Clinical trial NCT02193152
Conditions: Carcinoma, Non-Small Cell Lung Non-Small Cell Lung Cancer Nonsmall Cell Lung Cancer
Keywords: Advanced Non-Small Cell Lung Cancer NSCLC Pazopanib
Sponsor: Washington University School of Medicine
Start date: 2015-04-27; Completion date: 2019-12-24
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate how participants with advanced non-small cell lung cancer (NSCLC) that have certain abnormalities in the pazopanib target genes respond to pazopanib treatment.

Detailed description:
There has been a limited benefit from anti-angiogenesis drugs in patients with NSCLC. Bevacizumab provides a modest survival improvement when added to chemotherapy and VEGFR tyrosine kinase inhibitors have been associated with minimal efficacy as single agents and increased toxicity when combined with chemotherapy. We postulate that the response rates and survival may be improved with a better selection of patients based on abnormalities of the targets for the drugs. According to the preliminary data from the cancer genome atlas (TCGA), the targets of pazopanib are altered in 28% of patients with adenocarcinoma and 24% of patients with squamous cell lung cancer. Since, despite the molecular selection prior to treatment, only a small percentage of patients will benefit from the treatment, we plan to further investigate those patients with whole exome sequencing in both the pre-treatment samples to identify the predictors for response and at the time of progression, with repeated biopsy, in an attempt to identify the predictors for secondary resistance. By identifying more reliable predictors for response to pazopanib, our study may help to establish its role in the treatment of NSCLC.

Arms: arm 1: Pazopanib 800 mg daily 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 documents:
Prot_SAP_000.pdf: 
Protocol Version: 02/01/18 
 
Page 1 of 48 
 
 
 
 
A Pilot Study of Pazopanib in Molecularly Selected Patients with Advanced Non-Small Cell 
Lung Cancer (NSCLC) 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201408009  
Version Date: 02/01/18 
 
 
Principal Investigator: 
Daniel Morgensztern, M.D. 
Phone:  (314) 362-5737 
E-mail:  danielmorgensztern@wustl.edu 
 
Sub-Investigators 
 
 
Modality 
Ramaswamy Govindan, M.D. 
Medical Oncology 
Maria Baggstrom, M.D. 
 
Medical Oncology 
Saiama Waqar, M.D.  
 
Medical Oncology 
Feng Gao, M.D., Ph.D. 
 
Biostatistics 
 
 
Study Drug:  
 
Pazopanib (GW786034, Votrient) 
IND #: 
 
 
123480 EXEMPT 
Clinical Trials.gov #: 
NCT02193152 
 
 
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 Pilot Study of Pazopanib in Molecularly Selected Patients with Advanced Non-Small Cell 
Lung Cancer (NSCLC) 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
08/21/2014 
Amendment #1 Version 
 
 
 
 
 
 
08/25/2014 
Amendment #2 Version 
 
 
 
 
 
 
02/26/2015 
Amendment #3 Version 
 
 
 
 
 
 
06/18/2015 
Amendment #4 Version 
 
 
 
 
 
 
01/13/2016 
Amendment #5 Version 
 
 
 
 
 
 
11/09/2016 
Amendment #6 Version 
 
 
 
 
 
 
02/01/2018 
 
 


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Glossary of Abbreviations 
 
ADL 
Activities of daily living 
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) 
ATP 
Adenosine triphosphate 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
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 
DSM 
Data and Safety Monitoring  
DVT 
Deep venous thrombosis 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
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 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PR 
Partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 


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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 
TCGA 
The Cancer Genome Atlas 
TKI 
Tyrosine kinase inhibitor 
TSH 
Thyroid stimulating hormone 
UPC 
Urine protein creatinine 
UPN 
Unique patient number 
VEGF 
Vascular endothelial growth factor 
 
 


