Conditions: Sarcoma, Soft Tissue Soft Tissue Sarcoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 56
Healthy volunteers: no

Brief summary:
Pazopanib is FDA approved as a second line and beyond treatment for metastatic soft tissue sarcoma. There is a population of elderly and debilitated soft tissue sarcoma patients that are not fit for standard first line chemotherapy that is doxorubicin based. As pazopanib is well tolerated with minimal side effects, the investigators propose a phase II study to evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic disease who are not candidates for cytotoxic chemotherapy.

Detailed description:

Arms:
arm 1: Pazopanib will be started at a dose of 200 mg BID for four days, then escalated to a dose of 400 mg BID for four days, then escalated once more to a dose of 800 mg QD for the duration of participation (or until dose reduction, if necessary). Pazopanib should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.

Interventions: intervention 1: Pazopanib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
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Page 1 of 52 
 
 
 
A Phase II Study of Pazopanib as Front-Line Therapy in Patients with Non-Resectable or 
Metastatic Soft Tissue Sarcomas Who Are Not Candidates for Chemotherapy 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201501057  
Version Date: 06/04/18 
Coordinating Center:         Washington University School of Medicine 
 
Principal Investigator: 
Brian A. Van Tine, M.D., Ph.D. 
Phone:  (314) 747-8475 
E-mail:  bvantine@ wustl.edu  
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Angela C. Hirbe, M.D., Ph.D. 
 
Washington University  
Medical Oncology 
Jingqin (Rosy) Luo, Ph.D. 
 
Washington University  
Biostatistics 
Mark Agulnik, M.D. 
 
 
Northwestern University 
Hematology/Oncology 
Steven Attia, D.O. 
 
 
Mayo Clinic – Jacksonville 
Hematology/Oncology 
Scott Okuno, M.D. 
 
 
Mayo Clinic – Rochester 
Medical Oncology 
Randolph S. Marks, M.D. 
 
Mayo Clinic – Rochester 
Medical Oncology 
Steven I. Robinson, MBBS 
 
Mayo Clinic – Rochester 
Medical Oncology 
Kelly K. Curtis, M.D. 
 
 
Mayo Clinic – Scottsdale 
Hematology/Oncology 
Kevin R. Kozak, M.D.  
 
University of Wisconsin 
Radiation Oncology 
Thomas McFarland, M.D. 
 
University of Wisconsin 
Medical Oncology 
Mohammed Milhem, MBBS 
 
University of Iowa 
 
Hematology/Oncology 
 
 
Study Drug:  
 
Pazopanib (GW786034, Votrient) 
IND #: 
 
 
125209 EXEMPT 
Clinical Trials.gov #: 
NCT02300545 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary 
to obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


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A Phase II Study of Pazopanib as Front-Line Therapy in Patients with Non-Resectable or 
Metastatic Soft Tissue Sarcomas Who Are Not Candidates for Chemotherapy 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
01/13/2015 
Amendment #1 Version (PRMC Only) 
 
 
 
 
05/15/2015 
Amendment #1 Version 
 
 
 
 
 
 
06/29/2015 
Amendment #2 Version 
 
 
 
 
 
 
10/12/2016 
Amendment #3 Version 
 
 
 
 
 
 
05/31/2017 
Amendment #4 Version 
 
 
 
 
 
 
06/04/2018 
 
 
 


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A Phase II Study of Pazopanib as Front-Line Therapy in Patients with Non-Resectable or 
Metastatic Soft Tissue Sarcomas Who Are Not Candidates for Chemotherapy 
 
Principal Investigator Signature Page 
 
 
Principal Investigator: 
 
Brian A. Van Tine, M.D., Ph.D. 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
BID 
Bis in die (twice a day) 
BP 
Blood pressure 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMP 
Comprehensive metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DBP 
Diastolic blood pressure 
DSMC 
Data and Safety Monitoring Committee 
DVT 
Deep venous thrombosis 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
LFT 
Liver function tests 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Prothrombin time 


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QASMC 
Quality Assurance and Safety Monitoring Committee 
QD 
Quaque die (every day) 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TKI 
Tyrosine kinase inhibitor 
TSH 
Thyroid stimulating hormone 
UPC 
Urine protein creatinine 
UPN 
Unique patient number 
VEGF 
Vascular endothelial growth factor 
WUSM 
Washington University School of Medicine 
 
 


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Table of Contents 
1.0 
BACKGROUND AND RATIONALE .............................................................................. 8 
1.1 
Soft Tissue Sarcomas ...................................................................................................... 8 
1.2 
Pazopanib ........................................................................................................................ 8 
1.3 
Rationale ......................................................................................................................... 8 
1.4 
Background of Correlative Studies ................................................................................. 8 
2.0 
OBJECTIVES .................................................................................................................... 9 
2.1 
Primary Objective ........................................................................................................... 9 
2.2 
Secondary Objectives ..................................................................................................... 9 
3.0 
PATIENT SELECTION ..................................................................................................... 9 
3.1 
Inclusion Criteria ............................................................................................................ 9 
3.2 
Exclusion Criteria ......................................................................................................... 10 
3.3 
Inclusion of Women and Minorities ............................................................................. 12 
4.0 
REGISTRATION PROCEDURES .................................................................................. 13 
4.1 
Confirmation of Patient Eligibility ............................................................................... 13 
4.2 
Patient Registration in the Siteman Cancer Center Database ....................................... 13 
4.3 
Assignment of UPN ...................................................................................................... 14 
5.0 
TREATMENT PLAN ...................................................................................................... 14 
5.1 
Agent Administration ................................................................................................... 14 
5.2 
General Concomitant Medication and Supportive Care Guidelines ............................. 14 
5.3 
Women of Childbearing Potential ................................................................................ 17 
5.4 
Duration of Therapy ..................................................................................................... 18 
5.5 
Duration of Follow-up .................................................................................................. 18 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ................................................................... 18 
7.0 
REGULATORY AND REPORTING REQUIREMENTS .............................................. 24 
7.1 
Definitions .................................................................................................................... 24 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
26 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University ............................................................................................................ 26 
7.4 
Reporting Requirements for Secondary Sites ............................................................... 27 
7.5 
Reporting to Secondary Sites ........................................................................................ 27 
7.6 
Reporting to Novartis ................................................................................................... 27 
7.7 
Timeframe for Reporting Required Events .................................................................. 29 
8.0 
PHARMACEUTICAL INFORMATION ........................................................................ 29 
8.1 
Pazopanib ...................................................................................................................... 29 
9.0 
CORRELATIVE STUDIES ............................................................................................. 30 
9.1 
Quality of Life .............................................................................................................. 30 
9.2 
Biomarkers .................................................................................................................... 31 
9.3 
Pharmacokinetics .......................................................................................................... 31 
10.0 STUDY CALENDAR ...................................................................................................... 32 
11.0 DATA SUBMISSION SCHEDULE ................................................................................ 32 
12.0 MEASUREMENT OF EFFECT ...................................................................................... 33 
12.1 Antitumor Effect – Solid Tumors ................................................................................. 33 
12.2 Disease Parameters ....................................................................................................... 34 
12.3 Methods for Evaluation of Measurable Disease ........................................................... 35 


