Clinical trial NCT01468909
Conditions: Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2011-12-12; Completion date: 2018-01-27
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well paclitaxel when given together with or without pazopanib hydrochloride works in treating patients with ovarian epithelial, fallopian tube, or peritoneal cavity cancer that is persistent or has come back. Drugs used in chemotherapy, such as paclitaxel work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking blood flow to the tumor or by blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel is more effective when given with or without pazopanib hydrochloride in treating ovarian epithelial, fallopian tube, and peritoneal cavity cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the progression-free survival hazard ratio of the combination of weekly paclitaxel and pazopanib (pazopanib hydrochloride) compared to weekly paclitaxel and placebo in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer.

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE).

II. To estimate and compare the proportion of patients responding to therapy by Response Evaluation Criteria in Solid Tumors (RECIST), cancer antigen 125 (CA125) response, the overall survival (OS), and the duration of response in each arm.

TERTIARY OBJECTIVES:

I. To explore the association between plasma cytokines and angiogenic markers and progression-free and overall survival.

II. To explore the association between single-nucleotide polymorphisms (SNPs) and progression-free and overall survival.

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

ARM I: Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 and placebo orally (PO) daily on days 1-28.

ARM II: Patients receive paclitaxel as in Arm I and pazopanib hydrochloride PO daily on days 1-28.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms: arm 1: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo PO daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive paclitaxel as in arm I and pazopanib hydrochloride PO daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Paclitaxel intervention 3: Pazopanib Hydrochloride intervention 4: Placebo
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV intervention 3: Given PO intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Philip J. DiSaia, M.D. 
President 
 
Administrative Office 
Four Penn Center 
1600 John F. Kennedy Boulevard, Suite 1020 
Philadelphia, Pennsylvania 19103 
Phone: 215-854-0770 Fax: 215-854-0716 
 
Laura L. Reese 
Executive Director of Operations 
Larry J. Copeland, M.D. 
Vice President  
 
Finance/Development Office 
2127 Espey Court 
Suite 100 
Crofton, Maryland 21114 
Phone: 410-721-7126 Fax: 301-261-3972 
 
Mary C. Sharp 
Chief Financial Officer 
 
i 
SUMMARY OF CHANGES 
 
For Protocol Revision #6 to GOG-0186J 
 
NCI Protocol #: GOG-0186J 
Local Protocol #: GOG-0186J 
 
NCI Version Date: 03/09/2015 
Protocol Date:  
 
This amendment is being submitted in response to an RRA from Dr. Pamela Harris 
(harrispj@mail.nih.gov).  
 
 
# 
Section 
Page(s) 
Change 
1 
Title Page 
1 
• NCI Version Date is now 03/09/2015. 
• Includes Revisions 1-6.  
 
2 
4.216 
 
• The Pazopanib CAEPR has been updated; version 2.6 
has been inserted: 
Added New Risk: 
o Rare but Serious: Respiratory, thoracic and mediastinal 
disorders - Other (interstitial lung disease) 
 
3 
IC 
 
Additional changes have been made to the IC document. 
 
 
 
 
 
 
 
 
 


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PROTOCOL GOG-0186J 
A RANDOMIZED PHASE IIB EVALUATION OF WEEKLY PACLITAXEL (NSC #673089) 
PLUS PAZOPANIB (NSC #737754) (IND #75648) VERSUS WEEKLY PACLITAXEL PLUS 
PLACEBO IN THE TREATMENT OF PERSISTENT OR RECURRENT EPITHELIAL 
OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CARCINOMA (02/06/2012) 
NCT #01468909 (01/12/2015) 
NCI Version Date: 03/09/2015 
Includes Revisions #1- 6 
POINTS: 
PER CAPITA – 20 
MEMBERSHIP – 6 (06/11/2012) 
TR PER CAPITA – Award based on specimen submission with 1.0 point for each whole blood and plasma specimen 
(TOTAL = 4.0 points). 
 
Lead Organization: NRG/NRG Oncology (01/12/2015) 
 
 
 
 
 
 
OPEN TO PATIENT ENTRY DECEMBER 12, 2011; REVISED FEBRUARY 6, 2012; REVISED 
JUNE 11, 2012; REVISED OCTOBER 9, 2012; CLOSED TO PATIENT ENTRY APRIL 22, 2013; 
REVISED JULY 12, 2013; REVISED JANUARY 12, 2015; REVISED 
 
STUDY CHAIR 
NURSE CONTACT (10/09/2012) 
 
DEBRA L. RICHARDSON, M.D. 
PAULA F. ROGERS, RN, OCN, CCRC 
UT SOUTHWESTERN MED CTR AT DALLAS 
GYNECOLOGIC ONCOLOGY RESEARCH 
GYN ONCOLOGY 
GYN/ONC REPRODUCTIVE MEDICINE 
5323 HARRY HINES BLVD.  J07.124 
CPB6.3583 
DALLAS, TX 75390-9032 
1155 PRESSLER ST. 
(214) 648-3026 
HOUSTON, TX 77030 
FAX:  (214) 648-8404 
713- 563-4598 
E-MAIL: debra.richardson@utsouthwestern.edu  
FAX: 713-792-7586 
 
E-MAIL: pfrogers@mdanderson.org  
STUDY CO–CHAIR 
 
ROBERT COLEMAN, MD 
TRANSLATIONAL RESEARCH CHAIR 
See GOG Website Directory 
ANIL K. SOOD, M.D. 
 
 
See GOG Website Directory 
STATISTICIAN 
 
MICHAEL SILL, PH.D. 
TRANSLATIONAL RESEARCH SCIENTIST 
See GOG Website Directory 
HEATHER A. LANKES, PH.D., M.P.H 
 
See GOG Website Directory 
SCHEMA 
Regimen 1:  Paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 (1-hr IV infusion) with 
Placebo PO daily 
Regimen 2:  Paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 (1-hr IV infusion) with 
Pazopanib 800 mg PO daily 
Until disease progression or adverse effects prohibit further therapy  
One cycle = 28 days 
This protocol was designed and developed by the Gynecologic Oncology Group (GOG). It is intended to be used 
only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized 
by GOG nor does GOG assume any responsibility for unauthorized use of this protocol. 


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TABLE OF CONTENTS 
PAGE 
1.0 
OBJECTIVES 
- 4 - 
1.1 
Primary Objectives: 
- 4 - 
1.2 
Secondary Objectives: 
- 4 - 
1.3 
Translational Research Objectives: 
- 4 - 
2.0 
BACKGROUND AND RATIONALE 
- 4 - 
2.1 
Ovarian Cancer 
- 4 - 
2.2 
Pazopanib 
- 4 - 
2.3 
Rationale for the use of pazopanib in ovarian, peritoneal and tubal cancers 
- 11 - 
2.4 
Weekly Paclitaxel and Safety of Combination Weekly Paclitaxel/Pazopanib 
- 12 - 
2.5 
Translational Research 
- 13 - 
2.6 
Rationale for Clinical Trial Design 
- 14 - 
2.7 
Inclusion of Women and Minorities 
- 14 - 
3.0 
PATIENT ELIGIBILITY 
- 15 - 
3.1 
Eligibility Criteria 
- 15 - 
3.2 
Ineligibility Criteria 
- 19 - 
4.0 
STUDY MODALITIES 
- 22 - 
4.1 
Paclitaxel (NSC #673089) 
- 22 - 
4.2 
Pazopanib (CTEP IND#75648, NSC#737754) or placebo 
- 23 - 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
- 35 - 
5.1 
Patient Entry and Registration (10/09/2012) 
- 35 - 
5.2 
Treatment Plan 
- 36 - 
5.3 
Concomitant Medications: 
- 37 - 
5.4 
Precautions/Warnings (See Appendix III) 
- 39 - 
5.5 
Criteria for removal from treatment 
- 41 - 
6.0 
TREATMENT MODIFICATIONS 
- 42 - 
6.1 
Hematologic toxicity 
- 42 - 
6.2  
Dose and Treatment Modifications for Pazopanib/Placebo 
- 44 - 
6.3  
Dose and Treatment Modifications for Paclitaxel Non-Hematologic Toxicity 
- 55 - 
6.4 
Dose escalations 
- 55 - 
7.0 
STUDY PARAMETERS & SERIAL OBSERVATIONS 
- 56 - 
7.1 
Tests and Observations 
- 56 - 
7.2 
Pathology Requirements 
- 59 - 
7.3 
Translational Research 
- 59 - 
7.4 
Quality of Life 
- 60 - 
8.0 
EVALUATION CRITERIA 
- 61 - 
8.1 
Antitumor Effect – Solid Tumors 
- 61 - 
9.0 
DURATION OF STUDY 
- 70 - 
9.1 
Patients will receive therapy until disease progression or intolerable toxicity intervenes.  
The patient can refuse the study treatment at any time. 
- 70 - 
9.2 
All patients will be treated (with completion of all required case report forms) until 
disease progression, initiation of a subsequent cancer treatment, or study withdrawal.  Patients 
will then be followed every three months for the first two years and then every six months for the 
next three years.  Patients will be monitored for delayed toxicity and survival for this 5-year 
period with Q forms submitted to the GOG Statistical and Data Center, unless consent is 


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withdrawn.  Q forms will no longer be required if the study is terminated prior to the completion 
of the 5-year follow-up period. 
- 70 - 
9.3 
A patient is considered off study therapy when the patients has progressed or died, a 
subsequent drug or therapy (directed at the disease) is initiated or all study therapy is 
discontinued.  Report all treatment received on From D2R and adverse events on Form T until 
the patient qualifies as being off study therapy. 
- 70 - 
10.0 
STUDY MONITORING AND REPORTING PROCEDURE 
- 71 - 
10.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT (CTEP 
IND) - 71 - 
10.2 
GOG DATA MANAGEMENT FORMS 
- 74 - 
11.0 
STATISTICAL CONSIDERATIONS 
- 76 - 
11.1 
Parameters employed to evaluate treatment efficacy and toxicity are: 
- 76 - 
11.2 
The anticipated annual accrual is approximately 50 patients. 
- 76 - 
11.3 
Study Plan: 
- 77 - 
11.4 
Data sheets from studies on this protocol will be reviewed before each semi-annual 
meeting and will also be reviewed by the Study Chair in conjunction with the Statistical and Data 
Center.  In some instances, because of unexpectedly severe toxicity, the Statistical and Data 
Center may elect, after consultation with the Study Chair and the Medical Oncology Committee, 
to recommend early closure of a study. 
- 79 - 
11.5 
Secondary and Exploratory Analyses: 
- 80 - 
11.6 
Translational Research 
- 80 - 
11.7 
Women and Minority Inclusion 
- 83 - 
12.0 
BIBLIOGRAPHY 
- 85 - 
APPENDIX I 
- 91 - 
APPENDIX II 
- 92 - 
APPENDIX III 
- 94 - 
APPENDIX IV 
- 96 - 
APPENDIX V 
- 101 - 
APPENDIX VI 
- 102 - 
APPENDIX VII 
- 104 - 
 
 
 
 
 
 
 


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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 paclitaxel and pazopanib compared to weekly paclitaxel and 
placebo 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. 
 
1.22 
To estimate and compare the proportion of patients responding to therapy 
by RECIST, CA125 response, the overall survival (OS), and the duration 
of response in each arm. 
 
1.3 
Translational Research Objectives: 
 
 
1.31 
To explore the association between plasma cytokines and angiogenic 
markers and progression-free and overall survival. 
 
1.32 
To explore the association between single-nucleotide polymorphisms 
(SNPs) and progression-free and overall survival. 
 
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 13,850 women will 
die of ovarian cancer in 2010.1 Although about 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 recur. 
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.   
 
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, 
2010).  In human umbilical vein endothelial cells (HUVECs), pazopanib inhibited 


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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 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, 2010).3,4 
 
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.5,6  Reported data suggest that combined 
pharmacologic disruption of PDGFR-β and VEGFR-2 signaling results in 
profound antiangiogenic effects in tumors.7  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 


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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 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.  Follow-up studies were 
done with pazopanib and docetaxel with an endpoint of time to reach two tumor 
doublings.  Pazopanib was administered orally (PO) at 100 mg/kg daily and 
docetaxel was administered intraperitoneally (IP) at 50 mg/kg once weekly for 3 
weeks.  In two independent experiments, the median time to reach two tumor 
doublings was longest in mice treated with both pazopanib and docetaxel 
concomitantly.  These results clearly show an advantage of combining pazopanib 
with docetaxel (and likely other chemotherapeutic agents) for better tumor 
control. 
 
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 


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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 
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 
Approximately 3000 subjects with cancer have been enrolled in clinical studies of 
pazopanib as of September 2009.  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), 


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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 .8  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, 2010).  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.9  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.10  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%.11  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. 12  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.13 Interim analysis of data from 26 subjects showed that 
pazopanib has both a favorable toxicity profile and promising clinical activity in 
subjects with advanced and progressive differentiated thyroid cancers.14  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, 
2010) 
 
Safety  
The randomized, phase 3 study in mRCC subjects provided a key comparison of 
safety with pazopanib compared to placebo.8  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 


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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, 2010).  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 SAEs of pleural effusion, the body of data does not 
suggest that any of these cases were 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. 
 


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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, 2010).15  
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. 16  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. 16 
 
Preliminary PK information on the combination of pazopanib and paclitaxel 
administered to subjects with advanced cancer has been reported.17  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%.17 
 
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 medications that have narrow therapeutic windows and are 
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possible, medications 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, 2010).  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.18   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, 2010).  
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).19  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.20-24  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.25  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.19  
Nevertheless, new agents are vitally necessary, specifically those that may offer 
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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.26 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.27 Unfortunately, targeting just the pericyte 
with PDGF inhibitors has led to 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 to a more immature vascular phenotype devoid 
of pericytes.28 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.27,29  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.  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.  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. 37 
 
2.4 
Weekly Paclitaxel and Safety of Combination Weekly Paclitaxel/Pazopanib 
 
Weekly paclitaxel has been studied in recurrent ovarian cancer as a single agent in 
a number of clinical settings including in the GOG-0126 mechanism.38-40 In each 
of these cases, real or suspected taxane-resistance has been a feature of enrolled 
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approximately 20% and appears to be among the most active chemotherapeutics 
in the resistant phenotype.  Dose-dense therapy of taxanes has recently proved to 
be a significant advance in primary ovarian cancer with the reporting of a 
Japanese phase III trial comparing weekly administration to bolus administration 
of paclitaxel, both in combination with bolus carboplatin. PFS was improved by 
11 months in the dose-dense arm (17 mos vs 28 mos, P = 0.0014).41 Unique to the 
infusion schedule was the absence of a “break” week, which is attributed to the 
low rate of completion of unaltered infusion. Compliance is improved with this 
recovery week but the impact on response remains to be tested.  The theoretical 
advantage to lower dose, frequent administration of paclitaxel is its impact on 
local cytokines, which may provide an addition anti-angiogenic effect.42-46  It has 
been shown pre-clinically that low dose paclitaxel is synergistic with anti-VEGF 
targeted therapies and has substantial clinical activity in uncontrolled study 
settings.47  It also appears to impact the expression of thrombospondin-I, a natural 
inhibitor of neovascularization and angiogenesis.  Phase I data support the safety 
of pazopanib at 800 mg po daily with paclitaxel 80 mg/m2. 48  In this study 25 
patients with advanced cancer were treated with escalating doses of pazopanib 
(400 mg – 800 mg) in combination with weekly paclitaxel (15 mg/m2 – 80 
mg/m2) days 1, 8 ,15 on a 28 day cycle.  One DLT was observed at this dose (Gr 3 
groin abscess).  Dose alterations for each agent at this dose over the course of 
therapy occurred in 7 patients for pazopanib (liver enzyme elevation) and in 11 
patients for paclitaxel (dose delay) or dose reductions (5 patients).  Pazopanib 
increases the bioavailability of paclitaxel by 40% (Cmax) to 45% (AUC). The 
optimal treatment dose in this trial was determined to be pazopanib at 800 mg po 
daily with paclitaxel 80 mg/m2 IV, days 1, 8, and 15 of a 28-day cycle. 
 
2.5 
Translational Research 
 
Cytokine levels have been evaluated as potential diagnostic and prognostic 
markers in ovarian cancer.  They function primarily to regulate immunity, 
hematopoiesis, and inflammation.  Systemic cytokine levels differ in cancer 
patients, possibly due to an interaction between the disease and the immune 
system resulting in cytokine production.49  Various cytokines, including IL-6, IL-
7, and IL-8, have been associated with ovarian cancer and identified as potential 
therapeutic and diagnostic tools for the disease.50-52  Additionally, levels of 
vascular endothelial growth factor (VEGF) have been found to correlate 
significantly with patient survival and to be an independent prognostic indicator 
in overall survival in patients with ovarian cancer.53 
 
There is growing recognition that serum markers such as VEGF cannot predict the 
response to anti-VEGF treatment. As such, we have included plasma studies to 
evaluate the correlation between cytokine levels (e.g., IL-6, IL-8, IL 11, IL-1a, Il-3, 
IL-4, VEGF, TPO, G-CSF, GM-CSF, osteopontin, and sVEGFRs ) with progression-
free and overall survival in patients treated with pazopanib, which targets VEGFR 
1,2, and 3.  Previous studies indicate that the pre-treatment levels of VEGF in 
plasma, not serum, are associated with progression-free and overall survival in 


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patients with persistent or recurrent gynecologic malignancies, including ovarian, 
uterine, and uterine leiomyosarcoma.54-56 Since platelets can upload cytokines and 
the actual level of cytokines/growth factors can be affected by thrombocytosis, 
plasma markers are preferable for identifying potential predictive markers to 
treatment. In addition, SNPs will be examined for associations with progression-
free and overall survival. 
 
