; Small intestinal 
obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Fever; Non-cardiac chest pain 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase increased; 
Creatinine increased; INR increased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hypernatremia; Hypocalcemia; 
Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Generalized muscle 
weakness 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Hematuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; Pleuritic 
pain; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Pruritus 
 
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. 
 
 
5.0 
TREATMENT PLAN AND ENTRY PROCEDURE 
5.1 
Patient Entry and Registration 
All eligible participants must sign an informed consent form.  Consented 
patients should be entered in the Cancer Center Clinical Trials Database 
(OnCore) prior to randomization. Prior to randomization, the signed informed 
consent, completed eligibility checklist along with supporting documentation 
should be submitted to the Sponsor (UVa) for review. Detailed registration 
information is included in a study procedures manual. 
 
Randomization will be discussed with subjects during the process of informed consent and 
informed consent must be documented prior to randomization. All participants who meet the 
inclusion/exclusion criteria may be randomized.  Randomization will be based on equal 
allocation among arms.  Randomization will not be stratified by institution. The randomization 
codes are generated by the study statisticians and stored in the UVa Cancer Center Clinical 
Trials Database (OnCore).  Randomization occurs at the time of registration into the Cancer 
Center database.   Randomization will not occur more than 1 day (+/- 2 days to allow for 
weekends and/or holidays) prior to the anticipated treatment date.  
 
 
This study will be conducted on an outpatient basis.   
 
5.2 
Treatment Plan 


  
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5.21 
Eligible patients will receive: 
Regimen 1:  Gemcitabine 1000 mg/m2 administered weekly on days 1 
and 8 (30-60 minutes IV infusion)  
 
Regimen 2:  Gemcitabine 1000 mg/m2 administered weekly on days 1 
and 8 (30-60 minutes IV infusion) with Pazopanib 800mg 
PO daily for 21 days 
 
One cycle equals 21 days. 
Maximum body surface area used for gemcitabine dose calculations will 
be 2.0 m2 
 
Chemotherapy doses will be based on the subject’s weight at baseline 
and will remain the same throughout the study. However, the doses will 
be recalculated if the patient has a weight change of greater than or equal 
to 10% from baseline. 
 
Patients are instructed to swallow tablets once a day (preferably in the 
morning) on an empty stomach, either 1 hour before or 2 hours after food 
with about 1 cup (240 mL) water.  Tablets should be swallowed whole; 
they must not be chewed, broken, or crushed. 
 
Patients will be given a Patient Medication Calendar to complete daily..  
The Patient Tablet Calendar should be reviewed prior to the start of each 
cycle. 
 
All prescription and over-the-counter medications as well as alternative 
medicines that have been taken within 4 weeks prior to the first dose of 
pazopanib should be reviewed for potential drug-drug interactions (see 
Section 4.211, 5.33 and Appendices III). 
 
5.211 Recommended preparative regimen for gemcitabine (to reduce 
the risk associated with hypersensitivity reactions):  This regimen 
should include a standard dose of dexamethasone (either IV or 
PO), an anti-histamine H1 (diphenhydramine 25-50 mg IV or 
orally, or an equivalent dose of an alternate H1blocker such as 
loratadine or fexofenadine), and a standard dose of antihistamine 
H2 IV (such as cimetidine, ranitidine, or famotidine). 
Dexamethasone is allowed here as a preparative treatment despite 
the CYP3A4 interactions. The preparative regimen can be altered 
at the discretion of the treating investigator. 
 
5.22 
If side effects are not severe, a patient may remain on study indefinitely 
until evidence of disease progression or unacceptable toxicity. 
 


  
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5.3 
Concomitant Medications:  Information for drug interactions with 
cytochrome P450 isoenzymes may be found at 
http://medicine.iupui.edu/flockhart/  
Additional information can be found in Appendix II and Section 4.211. 
5.31 
Specific recommendations regarding anticoagulants:  Results from drug-
drug interaction studies conducted in subjects with cancer suggest that 
pazopanib has no effect on the metabolism of S-warfarin.  Hemorrhagic 
events, however, have been reported in clinical studies with pazopanib; 
therefore, pazopanib should be used with caution in subjects with 
increased risk of severe bleeding or who are receiving concomitant 
anticoagulant therapy (e.g., warfarin or its derivatives, low molecular 
weight heparin).  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. 
 
5.32 
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. 
 
5.33 
The Effects of Pazopanib on Other Drugs: In vitro data indicate that 
pazopanib is a potential inhibitor for CYP3A4, CYP2C8, CYP2D6, 
CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.  
Pregnane X receptor transient transfection assay suggested some 
potential for human CYP3A4 induction at high concentrations.  Results 
from drug-drug interaction studies conducted in subjects with cancer 
suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and 
CYP2D6 in vivo, but had no clinically relevant effect on CYP1A2, 
CYP2C9 or CYP2C19 metabolism.  Therefore, concomitant use of 
pazopanib with certain medications (substrates of CYP3A4, CYP2C8, 
and CYP2D6) with a narrow therapeutic window should be undertaken 
with CAUTION due to the potential for alterations in the pharmacologic 
effects of these medications or an increased risk for serious or life 
threatening adverse events associated with such medications secondary 
to the inhibition of specific CYP enzymes by pazopanib.  
 


  
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See Section 4.211.  Additional information for drug interactions with 
cytochrome P450 isoenzymes may be found at 
http://medicine.iupui.edu/flockhart/ 
 
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.  
 
5.34 
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.   
 
 
Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2, or 
CYP2C19 in vivo but does in vitro.  Therefore, therapeutic doses of 
warfarin, a substrate of CYP2C9, and omeprazole, a substrate of 
CYP2C19 are permitted.  Caffeine, a substrate of CYP1A2, is also 
permitted.    
 
 
Medications that inhibit CYP3A4 may result in increased plasma 
pazopanib concentrations.  Selection of an alternate concomitant 
medication with no or minimal potential to inhibit CYP3A4 is 
recommended.    
 
See Section 4.211. Additional information for drug interactions with 
cytochrome P450 isoenzymes may be found at 
http://medicine.iupui.edu/flockhart/  
 
5.4 
Precautions/Warnings (See Appendix II)  
5.41 
QTc prolongation and Torsades de Pointes is a rare but serious adverse 
event associated with pazopanib.  Therefore, the following is required:  
 
5.411 Intensive QTc monitoring.  A baseline ECG is required prior 
to study registration, and subjects with QTc > 480 msec are 
excluded.  Repeat ECG must be performed during the day 1, 
cycle 2 visit.  If the QTc interval at 3 weeks is ≥ 500 msec, the 
subject should be removed from the study.   
 
5.412 Subjects must be questioned about family history of prolonged 
QTc, personal history of prolonged QTc, cardiac disease, and 
concomitant medications which are associated with a high risk of 
causing QTc prolongation prior to study registration (see sections 
3.114 and 3.25).   


  
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5.413 Concomitant treatment with drugs that are associated with a high 
risk of causing QTc prolongation should be changed to similar 
agents that do not pose such a risk, if possible, prior to a subject 
receiving the first dose of pazopanib.  A comprehensive list of 
agents that are associated with a risk of prolonging the QTc interval 
is provided in Appendix II.  Subjects who begin any drugs with a 
high risk for QTc prolongation while receiving pazopanib should 
be monitored carefully for signs of potential problems with QTc 
prolongation (syncope, etc.).  An ECG is not mandated in this 
circumstance; however, it should be performed at the treating 
physician’s discretion.    
 
5.42 
Hypertension is an important AE associated with pazopanib.  Frequent 
blood pressure (BP) monitoring is important in subjects receiving 
pazopanib starting on day 8 and continuing until subject is off study.  
Experience to date suggests that increases in BP may occur following 
dosing with pazopanib for a number of weeks and that these increases 
may occur relatively quickly.  It is imperative that the investigator 
institute appropriate measures to control BP.  This may necessitate 
changes to existing antihypertensive medication, addition of new 
medication(s) and/or interruption/withdrawal of pazopanib.  
Recommendations for hypertension management are presented in 
Appendix II. 
 
5.43 
Renal function (creatinine and urinary protein) should be frequently 
monitored as suggested by the pathologic changes noted in animal 
studies and evidence from studies of other antiangiogenic agents.  
Specific guidelines for management of proteinuria and elevated 
creatinine are presented in Appendix III. 
 
5.5 
Criteria for removal from treatment 
5.51 
Inability to tolerate the lowest doses of gemcitabine or pazopanib 
because of toxicity. 
 
5.52 
Patient may withdraw from study at any time for any reason.  Patients 
with evidence of progressive disease or patients with significant side 
effects will be removed from study treatment. 
 
5.53 
Patient may be withdrawn from the study treatment at any time at the 
discretion of the Primary Investigator. 
 
 


  
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6.0 
TREATMENT MODIFICATIONS     
Study Drug 
Initial dose level 
1 level reduction 
2 level reduction 
Gemcitabine 
1000  mg/m2 
800 mg/m2 
600 mg/m2 
Pazopanib 
800 mg PO 
600 mg PO 
400 mg PO 
 
Please note all CTCAE grading below refers to version 4.0. 
 
6.1 
Hematologic toxicity 
6.11 
Initial treatment modifications will consist of cycle delay and/or 
dose reduction as indicated below.  The use of hematopoietic 
cytokines and protective reagents are restricted as noted: 
 
6.111 Patients will NOT receive prophylactic growth factors 
[filgrastim (G-CSF), sargramostim (GM-CSF), 
pegfilgrastim (Neulasta)] unless they experience recurrent 
neutropenic complications after treatment modifications 
specified below. 
 
6.112 Patients will NOT receive prophylactic thrombopoietic 
agents. 
 
6.113 Patients may receive erythropoietin (EPO), iron 
supplements, and/or transfusions as clinically indicated 
for management of anemia. Treating physicians should be 
aware of prescribing information for the erythropoiesis 
stimulating agents (including Aranesp, Epogen and 
Procrit) which note that there is a potential risk of 
shortening the time to tumor progression or disease-free 
survival, and that these agents are administered only to 
avoid red blood cell transfusions. They do not alleviate 
fatigue or increase energy. They should not be used in 
patients with uncontrolled hypertension. They can cause 
an increased incidence of thrombotic events in cancer 
patients on chemotherapy. The updated package inserts 
should be consulted.   
http://www.fda.gov/Medwatch/safety/2007/safety07.htm 
 
6.114 Patients may NOT receive amifostine or other protective 
reagents. 
 
6.12 
Treatment decisions will be based on the absolute neutrophil 
count (ANC) rather than the total white cell count (WBC). 
 


  
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6.13 
Subsequent cycles of therapy will not begin (Day 1 of each cycle) 
until the ANC is  1500 cells/mcl and the platelet count is  
100,000/mcl.  Therapy will be delayed for a maximum of two 
weeks until these values are achieved.  Patients who fail to 
recover adequate counts within a two week delay will be 
removed from study. In the event a patients counts do not qualify 
for gemcitabine treatment, but are sufficient for pazopanib (See 
Appendix), pazopanib may be continued while gemcitabine is 
held. This will be considered a continuation of the previous cycle. 
A new cycle is defined by gemcitabine administration.  
 
 
Day 8 gemcitabine treatment will not be given unless ANC is  
1000 cells/mcl and the platelet count is  75,000/mcl.  If Day 8 is 
held, it should not be made up. 
 
6.14 
Patients requiring greater than two dose reductions of 
gemcitabine for any cause will result in discontinuation of study 
treatment.  Patients requiring greater than two dose reductions of 
pazopanib for any cause will result in discontinuation of 
pazopanib (with continuation of gemcitabine, if appropriate, 
until unacceptable toxicity or progression of disease).  Patients 
who have received at least one study treatment will continue to 
be followed and included in the primary analysis. 
 
6.15 
Dose modification for gemcitabine: 
 
 
ANC1 
PLT 
ACTION 
Day 1 
<1500 
 
 
 
< 100,000 
Delay.  Monitor counts weekly until 
adequate for gemcitabine treatment.  
 
Restart when counts are adequate for 
treatment; reduce gemcitabine one 
dose level. 
 
If counts do not recover after 2 weeks 
delay, remove from study. 
Day 8 
 
< 1000  
< 75,000 
Hold gemcitabine  
 
Reduce gemcitabine one dose level at 
subsequent cycle day 1 
1For febrile neutropenia, and/or documented grade 4 neutropenia persisting greater than or 
equal to 7 days, reduce gemcitabine by one dose level on subsequent cycles. 
 
6.2 
Dose interruption and modification of pazopanib 
Recommendations of dose modifications and management of patients 
experiencing adverse events, including but not limited to liver toxicity, 
hypertension and QTc prolongation, are provided in Tables A and B in 
Appendix II.  
 
 


  
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6.3  
Dose and Treatment Modifications for Gemcitabine Non-Hematologic Toxicity 
 
6.31 
Grade 2 (or greater) renal toxicity requires reduction of one dose level 
and delay in subsequent therapy for a maximum of 2 weeks until 
recovered to Grade 1.  Patients who fail to recover from Grade 2 or 
worse renal toxicity to Grade 1 or less will discontinue gemcitabine. 
Patients may continue with pazopanib as a single agent. For both groups, 
imaging studies (CT scans) should continue to be done on time 
(approximately every 6 weeks) in order to document time to progression. 
 