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12.4 Response Criteria .......................................................................................................... 37 
13.0 DATA AND SAFETY MONITORING .......................................................................... 41 
14.0 AUDITING ...................................................................................................................... 42 
15.0 STATISTICAL CONSIDERATIONS ............................................................................. 42 
15.1 Sample Size .................................................................................................................. 42 
15.2 Statistical Analysis ........................................................................................................ 42 
16.0 MULTICENTER REGULATORY REQUIREMENTS .................................................. 43 
17.0 REFERENCES ................................................................................................................. 44 
APPENDIX A: ECOG Performance Status Scale ...................................................................... 45 
APPENDIX B: New York Heart Association (NYHA) Functional Classification ..................... 46 
APPENDIX C: Medication Diary – Cycle 1 ................................................................................. 0 
APPENDIX D: Medication Diary – Cycle 2 & Beyond (200 mg) ........................................... 2 
Medication Diary – Cycle 2 & Beyond (200 mg and/or 400 mg) ................................................. 4 
APPENDIX E: FACT-G7 ............................................................................................................. 0 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Soft Tissue Sarcomas 
 
Soft-tissue sarcomas make up approximately 1% of adult malignancies and encompass 
approximately 70 different histologic subtypes 1.  Most of these tumors are genetically 
complex and are highly unlikely to share a common mutation or alteration in signaling 
that would allow for treatment with an inhibitor to one molecule across all subtypes.  
Surgery is usually the first line of treatment in localized disease, while radiation or 
chemotherapy can be used in local disease that is unresectable due to size or location.  
Cytotoxic chemotherapy remains the standard of care for advanced and metastatic 
disease.  Doxorubicin is the most active single agent with a response rate of 
approximately 20-25% 2.  In some instances, patients may not be a candidate for either 
one of these therapies based on age or other comorbidities leaving no viable treatment 
options.  Prognosis is dismal in the metastatic setting with a median survival of less than 
12 months even with therapy. 
 
1.2 
Pazopanib 
 
Pazopanib is a multitargeted tyrosine kinase inhibitor that has been shown to have 
efficacy in sarcoma patients.   Preclinical data has demonstrated comparable inhibitory 
effects of pazopanib against a number of targets including VEGFR-1, VEGFR-2, 
VEGFR-3, PDGFR-α, PDGFR-β, and c-Kit 3.  In a phase II study published in JCO in 
2009, Sleijfer et al. demonstrated that pazopanib is well-tolerated in patients with 
relapsed or refractory advanced soft-tissue sarcoma 4.  Further, there is data from a phase 
III study of pazopanib in previously treated metastatic soft tissue sarcoma patients which 
demonstrated a progression free survival of 4.6 months for pazopanib vs. 1.6 months for 
placebo.  Overall survival in the pazopanib group was 12.5 months 5. 
 
1.3 
Rationale 
 
Pazopanib is FDA approved as a second line and beyond treatment for metastatic soft 
tissue sarcoma.  There is a population of elderly and debilitated soft tissue sarcoma 
patients that are not fit for standard first line chemotherapy that is doxorubicin based.  
As pazopanib is well tolerated with minimal side effects, we propose a phase II study to 
evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic 
disease who are not candidates for cytotoxic chemotherapy. 
 
1.4 
Background of Correlative Studies 
 
Sleijfer et al. recently published a translational study in which they evaluated whether 
cytokine levels in the patients enrolled in EORTC 62043, the phase II study of 
pazopanib in soft tissue sarcoma, correlated with PFS and OS.  They measured levels of 
several cytokines at baseline and 12 weeks after beginning pazopanib therapy and 
demonstrated that baseline levels were not predictive, but that high sVEGFR2 and low 
PIGF were associated with a more favorable PFS at 12 weeks (OR 0.636, 95% CI 0.413-


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0.977, P=0.039) and (OR 1.081, 95% CI 1.007-1.160, P=0.0318) respectively.  There 
was also a trend toward high sVEGFR2 at week 12 and increased OS and a statistically 
significant association between low PIGF levels at week 12 and longer OS (HR 1.061, 
95% CI 1.025-1.099, P=0.0009) 6. 
 
We propose to measure sVEGFR2 and PIGF levels at baseline, 4 weeks, 8 weeks, and 
12 weeks to both verify the results of Sleijfer et al and to determine if there is an even 
earlier correlation that can be detected between levels of these cytokines and PFS as well 
as OS which may allow us to better predict treatment response early on in therapy 
 
In addition, plasma pazopanib concentrations will be determined immediately prior to 
the first dose of each dose escalation, then after steady-state is reached at 800 mg QD 
(after at least 10 days of 800 mg QD administration). These PKs will only be performed 
in the first 10-20 patients enrolled at Washington University. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the clinical benefit rate (CR + PR + SD) in patients with soft tissue 
sarcoma not candidates for chemotherapy treated with first-line pazopanib at 16 weeks. 
 
2.2 
Secondary Objectives 
 
1. To determine the rate of progression-free survival (PFS) in patients with soft tissue 
sarcoma not candidates for chemotherapy treated with first-line pazopanib. 
2. To determine the rate of overall survival (OS) in patients with soft tissue sarcoma 
not candidates for chemotherapy treated with first-line pazopanib. 
3. To evaluate the quality of life of patients with soft tissue sarcoma not candidates for 
chemotherapy treated with first-line pazopanib. 
4. To correlate serum sVEGFR2 and PICG levels with outcomes. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically confirmed diagnosis of nonresectable or metastatic soft tissue 
sarcoma.  The following histologies are excluded: embryonal rhabdomyosarcoma, 
chondrosarcoma, osteosarcoma, Ewing tumors, primitive neuroectodermal tumors, 
gastrointestinal stromal tumors, dermatofibrosarcoma protuberans, inflammatory 
myofibroblastic sarcoma, and mixed mesodermal tumors of the uterus.  
 
 
 


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2. Evaluable disease by imaging or physical exam OR measurable disease defined as at 
least one lesion 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. 
 
3. Not a candidate for chemotherapy as determined by the treating physician. 
 
4. Age ≥ 18 years 
 
5. ECOG performance status ≤ 2 (see Appendix A). 
 
 
6. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcl 
b. Platelets ≥ 100,000/mcl 
c. Hemoglobin ≥ 9.0 g/dL 
d. PT or INR ≤ 1.2 x IULN (if not receiving anticoagulation therapy) 
e. PTT ≤ 1.2 x IULN (if not receiving anticoagulation therapy) 
f. Total bilirubin ≤ 1.5 x IULN or ≤ 3.0 x IULN with normal AST and ALT in 
patients with Gilbert’s disease 
g. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
h. Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m2 for 
patients with creatinine levels above 1.5 mg/dL 
i. UPC < 1 (in like units) or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine 
dipstick for renal function assessment is not acceptable. 
 
Notes: 
Subjects may not have had a transfusion within 7 days of screening assessments. 
Concomitant elevation of bilirubin and AST/ALT above the IULN is not 
allowed. 
Patients receiving anticoagulation therapy are eligible if their INR is stable and 
within the recommended range for the desired level of anticoagulation. 
 
