Conditions: Solid Tumours
Keywords: VEGF Pazopanib Sarcoma GW786034 Refractory Solid Tumors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
The study design was an open-label Phase II pediatric clinical study. The purpose of Study X2203 was to identify any efficacy signal in subjects with the disease subtypes under study, when treated with pazopanib monotherapy. Furthermore, it was to define the toxicities of pazopanib in children, as well as examine biological markers, e.g. cytokines and angiogenic factors, that could help further characterize any response of pazopanib in children. Pazopanib was administered as monotherapy in tablet and powder suspension formulations at daily doses of 450 mg/m2/dose or 225 mg/m2/dose, respectively. The first 6 enrolled subjects receiving oral suspension formulation were assessed for tolerability and extended PK sampling; and, only if pazopanib was tolerated, subsequent subjects were enrolled at the same starting dose with the suspension. Dose escalation was not permitted. For the tablet, a dosing nomogram was used based on the subject's BSA. Dose reduction was dependent upon the toxicity of pazopanib and disease status of the infants, toddlers, children, adolescents, and young adults. Subjects could be as young as 1 year-old infants to screen for enrollment. Subjects were assessed for initial response after 8 weeks of treatment prior to Cycle 3. A cycle was defined as 28 days of pazopanib treatment with no rest period between cycles. Treatment was administered continuously once daily. Treatment was to be discontinued if there was evidence of disease progression, unacceptable treatment-related toxicity, pregnancy. Histological classification was an important diagnostic inclusion in these subjects with a wide variety of refractory solid tumors, i.e. 7 different tumor types and each being a cohort.

Detailed description:
The study design included a hierarchical 2-stage tumor response assessment with each cohort independent from one other. First, an initial 10 subjects were enrolled into each cohort. In the event of ≥ 1 response in any of these initial subjects, an additional 10 subjects may be enrolled in that cohort to proceed. In the event of ≥ 3 responses, the agent was considered effective. However after end of-stage 1, study enrollment stopped due to insufficient antitumor activity. Subjects who discontinued study treatment were followed for survival status. The study was to continue accruing data and thus, remained open for approximately 1 year from Last Subject Last Visit (LSLV).

Arms:
arm 1: All subjects were treated with pazopanib GW786034 tablets at a dose of 450 mg/m\^2/dose or as a powder in suspension at a dose of 225 mg/m\^2/dose. The maximum daily dose administered was to be 800 mg for the tablet and 400 mg for suspension. If 225 mg/m\^2/dose was not tolerated (\>=2 DLTs in 6 evaluable subjects), the dose for subjects who required suspension was reduced to 160 mg/m\^2/dose. A cycle was defined as 28 days with no rest periods between cycles.

Interventions: intervention 1: Pazopanib
Intervention descriptions: intervention 1: Pazopanib was supplied as a series of aqueous film-coated tablets containing 200 mg (oval-shaped, white, packaged in bottles containing 34 tablets each), and 400 mg (oval-shaped, white, packaged in bottles containing 68 tablets each). Pazopanib Powder for Oral Suspension was a white to slightly colour powder supplied to the clinical sites in amber glass (United State Pharmacopeia (USP) Type III) bottles with child-resistant closures. Each bottle contains 5 g of pazopanib.

Protocol document:
Prot_000.pdf: 
Clinical Development
GW786034
Protocol VEG116731 / NCT01956669
A Phase II Study of Pazopanib (GW786034, NSC# 737754) in 
Children, Adolescents and Young Adults with Refractory Solid 
Tumors
Authors
Document type
Amended Protocol Version (Clean)
EUDRACT number
2013-003595-12
Version number
05
Development phase
II
Document status
Final
Release date
23-May-2017
Novartis internal 
reference number
PZP034X2203
COG number
ADVL1322
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amendment 5 (23-May-2017)
Amendment rationale
As of 04-May-2017, enrollment is ongoing with 35 patients randomized, and 4 patients currently 
receiving study treatment. The purpose of this protocol amendment is to:
-
To add duration of response among the secondary study objectives to better characterize 
the clinical benefit in patients responding to treatment. This information may contribute to 
define the benefit/risk profile in this patient population. 
-
To provide clarification in the description of the secondary objective on the assessment of 
genotype/phenotype relationships of VEGF or other members of the VEGF signaling 
pathway.
-
To add the option of closing recruitment of further patients in a given study cohort if no 
objective responses are observed in patients treated in two out of the three cohorts of 
primary interest during stage 1 of the study. 
-
To update the allowed timeframe for prior use of monoclonal antibodies under eligibility 
criteria. 
-
To update the contraception/pregnancy language to align with the most recent Investigator 
Brochure version 15 (IBv.15) referring to specific requirements in male and female patients 
while receiving study treatment as well as during follow up period. 
-
To remove the exclusion criterion on concomitant treatment with anti-inflammatory and 
anti-platelet agents. Based on clinical data in adult patients a drug-to-drug interaction when 
pazopanib is co-administered with anti-inflammatory agents is not expected.
-
To modify the criteria for starting subsequent treatment cycles. This modification will 
clarify the criteria for starting subsequent cycles when no radiological tumor assessments 
are performed and align the conditions to resume/interrupt study treatment with toxicity 
management guidelines.
-
The sentence on “medications that increase gastric pH” is now updated to Proton Pump 
Inhibitors (PPI). This change is reflected in the protocol section on “Prohibited 
medications.”
-
To add anti-inflammatory and anti-platelet agents in the protocol section “Permitted 
medication to be used with caution”. The use of these agents as a concomitant treatment 
should be monitored since pazopanib may result in an increase of blood pressure and 
bleeding episodes.
-
To clarify that re-initiation of study treatment following hepatotoxicity requires approval 
from the Study Chair.
-
To clarify that PK sampling is not required beyond Cycle 11 since it is unlikely that data 
beyond cycle 11 will provide any modification in the clinical pharmacology assessment of 
the study drug.
-
To define the Per Protocol population and specify which analysis will be conducted in the 
different protocol defined datasets (Per Protocol Population and mITT population).


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underline for insertions.

Section 1.2: Added duration of response as secondary objective and clarified genotyping 
assessments. 

Section: 3.1.4: Clarified end of study criteria and addition of the option of closing recruitment of 
further patients in a given study cohort according to the efficacy results observed in two out of 
the three cohorts of primary interest at the end of stage 1.

Section: 3.2.7: Update on the allowed timeframe for prior use of monoclonal antibodies.

Section: 3.3.1: Updated timeframe for contraceptive requirements in females, and addition of 
contraceptive instructions for males with partners who can become pregnant. 

Section 3.3.2: Removed exclusion criterion regarding patients currently receiving anti-
inflammatory and anti-platelet agents.

Section: 4.2: Clarification of criteria for starting subsequent cycles when no radiological tumor 
assessments are performed and alignment with safety management guidelines. 

Section: 4.5: Clarification of use of concomitant medications that increase gastric pH and 
addition of anti-inflammatory and anti-platelet agents in the protocol section of permitted 
medications to be used with caution.

Section: 4.8: Change in the Prohibited Medications section, the reference of “medications that 
increase gastric pH” to “Proton Pump Inhibitors” (PPI).

Section: 5.4.3: Clarification regarding approval from Study Chair to re-initiate treatment 
following hepatotoxicity.

Section 7.2.4: Updated timeframe for female use of adequate contraception to align with 
Investigator Brochure version 15.

Section 7.3.2: Clarified that PK sampling schedule is not required beyond cycle 11.

Section 9.3: Introduced the definition of Per Protocol (PP) population 

Section 9.4: Clarified data sets to be used for efficacy assessment, objective response analysis 
and all other efficacy analyses.

Section 9.8.2: Addition of Duration of Response (DoR) as secondary objective.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for approval 
a revised Informed Consent that takes into account the changes described in this protocol amendment.
Summary of previous amendments 
Amendment 4 (02-MAY-2016):


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Amendment rationale
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GW786034, the purpose of 
this protocol Amendment 4 is to:
-
Delete or replace references to GlaxoSmithKline or its staff with that of Novartis and its 
authorized agents to align with the change of sponsorship;
-
Make administrative changes to align with Novartis processes and procedures;
As of 02-MAY-16:
18 patients have received study treatment in 1 country;
16 patients have discontinued study treatment.
The changes described in this amended protocol require Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) approval prior to implementation.
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update and submit for 
approval, a revised Informed Consent that takes into account the change of study sponsorship 
described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study will sign 
a new informed consent form indicating Novartis is the new study sponsor and continue the 
appropriate visit schedule.
Amendments 1 to 3
Amendment rationale and summary of changes for previous amendments 1 to 3 are included below 
in Revision Chronology section and in the appendices 9, 10 and 11 to capture the tracked changes. 


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Revision Chronology:
Document Number
Effective Date
Rationale
2012N131371_00
2013-May-24
Original
2012N131371_01
2013-Jun-10
Amendment No. 01 corrected
the IND number throughout the
protocol (title, Sponsor/Medical 
Monitor Information page, 
Sections 4.9, 4.10 and 6.1
2012N141521_02
2014-May-01
Amendment No. 02
Sponsor’s medical monitor 
contact information updated.
The starting dose for suspension 
will be 225 mg/m2/dose; the first 
6 subjects enrolled who require 
suspension formulation will have 
extended PK and evaluation for 
DLT. Clarification around 
continuation of therapy 
following toxicity incorporated.
The minimum BSA for patients 
receiving tablets will be 0.84 
mg/m2 based on available tablet 
strengths (200mg, 400 mg).
 
 
 
 
 
Monitoring of pregnancy 
incorporated.
Protocol specific SAEs 
associated with a different 
investigation drug were 
removed.
General administrative changes 
including updating TOC, 
formatting and Appendix and 
Section references changed 
throughout the protocol.
2012N141521_03
2016-Feb-15
Amendment No. 03


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Assessment of overall survival 
added as secondary objective.
Evaluability of patients on 
powder suspension formulation 
for safety monitoring clarified.
End of study definition clarified.
To allow patients rescreening
Clarification around the 
enrollment into the different 
cohorts.
Clarification around inclusion 
criteria (relapsed/refractory 
disease, bone marrow 
evaluations, thyroid function).
Exclusion criteria regarding 
hemoptysis changed to exclude 
patients with history of clinically 
significant bleeding (within 6 
weeks prior to study enrollment).
Clarification around dose 
reductions, treatment 
interruptions, and missed doses.
Blood-product support added as 
supportive care.
Therapy delivery map and visit 
schedule clarified.
Clarifications around 
hematological dose- limiting 
toxicities and management of 
toxicities incorporated.
Pharmacokinetic 
Criteria for discontinuation of 
protocol therapy clarified.
Statistical considerations 
clarified and section on 
Evaluability for toxicity deleted.
Update on 
contraception/pregnancy 
language.


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General administrative changes, 
change language from subject to 
patient, change study 
treatment/study drug to protocol 
therapy, change GSK medical 
monitor to medical monitor, 
typos corrected.
2012N141521_04
2016-May-02
Amendment 04:
References to GSK or its staff 
were deleted or replaced with 
that of Novartis/Novartis and 
its authorized agents.
Administrative changes were 
made to align with Novartis 
processes and procedures.


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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
VEG116731
Sponsor Contact Information
Novartis Pharmaceuticals Corporation
In some countries, the clinical trial sponsor may be the local Novartis and its authorized agents. 
Where applicable, the details of the Sponsor and contact person will be provided to the relevant 
regulatory authority as part of the clinical trial submission.
Sponsor Serious Adverse Events (SAE) Contact Information:
For study conduct questions not related to study subject safety, the first line of contact should be 
with the designated local country company contact. In the event that the designated company 
contact is not available please contact the Medical Lead. Please refer to the Study Procedures 
Manual (SPM) for further details.
Sponsor Medical lead Contact Information
Novartis Pharma AG
Postfach
CH-4002 Basel
Switzerland
Email: 
If you have any 
questions regarding the protocol, please contact your local Novartis office.
Regulatory Agency Identifying Number(s):
IND No: 065747


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Sponsor Signatory:
Signature:
Date:
, MD
,
 
,
Novartis Pharmaceuticals 
Corporation


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number VEG116731:
I confirm agreement to conduct the study in compliance with the protocol, as amended by this 
protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described clinical study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study
are informed about their obligations. Mechanisms are in place to ensure that site staff receives the 
appropriate information throughout the study.
Investigator Name:
Investigator Signature
Date


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TABLE OF CONTENTS
EXPERIMENTAL DESIGN SCHEMA..................................................................................................... 17
1.
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)................................................................. 18
1.1
Primary Aims.................................................................................................................................... 18
1.2
Secondary Aims................................................................................................................................ 18
2
BACKGROUND ........................................................................................................................... 20
2.1
Rationale for Development.............................................................................................................. 20
2.2
Preclinical Studies ............................................................................................................................ 20
2.3
Adult Studies.................................................................................................................................... 22
2.4
Pediatric Studies............................................................................................................................... 27
2.5
Overview of Proposed Pediatric Phase II Trial................................................................................. 28
3
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA....................................... 31
3.1
Study Enrollment.............................................................................................................................. 31
3.2
Eligibility: Inclusion Criteria.............................................................................................................. 33
3.3
Exclusion Criteria.............................................................................................................................. 37
3.4
Regulatory........................................................................................................................................ 39
4
TREATMENT PROGRAM......................................................................................................... 40
4.1
Overview of Treatment Plan............................................................................................................ 40
4.2
Criteria for Starting Subsequent Cycles ........................................................................................... 43
4.3
Concomitant Therapy....................................................................................................................... 43
4.4
Permitted Medications .................................................................................................................... 43
4.5
Permitted Medications – Use with Caution..................................................................................... 43
4.6
The Effects of Pazopanib on Other Drugs........................................................................................ 45
4.7
The Effects of Other Drugs on Pazopanib........................................................................................ 45
4.8
Prohibited Medications.................................................................................................................... 46
4.9
Therapy Delivery Map (TDM) - Cycle 1 ............................................................................................ 47
4.10
Therapy Delivery Map – Subsequent Cycles of Therapy.................................................................. 48
5
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY.......................................... 50
5.1
Definition of Dose Limiting Toxicity (DLT)........................................................................................ 50
5.2
Dose Modifications for Hematologic Toxicity.................................................................................. 51
5.3
Dose Modifications for Non-Hematological Toxicity ....................................................................... 51
5.4
Potential Pazopanib Specific Side Effects ........................................................................................ 52
6
DRUG INFORMATION.............................................................................................................. 61
6.1
PAZOPANIB....................................................................................................................................... 61
7
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED ................................... 66
7.1
Required 
 Clinical, Laboratory and Disease Evaluations ............................................. 66
7.2
Monitoring for Specific Toxicities .................................................................................................... 69
7.3
Pharmacokinetic studies.................................................................................................................. 70
71
8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA..................................................................................................................................... 72
8.1
Criteria for Removal From Protocol Therapy................................................................................... 72


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8.2
Follow-up assessments after Removal From Protocol Therapy ...................................................... 72
8.3
Criteria for Withdrawal from Study ................................................................................................. 73
9
STATISTICAL CONSIDERATIONS ........................................................................................ 73
9.1
Sample Size and Study Duration ...................................................................................................... 73
9.2
Study Design..................................................................................................................................... 73
9.3
Analysis Populations ........................................................................................................................ 74
9.4
Analysis Data Sets ............................................................................................................................ 74
9.5
Treatment Comparisons .................................................................................................................. 75
9.6
Primary Analysis and End of Study Analysis..................................................................................... 75
9.7
Key Elements of Analysis Plan.......................................................................................................... 75
9.8
Methods of Analysis......................................................................................................................... 76
9.9
Evaluability for Response................................................................................................................. 78
9.10
Gender and Minority Accrual Estimates.......................................................................................... 79
9.11
Analysis of the Pharmacokinetic Parameters .................................................................................. 79
9.12
Analysis of Biological and Correlative Endpoints............................................................................. 80
10
EVALUATION CRITERIA......................................................................................................... 81
10.1
Common Terminology Criteria for Adverse Events (CTCAE)............................................................ 81
10.2
Response Criteria............................................................................................................................. 81
10.3
Response Criteria for Patients with Solid Tumors and Measurable Disease................................... 81
10.4
Response Criteria for Neuroblastoma Patients with 123I-MIBG Positive Lesions........................... 82
10.5
Response Criteria for the Bone Marrow in Neuroblastoma Patients.............................................. 83
10.6
Response Criteria for Hepatoblastoma............................................................................................ 84
10.7
Best Response (Solid Tumors).......................................................................................................... 85
10.8
Survival Follow-Up............................................................................................................................ 87
11
ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENTS (SAE).................................. 88
11.1
Definition of Adverse Events (AEs)................................................................................................... 88
11.2
Definition of Serious Adverse Events (SAEs).................................................................................... 89
11.3
Method of Detecting AEs and SAEs.................................................................................................. 90
11.4
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs....................... 90
11.5
Recording of AEs and SAEs............................................................................................................... 90
11.6
Evaluating AEs and SAEs .................................................................................................................. 91
11.7
Follow-up of AEs and SAEs............................................................................................................... 91
11.8
Prompt Reporting of SAEs to Novartis and COG.............................................................................. 92
11.9
Regulatory Reporting Requirements for SAEs ................................................................................. 92
12
STUDY REPORTING AND MONITORING............................................................................ 93
12.1
Data and Safety Monitoring............................................................................................................. 93
13
APPENDICES............................................................................................................................... 94
13.1
APPENDIX IA: PATIENT DIARY FOR PAZOPANIB TABLETS ................................................................ 94
13.2
APPENDIX IB: PATIENT DIARY FOR PAZOPANIB POWDER IN SUSPENSION ..................................... 96
13.3
APPENDIX II: PAZOPANIB DOSING NOMOGRAM FOR TABLETS ...................................................... 97
13.4
APPENDIX IIIA: LIST OF ANTICONVULSANT DRUGS THAT ARE ALLOWED ....................................... 98
13.5
APPENDIX IIIB: MEDICATIONS THAT MAY CAUSE QTc PROLONGATION ......................................... 99
13.6
APPENDIX IV: URINE PROTEIN TO CREATININE (UPC) RATIO......................................................... 103
13.7
APPENDIX V: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT PERCENTILE.......... 104


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13.8
APPENDIX VI: PHARMACOKINETIC STUDY FORM.................................................................... 106
13.9
APPENDIX VII: INSTRUCTIONS TO PATIENT/CAREGIVER FOR ADMINISTERING PAZOPANIB ORAL 
SUSPENSION................................................................................................................................... 109
13.10
APPENDIX VIII: YOUTH INFORMATION SHEETS .............................................................................. 111
13.11
APPENDIX IX AMENDMENT 01 ....................................................................................................... 113
13.12
APPENDIX X AMENDMENT 02........................................................................................................ 114
13.13
APPENDIX XI AMENDMENT 03 ....................................................................................................... 137
13.14
APPENDIX XII AMENDMENT 04...................................................................................................... 176
14
REFERENCES............................................................................................................................ 181


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LIST OF ABBREVIATIONS
AE
Adverse Event
AFP
Alpha FetoProtein
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ASCO
American Society for Clinical Oncology
AST
Aspartate Aminotransferase
ATP
Adenosine tri-phosphate
AUC
Area Under the Curve
BM
Bone Marrow
BSA
Body Surface Area
c-fms or CSF-1
Colony Stimulating Factor 1
CD31
Cluster of Differentiation 31
CEC
Circulating Endothelial Cell
CI
Confidence Interval
COG
Children’s Oncology Group
CPK
Creatinine Phosphokinase
CR
Complete Response
CT
Computed Tomography
Ctrough
Steady-State Trough Concentration
CTCAE
Common Terminology Criteria for Adverse Events
CVL
Central Venous Line
DCE-MRI
Dynamic Contrast Enhanced MRI
DLT
Dose Limiting Toxicity
ECG/EKG
Electrocardiogram
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic acid
FGF, FGFR
Fibroblast Growth Factor (Receptor)
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B Surface Antigen
HR
Hazard Ratio
HVA
Homovanillic Test
GCIG
Gynecologic Cancer Intergroup
HRCT
High-Resolution Computed Tomography
IEC
Independent Ethics Committee
123I-MIBG
123I-metaiodobenzylguanidine
IND
Investigational New Drug
IRB
Institutional Review Board
IRC
Independent Review Committee
IWRS
Interactive Web Response System
KD, KDR
Kinase insert Domain (Receptor)
LC/MS/MS
Liquid Chromatography/Tandem Mass Spectrometry
LFT
Liver Function Test
LPFV
Last Patient First Visit
mITT
Modified Intent-to-Treat
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple-Gated Acquisition
NCI
National Cancer Institute


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NSCLC
Non-Small Cell Lung Cancer
NOAEL
No-Observed-Adverse-Effect-Level
ORR
Objective Response Rate
OS
Overall Survival
PlGF
Placental Growth Factor
PD
Progressive Disease
PDGF, PDGFR
Platelet Derived Growth Factor (Receptor)
PFS
Progression-Free Survival
PfOS
Powder for Oral Suspension
PHI
Protected Health Information
PK
Pharmacokinetic
PNET
Primitive Neuro Ectodermal Tumor
PPI
Proton Pump Inhibitor
PPTP
Pediatric Preclinical Testing Program
PR
Partial Response
QTc
Corrected QT
QTcB
Corrected QT using the Bazett’s formula
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RR
Response Rate
SAE
Serious Adverse Event
SD
Stable Disease
SPM
Study Procedure Manual
STS
Soft Tissue Sarcoma
TBI
Total Body Irradiation
TDM
Therapy Delivery Map
TOC
Table Of Content
TTP
Time To Progression
TUNEL
Terminal deoxynucleotidyl transferase dUTP Nick End Labeling
ULN
Upper Limit of Normal
UPC
Urine Protein to Creatinine Ratio
VEGF, VEGFR
Vascular Endothelial Growth Factor (Receptor)
VMA
Vanillylmandelic Acid
XRT
Radiotherapy


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ABSTRACT
Anti-angiogenic therapy via vascular endothelial growth factor (VEGF) blockade has been shown in several 
studies to be an effective cancer therapy. VEGF is a potent mediator of endothelial proliferation, survival,
and vascular permeability1 and is present in most malignancies; higher VEGF expression has been
correlated with advanced stage or poor prognosis disease.2-8 Platelet derived growth factor (PDGF) 
signaling via PDGFR also plays a key role in angiogenesis by recruiting vascular mural cells, which 
stabilize vessels when VEGF levels decline.9 There are a number of preclinical studies identifying VEGFR,
PDGFR10-20and stem cell factor receptor (KIT) in a wide range of pediatric tumors.17,21
Pazopanib (GW786034) is a small-molecule tyrosine kinase inhibitor that has been shown to prevent ligand
induced receptor autophosphorylation of VEGFR-1,-2,-3, PDGFR-α, -β and c-Kit. In addition, a number
of in vivo murine xenograft studies demonstrate growth inhibition of tumors by pazopanib. This study will
examine the efficacy of pazopanib in children with a variety of relapsed solid tumors. The study will
also seek to further define the toxicities of pazopanib in children, as well as examine biologic markers that 
may help to further define the response characteristics of pazopanib.