6.32 
There will be no dose modifications for alopecia or fatigue. 
 
6.33 
It is expected that patients with nausea, emesis, diarrhea, or constipation 
will receive appropriate medical management without dose modification.  
However, patients with persistent (greater than 24 hours) grade 3 (or 
greater) toxicity in spite of optimal medical management require 
reduction of one dose level of both drugs and delay in subsequent 
therapy for a maximum of 2 weeks until recovered to grade 1. 
 
6.34 
Unless otherwise specified within this protocol, non-hematologic 
toxicities with an impact on organ function of grade 2 (or greater) require 
reduction of one dose level and delay in subsequent therapy for a 
maximum of 2 weeks until recovered to grade 1, or pre-therapy baseline. 
 
6.4 
Dose escalations 
There will be no dose escalations or re-escalations on this study. 


  
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7.0 
STUDY PARAMETERS & SERIAL OBSERVATIONS    
 
Parameter 
 
Pre-
Study 
Prior to 
Each 
Cycle1 
Day 8 of 
each 
cycle 
Every 
other 
cycle 
Follow 
up2 
History & Physical 
X3 
X17 
 
 
X 
Vital signs (BP, HR, temp)4 
X3 
X 
X 
 
 
CBC/Differential/Platelets5 
X6 
X7 
X 
 
 
PT/INR and PTT8 
X6 
 
 
 
 
Electrolytes, BUN, creatinine, Ca, Mg, PO4 
X6 
X7 
 
 
 
Urine protein-creatinine ratio (UPCR) 
X9 
 
 
X10 
 
Bilirubin, AST (SGOT), ALT (SGPT), 
Alkaline Phosphatase 
X6 
X7 
X18 
 
 
Thyroid Function test (TSH) 
X6 
 
 
 
 
Serum Pregnancy Test (WOCBP) 
X6 
 
 
 
 
Electrocardiogram (ECG) 
X3,11 
X12 
 
 
 
LVEF Testing 
X3,13 
 
 
 
 
Chest imaging (x-ray or CT chest) 
X3 
 
 
X14 
X14 
Radiographic tumor measurement 
X3, 15 
 
 
X15 
X15 
Performance Status 
X3 
X17 
 
 
 
Clinical tumor measurement 
X3,16 
X16 
 
 
X16 
CA-125 
X6 
X 
 
 
X 
Toxicity Assessment 
X6 
X 
X 
 
X 
Patient Tablet Calendar 
 
X 
 
 
 
 
 
1 Can be done on Day 1 of the cycle 
2 Follow-up until progression of disease every three months for 2 yrs, every 6 months for 1 year and then yearly for 2 years for a maximum of 5 years.  AEs 
are collected through 30 days post last treatment dose. A visit should take place within this time frame to ensure all AEs are reported 
3 Must be done within 28 days prior to therapy..  
4 On day 15 of every cycle, patients taking pazopanib should have BP measured and recorded 
5 If grade 4 neutropenia is documented (ANC <500/µl), obtain twice per week until resolved to grade 3 
6 Must be done within 14 days prior to therapy.  
7 Must be done within 4 days of re-treatment with protocol therapy; ANC must be ≥ 1500 cells/µl and platelets ≥ 100,000/µl. Cycle 1 day 1 labs do not need 
to be repeated if screening labs were performed within 14 days of treatment.   
8 Patients on prophylactic or therapeutic anticoagulation with warfarin should have PT/INR monitored after starting and stopping pazopanib (e.g., weekly 
for the first cycle and weekly for a minimum of 2 weeks following discontinuation of pazopanib) and weekly for the first cycle of treatment following a 
warfarin or pazopanib dose modification 
9  If protein is 1+ or higher, 24-hour urine protein should be obtained and the level must be <1000 mg (<1 g/24hrs) 
10 Urine protein-creatinine ratio (UPCR) should be performed prior to every other cycle in subjects taking pazopanib. See the guidelines provided in 
Appendix III, Table A regarding treatment with pazopanib and proteinuria 
11 Baseline QTc must be < 480 ms 
12 In subjects taking pazopanib, ECG should be performed on day 1 of cycle 2 only. If QTc is > 500 ms, then subject is discontinued 
13 Required for patients who have received prior treatment with an anthracycline (including doxorubicin, excluding liposomal doxorubicin)  
14 Repeat chest imaging if initially abnormal or if required to monitor tumor response 
15 CT scan or MRI if used to follow lesion for measurable disease every other cycle during treatment and then every 3 months thereafter until disease 
progression is confirmed; also repeat at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease or 
rising serum tumor marker levels.  Responses (CR and PR) require confirmation at greater than or equal to 4 weeks from initial documentation (Section 
8). 
16 Every other cycle for those patients whose disease can be evaluated by physical examination according to RECIST 1.1 (Section 8) 
17 Cycle 1 day 1 Physical Exam and Performance status do not need to be repeated if performed within 5 days of treatment. Pelvic exam will be performed 
every other cycle, if clinically indicated 
18 In subjects taking pazopanib, testing should be performed on Day 8 of Cycle 1, 2 and 3.  


  
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8.0 
EVALUATION CRITERIA  
 
 
8.1 
 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
 
8.11 
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that 
can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >10 mm with CT scan, as >20 mm by 
chest x-ray, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in decimal fractions of 
centimeters. 
 
Note:  Tumor lesions that are situated in a previously irradiated 
area will not be considered measurable unless progression is 
documented or a biopsy is obtained to confirm persistence at least 
90 days following completion of radiation therapy. 
 
Malignant lymph nodes.  To be considered pathologically 
enlarged and measurable, a lymph node must be >15 mm in short 
axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), 
including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal/pelvic masses 
(identified by physical exam and not CT or MRI), are considered 
as non-measurable. 
 
Notes: 
Bone lesions:  Lytic bone lesions or mixed lytic-blastic lesions, 
with identifiable soft tissue components, that can be evaluated by 
CT or MRI can be considered as measurable lesions if the soft 
tissue component meets the definition of measurability described 
above.  Blastic bone lesions are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent 


  
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cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 
lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, and in 
addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in 
the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up.  
 
 
8.12 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric 
notation using a ruler or calipers.  All baseline evaluations should 
be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should 
be used to characterize each identified and reported lesion at 
baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered 
measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes) and 10 mm diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, 


  
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documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable 
lesions when they are clearly defined and surrounded by aerated 
lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined 
measurability of lesions on CT scan based on the assumption that 
CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable 
in certain situations (e.g. for body scans), but NOT lung.   
 
Use of MRI remains a complex issue.  MRI has excellent 
contrast, spatial, and temporal resolution; however, there are 
many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As 
with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was 
used at baseline, and the lesions should be measured/assessed on 
the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases.  Ideally, subsequent 
image acquisitions should use the same type of scanner and 
follow the baseline imaging protocol as closely as possible.  If 
possible, body scans should be performed with breath-hold 
scanning techniques. 
 
PET-CT: At present, the low dose or attenuation correction CT 
portion of a combined PET-CT is not always of optimal 
diagnostic CT quality for use with RECIST measurements.  PET-
CT scans are not always done with oral and IV contrast.  In 
addition, the PET portion of the CT introduces additional data 
which may bias an investigator if it is not routinely or serially 
performed.  For these reasons, this study will not allow PET-
CT use for RECIST 1.1 response criteria. 
     
FDG-PET:  While FDG-PET response assessments need 
additional study, it is sometimes reasonable to incorporate the 
use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible “new” disease).  
New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET 
at follow-up is a sign of PD based on a new lesion. 


  
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b. 
No FDG-PET at baseline and a positive FDG-PET at 
follow-up:  If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional 
follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of 
PD will be the date of the initial abnormal FDG-PET 
scan).  If the positive FDG-PET at follow-up corresponds 
to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is 
not PD. 
 
Note:  A “positive” FDG-PET scan lesion means one that is FDG 
avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image. 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size 
and should not be used as a method of measurement.  Ultrasound 
examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If 
new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT 
in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for 
objective tumor evaluation is not advised.  However, such 
techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response (CR) or 
surgical resection is an endpoint. 
 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer 
trials): CA125 alone cannot be used to assess response.  If CA125 
is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response.  Specific 
guidelines for CA-125 response (in recurrent ovarian cancer) 
have been published [JNCI 96:487-488, 2004].    In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 
progression criteria that are to be integrated with objective tumor 
assessment for use only in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology: These techniques can be used to 
differentiate between partial responses (PR) and complete 
responses (CR) in rare cases, e.g., residual lesions in tumor types, 


  
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such as germ cell tumors, where known residual benign tumors 
can remain. 
 
It is mandatory to obtain cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during 
treatment when measurable disease has met criteria for response 
or stable disease.  This confirmation is necessary to differentiate 
response or stable disease versus progressive disease, as an 
effusion may be a side effect of the treatment. 
 
 
 
8.13 
Response Criteria 
 
 
Determination of response should take into consideration 
all target (See 8.131) and non-target lesions (See 8.132) and, if 
appropriate, biomarkers (See 8.133). 
 
8.131 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis 
to <10 mm. 
 
 
 
 
 
 
 
 
Partial Response (PR): At least a 30% decrease in the 
sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in 
the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to 
qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters 
while on study. 
 
8.132 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-
target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Note:  If CA-125 is initially above the upper normal 
limit, it must normalize for a patient to be considered 
in complete clinical response. 
 


  
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Non-CR/Non-PD: Persistence of one or more non-
target lesion(s) Progressive Disease (PD): Appearance 
of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
Unequivocal progression should not normally trump 
target lesion status.  It must be representative of 
overall disease status change, not a single lesion 
increase. 
 
Not evaluable (NE):  When at least one non-target 
lesion is not evaluated at a particular time point. 
 
Although a clear progression of only “non-target” 
lesions 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). 
 
8.133 
Evaluation of Biomarkers 
If serum CA-125 is initially above the upper normal 
limit, it must normalize for a patient to be considered 
in complete clinical response. 
 
Progression cannot be based upon biomarkers, such 
as serum CA-125, for this study. 
  
8.134 Evaluation of Best Overall (unconfirmed) Response 
The best overall response is the best time point 
response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for 
progressive disease the smallest sum recorded since 
baseline).  The patient's best response assignment will 
depend on the achievement of both measurement and 
confirmation criteria in some circumstances. 
 
 
 


  
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Time Point Response for Patients with Measurable Disease at 
baseline (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
Biomarker 
CA-125 
New 
Lesions* 
Time Point  
Response 
CR 
CR 
Within 
normal limits 
No 
CR 
CR 
Non-CR/Non-PD 
Any value 
No 
PR 
CR 
NE 
Any value 
No 
PR 
PR 
Non-PD or NE 
Any value 
No 
PR 
SD 
Non-PD or NE 
Any value 
No 
SD 
NE 
Non-PD 
Any value 
No 
NE 
PD 
Any 
Any value 
Yes or No 
PD 
Any 
PD** 
Any value 
Yes or No 
PD 
Any 
Any 
Any value 
Yes 
PD 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion  
 
** In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Time Point Response for Patients with only Non-Measurable 
Disease at baseline (i.e., Non-Target Disease) 
 
Non-Target Lesions 
Biomarker 
CA-125 
New Lesions* 
Time Point 
Response 
CR 
Within normal limits 
No 
CR 
CR 
Above normal limits 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
Any value 
No 
Non-CR/non-PD* 
NE 
Any value 
No 
NE 
Unequivocal PD 
Any value 
Yes or No 
PD 
Any 
Any value 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion  
**  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
 


  
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8.135 Best Overall Confirmed Response  
 
Confirmation of CR and PR for determination of best overall 
response is required for studies with a primary endpoint that 
includes response. 
 
Confirmed CR and PR for best overall confirmed response 
 
Time Point Response 
First time point 
Time Point Response 
Subsequent time point 
BEST overall confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD  
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
 
*If a CR is truly met at first time point, then any disease seen at a 
subsequent time point, even disease meeting PR criteria relative 
to baseline, makes the disease PD at that point (since disease 
must have reappeared after CR).  However, sometimes ‘CR’ may 
be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the patient had PR or SD, not CR at 
the first time point. Under these circumstances, the original CR 
should be changed to PR or SD and the best response is PR or 
SD.  
 
In non-randomized trials where response is part of the primary 
endpoint, confirmation of CR or PR is needed to deem either one 
the “best overall response.”   Responses (CR and PR) require 
confirmation at greater than or equal to 4 weeks from initial 
documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring 
discontinuation of treatment or die without objective evidence of 
disease progression at that time should be reported to be off study 
treatment due to “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 


  
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8.14 
Duration of Response 
Duration of overall response:  The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
 
Patients who do not experience an event (recurrence/progression) will be 
censored at date of last contact. 
 
 
8.15 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from 
study entry to time of recurrence/progression or death from any cause, 
whichever occurs first. Patients who do not experience an event 
(recurrence/progression or death) will be censored at date of last contact. 
 