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Table of Contents 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 7 
1.1 
Non-Small Cell Lung Cancer ........................................................................................... 7 
1.2 
Angiogenesis .................................................................................................................... 7 
1.3 
Pazopanib ......................................................................................................................... 8 
1.4 
Next Generation Sequencing ............................................................................................ 8 
1.5 
Rationale........................................................................................................................... 8 
1.6 
Correlative Studies ........................................................................................................... 9 
2.0 
OBJECTIVES .................................................................................................................... 10 
2.1 
Primary Objectives ......................................................................................................... 10 
2.2 
Secondary Objectives ..................................................................................................... 10 
3.0 
PATIENT SELECTION .................................................................................................... 10 
3.1 
Inclusion Criteria ............................................................................................................ 10 
3.2 
Exclusion Criteria ........................................................................................................... 11 
3.3 
Inclusion of Women and Minorities............................................................................... 13 
4.0 
REGISTRATION PROCEDURES ................................................................................... 13 
4.1 
Confirmation of Patient Eligibility ................................................................................. 13 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 14 
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 ............................................... 23 
7.1 
Definitions ...................................................................................................................... 23 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
………………………………………………………………………………………….25 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 25 
7.4 
Reporting to Novartis ..................................................................................................... 26 
7.5 
Timeframe for Reporting Required Events .................................................................... 28 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 28 
8.1 
Pazopanib ....................................................................................................................... 28 
9.0 
CORRELATIVE STUDIES .............................................................................................. 29 
9.1 
Tumor Tissue for Research ............................................................................................ 29 
10.0 STUDY CALENDAR ....................................................................................................... 31 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 32 
12.0 MEASUREMENT OF EFFECT........................................................................................ 32 
12.1 Antitumor Effect – Solid Tumors................................................................................... 32 
12.2 Disease Parameters ......................................................................................................... 32 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 33 
12.4 Response Criteria ........................................................................................................... 36 
13.0 DATA AND SAFETY MONITORING ............................................................................ 38 


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14.0 STATISTICAL CONSIDERATIONS............................................................................... 39 
14.1 Study Objectives and Endpoints .................................................................................... 39 
14.2 Study Design and Analyses ............................................................................................ 39 
15.0 REFERENCES .................................................................................................................. 41 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 43 
APPENDIX B: New York Heart Association (NYHA) Functional Classification ...................... 44 
APPENDIX C: Medication Diary ................................................................................................. 45 
APPENDIX D: Investigator Sponsored Study (ISS) Drug Supply Request Form ....................... 46 
APPENDIX E: SAE Fax Cover Sheet-Suspected/Unknown ........................................................ 47 
APPENDIX F: SAE Fax Cover Sheet-Not Suspected .................................................................. 48 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Non-Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer related death in both men and women in the 
United States.19 Over 200,000 patients are diagnosed with lung cancer every year in the 
United States. More than 80% of these patients have non-small cell lung cancer (NSCLC) 
and over half of them present with advanced stage disease at the time of diagnosis.  
Platinum based chemotherapy remains the mainstay of first line treatment for patients 
with advanced stage NSCLC. In a prospective randomized study that compared four 
commonly used platinum-based chemotherapy regimens for patients with stage IIIB or 
stage IV disease: cisplatin plus paclitaxel, cisplatin plus gemcitabine, cisplatin plus 
docetaxel, and carboplatin plus paclitaxel, no regimen was found to have a significantly 
better response rate or survival time.20 The response rate for all 1,158 of the eligible 
patients was 19%, and the median survival time was 7.9 months (95% CI, 7.3-8.5 
months). The results from this study indicate that the combination of platinum with third 
generation chemotherapeutic agents (paclitaxel, docetaxel, vinorelbine, gemcitabine) has 
limited benefit in the treatment of patients with metastatic NSCLC.  Unfortunately 
treatment benefit from 1st line cytotoxic chemotherapy is usually short lived with a 
median time to progression of 3 to 5 months. However, only a limited number of options 
are available for second line treatment. Therefore it is essential to develop effective 
second line treatment options for patients with relapsed/refractory NSCLC. Many 
patients with relapsed/refractory NSCLC also have marginal performance status and it is 
important to develop therapies that are tolerable. 
 