7. Ability to swallow and retain oral tablets. 
 
8. Women of childbearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 
 
9. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
3.2 
Exclusion Criteria 
 


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1. Eligible for cytotoxic chemotherapy. 
 
2. Prior systemic therapy for this type of sarcoma. Neoadjuvant or adjuvant therapy 
more than two years prior would not apply. 
 
3. Prior treatment with any VEGFR tyrosine kinase inhibitor. 
 
4. Administration of any non-oncologic investigational drug within 30 days or 5 half-
lives (whichever is longer) prior to the first dose of pazopanib. 
 
5. Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study 
treatment (please refer to Section 5.2.5 and Appendix F). 
 
6. A history of other malignancy ≤ 5 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix. 
 
7. Known brain metastases. 
 
8. A history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pazopanib or other agents used in the study. 
 
9. Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is 
progressing in severity (except alopecia). 
 
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, uncontrolled seizure disorder, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
11. Corrected QT interval (QTc) > 480 msecs. 
 
12. History of any one or more of the following cardiovascular conditions within the 
past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable 
angina pectoris, coronary artery bypass graft surgery, symptomatic peripheral 
vascular disease, class III or IV congestive heart failure as defined by the New York 
Heart Association (see Appendix B). 
 
13. Poorly controlled hypertension (defined as systolic blood pressure of ≥ 140 mmHg 
or diastolic blood pressure of ≥ 90 mmHg).  Note: initiation or adjustment of 
antihypertensive medication(s) is permitted prior to study entry.  Following 
antihypertensive medication initiation or adjustment, blood pressure must be 
reassessed three times at approximately 2-minute intervals.  At least 24 hours must 
have elapsed between antihypertensive medication initiation or adjustment and blood 
pressure measurement.  These three values should be averaged to obtain the mean 
diastolic and systolic blood pressures, which must be < 140/90 mmHg in order for a 
patient to be eligible for the study. 


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14. Clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding, including (but not limited to) active peptic ulcer disease, 
known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel 
disease (e.g., ulcerative colitis, Crohn’s disease) or other GI conditions with 
increased risk of perforation, history of abdominal fistula or intra-abdominal abscess 
within 28 days prior to beginning study treatment. 
 
15. Clinically significant gastrointestinal abnormalities that may affect absorption of 
pazopanib, including (but not limited to) malabsorption syndrome or major resection 
of the stomach or small bowel. 
 
16. History of cerebrovascular accident including transient ischemic attack, pulmonary 
embolism (PE) (including asymptomatic or previously treated PE), or untreated deep 
venous thrombosis within the past 6 months.  Patients with DVT who are being 
treated with therapeutic anti-coagulating agents are eligible. 
 
17. Major surgery or trauma within 28 days prior to first dose of pazopanib and/or 
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter 
placement not considered to be major surgery). 
 
18. Evidence of active bleeding or bleeding diathesis. 
 
19. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels 
that increase the risk of pulmonary hemorrhage.  Note: lesions infiltrating major 
pulmonary vessels (contiguous tumor and vessels) are excluded; however, the 
presence of a tumor that is touching but not infiltrating (abutting) the vessels is 
acceptable (CT with contrast is strongly recommended to evaluate such lesions).  
Large protruding endobronchial lesions in the mail or lobar bronchi are excluded; 
however, endobronchial lesions in the segmented bronchi are allowed. Lesions 
extensively infiltrating the main or lobar bronchi are excluded; however, minor 
infiltrations in the wall of thee bronchi are allowed. 
 
20. Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of 
pazopanib). 
 
21. Pregnant and/or breastfeeding.  Patient must have a negative serum pregnancy test 
within 14 days of study entry. 
 
22. Known HIV-positivity.  Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 


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4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical 
Trials Core Protocol Procedures for Secondary Sites packet at least one business day 
prior to registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. 
Urgent late afternoon or early morning enrollments should be planned in advance and 
coordinated with the Washington University research coordinator.  Registration will be 
confirmed by the research coordinator or his/her delegate by email within one business 
day. Verification of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center database at 
Washington University. 
 
 
 


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4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  
Patients will also be identified by first, middle, and last initials.  If the patient has no 
middle initial, a dash will be used on the case report forms (CRFs).  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Pazopanib will be started at a dose of 200 mg BID for four days, then escalated to a dose 
of 400 mg BID for four days (if tolerated), then escalated once more to a dose of 800 mg 
QD for the duration of participation (if tolerated) or until dose reduction, if necessary.  
Pazopanib should be taken orally without food at least one hour before or two hours 
after a meal. One cycle of pazopanib is 28 days.  The tablets should be swallowed whole 
and must not be crushed or broken. The time of day the tablets are taken should be 
relatively constant.  
 
If a dose is missed, the subject should take the dose as soon as possible, but only if there 
are 12 or more hours remaining before the next dose is due. If the next dose is due in 
less than 12 hours, the subject should skip the missed dose and take the next dose as 
scheduled. 
 
If vomiting occurs after taking pazopanib, the subject should not take a replacement 
dose for that dose, but should resume taking pazopanib at the next scheduled dose.  If 
vomiting persists, the subject should be instructed to notify the investigator. 
 
Please note that a Monday or Thursday start is recommended to avoid weekend blood 
draws for pharmacokinetic testing. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, analgesics, erythropoietin, or 
bisphosphonates, when appropriate. 
   
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT3 
antagonists) may be administered prophylactically in the event of nausea.  Anti-
diarrheals, such as loperamide, may be administered as needed in the event of diarrhea.  
Although acetaminophen at doses of < 2 g/day is permitted, it should be used with 
caution in subjects with impaired liver function. 
   
5.2.1 Anticoagulants 
 


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Results from drug-drug interaction studies conducted in subjects with cancer 
suggest that pazopanib has no effect on the metabolism of S-warfarin.  
Hemorrhagic events, however, have been reported in clinical studies with 
pazopanib; therefore, pazopanib should be used with caution in subjects with 
increased risk of severe bleeding or who are receiving concomitant anticoagulant 
therapy (e.g., warfarin or its derivatives, low molecular weight heparin, 
unfractionated heparin).  Subjects taking concomitant anticoagulant therapy 
should be monitored regularly for changes in relevant coagulation parameters as 
clinically indicated, as well as for any clinical bleeding episodes. 
 
5.2.2 Hypoglycemic Therapy 
 
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[31].  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. 
 
5.2.3 Use of Statins 
 
Concomitant use of pazopanib and simvastatin increases the risk of ALT 
elevations.  If a patient receiving concomitant simvastatin develops ALT 
elevations, follow guidelines for pazopanib dose modification and discontinue 
simvastatin.  Insufficient data are available to assess the risk of concomitant 
administration of alternative statins and pazopanib. 
 
5.2.4 Medications that Raise Gastric pH 
 
In a drug interaction trial in patients with solid tumors, concomitant 
administration of pazopanib with esomeprazole, a proton pump inhibitor, 
decreased the exposure of pazopanib by approximately 40% (AUC and Cmax).  
Therefore, concomitant use of pazopanib with drugs that raise gastric pH should 
be avoided.  IF such drugs are needed, short-acting antacids such as Tums, 
Rolaids, Maalox, and Mylanta should be considered in place of proton pump 
inhibitors and H2 receptor antagonists.  Separate antacid and pazopanib dosing 
by several hours to avoid a reduction in pazopanib exposure. 
 