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EXPERIMENTAL DESIGN SCHEMA
Treatment Schedule
Time
Agent
Days 1 – 28
Oral Pazopanib once daily
This is an open label phase II trial designed to primarily assess the efficacy of pazopanib in children, 
adolescents and young adults with recurrent or refractory solid tumors. Patients will receive pazopanib 
monotherapy and the term “protocol therapy” will be used throughout this document to designate pazopanib 
monotherapy.
Pazopanib will be dosed daily as an oral tablet (450 mg/m2/dose, maximum 800 mg) or as an oral powder 
for suspension (225 mg/m2/dose, maximum 400 mg). Each cycle will be defined as 28 days, with no rest 
periods between cycles.
The first patients enrolled who receive powder suspension will be expected to complete extended 
pharmacokinetic (PK) sampling (Section 7.3.2) in order to obtain PK and safety data in 6 evaluable patients. 
If the 225 mg/m2/dose is not tolerated (≥2 patients with dose limiting toxicities (DLTs) in the first 6
evaluable patients), subsequent new patients will be enrolled at the160 mg/m2/dose level until 6 evaluable 
patients are available for the safety review and the PK analysis.
Patients with benefit (stable disease or an objective response) may continue therapy unless there is evidence
of progressive disease, unacceptable treatment-related toxicity, until death or until study closure [defined 
as 1 year after Last Patient First Visit (LPFV)], whichever occurs first.


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1.
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
1.1
Primary Aims
1.1.1 To determine the investigator- assessed objective response rate of pazopanib in 
children, adolescents and young adults (patients) with relapsed or refractory solid 
tumors of the following types (each defining a cohort):
1. rhabdomyosarcoma,
2. non-rhabdomyosarcomatous soft tissue sarcoma, or
3. Ewing sarcoma/peripheral Primitive Neuro Ectodermal Tumor (PNET).
1.2
Secondary Aims
1.2.1
To determine the investigator- assessed objective response rate of pazopanib in 
children, adolescents, and young adults (patients) with relapsed or refractory solid 
tumors of the following types (each defining a cohort):
1. osteosarcoma,
2. neuroblastoma (measurable),
3. neuroblastoma (evaluable), or
4. hepatoblastoma


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1.2.2
To further define and describe the toxicities of oral pazopanib in patients with 
recurrent/refractory solid tumors.
1.2.3
To further characterize
the pharmacokinetics (PK)
of pazopanib after 
administration of the powder suspension formulation in children, adolescents and 
young adults with cancer
1.2.4
To determine progression free- survival in patients with relapsed or refractory 
solid tumors, per cohort (described under Section 1.1.1 and 1.2.1).
1.2.5
To determine the time to progression in patients with relapsed or refractory solid 
tumors, per cohort (described under Section 1.1.1 and 1.2.1).
1.2.6
To determine the therapeutic activity (a confirmed complete or partial response or 
stable disease for at least 4 cycles) per cohort (described under Section 1.1.1 and
1.2.1).
1.2.7
To assess duration of response in patients with relapsed or refractory solid tumors, 
per cohort.
1.2.8
To further examine the biologic relationship between tumor response and 
angiogenic cytokines.
1.2.9
. To assess the genotype/phenotype relationships of VEGF or other members of the VEGF signaling 
pathway in children with soft tissue sarcoma.
1.2.10 To further explore pazopanib pharmacokinetic/pharmacodynamic relationships with 
biomarkers and clinical outcomes, including hypertension.
1.2.11 To assess overall survival (OS) in patients with relapsed or refractory solid tumors 
per cohort (described under Section 1.1.1 and 1.2.1).


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2
BACKGROUND
2.1
Rationale for Development
Vascular endothelial growth factor (VEGF) is a potent mediator of endothelial proliferation,
survival, and vascular permeability exerting its effects principally by induction of VEGFR-2 
auto-phosphorylation.1 VEGF is present in most malignancies; higher VEGF expression has been 
correlated with advanced stage or poor prognosis disease.2-8 Platelet derived growth factor (PDGF)
signaling via PDGFR also plays a key role in angiogenesis by recruiting vascular mural cells, which
stabilize vessels when VEGF levels decline.9 A number of preclinical studies have identified 
VEGFR and PDGFR as potential therapeutic targets in a wide range of pediatric solid tumors; these 
include osteosarcoma, synovial sarcoma, Ewing sarcoma, rhabdomyosarcoma, hepatoblastoma,
Wilms’ tumor, and neuroblastoma.10-22 The presence of the stem cell factor receptor (KIT) has also
been demonstrated by immunohistochemistry in osteosarcoma, synovial sarcoma, Ewing sarcoma, 
rhabdomyosarcoma, Wilms’ tumor, and neuroblastoma.17,23
Pazopanib (GW786034B) is a novel 2H-indazoylpyrimidine orally bioavailable, ATP competitive 
small-molecule tyrosine kinase inhibitor24 that has been shown to prevent ligand induced receptor 
autophosphorylation of VEGFR-1, -2, -3, PDGFR-α, -β and c-Kit with an IC50 < 0.085 μmol/L in 
in vitro studies. It also has modest activity against FGFR1, –R3 and c-fms but is otherwise highly 
selective. Pazopanib is highly protein bound (> 99.9%) thus in in vivo studies, steady state 
concentrations exceeding 18 μg/mL were required to prevent VEGFR2 signaling.24Pharmacokinetic 
studies in adults have shown that these concentrations are readily achievable.
2.2
Preclinical Studies
2.2.1
Antitumor Activity
Pazopanib treatment has been shown to inhibit the growth of a variety of
established (100-250 µL) human tumor xenografts in mouse models including renal
cell carcinoma (Caki-2), colon carcinoma (HT29), non-small-cell lung carcinoma
(NCI-H322), melanoma (A375), prostate carcinoma (PC3), and breast carcinoma
(BT474). Pazopanib demonstrated a wide therapeutic index as it had no effect on
mouse body weight and all animals appeared active and healthy throughout
preclinical studies. Histological analysis following pazopanib administration
demonstrated apoptosis or necrosis of tumor cells; TUNEL assays confirmed
increased apoptosis. This effect correlated with reduced angiogenesis as measured
by decreased concurrent endothelial (CD31) staining. The anti- angiogenic activity 
of pazopanib has also been demonstrated in mouse corneal micropocket and 
Matrigel plug analyses.24
There has been limited pediatric pre-clinical testing of pazopanib; however, growth
delay was observed in one subcutaneous model of neuroblastoma and was
significantly enhanced by concomitant administration of metronomic topotecan.25
The pediatric preclinical testing program (PPTP) also tested the activity of
pazopanib against a limited panel of pediatric sarcoma xenografts and observed
delayed time to progression, but no tumor regression.26 Other multi- targeted
tyrosine kinase inhibitors have been screened by the PPTP using a more complete
solid tumor xenograft panel. The pan-VEGFR inhibitor cediranib demonstrated
broad in vivo antitumor activity (78%; primarily tumor growth delay) including:
3/3
rhabdoid,
2/3
Wilms',
3/3
Ewing,
5/5
rhabdomyosarcoma, 1/3
medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma, with one 
complete response each in a rhabdoid and osteosarcoma xenograft. Similarly the
multi-tyrosine kinase inhibitor sunitinib (VEGFR-1,-2,-3, PDGFR- α, -β, c-Kit,


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and FLT3 receptors) showed intermediate (13/34) and high (1/34) levels of
activity against 14 of 34 evaluable solid tumor xenografts, including 4 of 6 
rhabdomyosarcoma, 4 of 5 Ewing tumor, and 2 of 3 rhabdoid tumor. The 
overlapping spectrum of receptors targeted by these agents suggests the broad 
potential of pazopanib for pediatric anti-tumor activity.
2.2.2
Animal Toxicology
In monkeys, no specific toxic effects were seen after 1 month with oral doses of 
up to 500 mg/kg/day, a dose resulting in a Cmax and AUC0-t of 36 μg /mL and 
316 μg•h/mL respectively. However, a dose of 500 mg/kg/day could not be
tolerated for more than 34 weeks due to severe toxicity, consisting of diarrhea, 
anorexia, moribundity and accumulation of crystalline material in a number of 
organs. Monkeys were given 5 or 50 mg/kg/day pazopanib for 1 year, without 
observed toxicity. The no observed adverse effect level (NOAEL) after 1 year 
was 50 mg/kg/day. Mean plasma Cmax and AUC0-t values at 50 mg/kg/day were 
31.8 μg/mL and 235 μg•h/mL, respectively, in male monkeys and 44.0 μg/mL
and 289 μg•h/mL, respectively, in female monkeys after 1 year (Pazopanib 
GW786034 Investigator's Brochure).
There are no published data describing the toxicity of pazopanib in juvenile 
primates. However, doses ≥ 30 mg/kg/day were not tolerated in juvenile rats with 
marked reductions in body weight as well as mortality seen. These effects occurred
at exposures that were similar to or below those expected in pediatric cancer
patients. The specific nature of the effects in these animals is not currently known
but is presumed to be related to vasculogenesis in critical organs such as the heart, 
liver, or kidney. In the two surviving groups, 0.3 and 3 mg/kg/day there did not 
appear to be an effect on body weight although one animal at 3 mg/kg/day had
bilateral broken incisors. Hypertrophy of epiphyseal growth plates, and tooth
abnormalities (including excessively long, brittle, broken and missing teeth, and
dentine and enamel degeneration and thinning) were also observed during
repeated dose administration in mature rat and murine models but notably not in
adult monkeys (Pazopanib GW786034 Investigator's Brochure).
These findings are consistent with previous observations of physeal dysplasia and 
ovarian and uterine changes in juvenile animals, including cynomolgus monkeys, 
during the preclinical testing of other potent VEGF blocking agents raising concern 
of
potential pediatric-specific adverse effects on
long-term
growth and 
development.27,28 Nonetheless, at least in murine models, the changes in bone 
growth appeared reversible after cessation of therapy.27 Consistent with the known
roles of VEGF in follicle maturation and corpus luteum formation there were
significant reductions in female rat fertility at pazopanib doses > 30 mg/kg/day.
In males, reductions in testicular and epididymal weights were observed at ≥30 
mg/kg/day and sperm production, motility and concentration were reduced at
100 mg/kg/day, but this did not result in a functional effect on mating or male
fertility. Consistent with the critical role of VEGF in embryogenesis, cardiac 
malformations were observed in rat fetuses at maternal doses of 3 and 10 mg/kg/day.
Delayed ossification (≥3 mg/kg/day), embryo lethality and reduced fetal body
weight were observed at 10 mg/kg/day. The NOAEL for developmental toxicity 
in the rat was 1 mg/kg/day (Pazopanib GW786034 Investigator's Brochure).
2.2.3
Preclinical Pharmacology
14C-pazopanib demonstrates wide tissue distribution. The majority of pazopanib 
measured in plasma is unmodified, minor metabolites including mono-oxygenated


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and de-methylated forms. In rats and monkeys, pazopanib is predominately 
excreted in the feces with a small amount eliminated in the urine. Following
absorption in the monkey, pazopanib is principally metabolized in the liver by
oxidation and di-demethylation with glucuronidation. In vitro studies indicate that
the oxidative metabolism of pazopanib in human liver microsomes is primarily
mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.
There appears to be minimal potential for inductive effects on CYP enzyme
activities in rats or monkeys after oral doses (300 and 500 mg/kg, respectively) of
pazopanib for 1 month. (Pazopanib GW786034 Investigator's Brochure)
In order to optimize in vivo dosing for pazopanib and determine whether Csteady
state or Cmax best correlated with activity, once and twice daily p.o. dosing was
compared with a continuous infusion of a pazopanib analogue (GW771806). Both
HT29 tumor growth inhibition and anti-angiogenic activity in the Matrigel plug
assay correlated with steady state concentrations of pazopanib and not with Cmax
or exposure (AUC). Complete tumor growth inhibition was achieved with a steady-
state plasma concentration of 2.67 μMol/L pazopanib. This value corresponded
with a pazopanib steady-state concentration of 18 μg/mL. At this level, pazopanib
also demonstrated inhibition of VEGF-induced VEGFR2 phosphorylation in vivo,
but if the concentration dropped below this level, inhibition was minimal, again 
indicating the need to sustain effective levels.24
2.3
Adult Studies
As of 09 September 2012, approximately 5000 patients have received pazopanib as monotherapy 
or in combination out of approximately 7000 patients enrolled in pazopanib oncology clinical 
studies. Data collected to date show that pazopanib administration at 800 mg daily is associated 
with a reasonable safety profile and encouraging efficacy in various oncology settings. Pazopanib 
is approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) and for
the treatment of adult patients with soft tissue sarcoma who have received prior chemotherapy. 
Results of pharmacokinetic and pharmacodynamic analyses demonstrate that (a) pazopanib is 
absorbed after oral administration; (b) a plateau is reached in steady-state systemic exposure at a 
dose of 800 mg daily; (c) a maximum tolerated dose has not been reached at pazopanib doses up 
to 2000 mg daily; and (d) doses of pazopanib that maintain plasma pazopanib concentrations 
above 15 μg/mL (i.e., 800 mg daily and 300 mg twice daily [BID]) are associated with 
pharmacodynamic and clinical effects. Pazopanib administered as oral doses up to 800 mg daily 
is being developed by Novartis for the treatment of a variety of cancers.
2.3.1
Pharmacokinetic and Pharmacodynamic Data in Adults with Cancer
The oral bioavailability of pazopanib reflects absorption that is limited by solubility
above doses of 800 mg once daily; therefore, increases in doses above 800 mg, up
to the highest dose evaluated (2000 mg), in the fasted state will not result in
increased systemic exposure. Geometric mean pazopanib t½ values ranged from
18.1 to 52.3 hours. The geometric mean t½ was 30.9 hours in the 800 mg once
daily dose group, the monotherapy dose selected for administration in Phase II and
Phase III clinical trials. The tmax was 3 to 4 hours. The oral bioavailability of
pazopanib may also be affected by its substrate affinity for gut efflux transporters.
Oral absorption is significantly enhanced when pazopanib is dosed with food; 
therefore, it is recommended to administer pazopanib on an empty stomach, at least 
1 hour before or 2 hours after a meal.
The absolute bioavailability of pazopanib (median 21%) suggests that the majority 


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(67%) of the oral dose recovered unchanged in feces represents unabsorbed drug.
Pazopanib is not extensively metabolized and first-pass metabolism is minor,
consistent with its low plasma clearance and small volume of distribution.
Age, race, and gender had no effect on pazopanib PK. Mild/moderate renal 
impairment is not expected to influence pazopanib exposure, and dose adjustment 
is not necessary. Based on baseline hepatic function, 400 mg pazopanib is
recommended for patients with mild impairment (defined as either normal bilirubin
and any degree of alanine aminotransferase [ALT] elevation or as an elevation of
bilirubin up to 1.5x upper limit of normal [ULN] regardless of the ALT value),
and 200 mg for patients with moderate impairment (defined as an elevation of
bilirubin >1.5 to 3xULN regardless of the ALT values). The maximum dose of
pazopanib (200 mg) administered to patients with severe hepatic impairment did 
not achieve therapeutic plasma concentrations. Therefore, pazopanib is not 
recommended in patients with severe hepatic impairment (defined as total bilirubin 
>3xULN regardless of any level of ALT).
In clinical studies with pazopanib, events of QT prolongation or torsade de pointes 
have occurred. Pazopanib should be used with caution in patients with a history of
QT interval prolongation, patients taking antiarrythmics or other medications that
may potentially prolong QT interval, or those with relevant pre- existing cardiac 
disease. When using pazopanib, baseline and periodic monitoring of ECGs and
maintenance of electrolytes (calcium, magnesium, potassium) within normal range 
is recommended.
Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 
mg once daily, results in effects consistent with inhibition of the VEGF receptors 
it was designed to target (i.e., increases in VEGF and decreases in soluble 
VEGFR2). Concentration-effect relationships were observed between trough 
plasma pazopanib concentrations and an increase in blood pressure in the First 
Time in Human study, as well as in the percent change from baseline in soluble 
VEGFR2 nadir in the Phase II study in renal cell carcinoma. The trough plasma 
pazopanib concentrations associated with one-half the maximal effect (EC50) in 
both concentration effect relationships were similar (12 to 15.3 μg/mL for 
hypertension and 21.3 μg/mL for soluble VEGFR2), which demonstrates that there
is a consistent inhibition of VEGF receptor(s) in patients with cancer when plasma 
pazopanib concentrations are maintained above 15-20 μg/mL.
2.3.2
Safety Data in Adults with Cancer (adverse events and serious adverse events)
In a randomized, double-blind, placebo-controlled Phase III study of pazopanib 
monotherapy in patients with advanced RCC, the median time on treatment was 
approximately twice that on placebo (7.4 months versus 3.8 months).29 The overall
frequency of adverse events (AEs) reported during the study was higher in the
pazopanib arm (92%) compared with placebo (74%). Most common AEs reported
in >20% patients in the pazopanib arm (as of 23 May 2008) were diarrhea
(52%), hypertension (40%), hair color change (depigmentation; 38%), nausea 
(26%), anorexia (22%), and vomiting (21%). These AEs were all reported at a 
higher incidence in the pazopanib arm than in the placebo arm. Most of these events
were Grade 1 or 2 using the National Cancer Institute Common Toxicity Criteria 
for Adverse Events (NCI CTCAE) Version 3.0. More Grade 3 AEs were reported
in the pazopanib arm (33%) compared with the placebo arm (14%). The frequency


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of Grade 4 AE and Grade 5 events was similar between the pazopanib and placebo
arms: Grade 4 in 7% and 6%, respectively; Grade 5 in 4% and 3%, respectively.29
At the time of the final overall survival (OS) analysis, a subsequent review of
safety data did not reveal any changes to the previously observed safety profile; no 
new safety signals were detected.
Based on the analysis of the safety data integrated across 3 RCC studies, including 
a Phase II study of pazopanib monotherapy in patients with advanced RCC and a
single arm Phase III extension study of pazopanib monotherapy in patients with
advanced RCC as of January 9, 2009 (N=593), the most common AEs and serious 
adverse events (SAEs) were similar to those observed in the pazopanib arm of the 
monotherapy Phase III study.
In a randomized placebo-controlled Phase III study of pazopanib monotherapy in 
patients with soft tissue sarcoma [STS]), the median time on pazopanib was 19.4 
weeks, as compared with 8.1 weeks in the placebo arm. The most common AEs 
(≥20%) reported in the pazopanib arm (as of May 23, 2011) were fatigue (65%), 
diarrhea (59%), nausea (56%), weight decreased (51%), hypertension (42%), 
decreased appetite (40%), hair color changes (39%), vomiting (33%), tumor pain 
(30%), dysguesia (28%), headache (23%), musculoskeletal pain (23%), myalgia 
(23%), gastrointestinal pain (23%), and dyspnea (20%). Twenty-eight percent of 
patients on placebo and 63% of patients on pazopanib experienced an AE of 
maximum Grade 3 or higher. The proportion of patients who experienced 
maximum Grade 4 and Grade 5 AEs was similar in both treatment arms. 30
An analysis of integrated safety data from a Phase III study in patients with STS 
and a single arm Phase II study of pazopanib monotherapy in patients with STS 
showed a safety profile similar to that observed in the pazopanib arm of the 
Phase III study alone. Increased rates of myocardial dysfunction, venous thrombo-
embolic events, and pneumothorax were newly observed in the STS studies as
compared to RCC. Rare but severe AEs previously described for VEGFR inhibitors, 
such as cardiac/cerebral ischemia, hemorrhage, and bowel perforation, were 
observed with pazopanib treatment.
A review of SAEs across oncology studies revealed that the most frequently 
reported SAEs (≥70 events), regardless of causality and treatment regimen, as of 
September 9, 2011 in decreasing order of frequency were increased ALT, dyspnea, 
vomiting, abdominal pain, pyrexia, diarrhea, anemia, pneumonia, dehydration, and 
aspartate aminotransferase (AST) increased.
2.3.3
Efficacy Data in Adults with Cancer
Pazopanib 800 mg once daily has shown efficacy and/or encouraging efficacy 
signals in the following settings:

RCC: The primary analysis of the primary endpoint, progression-free survival 
(PFS), revealed a large and highly statistically significant improvement in PFS
in the pazopanib-treated patients compared to placebo- treated patients (hazard 
ratio [HR] 0.46, 95% confidence interval [CI] 0.34 to 0.62, p<0.0000001). The 
median PFS in the pazopanib arm was more than double that in the placebo
arm: 9.2 months (95% CI, 7.4, 12.9) versus 4.2 months (95% CI, 2.8, 4.2),
respectively. The response rate (RR), defined as the percentage of patients who 
achieved either a confirmed complete response (CR) or partial response (PR)


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according to Response Evaluation Criteria in Solid Tumors (RECIST) was 
significantly higher for the pazopanib arm compared with the placebo arm by 
Independent Review Committee (IRC) assessment (30% vs. 3%, p<0.001). In
the pazopanib arm, the median duration of response was 58.7 weeks (95%
CI, 52.1 to 68.1 weeks) and the median time to response was 11.9 weeks (95% 
CI, 9.4 to 12.3 weeks) by IRC assessment.29 The median OS at final analysis
was 22.9 months in the pazopanib arm and 20.5 months in the placebo arm. The
final OS was not statistically different between the pazopanib arm and the
placebo arm in (HR = 0.91, stratified log-rank p-value, 0.224). Of note, 54% of 
patients in the placebo arm received pazopanib, many starting early in the study, 
and an additional 12% received other systemic therapies.

Soft Tissue Sarcoma: In a Phase III study a statistically significant 
improvement in PFS but not OS was observed in the pazopanib arm compared
with the placebo arm. Median progression-free survival was 4.6 months for
pazopanib compared with 1.6 months for placebo (hazard ratio [HR] 0.31, 95%
CI 0.24-0.40; p<0.0001). Overall survival was 12.5 months with pazopanib 
versus 10.7 months with placebo (HR 0.86, 0.67-1.11; p=0.25).30 In a Phase II 
Study, the PFS rate at 12 weeks, based on investigator assessment, was 18 of
41 patients (43.9%) for leiomyosarcoma;18 of 37 patients (48.6%) for synovial 
sarcoma; 5 of 19 (26.3%) for adipocytic sarcoma; and 16 of 41 patients (39.0%)
for other types of sarcoma.31

Ovarian cancer: 11 of 36 patients (31%) experienced a cancer antigen-125 
(CA-125) response to pazopanib, with a median time to CA-125 response of
29 days and median duration of response of 113 days. Excluding one patient 
whose CA-125 decreased before she received the first dose, the biochemical
response was 28% (10 patients). Overall response rate based on modified
Gynecologic Cancer Intergroup (GCIG) criteria (incorporating CA-125, 
RECIST, and clinical assessment) was 18% in patients with measurable disease 
at baseline, and was 21% in patients without measurable disease at baseline. 
Median PFS was 84 days.32

Early-stage Non-Small Cell Lung Cancer (NSCLC): 30 of 35 patients 
(86%) experienced a reduction in tumor volume after short-term use of 
pazopanib (median duration of 16 days) as assessed by high-resolution 
computed tomography (HRCT) after preoperative pazopanib treatment.33

ErbB2-positive advanced or metastatic breast cancer: A higher response 
rate (36.2% versus 22.2%) by independent review at Week 12 was observed in
patients on combination lapatinib 1000 mg once daily + pazopanib 400 mg once
daily compared with lapatinib 1500 mg once daily as a monotherapy, 
respectively.34

Cervical cancer: There was a 34% reduction in risk for progression for 
patients receiving pazopanib relative to lapatinib (hazard ratio: 0.66; 90% CI: 
0.48, 0.91). The median time to investigator-assessed PFS was 17.1 weeks in 
the lapatinib group and 18.1 weeks in the pazopanib (one-sided p=0.013).35
Pazopanib has not shown signals of efficacy in Phase II studies conducted in 
multiple myeloma (VEG20006) 36 or glioma (VEG102857).
Most important to the rationale for this current trial are the results from the study 
of pazopanib in adult patients with advanced or metastatic soft tissue sarcoma. 
These combined findings form the basis for including several cohorts for soft tissue 
and bone sarcoma as well as the embryonal tumors specific to pediatrics, which are 
of mesenchymal origin.