2.6 
Rationale for Clinical Trial Design 
 
This is a double-blind, placebo-controlled phase II trial. All patients will receive 
IV paclitaxel days 1, 8, and 15 every 28 days  in combination with either oral 
pazopanib or an oral placebo.  Blinding will preserve the integrity of the 
progression-free survival and overall survival endpoints by eliminating biases in 
disease assessment monitoring, the declaration of disease progression and the 
institution/selection of future therapies. Therefore, it is understood that 
investigators, patients and research personnel will not know whether or not 
patients have received pazopanib or placebo. Because of the intent-to-treat 
analysis, this rule applies to patients who enter the study and then are later found 
to be ineligible. The only indication for un-blinding to treatment arm is a serious 
adverse event in which it is determined by the Study Chair that un-blinding would 
improve patient safety. 
 
2.7 
Inclusion of Women and Minorities 
 
The Gynecologic Oncology Group and GOG participating institutions 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 by participating institutions. 


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3.0 
PATIENT ELIGIBILITY   
 
 
3.1 
Eligibility 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 non-measurable (detectable) 
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 Non-measurable (detectable) disease in a patient is defined in this 
protocol as one who does not have measurable disease but has at 
least one of the following conditions: 
 
    •  Ascites and/or pleural effusion attributed to tumor; 
•  Solid and/or cystic abnormalities on radiographic imaging that 
do not meet RECIST 1.1 (see Section 8.1) definitions for target 
lesions. 
 
3.13 
Patients with measurable disease must have at least one “target lesion” to 
be used to assess response on this protocol as defined by RECIST 1.1 
(Section 8.1).  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. 
 
3.14 
Patients must not be eligible for a higher priority GOG protocol, if one 
exists.  In general, this would refer to any active GOG phase III or Rare 
Tumor protocol for the same patient population.  In addition, patients must 
not be eligible for the currently active phase II cytotoxic protocol in 
platinum resistant disease. 
 
3.15 
Patients who have received one prior regimen must have a GOG 
Performance Status of 0, 1, or 2. 
 
 
Patients who have received two or three prior regimens must have a GOG 
Performance Status of 0 or 1. 


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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 (non-cytotoxic) agents and 
immunologic agents, 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 12 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).  There is 
no restriction on minor procedures (e.g., minor: central venous 
access catheter placement, ureteral stent placement or exchange, 
paracentesis, thoracentesis). (02/06/2012) 
 
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, biologic/targeted (non-cytotoxic) agents (e.g., 
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, with no more than 1 non-platinum, non-taxane 
regimen.  Treatment with weekly paclitaxel for recurrent or 
persistent disease is NOT allowed. 
 
3.173 Patients are allowed to receive, but are not required to receive, 
biologic/targeted (non-cytotoxic) therapy as part of their primary 
treatment regimen.     
 


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Patients must have NOT received any biologic/targeted (non-
cytotoxic) therapy targeting the VEGF and/or PDGF pathways for 
management of recurrent or persistent disease.  
 
 
For the purposes of this study, Poly (ADP-ribose) polymerase 
(PARP) inhibitors will be considered “cytotoxic”.  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 will 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. 
 
3.182 Blood coagulation parameters: PT such that international 
normalized ratio (INR) is less than or equal to 1.5 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 1.5 x ULN.    
 
3.183 Renal function:  Creatinine less than or equal to 1.5 x institutional 
upper limit normal (ULN).  
 
3.184 Urine Protein:  Urine protein should be screened by urinalysis.  If 
protein is 2+ or higher, 24-hour urine protein should be obtained 
and the level must be <1000 mg (<1.0 g/24hrs) for patient 
enrollment. 
 
3.185 Hepatic function:  
• Bilirubin less than or equal to 1.5 x ULN. 
• AST and ALT less than or equal to 2.5 x ULN and alkaline 
phosphatase less than or equal to 2.5 x ULN.   
• Subjects who have BOTH bilirubin greater than ULN and 
AST/ALT greater than ULN are not eligible 
 
3.186 Thyroid function:  Patients must have normal baseline thyroid 
function tests (TSH, T3, T4).  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. 
 
3.187   Neurologic function:  Neuropathy (sensory and motor) less than or 
equal to grade 1. 


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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 III for a list of concomitant medications 
associated with QTc and Torsades de Pointes. 
 
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. 
CYP Substrates:  Concomitant use of agents with narrow therapeutic 
windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not 
recommended.  See Section 4.211.  Additional information for drug 
interactions with cytochrome P450 isoenzymes may be found at 
http://medicine.iupui.edu/flockhart/ 
 
 


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3.2 
Ineligibility Criteria 
 
3.21 
Patient who have had previous treatment with pazopanib.  Patients who 
have had previous treatment with weekly paclitaxel 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 three years.  Patients are also 
excluded if their previous cancer treatment contraindicates this protocol 
therapy. 
 
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 
radiation for localized cancer of the breast, head and neck, or skin is 
permitted, provided that it was completed more than three 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 140 
mm Hg or diastolic greater than 90 mm Hg despite 
antihypertensive medications. 
 
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 II 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. 


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3.256 Patients who have received prior treatment with an anthracycline 
(including doxorubicin and/or liposomal doxorubicin) must have 
an echocardiogram assessment and are excluded if they have an 
ejection fraction less than 50%. 
 
3.257 CTCAE 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. 
 
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 
Patients with history or evidence upon physical examination of CNS 
disease, including primary brain tumor, seizures which are not controlled 
with non-enzyme inducing anticonvulsants, any brain metastases, or 
history of cerebrovascular accident (CVA, stroke), transient ischemic 
attack (TIA) or subarachnoid hemorrhage within six months prior to the 
first date of study treatment. 
 
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) 


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• patients with clinical symptoms or signs of gastrointestinal 
obstruction and patients who require parenteral hydration and/or 
nutrition. 
 
 
3.212   Patients who are pregnant or nursing. 
 
3.213   History of hemoptysis in excess of 2.5 mL (1/2 teaspoon) within 8 weeks 
prior to first dose of pazopanib. 
 
3.214   Uncontrolled intercurrent illness including, but not limited to, psychiatric 
illness/social situations that would limit compliance with study 
requirements. 
 
 


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4.0 
STUDY MODALITIES    
 
4.1 
Paclitaxel (NSC #673089) 
 
4.11 
Formulation:  Paclitaxel is supplied as a 6mg/mL non-aqueous solution in 
multi dose vials containing 30mg/5mL, 100mg/16.7mL, or 300mg/50mL 
of paclitaxel.  In addition to 6mg of paclitaxel, each mL of sterile non-
pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
 
4.12 
Storage:  Unopened vials of paclitaxel are stable to the date indicated on 
the package when stored between 20 to 25°C (68 to 77°F).  Protect from 
light. 
 
4.13 
Stability: Commercially available paclitaxel will be labeled with an 
expiration date.  All solutions of paclitaxel exhibit a slight haziness 
directly proportional to the concentration of drug and the time elapsed 
after preparation, although when prepared as described below, solutions of 
paclitaxel (0.3-1.2mg/ml) are physically and chemically stable for 27 
hours. 
 
4.14 
Preparation:  Paclitaxel must be diluted prior to infusion.  Paclitaxel 
should be diluted in 0.9% Sodium Chloride for Injection, USP; 5% 
Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride 
Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2mg/mL.  The solutions are physically and 
chemically stable for up to 27 hours at ambient temperature 
(approximately 25°C / 77°F) and room lighting conditions. 
 
NOTE:  In order to minimize patient exposure to the plasticizer DEHP, 
which may be leached from PVC infusion bags or sets, diluted paclitaxel 
solutions should be stored in bottles (glass, polypropylene) or plastic 
(polypropylene, polyolefin) bags and administered through polyethylene-
lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a 
microporous membrane not greater than 0.22 microns.  Use of filter 
devices such as IVEX-2® or IVEX-HP®, which incorporate short inlet 
and outlet PVC-coated tubing, has not resulted in significant leaching of 
DEHP. 
 
All patients should be premedicated with corticosteroids, 
diphenhydramine, and H2 antagonists prior to paclitaxel administration in 
order to prevent severe hypersensitivity reactions.  Patients who 
experience severe hypersensitivity reactions to drug may need to repeat 
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infusion.  Severe hypersensitivity reactions to paclitaxel do not have to 
proceed with a re-challenge.   
 
4.15 
Adverse Effects:  Consult the package insert for the most current and 
complete     information. 
 
4.16 
Supplier:  Commercially available both from Bristol-Myers Squibb 
Oncology as well as generic manufacturers.  Consult the American 
Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
4.2 
Pazopanib (CTEP IND#75648, NSC#737754) or placebo 
 
All investigators who receive a copy of the protocol should also obtain a copy of 
the Investigator’s Brochure (IB). IB’s are available from the Pharmaceutical 
Management Branch, CTEP, DCTD, NCI and may be obtained by emailing the 
IB Coordinator (ibcoordinator@mail.nih.gov) or by calling the IB Coordinator at 
301-496-5725. 
 
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 and matching placebo are supplied as aqueous 
film-coated tablets.   
 
Each tablet contains 200 mg or 0 mg of the free base.  Tablets are oval-
shaped, white and packaged in white high density polyethylene (HDPE) 
induction-sealed bottles with white, plastic child-resistant caps.   


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Each bottle contains 34  tablets.  Tablet excipients in all tablets include 
microcrystalline cellulose, povidone, sodium starch glycolate, and 
magnesium stearate.   The film-coat consists of titanium dioxide, 
hypromellose, polyethylene glycol 400, and polysorbate 80. (01/12/2015) 
 
4.28 
Storage: Store tablets at USP controlled room temperature (20° to 25° C or 
68° to 77° F). (01/12/2015) 
 
4.29 
Stability: Stability studies are ongoing. An opened original container of 
tablets is stable for 3 months.  If exact quantity must be dispensed, then extra 
tablets must be removed, documented and destroyed immediately. 
Alternatively, if exact quantity is dispensed in a pharmacy bottle, the supply 
should be assigned a 30-day expiration.  If tablets of patient-
specific/blinded supply are dispensed in a pharmacy bottle, all of the 
information of the CTEP applied label (including the Julian Date) 
MUST be on the bottle dispensed to the patient. (01/12/2015) 
 
4.210 Administration: Oral. Take on an empty stomach either 1 hour before or 2 
hours after food.  The tablets should be swallowed whole and cannot be 
crushed or broken. (01/12/2015) 
 
4.211 Potential Drug Interactions: In vitro data indicate that pazopanib is 
primarily metabolized by CYP3A4 isoenzyme.  Potent CYP3A4 inducers 
and inhibitors are prohibited on pazopanib trials.  Pazopanib is also a 
substrate for p-glycoprotein and breast cancer resistance protein (BCRP) 
transporters and concomitant administration of inhibitors such as lapatinib 
will result in increased plasma pazopanib concentrations. 
 
Clinical studies indicate that pazopanib is a weak inhibitor of CYP3A4, 
CYP2C8, and CYP2D6.  Use caution when combining pazopanib with 
CYP3A4, CYP2C8, and CYP2D6 substrates known to have a narrow 
therapeutic window.   
 
In vitro studies also showed that pazopanib is a potent inhibitor of 
UGT1A1 and OATP1B1. Pazopanib may increase concentrations of drugs 
primarily eliminated through these systems.  
 
Avoid co-administration of pazopanib with medicines that increase gastric 
pH. If the concomitant use of a proton pump inhibitor (PPI) is medically 
necessary, pazopanib should be taken without food once daily in the 
evening with the PPI. If the concomitant administration of an H2-receptor 
antagonist is medically necessary, pazopanib should be taken without food 
at least 2 hours before or at least 10 hours after a dose of an H2-receptor 
antagonist. Administer pazopanib at least 1 hour before or 2 hours after 
administration of short-acting antacids.  


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Avoid co-administration of pazopanib with simvastatin. Concomitant use 
of pazopanib and simvastatin increases the risk of ALT elevation. Data are 
not sufficient to assess the risk of concomitant administration of other 
statins and pazopanib. 
 
Precautions: Pazopanib/placebo should be used with caution in patients 
with a history of QT interval prolongation, in patients taking 
antiarrhythmics or other medications that may prolong QT interval, and 
those with relevant pre-existing cardiac disease. Monitor ECGs and serum 
electrolytes (e.g., calcium, magnesium, potassium) at baseline and 
periodically and maintain within the normal range.   
 
For patients who develop hepatic impairment, refer to the protocol 
document for appropriate dose modification or dose delay. (01/12/2015) 
 
4.212   Availability: Pazopanib is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), 
NCI. 
 
Pazopanib is provided to the NCI under a Collaborative Agreement 
between Novartis Pharmaceuticals Corporation and the DCTD, NCI (see 
Appendix VI). 
 
4.213 Clinical Supplies / Drug Ordering 
 
Clinical Supplies:  Pazopanib (IND#75648, NSC 737754) and matching 
Placebo will be provided free of charge by Novartis Pharmaceuticals 
Corporation and distributed by the Pharmaceutical Management Branch 
(PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer 
Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). 
 
Each blinded, patient-specific bottle will be labeled with … 
 
• the protocol number (i.e., “GOG-0186J”) 
• the bottle number (i.e., “Bottle 1 of 2” and “Bottle 2 of 2”) 
• the number of capsules (i.e., “34 tablets”) 
• the patient ID number (e.g.,"0186J-YYY", where “0186J-YYY” 
represents the protocol number and sequence number which represents 
the unique patient ID number assigned by GOG at the time of patient 
registration) 
• the patient initials (i.e., First initial, Middle initial, Last initial [e.g., 
“FML”]) 
• the agent identification (i.e., “Pazopanib 200 mg or Placebo”) 
• a blank line for the pharmacist to enter the patient’s name  


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• administration instructions (i.e., “Take __ tablets every day for 28 
days.”) 
• storage instructions (i.e., “Store at controlled room temperature 
between 20° and 25° C).” 
• emergency contact instructions 
• a Julian date 
 
The Julian date indicates the day the bottle was labeled and shipped and is 
composed of the last two digits of the calendar year (e.g., 2009 = 09, 2010 
= 10) and a day count (e.g., January 1 = 001, December 31 = 365).  For 
example, a bottle labeled and shipped on January 1, 2009 would have a 
Julian date of ‘09001’ and a bottle labeled and shipped on December 31, 
2009 would have a Julian date of ‘09365’.  The Julian date will be used by 
PMB for recalls.  When a lot expires, PMB will determine the last date the 
expired lot was shipped and will recall all bottles (i.e., both pazopanib and 
Placebo) shipped on or before that date thus eliminating any chance of 
breaking the blind. 
 
Drug Ordering: 
 
BLINDED (pazopanib or placebo) THERAPY   
 
No blinded starter supplies will be available for this study.  Blinded, 
patient-specific clinical supplies will be sent to the registering investigator 
at the time of randomization.  This randomization will be performed by 
the GOG Statistical and Data Center (SDC) in Buffalo, NY.  The patient 
ID number assigned by the GOG SDC must be recorded by the registering 
institution for proper study medication dispersion.  Once a patient has 
been registered with the GOG SDC, the GOG SDC will electronically 
transmit a clinical drug request for that patient to the PMB.  This request 
will be entered and transmitted by the GOG SDC the day the patient is 
registered and will be processed by the PMB the next business day and 
shipped the following business day.  Shipments within the United States 
will be sent by US Priority Mail (generally two to three day delivery).  
Thus, if a patient is registered on Monday, the GOG SDC would enter a 
clinical drug request for that patient on Monday and PMB would process 
that request on Tuesday and ship the drug on Wednesday.  Sites could 
expect to receive their order approximately Friday or Monday.  Shipments 
to United States sites can be expedited (i.e., receipt on Thursday in 
example above) by the provision of an express courier account name and 
number to the GOG SDC at the time the patient is registered/randomized. 
 
The initial shipment will be for 8 – 34 tablet bottles (a 2-cycle / 8-week 
supply at a dose of 4 tablets per day) of pazopanib or matching Placebo.  
Six weeks after the initial shipment, sites may reorder an additional 8 – 34 
tablet bottles (a 2-cycle / 8-week supply at a dose of 4 tablets per day) by 


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completing an NCI Clinical Drug Request form and faxing it to the PMB 
at 301-480-4612 or by using the Online Agent Ordering Processing system 
(OAOP).  The assigned patient ID number (e.g., "0186J-YYY") and the 
patient initials (e.g., "FML") should be entered in the "Patient or Special 
Code" field.  The agent name for the pazopanib must be written on the 
order form as “Pazopanib or Placebo”.  All drug orders should be shipped 
directly to the physician responsible for treating the patient.  
 