5.2.5 Medications to Use with Caution 
 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CP2C8, 


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CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.  
Pregnane X receptor transient transfection assay suggested some potential for 
human CYP3A4 induction at high concentrations.  Results from drug-drug 
interaction studies conducted in subjects with cancer suggest that pazopanib is a 
weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no clinically 
relevant effect on CYP1A2, CYP2C9, or CYP2C19 metabolism.  Therefore, 
concomitant use of pazopanib with certain medications (substrates of CYP3A4, 
CYP2C8, and CYP2D6) with a narrow therapeutic window should be undertaken 
with CAUTION due to the potential for alterations in the pharmacologic effects 
of these medications or an increased risk for serious or life threatening adverse 
events associated with such medications (see below) secondary to the inhibition 
of specific CYP enzymes by pazopanib.  In addition, the potential for drug 
interaction with such medications, although diminished, may persist after the last 
dose of pazopanib due to its long half-life (i.e., mean 30.9 hours); therefore, 
continue to exercise CAUTION for at least 7 days and up to 15 days after the 
last dose of pazopanib when administering these medications.  These 
medications include (but are not limited to): 
 Ergot 
derivatives: 
 
dihydroergotamine, 
ergonovine, 
ergotamine, 
methylergonovine (potential increased risk for developing ergot toxicity 
that includes severe vasospasm leading to peripheral as well as cerebral 
ischemia) 
 Neuroleptics: pimozide (potential increased risk for QT interval 
prolongation, ventricular arrhythmia, and sudden death) 
 Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, 
quinidine, propafenone (potential increased risk for QT interval 
prolongation and Torsade de Pointes) 
 Immune modulators: cyclosporine, tacrolimus, sirolimus (potential 
increased risk for nephrotoxicity and neurotoxicity) 
 Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
 
The results from in vitro studies suggested that the oxidative metabolism of 
pazopanib in human liver microsomes is mediated primarily by CYP3A4, with 
minor contributions from CYP1A2 and CYP2C8.  Furthermore, in vitro data 
suggest that pazopanib is a substrate for p-glycoprotein.  Substances that induce 
or inhibit CYP3A4 may alter the pharmacologic effects of pazopanib and should 
be used with CAUTION.  
  
Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations.  Co-administration of strong CYP3A4 inhibitors is prohibited 
(see Section 5.2.5); therefore selection of an alternate concomitant medication 
with no or minimal potential to inhibit CYP3A4 is recommended.  
 
CYP3A4 inducers may decrease plasma pazopanib concentrations.  Selection of 
an alternate concomitant medication with no or minimal enzyme induction 
potential is recommended.   
 


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Drugs that induce CYP3A4 and may decrease pazopanib plasma concentrations 
include (but are not limited to): 
 Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone (>10 mg), methylprednisolone (>8 mg), dexamethasone (>1.5 
mg) 
 Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
 HIV antivirals:  efavirenz, nevirapine 
 Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene 
 Miscellaneous:  St. John’s Wort, modafinil, pioglitazone  
 
5.2.6 Prohibited Medications 
 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is 
PROHIBITED beginning 14 days prior to the first dose of study drug until 
discontinuation from the study.  Strong CYP3A4 inhibitors include (but are 
not limited to): 
 
 Antibiotics: clarithromycin, telithromycin, troleandomycin 
 HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir,  
lopinavir) 
 Antifungals:  itraconazole, ketoconazole, voriconazole 
 Antidepressants:  nefazodone 
 
Refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP). Therefore, absorption and 
subsequent elimination of pazopanib may be influenced by products that affect 
P-gp and BCRP. 
 
Concomitant treatment with strong inhibitors of P-gp or BCRP should be 
avoided due to risk of increased exposure to pazopanib. Selection of alternative 
concomitant medicinal products with no or minimal potential to inhibit P-gp or 
BCRP should be considered. 
   
 
5.3 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required 
to have a negative serum pregnancy test within 14 days prior to the first dose of 
pazopanib.   
 


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Female patients are required to use two forms of acceptable contraception, including one 
barrier method, during participation in the study and for 28 days following the last dose 
of pazopanib.  
 
If a patient is suspected to be pregnant, pazopanib should be immediately discontinued.  
In addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient becomes pregnant during therapy or within 28 days after the last dose 
of pazopanib, the investigator must be notified in order to facilitate outcome follow-up. 
 
5.4 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely until one of the following criteria applies: 
 Documented and confirmed disease progression 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason other than withdrawal of 
consent will be followed as indicated in the study calendar. 
 
5.5 
Duration of Follow-up 
 
After cessation of study treatment, patients will be followed every 3 months until death.  
Either phone contact or review of the Social Security Death Index is acceptable to 
monitor for overall survival. Patients removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 


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As a general rule, if dose reduction of pazopanib is necessary, the dose should be reduced 
stepwise by 200 mg at each step, and the patient should be monitored for approximately 10 to 
14 days at each dose level.  If toxicity does not abate during this monitoring time, the pazopanib 
may need to be interrupted and/or the dose further decreased with continued monitoring for an 
additional 10-14 days at each dose level, and so on. 
  
If the toxicity has abated with reduction of the dose and dose re-escalation is considered safe by 
the investigator, the pazopanib dose can then be increased step-wise back to the pre-event dose 
(in 200 mg increments, after monitoring for 10-14 days at each dose level to ensure that toxicity 
did not recur or worsen).  
 
Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
(A). Asymptomatic and 
persistent SBP of >140-
<170 mmHg, or DBP >90-<110 
mmHg, or a clinically significant 
increase in DBP of 20 mmHg 
(but still below 110 mmHg). 
Step 1. Continue pazopanib at the current dose.  
Step 2. Adjust current or initiate new antihypertensive               
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2         
weeks as indicated to achieve well-controlleda blood pressure 
(BP). If BP is not well-controlled within 2 weeks, consider 
referral to a specialist and go to scenario (B). 
(B). Asymptomatic SBP >170 
mmHg, or DBP >110 mmHg, or 
failure to achieve well-controlled 
BP within 2 weeks in scenario 
(A).  
Step 1.Consider reducing or interrupting pazopanib, as 
clinically indicated. 
Step 2. Adjust current or initiate new antihypertensive 
medication.                
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP.  
Step 4. Once BP is well-controlled, restart pazopanib dose-
reduced by 200 mg if it was interrupted. 
(C). Symptomatic hypertension 
or recurring SBP >170 mmHg, 
or DBP >110 mmHg, despite 
modification of antihypertensive 
medication(s) 
Step 1. Interrupt pazopanib.  
Step 2. Adjust current or initiate new antihypertensive 
medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2         
weeks as indicated to achieve well-controlled BP.  Referral to a 
specialist for further evaluation and follow-up is also 
recommended. 
Step 4. Once BP is well-controlled, restart pazopanib dose-
reduced by 200 mg. 
(D). Refractory hypertension 
unresponsive to above 
interventions. 
Discontinue pazopanib and continue follow-up per protocol. 
Proteinuria 
UPC <3 
Continue pazopanib at the current dose; monitor as clinically       
indicated 
UPC ≥3 or 24-h urine protein 
>3g 
Step 1. Interrupt pazopanib. 
Step 2. Weekly UPC or 24-hr urine protein monitoring until 