1.2 
Angiogenesis 
 
Angiogenesis, an essential step for tumor growth and progression is defined as the growth 
of new blood vessels from existing vasculature.1 Due to its critical role in several tumors 
including NSCLC, its inhibition represents a rational therapeutic strategy. VEGF is key 
ligand and regulator of both physiological and pathological angiogenesis, including from 
tumors, with the signaling occurring mostly through VEGFR2.2 The two main 
mechanisms of VEGF inhibition are the use of monoclonal antibodies against circulating 
VEGF and small molecules that inhibit its tyrosine kinase activity. Bevacizumab, a 
humanized monoclonal antibody against circulating VEGF was the first antiangiogenic 
drug to be approved for NSCLC, with its use restricted to patient with non-squamous 
histology due to the increased risk of life-threatening bleeding in squamous cell 
carcinoma.3 Two randomized clinical trials, Eastern Cooperative Oncology Group 
(ECOG) 4599 and Avastin in Lung (AVAiL), comparing chemotherapy alone or with 
bevacizumab, showed improved response rate and progression-free survival (PFS) for the 
combination therapy.4,5 However, only the ECOG 4599 study showed a survival benefit. 
VEGFR tyrosine kinase inhibitors (TKIs) compete with adenosine triphosphate (ATP) for 
the active site of the kinase domain. Due to the well-conserved ATP binding site of the 
kinases, most VEGFR TKIs inhibit multiple receptors including PDGFR and KIT.6,7 
Several VEGFR TKIs have been tested in unselected patients with NSCLC. Although 


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well tolerated as single agents, the response rates have been disappointing.8-10 
Furthermore, the addition of VEGFR TKIs to chemotherapy was generally associated 
with increased toxicity without a survival benefit.11-13 Additionally, recently published 
research shows that expression of VEGF-A correlated with mutations in TP53, 
suggesting that TP53 mutational status may also play a role in response to antiangiogenic 
therapies.14,15 
 
PDGF promotes tumor cell proliferation, invasion, migration and angiogenesis.16 The 
PDGF pathway plays a significant role in angiogenesis through its effects on pericytes 
and vascular smooth muscle cells, which in turn secrete VEGF.17 This signaling 
cooperation could be explored with a dual inhibitor. One of the major obstacles for 
further development of anti-angiogenesis inhibitors is the lack of reliable predictors for 
response. We believe that with the use of a potent single agent TKI against VEGFR and 
PDGFR in a molecularly selected patient population may lead to a significant benefit in 
some patients and further evaluation of responders with a comprehensive molecular 
profile both at diagnosis and at progression, may provide valuable information predictors 
for response and mechanisms of resistance.  
 
1.3 
Pazopanib 
 
Pazopanib is a potent inhibitor of VEGFR1-3, PDGFRA, PDGFRB and KIT, with a 
broad in vivo antitumor activity.18 In the phase I study, pazopanib was well tolerated in 
63 patients with advanced cancer.19 The maximum tolerated dose (MTD) was not 
determined, with hypertension as the most common grade 3 toxicity. The recommended 
phase 2 dose was 800 mg daily. Among the five patients with lung cancer, one patient 
achieved a prolonged disease stabilization lasting 13.6 months. 
 
1.4 
Next Generation Sequencing 
 
It is a standard of care at Washington University School of Medicine to do next-
generation sequencing in the tumor specimens from patients with metastatic NSCLC and 
at the time of disease progression when feasible following targeted therapies.  Next 
generation sequencing involves targeted exon sequencing of ‘clinically significant’ 
cancer genes using next-generation sequencing technology. 
 
1.5 
 Rationale 
 
There has been a limited benefit from anti-angiogenesis drugs in patients with NSCLC. 
Bevacizumab provides a modest survival improvement when added to chemotherapy and 
VEGFR tyrosine kinase inhibitors have been associated with minimal efficacy as single 
agents and increased toxicity when combined with chemotherapy. We postulate that the 
response rates and survival may be improved with a better selection of patients based on 
abnormalities of the targets for the drugs. Since, despite the molecular selection prior to 
treatment, only a small percentage of patients will benefit from the treatment, we plan to 
further investigate those patients with whole exome sequencing in both the pre-treatment 
samples to identify the predictors for response and at the time of progression, with 


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repeated biopsy, in an attempt to identify the predictors for secondary resistance. By 
identifying more reliable predictors for response to pazopanib, our study may help to 
establish its role in the treatment of NSCLC. 
 