4.214 Drug Accountability:  The investigator, or a responsible party designated 
by the investigator, must maintain a careful record of the receipt, 
disposition, and return of all drugs received from the PMB using the NCI 
Investigational Agent Accountability Record available on the CTEP home 
page (http://ctep.cancer.gov).  A separate NCI Investigational Agent 
Accountability Record must be maintained for each patient ID number 
(e.g., "0816J-YYY”) on this protocol. 
 
The Julian Date-Order number (e.g., 2014352-003) from the patients-
specific label must be used as the Lot number on the NCI DARF. 
(01/12/2015) 
 
4.215 Drug Returns:  Only undispensed clinical supplies should be returned 
to the PMB.  When it is necessary to return study drug (e.g., sealed bottles 
remaining when a patient permanently discontinues protocol treatment, 
expired bottles recalled by the PMB), investigators should return the study 
drug to the PMB using the NCI Return Drug List available on the CTEP 
home page (http://ctep.cancer.gov).  The patient ID number (e.g., "0816J-
YYY”) and the patient initials (e.g., "FML") should be entered in the "Lot 
Number" field.  Opened bottles with remaining capsules should be 
documented in the patient-specific NCI Investigational Agent 
Accountability Record (i.e., logged in as “returned by patient” and logged 
out as “destroyed on site”) and destroyed on-site in accordance with 
institutional policy. 
 
Questions about drug orders, transfers, returns, or accountability 
should be addressed to the PMB by calling (301) 496-5725 Monday 
through Friday between 8:30am and 4:30pm Eastern Time.  You may 
also contact PMB via e-mail at PMBAfterHours@mail.nih.gov. 
 
Drug Transfers:  Bottles MAY NOT be transferred from one patient to 
another patient or from one protocol to another protocol.  All other 
transfers (e.g., a patient moves from one participating clinical site to 
another participating clinical site, the principal investigator at a given 
clinical site changes) must be approved in advance by the PMB.  To obtain 
an approval for transfer, investigators should complete and submit to the 
PMB (fax number 301-480-4612) a Transfer Investigational Agent Form 
available on the CTEP home page (http://ctep.cancer.gov).  The patient ID 


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number (e.g., "0816J-YYY”) and the patient initials (e.g., "FML”) should 
be entered in the "Received on NCI Protocol No." and the "Transferred to 
NCI Protocol No." fields in addition to the protocol number (i.e., "GOG-
0186J"). 
4.216 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
GW786034 (Pazopanib, GW786034, NSC 737754) (06/11/2012) 
(07/12/2013) (  ) 
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 Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI via AdEERS (except as noted below).  Refer to 
the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
2383 patients. Below is the CAEPR for GW786034 (pazopanib, 
GW786034). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.61, January 21, 2015 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Hemolytic uremic syndrome2   
 
 
Thrombotic thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
 
Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  


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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
Hypothyroidism 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
 
 
Gastrointestinal fistula3 
 Gastrointestinal fistula3 (Gr 2) 
 
 
Gastrointestinal hemorrhage4   
 
 
Gastrointestinal perforation5 
 Gastrointestinal perforation5 (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time 
prolonged 
 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 2) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase increased 
(Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased (Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
Lymphocyte count 
decreased 
 
 
 Lymphocyte count decreased (Gr 3) 
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 3) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypercalcemia 
 
  


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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypermagnesemia 
 
  
 
Hypernatremia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
Hyponatremia 
 
 
 Hyponatremia (Gr 2) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 3) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Urinary fistula 
 Urinary fistula (Gr 2) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
 
Female genital tract fistula 
 Female genital tract fistula (Gr 2) 
 
 
Uterine fistula 
 Uterine fistula (Gr 2) 
 
 
Vaginal fistula 
 Vaginal fistula (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Respiratory hemorrhage6  
 Respiratory hemorrhage6 (Gr 2) 
 
 
Respiratory, thoracic and 
mediastinal disorders – Other 
(interstitial lung disease)7 
  


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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
Skin and subcutaneous 
tissue disorders - Other (hair 
color change/hair 
depigmentation) 
 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
change/hair depigmentation) (Gr 2) 
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event8 
  
 
 
Vascular disorders - Other 
(arterial thromboembolic 
event)8 
  
 
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. 
 
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and 
Thrombotic thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical 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.  
 
4Gastrointestinal 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.  
 
5Gastrointestinal 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.  
 
6Respiratory 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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7Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary 
fibrosis, Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress syndrome), 
Respiratory, thoracic and mediastinal disorders - Other (Aveolitis), Respiratory, thoracic and mediastinal 
disorders - Other (Bronchiolitis obliterans), Respiratory, thoracic and mediastinal disorders - Other 
(Interstitial fibrosis), Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonia), 
Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonitis), Respiratory, thoracic and 
mediastinal disorders - Other (Organizing pneumonia), Respiratory, thoracic and mediastinal disorders - 
Other (Pulmonary infiltrates), Respiratory, thoracic and mediastinal disorders - Other (Toxic pneumonitis). 
 
8These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications.  
 
9Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events also reported on Pazopanib (GW786034) trials but with the relationship to 
Pazopanib (GW786034) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other (sinus 
arrest); Cardiac disorders - Other (supraventricular extrasystoles); Cardiac disorders - Other (Takotsubo 
[Broken Heart Syndrome]); Cardiac disorders - Other (Torsades de Pointes); Chest pain - cardiac; 
Pericardial effusion; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders – Other 
(eye/retinal hemorrhage); Eye disorders - Other (foreign body sensation in eyes); Eye pain; Floaters; 
Glaucoma; Photophobia; Retinal tear 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Duodenal obstruction; 
Dysphagia; Esophagitis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(hyperactive bowel); Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Gastrointestinal pain; Oral pain; Pancreatitis; Periodontal disease; 
Proctitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Malaise; 
Non-cardiac chest pain; Pain 
INFECTIONS AND INFESTATIONS - Infection9 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Cardiac troponin T increased; Cholesterol high; Ejection fraction decreased; GGT 
increased; INR increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations 
- Other (blood TSH increased); Lipase increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Head soft tissue necrosis; Muscle weakness lower limb; Muscle 
weakness upper limb; Musculoskeletal and connective tissue disorder - Other (muscle spasms); Neck 
pain 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Intracranial hemorrhage; Ischemia 
cerebrovascular; Memory impairment; Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive system 
and breast disorders - Other (vaginal necrosis); Vaginal discharge; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; Pharyngolaryngeal 
pain; Pleural effusion; Pleuritic pain; Pneumothorax; Postnasal drip; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Purpura; Skin 
hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis 
 


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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. 
 
 
 


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4.217 Emergency Unblinding 
In the event of an emergency during normal business hours (Monday 
through Friday 9:00 am to 5:00 pm Eastern Time), contact the GOG 
Statistical and Data Center by phone at 1-800-523-2917. At all other 
times, call: 716-901-2853.  If there is no answer, leave a message 
including a telephone number for a return call. A staff member from the 
GOG Statistical and Data Center will return your call. Remember, this is 
only in the event of an emergency! This procedure is to be used by the 
physician when the physician needs to know whether the patient is taking 
pazopanib or a placebo to manage the acute illness. Patients should be 
instructed that if they have any questions or symptoms they should contact 
the treating physician’s office. The GOG Statistical and Data Center will 
require the protocol number (i.e., “GOG-0186J”), the patient ID number 
(e.g., “999-0186J-001”), and the patient initials (e.g., “FML”) to unblind 
the patient. 
 
 


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5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
 
Sites must submit all IRB approvals (initial and continuing) on NCI-sponsored adult 
Cooperative Group phase I, II & III prevention and treatment studies to the CTSU 
Regulatory Office, at the Coalition of Cancer Cooperative Groups in Philadelphia. A 
CTSU IRB/Regulatory Approval Transmittal Sheet should be submitted along with the 
CTSU IRB Certification Form or its equivalent. (CTSU forms can be downloaded at 
https://www.ctsu.org/public/rss2_page.aspx).  IRB submissions can be faxed or e-mailed 
(preferred methods) or mailed to: 
  
Cancer Trials Support Unit (CTSU) 
ATTN: Coalition of Cancer Cooperative Groups (CCCG) 
Suite 1100 
1818 Market Street 
Philadelphia, PA 19103 
FAX: 1-215-569-0206 
CTSURegulatory@ctsu.coccg.org  
 
5.1 
Patient Entry and Registration (10/09/2012) 
 
When a suitable candidate has been identified for protocol entry, the following 
steps should be taken: 
 
OPEN (Oncology Patient Enrollment Network) Registration: All site 
staff will use OPEN to enroll patients to this study.  OPEN can be accessed on the 
GOG web menu page by clicking on the OPEN link.  
  
Prior to accessing OPEN, site staff should verify the following: 
  
• 
All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should use the registration forms provided on the 
group web site as a tool to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
Access requirements for OPEN: 
  
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) used 
for the CTSU members' web site.  
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the GOG or CTSU roster.  
• 
To perform registrations you must have an equivalent 'Registrar' role on 
the Lead Group roster.  Role assignments are handled through the Groups 
in which you are a member.  
  


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Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records.  
  
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
5.2 
Treatment Plan 
 
5.21 
Patients will be stratified according to their platinum-free interval PFI 
(those with a PFI less than or equal to 182 days versus those with PFI 
greater than 182 days), measurable disease status (measurable versus non-
measurable or “detectable” disease), and prior use of bevacizumab therapy 
(no use versus prior use). 
 
Regimen 1: Paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 
(1-hr IV infusion) with placebo PO daily. 
 
Regimen 2:  Paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 
15 (1-hr IV infusion) with pazopanib 800mg PO daily. 
 
One cycle equals 28 days. 
 
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 
(Appendix II).  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/placebo should be reviewed for potential drug-drug interactions 
(see Section 4.211, 5.33 and Appendices III). 
 
5.211 Recommended preparative regimen for paclitaxel (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 H1 blocker such as 
loratadine or fexofenadine), and a standard dose of antihistamine 
H2 IV (such as cimetidine, ranitidine, or famotidine). The 


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preparative regimen can be altered at the discretion of the treating 
investigator. 
 
5.22 
See the GOG General Chemotherapy Guidelines (Appendix V). 
 
5.23 
If side effects are not severe, a patient may remain on study indefinitely 
until evidence of disease progression or unacceptable toxicity. 
 
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 III 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, 


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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.  
 
 
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/  
 


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5.4 
Precautions/Warnings (See Appendix III)  
 
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 EKG is required prior to 
study registration, and subjects with QTc > 480 msec are 
excluded.  Repeat EKG must be performed during the week 4, 
cycle 1 visit.  If the QTc interval at 4 weeks is ≥ 500 msec, the 
EKG should be repeated within 7 days and, if the QTc interval 
remains ≥ 500 msec, the subject should be removed from the 
study.  Additionally, if the QTc interval is increased by 60 msec or 
more from baseline but the QTc interval remains at < 500 msec, an 
EKG should be repeated within 7 days.  If the repeat EKG again 
shows a ≥ 60 msec increase in the QTc interval from baseline, 
consideration should be given to removing the subject from the 
study or increasing monitoring, after discussion with the study 
chair. 
 
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).   
 
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/placebo.  A comprehensive list of agents that 
are associated with a risk of prolonging the QTc interval is provided 
in Appendix III.  Subjects who begin any drugs with a high risk for 
QTc prolongation while receiving pazopanib/placebo should be 
monitored carefully for signs of potential problems with QTc 
prolongation (syncope, etc.).  An EKG is not mandated in this 
circumstance; however, it should be performed at the treating 
physician’s discretion.    
 
5.414 Potassium, calcium, phosphate, and magnesium levels must be 
obtained before administration of the first dose of pazopanib/placebo 
and frequently thereafter (as described in Section 7.1).   
 
Abnormalities in potassium, calcium, phosphate, and magnesium 
levels should be managed as detailed in Section 6.26.  
 
 
 
5.42 
Hypertension is an important AE associated with pazopanib.  Frequent 
blood pressure (BP) monitoring is important in subjects receiving 


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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 IV. 
 
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 Section 6.273. 
 
5.44 
Hepatotoxicity (07/12/2013) 
 
Cases of hepatic failure, including fatalities, have been reported during the 
use of GW786034.  Two of 977 patients (0.2%) died with disease 
progression and hepatic failure in trials that supported the renal cell 
carcinoma (RCC) indication.  One of 240 patients (0.4%) died of hepatic 
failure in the randomized soft tissue sarcoma (STS) trial.  In RCC 
monotherapy trials using GW786034, increased alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) have been reported as very 
common (≥10%), and abnormal hepatic function and hyperbilirubinemia 
have been reported as common (≥1% to <10%) adverse reactions.  In STS 
monotherapy trials using GW786034, increased ALT and AST have been 
reported as common (≥1% to <10%) adverse reactions. 
 
Elevated ALT (>3X ULN) and concurrent elevated ALT (>3X ULN) and 
bilirubin (>2X ULN) have been observed primarily between weeks 3 and 
9 of therapy in GW786034 clinical trials.  A comparison across trials with 
GW786034 indicates ALT >3X ULN in 1% and approximately 5% of 
patients treated with GW786034 at weeks 2 and 3, respectively.  Most new 
cases of ALT >3X ULN occurred by week 9.  More frequent monitoring 
between weeks 3 and 9 may lead to earlier detection of elevated serum 
liver tests and hepatotoxicity in patients taking GW786034. 
 
See Section 7.1 for the Risk Mitigation Plan where serum liver function 
tests should be monitored before initiation of treatment with GW786034 
and at weeks 3, 5, 7, and 9.  Thereafter, monitoring should occur at 
months 3 and 4, and as clinically indicated.  Periodic monitoring should 
continue after month 4. 
 
 
 


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5.5 
Criteria for removal from treatment 
 
5.51 
Inability to tolerate the lowest doses of paclitaxel 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. 
 
 


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6.0 
TREATMENT MODIFICATIONS    
  
Study Drug 
Initial dose level 
1 level reduction 
2 level reduction 
Paclitaxel 
80 mg/m2 
60 mg/m2 
40 mg/m2 
Pazopanib/Placebo 
800 mg PO 
600 mg PO 
400 mg PO 
 
Please note all CTCAE grading below refers to version 4.0. 
 
A maximum of two dose reductions is allowed for each patient.  Patients experiencing 
toxicity (hematologic or non-hematologic) that meets criteria for further dose reduction, 
after this maximum, will be removed from study therapy. 
 
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 
 
6.12 
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 therapy. 
 
 
Day 8 and Day 15 paclitaxel treatment will not be given unless ANC is  
1000 cells/mcl and the platelet count is  75,000/mcl.  If Day 8 or Day 15 
paclitaxel is held, it should not be made up. 
 
 
6.14 
Patients requiring greater than two dose reductions of paclitaxel for any 
cause will result in discontinuation of study treatment.  Patients requiring 
greater than two dose reductions of pazopanib/placebo for any cause will 
result in discontinuation of pazopanib/placebo (with continuation of 
paclitaxel, if appropriate, until unacceptable toxicity or progression of 
disease).   
 
6.15 
Dose modification for paclitaxel: 
 
 
ANC1 
PLT 
ACTION 
Day 1 
<1500 
 
 
 
< 100,000 
Delay.  Monitor counts weekly until 
adequate for treatment.  
 
Restart when counts are adequate 
for treatment; reduce one dose level. 
 
If counts do not recover after 2 
weeks delay, remove from study. 
Day 8 
< 1000  
< 75,000 
Hold dose 
Day 15 < 1000  
< 75,000 
Hold dose 
1For febrile neutropenia, and/or documented grade 4 neutropenia persisting greater 
than or equal to 7 days, reduce paclitaxel by one dose level on subsequent cycles. 
 
6.16 
Dose interruption and modification of pazopanib/placebo: 
 
Thrombo-
cytopenia/ 
Neutropenia/
Anemia 1 
Grades 1 or 2 
No interruption in treatment; maintain current dose. 
Grade 3 or 4 
Interrupt treatment until toxicity is ≤grade 2; reduce one 
dose level.  
 
If no recovery to ≤grade 2 or recurrent grade 3 or 4, 
discontinue pazopanib/placebo.  
 
Maximal interruption is 2 weeks.   
1 The dose delays and modifications for anemia apply only to anemia which is due to hemorrhage or 
bleeding.  No specific dose delays or dose reductions are required for anemia due to other causes, but 
the investigator should dose delay and dose-decrease, if he/she feels it is necessary, in a manner 
consistent with good medical practice. 
 


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6.2  
Dose and Treatment Modifications for Pazopanib/Placebo 
 
6.21  Management of Hypertension: See Appendix IV 
 
Increases in blood pressure (BP) and cases of hypertension have been 
associated with many drugs acting on the VEGF pathway.  The proposed 
mechanism for this increase is through inhibition of VEGF-induced 
peripheral vasodilation.  Hypertension following pazopanib treatment has 
been seen in animal studies as well as clinical trials.  Specific guidelines 
for monitoring and management of this AE are provided below and in 
Appendix IV. 
 