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AE Terms & Descriptions 
Dose Modification Algorithms 
UPC is <3 or 24-hr urine protein is <3 g.  Then restart 
pazopanib dose-reduced by 200 mg. 
Step 3.  If UPC ≥3 or 24-h urine protein 3g recurs, repeat 
steps 1 and 2 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the 
pazopanib dose can no longer be reduced, discontinue 
pazopanib and continue follow-up per protocol. 
Hemorrhage/Bleeding: Investigate and document underlying etiology of the bleeding 
Grade 1 
For hemoptysis, interrupt pazopanib and consider whether 
further treatment with pazopanib is appropriate. 
For other grade 1 hemorrhage/bleeding event, continue 
pazopanib at the current dose; monitor as clinically indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal 
bleeding), discontinue pazopanib and continue follow-up per 
protocol. Otherwise, interrupt pazopanib until the AE resolved 
to < grade 1.  
Step 2. Restart pazopanib; consider reducing dose and monitor 
as clinically indicated.  
Grade 3 or 4, or recurrent > 
grade 2 event after dose 
interruption/reduction. 
Discontinue pazopanib and continue with follow-up per 
protocol.  
   
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue pazopanib at the current dose; monitor as clinically 
indicated 
Grade 3   
 
Step 1. Interrupt pazopanib.  
Step 2. Initiate and monitor anticoagulation as clinically 
indicated.  
Step 3. Resume pazopanib at reduced dose only if all of the 
following criteria are met:  
 The subject must have been treated with anticoagulant at 
the desired level of anticoagulation for at least one week. 
 No grade 3 or 4 or clinically significant grade 2 
hemorrhagic events have occurred while on anticoagulation 
treatment. 
Subject should be monitored as clinically indicated during 
anticoagulation treatment and after resuming study treatment. 
When treating with warfarin, international normalized ratio 
(INR) should be monitored within three to five days after any 
change in pazopanib dosing (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 and/or PE 
Discontinue pazopanib and continue follow-up per protocol.  
Arterial Thrombosis/Ischemia 
 


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AE Terms & Descriptions 
Dose Modification Algorithms 
Any grade 
Discontinue pazopanib and continue follow-up per protocol.  
Thrombocytopenia: Investigate and document underlying cause 
Grade 1 or 2 
Continue pazopanib with current dose; monitor as clinically 
indicated.  
Grade 3 or 4 
Step 1. Interrupt pazopanib until toxicity resolves to < grade 2. 
Step 2. Restart pazopanib dose-reduced by 200 mg and monitor 
as clinically indicated.  
If no recovery to ≤ grade 2 or recurrent grade 3 or 4 
thrombocytopenia, discontinue pazopanib and follow-up per 
protocol 
Anemia:  No specific dose reduction rules are indicated for anemia unless due to hemorrhage or 
bleeding as noted above. 
 
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or 
dermatitis without pain 
(erythema, edema, 
hyperkeratosis) 
Continue pazopanib with current dose. 
Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily 
living (peeling, blisters, edema, 
bleed, hyperkeratosis) 
Step 1. Hold pazopanib. 
Step 2. Treat as clinically appropriate. 
Step 3. Upon resolution to grade 1 or better, restart pazopanib 
with a dose reduction to 400 mg. 
Step 4. If recurrent, consider a further dose reduction to 200 
mg or discontinuation. 
Grade 3 
Severe skin changes with pain 
and limiting self-care activities 
of daily living 
Discontinue pazopanib 
Other Clinically Significant Drug-Related Adverse Eventsb 
Grade 1 
Continue pazopanib; monitor as clinically indicated. 
Grade 2 or 3, if clinically 
significant  
Step 1. Interrupt pazopanib until toxicity resolves to < Grade 1. 
Step 2. Restart pazopanib dose-reduced by 200 mg and monitor 
as clinically indicated.  
Grade 4 
Discontinue pazopanib and continue follow-up per protocol.  
(study drug can be interrupted for up to 28 days)  
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to 
ensure accuracy of the reading.  The values below refer to manually-read ECGs. 
QTc > 480-500 msec 
Continue pazopanib; monitor as clinically indicated. 
QTc > 500 msec 
Discontinue pazopanib and continue follow-up per protocol. 
a. Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. 
b. AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI 
CTCAE v4) 
 
Guidelines for Management of Treatment Emergent Hepatotoxicity 


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


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Event 
Dose Modification Algorithms 
(D). ALT >3.0 x ULN with 
concomitant elevation in 
bilirubinb (defined as total 
bilirubin 2.0 x ULN; with 
direct bilirubin >35%) or with 
hypersensitivity symptoms (e.g., 
fever, rash).  
Liver Event Stopping Criteria: 
Step 1. Discontinue pazopanib immediately; report the event 
to Novartis as an SAE within 24 hours of learning of its 
occurrence.  Make every reasonable attempt to have subjects 
return to the clinic within 24 hours for repeat liver 
chemistries and liver event follow up assessments. 
Step 2. Consult a gastroenterologist / hepatologist and 
perform the following assessments to identify potential co-
factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, 
cytomegalovirus, Epstein-Barr virus (IgM antibody, 
heterophile antibody, or monospot testing)  
- Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies. 
- Serum creatinine phosphokinase for possible muscle 
injury caused LFT elevation 
- Liver imaging 
- Consider toxicological blood screen for possible 
contributing chemical/medical entities  
Step 3. Monitor subject closely for clinical signs and 
symptoms; record the appearance or worsening of clinical 
symptoms of hepatitis, or hypersensitivity, such as fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever rash or eosinophilia as relevant on the AE report form.  
Perform full panel LFTsa weekly or more frequently if 
clinically indicated until LFTs are reduced to grade 1.   
For isolated total bilirubinb 
elevation without concurrent 
ALT increases (defined as ALT 
< 3 X ULN). 
Step 1. Isolated hyperbilirubinemia (i.e., in the absence of 
elevated ALT or other signs/symptoms of liver injury) does 
not require dose modification.  Pazopanib inhibits UGT1A1 
and OATP1B1, which can cause elevation of indirect 
(unconjugated) bilirubin in the absence of liver injury. 
Step 2. If bilirubin is >1.5 x ULN in the absence of ALT 
elevation, fractionation of bilirubin elevation should be 
performed.  If bilirubin is >35% direct (conjugated), further 
evaluation for underlying cause of cholestasis should be 
performed. 
a. Full panel LFTs include: AST, ALT, alkaline phosphatase, and total bilirubin.  Coagulation 
tests should be performed as clinically indicated. 
b. Serum bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable and a subject meets the criterion of total bilirubin >1.5 x ULN, then the event 
should be promptly reported as an SAE. 
 
Please see Section 7.8 for adverse event reporting instructions for hepatotoxicity. 
 


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7.0 
REGULATORY AND REPORTING REQUIREMENTS 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as 
outlined in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in 
Section 7.4.  In addition, any fatal or life-threatening adverse experiences where there is a 
reasonable possibility of relationship to study intervention must be reported. 
 