1.6 
Correlative Studies 
 
Patients enrolled in this study will undergo  optional next generation sequencing of tumor 
samples taken prior to treatment and at the time of disease progression. Archived 
formalin fixed paraffin embedded (FFPE) samples must have adequate viable cells for 
next generation sequencing to be performed.  This routine sequencing involves targeted 
exon sequencing of “clinically significant” cancer genes, and allows for targeted “deep” 
sequencing to detect single nucleotide variants, copy number variants, and structural 
variations which are frequently associated with mutated solid and hematological 
genomes.  The assay interrogates the exon sequences of a number of genes that have been 
selected based on current sequencing test order patterns by oncologists or literature-based 
knowledge of known clinical relevance to specific tumor types. 
  
The genomic landscape of cancer is complex and evolves through the process of clonal 
evolution innately and in response to treatment. Unbiased whole exome and 
transcriptome sequencing performed on tumor samples at time of diagnosis in responders 
and non-responders will help us identify unique variations that confer susceptibility to 
pazopanib. Moreover, genomic analysis at time of progression after treatment with 
pazopanib (after response lasting for 6 months or longer) will provide some unique 
insights into mechanisms underlying acquired resistance. 
 
 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. To evaluate the response rates by RECIST 1.1 for patients with advanced NSCLC 
with mutations in the target genes for pazopanib. 
2. To evaluate progression-free survival for patients with advanced NSCLC with 
mutations in the target genes for pazopanib. 
 
2.2 
Secondary Objectives 
 
1. To correlate outcomes with specific mutations. 
2. To further evaluate extreme responders with whole genome and transcriptome 
sequencing. 
3. To evaluate the mechanisms of secondary resistance. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically confirmed diagnosis of advanced (metastatic or unresectable) non-
small cell lung cancer (NSCLC) with mutations, rearrangement and fusion involving 
RET oncogene, or abnormalities in the pazopanib target genes defined as VEGFR1-3, 
PDGFRA, PDGFRB, or TP53 with abnormalities including deletion, insertion, early 
stop codon, and/or nonsynonymous mutations with functional consequences.  CLIA 
certified lab testing for pazopanib target genes using cell free DNA from peripheral 
blood and/or assays performed on tumor tissues are acceptable.  
 
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. Failed at least one standard chemotherapeutic treatment for NSCLC. 
 
4. At least 18 years of age. 
 
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 


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d. PT or INR ≤ 1.2 x IULN 
e. aPTT ≤ 1.2 x IULN 
f. Total bilirubin ≤ 1.5 x IULN 
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 or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine dipstick for 
renal function assessment is not acceptable. 
 
 
7. Patients receiving anticoagulation therapy are eligible if their INR is stable and within 
the recommended range for the desired level of anticoagulation. 
 
8. Ability to swallow and retain oral tablets. 
 
9. Women of childbearing potential and men 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. 
 
10. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
3.2 
Exclusion Criteria 
 
1. Treatment with any of the following anti-cancer therapies: 
a. Radiation therapy, surgery, or tumor embolization within 14 days prior to the first 
dose of pazopanib OR 
b. Chemotherapy, immunotherapy, investigational therapy or hormonal therapy 
within 14 days prior to the first dose of pazopanib. 
 
2. Prior treatment with any VEGFR tyrosine kinase inhibitor. 
 
3. Administration of any non-oncologic investigational drug within 30 days or 5 half-
lives (whichever is longer) prior to the first dose of pazopanib. 
 
4. Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study 
treatment (please refer to Section 5.2.5). 
 
5. 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. 
 
6. Symptomatic brain metastases.  Patients with known brain metastases are allowed if 
they are asymptomatic. 


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7. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to pazopanib or other agents used in the study. 
 
8. Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is 
progressing in severity (except alopecia). Any IO related adverse events must be        
≤ grade 1 to be eligible.  
 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, uncontrolled seizure disorder, chronic underlying liver disease unrelated to 
cancer, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
10. Corrected QT interval (QTc) > 480 msecs. 
 
11. 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). 
 
12. Poorly controlled hypertension (defined as systolic blood pressure of ≥ 160  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. 
 
13. 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. 
 
14. 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. 
 
15. History of cerebrovascular accident including transient ischemic attack, pulmonary 
embolism (including asymptomatic or previously treated PE), or untreated deep 
venous thrombosis within the past 6 months.  Patients with recent DVT who have 
been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible. 


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16. 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). 
 
17. Evidence of active bleeding or bleeding diathesis. 
 
18. 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. 
 
19. Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of 
pazopanib). 
 
20. Pregnant and/or breastfeeding.  Patient must have a negative serum pregnancy test 
within 14 days of study entry. 
 
21. 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. 
 
 
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 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
 
4.1 
Confirmation of Patient Eligibility 
 


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Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All 
data will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Pazopanib at a dose of 800 mg QD 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 
on that day.  The subject should resume taking pazopanib at the next scheduled dose on 
the following day.  If vomiting persists, the subject should be instructed to notify the 
investigator. 
 
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-


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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 
 
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, 
sunitinib20.  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 should be considered 
in place of proton pump inhibitors and H2 receptor antagonists.  Separate antacid 


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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, 
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 


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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.   
 
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 
 
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.   
 
Female and male patients (along with their female partners) 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 or female partner of a male patient becomes pregnant during therapy 


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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 
 
Patients will be followed every 2 months until death.  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 
 
As a general rule, if dose reduction of pazopanib is necessary, the dose should be reduced 
stepwise by 200 mg at each step, and the subject should be monitored for approximately 10 to 14 
days at each dose level.  If toxicity does not abate during this monitoring time, the 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 


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(in 200 mg increments, after monitoring for 10-14 days at each dose level to ensure that toxicity 
did not recur or worsen).  
 
Dose-level 
0 
-1 
-2 
-3 
-4 
Dose 
800 mg QD 
600 mg QD 
400 mg QD 
200 mg QD 
Discontinue 
 
For patients at dose-level -3, 200 mg QD, a maximum dose delay of 14 days is allowed for 
management of toxicities.  If toxicity does not resolve in 14 days, the patient should be 
discontinued from study.   
 
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 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. 


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AE Terms & Descriptions 
Dose Modification Algorithms 
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 
 
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, 
Continue pazopanib with current dose. 


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AE Terms & Descriptions 
Dose Modification Algorithms 
hyperkeratosis) 
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 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.    
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 
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 may be considered if ALL following criteria are met:  
- ALT reduced to Grade 1 


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Event 
Dose Modification Algorithms 
- 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.  
(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. 


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Event 
Dose Modification Algorithms 
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. 
 
 
 
 
 
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. 
 
Novartis requires that all events be reported as outlined in Section 7.4. 
 
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 


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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 
 
 
 
 
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). 
 
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. 
 
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 


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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 
 
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. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
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.) 


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QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Reporting to Novartis 
 
All events must be reported to Novartis within 24 hours of learning of its occurrence.  
Information about all SAEs is collected and recorded on a Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of 
each SAE to each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form in English, 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. (See Appendices E and F).  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. 
 
From the time a subject consents to participate in and completes the study all SAEs 
assessed as related to study participation (e.g., protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to Novartis concomitant medication, will 
be reported promptly to Novartis. 
 
Any SAE brought to the investigator’s attention within 30 days following completion of 
the study considered by the investigator as possibly related to investigational product 
must be reported to Novartis. 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. 
 
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 


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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. 
 
 
Please note that all events meeting liver stopping criteria must be recorded as an 
SAE. 
 
Pregnancy 
Any pregnancy that occurs during study participation must be reported to Novartis.   To 
ensure subject safety, each pregnancy must be reported to Novartis within 24 hours of 
learning of its occurrence using the pregnancy reporting form.  The pregnancy must be 
followed up to determine outcome (including premature termination) and status of 
mother and child.  Pregnancy complications and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the investigational product, must be promptly reported to Novartis. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study. Pregnancy information must be reported to Novartis as described above. 
 
All serious adverse events must be reported by facsimile within 24 hours to 
Novartis.  
FAX: 1-877-778-9739 
Email: ct.suspected@novartis.com 
Phone: Sheila Bell, 862-778-6763 (if you experience difficulty faxing the form) 
Please use the attached fax cover sheet, located in Appendices E and F.  
 