• While subjects are receiving treatment with pazopanib/placebo, the early 
initiation of antihypertensive treatment for grade 1 or 2 hypertension to 
minimize more severe or persistent hypertension is not considered a grade 
3 AE. 
 
• Decisions to hold or decrease the pazopanib/placebo dose during treatment 
must be based on BP readings taken in the clinic by a medical 
professional. 
 
Recommended Hypertension Monitoring and Management 
                                            (BP in mmHg) 
 
Grade 
(CTCAE v4) 
Antihypertensive  
Therapy 
Blood Pressure 
Monitoring 
Pazopanib/Placebo 
Dose Modification 
Persistent Grade 
1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-89 
 
Standard 
No change 
Grade 2 
Systolic 140-159 
or 
Diastolic 90-99; 
medical 
intervention 
indicated; 
recurrent or 
persistent (>=24 
hrs); symptomatic 
increase by >20 
mmHg (diastolic) 
or to >140/90 mm 
Hg if previously 
WNL; 
Step 1) Initiate BP 
treatment and if 
needed, 
after 24-48 hr Rx, 
increase dose in 
stepwise 
fashion every 24-48 
hours until BP is 
controlled or 
at max dose of Rx 
 
Step 2) If BP still not 
controlled, add another 
anti-hypertensive Rx, a 
LA DHP-CCB, ACE1, 
BP should be 
 
monitored as 
recommended by 
the 
treating 
physician 
No change except 
as 
described in step 4 


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monotherapy 
indicated 
ARB, or ABB; 
increase 
dose of this drug as 
described in step 1 
 
Step 3) If BP still not 
controlled, add 3rd 
drug 
from the list of 
antihypertensives in 
step 
2; increase dose of this 
drug as described in 
step 
1 
 
Step 4) If BP still not 
controlled, consider 
either 
1 dose reduction of 
Pazopanib/placebo or 
stopping 
Pazopanib/placebo 
 
NOTE: Stopping or 
reducing the dose of 
pazopanib/placebo is 
expected to 
cause a decrease in 
BP. 
The treating physician 
should monitor the 
subject for hypotension 
and adjust the number 
and dose of 
antihypertensive 
medication(s) 
accordingly 
BP should be 
monitored as 
recommended by the 
treating physician 
No change except as 
described in step 4 


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Grade 3 
Systolic ≥160 or 
Diastolic ≥100; 
medical 
intervention 
indicated; more 
than one drug or 
more intensive 
therapy than 
previously 
indicated 
HOLD 
pazopanib/placebo 
until 
systolic BP ≤159 and 
diastolic BP ≤99. 
 
BP management is 
identical to that for 
Grade 
2 (see steps 1-4 above) 
with 2 major 
exceptions: 
1) If systolic BP >180 
or 
diastolic BP >110 and 
the subject is 
symptomatic: optimal 
management with 
intensive IV support 
in 
ICU; STOP 
pazopanib/placebo 
and notify hospital 
staff 
that stopping 
pazopanib/placebo 
may result in a 
decrease 
in BP 
and 
2) If systolic BP >180 
or 
diastolic BP >110 and 
the subject is 
asymptomatic, 
2 new 
antihypertensives 
must be given 
together 
in step 1 (and dose 
escalated 
appropriately 
as in step 1). 
 
NOTE: Stopping or 
reducing the dose of 
BP should be 
monitored as 
recommended by 
the 
treating 
physician 
unless the 
subject is 
symptomatic 
with 
systolic BP >180 
or 
diastolic BP 
>110 in 
which case, 
monitoring 
should 
be intensive. 
HOLD 
pazopanib/placebo 
until systolic BP 
≤159 and diastolic 
BP ≤99. After this, 
Pazopanib/placebo 
may be 
readministered. 
If BP 
is still grade 2, 
manage as 
described 
above for grade 2 
hypertension. 
 
In most 
circumstances, if 
BP 
cannot be controlled 
after an optimal trial 
of antihypertensive 
medications, 
consider 
either 1 dose 
reduction of 
pazopanib/placebo 
when 
systolic BP ≤159 
and 
diastolic BP ≤99 or 
stopping 
pazopanib/placebo. 
 
HOWEVER, 
If the subject 
requires 
hospitalization for 
management of 
symptomatic 
systolic BP >180 or 
diastolic BP >110, 
permanently 
discontinue 
pazopanib/placebo 
or if BP is 


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pazopanib/placebo is 
expected to 
cause a decrease in 
BP. 
The treating physician 
should monitor the 
subject for hypotension 
and adjust the number 
and dose of 
antihypertensive 
medication(s) 
accordingly 
controlled to 
systolic 
BP ≤159 and 
diastolic BP ≤99, 
consider re-starting 
pazopanib/placebo 
at 1 lower 
dose level after 
consultation with 
the 
Study Chair 
Grade 4 
Life-threatening 
Consequences 
(e.g., malignant 
hypertension, 
transient or 
permanent 
neurologic deficit, 
hypertensive 
crisis); urgent 
intervention 
indicated 
Optimal management 
with intensive IV 
support in ICU; 
STOP 
pazopanib/placebo 
and notify 
hospital staff that 
stopping 
pazopanib/placebo 
may 
result in a decrease in 
BP 
Intensive 
Permanently 
discontinue 
pazopanib/placebo 
or if 
systolic BP ≤159 
and 
diastolic BP ≤99, 
consider re-starting 
pazopanib/placebo 
at 1 lower 
dose level after 
consultation with 
the 
Study Chair 
 
Abbreviations: LA (long acting), Dihydropyridine calcium-channel blockers (DHP-
CCB), selective beta blockers (BB), Angiotensin Converting Enzyme Inhibitors (ACEI), 
Angiotensin II Receptor Blockers (ARB), alpha beta blocker (ABB) 
• *See table below for suggested antihypertensive medications by class 
• If subjects require a delay of >2 weeks for management of hypertension, 
discontinue 
protocol therapy 
• If subjects require >2 dose reductions, discontinue protocol therapy 
• Subjects may have up to 2 drugs for management of hypertension prior to any 
dose reduction in pazopanib/placebo 
• 24-48 hours should elapse between modifications of antihypertensive therapy 
• Hypertension should be graded using CTCAE v4 
 
In some instances of treatment for hypertension, a lower dose of the medication 
may be sufficient to provide the required antihypertensive control. In other 
instances, the standard dose of such a medication may be associated with AEs 
because of increased exposure. Alternatively, the investigator may choose to 
replace the medication with another in the same pharmacologic class that is less 
likely to interact with pazopanib/placebo. If  such a medication is discontinued 


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and replaced, the transition period should occur no less than 7 days prior to the 
first dose of pazopanib/placebo. Based on prior clinical experience with 
pazopanib, the use of calcium channel blockers (dihydropyridine category) and 
ACE inhibitors as first-line and second-line therapy is recommended. 
 
 


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Oral Antihypertensive Medications 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential 
drug-interactions with pazopanib/placebo through CYP450. 
 
Agent Class 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
Metabolism 
Dihydropyridine 
Calcium- 
Nifedipine 
XL 
30 mg 
daily 
60 mg daily 
90 mg daily CYP 3A4 
substrate 
Channel 
Blockers 
(DHP-CCB) 
amlodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily CYP 3A4 
substrate 
 
 
felodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
and 
inhibitor 
 
metoprolol 
25 mg 
twice 
daily 
50 mg twice 
daily 
100 mg 
twice daily 
CYP 2D6 
substrate 
Selective β 
Blockers 
atenolol 
25 mg 
twice 
daily 
50 mg twice 
daily 
100 mg 
twice daily 
No 
(BB) 
acebutolol 
100 mg 
twice 
daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes 
(CYP450 
unknown) 
 
bisoprolol 
2.5mg 
twice 
daily 
5-10 mg 
twice daily 
20 mg twice 
daily 
Yes 
(CYP450 
unknown) 
 
captopril 
12.5mg 
3x daily 
25mg 3x 
daily 
50mg 3x 
daily 
CYP 2D6 
substrate 
 
enalapril 
5 mg daily 10-20 mg 
daily 
40 mg daily 
CYP 3A4 
substrate 
Angiotensin 
Converting 
Enzyme 
ramipril 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
Yes 
(CYP450 
unknown) 
Inhibitors 
(ACEIs) 
lisinopril 
5 
mg 
daily 
10-20 mg 
daily 
40 mg daily No 
 
fosinopril 
10 mg 
daily 
20 mg daily 
40 mg daily 
Yes 
(CYP450 
unknown) 
 
Rarely used: 
perindopril 
4 
mg 
daily 
None 
8 mg daily 
Yes, but 
not 
CYP450 
 
Rarely used: 
quinapril 
10 mg 
daily 
20 mg daily 
40 mg daily No 
 
losartan 
25 mg 
daily 
50 mg daily 
100 
mg 
daily 
CYP 3A4 
substrate 


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Angiotensin II 
Receptor 
candesartan 
4 mg daily 8-16 mg 
daily 
32 mg daily 
CYP 2C9 
substrate 
Blockers  
(ARBs) 
irbesartan 
75 mg 
daily 
150 mg daily 
300 
mg 
daily 
CYP 2C9 
substrate 
 
telmisartan 
40 mg 
daily 
None 
80 mg daily Yes, but 
not 
CYP450 
 
valsartan 
80 mg 
daily 
None 
160 
mg 
daily 
Yes, but 
not 
CYP450 
α and β Blocker 
labetalol 
100  mg 
twice 
daily 
200 mg twice 
daily 
400 
mg 
twice daily 
CYP 2D6 
substrate 
and 
inhibitor 
 
6.22 Pazopanib/placebo should be held for: 
• hypokalemia or hyperkalemia ≥ grade 2; 
• hypocalcemia or hypercalcemia ≥ grade 3*; 
• hypophosphatemia ≥ grade 3;  
• hypomagnesemia or hypermagnesemia ≥ grade 3 
 
*Formula: Corrected Calcium = (0.8 x (Normal Albumin - Pt's Albumin)) 
+ Serum Ca 
Normal Albumin is 4.0 g/dL in most laboratories 
 
Management of Abnormal Laboratory  
Assessments 
Hypokalemia or hyperkalemia ≥ grade 2, 
• EKG must be performed. 
Hypocalcemia or hypercalcemia* ≥ grade 3, 
Hypophosphatemia ≥ grade 3, or 
Hypomagnesemia or hypermagnesemia ≥ grade 3 
• Laboratory values should be corrected as 
soon as possible in a manner consistent 
with good medical judgment. 
• Pazopanib/placebo may be re-
administered when  
- 
hypokalemia or hyperkalemia is 
                  ≤grade 1; 
- 
hypocalcemia or hypercalcemia*   
 is ≤grade 2; 
            -     hypophosphatemia is ≤grade 2; 
and             
-     hypomagnesemia or 
               hypermagnesemia is ≤grade 2 
• Even though pazopanib/placebo 
administration is allowed at these 
lower grades, every  effort should 
be made to correct the abnormal lab 
values to normal if possible. 
 
 


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*Calcium should be corrected for albumin 
 
6.23 
 Management of QTc Prolongation: Management of QTc prolongation 
           of >500 msec and management of QTc prolongation of >60 msec          
from baseline. 
 
Management of QTc Prolongation 
 
If EKG reveals an increase in the QTc to >500 
msec or 
an increase in the QTc >60 msec from baseline 
Repeat EKG before re-administration 
of 
Pazopanib/placebo. 
If repeat EKG shows QTc interval is >500 msec 
Remove patient from study treatment. 
If on repeat EKG, QTc remains >60 msec longer 
than baseline but is less than 500 msec 
Consider removing patient from study 
treatment. 
 
6.24 
Management of Proteinuria: 
 
Proteinuria will be monitored by urine analysis dipstick.  
 
Increases in proteinuria may occur during treatment and should be 
managed as follows: 
 
Management of Proteinuria 
 
Dipstick 2+ or greater 
Hold pazopanib/placebo and obtain 24 hour urine 
If 24-hour urine protein <3 
grams 
Continue pazopanib/placebo 
If 24-hour urine protein is 
greater than or equal to 3 grams 
Step 1:  Interrupt pazopanib/placebo treatment 
Step 2:  Monitor 24-hour urine protein (weekly) until 24 
hour urine protein is < 3 grams, then restart 
pazopanib/placebo dose-reduced by one dose level. 
 
Discontinue pazopanib/placebo if urine protein does not 
recover to < 3 grams after 8 weeks of pazopanib/placebo 
interruption 
Nephrotic syndrome 
Permanently discontinue pazopanib/placebo 
 
6.25  Management of Subjects with Elevations in AST, ALT and/or 
Bilirubin (01/12/2015) 
 


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Management of Subjects with Elevations in AST, ALT and/or Bilirubin 
Event 
Dose Modification Algorithms 
ALT ≤3.0 x ULN 
Continue at current dose.  Discontinue simvastatin if patient has been receiving 
simvastatin and has ALT >ULN. 
ALT >3.0 x ULN to 
≤8.0 x ULN without 
bilirubin elevation 
(defined as total 
bilirubin <2.0 x ULN or 
direct bilirubin ≤35%)a 
and without 
hypersensitivity 
symptoms (e.g., fever, 
rash)  
 
(1) Continue pazopanib at current dose levels.  Discontinue simvastatin if patient has 
been receiving simvastatin. 
(2) Monitor patient closely for clinical signs and symptoms; perform full panel LFTsb 
at least weekly until ALT/AST is reduced to Grade 1. 
ALT >8.0 x ULN 
without bilirubin 
elevation (defined as 
total bilirubin <2.0 x 
ULN or direct bilirubin 
≤35%)a and without 
hypersensitivity 
symptoms (e.g., fever, 
rash) 
1st occurrence  
(1) 
Interrupt pazopanib until toxicity resolves to ≤Grade 1 or baseline.  Discontinue 
simvastatin if patient has been receiving simvastatin. Repeat full panel LFTs and 
clinical liver assessment within 24-72 hours, then full panel LFTs at least weekly 
until ALT/AST is reduced to Grade 1.  Follow patient clinically as appropriate. 
(2) 
If the potential benefit for reinitiating pazopanib treatment is considered to 
outweigh the risk for hepatotoxicity, then consult a CTEP medical monitor 
before reintroducing pazopanib at a reduced dose (usually 400 mg daily.) Re-
challenge 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 
- Patient is benefiting from therapy.  
If approval for re-treatment is granted, the patient must be re-consented (ensuring 
documentation that patient is aware of all associated hepatotoxicity risks).  Measure 
full panel LFTs at least weekly for 8 weeks at the reduced dose.  
 
Recurrence  
Discontinue pazopanib permanently and monitor patient closely for clinical signs and 
symptoms; perform full panel LFTs at least weekly until ALT/AST is reduced to 
Grade 1.  
ALT >3.0 x ULN with 
concomitant elevation in 
bilirubin (defined as 
total bilirubin <2.0 x 
ULN; with direct 
bilirubin >35%)a or with 
hypersensitivity 
symptoms (e.g., fever, 
rash).  
(1) Permanently discontinue pazopanib (and simvastatin, if patient is receiving 
simvastatin) and report the event to the CTEP medical monitor within 24 hours.  
Have patients return to the clinic within 24 hours, if possible, for repeat full panel 
LFTs and liver event follow up assessments. 
(2) Consult a gastroenterologist / hepatologist to identify potential co-factors. 
(3) Monitor patient closely for clinical signs and symptoms.  Perform full panel LFTs 
at least weekly until LFTs are reduced to Grade 1.   


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Management of Subjects with Elevations in AST, ALT and/or Bilirubin 
Event 
Dose Modification Algorithms 
For isolated total 
bilirubin elevation 
without concurrent 
ALT increases (defined 
as ALT <3 X ULN). 
 
Continue at current dose.  Discontinue simvastatin if patient has been receiving 
simvastatin and has ALT > ULN. 
a.    Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a 
patient meets the criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an 
SAE. 
b.    Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.  Coagulation tests 
should be performed as clinically indicated. 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; SAE, 
serious adverse event; ULN, upper limit of normal 
 
 
 
AST, ALT and/or Bilirubin 
AST/ALT elevations between >3X 
ULN and 8X ULN 
Continue pazopanib, but monitor weekly until 
AST/ALT returns to < 2.5 or baseline  
AST/ALT >8 X ULN 
Hold pazopanib/placebo until AST/ALT 
returns to < 2.5 X ULN or baseline.   
 
If the potential benefit of reinitiating 
pazopanib/placebo treatment is considered to 
outweigh the risk for hepatotoxicity, then 
consider reintroducing  pazopanib/placebo at a 
reduced dose of 400 mg once daily (2 level 
dose reduction) and measure serum liver tests 
weekly for 8 weeks only after discussion with 
the Study Chair and CTEP.   
 
If AST/ALT elevations >3 X ULN recur, then 
pazopanib/placebo should be permanently 
discontinued. 
AST/ALT >3 X ULN and concurrent 
bilirubin elevations >2 X ULN 
Permanently discontinue pazopanib/placebo. 
 
6.26 Management of Other Adverse Events 
 
Adverse 
Event 
 
Grade 
 
Treatment Modification 
Hemorrhage/ 
Bleeding/ 
 
Grade 1 
No interruption in treatment unless hemoptysis.  If 
hemoptysis, contact PI to determine if it is appropriate to 
continue pazopanib/placebo.   