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To date, results of correlative biologic assays specific to pazopanib are limited. 
Most studies sample platelet-poor plasma and serum for cytokine/angiogenic factor 
profiling which include VEGF, sVEGFR1, and sVEGFR2 and whole blood for
circulating endothelial cell subsets (CECs). In two separate Phase II studies of
renal cell and NSCLC presented at the 2008 annual meeting of the American
Society for Clinical Oncology (ASCO) a decrease in sVEGFR2 compared with
baseline was significantly correlated with tumor response (p <0.05).37,38 In adult
patients with metastatic imatinib-refractory gastrointestinal stromal tumors treated 
with sunitinib, another VEGF and c-kit targeting multityrosine kinase inhibitor, 
biomarker analysis of CECs, monocytes, VEGF, and sVEGFR-2 were consistently 
modulated by treatment. In this study, changes in CECs and monocytes rather than 
plasma markers differed between the patients with clinical benefit and those with
progressive disease.39 In pediatric patients with refractory solid tumors treated
with pazopanib, baseline levels of plasma soluble VEGFR-2 and endoglin levels
were significantly decreased when measured after 2 weeks of treatment, while
placental growth factor levels were significantly increased over the same time 
points. There was no significant change in VEGF or plasma soluble VEGFR-1
levels with pazopanib therapy.40
This study will continue to examine the effects of pazopanib therapy on cytokines 
and angiogenic factors.
In part, genetic predisposition may account for the variability in biomarker or 
clinical response to anti-VEGF treatment. Three lines of ongoing investigation 
justify voluntary collection of DNA in this trial to evaluate relationships between 
discovered associations in the adult population and pazopanib effects in the 
pediatric population, and to assess age as a covariate in these relationships.
1)
Recently, Dr.
and
 colleagues identified a single nucleotide 
polymorphism in KDR (the gene that encodes VEGFR2) that is reproducibly 
associated with the baseline levels of circulating soluble VEGFR2 in three 
separate cohorts: healthy volunteers of the Old Order Amish community; 128 
unrelated cancer patients at the 
; and adult RCC patients
enrolled on the phase II trials of pazopanib. Subsequently, they demonstrated
that in the RCC patients treated with pazopanib for 4 weeks, this
polymorphism is associated with a greater magnitude decline in plasma 
sVEGFR2 (Late Breaking Abstract, 2011 Am Soc Clin Pharm & Therapeutics
Meeting). This genotype/phenotype relationship is currently being studied by 
another cooperative group (the CALGB Pharmacology and Experimental 
Therapeutics Committee) in adult patients who are taking agents in this class.
Determination of the effect of this KDR polymorphism and sVEGFR2 degree
of change on disease response to therapy is ongoing.
2)
Several genotypes at the VEGFA locus have been associated with increased 
or decreased VEGF production and prognostic and predictive marking of 
treatment outcomes. In most VEGF signaling pathway inhibitor trials 
analyzed so far, 4 SNPs in the promoter region have been evaluated for 
associations with clinical outcomes: -2578, -1498, -1154, and -634. These 
studies have yielded inconsistent findings. In amyotrophic lateral sclerosis, 
similar inconsistencies led to confusion on the predictive role of VEGF alleles
until a meta-analysis by Lambrechts, et al.41 revealed only -2578 to have a
clinically relevant and consistent effect. Such studies in oncology are ongoing.


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We propose to evaluate all common variation across the VEGFA locus with
tagging SNPs representing all common variation in the haplotype analyzed
for association with changes in VEGF-A post pazopanib exposure, response 
rate, and progression-free survival.
3)
GlaxoSmithKline has recently published results
of a candidate gene 
association study in adult RCC patients treated with pazopanib.25 Several 
polymorphisms in candidate genes demonstrated associations with response 
rate and progression-free survival. Validation and elaboration of these 
findings will become available prior to completion of this trial. Based on the 
adult findings, additional
markers may
be explored
in
the
pediatric 
population.
2.4
Pediatric Studies
2.4.1
Pediatric Phase I Studies
The Children’s Oncology Group (COG) conducted a phase I study of pazopanib 
in children with STS or other refractory solid tumors (ADVL0815). This study was
performed to determine the maximum tolerated dose (MTD) of two formulations
of oral pazopanib; to define and describe the toxicities, pharmacodyamics and
pharmacokinetics (PK) of pazopanib administered as a tablet (Part 1) or powder 
suspension (Part 2a); and to explore pazopanib induced changes in tumor blood
volume and vascular permeability (Ki) using dynamic contrast enhanced MRI
(DCE-MRI) in a subset of patients with STS (Part 2b). During part 1, pazopanib 
(tablet formulation) was administered once daily in 28 day cycles at 4 dose levels 
(275 to 600 mg/m2) using the rolling-six design. Dose determination for a powder 
suspension (Part 2a) was initiated at 50% of the MTD for the intact tablet. Ten
patients with STS underwent DCE-MRI scanning at baseline and 15 ± 2 days after 
initiation of pazopanib at the tablet MTD (Part 2b). A total of 53 patients were
enrolled; 51 were eligible [26 male, median age 12.9 yrs (range 3.8-23.9)].
Hematologic and non-hematologic toxicities were generally mild. Diarrhea, nausea,
vomiting, fatigue, proteinuria and hypertension were the most commonly reported
side effects. Only cycle 1 DLTs were considered for determination of the MTD 
and included Grade 3 lipase, amylase and ALT elevation, proteinuria and
hypertension. One patient with occult brain metastasis in the imaging expansion
cohort also had Grade 4 intracranial hemorrhage. The MTD was 450 mg/m2/dose
for tablets, and 160 mg/ m2/dose for powder suspension; two isolated and reversible 
Grade 3 ALT elevations were seen at the powder suspension dose of 225 mg/
m2/dose. Toxicities requiring dose modification and/or discontinuation in later 
cycles included tumor pain (n=2), ALT elevation (n=2), diarrhea, myalgia 
associated with microangiopathic hemolytic anemia, hand foot syndrome, weight 
loss, fistula formation at a site of prior RT, growth plate abnormality and recurrent
neutropenia (each n=1). Three of 27 patients treated at the MTD had asymptomatic
decreases in left ventricular systolic function; all were reversible and the drug was
successfully reintroduced in two. Asymptomatic sinus bradycardia was noted in 4
patients, all ≥12 years. No QTc prolongation was observed.
Steady state trough concentration (Ctrough) was reached by day 15 and exceeded
15µg/ml at all dose levels. There was marked inter-patient variability in PK 
parameters resulting in substantial overlap between dose levels and trough 
concentrations did not appear dose-dependent. Patients received 1-22+ cycles 


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(median = 2). One patient each with hepatoblastoma or desmoplastic small round 
and all 5 who received therapy for a year or more had Ctrough ≥30 μg/ml. All 
patients with evaluable DCE-MRI (n=8) experienced decreases in tumor blood 
volume and permeability (Ki; p<0.01). PlGF increased, whereas endoglin and 
soluble VEGFR2 decreased (p<0.01; n=31).40
2.4.2
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
Hypertension was seen in several patients in the pediatric Phase I dose escalation 
study, which is a class effect seen with
other VEGF blocking agents. Such
hypertension has been treatable with anti-hypertensives and may ultimately be a 
biomarker of treatment effect. Pediatric specific guidelines for the management 
of VEGF blocking agent-induced hypertension have been developed for other COG
Developmental Therapeutics studies (e.g. ADVL0413, ADVL0612, ADVL0714,
and ADVL0815) and will be used for this trial. In the adult Phase I pazopanib trial,
a relationship between steady-state trough concentrations and the occurrence of
hypertension could be described by a logistic regression model. Twenty (77%) of
the 26 patients with Ctrough values > 15 μg/mL on Day 22 developed
hypertension, versus 11 (39%) of the 28 patients who had lower Ctrough values.42
In the pediatric phase I trial, the mean Ctrough in patients with drug related
hypertension (n=13) was 42±13 g/ml versus 29±13 g/ml in normotensive 
patients (n=27; p=0.008), suggesting a relationship between blood pressure
elevation and drug exposure. In addition pediatric patients with a best response of 
stable disease had a 30% incidence of blood pressure elevation within the first two 
cycles, and 47% incidence over all cycles. This trial will seek to expand our
understanding of the relationship of pazopanib Ctrough to hypertension, and the 
utility of hypertension as a pharmacodynamic or predictive marker.
2.5
Overview of Proposed Pediatric Phase II Trial
This is a two-stage open label phase II trial of pazopanib in children, adolescents and young 
adults
with recurrent or refractory solid tumors. Tumors of primary interest are 
rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma (including synovial sarcoma,
alveolar soft part sarcoma and desmoplastic small round cell tumor) and Ewing sarcoma/peripheral
PNET. Tumors of secondary interest include hepatoblastoma, neuroblastoma (measurable and 
evaluable), and osteosarcoma.
Each tumor type defines a cohort resulting in 7 total cohorts. The first stage of the study involves 
enrolling an initial 10 patients into each cohort. The response rate will be determined for each cohort
after the target enrollment of 10 patients is reached for that cohort. If one or more confirmed
responses are observed in the first 10 evaluable patients in a cohort, an additional 10 patients will 
be enrolled into that cohort in the second stage of study. Thus, for cohort(s) with one or more
confirmed responses in the first stage of study, a total of 20 patients will be enrolled and evaluated 
to determine efficacy.
Eligible patients will receive pazopanib monotherapy. Pazopanib will be dosed daily as an oral 
tablet (450 mg/m2/dose, maximum 800 mg) or as a powder for oral suspension (225 mg/m2/dose, 
maximum 400 mg) in 28 day cycles.
The MTD for pazopanib tablets was 450 mg/m2/dose as determined by ADVL0815/PZP114411, 
the COG Phase I study in children with relapsed or refractory solid tumors. For the powder 
suspension formulation, the selected starting dose is higher than the protocol-defined MTD of 160 
mg/m2/dose established in ADVL0815. This decision is driven by the considerations that the 160


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isolated and reversible laboratory-defined DLTs were observed at the 225 mg/m2/dose.
The first patients who are enrolled to receive pazopanib as powder suspension at 225 mg/m2/dose 
daily will be closely monitored for safety and for the occurrence of dose-limiting toxicity during 
the first cycle (28 days) of therapy. Patients who either receive 225 mg/m2/dose daily for at least 24
days (85% of the dose for a 28-day cycle with powder suspension at 225 mg/m2/dose) or are 
withdrawn from dosing due to one or more protocol-defined dose-limiting toxicities (Section 5.1) 
during the first cycle will be considered evaluable for the purpose of this safety review. Six
evaluable patients are required.
The first patients enrolled to receive powder suspension at 225 mg/m2/dose will also be expected 
to complete extended PK sampling (Section 7.3.2) with blood samples collected prior to dosing, 
and 30 min, 1, 2, 4, 6, and 8 hours after the pazopanib dose on Day 1 and Day 15 ± 1 day of 
Cycle 1 (with no pazopanib dose modification or adjustment in the 10 days before Cycle 1 Day
15 sample collection). Patients who can provide adequate blood samples for the 2 scheduled 
extended PK collections will be considered to be evaluable patients for the purpose of this PK
analysis, and PK data are required from 6 evaluable patients. If one or more of the first 6 patients 
fails to provide blood samples as specified in the protocol or if it is known that for some reason a 
patient’s collected blood sample(s) cannot be analyzed, that patient will be determined to be non-
evaluable for this analysis, and one or more additional patients will be enrolled for treatment with 
pazopanib as powder suspension for the purpose of obtaining the extended PK samples.
Because patients receiving the powder suspension enrolled in the safety review group may be 
different from those in the PK analysis group, enrollment onto powder suspension may follow 
several different paths:

If ≥2 out of 6 evaluable patients have dose- limiting toxicities (DLT and as defined in 
Section 5.1) within the first cycle, then enrollment onto 225 mg/m2/dose pazopanib will
be halted. Subsequent new patients will be enrolled at the 160 mg/m2/dose level until 6
evaluable patients from this dose group are available for the safety review and 6 patients 
are available for PK analysis at 160 mg/m2/dose.

If 6 PK evaluable patients are enrolled prior to enrollment of 6 patients who are 
evaluable for the safety review, the extended PK sample collection may be suspended.

If < 2 DLTs are observed during the first cycle in 6 patients evaluable for safety at 225
mg/m2/dose and these 6 patients are not all evaluable for the PK analysis, then 
enrollment will continue until 6 PK evaluable patients are available.
All patients will be closely monitored with clinical and laboratory observations for adverse 
events.
Tumor response will be evaluated using appropriate imaging assessments at baseline, prior to
Cycle 3, Cycle 5, Cycle 8, Cycle 11 and then every 3rd cycle thereafter.
 
In addition, we will assess KDR polymorphism and 
pazopanib-induced change in soluble VEGFR2; VEGF-A genotype and changes in VEGF-A 
concentration; KDR and VEGF-A genotypes and response rate, and progression-free survival; 
and candidate SNPs and clinical endpoints as identified in the adult population.
The primary analysis will be performed 20 weeks after the last patient’s first visit in the three 
cohorts of primary interest (rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma 
and Ewing sarcoma/peripheral PNET).
The study will be completed one year from the date of the last patient’s first visit and the end of 
study analysis will be performed at the time of study completion.


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For patients who are still on treatment and continue to derive benefit from it at the time of study 
completion, and for whom no other treatment options are available, Novartis will discuss individual
patient cases with investigators to identify possible access to study treatment after termination of
the VEG116731/ADVL1322/PZP034X2203 trial.
A patient will be considered to have completed the study if the patient:

Dies while on study and prior to study completion

Stays on study in follow-up until the time of study completion


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3
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA
3.1
Study Enrollment
3.1.1
Patient Registration
No study-specific procedure will start before the signature of the informed 
consent form (and assent, according to institutional guidelines), defining the 
study entry.
Prior to enrollment on study, patients must be assigned a COG patient ID 
number. This number is obtained once authorization for the release of
protected health information (PHI) has been obtained. The COG patient ID
number is used to identify the patient in all future interactions with COG. If
you have problems with registration, please refer to the online help.
Upon completion of all required baseline assessments, the investigator or 
authorized site staff will assign each eligible patient a Sponsor study-specific 
patient identification number. Each site will be assigned a range of patient 
numbers, and this information is provided in the Study Procedure Manual
(SPM). The patient ID number consists of 6 digits including leading zeros.
Using
this 
patient
ID 
number
and 
patient’s 
histology
cohort 
(rhabdomyosarcoma, non- rhabdomyosarcomatous soft tissue sarcoma, Ewing 
sarcoma/peripheral
PNET, osteosarcoma,
neuroblastoma
(measureable),
neuroblastoma (evaluable) or hepatoblastoma), each patient will then be
registered into the interactive webresponse system (IWRS). The IWRS will
then provide a randomization number consistent with the patient’s tumor type.
All sessions to IWRS are confirmed with an onscreen confirmation which
will be also sent via e-mail to the site upon completion of each call. Study-
specific instructions will be provided for the use of IWRS in the Study 
Procedures Manual and in the user manual.
3.1.2
Patient Rescreening
Patients may be rescreened if the reasons for the initial screen failure were non-
medical or if the medical issues leading to screen failure have resolved. 
Approval by the Study Chair is required prior to rescreening. A new informed 
consent form must be signed. Please refer to detailed instructions in the
Study Procedure Manual for rescreening.
3.1.3
Institutional Review Board (IRB) Approval
Local IRB/REB approval of this study must be obtained by a site prior to 
enrolling patients.
Sites must submit the following documents to Novartis prior to approval to
enroll subjects and receive study drug:

FDA 1572 (for U.S. sites)

Investigator Agreement Page in Protocol

Financial Disclosure Forms


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
IRB approval (ICF, protocol, subject related materials)

CV’s (Investigator and sub-investigators)

Laboratory Certifications and Normal Lab Values
IRB/REB approval documents may be faxed, e-mailed, or mailed to Novartis. 
Further details will be provided in the Study Procedures Manual.
3.1.4
Study Enrollment Status
The study will remain open for enrollment into any of the 7 cohorts until the 
following:
1.
The cohorts with the tumors of primary interest have completed 
enrollment 
and
2.
All patients with tumors in the primary interest cohorts have either 
discontinued from study treatment or have completed a minimum of 5 
cycles of treatment
While the study remains open for enrollment, enrollment into each cohort will 
proceed independently from the other cohorts (see Section 9.2 for details). The 
enrollment in the cohorts of secondary interest may remain open if after
review of the data, an efficacy signal is seen.
The Sponsor in agreement with 
COG may consider the option of 
closing recruitment of further patients in a given study cohort in the case that no 
objective responses are observed in the first 10 evaluable patients in two out of 
the 3 cohorts of primary interest during stage 1 of the study. 
3.1.5
Study Enrollment
Patients may be enrolled on the study once all eligibility requirements for the 
study have been met. Specific procedures related to the requirements for patient 
enrollment are described in protocol Section 3 and in the Study Procedures 
Manual. Sites will be required to complete a session into the (IWRS) to record 
patient information as described in Section 3.1.1.
3.1.6
Timing
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than 5 calendar days after the date of
study enrollment. See Section 3.2 for timing requirements for eligibility studies.
See Section 3.1.7 for timing requirements for baseline studies to be obtained
prior to start of therapy. Note: Repeat laboratory and imaging studies may
be required if enrollment and start of therapy do not occur on the same 
day.
3.1.7
Requirements to Initiate Protocol Therapy
3.1.7.1
LaboratoryStudies: If more than 7 calendar days elapse between
the date laboratory studies to determine eligibility were obtained


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(Section 3.2.8) and the start date of treatment, then the following
studies must be repeated prior to initiating protocol therapy: CBC
with differential, bilirubin, ALT (SGPT) and serum creatinine. If any
of these repeat laboratory assessments are outside the parameters 
required for eligibility (labs may again be repeated within 48-72 
hours), then the patient is not eligible for protocol therapy.
Note: For hepatoblastoma patients, blood for serum alpha fetoprotein 
(AFP) must be drawn within 48 hours prior to initiating protocol 
therapy. It is not required that the results be known prior to 
enrollment.
3.1.7.2
Imaging Studies: Imaging studies must be performed within 14
calendar days prior to initiating protocol therapy. If more than 14 
calendar days have elapsed between the date imaging studies to 
determine eligibility were obtained (Section 3.2) and the enrollment 
date, then repeat imaging assessments must be obtained prior to 
initiating protocol therapy.
3.1.7.3
Cardiac studies: Cardiac ECHO and electrocardiogram (ECG) must
be performed within 14 calendar days prior to initiating protocol
therapy. If more than 14 days have elapsed between the date cardiac
studies to determine eligibility were obtained (Section 3.2.8.4) and the 
enrollment date, then repeat cardiac studies must be obtained prior to 
initiating protocol therapy.
3.1.7.4
Bone Marrow (BM) Evaluations (Solid Tumors with known Marrow
Involvement): Bone Marrow aspirate and/or biopsy must be
performed within 14 calendar days prior to initiating protocol therapy.
If the Bone Marrow evaluation was performed more than 14 days
prior to enrollment date and if it was negative, then BM aspirate 
and/or biopsy must be repeated prior to initiating protocol therapy. If 
the Bone Marrow evaluation was obtained more than 14 calendar days
prior to enrollment and it was positive, and there was no intervening
treatment provided to the patients, then there is no need to repeat the
Bone Marrow evaluation.
3.2
Eligibility: Inclusion Criteria
Important note: The inclusion criteria listed below are interpreted literally
and cannot be waived. All clinical and laboratory data required for determining 
eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record. These source documents must be available for
verification at the time of audit.
All clinical and laboratory studies to determine eligibility must be performed
within 7 days prior to the date of enrollment. Imaging studies must be performed
within 14 days prior to the date of enrollment. The cardiac ECHO, electrocardiogram
(EKG) and baseline knee radiograph must be obtained within 14 days prior to the date 
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3.2.1
Age: Patients must be at least 1 year and less than or equal to 18 years of age
at the time of study entry.
3.2.2
Diagnosis: Patients must have had histologic verification of one of the 
malignancies listed below at original diagnosis or at relapse.
1. Rhabdomyosarcoma
2. Non-rhabdomyosarcomatous Soft Tissue Sarcoma (including 
desmoplastic small round cell tumor)
3. Ewing Sarcoma/Peripheral PNET
4. Osteosarcoma
5. Neuroblastoma (Measurable)
6. Neuroblastoma (Evaluable)
7. Hepatoblastoma
 
 
3.2.3
Patient must have disease that has either relapsed or is refractory to prior 
therapy
3.2.4
Body Surface Area (BSA) (for subjects taking tablet formulation only):
Patients who will be receiving the tablet formulation must have a BSA ≥0.84
m2 at baseline. The same method should be used to calculate a given patient’s
BSA throughout their study participation.
3.2.5
Disease Status
3.2.5.1
Patients must have radiographically measurable disease (with the 
exception of neuroblastoma – see Section 3.2.5.2).
Measurable disease is defined as the presence of at least one lesion on MRI or
CT scan that can be accurately measured with the longest diameter a minimum 
of 10 mm in at least one dimension (CT scan slice thickness no greater than 5
mm).
Note: The following do not qualify as measurable disease:

malignant fluid collections (e.g. ascites, pleural effusions)

bone marrow infiltration

lesions only detected by nuclear medicine studies (e.g., bone, gallium 
or PET scans)

elevated tumor markers in plasma

previously radiated lesions that have
not demonstrated clear 
progression post radiation
3.2.5.2
Patients with neuroblastoma who do not have measurable disease but 
have metaiodobenzylguanidine (MIBG+) evaluable disease are
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Note: If the patient has only one MIBG positive lesion and that lesion was
irradiated, a biopsy must be or have been done at least 4 weeks after
radiation was completed and must show viable neuroblastoma (see Section 
10.4.1).
3.2.6
Performance Level
Patients must have a Lansky or Karnofsky performance status score of ≥
50, corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients > 
16 years of age and Lansky for patients ≤16 years of age. Note: Patients who
are unable to walk because of paralysis, but who are up in a wheelchair, will
be considered ambulatory for the purpose of assessing the performance score.
3.2.7
Prior Therapy
3.2.7.1
Patients must have fully recovered from the acute toxic effects of all 
prior chemotherapy, immunotherapy, or radiotherapy prior to entering 
this study.
a. Myelosuppressive 
chemotherapy: 
Must 
not 
have 
received 
myelosuppressive chemotherapy within 3 weeks of enrollment onto this 
study (6 weeks if prior nitrosourea).
b. Hematopoietic growth factors: At least 7 days must have elapsed since
the completion of therapy with a growth factor that supports platelet or
white cell number or function. At least 14 days must have elapsed after 
receiving peg-filgrastim.
c. Biologic (anti-neoplastic agent):

At least 7 days must have elapsed since the completion of therapy with 
a biologic agent.