 
8.16 
Survival 
Survival is defined as the duration of time from study entry to time of 
death from any cause. Patients who do not experience an event (death) 
will be censored at date of last contact. 
 
8.2 
Recurrence-Free or Progression-Free Survival (non-measurable disease studies) 
is the period from study entry until disease recurrence, progression, death 
(regardless of the cause). Patients who do not experience an event (disease 
recurrence, progression, death) will be censored at date of last contact.  
 
The defined date of disease progression will depend on the method of 
determination as follows: 
 
8.21 
For disease recurrence or progression defined by imaging, the 
appearance of one or more new lesions, or unequivocal progression of 
existing non-target lesions, the date of progression will be defined as the 
date such lesions were first found to be progressed by imaging. 
 
8.22 
For disease progression defined by development or worsening of ascites 
or pleural effusions, the date of progression will be defined as the date 
when a sample was taken for cytologic verification. 
 


  
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8.23 
For disease progression defined by CA125 criteria alone, the date of 
progression will be defined as the first date of the initial CA125 of 
greater than or equal to two times the nadir value or upper limit of 
normal, whichever of these is applicable.  Since radiographic imaging is 
required within 2 weeks of the confirmatory (second) CA125 value, then 
if the imaging criteria are met for recurrence, then the date of 
progression would be defined as the date of the imaging study (See 
8.21). 
 
8.24 
If global deterioration in health status attributable to the disease is used 
to define progression, then a date indicating this event (e.g. transfer to 
hospice care) can be used to define the date of progression. 
 
In cases where several events can determine a date of progression, the 
earliest event should be used to establish the date of progression (with 
the exception provided in section 8.23). 
 
 
9.0 
DURATION OF STUDY    
Patients will receive therapy until disease progression or intolerable toxicity intervenes.  
The patient can refuse the study treatment at any time. 
 
All patients will be treated until disease progression or treatment withdrawal.  Patients 
will then be followed (with physical exams and histories) every three months for the 
first two years and then every six months for 1 year and then yearly for 2 years. The 
maximum follow-up period is 5 years. Off study tumor measurements should be 
continued for those patients who did not progress on therapy according to the schedule 
listed in Section 7.  Patients will be monitored for delayed toxicity and survival for the 
5-year period unless consent is withdrawn. 
 
10.0 
STUDY MONITORING & REPORTING PROCEDURE 
 
10.1 
 
Definitions 
10.1.1 Adverse Events 
An adverse event is any undesirable medical experience occurring to a 
subject who has been given an investigational product, whether or not 
related to the study drug(s). Medical conditions present before starting 
the investigational drug/intervention will be considered adverse events 
only if they worsen after starting study treatment. The following are 
adverse events: 
 All unfavorable, harmful or pathological changes in the general condition of 
a patient. 
 Subjective or objective symptoms (spontaneously offered by the patient 
and/or observed by the Investigator or the study nurse). 
 All intercurrent events or exacerbation of pre-existing diseases which 
occurred after the administration of the study drug. 
 All clinically significant changes in laboratory abnormalities. 


  
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 Any undesirable and unintended effect of research occurring in human 
subjects as a result of the collection of identifiable private information under 
the research. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).  
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious (see below, definition of SAE).  This also applies to patients 
experiencing AEs that cause interruption or discontinuation of investigational product, 
or those experiencing AEs that are present at the end of their participation in the study.  
Such patients should receive post-treatment follow-up as appropriate.  AEs will be 
collected up to 30 days post last dose of study drug in all cases including early study 
termination.  If an ongoing AE changes in its severity or in its perceived relationship to 
study drug, a new AE entry for the event should be completed. 
 
10.1.2 Unexpected Adverse Event 
Expected are those Adverse Events (AEs) that are bold and italicized in 
the CAEPR (see above).  Any AE that is higher than grade 2 or not 
included in the CAEPR is considered an unexpected AE. 
 
10.1.3 Serious Adverse Event 
A serious adverse event or experience (SAE) or serious adverse drug 
reaction (ADR) is any adverse event temporally associated with the 
subject’s participation in research that meets any of the following 
criteria: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
 Requires inpatient hospitalization or prolongation of existing 
hospitalization;* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant disability/incapacity; 
 Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the 
occurrences of pregnancy as an event which must be reported as an 
important medical event. 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 


  
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For the purposes of this study, the following must also be considered as an SAE: 
1. 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).  Note: bilirubin 
fractionation should be performed if testing available. 
2. 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).  Note: bilirubin 
fractionation should be performed if testing available. 
 
 
10.1.4 Attribution Assessment. 
The Principal Investigator will evaluate all AEs and assess their toxicity and 
attribution, if any, to study drug.  The following criteria will define the 
attribution: 
 
Definite: 
The AE is clearly relation to the investigational agent. 
Probable: The AE is likely related to the investigational agent. 
Possible: 
The AE may be related to the investigational agent. 
Unlikely: The AE is doubtfully related to the investigational agent. 
Unrelated: The AE is NOT related to the investigational agent. 
 
10.1.5 Hospitalization  
Hospitalization or prolongation of hospitalization associated with Grade 3, 4, 
or 5 events, unexpected and expected, and regardless of attribution.  
Hospitalization for expedited AE reporting purposes is defined as an inpatient 
hospital stay equal to or greater than 24 hours.  Hospitalization is used as an 
indicator of the seriousness of the adverse event and should be reserved for 
situations where the adverse event truly fits this definition and not for 
hospitalizations associated with less serious events.  For example, a hospital 
visit where a patient is admitted for observation or minor treatment (e.g. 
hydration) and released in less than 24 hours.   
 
10.1.6 Pregnancy  
Patients who become pregnant during the study should discontinue the study 
immediately. Patients should be instructed to notify the investigator if it is 
determined after completion of the study that they become pregnant either 
during the treatment phase of the study or within five days after the treatment 
period. Whenever possible a pregnancy should be followed to term, any 
premature termination reported, and the status of the mother and child should be 
reported to the Sponsor-Investigator after delivery. 
 
10.2 
Protocol violation 
A protocol violation is defined as any change, deviation, or departure from the study 
design or procedures of a research project that is NOT approved by the IRB prior to its 
initiation or implementation, OR deviation from  standard operating procedures, Good 


  
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Clinical Practices (GCPs), federal, state or local regulations. Protocol violations may or 
may not be under the control of the study team or staff. These protocol violations may 
be major or minor violations. 
 
10.3 
Data collection 
Data will be collected using a centralized electronic case report form called ON-line 
Clinical Oncology Research Environment = Oncore. Oncore is a highly secure, web 
based, cancer specific, and customizable system that provides fully integrative clinical 
data management and study administration capabilities developed in an ongoing 
collaborative effort with NCI designated Comprehensive Cancer Centers.  
 
10.4 
Reporting Requirements 
 
10.4.1 Expedited Reporting of Adverse Events 
Reporting of AEs will begin when the subject is administered the study drug or 
has a study related procedure. Events occurring in each subject will be recorded 
until 30 days post administration of the last treatment regardless of attribution.  
Adverse events that are possibly, probably, or definitely related to the study drug 
will be recorded until the subject completes treatment follow-up.   
 
All adverse events occurring at all participating sites must be recorded into the 
University of Virginia Cancer Center OnCore database within the time frame 
specified below: 
 
* For Hospitalization Only — Any medical event equivalent to CTC Grade 3, 4, 5 which precipitated hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of requirements for Phase of study, expected 
or unexpected and attribution.  
 
IRB Reporting Requirements 
Serious and unexpected adverse events must be submitted to the site Institutional 
Review Board according to the participating site institutional policies. 
 
For the University of Virginia clinical site, the Principal Investigator (PI) or designee is 
responsible for reporting AEs and unanticipated problems to the UVA HSR-IRB 
according to the following guidelines.   
 
Table B: Therapeutic Medium Risk Phase II Studies 
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 & 5 
 
Expected 
and 
unexpect
ed 
 Expected 
 
Unexpected 
Expected 
 
Unexpected 
 
Expected 
 Unexpected 
Without 
hospitalizati
on 
With 
hospitalizati
on 
Without 
hospitalizati
on 
With 
hospitalizati
on 
Unrelated 
Unlikely 
Not 
required 
Not 
required 
Not 
required 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
30 days 
ONCORE 
15 days 
ONCOR
E 
15 days 
ONCORE 
15 days 
Possible 
Probable 
Definite 
ONCOR
E 
30 days 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
30 days 
ONCORE 
15 days 
ONCORE 
15 days 
ONCORE 
15 days 
ONCOR
E 
15 days 
ONCORE 
(24-hrs)* 
7 days 
 
*Enter into Oncore within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 


  
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Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting 
in death that is deemed 
DEFINITELY related to 
(caused by) study 
participation 
An internal event is one that 
occurs in a subject enrolled 
in a UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected
adverse event  
 
See Oncore reporting 
requirement (sponsor's 
protocol section 10.5).  
 
IRB-HSR 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that 
are not adverse events or 
protocol violations  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vprgs/ir
b/HSR_docs/Forms/Reporting_R
equirements-
Unanticipated_Problems.doc ) 
 
  
Protocol Violations 
 (The IRB-HSR only requires 
that MAJOR violation be 
reported, unless otherwise 
required by your sponsor, if 
applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
 
Protocol Violation and 
Enrollment Exception Reporting 
Form 
 
 
http://www.virginia.edu/vprgs/ir
b/hsr_forms.html 
 
Go to 3rd bullet from the bottom. 
  
Data Breach  
The UVa 
Corporate 
Compliance and 
Privacy Office, a 
 
 
ITC:  if breach 
involves  
electronic data-  
 
 
 
UVa Police if 
breach includes 
such things as 
stolen 
computers.  
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
IMMEDIATELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/secur
ity/reporting.html 
 
 
Phone- (434) 924-7166 
 


  
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INDEPENDENT DSMB/DSMC 
DSMB/DSMC Reports 
IRB 
  
15 calendar days of 
the study team 
receiving the report 
Copy of DSMB/ DSMC report 
 
Major Protocol Violations OR enrollment Exceptions will be reported within 7 calendar 
days from the time the study team received knowledge of the event. 
 
10.4.2 Additional Reporting Requirements for Participating Clinical Sites 
In addition to the OnCore and IRB reporting requirements described above, all 
participating sites are required to report specific events to the Sponsor (UVa) to 
comply with GSK reporting requirements. These additional reporting 
requirements are as follows: 
 
Serious Adverse Events:  
SAEs should be initially reported to the Sponsor (UVA) using the Safety Reporting 
Cover Sheet within 24 hours of awareness. Complete SAE information should be 
reported to the Sponsor (UVa) via Oncore within 3 calendar days for deaths or life-
threatening events and 5 calendar days for other serious adverse events. Relevant 
hospital case records and autopsy reports (where applicable) should be sent to the 
Sponsor (UVA) at the time of Oncore data entry.  
 
The Safety Reporting Cover Sheet and supporting information should be sent to:  
Linda Duska, MD 
UVaPAZ@Virginia.edu 
 
Pregnancy:  
Pregnancy must be reported within 7 days of when the site is aware of the pregnancy to 
the Sponsor (UVa). Each pregnancy should be reported to the Sponsor (UVa) using the 
Safety Reporting Cover Sheet.  
 
All pregnancy information should be sent to:  
Linda Duska, MD 
UVaPAZ@Virginia.edu 
 
 
 


  
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Reporting to the Participating Sites: 
Because UVA PI is the Sponsor for the study, the UVA PI or designee is 
responsible for providing safety updates to all participating sites per the 
following guidelines: 
 
UVA PI of MULTI-SITE TRIAL 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Serious, unexpected and 
related or possibly 
related adverse events 
All Research Sites 
Within 15 days after 
the Overall PI 
receives knowledge 
of the event.   
 
 
IND/IDE Safety Report 
(Cover letter, copy of 
MedWatch/narrative) 
Unanticipated Problem 
All Research Sites 
Within 15 calendar 
days from the time 
the Overall PI 
receives knowledge 
of the event. 
Letter to Participating PIs, 
Copy of MedWatch or narrative 
 
11.0 
DATA SAFETY AND MONITORING PLAN    
 
11.1 
Data Safety Monitoring 
The University of Virginia Cancer Center Data and Safety Monitoring Committee 
(DSMC) will provide oversight of the conduct of this study.  The CC DSMC reports to 
the UVA Protocol Review Committee (PRC). 
 
The DSMC will review the following: 
 All adverse events 
 Audit results 
 Application of study designed stopping/decision rules 
 Whether the study accrual pattern warrants continuation/action 
 Protocol violations 
 Endpoint data 
 
The CC DSMC will meet every month for aggregate review of data.  Issues of 
immediate concern by the DSMC are brought to the attention of the PI (and if 
appropriate to the PRC and IRB) and a formal response from the PI is requested.   
Auditing will occur according to the UVa Cancer Center Institutional Data & Safety 
Monitoring Plan.   
 
DSMC reports will be sent to participating sites every 6 months. 
 