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Maintain current dose. 
 
 
 
Grade 2 
For non-pulmonary bleeding, hold pazopanib/placebo 
unless resolved to ≤grade 1; reduce dose to next lower 
dose level, and continue treatment.  
 
For pulmonary bleeding, permanently discontinue 
pazopanib/placebo and remove subject from study. 
 
If grade 2 or greater hemorrhage/ bleeding recurs 
following dose reduction, stop pazopanib/placebo and 
remove subject from study. 
Grades 3 or 4 
Discontinue treatment and withdraw subject from study. 
Vascular/ 
Thrombosis 
 
Grade 1 
No interruption in treatment; maintain current dose. 
 
 
 
 
Grade 2, 3  
 
Hold pazopanib/placebo until subject is receiving a stable 
dose of Low Molecular Weight Heparin (LMWH). 
Treatment  may resume during the period of full-dose 
anticoagulation if all of the following criteria are met: 
• The subject must be have been treated with an 
anticoagulant at the desired level for at least one week. 
• The subject must not have had a grade 3 or 4 or 
significant grade 2 hemorrhagic event while on 
anticoagulant. 
Subject should be monitored as clinically indicated during 
anticoagulation treatment and after resuming study 
treatment.  When treating with warfarin, international 
normalized ratio (INR) should be monitored within three 
to five days after any change in pazopanib/placebo dosing 
(e.g., re-initiating, escalating/de-escalating, or 
discontinuing pazopanib), and then at least weekly until 
the INR is stable.  The dose of warfarin (or its derivatives) 
may need to be adjusted to maintain the desired level of 
anticoagulation. 
Grade 4 
or pulmonary 
embolus 
 
Discontinue treatment and remove subject from study. 
Arterial 
Thrombosis/ 
ischemia 
All grades  
Discontinue pazopanib/placebo and remove subject from 
study. 
Thrombo-
cytopenia/ 
Neutropenia/
Anemia 1 
Grades 1 or 2 
No interruption in treatment; maintain current dose. 
Grade 3 or 4 
Interrupt treatment until toxicity is ≤grade 2; reduce one 
dose level.  
 
If no recovery to ≤grade 2 or recurrent grade 3 or 4, 
discontinue pazopanib/placebo and remove subject from 
study.  However, if the subject is benefiting from therapy, 
contact the sponsor (DCTD, NCI) to discuss course of 
action. 
1 The dose delays and modifications for anemia apply only to anemia which is due to hemorrhage or 
bleeding.  No specific dose delays or dose reductions are required for anemia due to other causes, but 
the investigator should dose delay and dose-decrease, if he/she feels it is necessary, in a manner 
consistent with good medical practice. 
 
 


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6.27 
Management of Other Clinically Significant Toxicities which are not 
Specifically Addressed Above 
 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
1. 
Lower grade but related AEs (e.g., abdominal pain) 
 
 
Reduce one dose level* 
AE does not resolve to grade 2 or below after treating subject at the 
lowest (i.e., 400 mg daily) reduced dose level. 
In general, remove subject from 
study ** 
* 
Alternatively and if medically appropriate, investigators may choose to hold dose for up to 14 days 
or withdraw subject from study. 
** After consultation with study sponsor (DCTD, NCI), a dose of 400 mg daily may be considered for 
subjects on study ≥3 months who are benefiting from the agent.  
 
 
6.3  
Dose and Treatment Modifications for Paclitaxel Non-Hematologic Toxicity 
 
6.31 
Grade 2 (or greater) peripheral neuropathy requires reduction of one dose 
level of  paclitaxel and delay in subsequent therapy for a maximum of 2 
weeks until recovered to grade 1. If no recovery after 2 weeks, patient 
should be removed from study. 
 
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 paclitaxel and delay in subsequent therapy for a 
maximum of 2 weeks until recovered to grade 1. 
 
6.34 
Other non-hematologic toxicities with an impact on organ function of 
grade 2 (or greater) require reduction of one dose level of paclitaxel 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    
 
7.1 
Tests and Observations 
The following observations and tests are to be performed and recorded on the 
appropriate form(s): 
 
 
Parameter 
 
 
Pre-Therapy 
(02/06/2012) 
 
Weekly 
 
Prior to 
Each cycle 
Every 
other 
cycle 
Off of all study 
therapy  
History & Physical 
1 
 
X 
 
 
Vital Status 
 
 
 
 
2 
Vital signs (Blood 
Pressure, Heart Rate and 
Temperature) 
1 
3 
X 
 
 
Performance Status 
1 
 
 
 
 
Toxicity Assessment  
4 
3 
X 
 
2, 5 
CBC/Differential/Platelet
s
4 
6 
7 
 
 
PT/INR and PTT 
4, 8 
 
 
 
 
Electrolytes, BUN, 
creatinine, Ca, Mg, PO4 
4, 9 
3, 9 
X 
 
 
Bilirubin, AST, ALT, 
Alkaline Phosphatase 
4 
3 
X§ 
(07/12/2013) 
 
 
Thyroid Function tests 
(TSH, T3, T4) 
4 
 
 
 
 
Pregnancy Test (if 
childbearing potential 
exists)
4 
 
 
 
 
Chest imaging (x-ray or 
CT of chest) 
1 
 
 
10 
10† 
Radiographic tumor 
measurement 
1, 11 
 
 
11 
11† 
CA-125 
4 
 
X 
 
 
Electrocardiogram (ECG) 
1 
12 
 
 
 


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LVEF Testing 
(Required for subjects 
who have received prior 
anthracycline – including 
doxorubicin and/or 
liposomal doxorubicin) 
1 
 
 
 
 
Urinalysis (Dipstick) to 
evaluate for proteinuria 
13 
 
 
14 
 
Patient Tablet Calendar 
 
 
15 
 
 
 
One cycle = 28 days 
†       Until disease progression or until patient initiates a subsequent cancer therapy 
§ 
Serum liver tests should be monitored before initiation of treatment with 
GW786034 and at weeks 3, 5, 7 and 9.  Thereafter, monitoring should occur at 
months 3 and 4, and as clinically indicated.  Periodic monitoring should continue 
after month 4. (07/12/2013) 
 
Notes: 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2. Follow-up every 3 months for 2 years and then every 6 months for 3 years.  Follow-up forms (Form 
Q) are collected for the 5-year follow-up period or until study termination. 
3. During the first cycle of therapy patients should be seen every week; thereafter the patient can be seen 
prior to each cycle.  
4. Must be obtained within 14 days prior to initiating protocol therapy. 
5. Report all adverse events that occur within 30 days of last protocol treatment on the T form for the 
last cycle of therapy administered.  For reporting of delayed toxicity, see Section 10.1. 
6. If grade 4 neutropenia is documented (ANC <500/mcl), obtain twice per week until resolved to grade 
3. 
7. CBC/Differential/Platelets must be obtained within 4 days of re-treatment with protocol therapy. 
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, according to CTCAE version 4 criteria, the potassium level is grade 2 or greater and/or if the 
      calcium, magnesium and/or phosphorous are grade 3 or higher, an EKG must be performed and 
      appropriate action taken based on the results in Section 6.24. 
10. Repeat chest imaging every other cycle (or equivalent time frame for patients off treatment prior to 
disease progression) for the first 6 months if initially abnormal or if required to monitor tumor 
response. 
11. CT scan or MRI if used to follow lesion for measurable disease every other cycle (or equivalent time 
frame for patients off treatment prior to disease progression) for the first 6 months;  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.  Responses (CR 
and PR) require confirmation at greater than or equal to 4 weeks from initial documentation (see 
section 8). 
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      >500msec, the EKG should be repeated within 7 days and, if the QTc interval remains >500 msec  
      the patient should be removed from the study. Additionally, if the QTc interval is increased by >60 
      msec from baseline but the QTc interval remains at <= 500 msec, an EKG should be 
      repeated within 7 days. If the repeat EKG again shows a >60 msec increase in the QTc interval 
      from baseline, consideration should be given to removing the patient from the study or increasing 
      monitoring, after discussion with the study chair. 
13. Urinalysis (dipstick) to evaluate for proteinuria must be obtained 14 days prior to initiating protocol 
therapy.  If protein is 2+ or higher, 24-hour urine protein should be obtained and the level must be 
<1000 mg (<1 g/24hrs) for patient enrollment (see section 3.184). Please record value on the D2R 
form. 
14. Urinalysis (dipstick) to evaluate for proteinuria should be performed prior to every other cycle (for 
example, prior to cycles 1, 3, 5, 7, ETC). See the guidelines provided in Section 6.0 regarding 
treatment with pazopanib and proteinuria. Each value should be recorded on the D2R form, for the 
appropriate cycle. 
15. See Appendix II. 
 
 


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7.2 
Pathology Requirements 
 
Stained slides to confirm eligibility by Central Pathology Committee Review are 
not required for this protocol. 
 
7.3 
Translational Research 
 
 
 
7.31 
Specimen Requirements 
 
If the patient gives permission for her specimens to be collected for this 
optional translational research study component, then the participating 
Institution is required to submit the patient’s specimens as outlined below 
(unless otherwise specified). 
 
A detailed description of the specimen requirements and procedures can 
be found in Appendix VII. 
 
Required Specimens 
(Specimen Codes) 
 
Form SP 
Collection Time Points 
Deadlines and 
Recommendations 
Whole Blood (WB01) 
7-10mL drawn into a 
purple-top (EDTA) tube 
SP-WB01-186J 
Collect prior to or after starting 
therapy 
Ship to the GOG Tissue Bank 
the day the blood is collected1 
 
Submit Form SP online within 
26 weeks of registration 
Pre-Cycle 1 Plasma (PB01) 
prepared from 7-10mL of 
blood drawn into a purple 
top (EDTA) tube 
SP-PB01-186J 
Collect within 14 days of starting 
cycle 1 of therapy 
Ship to the GOG Tissue Bank 
within 26 weeks of 
registration1 
 
Submit Form SP online within 
26 weeks of registration 
Pre-Cycle 2 Plasma (PB02) 
prepared from 7-10mL of 
blood drawn into a purple 
top (EDTA) tube 
SP-PB02-186J 
Collect prior to starting cycle 2 of 
therapy or at the time the patient 
goes off-study due to disease 
progression or toxicity 
Pre-Cycle 6 Plasma (PB03) 
prepared from 7-10mL of 
blood drawn into a purple 
top (EDTA) tube 
SP-PB03-186J 
Collect prior to starting cycle 6 of 
therapy or at the time the patient 
goes off-study due to disease 
progression or toxicity 
1 
 Ship specimens to: GOG Tissue Bank / Protocol GOG-186J, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, 
Columbus, 
OH 
43205, 
Phone: 
(614) 
722-2865, 
FAX: 
(614) 
722-2897, 
E-mail: 
gogbank@nationwidechildrens.org. 
 
7.32 
Laboratory Testing 
 
 
7.321 Analysis of Plasma Cytokines and Angiogenic Markers 
 
Plasma will be used to detect various cytokines and angiogenic markers 
(e.g., IL-6, IL-8, IL 11, IL-1a, Il-3, IL-4, VEGF, TPO, G-CSF, GM-CSF, 
osteopontin, and sVEGFRs) using the Luminex MILLIPLEX MAG 
Human Cytokin/Chemokine panel (Millipore Corp, Billerica, MA). 
 
 
 
 
7.322 SNP Anlaysis 
 


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DNA will be isolated from whole blood specimens. SNPs will be 
assessed using the iPLEX assay on the Sequenome MassARRAY 
platform (Sequenom Inc, San Diego, CA). 
 
7.33 
Future Research 
 
Details regarding the banking and use of specimens for future research can 
be found in Appendix VII. 
 
7.4 
Quality of Life 
 
 
Not applicable. 
 
 


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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. 
 


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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 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 


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mm diameter as assessed using calipers (e.g., skin nodules).  In the case of 
skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
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, the GOG 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 cannot be used to assess response or progression in this study.  
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, such as germ cell tumors, where 
known residual benign tumors can remain. 
 


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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. 
 
Non-CR/Non-PD: Persistence of one or more non-target 
lesion(s) Progressive Disease (PD): Appearance of one or more 


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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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
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 
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. 


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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. 
  
 
 
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). 


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The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since date of study entry, including the 
baseline measurements.  
 
 
8.15 
Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from 
study entry to time of progression or death, whichever occurs first. 
 
 
8.16 
Survival 
 
Survival is defined as the duration of time from study entry to time of 
death or the date of last contact. 
 
 


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9.0 
DURATION OF STUDY    
 
9.1 
Patients will receive therapy until disease progression or intolerable toxicity 
intervenes.  The patient can refuse the study treatment at any time. 
 
9.2 
All patients will be treated (with completion of all required case report forms) 
until disease progression, initiation of a subsequent cancer treatment, or study 
withdrawal.  Patients will then be followed every three months for the first two 
years and then every six months for the next three years.  Patients will be 
monitored for delayed toxicity and survival for this 5-year period with Q forms 
submitted to the GOG Statistical and Data Center, unless consent is withdrawn.  
Q forms will no longer be required if the study is terminated prior to the 
completion of the 5-year follow-up period. 
 
9.3 
A patient is considered off study therapy when the patients has progressed or died, 
a subsequent drug or therapy (directed at the disease) is initiated or all study 
therapy is discontinued.  Report all treatment received on From D2R and adverse 
events on Form T until the patient qualifies as being off study therapy. 
 
 


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10.0 
STUDY MONITORING AND REPORTING PROCEDURE    
 
 
10.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT 
(CTEP IND) 
   
10.11 Definition of Adverse Events (AE) 
 
Adverse event (21 CFR 312.32(a)):  Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered 
drug related. 
 
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). 
The CTCAE v4.0 Manual is also available on the GOG member web site 
(http://www.gog.org under MANUALS). 
 
10.12 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational agents, and 
role of the pharmaceutical sponsor, an expedited AE report may need to 
reach multiple destinations.  For patients participating on a GOG trial, all 
expedited AE reports should be submitted by using the CTEP automated 
system for expedited reporting (AdEERS).  All AdEERS submissions are 
reviewed by GOG before final submission to CTEP.  Submitting a report 
through AdEERS serves as notification to GOG, and satisfies the GOG 
requirements for expedited AE reporting. All AdEERS reports will be 
immediately directed to the Study Chair for further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 
to the NCI.  In compliance with FDA regulations, as contained in 21 CFR 
312.64, AEs should be reported by the investigator. 
 
10.13 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under a CTEP IND/IDE within 30 
Days of the Last Administration of the Investigational Agent/Intervention1, 
2 
 
 
 
 
 
 


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Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
AdEERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements: 
• All Grades 2 and 3 myelosuppression (including neutropenia, anemia, and 
thrombocytopenia) that does not require hospitalization is exempt from expedited 
reporting. 


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10.14 Procedures for Expedited Adverse Event Reporting: 
 
10.141 AdEERS Expedited Reports: Expedited reports are to be submitted 
using AdEERS available at http://ctep.cancer.gov. The CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements for expedited 
adverse event reporting requirements are also available at this site.  
 
AML/MDS events must be reported via AdEERS (in addition to  
routine AE reporting mechanisms). In CTCAE v4.0, the event(s) 
may be reported as either: 1) Leukemia secondary to oncology 
chemotherapy, 2) Myelodysplatic syndrome, or 3) Treatment-
related secondary malignancy. 
 
For the purposes of expedited reporting of adverse events to CTEP, 
unexpected events are those not listed in the Agent Specific 
Adverse Event List (ASAEL). The ASAEL is a subset of AE’s 
within the Comprehensive Adverse Event and Potential Risks List 
(CAEPR). This list of events is based on CTEP’s clinical 
experience with this agent and defines “expected” Grade 2 and 3 
AE’s not requiring hospitalization as exempt from expedited 
reporting. The CAEPR is a complete list of reported and/or 
potential AE’s associated with an agent under a CTEP IND. For 
questions or comments regarding the ASAEL or CAEPR, please 
contact the AdEERS MD Help Desk at adeersmd@tech-res.com. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at: 301-897-7497. 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. Please note that all paper 
AdEERS forms have been removed from the CTEP website and 
will NO LONGER be accepted. 
 
10.15 Regular adverse events reporting  
 
For studies using investigational agents, the GOG Statistical and Data 
Center (SDC) routinely reports adverse events electronically to the CTEP 
Clinical Data Update System (CDUS Version 3.0).  The SDC submits this 
data quarterly.  The AEs reported through AdEERS will also be included 
with the quarterly CDUS data submissions. 
 
 


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10.2 
GOG DATA MANAGEMENT FORMS 
 
The following forms must be completed and submitted to the GOG Statistical and 
Data Center (SDC) in accordance with the schedule below.  All forms except the 
BDR Form and Pathology report must be submitted via the SDC Electronic Data 
Entry System (SEDES) which is available through the GOG website 
(www.gogstats.org).  The BDR Form should be submitted via mail.  The GOG 
Uploader Application in SEDES is an alternate method for submitting pathology 
reports and BDR to the GOG SDC. 
 