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Initial Reports 
Follow-up Information on a Previous 
Report 
Type of Event 
Time Frame 
Documents 
All SAEs 
24 hours 
For follow-up report, please submit 
findings from the previous report, if 
appropriate  
Pregnancy 
24 hours 
 
Liver Chemistry Abnormalities 
(the below are not always considered an SAE unless they fulfill the definition of an SAE in Section 7.7) 
ALT: >3.0 x ULN  
with concomitant elevation in bilirubina 
(defined as total bilirubin 2.0 x ULN;  
with direct bilirubin >35%)  
or with hypersensitivity symptoms (e.g., 
fever, rash). 
24 hours 
For follow-up report, please submit 
findings from the previous report, if 
appropriate 
ALT >8.0 x ULN  
without bilirubin elevation (defined as total 
bilirubina <2.0 x ULN or direct bilirubin ≤35%) 
and without hypersensitivity symptoms (e.g., 
fever, rash) 
24 hours 
For follow-up report, please submit 
findings from the previous report, if 
appropriate 
a. 
Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject meets the 
criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an SAE. 
 
 
 
7.5 
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) being developed 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 


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Molecular Weight: 473.99 g/mol (monohydrochloride salt); 437.53 g/mol (free 
base) 
 
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.  Please use the ISS Drug 
Supply Request form (Appendix D) to order drug. Contact Marybeth Nyhuis 
(mary.nyhuis@novartis.com) 
and 
Desiree 
Hiraman 
(desiree.hiraman@novartis.com) and cc Lixian Jin (lixian.jin@novartis.com) on 
ALL requests.    
 
8.1.4 Dosage Form and Preparation 
 
Pazopanib is supplied as 200 mg tablets. 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 at a dose of 800 mg QD (four 200 mg tablets) should be taken orally 
without food at least one hour before or two hours after a meal. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Tumor Tissue For Research Purposes 
 
With patient consent, archived formalin fixed paraffin embedded specimens from the 
time of diagnosis  may be sequenced as part of the patient’s routine care.   If archival 
tissue samples are available and/or biopsy is obtained for clinical purposes at the time of 
disease progression, WUSM may request a tumor sample, with patient consent, for 
research purposes, including whole exome and transcriptome sequencing.  The specimens 
will be collected in accordance with standard of care practice and will be taken to the 
Washington University Tissue Procurement Core for processing and storage per 
institutional practice.   


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For the purpose of eligibility, patients expressing pazopanib targeted genes in either 
tissue assays or peripheral blood should be considered for study. 
 
 


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10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted no more than 14 days prior to start of 
protocol therapy. Scans and x-rays must be done no more than 4 weeks prior to the start of the 
protocol therapy. All visits have a window of +/- 3 days.  
 
 
Screening 
D1 of 
each 
cycle 
C1D8 
C1D15 
and 
C2D15 
End of every 
even-numbered 
cycle 
EOT 
F/U9 
Informed consent 
X 
 
 
 
 
 
 
PE, H&P, PS 
X 
X 
 
 
 
X 
 
VS 
X 
X1 
X 
 
 
X 
 
CBC 
X 
X 
X 
 
 
X 
 
CMP 
X 
X 
X 
 
 
X 
 
LFTs2 
X 
X2 
X2 
X2 
 
X 
 
Pregnancy test3 
X 
 
 
 
 
X 
 
UPC 
X 
X10 
 
 
 
X 
 
TSH, T4 
X 
X4 
 
 
 
 
 
PT/PTT, INR 
X 
 
 
 
 
X 
 
ECG 
X 
X5 
 
 
 
 
 
CT scan 
X 
 
 
 
X 
X 
 
Pazopanib 
 
X --------------------------------- X6 
 
 
Collect/review 
medication diary  
 
X 
 
 
 
 
 
Toxicity assessment 
X 
X 
 
 
 
X11 
 
Tissue for Research 
Purposes 
X7 
 
 
 
 
X7 
 
1. Monitoring of BP only at Day 7 +/- 3 days.  Can be assessed by any method as long as the study physician is informed of 
the measurement, verifies any measurement that is not normal, and takes appropriate action. 
2. Monitor serum liver tests before initiation of treatment with pazopanib and C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, and 
as clinically indicated.  Periodic monitoring should continue after C5. 
3. Women of childbearing potential only. 
4. Monitor between every 8 to every 16 weeks. 
5. C2D1, C4D1, C7D1 and then every 16 weeks (Day 1 of every fourth cycle) until EOT. 
6. To be taken PO QD.  Each cycle is 4 weeks long. 
7. Optional tissue for research purposes per section 9.1.9. Patients will be followed every 2 months for recurrence and survival 
until death. 
10. Day 1 of each cycle through Cycle 6, then Day 1 of every even-numbered cycle thereafter. 
11. Last assessment to take place 30 days following end of treatment. 
 