For biologic agents that have known adverse events occurring 
beyond 7 days after administration, the period prior to enrollment must 
be extended beyond the time during which adverse events are known 
to occur.

Patients may have received bevacizumab, VEGF-Trap, or other 
VEGF blocking tyrosine kinase inhibitors, provided that they did not
progress while receiving one of these agents. Patients may not have 
previously received pazopanib.

At least 21 days must have elapsed since the completion of the last
dose of VEGF-Trap, and at least 7 days since a VEGF blocking
tyrosine kinase inhibitor. Patients must have recovered from
any 
VEGF blocking drug-related toxicity (e.g., proteinuria).
d. Monoclonal antibodies: ≥ 21 days must have elapsed from infusion of last 
dose of antibody, and toxicity related to prior antibody therapy must have
recovered to Grade ≤ 1.
e. Radiotherapy (XRT): ≥2 weeks must have elapsed since local palliative
XRT (small port); ≥3 months must have elapsed if prior total body
irradiation (TBI), craniospinal XRT or if ≥50% radiation of pelvis; ≥6
weeks must have elapsed if other substantial bone marrow irradiation 
was given.


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f. Stem CellTransplantor Rescue without TBI: No evidence of active graft vs. 
host disease and ≥2 months must have elapsed since transplant or rescue
3.2.8
Organ Function Requirements
3.2.8.1
Adequate Bone Marrow Function defined as:

Peripheral absolute neutrophil count (ANC) 1000/L

Platelet count 75,000/L (transfusion independent,
defined as not receiving platelet transfusions within a 7-
day period prior to enrollment); and

Hemoglobin 8.0 g/dL (may receive RBC transfusions)
Note: Patients with bone marrow involvement will be eligible for 
study (provided they meet the criteria above) but will not be 
evaluable for hematologic toxicity.
3.2.8.2
Adequate Renal and Metabolic Function defined as:
a.
Creatinine clearance or radioisotope glomerular filtration rate
(GFR) ≥70 mL/min/1.73 m2, or
b.
A serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1
1
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the 
Schwartz formula43 for estimating GFR utilizing child length and 
stature data published by the CDC.
c.
Urine protein:creatinine (UPC) ratio of <1; or a urinalysis
that is negative for protein; or 24-hour urine protein level <
1000 mg/dL (see Appendix IV).
d.
Adequate thyroid function: either normal TSH or on a stable
dose of thyroid replacement for at least 4 weeks (see Section
3.3.2.8)
e.
No more than Grade 1 abnormalities of:
a. Potassium
b. Calcium (confirmed by ionized calcium)
c. Magnesium
d. d. Phosphorous
Oral supplementation is allowed.
3.2.8.3
Adequate Liver Function defined as:
a.
Total bilirubin ≤1.5 x upper limit of normal (ULN) for age;
b.
SGPT (ALT) ≤2.5 x ULN (for the purpose of this study, the
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c.
Serum albumin ≥2 g/dL.
d.
Must not have active liver or biliary disease (with the
exception of Gilbert’s syndrome or asymptomatic gallstones,
liver metastases or otherwise stable chronic liver disease per 
investigator assessment).

NOTE: Stable chronic liver disease should generally be 
defined by the absence of ascites, encephalopathy,
coagulopathy, hypoalbuminemia, oesophageal or gastric 
varices, persistent jaundice, or cirrhosis.
e.
No known positivity of hepatitis B surface antigen (HBsAg)
or of positive hepatitis C antibody
3.2.8.4
Adequate Cardiac Function defined as: 
a.
Shortening fraction of ≥27% by echocardiogram (while not 
receiving medications for cardiac function), or
b.
Ejection fraction of ≥50% by gated radionuclide study
(while not receiving medications for cardiac function)
c.
Corrected QT according to the Bazett’s formula QTcB must 
be < 450 msec (See Section 5.4.6.2 to determine QTcB)
d.
Must not have a history of myocardial infarction, severe or
unstable angina, peripheral vascular disease or familial QT 
prolongation.
3.2.8.5
Adequate Blood Pressure Control defined as: 
A blood pressure (BP) ≤the 95th percentile for age, height, and
gender (Appendix V) measured as described in Section 5.4.1.

Patients on stable doses of no more than one anti-hypertensive 
medication, with a baseline BP ≤95th percentile for age, height
and gender (Appendix V), will be eligible.
3.2.8.6
Central Nervous System Function defined as: 
a.
Patients with a known history of seizures must have well-
controlled seizures and may not be receiving enzyme-inducing
anti-convulsants (See Appendix IIIA)
b.
CNS toxicity ≤ Grade 2.
3.2.8.7
Adequate Coagulation defined as:
PT and PTT ≤ 1.2 x upper limit of normal and an INR ≤ 1.2.
3.3
Exclusion Criteria
Important note: The exclusion criteria listed below are interpreted literally
and cannot be waived. All clinical and laboratory data required for determining 
eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record. These source documents must be available for
verification at the time of audit.
3.3.1
Pregnancy or Breast Feeding/contraception
Pregnant or breast-feeding women are not eligible for this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies. Negative 


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pregnancy tests must be obtained in girls who are post-menarchal. Females of 
reproductive potential may not participate unless they have agreed to use an 
effective contraceptive method beginning at the signing of the informed 
consent until at least 2 weeks after the last dose of the study drug. The
definition of adequate contraception will be based on the judgment of the 
principal investigator or a designated associate. Study drug may also potentially 
be secreted in milk and therefore breastfeeding women are excluded.
Males (including those who have had vasectomies) with partners who can 
become pregnant will need to use birth control while on this study, as will their 
partner. Men are advised to use condoms during sexual intercourse while on 
study drug and continue to use adequate contraception for at least 2 weeks after 
the last dose of protocol therapy.
3.3.2
Concomitant  Medications
3.3.2.1
Corticosteroids: Patients requiring corticosteroid who have not been 
on a stable or decreasing dose of corticosteroid for the 7 days prior
to enrollment are not eligible.
3.3.2.2
Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible.
3.3.2.3
Anti-Cancer Agents or Radiation Therapy:
Patients
who
are
currently receiving other anti-cancer agents or radiation therapy are 
not eligible.
3.3.2.4
Anti-hypertensive: Patients who are currently receiving more than
one anti-hypertensive medication (Grade 3) or whose blood pressure 
is not controlled (i.e. as defined in Section 3.2.8.) are not eligible for
study enrollment.
3.3.2.5
Anti-coagulation: Patients must not be on therapeutic anticoagulation. 
((Warfarin (coumadin®) and/or low molecular weight heparin are 
prohibited.) Prophylactic anticoagulation (ie intraluminal heparin) of 
venous or arterial access devices is allowed.
3.3.2.6
CYP3A4 Substrates and drugs causing QTc prolongation: Patients 
receiving drugs with a known risk of torsades de pointes are not
eligible. See Appendices IIIA and IIIB and Section 4.8 for a list of
enzyme inducing, enzyme inhibiting and other adversely interacting
drugs and the appropriate washout periods required prior to study 
enrollment
Note: This list includes the prohibition of grapefruit juice for 14
days prior to enrollment and while receiving pazopanib.
3.3.2.7
Thyroid Replacement Therapy:
Patients
who
require thyroid
replacement therapy are not eligible if they have not been receiving a
stable replacement dose for at least 4 weeks prior to study enrollment.
3.3.3
Patients who are unable to swallow tablets or liquid are not eligible.
Pazopanib cannot be administered via NG tube or G-tube.
3.3.4
Infection: Patients who have an uncontrolled infection are not eligible.


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3.3.5
Bleeding and Thrombosis: Patients will be excluded if any of the following
are present:
3.3.5.1
Evidence of active bleeding, intratumoral hemorrhage, or bleeding
diathesis.
3.3.5.2
History (within 6 months
prior to study
enrollment) of arterial 
thromboembolic events, including transient ischemic attack (TIA) or 
cerebrovascular accident (CVA).
3.3.5.3
History (within 6 months prior to study enrollment) of pulmonary 
embolism, DVT, or other venous thromboembolic event.
3.3.5.4
History of clinically significant bleeding (grade 3 hemorrhage) within
6 weeks prior to study enrollment, including CNS, pulmonary, or GI 
hemorrhage.
3.3.6
Patients with known involvement of the CNS by malignancy will be excluded.
3.3.7
Surgery: Patients who have had or are planning to have the following invasive 
procedures will be excluded:
a.
Major surgical procedure, laparoscopic procedure, open biopsy or 
significant traumatic injury within 28 days prior to Day 1 therapy.
(Subcutaneous port placement or central line placement is not 
considered major surgery but must be placed greater than 48 hours 
from planned Day 1 of therapy.)
b.
Core biopsy within 7 days prior to Day 1 therapy
Note: Routine bone marrow aspirate and biopsy for the purposes of 
disease staging are not part of these exclusion guidelines.
c.
Fine needle aspirate or central line placement within 48 hours prior to 
Day 1 therapy.
3.3.8
Patients with serious or non-healing wound, ulcer, or bone fracture.
3.3.9
History of abdominal fistula, gastrointestinal perforation, pneumothorax, or 
intra- abdominal abscess within 28 days of study enrollment.
3.3.10 Patients who in the opinion of the investigator may not be able to comply
with the safety monitoring requirements of the study are not eligible
3.4
Regulatory
3.4.1
All patients and/or their parents or legal guardians must sign a written
informed consent (and assent according to institutional guidelines).
3.4.2
All institutional, FDA and Health Canada requirements for human studies
must be met.


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4
TREATMENT PROGRAM
4.1
Overview of Treatment Plan
Pazopanib will be dosed daily as an oral tablet at 450 mg/m2/dose or as a powder for oral suspension 
at 225 mg/m2/dose.
For the tablet formulation, the maximum tolerated dose (MTD) was 450 mg/m2/dose as determined
by ADVL0815/PZP114411, the COG Phase I study. The maximum dose to be administered daily 
for tablets is 800 mg.
For the powder suspension formulation, the selected starting dose is 225 mg/m2/dose, higher than
the protocol-specified MTD of 160 mg/m2/dose established in study ADVL0815. This decision is
driven by the considerations that the 160 mg/m2/dose may result in exposure that is suboptimal to
demonstrate efficacy and that only two isolated and reversible laboratory- defined dose-limiting 
toxicities (DLTs) were observed at the 225 mg/m2/dose. The maximum dose to be administered
daily for oral suspension is 400 mg.
Note: The first patients enrolled who receive powder suspension will be reviewed for safety and
will be expected to complete extended PK sampling (Section 7.3.2). A minimum of 6 evaluable
patients for safety and 6 evaluable patients for PK are required as described in section 2.5.
Safety and PK data from these patients will be reviewed prior to further enrollment of patients
requiring powder suspension to determine if the 225 mg/m2/dose is tolerated and if the PK
exposure is similar to exposure in adults associated with clinical efficacy. If 225 mg/m2/dose is not
tolerated (≥2 patients with DLTs in the first 6 evaluable patients during their first cycle), all
subsequently enrolled patients will receive 160 mg/m2/dose, and an additional 6 subjects will be 
assessed for safety and PK.
Patients will take pazopanib continuously, once daily. A cycle will be defined as 28 days with no
rest periods between cycles. Patients with benefit (stable disease or an objective response) may 
continue therapy unless there is evidence of progressive disease or unacceptable treatment-related
toxicity, death or until study closure defined as 1 year after Last Patient First Visit.
Patients must remain on the same formulation of pazopanib throughout the duration of
their protocol therapy.
Drug dosing for the tablet formulation should be determined using the dosing nomogram in 
Appendix II. For patients receiving powder for suspension (50 mg/mL), the dose will be rounded 
to the nearest 5 mg. Drug doses should be adjusted based on the BSA as determined by the height
and weight obtained within 1 week prior to the beginning of each cycle.
Pazopanib should be taken on an empty stomach (at least 1 hour before a meal or 2 hours after
a meal) at approximately the same time each day. Pazopanib tablets should be taken with clear
liquids (approximately 4 ounces for children < 12 years of age and 4-8 ounces for children ≥12
years of age). Pazopanib suspension should be taken according to instructions in Appendix VII.
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care. Minor unavoidable departures
(up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for surgery)
for valid clinical, patient and family logistical, or facility, procedure and/or anesthesia scheduling issues are
acceptable (except where explicitly prohibited within the protocol). This does NOT apply to eligibility
requirements; but to therapy and evaluations post consent and post the start of protocol directed care. Novartis
will not grant protocol waivers.


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The pazopanib suspension should be swirled for at least 30 seconds prior to removal of the dose 
from the bottle, which should be given immediately. If a patient vomits after a dose of pazopanib, 
the dose should not be repeated.
A patient diary (see Appendices IA and IB) should be completed by the patient or their guardian
and collected at the end of each cycle.
See Section 5 for Dose Modifications in Response to Toxicities
4.1.1
Dose Reduction
For patients who receive pazopanib tablets: Dose reduction(s) in response to toxicity
may be implemented according to guidance in Sections 5.2, 5.3, and 5.4 of the protocol.
Outside the specific management guidance described in these sections, patients who 
recover from an adverse event to starting criteria as outlined in Section 4.2 within 14
days following planned administration will also be permitted to receive protocol 
therapy at a reduced dose. Dose reduction(s) will be based on the starting dose and
should follow the Dosing Nomogram in Appendix II.
Note: For patients receiving pazopanib tablets at a starting dose of 400 mg, there will 
only be one allowed dose reduction due to tablet size.
For patients who receive pazopanib as oral powder for suspension:
Dose reduction(s) in response to toxicity may be implemented according to guidance 
in Sections 5.2, 5.3 and 5.4 of the protocol. Outside the specific management guidance
described in these sections, patients who recover from an adverse event to starting 
criteria as outlined in Section 4.2 within 14 days following planned administration will 
also be permitted to receive protocol therapy at a reduced dose. Dose reduction(s)
will be based on the starting dose and should follow the guidance in Table 1 and 
Table 1a.
Table1: Dose Reduction for Toxicity if powder suspension starting dose is 225 
mg/m2
Starting Dose
225 mg/m2/dose
First Dose Reduction
160 mg/m2/dose
Second Dose Reduction
135 mg/m2/dose
Table1a: Dose Reduction for Toxicity if powder suspension starting dose has 
been reduced to 160 mg/m2
Starting Dose
160 mg/m2/dose
First Dose Reduction
135 mg/m2/dose
Any subsequent dose reduction would need to be discussed and agreed by the 
Study Chair.
4.1.2
Dose Escalation
Dose escalations will not be allowed.
4.1.3
Treatment Interruptions
If the protocol therapy has been interrupted for more than 14 days due to toxicity or 


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for reasons other than toxicity (unplanned travel or vacation, or lack of transportation 
to the site), the Study Chair must be notified to review the patient’s condition in order 
to resume treatment. In cases of toxicity, re-challenge at a reduced dose is possible if 
the patient’s condition has been stable and has not deteriorated and the patient must 
have recovered from the toxicity (Section 4.2).
If the protocol therapy has been interrupted for more than 28 days, the patient 
should be permanently discontinued from protocol therapy and will continue to be 
followed for survival.
4.1.4
Missed Doses
Missed doses should be documented in the electronic case report form (eCRF).
If a dose is missed, the patient should take the dose as soon as possible, but only if
there are 12 or more hours left before the next dose is due. If the next dose is due in
less than 12 hours, the patient should skip the missed dose and take the next dose
as scheduled.
4.1.5
Study Specific Supportive Care
4.1.5.1
Management of Hypertension: The algorithm in Section 5.4.1 will be used
to grade and manage pazopanib-related hypertension. Should initiation of
anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine, which are
permissible without notifying the Study chair) should be started and the blood
pressure should be monitored at least twice weekly until BP is within the
95th percentile for age, height, and gender per Section 5.4.1.
If patient is already on an anti-hypertensive medication at study enrollment, 
then their anti-hypertensive therapy should be adjusted (by either adjusting
the dose of their current anti-hypertensive medication or by adding another
anti-hypertensive agent) according to the algorithm in Section 5.4.1.
4.1.5.2
Management of Hypothyroidism: Patients with Grade 2 hypothyroidism 
should be evaluated by an endocrinologist for further management. Patients
with Grade 2 hypothyroidism adequately managed with thyroid hormone
replacement may continue on protocol therapy. Patients with Grade 3 or 
greater hypothyroidism attributable to pazopanib will be considered to have
had a dose-limiting toxicity. These patients should be managed according to
Section 5.3 and should also be evaluated by an endocrinologist for further
management. If Grade 3 or greater hypothyroidism
is 
adequately 
managed with thyroid hormone replacement and improves to grade 2 or less, 
pazopanib may be restarted.
4.1.5.3
Treatment of palmer-plantar erythrodysesthesia (Hand-foot syndrome): Oral
administration of vitamin B 6 (pyridoxine) may be considered for patients
who develop palmar-plantar erythrodysesthesia (hand-foot) syndrome:

BSA <0.5 m2: 50 mg per day

BSA 0.5-1.0 m2: 100 mg per day

BSA >1.0-1.5 m2: 200 mg per day

BSA >1.5 m2: 300 mg per day
Other supportive care measures for the treatment of hand-foot syndrome 
should be instituted as needed. If steroids are used, they must fall within the 


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dosing parameters in Section 4.8.
4.1.5.4
Blood-product Support: Patients should be supported with transfusion of 
blood and blood products (including platelet transfusion) per institutional 
standards.
4.1.5.5
SupportiveCare: General supportive care should be provided according to 
institutional standards. The COG Study Chair or Novartis Medical Lead can
be contacted for specific questions regarding supportive care.
4.2
Criteria for Starting Subsequent Cycles
A cycle may be repeated every 28 days if the patient has at least stable disease or progressive 
disease is ruled out based on clinical or laboratory evidence and
met the clinical and 
laboratory parameters as defined by the guidelines for dose modification and toxicity 
management (Section 5) and does not have a dose limiting toxicity requiring permanent
removal from protocol therapy (Section 5.1). A patient may resume protocol therapy at the
same or a reduced dose if they have a toxicity that is adequately managed (eg:
myelosuppression, hypertension, hepatotoxicity, electrolyte abnormality, bleeding, wound
healing, etc) as outlined in Sections 5.2, 5.3, and 5.4.
4.3
Concomitant Therapy
If new data become available showing an interaction between a concomitant medication and 
pazopanib that is considered significant enough to impact the risk/benefit balance of 
pazopanib, the list of permitted/prohibited medications in the Investigator Brochure will be 
updated either during the annual update or within an IB supplement. Any such changes will 
be communicated to the site via a letter which should be stored in the site’s study file.
4.4
Permitted Medications
All patients will be asked to provide a complete list of prescription and over-the-counter 
medications that have been taken within the previous 4 weeks prior to Screening. The 
investigator must be informed as soon as possible about any new medication(s) taken from 
the time of Screening until the completion of the post-treatment follow-up visit.
All concomitant medications taken during the study will be recorded in the eCRF with 
indication, dose information, and dates of administration.
Patients should receive full supportive care during the study, including transfusion of blood 
and blood products, treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, 
when appropriate.
Anti-emetics (such
as
prochlorperazine,
lorazepam, ondansetron
or
other 5-HT3 
antagonists) may be administered prophylactically in the event of nausea. However, it is 
important to note that 5-HT3 blockers that are given daily for a prolonged period of time 
may prolong QTc and should be used with caution. (Appendix IIIB). Anti-diarrheals, such 
as loperamide, may be administered as needed in the event of diarrhea. Although 
acetaminophen at doses of 2 g/day is permitted, it should be used with caution in patients 
with impaired liver function.
4.5
Permitted Medications – Use with Caution
4.5.1
Specific recommendations regarding anticoagulants:
Results from drug-drug interaction studies conducted in patients with cancer suggest


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that pazopanib has no effect on the metabolism of S-warfarin. Hemorrhagic events,
however, have been reported in clinical studies with pazopanib. Therefore, if the
investigator decides to continue pazopanib and anticoagulants use concomitantly, it
should be used with caution in patients with increased risk of severe bleeding or
who are benefitting from treatment and require the initiation of concomitant 
anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight heparin, 
unfractionated heparin) while on study. Note: Patients are excluded from enrolling
on the study if they are taking therapeutic doses of S-warfarin at the time of screening.
Patients 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.
4.5.2
Specific recommendations regarding hypoglycemic therapy including insulin: 
Results from drug-drug interaction studies conducted in patients 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 reported in patients treated with 
another small molecule tyrosine kinase inhibitor, sunitinib (British Journal of Cancer
2008: 99, 1380). Such changes may require an adjustment in the dose of
hypoglycemic and/or insulin therapy. Patients should be advised to report symptoms
of hypoglycemia (e.g., confusion, visual disturbances, palpitations, and sweating). 
Serum glucose should be tested during treatment with pazopanib as outlined in the 
protocol and as clinically indicated.
4.5.3
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations 
and should be undertaken with caution and close monitoring. If a patient receiving 
concomitant simvastatin develops ALT elevations, follow dosing guidelines for 
pazopanib or consider discontinuing simvastatin.
4.5.4
Concomitant administration of pazopanib with esomeprazole decreases the 
bioavailability of pazopanib by 40% (AUC and Cmax). Co-administration of 
pazopanib
with
Proton Pump Inhibitors (PPIs)
should
be avoided.
Co-
administration of pazopanib with PPIs is PROHIBITED from 24 hours before
the first dose of pazopanib until after the final PK blood sample is collected on
Day 15 ± 1 day of Cycle 1. After this, if the concomitant use of a proton-pump
inhibitor (PPI) is medically necessary, it is recommended that the dose of pazopanib
be taken without food once daily in the evening concomitantly with the PPI (Section
4.8). If the concomitant administration of an H2-receptor antagonist is medically
necessary, pazopanib should be taken without food at least 2 hours before or at
least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be
administered at least 1 hour before or 2 hours after administration of short-acting 
antacids.
4.5.5
Concurrent Anti-Hypertensive Therapy: The algorithm in Section 5.4.1 will be 
used to grade and manage pazopanib related hypertension. Should initiation of 
anti-hypertensive therapy be required, single agent therapy (commonly including the
calcium channel blockers amlodipine or nifedipine) may be started without notifying 
the study chair.