12.0 
STUDY MANAGEMENT    
 
12.1 
Institutional Review Board (IRB) Approval and Consent 
 
 
 
It is expected that the IRB will have the proper representation and function in  
 
 
accordance with federally mandated regulations.  The IRB should approve the consent 
 
 
form and protocol. 


  
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In obtaining and documenting informed consent, the investigator should comply with 
 
 
the applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
 
 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full  
 
 
explanation of the study and will be given the opportunity to review the consent form. 
 
 
Each consent form must include all the relevant elements currently required by the FDA 
 
 
Regulations and local or state regulations. Once this essential information has been 
 
 
provided to the patient and the investigator is assured that the patient understands the 
 
 
implications of participating in the study, the patient will be asked to give consent to 
 
 
participate in the study by signing an IRB-approved consent form. 
 
 
 
Prior to a patient’s participation in the trial, the written informed consent form should 
 
 
be signed and personally dated by the patient and by the person who conducted the 
 
 
informed consent discussion. 
 
12.2 
Registration Procedures 
 
 
Registration procedures are outlined in Section 5.0.   
 
12.3 
Adherence to the Protocol 
 
 
Except for an emergency situation in which proper care for the protection, safety, and 
 
 
well-being of the study patient requires alternative treatment, the study shall be  
 
 
conducted exactly as described in the approved protocol.   
 
12.4 
Emergency Modifications 
 
 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
 
 
an immediate hazard(s) to trial subjects without prior IRB-HSR approval/favorable 
 
 
opinion.   
 
 
 
For any such emergency modification implemented, a UVA IRB modification form 
 
 
must be completed by study Personnel within five (5) business days of making the 
 
 
change.   
 
12.5 
Single Patient/Subject Exceptions 
 
 
Any request to enroll a single subject who does not meet all the eligibility criteria of this 
 
 
study requires the approval of the Principal Investigator  
 
12.6 
Other Protocol Deviations/Violations 
 
 
All other planned deviations from the protocol must have prior approval by the  
 
 
Principal Investigator  
 
12.7 
Protocol Deviations:  A protocol deviation is any unplanned variance from an IRB 
approved protocol that: 
 
 Is generally noted or recognized after it occurs 
 Has no substantive effect on the risks to research participants 


  
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 Has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected  
 Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
 
The clinical research team will record the deviation, and report to any sponsor or data 
 
 
and safety monitoring committee in accordance with their policies.  Deviations should 
 
 
be summarized and reported to the IRB at the time of continuing review. 
 
 
12.7.1 Protocol Violations: An unplanned protocol variance is considered a violation if 
the variance: 
 Has harmed or increased the risk of harm to one or more research 
participants. 
 Has damaged the scientific integrity of the data collected for the study. 
 Results from willful or knowing misconduct on the part of the 
investigator(s). 
 Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.  
 
 
 


  
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12.8 
Record Retention 
 
 
Study documentation includes all Case Report Forms, data correction forms or queries, 
 
 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
 
 
regulatory documents (e.g., protocol and amendments, IRB correspondence and  
 
 
approval, signed patient consent forms). 
 
 
 
Source documents include all recordings of observations or notations of clinical  
 
 
activities and all reports and records necessary for the evaluation and reconstruction of 
 
 
the clinical research study. 
 
 
 
Government agency regulations and directives require that all study documentation 
 
 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
 
 
the case of a study with a drug seeking regulatory approval and marketing, these  
 
 
documents shall be retained for at least two years after the last approval of marketing 
 
 
application in an International Conference on Harmonization (ICH) region.  In all other 
 
 
cases, study documents should be kept on file until three years after the completion and 
 
 
final study report of this investigational study. 
 
12.9 
Obligations of Investigators 
 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
 
 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
 
 
Helsinki.  The Principal Investigator is responsible for personally overseeing the  
 
 
treatment of all study patients.  The Principal Investigator must assure that all study site
 
 
personnel, including sub-investigators and other study staff members, adhere to the 
 
 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical 
 
 
trials both during and after study completion. 
 
 
 
The Principal Investigator at each institution or site will be responsible for assuring that 
 
 
all the required data will be collected and entered onto the Case Report Forms.  
 
 
Periodically, monitoring visits will be conducted and the Principal Investigator will 
 
 
provide access to his/her original records to permit verification of proper entry of data. 
 
 
At the completion of the study, all case report forms will be reviewed by the Principal 
 
 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
13.0 
STATISTICAL CONSIDERATIONS 
This is a multi-center, stratified, randomized phase II trial to evaluate the potential activity of 
the combination of weekly gemcitabine and pazopanib (experimental) compared to weekly 
gemcitabine alone (control) in patients with persistent or recurrent epithelial ovarian, fallopian 
tube or primary peritoneal carcinoma.  Specifically, the study is designed to estimate the 
progression-free survival hazard ratio of the combination compared to gemcitabine alone, and 
determine if the data support further research.  Secondary objectives include determination, by 
arm, of the adverse event profile; preliminary estimates of response, duration of response, and 
overall survival; and relevant hazard ratios of the combination to gemcitabine alone. 
 
13.1 
Study Design/Endpoints 
The primary endpoint is progression-free survival (PFS).  In order to consider the 
combination worthy of further study the data need to support an improvement in median 


  
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PFS of approximately 60% (or a reduction in the hazard rate by 37.5%).  The treatment 
arms/regimens will be: 
 
Regimen 1. 
Gemcitabine 1000 mg/m2 administered weekly on days 1 and 8 (30-
60 minutes IV infusion)  
Regimen 2. 
Gemcitabine 1000 mg/m2 administered weekly on days 1 and 8 (30-
60 minutes IV infusion) with Pazopanib 800mg PO daily days 1-21 
 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of recurrence/progression or death from any cause, whichever occurs first. Patients 
who do not experience an event (recurrence/progression or death) will be censored at 
date of last contact (Section 8.15). Secondary endpoints include the adverse event 
profile, tumor response (Section 8.13) and duration (Section 8.14), and overall survival 
(Section 8.16) by arm. 
 
13.2 
Sample Size/Accrual Rate 
There are no published data estimating PFS using gemcitabine alone in a stratified 
analysis of patients who are platinum sensitive and those who are resistant in the target 
population, although Safra (2006)51 provides an overall estimate where the patient 
population was equally divided between platinum sensitive and platinum resistant 
patients. Specifically, data51,56 for treatment with gemcitabine alone indicate an 
approximate PFS of 2.4 – 2.8 months for platinum resistant and 5 months for platinum 
sensitive patients.  The combined sample in Safra (2006) 51 indicates an overall median 
PFI of 3.73 months which is consistent with a linear relationship of median PFS 
between the two cohorts.  If our patient population of platinum resistant to platinum 
sensitive is 1:1 then based upon a simple average the median PFS for the control 
regimen of gemcitabine alone would be approximately 3.8 months.  
 
If we assume type I and type II error rates of 10% for a one-sided logrank test; the 
ability to detect a relative reduction in the hazard for PFS of 37.5% (HR of 0.625) 
requires approximately 122 observed events (recurrences/progressions or deaths). 
Uniform accrual will not be assumed since the study will be opened at the PIs 
institution (UVA) approximately 6 months earlier than for other participating sites.  
Therefore, sample size was estimated for this accrual pattern in 6 months blocks for a 
total accrual period of 2½ years and minimum follow-up of 6 additional months using 
the methods of Lakatos (1988, 2002).57-58 
 
With the target population expected to be 1:1 for platinum resistant to platinum 
sensitive with a yearly dropout/loss rate of 10% then approximately 148 patients are 
required if 1-2 patients/month will be accrued at UVA in the 1st 6 month accrual period.  
Under this scenario, monthly accrual will need to increase to 4-5 patients per month in 
order to complete accrual in 2½ years. 
 
13.3 
Stratification Factors 
Patients will be stratified according to their second line platinum-free interval PFI 
(resistant: those with a PFI less than or equal to 182 days versus sensitive: those with 
PFI greater than 182 days), and number of previous chemotherapy regimens (one versus 
two or more). PFI will be measured from the end of the most recent platinum induction 


  
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treatment. Patients will be randomized with equal allocation to each arm using a 
stratified block randomization scheme with varying block sizes (of size 4-6). 
 
13.4 
Futility Analysis 
An interim analysis will be performed after approximately ½ of the expected events (61 
recurrences/progressions or deaths) have been observed.  The futility stopping bound 
was based upon the beta spending function where a quarter of the beta is spent at the 
interim analysis.  The interim decision will indicate termination of the study and 
acceptance of the null if the stratified estimate of the hazard ratio has a p-value outside 
the futility boundary p-value which is estimated at 0.312.  This estimate was generated 
under the assumptions specified for sample size determination and were based upon 
10,000 simulations for a non-binding beta spending function where a quarter of the beta 
is spent at the interim analysis.  The PASS 11 Power Analysis and Sample Size package 
was used to generate the futility bound and sample size estimate. 
 
13.5 
Analysis of Primary and Secondary Endpoints 
The primary analysis for PFS will occur after 122 events have been observed or 
approximately 6 months after the last patient has been accrued to the study. PFS 
distributions will be estimated by the product limit method of Kaplan and Meier, and 
the Cox proportional hazards stratified maximum likelihood estimate will be used to 
estimate the hazard ratio of regimen 2 to regimen 1, and the stratified logrank statistic 
will be used to determine if the data support a 60% increase in median PFS of regimen 
2 compared to regimen 1 with a one-sided 10% level test. 
 
Adverse events will be tabulated by frequency and severity, overall and by arm.  
Differences in the level of adverse events by treatment regimen will be assessed by 
classifying them as severe or not severe and examining the relative proportion of severe 
toxicities. 
 
Response as assessed by the proportion responding by RECIST and CA125 will be 
summarized. Association between measurable and non-measurable disease status on 
PFS and OS will be examined with plots of survival curves, estimates of quartiles and 
hazard ratios. The Cox proportional hazards stratified maximum likelihood estimate 
will be used to estimate the hazard ratio of regimen 2 to regimen 1 for the relevant time 
to event distributions. Formal tests for differences will be carried out with a Cox model 
or log-rank test if appropriate.  The impact of additional, various prognostic factors or 
biological markers may be explored if sufficient data are obtained. 
 
All analyses pertaining to OS will occur after all patients have been followed for a 
minimum of 3 years. This follow-up period with accrual of 148 patients (over a 2½ year 
accrual period) provides approximately 85% power to detect a relative reduction in the 
hazard for OS of 37.5% (HR of 0.625) from an estimated median survival of 13.1 
months for the control regimen of gemcitabine alone. As with median PFS, median OS 
was approximated from reported data51,56 for treatment with gemcitabine alone. 
 
13.6 
Reporting and Exclusions 
The primary analysis will be based upon all eligible patients who received any protocol 
treatment, and will be based upon the arm they were randomized to regardless of 
treatment received (intent-to-treat). 


  
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13.6.1 Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of their first study treatment. 
 
13.6.2 Evaluation of response and progression-free survival 
All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible.  Each patient 
will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical 
database.] 
 
All of the patients who received any protocol treatment will be included in the main 
analysis of the response rate.  Patients in response categories 4-9 should be 
considered to have a treatment failure (disease progression).   
 
Sub-analyses may be performed within resistant or sensitive subpopulations or on 
the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these sub-
analyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis will be clearly 
reported.  
 
 


  
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epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Ann 
Oncol 2011;22:335-40. 
32. Welch SA, Hirte HW, Elit L, et al. Sorafenib in combination with gemcitabine in recurrent 
epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium. Int J 
Gynecol Cancer 2010;20:787-93. 
33. Matei D, Sill MW, Lankes HA, et al. Activity of sorafenib in recurrent ovarian cancer and 
primary peritoneal carcinomatosis: a gynecologic oncology group trial. J Clin Oncol 2011;29:69-
75. 
34. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from 
mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and 
antiangiogenic activity. Mol Cancer Ther 2007;6:2012-21. 
35. Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer 
therapy. Curr Opin Investig Drugs 2008;9:1324-35. 
36. Podar K, Tonon G, Sattler M, et al. The small-molecule VEGF receptor inhibitor pazopanib 
(GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci 
U S A 2006;103:19478-83. 