 
 


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11.0 
DATA SUBMISSION SCHEDULE 
 
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 
On-Study Form 
Tumor Biopsy Form 
Prior to starting treatment 
Treatment Form 
Pill Diary 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Tumor Biopsy Form 
Completion of treatment 
Follow Up Form 
Every 2 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 
 
 
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 4 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 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 


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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. 
 
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 


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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. 
 
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 


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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:  
 
• 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 


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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 
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 


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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 
* 
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 
 
 
 


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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.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the 
Washington University Quality Assurance and Safety Monitoring Committee (QASMC) semi-
annually beginning six months after accrual has opened (if at least five patients have been 
enrolled) or one year after accrual has opened (if fewer than five patients have been enrolled at 
the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the 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 


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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 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date  
• 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 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
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. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Objectives and Endpoints 
 
The primary objective of this study is to investigate the response rate and progression-
free survival of single agent pazopanib in a molecularly selected population of patients 
with advanced NSCLC. Patients with advanced NSCLC and abnormalities in VEGFR or 
PDGFR will receive single agent pazopanib at 800 mg daily. Patients may elect at study 
entry to provide tissue, from either archival or freshly obtained tissue, for research 
purposes.  Optional tumor tissue testing will include whole exome and transcriptome 
sequencing performed in 10 patients.  This willinclude 4 to 6 responders and 4 to 6 non-
responders in order to identify the predictors for benefit; initial predictors are the 
mutations in VEGFR or PDGFR, but sequencing will be used to evaluate for other 
predictors as well. Patients  mayalso elect to submit tissue from any standard of care 
biopsy performed at the time of progression in an attempt to identify the mechanisms for 
secondary resistanc. 
 
14.2 
Study Design and Analyses 
 
This is an open label, single-arm pilot study to obtain preliminary information of the 
efficacy of single agent pazopanib.  A total of N=20 patients will be enrolled for this 
study. The sample size is determined primarily based on clinical feasibility rather than 
statistical power.  According to the general guidelines regarding sample size for pilot and 
translational study18, however, the proposed sample size will provide us a reasonable 
precision to estimate the preliminary information. If 4 responders are observed out of 20 


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patients, for example, we would have 80% confidence that the “true” rate would fall 
between 9% and 36%. If the “true” response rate is 20% or higher, there would be 80% 
chance of observing at least 3 responders out of 20 patients. Conversely, there would be 
<10% chance to observe 3 or more responders if the true rate is less than 5%. 
 
As a pilot study for proof of principal, the data analysis will be descriptive in nature. 
Demographic and clinical characteristics of the sample, as well as response, toxicity by 
grade and loss to follow up will be summarized using descriptive statistics. Kaplan-Meier 
product limit estimator will be used to describe the distribution of progression free 
survival. The 95% confidence interval (CI) for RR and 6-month PFS will also be 
calculated. The association between response and specific mutation status will be 
assessed by permutation analysis. Taking the relationship between VEGFR1 expression 
and RR as an example, for instance, we first compute the observed test statistics, e.g., the 
sample mean difference between responders versus non-responders.  Then to simulate the 
null distribution of the test statistics, or the distribution of the observed mean differences 
if there were truly no difference, we repeat the following 10,000 times: we randomly 
shuffle the response status, and then calculate the sample difference between the newly 
designated groups. The permutation p-value equals the proportion of simulations from the 
null distribution that exceed the observed test statistics.  
 
 
 


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15.0 
REFERENCES 
 
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Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for 
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Blumenschein GR, Jr., Gatzemeier U, Fossella F, et al. Phase II, multicenter, 
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Goss GD, Arnold A, Shepherd FA, et al. Randomized, double-blind trial of carboplatin 
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Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-
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Said R, Hong DS, Warneke CL, et al. P53 mutations in advanced cancers: clinical 
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15. 
Schwaederle M, Vladimir L, Validire P, et al. VEGF-A Expression Correlates with TP53 
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research 2015. 