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4.5.6
Anti-inflammatory and anti-platelet agents (e.g. aspirin, and/or ibuprofen, or other 
NSAIDs) could result in elevated blood pressure or increased bleeding episodes 
when co-administered with pazopanib and therefore should be used with caution.
4.5.7
Patients’ medications should be reviewed at eligibility, before treatment initiation, 
and during treatment. Any concomitant medications that are “generally accepted” to
cause a risk of Torsade de pointes are prohibited (see Appendix IIIB). Those
“associated” with a risk of QTc prolongation and/or Torsades de pointes should be
discontinued or replaced with drugs that do not carry these risks, if possible.
Patients who must take these medications should be watched carefully for symptoms 
of QTc prolongation, such as syncope. Performing additional EKGs on patients who
must take one or more of these medications is recommended but not required, at the 
investigator’s discretion.
4.6
The Effects of Pazopanib on Other Drugs
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CYP2C8, CYP2D6,
CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1. Pregnane X receptor 
transient transfection assay suggested some potential for human CYP3A4 induction at high 
concentrations. Results from drug-drug interaction studies conducted in patients 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.
4.7
The Effects of Other Drugs on Pazopanib
Results from in vitro studies suggest that the oxidative metabolism of pazopanib in human 
liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2
and CYP2C8. Furthermore, in vitro data suggest that pazopanib is a substrate for P-
glycoprotein and for breast cancer resistance protein. Substances that induce or inhibit 
CYP3A4 may alter the pharmacologic effects of pazopanib and should be used with 
CAUTION.


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Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations. 
Co-administration of strong CYP3A4 inhibitors is prohibited (see Section 4.8); therefore 
selection of an alternate concomitant medication with no or minimal potential to inhibit 
CYP3A4 is recommended.
Medications that induce CYP3A4 may result in decreased plasma pazopanib concentrations 
and a loss of efficacy and therefore are prohibited (See Section 4.8). Anticonvulsant drugs 
that do not induce CYP enzymes are allowed. Refer to Appendix IIIA for a list of 
anticonvulsant drugs with little or no enzyme induction. The use of azithromycin or 
fluconazole is discouraged but allowed.
4.8
Prohibited Medications
Patients should not receive other anti-cancer therapy [cytotoxic, biologic, radiation, or 
hormonal (other than leuprolide or other GnRH agonists)] while on treatment in this study. 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations; 
therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED beginning 14 
days prior to the first dose of protocol therapy until discontinuation of the protocol therapy. 
Strong CYP3A4 inhibitors include (but are not limited to):

Antibiotics: clarithromycin, telithromycin, troleandomycin, roxithromycin

HIV protease inhibitors: ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir

Antifungals: itraconzaole, ketoconazole, voriconazole

Antidepressants: nefazodone
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 are
PROHIBITED and include (but are not limited to):

Glucocorticoids for greater than 2 weeks duration:
cortisone (>50 mg/day), 
hydrocortisone (>40 mg/day), prednisone (>10 mg/day), methylprednisolone (>8 
mg/day), dexamethasone (>1.5 mg/day)

Anticonvulsants: 
phenytoin, 
carbamezepine, 
phenobarbital, 
oxcarbazepine, 
primidone, fosphenytoin

HIV antivirals: efavirenz, nevirapine, tipranavir

Antibiotics: rifampin (rifampicin), rifabutin, rifapentene

Miscellaneous: St. John’s Wort, modafinil, pioglitazone
Grapefruit or grapefruit juice is prohibited as it inhibits CYP3A4 activity and may also 
increase plasma concentrations of pazopanib.
As noted above, co-administration of pazopanib with PPIs should be avoided and is
prohibited from 24 hours before the first dose of pazopanib until after the final PK blood 
sample is collected on Day 15 ± 1 day of Cycle 1.
The therapy delivery maps (TDMs) are on the next 2 pages.


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Date
Due
Date
Given
Week
Day
Pazopanib
mg
Assessments
Comments (Include any held doses, or dose
modifications)
Please refer to the Visit Schedule in Section 7 for Screening assessments.
Enter calculated dose above and then dose administered below
1
1
mg
a, b, c1, d2, h3, i3
2
mg
3
mg
4
mg
5
mg
6
mg
7
mg
2
8
mg
a, d2
9
mg
10
mg
11
mg
12
mg
13
mg
14
mg
3
15
mg
a, d2, h4
16
mg
17
mg
18
mg
19
mg
20
mg
21
mg
4
22
mg
a, d2
23
mg
24
mg
25
mg
26
mg
27
mg
28
mg
See Section 4.2 for criteria for starting a subsequent cycle. See section 5 for dose modifications
4.9 Therapy Delivery Map (TDM) - Cycle 1
This therapy delivery map relates to Cycle 1: Pazopanib treatment given once daily continuously for 28 days. 
See Section 4.10 for the therapy delivery map for subsequent cycles. 1 cycle = 28 days. Dosing is continuous. 
There is no interruption between cycles.
Patient name/initials
DOB
Criteria to start Cycle 1 are described in Section 3.2. Extensive details are in Section 4.1 (treatment overview). Cycle 1 lasts 28 days.
DRUG
ROUTE
DOSAGE
Circle applicable
formulation and 
strikethrough unused 
formulation to avoid 
confusion
DAYS
IMPORTANT 
NOTES
OBSERVATIONS
OBTAIN OTHER ASSESSMENTS AS REQUIRED FOR 
GOOD PATIENT CARE
Pazopanib
(GW786034) 
IND# 065747
PO
If tablets:
450 mg/m2/dose given 
once daily (Max dose:
800 mg)
If powder in 
suspension:
225 mg/m2/dose given 
once daily (Max dose:
400 mg)
1-28
Take on an
empty
stomach 
(at least 1 hour 
before a meal or
2 hours after a 
meal).
See Section 4.1 
for further 
details.
a History, physical exam, vital signs, blood pressure
b Urinalysis (including UPC) and/or 24 hour urine for protein 
c Ht, Wt, BSA, performance status
d CBC, differential, platelets, electrolytes including K +, Ca++,
3-
++
PO4 , Mg , creatinine, total protein, albumin, ALT, bilirubin,
amylase, lipase
e PT/PTT/INR, pregnancy test, TSH
f ECHO, EKG, plain x-ray of knee (see Section 7.2.1)
g Disease evaluation including BMA/Bx, Urine VMA/HVA, 
AFP as indicated (see Section 7.1).
h PK (see Section 7.3 & Appendix VI).
i PD (see Sections 7.1 and 7.4)
Ht____
cm Wt
kg
BSA
m2


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1Evaluations obtained for screening will ONLY be repeated at Cycle 1 Day 1 if they are older than 7 days.
2 If Grade 4 neutropenia or thrombocytopenia, CBCs should be checked at least twice a week (every 3 to 4 days) until ANC ≥750/µL and platelets ≥
75,000/µL (transfusion independent).
3 Prior to the first dose
4 Obtain at the same time as safety labs.
4.10
Therapy Delivery Map – Subsequent Cycles of Therapy
This therapy delivery map applies to all cycles given after Cycle 1: Pazopanib treatment given once daily
continuously for 28 days (1 cycle = 28 days). Patient may receive additional cycles (if they meet requirements 
described in Section 4.2.
See Section 4.2 for criteria for starting next cycle.
Patient name/initials
DOB
DRUG
ROUTE
DOSAGE
Circle applicable 
formulation and
strikethrough unused
formulation to avoid 
confusion
DAYS IMPORTANT 
NOTES
OBSERVATIONS
OBTAIN OTHER ASSESSMENTS AS REQUIRED FOR 
GOOD PATIENT CARE
Pazopanib
(GW786034) 
IND# 065747
PO
If tablets:
450 mg/m2/dose 
given once daily
(Max dose: 800 mg)
If powder in
suspension:
225mg/m2/dose given
once daily
(Max dose: 400 mg)
1-28
Take on an empty 
stomach (at least 1
hour before a meal
or 2 hours after a
meal).
See Section 4.1 for
further details.
a History, physical exam, vital signs, blood pressure
b Urinalysis (including UPC) and/or 24 hour urine for protein 
c Ht, Wt, BSA, performance status
d CBC, differential, platelets, electrolytes including K +, Ca++,
3-
++
PO4 , Mg , creatinine, total protein, albumin, ALT,
bilirubin, amylase, lipase
e Pregnancy test 
f TSH
g PT/PTT/INR
h ECHO, EKG, plain x-ray of knee (see Section 7.2.1)
i Disease evaluation including BMA/Bx, Urine VMA/HVA, 
AFP as indicated (see Section 7.1).
j PK (see Section 7.3 & Appendix VI). 
k PD (see Sections 7.1 and 7.4)
Cycle of Therapy:
Ht
cm
Wt
kg
BSA
m2
Date
Due
Date
Given
Week
Day
Pazopanib
mg
Assessments
Comments (Include any held 
doses, or dose modifications)
Enter calculated dose above and then dose administered below
1
1
mg
a1, b2, c2, d3, e2, f4, g5, h6, i4, 
j7, k8
2
mg
3
mg
4
mg
5
mg
6
mg
7
mg
2
8
mg
d3
9
mg
10
mg
11
mg
12
mg
13
mg
14
mg
3
15
mg
a1, d3
16
mg
17
mg
18
mg
19
mg
20
mg
21
mg
4
22
mg
d3
23
mg
24
mg
25
mg
26
mg


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27
mg
28
mg
See Section 4.2 for criteria for starting next cycle. See section 5 for dose 
modifications.
1 Every other week for Cycle 2 and 3, and then prior to the start of each 
subsequent cycle.
2 Prior to the start of each subsequent cycle.
3 Weekly during Cycle 2, every other week in Cycle 3, and then prior to 
the start of each subsequent cycle.
4.Prior to Cycle 3, 5, 8, and 11 and every 3rd cycle thereafter
5.Prior to Cycle 3 and every 6 cycles thereafter
6 Prior to Cycle 2 and Cycle 5, and then every 6 cycles.
7.Pre-dose at every odd cycle.
8.Pre-dose on either Day 1 of Cycle 2 or Day 1 of Cycle 3.


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5
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY
All dose modifications should be based on the worst preceding toxicity. The severity of adverse 
events will be graded utilizing the National Cancer Institute (NCI) CTCAE, version 4.
The cycle duration remains 28 consecutive days in patients who have dose interruption.
5.1
Definition of Dose Limiting Toxicity (DLT)
DLT will be defined as any of the following events that are at least possibly, probably, or
definitely attributable to pazopanib. See Section 5.4 for the Potential Pazopanib Specific 
Side Effects. Dose-limiting hematological and non-hematological toxicities are defined 
differently.
5.1.1
Hematological Dose-Limiting Toxicity
a) For patients who are evaluable for hematologic toxicity assessment (patients
without bone marrow involvement)

Grade 4 Thrombocytopenia (platelet count < 25,000/mm3) or Grade 4 
neutropenia

Any hematologic toxicity requiring dose reduction or treatment interruption 
for >14 days
b) For all patients:

≥Grade 2 arterial thromboembolic events (visceral arterial ischemia, 
peripheral ischemia, or ischemia cerebrovascular)

Grade 3 or 4 venous thromboembolic event

Any thrombotic event (other than central venous line [CVL] associated 
thrombosis) requiring systemic anticoagulation
5.1.2
Non-Hematological Dose-Limiting Toxicity
5.1.2.1
Any Grade 4 non-hematologic toxicity
5.1.2.2
Any Grade 3 non-hematological toxicity, with the specific exclusion of the 
following:

Grade 3 nausea and vomiting of less < 3 days duration

Grade 3 fever or infection,

Grade 
3 
hypophosphatemia,
hypokalemia,
hypocalcemia
or 
hypomagnesemia responsive to oral supplementation within 7 days
of start of supplement (see Section 5.4.4 for dose modifications)
5.1.2.3
Grade 2 allergic reactions that necessitate discontinuation of protocol 
therapy will not be considered a dose-limiting toxicity.
5.1.2.4
Any Grade 2 non-hematological toxicity that persists for ≥7 days and is 
considered sufficiently medically significant or sufficiently intolerable by
patients that it requires treatment interruption may also be considered a DLT
following discussion with the Study chair and a Novartis Medical Lead.
5.1.2.5
Hypertension will be graded according to the NCI CTCAE; however, 
dose limiting hypertension will be considered as the following:


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
Grade 4 hypertension

A blood pressure >25 mmHg above the 95th percentile for age, 
height, and gender (see Appendix V) confirmed by repeated
measurement on the same day (See Sections 5.4.1 and 4.1.5.1 for 
management)

In patients already on anti-hypertensive therapy due to previous 
hypertension (see Section 3.2.8.5), any blood pressure 1-25 mmHg
above the 95th percentile for age, height, and gender (Appendix V) 
for > 14 days (See Sections 5.4.1 and 4.1.5.1 for management)
5.2
Dose Modifications for Hematologic Toxicity
All dose modifications should be based on the worst preceding toxicity.
Pazopanib tablets: For step-wise dose reductions, see Appendix II for the dosing nomogram. 
Pazopanib powder in suspension: For step-wise dose reductions see Tables 1 and 1a (Section 
4.1.1).
5.2.1
For all patients:
If Grade 4 neutropenia occurs,                                                          
a)
Pazopanib should be held.
b)
CBCs should be checked at least twice a week (every 3 to 4 days)
until ANC ≥ 750/µL.
c)
Subsequent doses of pazopanib should be given at a reduced dose, when
ANC ≥750/µL.
If Grade 4 thrombocytopenia occurs,                                        
a)
Pazopanib should be held.
b)
CBCs should be checked at least twice a week (every 3 to 4 days) until
platelet count ≥75,000/L without need for platelet transfusion in the 
preceding 7 days.
Subsequent doses of pazopanib should be given at a reduced dose, when 
platelet count ≥ 75,000/L without need for platelet transfusion in the 
preceding 7 days.
5.2.1.1
If dose-limiting myelosuppression occurs as noted in Section 5.1.1,
a)
The dose of pazopanib should be resumed at a reduced dose, once
ANC ≥750/L and platelet count ≥75,000/L without need for 
platelet transfusion in the preceding 7 days.
5.2.2
For patients who have a dose limiting hematological toxicity that does not resolve to
the parameters defined in Section 5.2.1 within 14 days of holding pazopanib: if re-
challenge is to be considered the Study Chair must be contacted and provide approval 
prior to re-challenge.
5.3
Dose Modifications for Non-Hematological Toxicity
Specific instructions for the management of potential pazopanib side effects are included in
Section 5.4.


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5.3.1
For any non-hematologic dose limiting toxicity as detailed in Section 5.1.2:
a)
Pazopanib should be held
b)
If the non-hematologic DLT is a pazopanib specific toxicity, the dosing 
guidelines in Section 5.4 should be followed
c)
If the non-hematologic DLT returns to baseline within 14 days of holding 
pazopanib, subsequent doses of pazopanib should be given at a reduced dose.

If toxicity does not resolve to meet continued treatment parameters 
within 14 days of drug discontinuation, and if re-challenge is to be
considered, the Study Chair must be contacted as outlined in Section 4.2 
to discuss.

If DLT recurs in a patient who has resumed treatment after the maximum
allowed dose reductions, the patient must be removed from protocol
therapy, unless the patient has been approved for a further dose 
reduction following discussion with the Study Chair.
5.4
Potential Pazopanib Specific Side Effects
5.4.1
Hypertension

Baseline blood pressure (BP) is defined as the blood pressure obtained at the
examination used for study enrollment. This baseline BP should be obtained as 
follows:
1)
Obtain 3 serial blood pressures from the same extremity with the patient in
the same position that are separated by at least 5 minutes. Avoid using the 
lower extremity if possible.
2)
Average the systolic blood pressure from the 2nd and 3rd measurements.
3)
Average the diastolic blood pressure from the 2nd and 3rd measurements.
4)
The baseline BP is the average of the systolic over the average of the 
diastolic measurements.

Elevation in either the systolic or diastolic blood pressure should be considered 
when following the algorithm below.

The upper limit of normal (ULN) is defined as a BP equal to the 95th
percentile for age, height, and gender. If ≥ 18 yrs of age, ULN will be defined 
as a BP of 140/90. See Appendix V.

The NCI CTCAE version 4.0 will be utilized to determine the grade of 
hypertension for reporting purposes.

Elevated BP measurements should be repeated on the same day to confirm the
elevation. Patients with an elevated BP should have BP measurements performed 
at least twice weekly until BP is ≤ ULN.

The algorithm below will be used to manage pazopanib related hypertension.

Hypertension should be managed with appropriate anti-hypertensive agent(s) as 
clinically indicated. It is strongly recommended that nephrology or cardiology be 
consulted in the evaluation and management of hypertension.

For patients who were on one anti-hypertensive medication at study enrollment 
and hypertension worsens while on study, further anti-hypertensive therapy may
include dose adjustment of the current medication or the addition of a second 
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Arm 1 of algorithm:

If blood pressure (BP) ≤ 95%ile for age, height, and gender: continue 
pazopanib at the same dose.
Arm 2 of algorithm:

If BP ≤10 mm Hg above the ULN: continue pazopanib at the same dose and 
recheck the BP within 72 hours.
o
If the BP is ≤ ULN on recheck, continue pazopanib at the same dose.
o
If the BP remains above the ULN on recheck, then start/adjust
antihypertensive therapy (Section 4.1.5.1) and follow Arm 3 of the
algorithm from the point that anti-hypertensive therapy is started/adjusted.
Arm 3 of algorithm:

If BP is 11 to 25 mm Hg above the ULN on ≥2 of 3 measurements or
> 35 mmHg above baseline on ≥2 of 3 measurements, start/adjust anti-
hypertensive therapy (see Section 4.1.5.1) and continue pazopanib at the 
same dose. Monitor BP at least twice weekly.
o
If the BP returns to ≤ULN within 14 days, continue pazopanib at the 
same dose and continue anti-hypertensive therapy.
o
If the BP remains elevated ≥25 mm Hg above the ULN or > 35 mm
Hg above baseline for more than 14 days after the institution/adjustment
of anti-hypertensive therapy, hold pazopanib, monitor BP at least
every 3 days, and follow Arm 4 of the algorithm from the point that
pazopanib is held. The anti-hypertensive therapy should be continued 
until the BP is less than the ULN.

If the BP returns to ≤ULN within 14 days, restart pazopanib at a reduced 


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dose.

If the BP remains > ULN for more than 14 days, patient must be removed 
from protocol therapy.
o
If the BP increases to > 25 mm Hg above the ULN despite anti-
hypertensive therapy, hold pazopanib, but continue the anti-hypertensive 
agent(s). Monitor the BP as clinically indicated and follow Arm 4 of the 
algorithm from the point that pazopanib is held.

If the BP is ≤ULN within 14 days, pazopanib may be restarted at a reduced 
dose.

If the BP is > ULN for > 14 days, the patient must be removed from protocol 
therapy (Section 8.1).
Arm 4 of algorithm:

If BP is > 25 mm Hg above the ULN hold pazopanib, monitor BP, and 
administer/adjust anti-hypertensive therapy as clinically indicated.
o
If the BP returns to ≤ ULN within 14 days, pazopanib may be restarted 
at a reduced dose.
o
If the BP is > ULN for >14 days, the patient must be removed from 
protocol therapy (Section 8.1).
Arm 5 of algorithm:
If the participant develops Grade 4 hypertension, discontinue pazopanib, monitor
BP and administer anti-hypertensive therapy as clinically indicated. A nephrology
and/or cardiology consult is recommended. The patient must be removed from
Protocol Therapy (Section 8.1).
5.4.2
Abdominal pain:
Abdominal pain is a common symptom with vascular endothelial growth factor 
(VEGF) receptor antagonists such as pazopanib. Bowel perforations have
been reported in clinical trials of pazopanib and with other agents in this class.
Bowel perforations have been associated in some patients with tumor in the
bowel wall, or diverticulitis, while in others there has been no clear explanation.
Although bowel perforation is a rare event, investigators and study staff at
the site are advised to be vigilant of this potential complication in patients 
receiving pazopanib. Abdominal complaints should be assessed during AE
review at every visit. In addition, every physical exam should include a
complete abdominal exam. For patients with abdominal complaints and/or
abnormal findings on clinical exam, follow the dose modifications and 
evaluations described below.


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Adverse events & descriptions
Dose Modifications & Evaluations
Mild to Moderate abdominal pain or other
abdominal complaints with no associated 
abnormal findings on physical exam
1. Continue pazopanib at current dose
2. Implement supportive care as indicated and 
per institutional standards; consider imaging
studies
3. Advise the patient to seek medical attention 
should their complaints worsen
4. Appropriate follow-up until complaints 
resolve or origin of the pain is identified. 
Imaging studies to confirm the absence of 
abdominal pathology should be performed 
based on the investigator judgment.
Severe abdominal pain or a concerning abdominal
exam
1. Hold pazopanib
2. Recommend obtaining appropriate imaging 
studies to evaluate the patient’s specific
complaints or exam findings
3. Resume pazopanib at previous dose if 
imaging studies confirm the absence of 
abdominal pathology
Confirmed diagnosis of abdominal perforation
1. Remove from protocol therapy
Contact the Study Chair if you need further guidance or would like to discuss an 
event involving abdominal pain or bowel perforations.
5.4.3 Hepatotoxicity:


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Adverse events & descriptions
Dose Modifications & Evaluations
Grade 1 ALT/AST elevation
1.
Continue pazopanib at current dose
2.
Check liver function tests (LFTs)1 as per 
Evaluations table in Section 7.1
Grade 2 ALT/AST elevation without
bilirubin elevation (defined as total
bilirubin2 ≤1.5 x ULN or direct bilirubin 
≤35% of total bilirubin) and without 
hypersensitivity symptoms (eg: fever, 
rash)
1.
Continue pazopanib at current dose
2.
Consider performing the following to exclude 
hypersensitivity and other contributing factors:

Eosinophil count

Viral serology4 for hepatitis A, B and C

Liver imaging (ultrasound)
3.
Monitor patient closely for clinical signs and 
symptoms
4.
Perform LFTs1 weekly (or more frequently if 
clinically indicated) until AST/ALT < Grade 1


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Grade 3 ALT elevation without bilirubin 
elevation (defined as total bilirubin2 ≤1.5 
x ULN or direct bilirubin ≤35% of total
bilirubin) and without hypersensitivity 
symptoms (e.g., fever, rash)
Liver Event Interruption/Stopping Criteria3:
1.
Hold pazopanib. Repeat LFTs1 within 72 hrs to
confirm Grade 3 ALT elevation; if confirmed:
2.
Perform the following assessments to exclude 
hypersensitivity and other contributing factors:

Eosinophil count

Optional viral serology4 for hepatitis A, B, 
C and E, cytomegalovirus4, Epstein Barr 
virus4 (IgM antibody, heterophile antibody, 
or monospot testing)

Liver imaging (Ultrasound)
3.
Monitor patient closely for clinical signs and 
symptoms
4.
Perform LFTs1 weekly (or more frequently if 
clinically indicated) until ALT reduced to <
Grade 1
5.
Pazopanib may be held for up to 14 days, if ALT 
returns to <  Grade 1 and patient is benefitting 
from treatment, pazopanib may be resumed at a 
reduced dose following Novartis / Study Chair
approval (contact the Sponsor Medical Lead
and the Study Chair via email or phone to 
start the approval process). If approval for re-
treatment is granted, the patient must be re-
consented (with a separate informed consent) 
specific to hepatotoxicity.