  
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37. D'Agostino G, Amant F, Berteloot P, Scambia G, Vergote I. Phase II study of gemcitabine in 
recurrent platinum-and paclitaxel-resistant ovarian cancer. Gynecol Oncol 2003;88:266-9. 
38. Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with 
pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 
2008;26:890-6. 
39. Fowler WC, Jr., Van Le L. Gemcitabine as a single-agent treatment for ovarian cancer. Gynecol 
Oncol 2003;90:S21-3. 
40. Friedlander M, Millward MJ, Bell D, et al. A phase II study of gemcitabine in platinum pre-
treated patients with advanced epithelial ovarian cancer. Ann Oncol 1998;9:1343-5. 
41. Fruscella E, Gallo D, Ferrandina G, D'Agostino G, Scambia G. Gemcitabine: current role and 
future options in the treatment of ovarian cancer. Crit Rev Oncol Hematol 2003;48:81-8. 
42. Lorusso D, Di Stefano A, Fanfani F, Scambia G. Role of gemcitabine in ovarian cancer 
treatment. Ann Oncol 2006;17 Suppl 5:v188-94. 
43. Lorusso D, Ferrandina G, Fruscella E, Marini L, Adamo V, Scambia G. Gemcitabine in epithelial 
ovarian cancer treatment: current role and future perspectives. Int J Gynecol Cancer 
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44. Lund B, Hansen OP, Neijt JP, Theilade K, Hansen M. Phase II study of gemcitabine in 
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45. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of gemcitabine (2',2'-
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1994;86:1530-3. 
46. Lund B, Neijt JP. Gemcitabine in cisplatin-resistant ovarian cancer. Semin Oncol 1996;23:72-6. 
47. Markman M. Second-line treatment of ovarian cancer with single-agent gemcitabine. Semin 
Oncol 2002;29:9-10. 
48. Markman M, Webster K, Zanotti K, Kulp B, Peterson G, Belinson J. Phase 2 trial of single-agent 
gemcitabine in platinum-paclitaxel refractory ovarian cancer. Gynecol Oncol 2003;90:593-6. 
49. Ozols RF. The role of gemcitabine in the treatment of ovarian cancer. Semin Oncol 2000;27:40-
7. 
50. Poveda A. Gemcitabine in patients with ovarian cancer. Cancer Treat Rev 2005;31 Suppl 4:S29-
37. 
51. Safra T, Ron I, Boaz M, et al. Heavily pretreated ovarian cancer patients treated by single-agent 
gemcitabine. A retrospective outcome comparison between platinum-sensitive and platinum-
resistant patients. Acta Oncol 2006;45:463-8. 
52. Shapiro JD, Millward MJ, Rischin D, et al. Activity of gemcitabine in patients with advanced 
ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996;63:89-93. 
53. von Minckwitz G, Bauknecht T, Visseren-Grul CM, Neijt JP. Phase II study of gemcitabine in 
ovarian cancer. Ann Oncol 1999;10:853-5. 
54. Watanabe Y, Koike E, Nakai H, Etoh T, Hoshiai H. Phase II study of single-agent gemcitabine in 
heavily pretreated Japanese patients with recurrent ovarian cancer. Int J Clin Oncol 2008;13:345-
8. 
55. Tonato M, Mosconi AM, Martin C. Safety profile of gemcitabine. Anticancer Drugs 1995;6 
Suppl 6:27-32. 
56.  Gonzalez B, Gonzalez MA, Bover barcel I, et al. A phase II trial of fixed-dosed rate gemcitabine 
in platinum-resistant ovarian cancer: a GEICO (Grupo Español de Investigación en Cáncer de 
Ovario) Trial. Am J Clin Oncol 2008;5:481-7. 
57.  Lakatos, Edward. 1988. 'Sample Sizes Based on the Log-Rank Statistic in Complex Clinical 
Trials', Biometrics, Volume 44, March, pages 229-241. 
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Medicine, Volume 21, pages 1969-1989. 


  
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Appendix I:  New York Heart Association (NYHA) classification 
 
 
New York Heart Association Criteria 
 
Class 
Definition 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even with rest. With any physical activity, 
increased discomfort is experienced. 
 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood vessels. 
Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 114. 


 
 
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Appendix II: Medications That May Cause QTc Prolongation 
The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the QTc. 
Please note that the list provided below has been prepared Feb 2012 and the full list is frequently 
updated. For the most current list of medications, users should be directed to the following website: 
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm. 
 
Drugs with a risk of Torsades de 
Pointes Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
Drugs with a possible risk of 
Torsades de Pointes: Drugs that 
prolong the QT interval and/or in 
some reports have been 
associated with torsades de 
pointes but at this time lack 
substantial evidence for causing 
torsades de pointes 
Drugs with a conditional risk of 
Torsades de Pointes: Drugs that 
carry a risk of torsades de pointes 
and/or QT prolongation under 
certain conditions, such as 
patients with congenital long QT 
syndrome, drug overdose or co-
administration of interacting 
drugs 
Generic 
Brand 
Name 
Generic 
Brand 
Name 
Generic 
Brand 
Name 
Amiodarone  
Cordarone® 
Alfuzosin 
Uroxatral® 
Amitriptyline 
Elavil® 
Amiodarone  
Pacerone® 
Amantadine 
Symmetrel® 
Ciprofloxacin 
Cipro® 
Arsenic trioxide  
Trisenox® 
Atazanavir 
Reyataz®  
Clomipramine 
Anafranil® 
Astemizole  
Hismanal® 
Azithromycin 
Zithromax® 
Desipramine 
Pertofrane® 
Bepridil  
Vascor® 
Chloral hydrate 
Noctec® 
Diphenhydramine 
Benadryl® 
Chloroquine 
Aralen® 
Clozapine 
Clozaril® 
Diphenhydramine 
Nytol® 
Chlorpromazine  
Thorazine® 
Dolasetron 
Anzemet® 
Doxepin 
Sinequan® 
Cisapride 
Propulsid® 
Dronedarone 
Multaq® 
Fluconazole 
Diflucan® 
Citalopram 
Celexa® 
Escitalopram 
Lexapro®  
Fluoxetine  
Sarafem® 
Clarithromycin 
Biaxin® 
Escitalopram 
Cipralex®  
Fluoxetine  
Prozac® 
Disopyramide  
Norpace® 
Famotidine 
Pepcid® 
Galantamine 
Reminyl® 
Dofetilide  
Tikosyn® 
Felbamate  
Felbatrol® 
Imipramine 
Norfranil® 
Domperidone 
Motilium® 
Fingolimod 
Gilenya® 
Itraconazole 
Sporanox® 
Droperidol  
Inapsine® 
Foscarnet  
Foscavir® 
Ketoconazole 
Nizoral® 
Erythromycin  
Erythrocin® 
Fosphenytoin 
Cerebyx® 
Nortriptyline 
Pamelor® 
Erythromycin  
E.E.S.®  
Gatifloxacin 
Tequin® 
Paroxetine 
Paxil® 
Flecainide 
Tambocor® 
Gemifloxacin 
Factive® 
Protriptyline 
Vivactil® 
Halofantrine  
Halfan® 
Granisetron 
Kytril® 
Ritonavir 
Norvir® 
Haloperidol  
Haldol® 
Indapamide 
Lozol® 
Sertraline 
Zoloft® 
Ibutilide 
Corvert® 
Isradipine 
Dynacirc® 
Solifenacin 
VESIcare® 
Levomethadyl 
Orlaam® 
Lapatinib 
Tykerb® 
Trazodone 
Desyrel® 
Mesoridazine 
Serentil® 
Lapatinib 
Tyverb® 
Trimethoprim-
Sulfa 
Sulfa® 
Methadone 
Methadose® 
Levofloxacin 
Levaquin® 
Trimethoprim-
Sulfa 
Bactrim® 
Methadone 
Dolophine® 
Lithium 
Lithobid® 
Trimipramine 
Surmontil® 
Moxifloxacin  
Avelox® 
Lithium 
Eskalith® 
 
 
Pentamidine  
Pentam® 
Moexipril/HCTZ  
Uniretic® 
 
 
Pentamidine  
NebuPent® 
Nicardipine  
Cardene® 
 
 
Pimozide 
Orap®  
Nilotinib 
Tasigna®  
 
 
Probucol 
Lorelco® 
Octreotide  
Sandostatin® 
 
 
Procainamide  
Pronestyl® 
Ofloxacin 
Floxin® 
 
 


 
 
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Drugs with a risk of Torsades de 
Pointes Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
Drugs with a possible risk of 
Torsades de Pointes: Drugs that 
prolong the QT interval and/or in 
some reports have been 
associated with torsades de 
pointes but at this time lack 
substantial evidence for causing 
torsades de pointes 
Drugs with a conditional risk of 
Torsades de Pointes: Drugs that 
carry a risk of torsades de pointes 
and/or QT prolongation under 
certain conditions, such as 
patients with congenital long QT 
syndrome, drug overdose or co-
administration of interacting 
drugs 
Procainamide  
Procan®  
Ondansetron 
Zofran® 
 
 
Quinidine 
Cardioquin®  
Oxytocin 
Pitocin® 
 
 
Quinidine 
Quinaglute® 
Paliperidone 
Invega® 
 
 
Sotalol  
Betapace®  
Perflutren lipid 
microspheres 
Definity®  
 
 
Sparfloxacin  
Zagam®  
Quetiapine  
Seroquel®  
 
 
Terfenadine 
Seldane® 
Ranolazine 
Ranexa®  
 
 
Thioridazine 
Mellaril®  
Risperidone  
Risperdal®  
 
 
Vandetanib 
Caprelsa® 
Roxithromycin* 
Rulide® 
 
 
 
 
Sertindole 
Serdolect® 
 
 
 
 
Sertindole 
Serlect® 
 
 
 
 
Sunitinib 
Sutent® 
 
 
 
 
Tacrolimus  
Prograf® 
 
 
 
 
Tamoxifen  
Nolvadex®  
 
 
 
 
Telithromycin 
Ketek® 
 
 
 
 
Tizanidine  
Zanaflex®  
 
 
 
 
Vardenafil 
Levitra®  
 
 
 
 
Venlafaxine  
Effexor®  
 
 
 
 
Voriconazole 
VFend®  
 
 
 
 
Ziprasidone 
Geodon®  
 
 
 
 
 


 
 
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Appendix III 
 
Table A. Dose Modification Algorithms for Potential Pazopanib 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 20 mmHg (but still 
below 110 mmHg). 
Step 1. Continue investigational product (IP) at the current dose.  
Step 2. Adjust current or initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks as 
indicated to achieve well-controlleda blood pressure (BP). If BP is not well-
controlled within 2 weeks, consider referral to a specialist and go to 
scenario (B). 
(B). Asymptomatic SBP 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.  
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 specialist for further 
evaluation and follow-up is also recommended. 
Step 4. Once BP is well-controlled, restart IP dose-reduced by 200 mg. 
(D). Refractory hypertension 
unresponsive to above interventions. 
Discontinue IP and continue follow-up per protocol. 
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to ensure accuracy of the 
reading.  The values below refer to manually-read ECGs.   
QTc   480 < 500 msec 
Continue IP; monitor as clinically indicated. 
QTc 500 msec 
Discontinue IP and continue follow-up per protocol. 
Proteinuria 
UPC <3 
Continue pazopanib at the current dose; monitor as clinically indicated 
UPC ≥3 or 24-h urine protein 3g 
Step 1. Interrupt IP. 
Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is <3 or 
24-hr urine protein is <3 grams.  Then restart pazopanib dose-reduced 
by 200 mg. 
Step 3.  If UPC ≥3 or 24-h urine protein 3g recurs, repeat steps 1 and 2. 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the pazopanib 


 
 
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AE Terms & Descriptions 
Dose Modification Algorithms 
dose can no longer be reduced, discontinue pazopanib and continue 
follow-up per protocol. 
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding 
Grade 1 
For hemoptysis, interrupt pazopanib and contact the Sponsor to discuss 
whether further treatment with pazopanib is appropriate. 
For other Grade I hemorrhage/bleeding events, continue pazopanib at the 
current dose; monitor as clinically indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding), 
discontinue 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 at the current dose; monitor as clinically indicated 
Grade 3   
 
Step 1. Interrupt IP.  
Step 2. Initiate and monitor anticoagulation as clinically indicated.  
Step 3. Resume IP at reduced dose <proposed: same dose> only if all of 
the following criteria are met:  
 
The subject must have been treated with anticoagulant at the 
desired level of anticoagulation for at least one week. 
 
No Grade 3 or 4 or clinically significant Grade 2, hemorrhagic 
events have occurred while on anticoagulation treatment. 
Subject 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.  
 
 


 
 
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Thrombocytopenia/Neutropenia/Anemia: 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, discontinue IP and 
follow-up per protocol. 
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or dermatitis 
without pain 
(erythema, oedema, hyperkeratosis) 
1. 
Continue IP at present dose 
 Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily living 
(ADLs) (peeling, blisters, oedema, bleed, 
hyperkeratosis) 
1. 
Hold IP  
2. 
Treat as clinically appropriate 
3. 
Upon resolution to Level 1 or better restart  IP with a dose 
reduction to 400 mg 
4. 
If recurrent consider a further dose reduction to 200mg or 
discontinuation 
Grade 3 
Severe skin changes with pain and 
limiting self care ADLs 
1. 
Discontinue IP 
Other Clinically Significant Adverse Eventsb  
Grade 1 
Continue IP; monitor as clinically indicated. 
Grade 2 or 3, if clinically significant  
Step 1. Interrupt IP until toxicity resolves to  Grade 1. 
Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically 
indicated.  
Grade 4 
Discontinue IP and continue follow-up per protocol.    
a. 
Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. 
b. 
AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4)  
       Abbreviations: BP, blood pressure; IP, investigational product. 
 