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16. 
Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology 
and medicine. Genes & development 2008;22:1276-312. 
17. 
Rogosin S, Sandler AB. Beyond bevacizumab: antiangiogenic agents. Clinical lung 
cancer 2012;13:326-33. 
18. 
Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation 
from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent 
antitumor and antiangiogenic activity. Molecular cancer therapeutics 2007;6:2012-21. 
19. 
Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced 
cancer. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2009;15:4220-7. 
20. 
Billemont B, Medioni J, Taillade L, et al. Blood glucose levels in patients with metastatic 
renal cell carcinoma treated with sunitinib. British journal of cancer 2008;99:1380-2. 
 
 
 


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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 
Today’s Date:    
 
 
 
 
 
 
Agent:  Pazopanib 
 
Cycle:    
 
 
 
 
 
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
1. Complete one form for each month.  Take 800 mg of pazopanib once daily under fasting 
conditions (at least one hour before a meal or two hours after a meal).  Take pazopanib with a 
glass of water and drink the glass of water in as little time as possible. 
2. Record the date, the amount taken, and when you took it. 
3. If you forgot to take your dose, you may make it up if there are more than 12 hours remaining 
before your next scheduled dose.  Otherwise, restart pazopanib at the next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next 
appointment.  
Day 
Date 
# of tablets 
taken 
Dose time 
 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 


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APPENDIX D: Investigator Sponsored Study (ISS) Drug Supply Request Form 
 
Principal Investigator: Daniel Morgensztern, MD 
 
GSK Study Number: 201566 
 
In order to facilitate your shipment for drug supply, please fill in the applicable information and 
send  by way of email to Marybeth Nyhuis (mary.nyhuis@novartis.com) and Desiree Hiraman 
(desiree.hiraman@novartis.com)  and  cc Lixian Jin (Lixian.jin@novartis.com) on  ALL 
requests.   
 
PLEASE NOTE: UPON RECEIPT OF THIS FORM, IT MAY TAKE UP TO THREE WEEKS TO RECEIVE 
YOUR DRUG SHIPMENT. 
 
Enter the full shipping address for drug supply: 
Institution Name: 
Pharmacist: 
Street and Room number: 
City, State, Zip: 
Phone (required): 
 
200 mg 
Pazopanib ( 34 
tablets per bottle) 
GSK1120212 
(0.5g) 
GSK1120212 
(2mg) 
Placebo  
Powder 
suspension 
# 
# 
# 
# 
# 
 
# patients 
currently receiving 
Investigational 
Product 
Estimated 
Monthly 
Accrual Rate 
Total Patient enrollment to date 
Estimated monthly supply quantities     
(Ex- # 200mg bottles, etc) 
# 
# 
# 
    #                                                                           
 
Pazopanib tablets are packaged in a sealed bottle.  A content label will be affixed to each bottle identifying the 
product.  Where possible please request a minimum of one month’s supply for all ongoing patients.  Quarterly 
supplies would be preferable if your site has capacity. 
 
For Investigator Sponsored Studies, the Investigator/Institution is responsible for following CFR and GCP for labeling 
and dispensing (21 CFR 312.6).   
 
You are required to label the drug supply provided to you for use in this study to indicate that the drug is being used for 
investigational purposes in this trial.  Per FDA regulation, "the package of an investigational new drug intended for human use 
shall bear a label with the statement "Caution: New Drug--Limited by Federal (or United States) law to investigational use." The 
label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall 
not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated."    
 
 
 
 
 


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APPENDIX E: SAE Fax Cover Sheet-Suspected/Unknown 
 
 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 
Fax Number:  877-778-9739 
(If you experience difficulty faxing this form, please contact   Sheila Bell at 862-778-6763. 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
 
 
 
 
This document contains important safety information. 
If fax is received in error, please forward to +44 1403 323500 
 
 
 
Version 3.0 Dec 2013 


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APPENDIX F: SAE Fax Cover Sheet-Not Suspected 
 
 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 
Fax Number:  877-778-9739 
(If you experience difficulty faxing this form, please contact   Sheila Bell at 862-778-6763. 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
 
 
 
 
This document contains important safety information. 
If fax is received in error, please forward to +44 1403 323500 
 
 
 
Version 3.0 Dec 2013