For patients on tablets dose reductions are as 
follows:
o
If on 800 mg, then reduce to 400 mg 
daily
o
If on 600 mg, then reduce to 400 mg 
daily
o
If on 400 mg, reduce to 200 mg daily

For patients on powder suspension:
o
Follow the sequential dose reduction 
(Section 4.1.1.), one dose level reduction 
is required (e.g. from 225 mg/m2 to 160 
mg/m2)
6.
Following re-introduction of pazopanib, continue 
to monitor ALT weekly for 2 cycles, if ALT 
Grade 2 recurs permanently discontinue 
pazopanib


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≥ Grade 2 ALT AND elevation in bilirubin2
(defined as total bilirubin > 1.5 x ULN and direct 
bilirubin > 35% of total bilirubin) or with
hypersensitivity symptoms (e.g., fever, rash)
Liver Event Stopping Criteria3:
1.
Discontinue pazopanib permanently
2.
Recheck LFT’s1, serum creatinine 
phosphokinase (CPK) and collect PK sample.
Also check:

Eosinophil count

Optional viral serology4 for hepatitis A, 
B, C and E, cytomegalovirus4, Epstein-
Barr virus4 (IgM antibody, heterophile 
antibody, or monospot testing)

Anti-nuclear antibody4, anti-smooth 
muscle antibody4, anti-mitochondrial 
antibody4

Liver imaging (Ultrasound)
3.
Recommend referral to (consult) a pediatric 
gastroenterologist/hepatologist.
4.
Monitor patient closely for clinical signs 
and symptoms. Perform full panel LFTs1
weekly or more frequently if clinically 
indicated until LFTs are reduced to 
Grade 1.
For isolated total bilirubin2 elevation without
concurrent ALT increase (defined as Grade 1 ALT
≤3 x ULN).
1.
Isolated hyperbilirubinemia (in the absence of 
elevated ALT or other signs/symptoms of liver 
injury) does not require dose modification.
Study treatment inhibits UGT1A1 and
OATP1B1, which can cause elevation of
indirect (unconjugated) bilirubin in the absence 
of liver injury
2.
If total bilirubin is >1.5 ULN in the absence of 
ALT elevation, fractionation of bilirubin should 
be performed. 

If the bilirubin is predominantly indirect 
(≥65%) indirect (unconjugated), continue 
study treatment at the same dose.

If bilirubin is >35% direct (conjugated), 
study treatment may also be continued 
however, further evaluation should be 
undertaken for underlying cause of 
cholestasis.
1LFTs include: AST, ALT, alkaline phosphatase, GGT and total bilirubin.
2Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable and a
patient meets the criterion of total bilirubin > 1.5 x ULN, then the event should be promptly reported as defined.
3When a liver chemistry event meets the Liver Event Interruption Criteria, or Liver Event Stopping Criteria,
blood samples should be obtained for clinical laboratory testing by the central laboratory (Liver Event
Kits will be provided for this purpose).
4These extra tests will be performed centrally
5.4.4 Electrolyte Abnormalities:
Serum K+, Ca++, Mg++, phosphate levels should be monitored given the risk of 
prolonged QTc. If serum Ca++ is abnormal, ionized calcium should be obtained and 
interventions based on ionized calcium only.
Pazopanib should be held and an EKG obtained for


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
Hypokalemia or hyperkalemia ≥ Grade 2

Hypocalcemia or hypercalcemia ≥ Grade 3

Hypophosphatemia or hyperphosphatemia ≥ Grade 3

Hypomagnesemia or hypermagnesemia ≥Grade 3
These laboratory values should be corrected as soon as possible in a manner 
consistent with good medical judgment. Pazopanib may be resumed at a reduced dose 
when:

Hypokalemia or hyperkalemia is Grade 1 or within institutional limits

Hypocalcemia or hypercalcemia is ≤ Grade 2

Hypophosphatemia or hyperphosphatemia is ≤ Grade 2

Hypomagnesemia or hypermagnesemia is ≤ Grade 2.
Even though pazopanib administration is allowed at these lower laboratory toxicity
grades, every effort should be made to correct the abnormal lab values to normal if 
possible.
5.4.5 Proteinuria:

If urinalysis shows ≥trace protein then obtain a urine protein: creatinine 
ratio (UPC).

If the UPC is ≥ 1, then obtain a 24-hour urine collection for protein 
estimation.

If the urine protein is ≥3.5 g/24-hours then hold pazopanib and re-
assess urine protein weekly.

If the urine protein decreases to < 3.5 g/24 hours in < 21 days then
resume pazopanib at a reduced dose.

Monitor the 24 hour urine protein or UPC weekly for 2 consecutive
weeks once pazopanib is resumed.

If pazopanib is held for ≥28 days then the patient must be removed
from protocol therapy.
5.4.6 Cardiac Function:
5.4.6.1
Left Ventricular Systolic Dysfunction:
Adverse events & descriptions
Dose Modifications & Evaluations
LV EF <LLN but > 50% OR
LV SF <LLN but > 24% without symptoms 
of cardiac dysfunction
Continue drug and repeat Echo on Day 28 of
subsequent cycle
LV EF 40 – 49% OR
LV SF 15 – 23% OR
Absolute decrease in SF ≥8 percentage 
points from baseline
Hold pazopanib and obtain repeat Echo in 7 
days. If toxicity confirmed, then remove
from protocol therapy.
If not confirmed, then resume drug at reduced 
dose and repeat Echo 14 and 28 days after 
resuming pazopanib. If any 2 Echos 
demonstrate LV EF 40 - 49% OR LV SF 15 -
23%
OR ≥8 percentage point decrease in SF then 
remove from protocol therapy and refer to 
pediatric cardiologist
Grade 3 LV EF decreased OR 
Grade 3 LV SF decreased
Remove from protocol therapy – refer to 
pediatric cardiologist


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
Cardiac evaluation by Echo but MUGA (Multiple-Gated Acquisition) 
may be used if clinically indicated
5.4.6.2
QT Prolongation:
Guidelines for the management of prolonged QT interval are as follows: 
Measure the QT interval (from the start of the Q wave to the end of the
T wave) and the preceding RR interval. The corrected QT interval using 
the Bazett’s formula (QTcB interval) will be calculated as the QT
interval (msec) divided by the square root of the RR interval (msec).
Only the Bazett’s formula should be used to calculate the corrected QT
interval.

QTcB interval < 500 msec: No specific therapy needed.
Continue pazopanib at the same dose. Serum K+, Ca++, Mg++, and Phos 
should be monitored and repleted if low (see Section 5.4.4).

QTcB interval ≥500 msec: Hold pazopanib, review concomitant 
medications, and replete serum K+, Ca++, Mg++, and Phos as needed.
The EKG should be repeated within 7 days and if the QTcB interval 
is < 500 msec then resume pazopanib at a reduced dose. If the QTcB 
interval remains ≥500 msec, the patient must be removed from
protocol therapy.
5.4.7 Delays in Wound Healing:
Patients treated with VEGF blocking agents appear to have an increased risk of 
wound healing complications. Therefore, if patients require elective major surgery
on study, pazopanib should be held for 14 days prior to surgery and for 14 days
after surgery (see Section 3.3.7). Pazopanib should not be restarted if there is
evidence of wound healing complications such as a wound infection. Patients who 
require surgery less than 14 days from treatment with pazopanib should be 
monitored closely for wound complications. Patients who require major surgery 
during Cycle 1 of therapy must be removed from protocol therapy.
5.4.8 Bleeding:
Dose Modifications & Evaluations
Grade 1
Continue pazopanib at the current dose
and monitor as clinically indicated.
Grade 2
1. Hold pazopanib until bleeding
resolves to ≤ Grade 1
2. Restart pazopanib at a reduced 
dose; monitor as clinically
indicated
Grade 3 or higher
OR
Recurrent ≥Grade 2 event after dose 
interruption/reduction
Discontinue pazopanib permanently
and remove from protocol therapy
5.4.9 VascularThrombosis:
Dose Modifications & Evaluations
Grade 2
Continue pazopanib at the current dose 
and monitor as clinically indicated.


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Grade 3 (CVL associated only)
1. Hold pazopanib
2. Treat thrombosis according to 
institutional standards; would 
consider removal of the CVL.
3. Resume pazopanib when all 
symptoms have resolved. If
anticoagulation is required, use with 
caution.
All non-CVL associated Grade 3 AND
all Grade 4
Discontinue pazopanib permanently
and remove from protocol therapy
6
DRUG INFORMATION
6.1
PAZOPANIB
(VotrientTM, GW786034, Pazopanib HCl, GW786034B (monohydrochloride salt)) 
NSC# 737754, IND# 065747
Source and Pharmacology:
The 
chemical 
name 
for 
pazopanib 
is 
5-[[4-[(2,3-Dimethyl-2H-indazol-6-
yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide 
monohydrochloride. The molecular formula is C21H23N7O2S-HCl. The molecular
weight is 474.0 (monohydrochloride salt) and 437.5 (free base). The monohydrochloride
salt is very slightly soluble in 0.1 M HCl (0.65 mg/mL), practically insoluble in pH 7.0
phosphate buffer (0.00005 mg/mL), and practically insoluble in pH 11 piperidine buffer
(0.0002 mg/mL).
Pazopanib is a multi-targeted inhibitor of vascular endothelial growth factor (VEGF) 
receptor tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth 
factor receptor kinases (PDGFR-α and –β), fibroblast growth factor receptor-1 and -3, 
cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-
specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor 
tyrosine 
kinase
(c-Fms). 
In
vitro,
pazopanib
inhibited
ligand-induced
autophosphorylation of VEGFR-2, Kit and PDGFR-β receptors. In vivo, pazopanib 
inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a
mouse model, and the growth of some human tumor xenografts in mice.
In adults, pazopanib is orally absorbed with median time to peak concentration of 2
to 4 hours after the dose. Also in adults, the administration of a single, crushed
pazopanib 400 mg tablet increased AUC(0-72) by 46%, increased Cmax by
approximately 2 fold, and decreased Tmax by approximately 2 hours compared to
administration of the whole tablet. Due to this potential for increased exposure
(increased bioavailability, increased rate of absorption), tablets of pazopanib should
not be crushed. Systemic exposure is increased when pazopanib is administered with
food. Administration with a high-fat or low-fat meal results in an approximately 2-fold
increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 
hour before or 2 hours after a meal. Pazopanib is more than 99% bound to human
plasma protein in vivo. In vitro studies suggest that pazopanib is a substrate for P-
glycoprotein (Pgp) and breast cancer resistant protein (BCRP).
In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor 
contribution from CYP1A2 and CYP2C8. In vitro data also indicate that pazopanib is
an inhibitor for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,


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and CYP3A4 with its most potent inhibition for the isoenzyme CYP2C9. In vivo,
however, pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 with no
effect on probes for CYP2C19, CYP2C9, and CYP1A2. Therefore, medications that
are potent inducers or inhibitors of CYP3A4 are prohibited (refer to Section 4.8).
Washout periods are specified in Sections 4.6, 4.7 and 4.8. If not specifically mentioned, 
it is at the discretion of the clinician based on the pharmacokinetic properties of each
individual agent. Concomitant use of pazopanib with agents with narrow therapeutic 
windows that are metabolized by CYP3A4,
CYP2C8,
or
CYP2D6
is
not
recommended. Coadministration may result in inhibition of the metabolism of these 
products and create the potential for serious adverse events.
In adults, pazopanib has a mean half-life of 30.9 hours after administration of the 
recommended dose of 800 mg. Elimination is primarily via feces with renal
elimination accounting for <4% of the administered dose. Based on baseline hepatic
function, 800 mg pazopanib is recommended for adult patients with mild impairment 
(defined as either normal bilirubin and any degree of alanine aminotransferase [ALT]
elevation or as an elevation of bilirubin up to 1.5x upper limit of normal [ULN]
regardless of the ALT value), and 200 mg for adult patients with moderate impairment
(defined as an elevation of bilirubin >1.5 to 3xULN regardless of the ALT values). The
maximum dose of pazopanib (200 mg) administered to adult patients with severe 
hepatic impairment did not achieve therapeutic plasma concentrations. Therefore,
pazopanib is not recommended in adult patients with severe hepatic impairment 
(defined as total bilirubin >3xULN regardless of any level of ALT).
Pazopanib may cause prolongation of the QT interval and torsades de pointes. Refer
to Appendix IIIB for agents to avoid during administration of pazopanib.
Pregnancy and lactation: 
Pregnancy Category D
Pazopanib can cause fetal harm when administered to a pregnant woman. Based on its 
mechanism of action, pazopanib is expected to result in adverse reproductive effects.
In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, 
fetotoxic, and abortifacient. In pre-clinical studies in rats and rabbits, pazopanib was
teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib
to pregnant rats during
organogenesis
at
a
dose
level
of
≥3 mg/kg/day
(approximately 0.1 times the human clinical exposure based on AUC) resulted in
teratogenic
effects
including cardiovascular malformations (retroesophageal 
subclavian artery, missing innominate artery, changes in the aortic arch) and 
incomplete or absent ossification. In addition, there was reduced fetal body weight, and
pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥
3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased
post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day
(approximately 0.007 times the human clinical exposure). In addition, severe 
maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day 
(0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 
mg/kg/day (AUC not calculated).
There are no adequate and well-controlled studies of pazopanib in pregnant women. 
Protocol therapy should be immediately discontinued if pregnancy occurs while the 
patient is on therapy. Women of childbearing potential should be advised to avoid 
becoming pregnant while taking pazopanib and for up to 30 days after stopping 
pazopanib.


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Excretion in breast milk unknown and breast-feeding while on pazopanib is not 
recommended.
Formulation and Stability:
Tablets
Pazopanib is supplied as a series of aqueous film-coated tablets containing, 200 mg, and
400 mg of the free base:

200 mg, oval-shaped, white, packaged in bottles containing 34 tablets each

400 mg, oval-shaped, white, packaged in bottles containing 68 tablets each
Tablet excipients in all tablet sizes include microcrystalline cellulose, povidone, sodium 
starch glycolate, and magnesium stearate. The film coating consists of titanium dioxide, 
hypromellose, polyethylene glycol, and polysorbate 80. Store the intact bottles at
controlled room temperature (20ºC-25ºC). Excursions are permitted between 5ºC and
25ºC. Do not store pazopanib tablets above 25ºC.
Pazopanib Suspension (to be prepared in pharmacies)
Pazopanib Powder for Oral Suspension is a white to slightly colored powder supplied to
the clinical sites in amber glass (USP Type III) bottles with child-resistant closures. Each
bottle contains 5 grams of pazopanib.
Pazopanib Powder for Oral Suspension should be reconstituted with 90 mL of sterilized
or purified water to provide a white oral suspension containing 50 mg/mL of GW786034
as free base as detailed below.
1. Tap the sides to the bottle to loosen the powder.
2. Add 90 mL of room temperature sterilized or purified water for injection to the 
bottle.
3. Replace the cap tightly and shake vigorously by inversion for at least 2 minutes to 
ensure complete powder reconstitution.
4. Allow the bottle to sit for at least 3 minutes to allow any foam to dissipate.
Suspension is then ready for use as a white, lemon-flavored, 50 mg/mL suspension.
Pazopanib oral suspension should be stored refrigerated (2o-8o C). Do not freeze. The 
powder suspension is designed for multiple use and may be used for up to 35 days when 
refrigerated (2o-8o C).
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. Also, see Appendix VII for Patient Instructions for Pazopanib suspension.
Pazopanib should be taken on an empty stomach at least 1 hour before or 2 hours after a 
meal. The tablets should be swallowed whole and cannot be crushed or broken.
Avoid concomitant strong CYP3A4 inhibitors as these may increase pazopanib 
concentrations. Avoid concomitant strong CYP3A4 inducers as these may decrease 


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pazopanib concentrations. Refer to Sections 4.5, 4.6, 4.7 and 4.8 for agents that should 
be avoided or used with caution. The consumption of grapefruit and its juice are not 
allowed for the duration of treatment with pazopanib. Concomitant use of pazopanib 
with agents with narrow therapeutic windows that are metabolized by CYP3A4,
CYP2D6, or CYP2C8 is not recommended.
If a dose is missed, refer to section 4.1.4 Missed doses. If a patient vomits the 
dose, do not repeat the dose.
Dosing Instructions for Pazopanib (50mg/mL) multiple use oral powder suspension:

Insert a Baxa 28 mm Press-In-Bottle Adapter (PIBA®) (these supplies will be
provided to the site by Novartis) into the neck of the bottle. Check to ensure that
the lip of the Adapter fits snugly with the top of the bottle.

Swirl gently for at least 30 seconds to ensure homogeneity of the suspension 
immediately prior to the removal of the required dose for administration.

Remove the required dose using a suitable graduated syringe (recommend
Exacta- Med® Baxa) as follows:
1.
Ensure that the syringe plunger is fully pushed into the barrel.
2.
Insert the syringe tip into the Adapter, then invert the bottle and dispense
at least 5 mL of suspension into the syringe and then pump the entire
suspension back into the bottle to purge the syringe of any air bubbles.
Repeat this step until the syringe is free from air bubbles.
3.
Withdraw the required dose. Then re-invert the bottle and remove the
syringe from the Adapter and administer the dose as soon as possible.
Supplier:
Pazopanib suspension is supplied and distributed by Novartis.
Obtaining the Agent
Agent Ordering:
Sites will be provided the information for ordering drug supplies in the Study
Procedures Manual.
Agent Accountability
The investigator is responsible for study medication accountability, reconciliation, and 
record maintenance. In accordance with local regulatory requirements, the investigator, 
designated site staff, or head of the medical institution (where applicable) must 
document the
amount of
Novartis
investigational product dispensed and/or 
administered to study patients, the amount returned by study patients (if applicable),
and the amount received from Sponsor and, when applicable, the amount returned to
Novartis. Product accountability records must be maintained throughout the course of 
the study.
After completion of the study, a final inventory of accountability records and
unused study medications will be performed by the study monitor and site personnel.
A record of the number of tablets dispensed to and returned by each patient at each
visit must be maintained and reconciled with the study medication and compliance


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records in the eCRF. At each site visit, the cause of any missed doses should be
discussed and documented.
A record of the number of milligrams (determined by weight) of pazopanib in
oral powder suspension dispensed to and returned by each patient at each visit must be 
maintained and reconciled with the study medication and compliance records in
the eCRF. At each site visit, the cause of any missed doses should be discussed and 
documented.
After completion of the study, a final review of accountability records and inventory
of unused study medications will be performed by the study monitor and site
personnel. If the site has received documented approval from Sponsor, unused study
medication may be destroyed, prior to inventory by the study monitor. In this case,
the study monitor would review only study medication accountability records at the
end of study visit. Additional information on the drug accountability process is
provided in the Study Procedure Manual.
Any AE(s) associated with missed doses must be recorded in the eCRF. Patients
should be instructed for the importance of compliance to study treatments.
Agent Destruction:
If allowed per site policy and procedures, unused study medications will be destroyed 
according to site-specific guidelines and proof of destruction will be forwarded to
Novartis.


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7
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED
7.1
Required 
 Clinical, Laboratory and Disease Evaluations
See Section 3.2 and Section 3.3 for eligibility requirements. See Section 3.1.7 for requirements to
initiate protocol therapy. Laboratory tests used to determine eligibility may be counted as the 
Week 1 studies if the tests were drawn within 7 days of treatment start and there have been no 
significant changes in the patient’s clinical status (Section 3.1.7.1)
Obtain indicated studies prior to the start of cycle unless otherwise indicated.
STUDIES TO BE OBTAINED
Pre-
Study
During
Cycle 1
Prior to Subsequent
Cycles1
During
Subsequent
Cycles
End of
Therapy2
Survival
Follow-up
History
X
Weekly
X
Every other week
for Cycles 2 & 3, 
then prior to each
subsequent cycle
X
Physical Exam, Vitals (including 
BP3)
X
Weekly
X
Every other week
for Cycles 2 & 3, 
then prior to each
subsequent cycle
X
Height, weight, BSA
X
Cycle 1 Day
14
X
Performance Status
X
Cycle 1 Day
14
X
X
CBC, differential, platelets
X
Weekly5,6
X
Weekly for 
Cycle 2; every 
other week for 
Cycle 3; then 
prior to each 
subsequent cycle
X
Electrolytes including K+, Ca++
(ionized Ca++), PO4, MG++
X
Weekly
X
Weekly for 
Cycle 2; every 
other week for 
Cycle 3; then 
prior to each 
subsequent 
cycle
X
Creatinine, ALT7, bilirubin,
Amylase, Lipase
X
Weekly
X
Weekly for 
Cycle 2; every 
other week for
Cycle 3; then 
prior to each
subsequent cycle
X
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based
on schedules derived from the experimental design or on established standards of care. Minor unavoidable
departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for
surgery) for valid clinical, patient and family logistical, or facility, procedure and/or anesthesia scheduling issues
are acceptable (except where explicitly prohibited within the protocol). This policy does NOT apply to eligibility
requirements; but to therapy and evaluations post consent and post the start of protocol-directed care. Novartis
will not grant protocol waivers.


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Total protein/albumin
X
Weekly
X
Weekly for 
Cycle 2; every 
other week for 
Cycle 3: then 
prior to each 
subsequent cycle
X
TSH8
X
Prior to Cycle 3, 5, 8, 
11 and every 3rd cycle 
thereafter
PT, PTT, and INR
X
Prior to Cycle 3 and
every 6 cycles thereafter
Urinalysis (UPC and/or 24 hour 
urine for protein)9
X
X
X
X
Disease Evaluation10(including
bone marrow aspirate/biopsy11)
X
Prior to Cycle 3, 5, 8, 
11 and every 3rd cycle 
thereafter12
X
Serum AFP (for hepatoblastoma 
patients only)13
X
Prior to Cycle 3, 5, 8, 
11 and every 3rd cycle 
thereafter12
X
Urine VMA/HVA (for 
neuroblastoma patients only)14
X
Prior to Cycle 3, 5, 8, 
11 and every 3rd cycle 
thereafter12
X
Serum Pregnancy Test15
X
-
X
-
Patient Diary
X
X
ECHO16
X
Prior to Cycle 2, 5 and
then every 6 cycles
EKG (including QTcB)17
X
Prior to Cycle 2, 5 and
then every 6 cycles
Plain radiograph of tibial growth 
plates18
X
Prior to Cycle 2, 5 and
then every 6 cycles
Pharmacokinetics19
X
Prior to every odd cycle
Survival status20
X
Antineoplastic therapies since 
protocol therapy discontinuation20
X
1.
Window for assessment is Day 25-28 of the preceding cycle for any assessment with the exception of disease 
evaluations. See footnote 12 for assessment window on disease evaluation.
2.
Should be performed, if possible, at the time the patient comes off protocol therapy regardless of the reason, unless the 
test or procedure has been performed within the past 2 weeks.
3.
Blood pressures will be measured with an appropriate sized cuff at rest. Blood pressure measurement will be repeated 
within the same day if the blood pressure (BP) is elevated (> the 95th percentile for age, height, and gender). If both BP 
measurements are > 95th percentile for age, height, and gender, follow the guidelines in Section 5.4.1. Patients with 
elevated BP (that is, BP greater than the 95th percentile for age, height, and gender) at any time should have BP 
measurements performed at least twice weekly until BP is within the 95th percentile for age, height, and gender (see
Appendix V). Guidelines for the grading and management of hypertension are in Section 5.1.2.5, 5.4.1, and Appendix V.
4.
Evaluations obtained for screening will ONLY be repeated at Cycle 1 Day 1 if they are older than 7 days.
5.
If patients have Grade 4 neutropenia, then CBCs should be checked every 3 to 4 days until recovery to Grade ≤3.
6.
If patients have Grade 3 or 4 thrombocytopenia, then CBCs should be checked twice a week until recovery to Grade ≤2.
7.
If patient has LFT elevation, monitor LFTs as described in Section 5.4.3.