Form 
Due within 
Copies* 
Comments 
Weeks 
Event 
Specimen Consent Application  
1 
Registration 
N/A 
Complete online 
Form R (Registration Form) 
 
2 
Registration 
1 
Mandatory submission via  
SEDES 
Form OHR (Recurrent 
Gynecologic Cancer-On Study 
History Form) 
2 
Registration 
1 
Mandatory submission via  
SEDES  
Form DR (Pre-Treatment 
Summary Form) 
 
4 
Registration 
1 
Mandatory submission via  
SEDES  
Form BDR (Pre-Treatment Body 
Diagram Form) 
4 
Registration 
2 
Submit to SDC via postal 
mail 
Form D2M (Solid Tumor 
Evaluation Form) 
4 
Registration 
1 
Mandatory submission via  
SEDES  
Primary disease:** 
Pathology Report 
 
Recurrent or Persistent 
Disease:** 
 Pathology Report (only if 
histologically documented) 
 
6 
 
 
 
6 
 
 
Registration 
 
 
 
Registration 
 
 
1 
 
 
 
1 
 
 
Submit to SDC via postal 
mail or via report uploader 
Form BMR (CA-125 reporting) 
(Biomarker Reporting Form) 
2 
Registration and 
completion of each cycle 
of therapy and disease 
assessment 
1 
Submit via SEDES 
Form D2R (Cycle Dose Drug 
Form) 
2 
Completion of each 
cycle of therapy 
1 
Mandatory submission via  
SEDES  
Form D2M (Solid Tumor 
Evaluation Form) 
2 
Clinical response 
assessment 
1 
Mandatory submission via  
SEDES  
Form T (Common Toxicity 
Reporting Form) 
2 
Beginning of each 
subsequent cycle 
1 
Mandatory submission via  
SEDES  
Form Q0 (Treatment Completion 
Form) 
2 
Completion of study Rx 
and change in Rx 
1 
Mandatory submission via  
SEDES 
Form SP-WB01-186J 
for whole blood 
26 
Registration 
 
Mandatory submission via  
SEDES † 


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Form SP-PB01-186J 
for pre-cycle 1 plasma 
26 
Registration 
 
Mandatory submission via  
SEDES † 
Form SP-PB02-186J 
for pre-cycle 2 plasma 
26 
Registration 
 
Mandatory submission via  
SEDES † 
Form SP-PB03-186J 
for pre-cycle 6 plasma 
26 
Registration 
 
Mandatory submission via  
SEDES † 
Form Q (Follow-up Form) 
 
2 
Disease progression; 
death; normal follow-up 
1 
Mandatory submission via  
SEDES quarterly for 2 
years, semi-annually for 3 
more years 
 
* 
The number of required copies including the original form which must be sent to the Statistical and Data 
Center. 
** 
 Pathology slides for Central Pathology Committee Review are not required on this study. 
† 
Form SP must be submitted online regardless of whether the specimen is submitted for research. 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 
 
 


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11.0 
STATISTICAL CONSIDERATIONS 
 
The purpose of this study is to assess the relative activity of Arm 2 (the combination 
regimen) to Arm 1 (the control of paclitaxel) through the hazard ratio of disease 
progression or death (PFS endpoint) as a superiority study.  The combination regimen 
must demonstrate a reduction in the hazard rate before it can be deemed interesting and 
worthy of further investigation.  A reduction in the hazard rate by 37.5% is considered 
important to detect.  If the combination regimen has a hazard rate roughly equal to the 
control, then there would be little benefit seen from adding the experimental drug to 
paclitaxel with a potential added risk through new drug toxicities.  Therefore, a 
combination regimen yielding roughly equal hazard rates to the control should be 
rejected. 
 
Patients will be stratified according to their platinum-free interval PFI (those with a PFI ≤ 
182 day versus those with PFI > 182 days), measurable disease status (measurable versus 
non-measurable or “detectable” disease), and prior use of bevacizumab therapy (no use 
versus prior use). 
 
11.1 
Parameters employed to evaluate treatment efficacy and toxicity are: 
 
11.11 Primary Endpoints 
 
11.111The Cox proportional hazards, (platinum-free interval, measurable 
disease status, prior use of bevacizumab) stratified, maximum 
likelihood estimate of the logarithm of the hazard ratio of Arm 2 to 
Arm 1 for disease progression or death (PFS endpoint). 
 
11.12 Secondary Endpoints 
 
11.121 Adverse events as assessed by CTCAE 
 
11.122 Frequency and duration of tumor response by RECIST, CA-125 as 
well as overall survival. 
 
11.13 Translational Research Endpoints 
 
11.131 Plasma cytokines and angiogenic markers against PFS and OS. 
 
11.132 Single-nucleotide polymorphisms (SNPs) against PFS and OS. 
 
11.2 
The anticipated annual accrual is approximately 50 patients. 
 
11.21 The anticipated period of active accrual is expected to be 16 to 30 months, 
depending on the results of an interim analysis and rates of local IRB 
approval. 
 


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11.3 
Study Plan: 
 
Given that this is a Phase 2 study, the probabilities of type I and type II errors 
being equal to 10% and 20% respectively, are considered acceptable.  Patients 
will be randomized equally to each arm.  The level of reduction in the hazard ratio 
of Arm 2 to Arm 1 that is considered interesting to detect is 37.5%.  The null 
hypothesis is therefore Ho: Δ ≥ 1 versus Ha: Δ ≤ 0.625 (or  
0 :
0
H

and
:
0.4700
a
H

where  is the natural logarithm of the hazard ratio).  This 
alternative hypothesis is comparable to the experimental therapy increasing the 
cumulative proportion of patients alive and progression-free at 5 months from 
50% to 65%.  Using Schoenfeld’s equation to approximate the number of required 
events to achieve the study’s desired operating characteristics, we obtain D = ( Zα 
+ Zβ )2 x (R + 1)2 / ( R x ln {Δ}2) = 81.63 when Zα = 1.2816, Zβ = 0.8416, and R = 
1.  Zα = 1.28 since the alternative hypothesis is one-sided.  R is the ratio of 
patients assigned to the experimental therapy to the control therapy which equals 
one since patients will be assigned to the arms with equal probability.  Based on 
these desired characteristics, it is necessary to observe approximately 82 events.  
To assure data maturation in a timely manner, up to 110 patients could be accrued 
to the clinical trial.  Further justification for the final sample size when utilizing 
an interim analysis is provided below: 
 
At approximately the 42nd event (taking events from both treatment arms), an 
interim futility analysis will be conducted using the method provided by Weiand’s 
et al.59 futility rule.  More specifically, the interim decision rule will reject the 
combination therapy as being uninteresting if the stratified estimate of the hazard 
ratio is greater than 1. This decision rule will stop the study early 50% of the time 
when the hazard ratio is truly one.  On the other hand, there could be a non-trivial 
probability of falsely declaring active regimens not interesting. To correct this 
problem, group sequential methods will be utilized that incorporate the futility 
rule as outlined by Jennison and Turnbull60 (p49, eq. 3.1).  The standardized test 
statistics, related to the log hazard ratio at the interim and final analyses will be 
designated by Z1 and Z2, respectively.  Specifically, 


ˆ
ˆ
ˆ
0 /
i
i
i
Z





 where 
1,2
i 
according the stage of the study.  According to Jennison and Turnbull, 
these statistics will be distributed as a multivariate normal distribution with the 
following parameters: 
 
1
1
2
1
2
2
1
2
1
/
~
,
/
1
I
I
I
Z
MVN
Z
I
I
I































 
where Ik is the information obtained at the kth stage of the design with
/ 4
k
k
I
d

and dk being the total number of observed events at that time.  Since the use of 
Weiand et al. plans on observing Z1 at 50% information time, the covariance 
between Z1 and Z2 is about 0.707.  The cumulative distribution function of Z1 and 


NCI Protocol #: GOG-0186J 
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Z2 is provided below by F(.): 
 




1
1
2
2
1
2
1
2
,
,
| , ,
P Z
z Z
z
F z z
I I




 
 
The design will reject the regimen if 
1
0
Z 
in the first stage or 
1
0
Z  in the first 
stage, but 
2
2
Z
c

in the second stage where 
2c is a critical value for rejecting H0.  
This is expressed mathematically as: 
 






















1
1
2
2
1
1
2
2
1
1
1
2
2
1
2
1
2
2
1
2
2
0
0
0
0,
1
0
0
0,
1
0,
| ,
,
0,
| ,
,
0,
| ,
,
1
0,
P Z
Z
Z
c
P Z
P Z
Z
c
P Z
P Z
P Z
Z
c
F
I I
F
I I
F
c
I I
F
c



































 
 
Under H0, the desired probability of rejecting the regimen is 90% (when the null 
hypothesis is true, alpha = 1 – 90% = 10%).  Searching algorithms can quickly 
find the value of 
2
1.25
c 
 which deviates slightly from the nominal value of -
1.28 obtained with a single stage test. 
 
The required number of events to obtain 80% power is 84 with the interim 
analysis.  That is to say: 
 


1
2
0, 1.25|
0.47,
10.5,
21
0.8001
F
I
I






 
 
In addition to the calculations above, the operating characteristics of the 
procedure is provided in the table below using simulation studies (n = 10,000) 
with exponential survival (median PFS = 5 months in the control group) and a 
study accrual rate of 4 patients per month with a maximum sample size of 110 (55 
patients per arm) 
 
Table 11.1: Operating Characteristics of Study  
 
Hazard 
Ratio 
Probability  
Reject Rx 
Theoretical1 
P(Rej. Rx) 
Probability 
Accept2 Rx 
PET3 
Time of 
Interim 
Analysis 
(mos.) 
Time of 
Final 
Analysis 
(mos.) 
0.500 
0.0361 
0.0339 
0.9639 
0.0120 
19.1 
31.8 
0.625 
0.1992 
0.1999 
0.8008 
0.0638 
18.4 
30.4 
0.667 
0.2976 
0.2909 
0.7024 
0.0962 
18.2 
30.0 
1.000 
0.8999 
0.8999 
0.1001 
0.5017 
17.0 
28.0 


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1.250 
0.9882 
0.9892 
0.0118 
0.7607 
16.5 
27.3 
1.500 
0.9989 
0.9991 
0.0011 
0.8974 
16.0 
26.9 
1  Theoretical calculations provided with the methods of Jennison and Turnbull60. 
2 Accept = Declaring the regimen interesting and worthy of further investigation. 
3 PET = Probability of early termination. 
 
It is unlikely that the interim analysis will be conducted at precisely 50% of the 
information time.  The realized information at the interim and final analyses will 
be used to determine the critical value of 
2c  under the null hypothesis so that the 
probability of a type I error does not exceed 10%, i.e.
2c will be found so that: 


2
1
2
0,
|
0, ,
0.10
F
c
I I


. 
 
Figure 11.1 
 
Figure 11.1: Probability of rejecting the 
treatment (solid line) and probability of early 
termination (dashed line) as a function of the 
hazard ratio. 
 
11.4 
Data sheets from studies on this protocol will be reviewed before each semi-
annual meeting and will also be reviewed by the Study Chair in conjunction with 
the Statistical and Data Center.  In some instances, because of unexpectedly 
severe toxicity, the Statistical and Data Center may elect, after consultation with 
the Study Chair and the Medical Oncology Committee, to recommend early 
closure of a study. 
 
 
The frequency and severity of all toxicities are tabulated from submitted case 
report forms and summarized for review by the Study Chair, Developmental 
Therapeutics Committee, and GOG SRC in conjunction with each semi-annual 
GOG meeting. For studies sponsored by the Cancer Therapy Evaluation Program 
(CTEP) of the National Cancer Institute (NCI), standardized toxicity reports are 
0.4
0.6
0.8
1.2
1.4
0.2
0.4
0.6
0.8
1.0


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also submitted to the drug and disease monitors at the Investigational Drug 
Branch (IDB) and Clinical Investigation Branch (CIB). 
 
 
All serious and/or unexpected events are communicated to the Study Chair, 
sponsor, and regulatory agencies as mandated in the protocol. These reports are 
reviewed by the Study Chair (or designated co-chair) for consideration of 
investigator notification, amendment, or immediate study suspension.  All 
participating institutions will then receive notification of the toxicities and reason 
for study suspension.   Under these circumstances, accrual cannot be re-activated 
until the study is reviewed by the GOG Data Safety Monitoring Board.   
However, patients currently receiving treatment may continue to receive treatment 
in accordance with protocol guidelines at the discretion of their physicians, unless 
directed otherwise. 
 
11.5 
Secondary and Exploratory Analyses: 
Toxicities will be characterized by their frequency and severity.  Differences in 
the level of toxicities by treatment regimen will be assessed by classifying them 
as severe or not severe and examining the relative proportion of severe toxicities.  
Differences between measurable versus non-measurable disease status on PFS 
and OS will be examined with plots of survival curves, estimates of quartiles and 
hazard ratios.  Formal tests for differences will be carried out with a Cox model or 
log-rank test if appropriate.  The effects of treatment on the proportion responding 
by RECIST and possibly by CA125 will be examined.  An examination of 
response by CA125 (stratified by treatment) will also be conducted in those 
patients who have measurable disease to assess the level of agreement between 
the two methods of evaluation.  The impact of additional, various prognostic 
factors or biological markers will be examined with exploratory analyses 
including log-rank tests with characterization with hazard ratio estimates. 
 
11.6 
Translational Research 
 
Translational research (TR) data can be fairly difficult to analyze statistically for 
various reasons including data that are highly skewed (non-normal) or of ordinal 
quality where differences between observations are not meaningful.  It has 
become customary to dichotomize biomarker data61 to help overcome these 
difficulties and ease the interpretation of the results. 
 
For this study, biomarker data will be dichotomized (if feasible) at the median or, 
less commonly, whether or not expression is observed in the patients.  
Dichotomizing at the median tends to have an advantage by increasing the 
sensitivity of the analysis (relative to other cut points) when there is a significant 
association between the biomarker and clinical outcome. 
 
Depending on the number of events and biomarkers under examination, one of 
two strategies will be taken with regard to prognostic variable assessment.  If the 
number of biomarkers is relatively large (but no more than 25) and the nature of 


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the analysis fairly exploratory, then the data will be randomly split into two 
groups.  One of the groups will be designated for exploratory analysis.  This 
dataset will be used to generate hypotheses of interest.  After consultation with the 
TR co-chair, a finalization of the primary questions (relatively few) will be done 
and recorded.  The other half of the data will then be addressed with these specific 
questions for validation.  On the other hand, if the number of questions is 
relatively small to begin with (no more than 3 questions) or the total number of 
events relatively small, then the entire dataset can be used to ask these questions.  
The benefit to having a smaller number of questions is greater statistical power, 
but important questions may be overlooked.  The benefit to data splitting is 
having validated conclusions after screening many prospects. 
 
The marginal probability of detecting a biomarker’s prognostic effects on the 
hazard of death or progression depends on its true hazard ratio,, the level of 
significance, , and the number of events in the study, D , through the normal 
cdf, provided by 

as follows: 
 
/2
Power = 
2
D
z











 
 
The equation above holds since we expect ½ of the patients to score high.  This 
study is planning a total of 84 PFS endpoints, so the probabilities of detection 
under this assumption are provided in Figure 11.2 (assuming a high proportion of 
patients participating in the TR aspect of this study). 
 
Figure 11.2 
Power as a function of the hazard ratio for patients with high levels of expression 
versus those with low levels of expression when assessed with the entire dataset 
(D=84) 
 


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Often the predictive value of a biomarker is of considerable interest.  Such a 
biomarker could help direct the physician towards one treatment over another 
because the effectiveness of the treatment depends on the level of expression of 
the biomarker.  In statistical terms, the hazard ratio for progression on the 
experimental treatment to the control treatment depends on the level of biomarker 
expression (high versus low).  Using Peterson and George’s notation, let Delta1 
be the hazard ratio for low levels of biomarker expression and Delta2 be the 
hazard ratio for the high levels of biomarker expression.  When 
1
2
/
1

, the 
biomarker contains no predictive value for treatment effectiveness.  The hazard 
ratios are the same regardless of the level of biomarker expression (however, the 
biomarker could still be prognostic). 
 
Because these tests amount to tests of interaction between treatment and 
biomarker level, the amount of power is drastically reduced.  Therefore, there is 
no luxury of data splitting.  All analyses will involve the full dataset and be 
exploratory (hypothesis generating) in nature.  The equation for calculating power 
is similar to the one above except the relevant number of events is now only 21 
(84 events for 2 treatments cut into four cells is 21; see Peterson and George for 
full details).  Note that roughly equal numbers of patients with high levels of 
biomarker expression are expected to be randomized to the treatments; also, the 
power calculations are robust as shown in Table 3 of publication. 
 
Figure 11.3 
Marginal power of tests for detecting predictive biomarkers. 
0.0
0.5
1.0
1.5
2.0
2.5
0.2
0.4
0.6
0.8
1.0


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TR analyses that examine the impact of changes in biomarker values over time on 
the hazard of progression will be adjusted with the Landmark Method (see Buyse 
and Piedbois62).  Patients that progress before the last time of tissue collection (in 
the entire sample) will not be included in the analysis.  The starting point will be 
adjusted from the date of entry to approximately the start of cycle 2 (when the 
post-treatment samples are collected) for these particular analyses.  Because a 
number of patients (and some events) will be eliminated, the overall power of 
these analyses will not be as high as described previously.  However, the powers 
listed previously should be fair approximations since the number of patients that 
progress should be few. 
 