Novartis requires that all serious adverse events be reported as outlined in Section 7.9. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including 
any abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for 
the terms listed that should be used are those provided by the Department of 
Health and Human Services’ Office for Human Research Protections (OHRP).  
A copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in 
any of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 


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Page 25 of 52 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is 
not consistent with the current investigator brochure (or risk information, if an IB 
is not required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of 
the investigator) at immediate risk of death from the reaction as it occurred, i.e., 
it does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
 related or possibly related to participation in the research (“possibly 
related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and 
 suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies 
that govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 


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Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the rights 
or welfare of participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a 
singular situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the 
event.  For secondary sites, the Washington University PI will issue approval of 
the exception, but it must also be submitted to the local IRB with documentation 
of approval forwarded to Washington University.  Washington University IRB 
approval is not required for protocol exceptions occurring at secondary sites. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct 
of the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event.  The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the 
occurrence of the event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU 
or any BJH or SLCH institution that has been reported to and acknowledged by HRPO 
as reportable.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email 
to a QASMC auditor. 
 


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7.4 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 
7.6) within 1 working day of the occurrence of the event or notification of the 
secondary site’s PI of the event.  This notification may take place via email if there is 
not yet enough information for a formal written report (using either an FDA MedWatch 
form if required or an institutional SAE reporting form if not).  A formal written report 
must be sent to the Washington University PI and research coordinator within 10 
working days of the occurrence of the event or notification of the secondary site’s PI of 
the event.  The death of a research participant that qualifies as a reportable event should 
be reported within 1 working day of the occurrence of the event or notification of the 
secondary site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines. 
The research team at Washington University is responsible for reporting all applicable 
events to the FDA. 
 
7.5 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each 
secondary site of all reportable events that have occurred at other sites within 10 
working days of the occurrence of the event or notification of the PI of the event.  This 
includes events that take place both at Washington University and at other secondary 
sites, if applicable. 
 
7.6 
Reporting to Novartis 
 
A serious adverse event (SAE) is an undesirable sign, symptom or medical condition 
which: 
 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 


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 is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 
 
The principal investigator has the obligation to report all serious adverse events to the 
IRB and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E) 
(For patients taking Pazopanib / Novartis drugs). 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 
 after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and 30 days after the patient has stopped study 
treatment 
 after the start of any period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g., treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication) 
and until 30 days after the patient has stopped study treatment 
 
All Events must be reported to Novartis within 24 hours of learning of its occurrence. 
Information about all SAEs is collected and recorded on a Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of 
each SAE to each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form in English, and send the completed, signed form by fax 
to (fax: 877-778-9739) within 24 hours to the oncology Novartis DS&E department 
with the provided FAX cover sheets. 
 
This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days 
following completion of active protocol therapy must be reported within 5 working 
days. 
 
Any SAEs experienced after this 30 day period should only be reported to Novartis if 
the investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. 
A SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.  The 
end date of the first event must be provided. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
 


Amendment 4; Version 06/04/18 
 
Page 29 of 52 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind 
was broken or not (if applicable), and whether the patient continued or withdrew from 
study participation. 
 
If the SAE is not previously documented in the Pazopanib Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, 
a DS&E associate may urgently require further information from the investigator for 
Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), 
to inform all investigators involved in any study with the same drug that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
 
7.7 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment.  
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Pazopanib 
 
8.1.1 Pazopanib Description 
 
GW786034 (pazopanib) is a vascular endothelial growth factor (VEGF) receptor 
tyrosine kinase inhibitor (TKI) manufactured by Novartis for oncology 
indications (as an oral formulation) and for ophthalmology indications (eye drops 
and low dose oral). Pazopanib has been approved by the U.S. Food and Drug 
Administration (FDA) for the treatment of patients with advanced renal cell 
carcinoma (RCC) (New Drug Application [NDA] #022465). 
 
Chemical Name: 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2- 
pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride 
 
Molecular Formula: C21H23N7O2S • HCl 
Molecular Weight: 473.99 g/mol (monohydrochloride salt); 437.53 g/mol (free 
base) 


Amendment 4; Version 06/04/18 
 
Page 30 of 52 
 
8.1.2 Pharmacokinetics and Drug Metabolism 
 
Pazopanib is absorbed orally with median time to achieve peak concentrations of 
2 to 4 hours after the dose.  Daily dosing at 800 mg results in geometric mean 
AUC and Cmax of 1,037 mcg·hr/mL and 58.1 mcg/mL (equivalent to 132 µM), 
respectively. 
 
8.1.3 Supplier(s) 
 
Pazopanib will be provided to the sites by Novartis Pharmaceuticals Corporation 
using a separate drug supply request form.   
 
8.1.4 Dosage Form and Preparation 
 
Pazopanib is supplied as 200 mg and/or 400 mgtablets.  Tablets are packaged in 
a sealed bottle with an affixed content label identifying the product. 
 
8.1.5 Storage and Stability 
 
Store at room temperature between 20°C and 25°C; excursions permitted to 15°C 
to 30°C. 
 
8.1.6 Administration 
 
Pazopanib should be taken orally without food at least one hour before or two 
hours after a meal.  Dosing will be as described in Section 5.1. 
 
8.1.7 Safety Information 
 
Information on safety, side effects and adverse events can be found in the most 
current Pazopanib Investigator Brochure. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Quality of Life 
 
Quality of life will be measured using the FACT-G7 validated survey (Appendix D) at 
baseline, C1D15, and on Day 1 of each cycle. 
 
 
 


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9.2 
Biomarkers 
 
Fill 3 red top SST (Tiger) tubes (8.5 mL each) with blood to measure levels of 
sVEGFR2 and PIGF at the following time points: 
 Baseline 
 C2D1 
 C3D1 
 C4D1 
 
Invert the tubes gently 10 times.  Let the tubes stand at room temperature to coagulate 
for 30-60 minutes.  Centrifuge within one hour of collection at 1600g for 15 
minutes.  Store tubes at -70°C or cooler until shipment.   
 
SHIP FROZEN IN BATCHES TO: 
Dr. Brian Van Tine – Research lab 
4515 McKinley Building, 3rd Floor 
4523 Clayton Avenue 
St. Louis, MO 63110 
 
9.3 
Pharmacokinetics 
 
Twenty mL of blood will be drawn at the following time points to measure plasma 
pazopanib concentrations: 
 Baseline (prior to initiation of treatment) 
 Cycle 1 Day 5 (prior to escalation to 400 mg BID) 
 Cycle 1 Day 9 (prior to escalation to 800 mg QD) 
 Cycle 2 Day 1 
 
Blood should be collected in 2 EDTA purple top tubes and 1 red top tube.  DNA (for 
future use), serum, and whole cells should be prepared and frozen down prior to 
shipment using standard laboratory techniques.  Samples should be labeled with the 
corresponding patient’s study ID number, initials, and date of collection.   
 
These PKs will only be performed in the first 11 patients enrolled at Washington 
University. This testing was completed as of amendment 4.  
 