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8.
Patients found to have an abnormal TSH level at baseline and/or at subsequent visits should have a free T4 level 
measured (See Section 7.2.2). Management of hypothyroidism is described in Section 4.1.5.2.
9.
See Appendix IV for UPC rationale and calculation and Section 5.4.5 for dose modifications if UPC ≥1. UPC
assessment is adequate to follow-up prior proteinuria. If a 24-hour urine for protein is obtained, UPC is not required.
10. A confirmatory disease evaluation should be obtained, if possible, on the next consecutive cycle after initial 
documentation of either a PR or CR. This confirmatory evaluation is in addition to the schedule as noted (eg: if 
confirmatoryscans are done prior to Cycle 4, the next disease evaluation should be done as scheduled prior to Cycle 5)
11. Bone marrow evaluation to be done only in patients with known marrow involvement.
12. Disease evaluation should be performed during Days 24 – 28 of the cycle for the first 2 assessments (prior to Cycles 3 
and 5) and during Days 21 – 28 of subsequent indicated cycles. Patients who achieve a PR or CR should undergo the
appropriate disease evaluation on the next consecutive cycle after initial documentation of either a PR or CR. If the
institutional investigator determines that the patient has progressed based on clinical or laboratory evidence, the 
investigator can remove the patient from protocol therapy, he/she may opt not to confirm this finding radiographically. ; 
however an end of study disease assessment should be completed.
13. For hepatoblastoma patients only – perform no more than 48 hours prior to starting treatment on Day 1 of Cycle 1 (results do
not need to be known) and then with each disease evaluation if the initial value is elevated.
14. For neuroblastoma patients only - VMA = vanillylmandelic acid; HVA = homovanillic test.
15. Females of childbearing potential require a negative serum pregnancy test prior to starting treatment. Patients of 
childbearing potential must use an acceptable method of birth control. Abstinence is an acceptable method of birth 
control.
16. See Section 5.4.6 for dose modifications regarding Left ventricular systolic dysfunction or decrease in shortening fraction.
17. More frequent EKG monitoring is recommended for patients receiving drugs “associated” with Torsades de pointes (See 
Appendix IIIB) and required for Grade 2 potassium and Grade 3 calcium (confirmed by ionized calcium), magnesium 
and phosphorous abnormalities. See Sections 5.4.4 and 5.4.6.2.
18. Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to the first dose of protocol 
therapy. In patients with open growth plates, follow-up plain radiographs of the same growth plate(s) should be obtained 
according to Section 7.2.1.
19. See Section 7.3 for timing of required PK sampling, and Appendix VI for the PK worksheet. No PK samples are required 
beyond Cycle 11
20. Survival follow-up will be completed every3 months
Obtain Other Studies As Needed For Good Patient Care.


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7.2
Monitoring for Specific Toxicities
7.2.1
Growth Plate Toxicity
Patients will have a plain AP radiograph of a single proximal tibial growth
plate obtained prior to the first dose of protocol therapy.
a. If patients are found to have a closed tibial growth plate, no further 
radiographs will be required.
b. If patients are found to have an open tibial growth plate, then repeat plain 
AP radiographs of the same tibial growth plate will be obtained prior to
starting Cycle 2, Cycle 5 and then every 6 months (prior to cycle 11, 17, 
etc).

Patients with evidence of growth plate thickening or other changes 
should have a knee MRI performed to further assess the degree of
physeal pathology and undergo more frequent x-ray follow up. MRI
should be performed without contrast. If no MRI changes are seen,
x- rays may be performed approximately every 2 months.

Patients with knee MRI changes should be managed in an individualized
manner. Decisions regarding continuation of pazopanib should take into 
account the presence of any symptoms referable to the knee as well
as the patient’s response to pazopanib. Consultation with an orthopedic
surgeon may also be indicated. Plans for follow-up imaging will also be 
made on an individualized basis, taking into account the presence of 
symptoms at the knee or other joints as well as the decision to continue 
pazopanib or not. Consultation with orthopedics and with the Study 
Chair is advised.
7.2.2
Thyroid Toxicity
Patients will have a TSH level measured prior to initial treatment, prior to 
starting Cycle 3, 5, and then every 3rd cycle thereafter (eg: prior to Cycle
8, Cycle 11, etc). Patients found to have an abnormal TSH level should have
a free T4 level measured. Thyroid toxicity will be handled like any other non-
hematological toxicity. Guidance on the management of patients who develop 
hypothyroidism is included in Section 4.1.5.2.
7.2.3
Cardiac Toxicity
Patients will have a baseline echocardiogram and EKG obtained pre-treatment, 
prior to Cycles 2 and 5, and then every 6 months (prior to Cycle 11, 17, etc)
and as clinically indicated. See Section 5.4.6 for management of changes
in left ventricular function and prolonged QTcB while on protocol therapy.
7.2.4
Pregnancy Testing and Reporting
The need for a screening pregnancy test depends on whether a female patient
is of childbearing potential or non-childbearing potential. If a female patient is
of childbearing potential, she must have a serum -Human Chorionic
Gonadotropin (-HCG) pregnancy test performed within 7 days prior to the
first dose of study treatment(s). Patients with a positive pregnancy test result 
must be excluded from the study. Patients with a negative pregnancy test result
must agree to use an adequate contraception method as described below during
the study until 2 weeks following the last dose of study treatment(s). Any
pregnancy that occurs during study participation must be reported using a
clinical trial pregnancy form. To ensure patient safety, each pregnancy must 


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be reported to Novartis within 24 hours of learning of its occurrence. Study 
treatment should be immediately discontinued if pregnancy occurs during
study participation. 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 (Section 11.8). Spontaneous abortions must be 
reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the
investigator’s attention after the patient has completed the study and
considered by the investigator as possibly related to the study treatment(s) must 
be promptly reported to Novartis.
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported 
to the Sponsor. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE
through spontaneous reporting.
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.
7.3
Pharmacokinetic studies
7.3.1
Description of Studies and Assay
Plasma samples will be collected and analyzed for pazopanib levels using a 
validated LC/MS/MS (Liquid Chromatography/Tandem Mass Spectrometry) 
method under the control of Novartis.
7.3.2
Sampling schedule:
All patients (whether receiving pazopanib as tablet or as oral powder 
suspension) will have a blood sample for analysis of the plasma pazopanib
concentration collected prior to the first dose on Day 1 of Cycle 1. In addition, 
all patients will have 2 blood samples collected on Day 15 ± 1 day of Cycle
1: one sample prior to the dose and one sample 3-4 hours after dosing.
Blood samples for analysis of steady-state trough plasma pazopanib 
concentrations will also be obtained prior to the start of every subsequent odd-
numbered cycle (that is, pre-dose prior to Cycle 3, pre-dose prior to Cycle 5, 
etc). These steady-state trough plasma concentration samples can be collected 
between Day 22 of the previous cycle to Day 1 of the odd-numbered cycle,
and the actual date and time of sample collection recorded on the PK sample 
collection form. No PK samples are required beyond Cycle 11.
The pre-dose sample on Day 15 ± 1 day of Cycle 1 and the trough plasma 
concentration samples taken prior to dosing for every odd-numbered cycle 
should be obtained between 22-26 hours after the previous dose of 
pazopanib. Patients should be instructed to hold their dose of pazopanib on
the day that a pre-dose PK sample is to be collected. Collection of these PK
samples should correspond to the timing of routine laboratory evaluations.


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Extended PK sampling will be done during Cycle 1 in the first patients who 
receive the powder suspension formulation, until 6 patients are considered 
evaluable for the PK analysis. These patients will have a blood sample for 
analysis of the plasma pazopanib concentration collected at the following
time points on Day 1 of Cycle 1: pre-dose and at 30 min, 1 hour, 2 hours, 4
hours, 6 hours, and 8 hours after the dose. Samples will also be obtained on
Day 15 ± 1 day of Cycle 1: pre-dose and at 30 min, 1 hour, 2 hours, 4 hours,
6 hours, and 8 hours after the dose. If one or more of these 6 patients fail to
provide blood samples as specified in the protocol or if it is known that for 
some reason a patient’s collected blood sample(s) cannot be analyzed, that 
patient(s) will be determined to be non-evaluable for this analysis and one or
more additional patients will be enrolled for treatment with pazopanib as
powder for oral suspension and provision of the extended PK samples. These
patients will also provide blood samples for analysis of steady-state trough
plasma pazopanib concentrations prior to the start of every subsequent odd-
numbered cycle as described in the preceding paragraph.
Pazopanib dosing of either tablet or powder suspension must have continued 
uninterrupted and at the same dose level for at least 10 days prior to
acquisition of the Cycle 1 Day 15 PK samples. If pazopanib dosing has been
interrupted or modified <10 days prior to Cycle 1 Day 15, then the PK samples
should be taken between Cycle 1 Day 15 and Cycle 1 Day 22 on a study day
that meets the condition of at least 10 consecutive days of dosing at the same
dose level. The Cycle 1 Day 15 PK kit should be used and the actual date and 
time of sample collections should be recorded in the eCRF.
If ≥2 out of 6 evaluable patients have dose-limiting toxicities as defined in 
Section 5.1) during the first cycle, then enrollment at the 225 mg/m2/dose dose 
level of pazopanib oral suspension will be halted. Subsequent new patients
will be enrolled at the 160mg/m2/dose level until 6 evaluable patients from this
dose group are available for the safety review and 6 patients are available for
PK analysis.
7.3.3
Sample Collection and Handling Instructions:
Blood samples (2 mL for each sample) will be collected for PK into tubes 
containing potassium EDTA as an anticoagulant. See the corresponding
Pharmacokinetic Study Form (Appendix VI) for specific details of Sample 
Collection, Processing, Handling, and Shipping.
7.3.4
Instructions for Ordering PK Kits:
Please refer to the Study Procedures Manual for PK kit ordering 
instructions.


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8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF
STUDY CRITERIA
8.1
Criteria for Removal From Protocol Therapy
Patients will be permanently discontinued of protocol therapy if any of the
following occur:
a)
Progressive disease
b)
Adverse Events requiring removal from protocol therapy, as stated in Section 5.
c)
Concurrent use of other anticancer or investigational therapy, as stated in
Section 3.3.2.
d)
Requirement for major surgery during Cycle 1, as stated in Section 5.4.7.
e)
Refusal of further therapy by patient/parent/guardian
f)
Physician determines it is in patient’s best interest
g)
Major protocol deviations including non-compliance
h)
Development of a second neoplasm
i)
Pregnancy
8.2
Follow-up assessments after Removal From Protocol Therapy
Patients who are removed from protocol therapy are to be followed until they meet at
least one of the criteria for withdrawal from study (see Section 8.3). Survival Follow-up
data will be required unless consent was withdrawn.
Safety follow-up:
All patients will be followed for adverse events and serious adverse events for 28 days
after last dose.


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Survival follow-up:
The following information will be collected and reported every 3 months:

Survival status

Antineoplastic therapies taken since discontinuation of protocol therapy
The primary reason protocol therapy was permanently discontinued must be documented
in the patient’s medical records and eCRF. If the patient discontinues from protocol
therapy due to toxicity, AE will be recorded as the primary reason for permanently 
discontinuation on the eCRF. Once a patient has permanently discontinued protocol
therapy, the patient will not be allowed to be retreated.
8.3
Criteria for Withdrawal from Study
Patients will be withdrawn from the study if any of the following
occur:

Death

Lost to follow-up

Withdrawal of consent

The study is closed/ terminated

Investigator discretion
9
STATISTICAL CONSIDERATIONS
9.1
Sample Size and Study Duration
9.1.1
Review of patient accrual onto recent Phase II solid tumor studies indicates the 
following entry rates for the various tumors under study can be expected:
DiseaseGroup/Cohorts
Patients/Year
Osteosarcoma
24
Ewing sarcoma
18
Rhabdomyosarcoma
18
Neuroblastoma (measurable disease)
12
Neuroblastoma (evaluable disease)
12
Non-rhabdomyosarcomatous soft tissue sarcomas
10 
(including synovial sarcoma, alveolar soft part 
sarcoma)
Hepatoblastoma
7
With these entry rates, the probability of accruing 10 patients to complete
the initial stage of evaluation in the seven named categories within 24
months is 88%. The corresponding probability for enrolling 20 patients in the
seven named disease categories in 48 months is 95%. The study will likely
require 2 to 3.5 years for sufficient patient enrollments to evaluate pazopanib in 
the stated disease groups. A minimum of 77 patients and a maximum of 154 
patients are anticipated, after accounting for historical rates of patient 
inevaluability for the primary endpoint in phase II studies.
9.2
Study Design
The primary endpoint will be objective response by protocol-specified, disease-specific 


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response criteria. The best response of disease to pazopanib will be examined separately 
in each of the seven disease cohorts. The following two stage design will be used in
each cohort.
Cumulative Number
of Responses
Decision
Stage 1: Enter 10 patients
0
Terminate the cohort: agent 
ineffective
1 or more
Inconclusive result, continue the 
cohort
(proceed to Stage 2)
Stage 2: Enter 10 additional
patients
2 or less
Terminate the cohort: agent 
ineffective
      3 or more
         Terminate the cohort: agent effective
We will consider the agent not of sufficient interest for further evaluation in a disease 
category if the true response rate is 5% and of sufficient activity if the true response
rate is 25%. If the agent has a true response rate of 5%, the rule described above will
identify it of sufficient activity for further study with probability 0.07 (1-sided type I
error), and the trial will have an expected sample size of 14 with 60% probability of 
early termination. If the agent has a true response rate of 25%, the rule described above
will identify it of sufficient activity for further study with probability 0.88 (power
against the alternative hypothesis P = 0.25).
9.3
Analysis Populations
The modified Intent-to-Treat (mITT) population is the primary analysis population. The 
mITT will consist of all patients who have received at least one dose of protocol therapy.
The Safety population will comprise all patients in the mITT population. The safety 
population will be used for the analysis of safety data.
The Per Protocol (PP) population is a subset of the mITT population who meet all eligibility 
criteria.
The Pharmacokinetic (PK) population will comprise all patients in the mITT population
for whom a pharmacokinetic sample is obtained and analyzed. The Pharmacokinetic 
Extended Sampling (PKES) population will comprise all subjects in the Pharmacokinetic 
population who received powder suspension and have at least one non-predose sample 
collected and analyzed using the extended sampling schedule in Section 7.3.2. PK analysis 
summaries, figures and listings will be based on PK and PKES populations.
9.4
Analysis Data Sets
The primary data set for assessing efficacy will comprise the mITT population. The PP and 
mITT populations will be used for objective response analysis. All other efficacy analyses 
will be based on mITT only.
The primary data set for assessing safety will comprise the safety population defined in
Section 9.3 (Analysis Populations).


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9.5
Treatment Comparisons
There will be no treatment comparisons as there is only one treatment arm. No comparisons 
across cohorts will be conducted.
9.6
Primary Analysis and End of Study Analysis
No formal interim analysis is planned outside of the study design. The study team will review 
safety data periodically over the course of the study.
Expansion of tumor specific cohorts will be done when there is at least one investigator
determined confirmed response in that cohort within the first 10 enrolled patients. A 
given tumor specific cohort will not be expanded if all the patients in the cohort have:

Progressed

Discontinued therapy

Withdrawn consent

Been determined to be lost-to-follow-up

Or have been treated for at least 20 weeks without a response, making
it unlikely that a response will occur.
The primary analysis will be performed 20 weeks after the last patient’s first visit in the 
three cohorts of primary interest (rhabdomyosarcoma, non-rhabdomyosarcomatous soft 
tissue sarcoma and Ewing sarcoma/peripheral PNET).
The study will be completed one year from the date of the last patient’s first visit and 
the end of study analysis will be performed at the time of study completion.
Any additional data collected after the primary analysis will be included in a 
supplementary analysis and reported in a final Clinical Study Report.
9.7
Key Elements of Analysis Plan
9.7.1
Study Withdrawal
All patients who withdraw from the study will be included in analyses up to the 
time of withdrawal, regardless of the duration of treatment.
9.7.2
Missing Data
As the period of treatment for any patient will be dependent on treatment efficacy 
and toxicity, the duration of follow-up will vary between patients. Consequently,
there will be no imputation for missing data. Where appropriate, available data 
will be summarized over specified intervals (e.g. from study entry until withdrawal
from the study) using suitable summary statistics. Details will be given in the 
Reporting and Analysis Plan (RAP).
For the secondary PFS endpoint, the date associated with the last adequate disease
assessment will be used for those patients who are alive and have not progressed
at the time of analysis; such patients will be considered censored in the analysis.
9.7.3
Other Issues
Data from all participating centers will be pooled prior to analysis. It is anticipated 
that patient accrual will be spread thinly across centers and summaries of data by
center would be unlikely to be informative and will not, therefore, be provided.
Demographic and baseline characteristics will be summarized.


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Two-sided 90% confidence limits will be used in the estimation of response rates 
and viewed as descriptive.
Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.
9.8
Methods of Analysis
9.8.1
Primary Endpoint: Objective Response Rate (ORR)
This is defined as the percentage of patients achieving either a complete or partial 
tumor response as per response criteria. The response rate will be calculated from 
the investigator review. Confirmation will be based on the disease assessment 
performed 1 cycle after the initial response. The objective response rate will be 
computed for the 3 tumor types of primary interest.
Patients in the mITT population with unknown or missing response will be treated
as non-responders (i.e., they will be included in the denominator when calculating 
the percentage).
In other words, ORR = (number of patients with a confirmed best overall response 
of CR + number of patients with a confirmed best overall response of PR) divided 
by the total number of patients in the cohort.
The assessment of activity of treatment within each histology cohort will be 
based on the decision rule outlined in Section 9.2.
90% confidence intervals will be provided to characterize the variability around 
the response rate. The data will be presented for each cohort.
9.8.2
Secondary Endpoints:
9.8.2.1
The objective response rate will be computed for the 4 tumor types of 
secondary interest. The analysis method will be the same as that described 
in Section 9.8.1.
9.8.2.2
If recruitment is stopped in the non-primary histology group(s) and it has 
less than 10 patients, the response data will display summary statistics 
and the rule in the table under Section 9.2 will not apply.
9.8.2.3
Progression-free survival (PFS) and overall survival (OS)
The analysis will evaluate the mITT population on PFS using data from 
the investigator review. PFS is defined as the interval between the date 
of first dose of protocol therapy and the earliest date of disease
progression or death due to any cause. Patients are considered to have
progressive disease if they have documented progression based on
radiologic assessment as determined by investigator review (defined in
Section 10). For patients who do not progress or die, progression-free 
survival will be censored at the date of last adequate assessment or date
of last adequate assessment prior to initiation of new anti-cancer
therapy if applicable. PFS will be summarized using a Kaplan-Meier


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survival curve. The Kaplan-Meier estimate for the median progression-
free survival time and the first and third quartiles will be presented, along 
with a naive approximate 90% confidence interval if there are a sufficient
number of progressions or deaths.
Overall survival is defined as the time from the first dose of the study 
medication until death due to any cause. The OS analysis will be 
performed on the mITT population and summarized using a Kaplan-
Meier survival curve. The Kaplan-Meier estimate for the median OS 
time and the first and third quartiles will be presented, along with a naive 
approximate 90% confidence interval if there are a sufficient number of 
deaths.
Details on how event and censoring times are assigned to a patient will 
be provided in the RAP.
9.8.2.4
Duration of response (DoR)
For the subset of patients with a confirmed CR/PR, DoR is defined as the 
time from first documented evidence of complete or partial response to 
the earliest date of disease progression or death due to any cause. For 
confirmed responders who have not experienced progression or death 
prior to the date of data cut-off for analysis or starting other anticancer 
therapy, duration of response will be right-censored on the date of their 
last adequate post-baseline tumor assessment prior to the cut-off or start 
of other anticancer therapy.
Duration of response will be summarized descriptively for each cohort 
using medians and quartiles if there are 5 or more responders (confirmed 
CR/PR) in one cohort, otherwise, only a listing with subject level details 
will be provided. 
9.8.2.5
Clinical Benefit
This is defined as the percentage of patients achieving either a complete 
or partial tumor response or stable disease for at least two protocol 
scheduled disease assessments as per RECIST criteria. 90% confidence 
intervals will be produced to characterize the variability around the point 
estimate.
Time to Progression (TTP)
The analysis will evaluate the mITT population on TTP using data from 
the investigator review. TTP is defined as the interval between the date 
of first dose of protocol therapy and the earliest date of disease
progression or death due to disease under study. Patients are considered 
to have progressive disease if they have documented progression based
on radiologic assessment as determined by investigator review (defined 
in Section 10). TTP will be summarized using a Kaplan-Meier survival 
curve. The Kaplan-Meier estimate for the median time to progression 
and the first and third quartiles will be presented, along with a naive 
approximate 90% confidence interval if there are a sufficient number of 
events.
Details on how event and censoring times are assigned to a patient will 


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be provided in the RAP.
9.8.2.6
Safety Measures:
Safety data will be presented for all patients in the safety population 
(mITT) regardless of cohort. If there are multiple dose levels for the 
powder suspension formulation group, then data for each dose level will 
be presented in separate columns.
Clinical Laboratory Evaluations
Hematology, coagulation parameters, clinical chemistry, lipase and 
amylase, thyroid function tests, and UPC data will be summarized at 
each scheduled assessment. Hematology, coagulation parameters and 
clinical chemistry will be summarized by NCI-CTCAE version 4.0 and 
by data outside the reference range for each scheduled assessment.
Other Safety Measures
Vital signs (blood pressure, heart rate, temperature), height and weight 
will be listed for each patient and change from baseline will be included 
for blood pressure and heart rate. A descriptive summary including 
change from baseline pre-dose will also be presented. Individual profiles 
of blood pressure will be plotted by time.
The corrected QTcB interval (QTcB) will be listed for each patient and 
summarized at each scheduled assessment time. Change from baseline 
will be summarized and an analysis of central tendency (means, medians)
will be presented. A categorical analysis for each QTcB parameter will
be performed to determine the number of patients at each time point for 
the following categories:
QTcB. <450, 450 to <480, 480 to 500, and >500 msec.
QTcB change from baseline, 30 to <60 msec, and ≥60 msec.
9.9
Evaluability for Response
Response will be determined on the modified intent to treat (mITT) population consisting 
of all patients who are eligible and received at least one dose of protocol therapy.
For hepatoblastoma patients, RECIST criteria as described below will be used to provide 
an evaluation of RECIST-based response. For patients without serum alpha fetoprotein 
(AFP) elevated beyond the institutional upper limit of normal for age at the time of the start
of protocol therapy, the RECIST-based response will determine the response for the 
application of the statistical rule described in Section 9. Patients whose serum AFP level 
is elevated beyond the institutional upper level of normal for age at the start of protocol 
therapy will also be assessed for AFP-based response. Any such patient considered 
evaluable for response as described in Section 9.8 will be considered: (1) an AFP complete
responder (AFP-CR) if any serum AFP obtained on or after the start of Cycle 3 but before
the start of Cycle 7 is considered at or below the institutional upper limit of normal for 
age; or (2) an AFP partial responder (AFP-PR) if any serum AFP obtained on or after the 
start of Cycle 3 but before the start of Cycle 7 is 50% or less than that individual’s initial 
AFP but is still considered above the institutional upper level of normal age; and (3) AFP-
non-responder in any other case. The initial AFP obtained on Day 1 of protocol therapy or