 
 
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Table B. Guidelines for Management of Treatment Emergent Hepatotoxicity 
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x ULN 
Continue pazopanib at current dose with full panel LFTsa monitored as per protocol. 
(B). ALT >3.0 x ULN to 
≤8.0 x ULN without 
bilirubin elevation (defined 
as total bilirubinb <2.0 x 
ULN or direct bilirubin 
≤35%) and without 
hypersensitivity symptoms 
(e.g., fever, rash)  
Liver Event Monitoring Criteria: 
(1) Continue pazopanib at current dose levels.  
(2) Monitor subject closely for clinical signs and symptoms; perform full panel LFTsa weekly or 
more frequently if clinically indicated until ALT/AST is reduced to Grade 1. 
(C). ALT >8.0 x ULN 
without bilirubin elevation 
(defined as total bilirubinb 
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, rash) 
1st occurrence – Liver Event Interruption Criteria: 
(1) Interrupt pazopanib until toxicity resolves to Grade 1 or baseline.  Report the event to 
Sponsor as an SAE within 24 hours of learning of its occurrence.  Make every reasonable 
attempt to have subjects return to the clinic within 24 to 72 hours for repeat liver chemistries 
and liver event follow up assessments. 
(2)  Liver imaging and other laboratory investigations should be considered as clinically 
appropriate. 
(3) Monitor subject closely for clinical signs and symptoms; perform full panel LFTs a weekly or 
more frequently if clinically indicated until ALT/AST is reduced to Grade 1.   
(4) If the subject is benefiting from the study treatment, contact Sponsor 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.  
 (5) Reintroduce pazopanib at a reduced dose of 400 mg once daily and measure serum liver 
tests weekly for 8 weeks.  
 
Recurrence – Liver Event Stopping Criteria: 
Discontinue pazopanib permanently and monitor subject closely for clinical signs and symptoms; 
perform full panel LFTs a weekly or more frequently if clinically indicated until ALT/AST is reduced 
to Grade 1.   
 (D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubinb (defined as total 
bilirubin 2.0 x ULN; with 
direct bilirubin >35%) or 
with hypersensitivity 
symptoms (e.g., fever, rash) 
or bilirubin is >3.0 x ULN 
regardless of ALT values.  
Liver Event Stopping Criteria: 
(1) Discontinue pazopanib immediately, report the event to Sponsor as an SAE within 24 hours 
of learning of its occurrence.  Make every reasonable attempt to have subjects return to the 
clinic within 24 hours for repeat liver chemistries and liver event follow up assessments. 
 (2) Monitor subject closely for clinical signs and symptoms; record the appearance or worsening 
of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report 
form.  Perform full panel LFTs a weekly or more frequently if clinically indicated until LFTs are 
reduced to Grade 1.   


 
 
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Event 
Dose Modification Algorithms 
For isolated total bilirubinb 
elevation (>1.5 x to 3x ULN)  
without concurrent ALT 
increases (defined as ALT 
<3 X ULN). 
 
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other signs/symptoms of 
liver injury) does not require dose modification.  Pazopanib inhibits UGT1A1 and OATP1B1, 
which can cause elevation of indirect (unconjugated) bilirubin in the absence of liver injury. 
(2)  If bilirubin is >1.5 x ULN in the absence of ALT elevation, fractionation of bilirubin elevation 
should be performed.  If bilirubin is >35% direct (conjugated), further evaluation for 
underlying cause of cholestasis should be performed. The dose of pazopanib should be 
reduced to 200 mg per day in patients with moderate hepatic impairment.  
a. 
Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.  Coagulation tests should be performed 
as clinically indicated. 
b. 
Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject meets the 
criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an SAE. 
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; IP investigational product; LFT liver function 
tests; SAE serious adverse event; ULN upper limit of normal 
 
 
 


 
 
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Appendix IV.  General Chemotherapy Guidelines: 
 
 For 21 day cycles, a patient will be permitted to have a new cycle of chemotherapy 
delayed up to 7 days (without this being considered to be a protocol violation) for major 
life events (e.g., serious illness in a family member, major holiday, vacation which is 
unable to be re-scheduled). Documentation to justify this decision should be provided. 
 
 It will be acceptable for individual chemotherapy doses to be delivered within a “24-hour 
window before and after the protocol-defined date” for “Day 1” treatment of 21 day 
cycles. If the treatment due date is a Friday, and the patient cannot be treated on that 
Friday, then the window for treatment would include the Thursday (1 day earlier than 
due) through the Monday (day 3 past due). 
 
 For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on Day 
14, Day 15, or Day 16. 
 
 Chemotherapy doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 5% of 
the calculated dose). 
 
 Chemotherapy doses will be based on the subject’s weight at baseline and will remain the 
same throughout the study. However, the doses will be recalculated if the patient has a 
weight change of greater than or equal to 10% from baseline. 
 
 
Maximum body surface area used for chemotherapy dose calculations will be 2.0 m2. For 
chemotherapy dose calculations that use mg/kg, there will be no maximum kilogram 
amount used (doses will be calculated on actual weight in kg).  
 

ICF_000.pdf: 
IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 1 of 20 
Version: 01Feb2017 
 
 
 
 
 
 
 
Study Title: 
A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS 
PAZOPANIB VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF 
PATIENTS WITH PERSISTENT OR RELAPSED EPITHELIAL OVARIAN, FALLOPIAN TUBE 
OR PRIMARY PERITONEAL CARCINOMA 
 
 
Version Date: 
 
01 February 2017 
 
 
NCT#: 
NCT01610206 
 
 
 
 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 2 of 20 
Version: 01Feb2017 
 
 
 
Consent of an Adult to Be in a Research Study 
In this form "you" means a person 18 years of age or older who is being asked to volunteer to participate in 
this study.  
Participant’s Name ______________________________Medical Record # _________________________ 
Principal 
Investigator/Sponsor: 
Linda R. Duska, M.D. 
University of Virginia School of Medicine (UVA) 
PO Box 800712 
Charlottesville, VA 22908 
Telephone:  (434) 982-1719 
Fax:  (434) 982-1840 
lduska@virginia.edu 
Funding Source 
Novartis Pharmaceuticals 
 
What is the purpose of this form? 
This form will provide you with information about this research study. You do not have to be in the study if 
you do not want to. You should have all your questions answered before you agree to be in this study.  
 
Please read this form carefully.  If you want to be in the study, you will need to sign this form. You will be given 
a signed copy of this form.   
 
Who is funding this study? 
This study is being carried out under the sponsorship of Dr. Linda Duska at the University of Virginia Cancer 
Center.  Some financial support has been provided by Novartis, the manufacturer of pazopanib. 
 
Why is this research being done? 
Chemotherapy is the standard treatment for cancer of the ovary, fallopian tube or peritoneum when it returns 
after initial treatment. A number of chemotherapy options exist for patients when their cancer grows despite 
treatment with the most effective chemotherapy (such as carboplatin or cisplatin). One of these 
chemotherapy agents is gemcitabine. 
 
The purpose of this study is to compare the safety and effectiveness of an experimental drug called 
pazopanib when given in combination with gemcitabine versus gemcitabine alone for people with ovarian 
cancer, fallopian tube cancer, or primary peritoneal cancer that has re-grown or not responded after prior 
treatment.   
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 3 of 20 
Version: 01Feb2017 
 
 
 
 
Gemcitabine in combination with carboplatin is approved for use by the U.S. Food and Drug Administration 
(FDA) for the treatment of patients with advanced ovarian cancer that has relapsed at least six months after 
completion of therapy with carboplatin or cisplatin. Gemcitabine is also used as a single agent for cancer of 
the ovary, fallopian tube or peritoneum when it returns after initial treatment, although this is not an FDA-
approved treatment. 
 
Pazopanib is a different kind of chemotherapy drug. Pazopanib works by slowing or stopping the spread of 
cancer cells by blocking new blood vessel formation.  New blood vessel formation is required for tumor 
growth.  
 
Currently, Pazopanib is approved by the FDA for use in the treatment of patients with advanced kidney cancer 
and certain types of advanced soft tissue sarcoma (cancer of connective or supportive tissues such as bone, 
cartilage, fat, muscle…) but has not been approved for use in other cancer types.  Pazopanib alone or 
pazopanib + gemcitabine is NOT approved by the FDA for the treatment of ovarian, fallopian tube, and 
primary peritoneal cancer. In other words, the combination of pazopanib and gemcitabine is experimental.  
 
You are being asked to take part in this study because you have ovarian cancer, fallopian tube cancer, or 
primary peritoneal cancer that has regrown or not responded after prior treatment.  
 
Up to 60 people will be in this study at UVA.  Approximately 150 people will take part in this study at other 
institutions in the United States.  
  
How long will this study take? 
You will be required to make weekly office visits while you are receiving study treatment.   
 
You will continue to take pazopanib + gemcitabine or gemcitabine alone as long as there is evidence that your 
tumor is not growing and you are not experiencing any unacceptable side effects.  
 
After you are finished taking the chemotherapy drug(s), your doctor will ask you to visit the office for follow-
up exams every three months for the first two years, every six months for the next year and then yearly for 2 
years for a maximum of 5 years.   
 
Your participation in this study will, require an additional 30 minutes during your initial visit with your doctor 
and an additional 30 minutes during the routine clinical visits you will be making as part of your cancer 
treatment. 
 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 4 of 20 
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What will happen if you are in the study? 
 
SCREENING (will take approximately 1 hour to complete)  
Visit 1/Day 0 
 
If you agree to participate, you will sign this consent form before any study related procedures take place.  
Before you can start in the study, there will be a screening period.  You will have tests and procedures during 
this time to make sure you are eligible and it is safe for you to participate.   If you have had some of them 
recently, they may not need to be repeated.  This will be up to your study doctor.   
 
The following exams, tests or procedures are part of regular cancer care and will be done even if you do not 
join the study:   
 History and physical examination which may include pelvic exam.  You will also have your heart rate, 
blood pressure and temperature taken. 
 Chest imaging (X-ray or CT scan of the chest)  
 A left ventricular ejection fraction (LVEF) test to measure your heart function if you have had prior 
therapy with a certain type of drug (anthracyclines) 
 ECG (tracing of heart waves)-Electrocardiogram to see the electrical activity of your heart.  
 CT-scan or MRI of the abdomen and pelvis to measure detectable tumor 
 Review of medications and supplements you are currently taking.  If you agree to take part in this 
study, it is very important that you tell your study doctor before starting on this study about all of the 
medicines you are taking (over-the-counter medications, supplements, prescription medications, or 
illegal drugs) including any medicines you have taken within the past 2 weeks.  The reason this is 
important is that some medicines can change the way your body handles other medicines and this can 
increase the risk of side effects.  In addition, please talk with the study doctor before you begin taking 
any new medications or supplements during this study. Your study doctor will look at the medicines 
you are currently taking to make sure you are allowed to take them on the study.  You may be asked to 
change some of the medicines you are taking.  If you need to take a medicine that is not allowed and it 
cannot be replaced with another medicine, you will not be asked to stop taking it; however, you will 
not be able to take part in this study. 
 
The following exams, tests or procedures are not part of regular cancer care and will be done for research 
purposes: 
 A urinalysis (testing of urine) to check urine protein levels 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
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 A serum pregnancy test if you are capable of becoming pregnant (this will be done within 14 days prior 
to receiving study treatment) 
 Blood tests to assess blood cell counts; liver and kidney function; blood mineral levels; blood clotting 
function and the CA-125 tumor marker.    The amount of blood that will be drawn is approximately 2 
tablespoons. Blood tests to assess thyroid for research purposes will be done on the blood taken as 
part of your routine cancer care. These tests will not require additional blood samples. 
 
If these tests show you are eligible, you will return to the clinic (within 28 days) to begin study treatment.  
 
RANDOMIZATION  
Visit 2/Day 1 
 
You will be randomly assigned (like the flip of a coin) to 1 of 2 study treatment groups. You have an equal 
chance of being assigned to one of the groups.  Neither you nor your doctor can choose which study 
treatment you are assigned.  Both you and your doctor will know which of the two groups you are assigned to. 
 
GROUP 1: Gemcitabine given as intravenous (IV) infusion (standard of care) 
 
GROUP 2: Pazopanib (oral) + Gemcitabine (IV) (Experimental) 
 
Note:  Every 21-day period of time is called a cycle.   
 
Group 1 
Gemcitabine will be put into your vein over 30 minutes, weekly for 2 weeks (Day 1 and Day 8 of each cycle) 
every 21 days  
 
Group2 
Gemcitabine will be put into your vein over 30 minutes, weekly for 2 weeks (Day 1 and Day 8 of each cycle) 
every 21 days  
 
Pazopanib will be taken by mouth daily. Pazopanib should be taken on an empty stomach 1 hour before or 2 
hours after meals.  The tablets should be swallowed whole and must not be crushed or broken.   
 
STUDY VISITS (each visit will last about 60 – 90 minutes): 
 
You will visit your doctor weekly (Day 1 and Day 8 of each cycle) every 21 days. At these visits, you will need 
the following tests and procedures that are all being done as part of your regular cancer care.  