SHIP FROZEN IN BATCHES TO: 
Dr. Brian Van Tine – Research lab 
4515 McKinley Building, 3rd Floor 
4523 Clayton Avenue 
St. Louis, MO 63110 
 
 
 


Amendment 4; Version 06/04/18 
 
Page 32 of 52 
 
10.0 
STUDY CALENDAR 
 
Screening assessments must be performed no more than 14 days prior to start of study 
treatment, except scans which may take place up to 28 days prior to the start of treatment. After 
the start of study treatment, there is a ± 7 day window for all exams, scans, labs and procedures 
to be performed. Please note, there is also a ± 7 day window for treatment and for routine office 
visits. 
 
 
Screening 
D1 of 
each 
cycle 
C1D5 
C1D8 
C1D9 
C1D15 
and 
C2D15 
End of every 
even-
numbered 
cycle 
EOT 
F/U1 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
PE, H&P, PS 
X 
X 
 
 
 
 
 
X 
 
VS 
X 
X 
 
X 
 
 
 
X 
 
CBC 
X 
X 
 
X 
 
 
 
X 
 
CMP 
X 
X 
 
X 
 
 
 
X 
 
LFTs2 
X 
X2 
 
X2 
 
X2 
 
X 
 
Pregnancy test3 
X 
 
 
 
 
 
 
X 
 
UPC 
X 
X4 
 
 
 
 
 
X 
 
TSH, FT4 
X 
X5 
 
 
 
 
 
 
 
PT/PTT, INR 
X 
 
 
 
 
 
 
X 
 
ECG 
X 
X6 
 
 
 
 
 
 
 
ECHO10 
X 
 
 
 
 
 
 
 
 
CT scan 
X 
 
 
 
 
 
X 
X 
 
Pazopanib 
 
X ------------------------------------------------------- X7 
 
 
FACT-G 
 
X8 
 
 
 
X8 
 
 
 
Blood for 
biomarkers 
 
X9 
 
 
 
 
 
 
 
Collect/review 
drug diary 
 
X 
 
 
 
 
 
 
 
Toxicity 
assessment 
X 
X 
 
 
 
 
 
X 
 
1. Every 3 months until death. 
2. Monitor serum liver tests (total bilirubin, ALT/AST) before initiation of treatment with pazopanib and on 
C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, and as clinically indicated (± 3 days).  Periodic monitoring should 
continue after C5. 
3. Women of childbearing potential only. 
4. D1 of each cycle through C6, then D1 of every even-numbered cycle thereafter. 
5. Monitor between every 8 to every 16 weeks. 
6. C2D1, C4D1, C7D1, and then every 16 weeks (D1 of every 4th cycle) until EOT. 
7. To be taken PO each day. Each cycle is 4 weeks long.  See Section 5.1 for dosing instructions. 
8. Baseline (prior to C1D1), C1D15, and D1 of every cycle thereafter. 
9. Baseline (prior to C1D1), C2D1, C3D1, and C4D1. 
10. Baseline (prior to C1D1) and periodic reassessment as needed and/or as indicated. Consistent diagnostic 
imaging should be used throughout study. 
 
11.0 
DATA SUBMISSION SCHEDULE 


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Page 33 of 52 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Pill Diary 
Every cycle 
QOL Form 
Baseline 
C1D15 
Day 1 of every cycle thereafter 
Correlatives Form 
Baseline 
C1D5 
C1D9 
C2D1 
C3D1 
C4D1 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 3 months until death 
Tumor Measurement Form 
Baseline, end of every even numbered 
cycle, and end of treatment 
MedWatch Form 
See Section 7.0 for reporting 
requirements 
 
Any queries generated by Washington University must be responded to within 28 days of 
receipt by the participating site.  The Washington University research team will conduct a 
regular review of data status at all secondary sites, with appropriate corrective action to be 
requested as needed. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response 8 weeks after 
initiation of pazopanib and then every 8 weeks thereafter.  In addition to a baseline scan, 
confirmatory scans should also be obtained not less than 8 weeks following initial 
documentation of objective response. 
 
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 


Amendment 4; Version 06/04/18 
 
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diameter (unidimensional measurement) of the tumor lesions and the shortest diameter 
in the case of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
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 >20 mm by 
chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >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.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  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, but 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. 
 


Amendment 4; Version 06/04/18 
 
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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.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 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).   
 
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, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if possible. 
 


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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.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
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. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use 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). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
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:  
 


Amendment 4; Version 06/04/18 
 
Page 37 of 52 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
 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. 
 FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific 
medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET 
and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the 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. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 


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normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they 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) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 


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Page 39 of 52 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
 
                                      
    For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘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 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
12.4.5 Progression-Free Survival 
 
Progression-free survival is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. 
 
12.4.6 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) 
independent of the study at the study’s completion.  


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13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Data and Safety Monitoring Committee (DSMC) will meet to review toxicity data at least 
every 6 months following the activation of the first secondary site.  The report will be prepared 
by the statistician with assistance from the study team and will be submitted to the Quality 
Assurance and Safety Monitoring Committee (QASMC).  This report will include: 
 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date and accrual by site 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
 Summary of toxicities at all participating sites 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to 
be prepared by the study team will be submitted to the QASM Committee beginning 6 months 
after study activation at Washington University. 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC 
according to institutional guidelines. 
 
A DSMC will consist of no fewer than 3 members including 2 clinical investigators and a 
biostatistician.  Like investigators, DSMC members are subject to the Washington University 
School of Medicine policies regarding standards of conduct. Individuals invited to serve on the 
DSMC will disclose any potential conflicts of interest to the trial principal investigator and/or 
appropriate university officials, in accordance with institution policies. Potential conflicts that 
develop during a trial or a member’s tenure on a DSMC must also be disclosed.  


Amendment 4; Version 06/04/18 
 
Page 42 of 52 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources
/Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf 
 
14.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by 
Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing 
mechanism in place and can provide a report. The outside sites will be asked to send copies of 
all audit materials, including source documentation.  The audit notification will be sent to the 
Washington University Research Patient Coordinator, who will obtain the audit materials from 
the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the 
audit. Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list 
of the cases selected for review (up to 10 for each site) will be sent to the research team. 
However, if during the audit the need arises to review cases not initially selected, the research 
team will be asked to provide the additional charts within two working days. 
 
Additional details regarding the Auditing Policies and procedures can be found at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources
/Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurcance.pdf  
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Sample Size 
 
This is a single arm phase II trial. A single-stage design requires a total of 56 eligible 
patients to be enrolled in order to provide 81.64% power to test the desired 16 week 
clinical benefit rate (CBR) > 35% against an unfavorable CBR < 20% based on the exact 
binomial method at 5% significance level (actual significance level = 4.32%).  Clinical 
benefit rate is defined as CBR = CR + PR + SD lasting ≥ 16 weeks.  If 17 or more 
patients benefit at the end of the trial, the treatment regimen yields a higher clinical 
benefit rate and warrants further investigation.  
 