11.7 
Women and Minority Inclusion 
Based on previous studies in the GOG-0186 series, the following table gives the 
projected number of patients by ethnicity and race*: 
 
Accrual Targets 
 
Sex/Gender 
Females 
 
Males 
 
Total 
Ethnic Category 
Hispanic or Latino 
8 
+ 
0 
= 
8 
Not Hispanic or Latino 
102 
+ 
0 
= 
102 
Ethnic Category: Total of all subjects 
110 
+ 
0 
= 
110 
Racial Category 
American Indian or Alaskan Native 
3 
+ 
0 
= 
3 
Asian 
1 
+ 
0 
= 
1 
Black or African American 
4 
+ 
0 
= 
4 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
102 
+ 
0 
= 
102 
0
1
2
3
4
0.2
0.4
0.6
0.8
1.0


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Racial Category: Total of all subjects 
110 
+ 
0 
 
(B
2) 
= 
110 
 
*The projected racial and ethnic distributions are obtained from previously enrolled 
patients in the GOG-0186 series. 
 
 
 


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12.0 
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APPENDIX I 
 
Congestive Heart Failure – New York Heart Association Classification 
 
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 
Patient Medication Calendar  
 
This is a calendar on which you are to record the number of Pazopanib or Placebo 
tablet(s) you take each day.  The instructions on how to take the Pazopanib or Placebo are 
below.  
 
Use the calendar to record date, time and number of tablet(s) taken each day.  You will 
start taking a total of 800 mg of Pazopanib or placebo each day for 28 days.  (It is 
possible your doctor may reduce the amount of Pazopanib or placebo you take while 
participating in this study.  Your doctor will discuss the new treatment plan with you at 
that time.)  A 28-day period of time is called a cycle.  These cycles will be repeated as 
long as your tumor is not growing and you are not experiencing any unacceptable side 
effects.  Each medication calendar sheet should last you 4 weeks (one cycle).  Medication 
should be taken as instructed without skipping any days.  If you have missed a dose 
please mark down as “0” on the # slot for that day.  If your doctor changes the amount of 
Pazopanib or placebo you take, please be sure to write down the correct number of pills 
and correct amount taken in the columns below. 
 
Tablet(s) should be taken either 1 hour before or 2 hours after meals.  Tablets 
should be swallowed whole and can not be crushed or broken.  If you develop any 
side effects, please write side effects the day they occurred and anything else you 
would like to tell the doctor in the space provided below the calendar. 
 
Please note: You must not take Grapefruit juice or St. John’s Wort while on this 
study. 
 
Bring any unused tablets, empty medication containers, and your completed calendar to 
your next appointment.  Please use the upper left hand box in each square to record the 
date drug was taken.   
 
Note to staff:  Please give patient a drug log at initial enrollment and at every week 4 visit.  
Instruct patient how to complete the diary log.  If they are taking the first pill at a visit complete 
the log with them.  Remind them they must bring the log back at each visit along with pill bottles, 
empties included.   


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PATIENT MEDICATION CALENDAR 
 
Patient Name________________________________  Patient Study ID____________ 
Patient Signature _____________________________ 
 
Cycle # _______ 
 
 
Date 
 
Day 
# of 
tablet/s 
taken 
Comments 
 
Date 
 
Da
y 
# of 
tablet/s 
taken 
Comments 
 
1 
 
 
 
16 
 
 
 
2 
 
 
 
17 
 
 
 
3 
 
 
 
18 
 
 
 
4 
 
 
 
19 
 
 
 
5 
 
 
 
20 
 
 
 
6 
 
 
 
21 
 
 
 
7 
 
 
 
22 
 
 
 
8 
 
 
 
23 
 
 
 
9 
 
 
 
24 
 
 
 
10 
 
 
 
25 
 
 
 
11 
 
 
 
26 
 
 
 
12 
 
 
 
27 
 
 
 
13 
 
 
 
28 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
The above information has been reviewed with the patient.  Staff Signature: __________________  
Date:______________ 
 
Please note: Medication Calendar should be brought to each appointment along with medication 
bottles (empty included). 
 


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APPENDIX III 
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 this 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 that are generally 
accepted to have a risk of 
causing Torsades de 
Pointes 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
Drugs that, in some reports, 
have been weakly associated 
with Torsades de Pointes and/or 
QTc prolongation but that are 
unlikely to be a risk for Torsades 
de Pointes when used in usual 
recommended dosages and in 
patients without other risk 
factors (e.g., concomitant QTc 
prolonging drugs, bradycardia, 
electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism). 
  
  
  
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® 
Citalopram /Celexa® 
Astemizole /Hismanal® 
Azithromycin /Zithromax® 
Clomipramine /Anafranil® 
Bepridil /Vascor® 
Chloral hydrate /Noctec® 
Desipramine /Pertofrane® 
Chloroquine /Aralen® 
Clozapine /Clozaril® 
Diphenhydramine /Benadryl® 
Chlorpromazine 
/Thorazine® 
Dolasetron /Anzemet® 
Diphenhydramine /Nytol® 
Cisapride /Propulsid® 
Dronedarone /Multaq® 
Doxepin /Sinequan® 
Clarithromycin /Biaxin® 
Felbamate /Felbatol® 
Fluconazole /Diflucan® 
Disopyramide /Norpace® 
Flecainide /Tambocor® 
Fluoxetine /Sarafem® 
Dofetilide /Tikosyn® 
Foscarnet /Foscavir® 
Fluoxetine /Prozac® 
Domperidone /Motilium® 
Fosphenytoin /Cerebyx® 
Galantamine /Reminyl® 
Droperidol /Inapsine® 
Gatifloxacin /Tequin® 
Imipramine /Tofranil® 
Erythromycin 
/Erythrocin® 
Gemifloxacin /Factive® 
Itraconazole /Sporanox® 
Erythromycin /E.E.S.® 
Granisetron /Kytril® 
Ketoconazole /Nizoral® 
Halofantrine /Halfan® 
Indapamide /Lozol® 
Mexiletine /Mexitil® 
Haloperidol /Haldol® 
Isradipine /DynaCirc® 
Nortriptyline /Pamelor® 
Ibutilide /Corvert® 
Lapatinib /Tykerb® 
Paroxetine /Paxil® 
Levomethadyl /Orlaam® 
Lapatinib /Tykerb® 
Protriptyline /Vivactil® 
Mesoridazine /Serentil® 
Levofloxacin /Levaquin® 
Sertraline /Zoloft® 


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Drugs that are generally 
accepted to have a risk of 
causing Torsades de 
Pointes 
 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
 
Drugs that, in some reports, 
have been weakly associated 
with Torsades de Pointes and/or 
QTc prolongation but that are 
unlikely to be a risk for Torsades 
de Pointes when used in usual 
recommended dosages and in 
patients without other risk 
factors (e.g., concomitant QTc 
prolonging drugs, bradycardia, 
electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism). 
  
  
  
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Methadone /Dolophine® 
Lithium /Lithobid® 
Solifenacin /VESIcare® 
Methadone /Methadose® 
Lithium /Eskalith® 
Trimethoprim-Sulfa /Sulfa® 
Pentamidine /Pentam® 
Moexipril/HCTZ /Uniretic® 
Trimethoprim-Sulfa /Bactrim® 
Pentamidine /NebuPent® 
Moxifloxacin /Avelox® 
Trimipramine /Surmontil® 
Pimozide /Orap® 
Nicardipine /Cardene® 
  
Probucol /Lorelco® 
Nilotinib /Tasigna® 
  
Procainamide /Pronestyl® 
Octreotide /Sandostatin® 
  
Procainamide /Procan® 
Ofloxacin /Floxin® 
  
Quinidine /Cardioquin® 
Ondansetron /Zofran® 
  
Quinidine /Quinaglute® 
Oxytocin /Pitocin® 
  
Sotalol /Betapace® 
Paliperidone /Invega® 
  
Sparfloxacin /Zagam® 
Perflutren lipid microspheres 
/Definity® 
  
Terfenadine /Seldane® 
Quetiapine /Seroquel® 
  
Thioridazine /Mellaril® 
Ranolazine /Ranexa® 
  
  
Risperidone /Risperdal® 
  
  
Roxithromycin* /Rulide® 
  
  
Sertindole /Serlect® 
  
  
Sertindole /Serdolect® 
  
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  
  
Ziprasidone /Geodon® 
  
 


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APPENDIX IV 
 
Recommended Hypertension Monitoring and Management 
(BP in mmHg) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Pazopanib/Placebo 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90  
 
Standard       
 
No Change 
Persistent Grade 
2- Moderate 
Systolic 140-159  
Diastolic 90-99  
   
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines, 
including CTCAE 
v4  
Step 1)  Initiate BB 
treatment and if needed, 
after 24-48 hr Rx,  
increase dose in stepwise  
fashion every 24-48 hours  
until BP is controlled or 
at max dose of Rx 
 
Step 2) If BP still not 
controlled, add another 
anti-hypertensive Rx, a 
LA DHP CCB, ACE1, 
ARB, or ABB; increase 
dose of this drug as 
described in step 1   
 
Step 3) If BP still not 
controlled, add 3rd drug 
from the list of 
antihypertensives in step 
2; increase dose of this 
drug as described in step 
1 
 
Step 4) If BP still not 
controlled, consider either 
1 dose reduction of 
pazopanib/placebo or 
stopping 
pazopanib/placebo  
 
NOTE:  Stopping or 
reducing the dose of 
pazopanib/placebo is 
expected to cause a 
decrease in BP.  The 
treating physician should 
monitor the subject for 
hypotension and adjust 
the number and dose of 
BP should be 
monitored as 
recommended by 
the treating 
physician  
No change except 
as described in step 
4 


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antihypertensive 
medication(s) accordingly 
Persistent Grade 3 
Severe  
Systolic ≥160 
Diastolic ≥100  
 
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines, 
including CTCAE 
v4 
HOLD pazopanib/placebo 
until systolic BP ≤159 
and diastolic BP ≤99.  
 
BP management is 
identical to that for Grade 
2 (see steps 1-4 above) 
with 2 major exceptions:  
1)  If systolic BP >180 or 
diastolic BP >110 and 
the subject is 
symptomatic:  optimal 
management with 
intensive IV support in 
ICU; STOP 
pazopanib/placebo and 
notify hospital staff that 
stopping 
pazopanib/placebo may 
result in a decrease in 
BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and 
the subject is 
asymptomatic, 
2 new antihypertensives 
must be given together 
in step 1 (and dose 
escalated appropriately 
as in step 1). 
 
NOTE:  Stopping or 
reducing the dose of 
pazopanib/placebo is 
expected to cause a 
decrease in BP.  The 
treating physician should 
monitor the subject for 
hypotension and adjust 
the number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by 
the treating 
physician unless 
the subject is 
symptomatic 
with  
systolic BP >180 
or diastolic BP 
>110 in which 
case, monitoring 
should be 
intensive. 
 
 
HOLD 
pazopanib/placebo 
until systolic BP 
≤159 and diastolic 
BP ≤99.  After this, 
pazopanib/placebo 
may be re-
administered.  If BP 
is still grade 2, 
manage as 
described above for 
grade 2 
hypertension.  
 
In most 
circumstances, if 
BP cannot be 
controlled after an 
optimal trial of 
antihypertensive 
medications, 
consider either 1 
dose reduction of 
pazopanib/placebo 
when systolic BP 
≤159 and diastolic 
BP ≤99 or stopping 
pazopanib/placebo. 
 
HOWEVER, 
If the subject 
requires 
hospitalization for 
management of 
symptomatic 
systolic BP >180 
or diastolic BP 
>110, permanently 
discontinue 
pazopanib/placebo 
or if BP is 
controlled to 
systolic BP ≤159 
and diastolic BP 
≤99, consider  re-
starting 
pazopanib/placebo 
at 1 lower dose 
level after 
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the study Principal 
Investigator 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management 
with intensive IV 
support in ICU; STOP 
pazopanib/placebo and 
notify hospital staff that 
stopping pazopanib may 
result in a decrease in 
BP 
Intensive 
Permanently 
discontinue 
pazopanib/placebo 
or if systolic BP 
≤159 and diastolic 
BP ≤99, 
consider  re-starting 
pazopanib/placebo 
at 1 lower dose 
level after 
consultation with 
the study Principal 
Investigator 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta 
blockers (BB), Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin II Receptor 
Blockers (ARB), alpha beta blocker (ABB) 
• *See table below for suggested antihypertensive medications by class 
• If subjects require a delay of >2 weeks for management of hypertension, discontinue 
protocol therapy 
• If subjects require >2 dose reductions, discontinue protocol therapy 
• Subjects may have up to 2 drugs for management of hypertension prior to any dose 
reduction in pazopanib/placebo 
• 24-48 hours should elapse between modifications of antihypertensive therapy 


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• Hypertension should be graded using CTCAE v4 
 
In some instances of treatment for hypertension, a lower dose of the medication may be sufficient to 
provide the required antihypertensive control.  In other instances, the standard dose of such a 
medication may be associated with AEs because of increased exposure.  Alternatively, the 
investigator may choose to replace the medication with another in the same pharmacologic class that 
is less likely to interact with pazopanib/placebo.  If such a medication is discontinued and replaced, 
the transition period should occur no less than 7 days prior to the first dose of pazopanib.  Based on 
prior clinical experience with pazopanib, the use of calcium channel blockers (dihydropyridine 
category) and ACE inhibitors as first-line and second-line therapy is recommended.   
 
Oral Antihypertensive Medications 
 
Agents in bold characters are suggested as optimal choices to avoid or minimize 
potential drug-interactions with pazopanib/placebo through CYP450. 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine 
XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate and 
inhibitor 
Selective 
 Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x 
daily 
50 mg 3x 
daily 
CYP 2D6 
substrate 
enalapril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
CYP 3A4 
substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
No 


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fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 
substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 
substrate 
irbesartan 
75 mg daily 
150 mg daily 300 mg daily 
CYP 2C9 
substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
 and  
Blocker 
labetalol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 
substrate and 
inhibitor 
 
 
 


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APPENDIX V 
 
GOG General Chemotherapy Guidelines 
 
• For 21 or 28 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 or 
28 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 are required to be recalculated if the patient has a weight change 
of greater than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for <10% weight changes. (10/09/2012) 
• 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). 
 
 


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APPENDIX VI 
 
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered 
by a Clinical Trials Agreement (CTA) a Cooperative Research and Development Agreement 
(CRADA) or a Clinical Supply Agreement, hereinafter referred to as Collaborative Agreement: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)” and the NCI Division of Cancer Treatment and Diagnosis. 
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator.” (http://ctep.cancer.gov/industry/ipo.html) contained within the terms 
of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as 
such by the investigators. The protocol documents for studies utilizing investigational Agents 
contain confidential information and should not be shared or distributed without the permission 
of the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”: 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order, as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
(Agent may be requested by completing a Clinical Drug Request (NIH-986) and faxing it to the 


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Pharmaceutical Management Branch at (301) 480-4612.  For questions about drug orders, 
transfers, returns, or accountability call (301) 496-5725 Monday through Friday between 8:30 
am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime).    Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent with 
all applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth 
in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborators confidential 
proprietary information. 
 
. 
 
 


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APPENDIX VII 
Specimen Procedures (10/09/2012) 
I. 
Summary of Specimen Requirements 
 
If the patient gives permission for her specimens to be collected for this optional translational research 
study component, then the participating Institution is required to submit the patient’s specimens as 
outlined below (unless otherwise specified). 
 
Required Specimens 
(Specimen Codes) 
 
Form SP 
Collection Time Points 
Deadlines and 
Recommendations 
Whole Blood (WB01) 
7-10mL drawn into a 
purple-top (EDTA) tube 
SP-WB01-186J 
Collect prior to or after starting 
therapy 
Ship to the GOG Tissue Bank 
the day the blood is collected1 
 
Submit Form SP online within 
26 weeks of registration 
Pre-Cycle 1 Plasma (PB01) 
prepared from 7-10mL of 
blood drawn into a purple 
top (EDTA) tube 
SP-PB01-186J 
Collect within 14 days of starting 
cycle 1 of therapy 
Ship to the GOG Tissue Bank 
within 26 weeks of 
registration1 
 
Submit Form SP online within 
26 weeks of registration 
Pre-Cycle 2 Plasma (PB02) 
prepared from 7-10mL of 
blood drawn into a purple 
top (EDTA) tube 
SP-PB02-186J 
Collect prior to starting cycle 2 of 
therapy or at the time the patient 
goes off-study due to disease 
progression or toxicity 
Pre-Cycle 6 Plasma (PB03) 
prepared from 7-10mL of 
blood drawn into a purple 
top (EDTA) tube 
SP-PB03-186J 
Collect prior to starting cycle 6 of 
therapy or at the time the patient 
goes off-study due to disease 
progression or toxicity 
1 
Ship specimens to: GOG Tissue Bank / Protocol GOG-186J, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, 
Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, E-mail: gogbank@nationwidechildrens.org. 
 