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 6 of 20 
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 History and physical examinations which may include a pelvic exam about once every three weeks.  
You will also have your heart rate, blood pressure and temperature monitored at each study visit. 
 Blood tests to measure the CA-125 tumor marker blood level prior to each cycle of treatment.  
 Chest imaging (X-ray or CT scan of the chest) before the start of every other cycle (i.e. Cycle 2, 4, 6…).as 
needed  
 CT scan or MRI to measure tumor before the start of every other cycle (i.e. Cycle 2, 4, 6…)  
 Review of medications you are taking before starting each cycle. 
 If you are taking warfarin, your doctor will also check your blood clotting levels. 
 
The following will be done for research purposes: 
 
 Blood tests to measure blood counts, electrolytes, blood mineral levels, and check liver and kidney 
function prior to each cycle of treatment (more often if your doctor(s) feels it is needed.) 
 
In addition, if you are assigned to Group 2, the following tests and procedures will be done for research 
purposes: 
 Blood pressure will be monitored on Day 15 of every cycle; you may do this at home and provide the 
results to the study doctor or study nurse. (Note blood pressure done on other days will be performed 
per your regular cancer care). 
 An electrocardiogram will be done on Day 1 of cycle 2 
 Urine protein levels (UPC) will be examined by urinalysis (testing of urine) before the start of every 
other cycle (i.e. Cycle 2, 4, 6…).  
 You will be given a patient medication calendar to complete throughout the study.  The patient 
medication calendar is a monthly calendar on which you are to record the number of tablet(s) you 
take each day. You will need to bring the calendar with you to the doctor’s office before each cycle, 
along with any unused study medications and empty medication containers.  
 
FOLLOW UP: 
To monitor your well-being and the status of your cancer, you will undergo these tests and procedures that 
are part of regular cancer care every 3 months for 2 years and then every 6 months for 1 year and then yearly 
for 2 years. The maximum follow up period is 5 years: 
 History and physical examination which may include pelvic examination CT or MRI scan, if previously 
detectable tumor was monitored using these methods, as recommended by your physician. 
 CA-125 tumor marker blood level as recommended by your physician. 
 Chest imaging (X-ray or CT scan of the chest) as recommended by your physician. 
 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 7 of 20 
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END OF STUDY: 
After you have completed participation in the study, you will no longer receive the study drug.  You, together 
with your doctor, will determine the next steps in your care plan.  
 
Study Schedule: 
Every 21-day period of time is called a cycle.  Each cycle is numbered in order.  The schedule below shows 
what will happen to you during Cycle 1 and future cycles as explained previously.   
 
 
 
Cycle 1 
Cycles 2 + 
 
 
 
Visit 1 
Day 1 
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
Follow-up 
Informed Consent 
x 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
x 
 
 
x 
Physical Exam 
x 
 
 
 
x 
 
 
x 
CT/MRI (if applicable) 
x 
 
 
 
x 
 
 
x 
Chest x-ray (if applicable) 
x 
 
 
 
x 
 
 
x 
ECG 
x 
 
 
 
x * (Group 
2 only) 
 
 
 
Cardiac function (if 
applicable) 
x 
 
 
 
 
 
 
 
Blood draw (for laboratory 
testing) 
x* 
x* 
x* 
 
x* 
x* 
 
x  
(CA-125) 
Blood pressure  
x 
x 
x 
x (Group 
2 only) 
x 
x 
x (Group 
2 only) 
 
Heart rate and 
temperature 
x 
 
x 
 
x 
x 
 
 
Urine testing  
x* 
 
 
 
x* 
(Group 2 
only, even 
cycles) 
 
 
 
Pregnancy test (if 
applicable) 
x 
 
 
 
 
 
 
 
Review side effects 
 
x 
x 
x 
x 
x 
 
x 
Gemcitabine 
 
x 
x 
 
x 
x 
 
 
*Pazopanib (Group 2 only) 
 
Daily 
 
*Pill calendar (Group 2 
only) 
 
x 
x 
x 
x 
x 
x 
 
An * indicates procedures done for research purposes.  All other procedures are performed as part of your clinical care.  
 
 
 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 8 of 20 
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What are your responsibilities in the study? 
You have certain responsibilities to help ensure your safety. These responsibilities are listed below: 
 You must come to each study visit or notify the study doctor or study staff if you are unable to do so. 
 You must be completely truthful about your health history. 
 Follow all instructions given. 
 You should tell the study doctor or study staff about any changes in your health or the way you feel. 
 Ensure that the study drug is taken as instructed, keep the study drug in a safe place away from other 
children, return any unused study drug at each visit, and report any lost or missed tablets. 
 Ensure that the study drug is taken only by you, the person for whom it has been prescribed. 
 Answer all of the study-related questions completely. 
 You must not eat grapefruit or drink grapefruit juice during the course of your participation in this 
study. 
 Inform the study doctor or study staff as soon as possible if you have to take any new medications, 
including anything prescribed by a doctor or those that you can buy without a prescription (over-the-
counter), including herbal supplements and vitamins.  The study doctor will let you know if you can 
take these medications. 
 
If you want to know about the results before the study is done: 
During the study your study leader will let you know of any test results that may be important to your health.  
In addition, as the research moves forward, your study leader will keep you informed of any new findings that 
may be important for your health or may help you decide if you want to continue in the study.  The final 
results of the research will not be known until all the information from everyone is combined and reviewed.  
 At that time you can ask for more information about the study results.  
 
What are the risks of being in this study?  
Research studies often involve some risks. You should talk to your study doctor about any side effects that you 
have while taking part in the study.  The risks of this study are as follows: 
 
Risks and side effects related to the Gemcitabine include those which are: 
Likely: 
 Low white blood cell counts that could lead 
to infection 
 Low red blood cell counts that could cause 
anemia 
 Mild nausea 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 9 of 20 
Version: 01Feb2017 
 
 
 
 Fatigue 
 Hair loss 
 Numbness or tingling in the hands and/or 
feet 
 
Less Likely 
 Flu-like symptoms such as fatigue, muscle 
aches, fever lasting 1-2 days after 
gemcitabine treatments 
 Infection requiring treatment with 
medicines 
 Low platelets that could lead to bleeding 
 Nausea and vomiting 
 Diarrhea or constipation 
 Mouth sores may occur; you will be given 
treatment to make them more tolerable.  
Mouth sores improve over time. 
 Abnormalities in the blood tests that 
measure liver function 
 Fluid retention in the feet, legs, and weight 
gain 
 Kidney function abnormalities, with the 
appearance of protein or blood in the urine 
 Rash may occur, involving the body and/or 
legs. 
 Changes in taste, or a metallic taste 
 
Rare but serious 
 Confusion, hearing problems, heart failure, abnormal heart rhythms, high blood pressure, low blood 
pressure, blood clots in the legs or lungs, bowel obstruction, bleeding, severe infections leading to 
death.  The relationship of these events to the administration of the chemotherapy drugs has not been 
proven, since all patients who have received these drugs have underlying cancer, which may cause 
some or all of these effects by itself. 
 Rarely, severe lung damage has occurred in patients being treated with the combination of 
gemcitabine and docetaxel.  In most cases the lungs got better when the treatments were stopped.   
 Rarely, a condition affecting the blood and kidneys called hemolytic uremic syndrome has occurred.  
When this happens the kidney damage can sometimes be permanent. 
 
Risks and side effects related to Pazopanib: 
As of 9 September 2016, about 5919 patients and healthy volunteers had received pazopanib (either as 
monotherapy or in combination) out of more than 8746 patients enrolled in oncology, ophthalmology, and 
psoriasis studies. Pazopanib can cause side effects, although not everybody gets them.  Some side effects can 
be life-threatening or fatal.  The side effects below are those reported by patients who have taken pazopanib 
either in a clinical trial or as prescribed by their doctors. The side effects are listed according to the highest 
number of patients who had them in pazopanib studies, as very common, common, or uncommon.  Not all 
side effects of pazopanib are known and further studies are under way.  If you experience one or more side 
effects, please speak with your study doctor. 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 10 of 20 
Version: 01Feb2017 
 
 
 
Very common side effects occurring in greater than 10 out of 100 subjects included:  
 Increase in blood sugar 
 Stomach pain or discomfort  
 Diarrhea 
 feeling or being sick ( nausea, vomiting, 
abdominal pain/discomfort) 
 loss of strength and energy, weakness  
 loss of appetite 
 changes in hair color 
 high blood pressure 
 headache 
 weight loss 
 unusual hair loss or thinning  
 A skin reaction or pain on the palms of 
the hands or soles of the feet (including 
tingling, numbness, pain, swelling or 
reddening.   
 Loss of skin pigment 
 chest pain 
 problems with taste 
 mouth sores/inflammation of the lining 
in the mouth  
 cough 
 shortness of breath 
 dizziness 
 exfoliative rash (rash with skin peeling) 
 muscle pain  
 pain in the bones, muscles, ligaments, 
joints and tendons 
 swelling caused by fluid in the, hands, 
ankles, or feet 
 slow heart rate 
 increase in some substances (enzymes) 
produced by the liver. This may show up 
in your blood tests. Patients over 60 
years of age may be at greater risk of an 
increase of one of the enzymes, called 
ALT. 
 decrease in albumin (a protein found in 
the blood; may indicate a disruption of 
liver function) 
 
Common side effects occurring in between 1 and 10 out of 100 subjects included:  
 hoarse voice 
 blurry vision 
 heartburn (indigestion) 
 nosebleeds 
 blood in the urine 
 low white blood cell counts (the cells 
which fight infection) 
 a decrease in the number of cells 
involved in blood clotting 
 protein in the urine (a sign that kidneys 
are not working normally) 
 under active thyroid gland (a gland 
important in regulating metabolism) 
 abnormal liver function 
 increase in lipase (an enzyme from the 
pancreas); may be a sign of a pancreas 
problem 
 changes in heart’s electrical conduction 
(QT-prolongation) 
 temporary reduction in blood supply to 
the brain (mini-stroke) 
 reduction of blood supply to the heart 
(angina) 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 11 of 20 
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 sudden collapse of the lung 
 heart becomes less effective at pumping 
blood (cardiac dysfunction) 
 chest pain, shortness of breath, leg pain, 
and swelling of the legs/feet. These 
could be signs of a blood clot in your 
body (thromboembolism). If the clot 
breaks off, it may travel to your lungs 
and this may be life threatening or even 
fatal 
 severe bleeding in the lungs 
 heart attack  
 chills 
 skin rash 
 dry skin 
 nail disorder 
 excessive stomach or intestinal gas 
(flatulence) 
 muscle spasms 
 increase in bilirubin (substance 
produced by the liver; may indicate a 
disruption of  liver function) 
 increase in gamma-glutamyl 
transpeptidase (a liver enzyme; may 
indicate a disruption of  liver function) 
  
 severe bleeding in digestive tract 
(stomach and intestine) and brain 
 infection, with or without changes in 
white blood cells (cells that fight 
infection) 
 
Uncommon side effects occurring in less than 1 out of 100 subjects included:  
 Severe bleeding in the brain 
 a dangerous rapid fluttering of the heart 
(Torsades de Points) 
 hole in the gut wall (perforation) 
 abnormal connection between parts of 
the digestive tract (fistula) 
 stroke 
 liver failure (which could possibly result 
in death) 
 a sudden and severe rise in blood 
pressure  (hypertensive crisis) 
 inflammation of the pancreas 
 Separation or tear of the lining of the 
back part of the eye (retinal detachment 
or tear). This can result in blurry or 
impaired vision.  
 Abnormal increase in the number of red 
blood cells (polycythemia) 
 Blood clots accompanied by a decrease 
in red blood cells and cells involved in 
clotting. These clots may harm organs 
such as the brain and kidneys.  
 
Rare Side Effects (These may affect up to 1 in 1000 people):  
 Swelling of the brain that may be associated with high blood pressure, headache, loss of speech or 
vision, and/or seizure, which may be life threatening 
 Scarring of the lung tissue, leading to lung stiffness, affecting the ability to breathe (Interstitial Lung 
Disease) and inflammation of the lung tissue (pneumonitis), which can be fatal.  


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 12 of 20 
Version: 01Feb2017 
 
 
 
 
Other Risks of Pazopanib 
One patient developed liver failure and died shortly after beginning treatment with the combination of 
gemcitabine and pazopanib. 
 
Lung infection has been observed in 1 out of 1000 patients treated with pazopanib.  
 
Neutropenia (low white blood cell count), thrombocytopenia (decrease in the number of cells involved in 
blood clotting), and palmar-plantar erythrodysaethesia syndrome (hand-foot syndrome) were observed more 
frequently in patients of East Asian descent. 
 
Patients who carry a specific gene (HLA B*57:01 allele) have an increased chance of abnormal liver function 
(ALT elevations) due to Pazopanib.  
 
Studies in animals indicate that pazopanib may slow or stop bone growth.  There is a possibility that pazopanib 
may affect bone growth in children, adolescents and young adults who are still growing. 
 
Severe and fatal liver disease has occurred in patients treated with pazopanib and patients older than 65 years 
are at greater risk for this. During this study, blood tests will be checked to look for liver injury.  People with 
liver injury may feel very tired, or sick and not want to eat, have yellow skin or eyes, and they may also 
develop rash or fever.  
 