15.2 
Statistical Analysis 
 
Clinical benefit rate will be calculated with 95% confidence interval (CI) based on the 
Wilson score method and compared to the pre-specified unfavorable CBR of 20% based 
on one-sided exact binomial test.  The serum levels of sVEGFR2 and PIGF at each time 
point will plotted and Pearson or Spearman's correlation coefficient will be calculated to 
explore their relationship. PFS and OS in the overall cohort of patients and by 
dichotomized sVEGFR2, PIGF and their combinations at each time point will be 


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analyzed and plotted by the Kaplan-Meier method with 95% CI. PFS and OS 
probabilities, overall and by group will be reported with 95% CI at desired time point. 
Cox proportional hazard model will be used to report resulting hazard ratio and Wald 
test P-values on sVEGFR2 and PIGF in continuous format. 
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent 
document to be reviewed and approved by the Washington University Regulatory Coordinator 
(or designee) prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a 
minimum, each participating institution must have the following documents on file at 
Washington University prior to study activation: 
 
 Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
 Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including 
the Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
 Documentation of FWA, signed FDA Form 1572 (if applicable), and signed and 
dated the CVs of all participating investigators. 
 Protocol signature page signed and dated by the investigator at each participating 
site. 
 
The coordinating center is responsible for disseminating to the participating sites all study 
updates, amendments, reportable adverse events, etc.  Protocol/consent modifications and IB 
updates will be forwarded electronically to the secondary sites within 4 weeks of obtaining 
Washington University IRB approval.  Activated secondary sites are expected to submit 
protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt, unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of 
such shall be sent to the Washington University study team within 2 weeks of receipt of 
approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions 
must be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


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17.0 
REFERENCES 
 
1. 
Wilky BA, Meyer CF, Trent JC. Pazopanib in sarcomas: expanding the PALETTE. Curr 
Opin Oncol 2013; 25(4): 373-8. 
2. 
Verweij J, Lee SM, Ruka W, et al. Randomized phase II study of docetaxel versus 
doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue 
sarcomas in adults: a study of the european organization for research and treatment of cancer 
soft tissue and bone sarcoma group. J Clin Oncol 2000; 18(10): 2081-6. 
3. 
Hamberg P, Verweij J, Sleijfer S. (Pre-)clinical pharmacology and activity of pazopanib, 
a novel multikinase angiogenesis inhibitor. Oncologist 2010; 15(6): 539-47. 
4. 
Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis 
inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study 
from the European organisation for research and treatment of cancer-soft tissue and bone 
sarcoma group (EORTC study 62043). J Clin Oncol 2009; 27(19): 3126-32. 
5. 
van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue 
sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 
2012; 379(9829): 1879-86. 
6. 
Sleijfer S, Gorlia T, Lamers C, et al. Cytokine and angiogenic factors associated with 
efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: an EORTC-STBSG study. 
Br J Cancer 2012; 107(4): 639-45. 
 
 
 
 


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


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APPENDIX B: New York Heart Association (NYHA) Functional Classification 
 
NYHA Class 
Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, e.g., shortness of 
breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20-100 m). Comfortable only at rest. 
IV 
Severe limitations.  Experiences symptoms even while at rest.  Mostly 
bedbound patients. 
 
The Criteria Committee of the NYHA, Nomenclature and Criteria for Diagnosis of Diseases of 
the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
 
 


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APPENDIX C: Medication Diary – Cycle 1 
 
Today’s Date:    
 
 
 
Cycle 1  
 
Agent:  Pazopanib 
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID# 201501057 
 
1. Take pazopanib by mouth under fasting conditions (at least one hour before or two hours after a 
meal). 
2. Take pazopanib with a glass of water and drink the glass of water in as little time as possible. 
3. Record the date, time and amount of drug taken. Write “1-200mg”, “2-200mg”, “3-200mg”, or “4-
200mg.” 
4. If you forgot to take your dose, do not take that dose. Restart pazopanib at the next scheduled 
dose. 
5. If you vomit or notice any side effects, list in the comments section. Do not re-take a dose after 
vomiting. 
6. Return this form and used pill bottles to your study coordinator when you go to your next 
appointment. 
 
Important Dosing Instructions:  Slowing increase the dose when you first start taking pazopanib. 
First 4 days (Cycle 1, Days 1-4): Take one 200-mg pill in the morning, and one 200-mg pill in 
the evening. 
Next 4 days (cycle 1, Days 5-8): Take two 200-mg pills in the morning, and two 200-mg pills in 
the evening. 
Cycle 1, Day 9 and beyond:        Take four 200-mg pills in the morning. Do not take drug in the 
evening. 
Dose changes:  If you experience side effects, you may be asked to discontinue or reduce the 
dose. 
 
Day 
Date 
Morning 
Evening 
Comments 
Pill # and 
mg 
Time 
Taken 
Pill # and 
mg 
Time 
Taken 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 


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24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
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27 
 
 
 
 
 
 
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APPENDIX D: Medication Diary – Cycle 2 & Beyond (200 mg) 
 
Today’s Date:    
 
 
 
Cycle:_____ 
 
Agent:  Pazopanib 
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID# 201501057 
 
1. Take pazopanib by mouth under fasting conditions (at least one hour before or two hours after a 
meal). 
2. Take pazopanib with a glass of water and drink the glass of water in as little time as possible. 
3. Record the date, time and amount of drug taken. Write “4-200mg”, “3-200mg”, “2-200mg” or “1-
200mg.” 
4. If you forgot to take your dose, do not take that dose. Restart pazopanib at the next scheduled 
dose. 
5. If you vomit or notice any side effects, list in the comments section. Do not re-take a dose after 
vomiting. 
6. Return this form and used pill bottles to your study coordinator when you go to your next 
appointment.  
 
Important Dosing Instructions:  Take ____ 200-mg pills in the morning or appropriate dose as 
instructed by physician. 
Do not take drug in the evening. 
Dose changes:  If you experience side effects, you may be asked to discontinue or reduce the dose. 
 
Day 
Date 
Morning 
Comments 
Pill # and 
mg 
Time 
Taken 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 


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Medication Diary – Cycle 2 & Beyond (200 mg and/or 400 mg) 
 
Today’s Date:   
 
 
 
 
Cycle:_____ 
 
Agent:  Pazopanib 
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID# 201501057 
 
1. Take pazopanib by mouth under fasting conditions (at least one hour before or two hours after a meal). 
2. Take pazopanib with a glass of water and drink the glass of water in as little time as possible. 
3. Record the date, time and amount of drug taken. Write  “2-400mg” or 3-200mg, 2-200mg or 1-200mg. 
4. If you forgot to take your dose, do not take that dose. Restart pazopanib at the next scheduled dose. 
5. If you vomit or notice any side effects, list in the comments section. Do not re-take a dose after vomiting. 
6. Return this form and used pill bottles to your study coordinator when you go to your next appointment.  
 
Important Dosing Instructions:  Take _____ 400-mg pills and _____ 200-mg pills in the morning. Do not take 
drug in the evening. 
Dose changes:  If you experience side effects, you may be asked to discontinue or reduce the dose. 
 
Day 
Date 
Morning 
Comments 
Pill # and mg 
Time Taken 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
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APPENDIX E: FACT-G7 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
GE6 
I worry that my condition will get worse .......................... 
0 
1 
2 
3 
4 
GF5 
I am sleeping well ............................................................. 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ....................................................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ........... 
0 
1 
2 
3 
4 
  
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy ..................................................... 
0 
1 
2 
3 
4 
GP4 
I have pain ........................................................................ 
0 
1 
2 
3 
4 
GP2 
I have nausea .................................................................... 
0 
1 
2 
3 
4