II. 
Obtaining a GOG Bank ID (10/09/2012) 
 
Only one GOG Bank ID (# # # # - # # - G # # #) is assigned per patient. All specimens and 
accompanying paperwork must be labeled with this coded and confidential tracking number. A 
GOG Bank ID can be obtained online via the Tissue Bank Portal on the GOG website (under Tools 
on the Web Menu page).  
 
Obtain the patient study ID for all protocols with specimen requirements before requesting a GOG 
Bank ID from the Tissue Bank Portal. Be sure to indicate if the patient has a previous GOG # 
when registering. This will ensure that the patient is only assigned one Bank ID. 
 
The GOG ID – Bank ID Lookup on the Tissue Bank Portal can be used to search for an existing 
Bank ID.  To lookup an existing Bank ID, enter the patient’s GOG # and click Lookup Bank ID. To 
lookup GOG #(s) associated with a given Bank ID, enter the Bank ID (without dashes) and click 
Lookup GOG #. 
 
Please contact User Support at the GOG Statistical and Data Center if you need assistance or have 
assigned more than one Bank ID to a patient (Email: support@gogstats.org; Phone: 716-845-7767). 
 
 


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III. 
 Requesting Specimen Kits 
 
A.  Ordering Specimen Kits (10/09/2012) 
 
One specimen kit can be ordered for each patient enrolled on GOG-0186J. Specimen kits may 
be ordered online via the Kit Management link on the GOG website (under Data Entry on the 
Web Menu page). Each site may order two kits per protocol per day (daily max = 6 kits). 
 
Please contact the GOG Tissue Bank if you need assistance (Email: 
GOGBank@nationwidechildrens.org; Phone: 866-GOG-BANC/866-464-2262). 
 
Please plan ahead to allow time for kits to be shipped by ground transportation.  
  
B.  Materials Provided in the Specimen Kits (10/09/2012) 
 
The GOG-0186J specimen kit (for frozen plasma) will contain: 
 
* single-chamber shipping container 
* three 15mL conical tubes 
* three transfer pipettes 
* 15 cryovials in zip-lock bags 
* one biohazard envelope with absorbent material 
* one Tyvek envelope 
* dry ice label (UN1845) 
* Exempt Human Specimen Sticker 
 
C. 
Unused Materials or Unused Specimen Kits 
 
Specimen kits should only be used for the submission of GOG-0186J frozen plasma specimens. 
 
Unused materials or unused Specimen Kits need to be returned to the GOG Tissue Bank. 
Contact the Bank if you have any questions about the return of unused material.   
 
IV.  
Submitting Whole Blood Specimens 
 
A. 
Requirement 
 
 
If the patient gives permission for her blood to be collected for this optional 
translational research study component, then the participating Institution is required to 
submit the patient’s specimens as outlined in Section I. 
 
 
A purple top (EDTA) tube should be used for blood collection. 
 
 
The type of blood collection tube (EDTA) should be specified on Form SP. 
 
 


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B. 
Purpose 
 
 
The GOG Tissue Bank will isolate DNA from whole blood specimens. DNA will be 
used for analysis of single nucleotide polymorphisms (SNPs). 
 
C. Time Points 
 
Whole blood should be collected prior to or after starting therapy. 
 
Please note that whole blood should be shipped to the GOG Tissue Bank the day the blood is 
collected. Blood may be shipped Monday through Friday for Tuesday through Saturday 
delivery. Please do not ship blood the day before a holiday. 
 
D. Format for Labeling the Specimen 
 
Label the specimen with the GOG protocol number (GOG-186J), GOG Bank ID (# # # # - # # - 
G # # #), specimen code (WB01), and collection date (mm/dd/yyyy). 
 
E. Instructions for Preparing the Whole Blood Specimen 
 
1.  Label the Whole Blood Collection Tube. 
 
 
Label a purple top whole blood collection tube (containing EDTA) as described above.  
 
2. Draw Blood. 
 
 
Draw 7-10mL of blood into the labeled purple top tube.  
 
3.  Mix Blood with EDTA. 
 
 
Mix the blood with the EDTA by gently inverting the tube 5-10 times. 
   
4. Complete Form SP. 
 
 
Complete Form SP online using SEDES as specified in Section VI. Submit a copy of Form 
SP with the specimen when it is shipped to the GOG Tissue Bank and retain a copy in your 
files. 
 
5.  Ship the Blood. 
 
 
Ship the whole blood specimen to GOG Tissue Bank the day the specimens are collected* 
as specified in Section VII. 
 
 
* If the whole blood absolutely cannot be shipped the day it is collected, the tube may be 
placed in the refrigerator overnight. Please note that the blood was refrigerated overnight 
in the comment box on Form SP (item 15). 


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V.  Submitting Plasma Specimens 
 
 
A.  Requirement 
 
If the patient gives permission for her blood to be collected for this optional translational 
research study component, then the participating Institution is required to submit the patient’s 
specimens as outlined in Section I. 
 
A purple top (EDTA) tube should be used for blood collection to prepare plasma. 
 
The type of blood collection tube (EDTA) should be specified on Form SP. 
 
 
B.  Purpose 
 
Plasma will be used for multiplex ELISA analysis of plasma cytokines and angiogenic markers 
(e.g., IL-6, IL-8, IL 11, IL-1a, Il-3, IL-4, VEGF, TPO, G-CSF, GM-CSF, osteopontin, and sVEGFRs). 
 
C. Time Point 
 
Plasma specimens should be prepared from blood drawn: 
 
1. prior to cycle 1 (PB01), 
2. prior to cycle 2 (PB02)*, and 
3. prior to cycle 6 (PB03)* of therapy. 
 
*If the patient goes off-study due to disease progression or toxicity prior to cycle 2 or 6, the 
final plasma specimen should be collected at that time. 
 
 
D.  Format for Labeling the Specimen 
 
Label the specimen with the GOG protocol number (GOG-186J), GOG Bank ID (# # # # - # # - 
G # # #), specimen code (PB##, see above), and collection date (mm/dd/yyyy).  
 
 
E.  Instructions for Preparing Plasma 
 
1.  Label Cryotubes. 
 
 
 
Label five screw-cap cryotubes as described above.  
 
2.  Draw Blood. 
 
Draw 7-10mL of blood into a purple top tube (containing the anticoagulant EDTA).  
 
3.  Mix the Blood with EDTA. 
 
Mix the blood with the EDTA by gently inverting the tube 5-10 times. 
 


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4.  Centrifuge Blood. 
 
Centrifuge the blood at 1000g for 15 minutes at 4ºC or room temperature to separate the 
plasma (top, straw-colored layer) from the red blood cells (bottom, red layer).  
 
5.  Aliquot Plasma. 
 
Evenly dispense (aliquot) the plasma into the pre-labeled cryotubes and cap the tubes 
securely. 
 
6.  Freeze Plasma. 
 
Freeze the plasma in an upright position using an appropriate freezing/storage space (i.e., 
ultra cold ≤-70oC freezer, liquid nitrogen, or direct exposure with dry ice).  
 
7.  Complete Form SP.  
 
Complete Form SP online using SEDES as specified in Section VI. 
 
Submit a copy of Form SP with the specimen when it is shipped to the GOG Tissue Bank 
and retain a copy in your files. 
 
8. Ship the Plasma to the GOG Tissue Bank. 
 
Ship the frozen plasma to the GOG Tissue Bank using a specimen kit as described in 
Section VII. 
 
VI. 
 Submitting Form SP 
 
A. 
Form SP Requirements 
 
 
Form SP must be completed and submitted online to the GOG Statistical and Data 
Center (SDC) using the SDC Electronic Data Entry System (SEDES). Form SP must be 
submitted for each specimen required for the protocol regardless of the specimen 
submission status. Specific instructions for completing Form SP are available via 
SEDES by scrolling down to the SP Forms for the specific protocol.  
 
B. 
Instructions for Submitting Form SP Online (10/09/2012) 
 
Form SP must be submitted online using SEDES which is available on the GOG Web 
Menu under Registration/Data Entry. A copy of the completed form must also 
accompany each specimen shipped to the GOG Tissue Bank. Retain a printout of the 
completed form for your records. Form SP does not need to be sent to the GOG Tissue 
Bank when specimens are not collected. 
 
To access Form SP for online submission, log onto the GOG Web Menu and use 
SEDES to electronically enter Form SP data. Any questions about access or problems 


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should be directed to User Support at the GOG SDC (Email: support@gogstats.org; 
Phone: 716-845-7767). 
  
VII.  Shipping Specimens 
 
A.  
Whole Blood 
 
Whole blood should be shipped to the GOG Tissue Bank the day the specimens are 
collected*: 
 
GOG Tissue Bank / Protocol GOG-0186J 
Nationwide Children’s Hospital  
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
Fax: 614-722-2897 
E-mail: gogbank@nationwidechildrens.org 
 
Please do not ship blood the day before a holiday. Use your own shipping container to 
ship specimens using a pre-paid GOG Tissue Bank FedEx air bill obtained 
through the Kit Management application. 
 
* If the whole blood absolutely cannot be shipped the day it is collected, the tube may 
be placed in the refrigerator overnight. Please note that the blood was refrigerated 
overnight in the comment box on Form SP (item 15). 
 
When shipping whole blood specimens, please be aware that your Institution must 
comply with IATA standards (www.iata.org). If you have questions regarding your 
shipment, please contact the GOG Tissue Bank at 614-722-2865.  
 
To ship whole blood specimens you will need (1) a sturdy shipping container (e.g., a 
cardboard or styrofoam box), (2) a leak proof biohazard envelope with absorbent 
material*, (3) a puncture and pressure resistant envelope (e.g. Tyvek envelope), (4) an 
Exempt Human Specimen Sticker, and (5) a pre-paid FedEx air bill. 
 
*If you will be shipping whole blood specimens from more than one patient, please put 
each specimen in a separate plastic zip-lock bag before placing the specimens in the 
shipping bag. 
 
If you do not have these materials available at your Institution, you may order them 
from any supplier (e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
  
Instructions for Shipping Whole Blood Using Your Own Shipping Container* 
 
*Please note that you can include up to four different blood specimens in one biohazard 
envelope. 
 


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1. 
Place the whole blood specimen in a biohazard envelope containing absorbent 
material. Expel as much air as possible before sealing the bag. 
  
2. 
Wrap the biohazard envelope in bubble wrap or another padded material. 
 
3. 
Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible 
before sealing the envelope. 
 
4. 
Place the Tyvek envelope in a sturdy shipping contained (e.g., cardboard FedEx 
box). 
 
5. 
Insert a copy of the SP Form(s) into the box.  
 
6. 
Attach an Exempt Human Specimen Sticker to the outside of the shipping 
container. 
 
7. 
Print a pre-paid FedEx air bill using the Kit Management application (found under 
Data Entry on the Web Menu page) and attach to shipping container. 
 
8. 
Make arrangements for FedEx pick-up through your usual institutional 
procedure or by calling 800-238-5355. Ship the specimens and SP Forms to the 
GOG Tissue Bank via FedEx Priority Overnight delivery. Please ship whole 
blood specimens Monday through Friday for Tuesday through Saturday 
delivery. If the whole blood is collected on a Friday, select “yes” for Saturday 
delivery when completing the label online. Saturday delivery is only available 
for the shipment of whole blood. 
 
C. 
Frozen Plasma 
 
 
All frozen plasma specimens should be shipped using the specimen kits provided to the 
GOG Tissue Bank (address above). 
 
 
Frozen specimens should be shipped Monday through Thursday for Tuesday through 
Friday delivery. Do not ship frozen specimens the day before a holiday. 
 
 
Frozen specimens should be stored in an ultra-cold freezing/storage space (i.e., ultra 
cold ≤-70oC freezer, liquid nitrogen, or direct exposure with dry ice) until the specimens 
can be shipped. 
 
Instructions for Shipping Frozen Specimens in a Specimen Kit   
 
1. 
Pre-fill the chamber of the specimen kit about 1/3 full with dry ice. 
 
2. 
Place each set of frozen plasma specimens in a separate zip-lock bag. 
 
3. 
Place the zip-lock bags in the biohazard envelope containing absorbent material. 
Do not put more than 25 vials in the biohazard envelope. Put the secondary 


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envelope into a Tyvek envelope. Expel as much air as possible before sealing all 
envelopes. 
 
4. 
Place the Tyvek envelope containing the frozen specimens into the chamber of the 
kit and fill the chamber to the top with dry ice. 
 
5. 
Insert the SP Forms into the kit.  
 
6. 
Place the foam cover on top of the kit. Tape the outer box of the kit closed with 
filament or other durable sealing tape. (10/09/2012) 
 
7. 
Print a pre-paid FedEx air bill using the Kit Management application (found under 
Data Entry on the Web Menu page) and attach to kit. 
 
8. 
Complete and attach the dry ice label; attach the Exempt Human Specimen 
Sticker. 
 
9. 
Arrange for FedEx pick-up through your usual Institutional procedure or by 
calling 1-800-238-5355. Ship the specimens and SP Forms to the GOG Tissue 
Bank via Priority Overnight delivery. Please ship frozen specimens Monday 
through Thursday for Tuesday through Friday delivery. 
 
 
VIII.  Banking Specimens 
 
The GOG Tissue Bank staff will be responsible for all of the general activities associated with 
receiving, banking, and distributing clinical specimens. 
 
Upon receipt of specimen shipments, the GOG Tissue Bank will immediately (1) assess the 
type, quantity, and condition of the specimens received, (2) complete the appropriate fields in 
the GOG SP Form, (3) enter the specimens into their database system, and (4) store the 
specimens under the appropriate conditions. 
 
The GOG Tissue Bank should complete the bottom part of Form SP for each specimen and 
submit the data electronically to the GOG Statistical and Data Center within three business 
days of receipt. A copy of the completed Form SP will be retained in the GOG Tissue Bank 
files. 
 
As needed, the GOG Tissue Bank will work with the GOG Statistical and Data Center to 
reconcile specimen identifiers, information, condition, and quality. 
 
A. 
Whole Blood 
 
 
Whole blood will be processed by the Bank to isolate DNA. DNA will be stored at the 
Bank. Bank staff will make sure each whole blood and subsequent DNA specimen is 
labeled appropriately. 
 
 


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B. 
Frozen Plasma 
 
Frozen plasma will be stored at the Bank in an ultra-cold  -70oC freezer or in a liquid 
nitrogen storage tank. Bank staff will make sure each frozen specimen is labeled 
appropriately. 
 
IX. 
Distributing Specimens for Laboratory Testing 
 
The GOG Statistical and Data Center and the GOG Tissue Bank will work together to 
coordinate the distribution of batches of specimens to approved Investigators for laboratory 
testing. Specimen selection will be based on information regarding specimen procurement and 
condition as well as patient eligibility, evaluation criteria, statistical considerations, and 
relevant clinical information. 
 
For each shipment, the GOG Tissue Bank staff will provide the Investigator and the GOG 
Statistical and Data Center an electronic file that includes an inventory of all specimens 
included in the shipment (including the specimen specific identifiers and quantity and condition 
of the specimens being shipped). 
 
The GOG Statistical and Data Center will provide the Investigator an electronic file containing 
the specimen identifiers with relevant information regarding specimen condition, suitability for 
testing, eligibility/evaluability for a given component of the research study, and fields for the 
laboratory data. Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of the laboratory 
testing performed and for keeping accurate records of all specimen testing. 
 
Investigators will ensure that the laboratory testing results are linked to the appropriate 
specimen-specific identifiers and are responsible for transferring relevant laboratory data to the 
GOG Statistical and Data Center. 
 
A.  Frozen DNA and Plasma 
 
Frozen DNA and plasma will be distributed to DR. Anil Sood for analysis of plasma 
cytokines and angiogenic markers and SNPs. 
 
Laboratory of Dr. Anil Sood 
ATTN: Anil Sood and De-Yu Shen 
Departments of Gynecologic Oncology and Cancer Biology 
UT-MD Anderson Cancer Center 
7777 Knight Rd SRB1.440 (Unit 173) 
Houston, TX 77054 
Phone: 713-563-9030 
Fax: 713-792-3643 
Email: asood@mdanderson.org 
 


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X. 
Banking Specimens for Future Research 
 
Specimens will remain banked in the GOG Tissue Bank and made available for approved 
cancer and/or non-cancer research projects based on GOG Tissue Bank Specimen Distribution 
Policies if the following condition is satisfied: Each patient in question must have provided 
permission for the use of her specimens for cancer and/or non-cancer research. The patient’s 
choices will be documented on the informed consent document that the patient signs for the 
protocol and on the online Specimen Consent Application (available on the GOG web-site). 
 
GOG Institutions can amend a patient’s choices regarding the future use of her specimens 
at any time if the patient changes her mind. 
 
If the patient does not give permission for the use of her specimens, the GOG Tissue Bank will 
be instructed to destroy (incinerate) any remaining specimens to insure that the patient’s wishes 
are honored.