During this study, blood tests will be checked to look for liver injury. People with liver injury may feel very tired 
or sick and not want to eat, have yellow skin or eyes, and they may also develop rash or fever.  
 
Let your doctor know if you have any of these symptoms, especially if your doctor says you have abnormal 
liver blood tests.  If your doctor finds that your blood tests suggest liver injury that is not severe, your doctor 
may recommend you continue taking pazopanib and may ask you to stop taking other drugs which may cause 
liver injury.  Blood tests (about 1/3 tablespoon of blood per test) for possible liver injury will be repeated every 
week until they get better. These tests will be done per your clinical care. 
 
If your blood tests get worse, your doctor may tell you to stop taking pazopanib altogether.  If you have a liver 
injury from pazopanib, it will usually heal when pazopanib is stopped.  It is possible that a small number of 
people may continue to have liver injury after they stop taking pazopanib.   
 
If you are to have surgery, please speak with your doctor because pazopanib may affect wound healing. 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 13 of 20 
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There may be other side effects that may happen that are not known now.  For example, all drugs can cause 
an allergic reaction in some patients.  Certain problems can become worse if not treated quickly. Call the study 
doctor right away if: <Amend list below, as required> 
 You feel very tired or faint 
 You feel pain or sick in your stomach and you do not want to eat 
 You bruise easily or develop itching 
 You have yellow eyes or skin, or dark urine 
 You become confused. 
 
If you experience certain other serious problems (such as an allergic reaction, swelling, difficulty breathing, a 
bad skin rash, liver or kidney damage, or changes in your heart rhythm), you may be asked to return to the 
clinic for more tests.  This may include more blood tests.  The study doctor will explain these tests to you if 
they are needed.  You may also need to stop taking the study drug after talking with the study doctor. 
 
Risks of Sharing the Drug 
Do not share the study drug with anyone. It is prescribed only for you and could hurt someone else. Keep it 
out of reach of children and people not able to read or understand the label. 
 
Blood Donation 
If you participate in this study it may affect your ability to donate blood.  If you have any questions call the 
organization where you donate blood and talk to one of their nurses. 
 
Risks of having your blood drawn: 
Having blood drawn may cause: 
 pain (common), 
 a bruise (sometimes), 
 fainting or passing out (not very often), and  
 infection (rare). 
 
If the people doing the study are exposed to your blood or body fluids in a way that could give them a disease, 
your blood may be tested. The tests might check for: 
 hepatitis,  
 HIV (Human Immunodeficiency Virus), or  
 other infections.   
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 14 of 20 
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You and the person exposed would be told the test results. However, your name would be kept private. If your 
test is positive for hepatitis or HIV or any other infection that may affect your clinical care, we will tell you the 
results and help you understand what the results mean for you.  
 
Risks for women: Pregnancy and Contraception 
The drug(s) used in this study can harm an unborn or nursing baby.  Therefore, you cannot be in this study if 
you are pregnant or nursing a baby.  A pregnancy blood test will be done about 14 days before receiving any 
study treatment if you are a woman able to become pregnant as part of your clinical care.   This test must be 
negative in order to continue study participation.  
 
It is important you understand that if you could become pregnant, you need to use birth control while on 
this study.  You and your partner must use an approved form of birth control during this study.  Examples of 
birth control you may use are: 
 Norplant 
 Birth Control Pills 
 IUD (intrauterine device) 
 Birth Control Patch 
 Depo-Provera 
 Sterilization 
The birth control methods listed below are less effective.  They may be used if combined with other birth 
control methods: 
 Condoms 
 Diaphragm 
 Jellies or foam 
 Rhythm 
 Withdrawal 
 Cervical cap 
 Sponge 
 
 
Ask your doctor for more details about the proper birth control method for you.  If you become pregnant 
during this study, you must tell your doctor right away.  Your doctor will discuss your treatment and the effect 
on the pregnancy. 
 
As outlined earlier, there are certain medications and supplements that may interact with the study drug(s).  
You should not take any new medications or supplements without discussing it with your study doctor first. 
 
For more information about risks and side effects, ask your study doctor. 
 
Other unexpected risks: 
You may have side effects that we do not expect or know to watch for now.  Call the study leader if you have 
any symptoms or problems. 
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
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Could you be helped by being in this study? 
We cannot promise that you will be helped by being in this study. 
 
You may or may not benefit from being in this study. Possible benefits include: treatment with pazopanib + 
gemcitabine may be more effective in treating your cancer compared to gemcitabine alone,  however, there is 
no proof of this yet. In addition, information researchers get from this study may help others in the future. 
 
What are your other choices if you do not join this study? 
You do not have to be in this study to be treated for your illness or condition. You can receive the usual 
treatment even if you choose not to be in this study. If you do not take part in this study, your other choices 
may include: 
 
Getting standard treatment or care for your cancer without being in a study.  Other treatments include 
chemotherapy such as gemcitabine, other forms of immunotherapy, radiotherapy, or surgery, alone or 
in combination 
 
Taking part in another study 
 
Getting no treatment 
 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by the cancer.  It does not treat the cancer directly, but instead 
tries to improve how you feel.  Comfort care tries to keep you as active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
If you are an employee of UVa your job will not be affected if you decide not to participate in this study.  
If you are a student at UVa, your grades will not be affected if you decide not to participate in this study.   
 
Will you be paid for being in this study? 
You will not get any money for being in this study. 
 
Will being in this study cost you any money? 
The following procedures/tests, which are being done only for research purposes, will be provided at no cost to 
you or your health insurance: The cost of the drug pazopanib, urinalysis, thyroid, liver function tests, ECG on Day 1 
of Cycle 2, and blood pressure test on Day 15 of each cycle. 
 
You and/or your insurance company must pay for any tests or care given beyond what is required in this study.  
In addition, you and/or your health insurance may also have to pay for other drugs or treatments that are 
given to help you control any side effects.  You will have to pay for any costs not covered by your health plan.  
You may be responsible for any co-payments or deductibles.  You may wish to ask for an estimate of your 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
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financial costs.  You may also wish to check with your insurance company before the study starts. Ask what 
they will cover and if they require you to get their permission before you decide to be in the study. 
 
You will be responsible for the cost of travel to come to any study visit and for any parking costs.    
 
What if you are hurt in this study? 
 
You do not give up any legal rights, such as seeking compensation for injury, by signing this form.  If you feel 
you have been injured as a result of this study you may contact the Principal Investigator or the IRB (phone 
numbers are located near the end of this form).  If you are hurt as a result of being in this study, there are no 
plans to pay you for medical expenses, lost wages, disability, or discomfort. The charges for any medical 
treatment you receive will be billed to your insurance. You will be responsible for any amount your insurance 
does not cover.    
 
What happens if you leave the study early? 
You can change your mind about being in the study any time. You can agree to be in the study now and 
change your mind later. If you decide to stop, please tell us right away. You do not have to be in this study to 
get services you can normally get at the University of Virginia.  
 
Even if you do not change your mind, the study leader can take you out of the study.  Some of the reasons for 
doing so may include  
a) Your study physician is concerned about your health 
b) Your condition gets worse  
c) The side effects of the treatment are too dangerous for you 
d) New information shows the study treatment will not work or is not safe for you 
e) You do not follow your doctor’s instructions 
f) The study sponsor closes the study for safety, administrative or other reasons 
 
How will your personal information be shared? 
The UVa researchers are asking for your permission to gather, use and share information about you for this 
study.  If you decide not to give your permission, you cannot be in this study, but you can continue to receive 
regular medical care at UVA.  
 
If you sign this form, we may collect any or all of the following information about you: 
o Personal information such as name, address and  date of birth  


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
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o Your health information if required for this study.  This may include a review of your medical records and 
test results from before, during and after the study from any of your doctors or health care providers.  This 
may include mental health care records, substance abuse records, and/or HIV/AIDS records. 
 
Who will see your private information?   
o The researchers to make sure they can conduct the study the right way,  observe the effects of the study 
and understand its results   
o People or groups that oversee the study to make sure it is done correctly   
o The sponsor(s) of this study, and the people or groups it hires to help perform  or review this research 
o Insurance companies or other organizations that may need the information in order to pay your medical 
bills or other costs of your participation in the study   
o Tax reporting offices (if you are paid for being in the study) 
o People who evaluate study results, which can include sponsors and other companies that make the drug or 
device being studied, researchers at other sites conducting the same study, and government agencies that 
provide oversight such as the Food and Drug Administration (FDA) if the study is regulated by the FDA.  
o If you tell us that someone is hurting you, or that you might hurt yourself or someone else, the law may 
require us to let people in authority know so they can protect you and others.   
 
Some of the people outside of UVa who will see your information may not have to follow the same privacy 
laws that we follow. They may release your information to others, and it may no longer be protected by those 
laws. 
 
The information collected from you might be published in a medical journal.  This would be done in a way that 
protects your privacy.  No one will be able to find out from the article that you were in the study. 
 
A description of this clinical trial will be available on http:// www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
What if you sign the form but then decide you don't want your private information shared?  
You can change your mind at any time.  Your permission does not end unless you cancel it.  To cancel it, please 
send a letter to the researchers listed on this form.  Then you will no longer be in the study.  The researchers 
will still use information about you that was collected before you ended your participation.   
 
A copy of this consent form will be put in your medical record. (This is not the same as the record of this 
research study.) This means that everyone who is allowed to see your medical records will be able to find out 
that you are in this study. This is done so your regular doctors will know what you receive as part of this study.   
If you have other health problems during the study, they will be able to treat you properly. 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
Page 18 of 20 
Version: 01Feb2017 
 
 
 
 
Please contact the researchers listed below to: 
 Obtain more information about the study 
 Ask a question about the study procedures or treatments 
 Report an illness, injury, or other problem (you may also need to tell your regular doctors) 
 Leave the study before it is finished 
 Express a concern about the study 
 
Principle Investigator 
Linda R. Duska, M.D. 
University of Virginia School of Medicine (UVA) 
PO Box 800712 
Charlottesville, VA 22908 
Telephone:  (434) 982-1719         lduska@virginia.edu 
What if you have a concern about this study?  
You may also report a concern about this study or ask questions about your rights as a research subject by 
contacting the Institutional Review Board listed below. 
 
 
University of Virginia Institutional Review Board for Health Sciences Research 
PO Box 800483 
Charlottesville, Virginia 22908       Telephone: 434-924-9634 
 
When you call or write about a concern, please give as much information as you can. Include the name of the 
study leader, the IRB-HSR Number (at the top of this form), and details about the problem.  This will help 
officials look into your concern. When reporting a concern, you do not have to give your name. 
 
 
 
 
Signatures 
What does your signature mean? 
Before you sign this form, please ask questions about any part of this study that is not clear to you.  Your 
signature below means that you have received this information and all your questions have been answered.  If 
you sign the form it means that you agree to join the study.  You will receive a copy of this signed document.   


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
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Consent From Adult 
 
______________________ 
PARTICIPANT 
(SIGNATURE) 
 
________________________ 
PARTICIPANT 
(PRINT) 
 
_______ 
DATE 
 
 
 
To be completed by participant if 18 years of age or older.  
 
If an interpreter is involved in the consent process because the potential subject does not speak English well or at all, the 
participant should NOT sign on the line above – leave this line blank.  Instead, the participant should sign the Short Form or full 
consent written in the language they can understand.  
 
Person Obtaining Consent 
By signing below you confirm that you have fully explained this study to the potential subject, allowed them 
time to read the consent or have the consent read to them, and have answered all their questions.  
 
_______________________________ 
PERSON OBTAINING CONSENT 
(SIGNATURE) 
 
_____________________________ 
PERSON OBTAINING 
CONSENT 
(PRINT) 
 
________ 
DATE 
 
Interpreter 
 
By signing below you confirm that the study has been fully explained to the potential subject in a language 
they understand and have answered all their questions. 
 
____________________________ 
INTERPRETER 
(SIGNATURE) 
 _____________________________ 
INTERPRETER 
(PRINT) 
 ________ 
DATE 
If an interpreter was used to explain this study to a potential subject, the interpreter must sign and date the 
line above.  
 
Consent from Impartial Witness 
 
If this consent form is read to the subject because the subject is blind or illiterate, an impartial witness not 
affiliated with the research or study doctor must be present for the consenting process and sign the 
following statement.  The subject may place an X on the Participant Signature line above.  
 


IRB-HSR#16153: A RANDOMIZED OPEN LABEL PHASE II STUDY OF WEEKLY GEMCITABINE PLUS PAZOPANIB 
VERSUS WEEKLY GEMCITABINE ALONE IN THE TREATMENT OF PATIENTS WITH PERSISTENT OR RELAPSED 
EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA 
 
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I agree the information in this informed consent form was presented orally in my presence to the identified 
individual(s) who has had the opportunity to ask any questions he/she had about the study.   I also agree that 
the identified individual(s) freely gave their informed consent to participate in this trial.  
 
Please indicate with check box the identified individual(s): 
 Subject  
 
_______________________________ 
IMPARTIAL WITNESS 
(SIGNATURE) 
 _____________________________ 
IMPARTIAL WITNESS 
(PRINT) 
 ________ 
DATE