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the AFP obtained during enrollment (see Note in Section 3.1.7.1), if the Day 1 AFP is not 
available.
For patients evaluable for both RECIST-based and AFP-based response, the overall 
response for application of the statistical rule will be calculated as: (1) RECIST-CR or 
RECIST-PR, AFP-any response category – response; (2) RECIST-SD, AFP-CR or AFP-
PR – response; (3) Any other combination of RECIST and AFP response – non- responder.
9.10
Gender and Minority Accrual Estimates
The gender and minority distribution of the study population is expected to be:
Accrual Targets
Ethnic Category
Sex/Gender
Females
Males
Total
Hispanic or Latino
15
11
26
Not Hispanic or Latino
48
80
128
Ethnic Category: Total of all patients
63
91
154
Racial Category
American Indian or Alaskan Native
0
0
0
Asian
8
5
12
Black or African American
9
16
24
Native Hawaiian or other Pacific Islander
0
0
0
White
46
70
116
Racial Category: Total of all patients
63
91
154
* These totals must agree
This distribution was derived from ADVL0524 (Phase II trial of Ixabepilone (BMS-247750),
an Epothilone B Analog in Children and Young Adults with refractory Solid tumors.
9.11
Analysis of the Pharmacokinetic Parameters
Plasma pazopanib concentrations observed in the first 6 patients who receive pazopanib as
powder for oral suspension and are evaluable for pharmacokinetics will be analyzed with
standard non compartmental methods using WinNonlin version 5.2 or higher. Parameter
values for maximum plasma pazopanib concentration (Cmax), the time to Cmax (tmax),
and the area under the curve (AUC) from zero to the time of the last quantifiable 
concentration (AUC(0-t)) will be calculated. The AUC from zero to 24 hours after
administration (AUC (0-24)) on Day 15 will be calculated by using the predose plasma
pazopanib concentration as the concentration 24 hours after dosing. The analysis to assess
pazopanib pharmacokinetics after administration of the suspension prior to continuing 
enrollment on suspension may be performed using scheduled time. Calculations of
noncompartmental parameter values for the final analysis will be based on actual sampling
times.
Plasma pazopanib concentration values at each sampling occasion will be summarized by 
cohort as well as after combining the data from all cohorts, separately for each formulation
and each dose level, if needed. In addition, plasma pazopanib concentration values at each
sampling occasion will be summarized by age subgroups (28 days to <2 years, 2 to <12 years
of age, and 12 to 18 years of age) for each formulation and dose level, if needed. This analysis


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will combine data across all disease cohorts unless pharmacokinetic differences between the 
cohorts are observed.
The pharmacokinetic parameter values in the patients with extended sampling will be 
summarized for Cycle 1 Day 1 and Cycle 1 Day 15, combining data from all patients, 
separately by dose level, if needed.
9.12
Analysis of Biological and Correlative Endpoints
The secondary analyses for examining the biologic relationship between tumor response and
angiogenic cytokines as well as the effects on toxicity (including hypertension) of 
pharmacokinetic parameters (secondary objectives 1.2.7 and 1.2.9) will be conducted 
 For the response outcome measure,
patients will be classified as responders or non-responders according to paragraphs 2 and 3
of the Primary Endpoint (Section 9.8.1) above. If response occurs in 10% or more of 
patients, the following logistic model will be fitted:

The initial analysis will be carried out with the Day 15 trough plasma concentration.
 
Toxicities, which occur in a frequency of 10% or more of toxicity evaluable courses, will 
be analyzed for association between the risk of toxicity and the particular biological 
parameter. The data will be presented as a cross tabulation of the presence of frequency 
of the toxicity of interest in toxicity-evaluable cycles
 
accounting for possible patient frailty will be fitted to the data. This analysis will not be 
segregated by disease type.
The precision attendant with these analyses will depend on the overall frequency of 
response and toxicity amongst patients enrolled on the study. The precision observed will 
be quantified by 95% confidence intervals. Adjustment for multiple testing will not be used 
for these secondary objectives.


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10
EVALUATION CRITERIA
10.1
Common Terminology Criteria for Adverse Events (CTCAE)
This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity
and performance reporting. The descriptions and grading scales found in the revised 
CTCAE version 4.0 will be utilized for reporting. All appropriate treatment areas should
have access to a copy of the CTCAE version 4.0, which can be downloaded from the
CTEP web site (http://ctep.cancer.gov). Additionally, toxicities are to be reported on
the appropriate case report forms.
10.2
Response Criteria
As outlined, patients will be assigned to one of the following categories for assessment of 
response: a) solid tumor and measurable disease (Section 10.3); b) neuroblastoma with 
MIBG positive lesions (Section 10.4) c) hepatoblastoma (Section 10.6)
Note: Neuroblastoma patients who do not have MIBG positive lesions should be assessed 
for response as solid tumor patients with measurable disease.
10.3
Response Criteria for Patients with Solid Tumors and Measurable Disease
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].45 Key points are that 5 target lesions are identified and that changes in the
largest diameter (unidimensional measurement) of the tumor lesions are used in
the RECIST v 1.1 criteria.
10.3.1
Measurable Disease
The presence of at least one lesion that can be accurately measured in at least 
one dimension with the longest diameter at least 10 mm (CT scan slice
thickness no greater than 5 mm). The investigator will identify up to 5
measurable lesions to be followed for response. Previously irradiated lesions
must demonstrate clear evidence of progression to be considered measurable.
Serial measurements of lesions are to be done with appropriate imaging 
modalities (e.g., CT or MRI). Bone scans cannot be used to measure lesions. The 
same method of assessment is to be used to characterize each identified and 
reported lesion at baseline and during follow-up.
10.3.2
Quantification of Disease Burden
The sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the disease measurement.
10.3.3
End-of-Cycle Response
Note: Please also see Table 1 in Section 10.7.
a.
Complete Response (CR)
Disappearance of all target and non-target lesions. Normalization of
urinary catecholamines (for patients with neuroblastoma), immunocytologic 
findings, or other tumor markers if abnormal or elevated at study enrollment.


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b.
Partial Response (PR)
At least a 30% decrease in the disease measurement, taking as reference
the disease measurement done to confirm measurable disease at study
enrollment. No new lesions or progression of any non-target measurable 
lesion.
c.
Stable Disease
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest disease measurement since
the treatment started.
d.
Progressive Disease (PD)
At least a 20% increase in the sum of the disease measurements for 
measurable
lesions,
taking
as
reference
the
smallest
disease
measurement recorded since the start of treatment, or the appearance of
one or more new lesions.
10.3.4 Overall Best Assessment Response
Each patient will be classified according to their “best response” for the purposes 
of analysis of treatment effect. Best response is determined from the sequence
of the objective statuses described in Table 1 and 2 in Section 10.7.
10.4
Response Criteria for Neuroblastoma Patients with 123I-MIBG Positive Lesions
10.4.1
MIBG Positive Lesions
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
irradiated, a biopsy must be done at least 4 weeks after radiation was completed 
and must show viable neuroblastoma.
10.4.2 The following criteria will be used to report MIBG response by the treating 
institution:

Complete Response: Complete resolution of all MIBG positive 
lesions

Partial Response: Resolution of at least one MIBG positive
lesion, with persistence of other MIBG positive lesions.

Stable Disease: No change in MIBG scan in number of
positive lesions (includes patients who have same number of
positive lesions but decreased density).

Progressive Disease: Development of new MIBG positive lesions.
10.4.3 The response of MIBG lesions will be assessed using the Curie scale as outlined 
below.
The body is divided into 9 anatomic sectors for osteomedullary lesions, with
a 10th general sector allocated for any extra-osseous lesion visible on MIBG
scan. In each region, the lesions are scored as follows. The absolute extension 
score is graded as:
0 = no site per segment,
1 = 1 site per segment,
2 = more than one site per segment,


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3 = massive involvement (>50% of the segment).
The absolute score is obtained by adding the score of all the segments.
See diagram of sectors below:
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below:
1. Complete response: all areas of uptake on MIBG scan completely resolved.
If morphological evidence of tumor cells in bone marrow biopsy or aspiration is
present at enrollment, the patient will be determined to have a
complete response when no tumor cells can be detected by routine morphology
on two subsequent bilateral bone marrow aspirates and biopsies which are done at
least 3 weeks apart.
2. Partial response: Relative score ≤0.2 (lesions almost disappeared) to ≤0.5
(lesions strongly reduced).
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced).
4. Progressive disease: New lesions on MIBG scan
10.4.4
Overall Best Response Assessment
Each patient will be classified according to their “best response” for the 
purposes of analysis of treatment effect. Best response is determined from the
sequence of the objective statutes described in Table 3 in Section 10.7.
10.5
Response Criteria for the Bone Marrow in Neuroblastoma Patients
10.5.1
Bone Marrow Response
Bone Marrow response is determined by H&E staining of bilateral bone marrow 
biopsies and aspirates.

Complete Response: No tumor cells detectable by routine morphology
on 2 consecutive bilateral bone marrow aspirates and biopsies performed at 
least 3 weeks apart.

ProgressiveDisease:


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o
Patients who enroll with neuroblastoma in the bone marrow by 
morphology have progressive disease if there is a doubling in the 
amount of tumor in the marrow AND have a minimum of 25% tumor 
in the bone marrow by morphology. (For example, a patient entering
with 5% tumor in the bone marrow by morphology must increase to
≥25% tumor to have progressive disease; a patient entering with 30% 
tumor must increase to > 60%).
o
Patients who enroll without evidence of neuroblastoma in the bone 
marrow will be defined as progressive disease if tumor is detected
in 2 consecutive bone marrow biopsies or aspirations done at least 3 
weeks apart.

StableDisease: Persistence of tumor in bone marrow that does not meet
the criteria for either complete response or progressive disease.
10.5.2
The above Bone marrow response criteria will be utilized for Neuroblastoma
patients when determining the Overall Best Response in Section 10.7.
10.6
Response Criteria for Hepatoblastoma
10.6.1
For hepatoblastoma patients, RECIST criteria as described above will be used
to provide an evaluation of RECIST-based response. For patients without serum 
alpha fetoprotein (AFP) elevated beyond the institutional upper limit of
normal for age at the time of the start of protocol therapy, the RECIST-based
response will determine the response for the application of the statistical rule
described in Section 9. Patients whose serum AFP elevated beyond the
institutional upper level of normal at the start of protocol therapy will also be 
assessed for AFP- based response. Any such patient considered evaluable for
response as described in Section 9.4 above will be considered: (1) an AFP
complete responder (AFP- CR) if any serum AFP obtained on or after the
start of Cycle 3 but before the start of Cycle 7 is considered at or below the
institutional upper limit of normal for age; or (2) an AFP partial responder
(AFP-PR) if any serum AFP obtained on or after the start of Cycle 3 but before 
the start of Cycle 7 is 50% or less than that individual’s initial AFP but is still
considered above the institutional upper level of normal for age; and (3) AFP-
non-responder in any other case. The initial AFP is the AFP obtained on Day
1 of protocol therapy or the AFP obtained during enrollment, if the Day 1 
AFP is not available.
For patients evaluable for both RECIST-based and AFP-based response, the 
overall response for application of the statistical rule will be calculated as: (1)
RECIST-CR or RECIST-PR, AFP-any response category – response; (2) 
RECIST-SD, AFP-CR or AFP-PR – Response; (3) Any other combination of 
RECIST and AFP response – non-responder.
10.6.2
Measurement of serum AFP markers
The serum AFP should be collected immediately prior to starting therapy on
the first day of treatment, and again at each scheduled disease evaluation if the 
initial value is elevated. The value must be reported as a precise number, and
not as an estimate (e.g., > 50,000 ng/mL). This may require serial dilutions of
samples in order to obtain an accurate value. In addition, values that are
unexpectedly low should also be confirmed by serial dilutions.


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10.6.3
Overall Response Assessment
The overall response assessment for hepatoblastoma patients takes into account 
response in the measurable and non-measurable disease, and the appearance
of new lesions, where applicable, and decline of AFP according to the criteria 
described in Table 4 below.
10.7
Best Response (Solid Tumors)
Two objective status determinations of disease status, by CT or MRI, obtained on two 
consecutive determinations, separated by at least a 3 week time period, are required
to determine the patient’s overall best response. Two objective status determinations of
CR before progression are required for best response of CR. Two determinations of PR
or better before progression, but not qualifying for a CR, are required for a best response 
of PR. Two determinations of stable/no response or better before progression, but not 
qualifying as CR or PR, are required for a best response of stable/no response; if the first 
objective status is unknown, only one such determination is required. Patients with
an objective status of progression on or before the second evaluations (the first
evaluation is the first radiographic evaluation after treatment has been administered) 
will have a best response of progressive disease. Best response is unknown if the patient
does not qualify for a best response of progressive disease and if all objective statuses
after the first determination and before progression are unknown.
Table 1: Sequences of objective statuses with corresponding best response.
1st Status
2nd Status
3rd or 
subsequent 
Status
Best Response
Progression
Progressive disease
Stable, PR, CR
Progression
Progressive disease
Unknown
Progression
Progressive disease
Stable
Stable
Progression
Stable
Stable, Unknown
PR, CR
Progression
Stable
Stable, Unknown
Unknown
Progression
Unknown
PR
PR
Progression
PR
PR
CR
Progression
PR
PR, CR
Unknown
Progression
Unknown
CR
CR
Progression
CR
Unknown
Stable
Progression
Stable


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CT/MRI
MIBG
Bone Scan
Bone Marrow1
Catecholamines
Overall
PD
Any
Any
Any
Any
PD
Any
PD
Any
Any
Any
PD
Any
Any
PD
Any
Any
PD
Any
Any
Any
PD
Any
PD
SD
CR/PR/SD
Non-PD
Non-PD
Any
SD
PR
CR/PR
Non-PD
Non-PD
Any
PR
CR/PR
PR
Non-PD
Non-PD
Any
PR
CR
CR
Non-PD
Non-PD
Elevated
PR
CR
CR
CR
CR
Normal
CR
Table 2: Overall Response for Patients with Neuroblastoma and Measurable Disease
1 Bone marrow does not need to be routinely done for disease assessment if Negative at the start of 
protocol therapy


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Table 3: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive
Disease Only
If patients are enrolled without disease measurable by CT/MRI, any new or newly identified 
lesion by CT/MRI that occurs during therapy would be considered progressive disease.
MIBG
CT/MRI
Bone Scan
Bone Marrow1
Catecholamines
Overall
PD
Any
Any
Any
Any
PD
Any
New Lesion
Any
Any
Any
PD
Any
Any
PD
Any
Any
PD
Any
Any
Any
PD
Any
PD
SD
No New Lesion
Non-PD
Non-PD
Any
SD
PR
No New Lesion
Non-PD
Non-PD
Any
PR
CR
No New Lesion
Non-PD
Non-PD
Elevated
PR
CR
No New Lesion
CR
CR
Normal
CR
1 Bone marrow does not need to be routinely done for disease assessment if Negative at the start of 
protocol therapy
Table 4: Overall Response Assessment for Hepatoblastoma Patients
Target
Lesions
Non-target
Lesions
New Lesions
AFP1
Overall
Response
PD
Any
Yes or No
Any
PD
Any
PD
Yes or No
Any
PD
Any
Any
Yes
Any
PD
SD
Non-PD
No
Stable
SD
Non-PD
Non-PD
No
≥50%
decrease
from highest AFP
prior to treatment
PR
PR
Non-PD
No
Decreased
PR
CR
Incomplete 
response/SD
No
Decreased
PR
CR
CR
No
Normalized2
CR2
1 AFP is not part of the overall response assessment if it was NOT elevated at the start of protocol 
therapy
2An overall response of CR MUST include a normal AFP. Until the AFP has normalized, a patient 
can only be considered PR at best.
10.8
Survival Follow-Up
Patients who have discontinued protocol therapy will be followed for Survival status. The 
investigator site will collect and report Survival follow-up in the eCRF every 3 months,
which would include the patient’s survival status and any antineoplastic therapies taken
since discontinuation of protocol therapy, until death, lost to follow-up, or withdrawal of
consent from survival follow-up occurs or final cut-off for survival analysis.
The date and cause of death should be recorded in the eCRF.


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11
ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENTS (SAE)
The investigator or site staff is responsible for detecting, documenting and reporting events
that meet the definition of an AE or SAE.

AEs will be collected from the start of protocol therapy and until 28 days following last 
dose of protocol therapy.
SAEs will be collected over the same time period as stated above for AEs. From the time 
a patient consents to participate in and completes the study, all SAEs assessed as related 
to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or 
change in existing therapy)  will be reported promptly to Novartis as indicated in Section 
11.8.
Medical occurrences that begin prior to the start of protocol therapy but after obtaining 
informed consent should be recorded on the Medical History/Current Medical Conditions 
section of the eCRF.
Any new primary cancer must be recorded as an SAE and will be recorded from the time a
patient consents to participate in the study up to and including any follow-up contact.
All SAEs will be recorded and reported to Novartis and COG within 24 hours, as indicated 
in Section 11.8.
Investigators are not obligated to actively seek AEs or SAEs in former study participants.
However, if the investigator learns of any SAE, including a death, at any time after a patient
has been discharged from the study, and he/she considers the event reasonably related to the
study treatment or study participation, the investigator should promptly notify Novartis and
COG.
11.1
Definition of Adverse Events (AEs)
An AE is any untoward medical occurrence in a patient or clinical investigation patient, 
temporally associated with the use of a medicinal product, whether or not considered related
to the medicinal product. CTCAE criteria version 4.0 will be used to grade severity 
of adverse events.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product
Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)
or
other
safety
assessments
(e.g.,
ECGs,
radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. (Overdose per se will not be reported as an
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae.)

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE 
or SAE.


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Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition.

The disease/disorder being studied, or expected progression, signs, or symptoms of
the disease/disorder being studied, unless more severe than expected for the patient’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
11.2
Definition of Serious Adverse Events (SAEs)
Refer to Section 11.8 for reporting requirements including the within 24 hour time limit 
for all SAEs as defined below.
If an event is not an AE per Section 11.1 then it cannot be an SAE even if serious conditions
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease, etc).
An SAE is any untoward medical occurrence that, at any dose:

Results in death

Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the patient was at risk of death at the time of the event. It does not refer to an
event, which hypothetically might have caused death, if it were more severe.

Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the patient has been detained 
(usually involving at least an overnight stay) at the hospital or emergency department 
for observation and/or treatment that would not have been appropriate in the
physician’s office or out-patient
setting. Complications that occur
during
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in disability/incapacity
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, or accidental trauma (e.g.sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.

Is a congenital anomaly/birth defect

Medical or scientific judgment should be exercised in deciding whether reporting is
appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize


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the patient or may require medical or surgical intervention to prevent one of the other
outcomes listed in the above definition. These should also be considered serious.
Examples of such events are invasive or malignant cancers, intensive treatment in an
emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT > 3xULN and bilirubin > 1.5x ULN (>35% of total bilirubin is direct) or ALT
> 3xULN and INR>1.5, if INR measured termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to patients 
receiving anticoagulants).
NOTE: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable 
and a patient meets the criterion of total bilirubin 2xULN, then the event is still 
reported as an SAE. If INR is obtained, include values on the SAE form. INR 
elevations >1.5 suggest severe liver injury.
11.3
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” or “How does your child seem to feel?”

“Have you had any (other) medical problems since your last visit/contact?” or

“Has your child had any (other) medical problems or seem to act differently in 
any way since his/her last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” or “Has your child needed to take any medicines,
other than those provided in this study, since his/her last visit/contact?”
11.4
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as an
SAE. Death due to disease under study is to be recorded on the Death eCRF form. However,
if the underlying disease (i.e., progression) is greater than that which would normally be
expected for the patient, or if the investigator considers that there was a causal 
relationship between treatment with study medication(s) or protocol design/procedures and 
the disease progression, then this must be reported as an SAE.
11.5
Recording of AEs and SAEs
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to
the event. The investigator will then record all relevant information regarding an AE/SAE in 
the appropriate data collection tool.
It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to Novartis or COG in lieu of completion of the Novartis AE/SAE data collection
tool. However, there may be instances when copies of medical records for certain cases are 


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requested by Novartis and COG. In this instance, all patient identifiers, with the exception
of the patient number (both COG and Novartis study numbers), will be blinded on the copies 
of the medical records prior to submission to Novartis.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms,
and/or other clinical information. In such cases, the diagnosis will be documented as the 
AE/SAE and not the individual signs/symptoms.
11.6
Evaluating AEs and SAEs
11.6.1
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE
reported during the study and will assign it to one of the following categories:
Mild: An event that is easily tolerated by the patient, causing minimal discomfort 
and not interfering with everyday activities.
Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities.
Severe: An event that prevents normal everyday activities
An AE that is assessed as severe will not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event, and both AEs and SAEs can 
be assessed as severe. An event is defined as ‘serious’ when it meets at least one 
of the pre-defined outcomes as described in the definition of an SAE.
11.6.2
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and
the occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that 
there are facts/evidence or arguments to suggest a causal relationship, rather than a
relationship cannot be ruled out. The investigator will use clinical judgment to
determine the relationship. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal
relationship of the event to the study treatment will be considered and investigated.
The investigator will also consult the Investigator Brochure (IB) and/or Product
Information, for marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.
11.7
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
patient at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, 
until the condition stabilizes, until the event is otherwise explained, or until the patient is lost 
to follow-up.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by Novartis to elucidate
as fully as possible the nature and/or causality of the AE or SAE. The investigator is obligated 
to assist. This may include additional laboratory tests or investigations, histopathological 
examinations or consultation with other health care professionals. If a patient dies during
participation in the study or during a recognized follow-up period, the investigator will 


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provide Novartis with a copy of any post-mortem findings, including histopathology.
New or updated information will be recorded in the originally completed data collection tool.
The investigator will submit any updated SAE data to Novartis within the designated 
reporting time frames
11.8
Prompt Reporting of SAEs to Novartis and COG
Once the investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to Novartis and COG within 24 hours. Any follow-up information 
on a previously reported SAE will also be reported to Novartis and COG within 24 hours. If 
the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying Novartis and COG of the event and 
completing the appropriate data collection tool. The investigator will always provide an 
assessment of causality at the time of the initial report as described in Section 11.6.2, 
Assessment of Causality.
The primary mechanism for reporting SAEs to Novartis and COG will be the electronic data 
collection tool. If the electronic system is unavailable for greater than 24 hours, the site will 
use the paper SAE data collection tool and fax it to the number included in the Study 
Procedures Manual. Then the site will enter the SAE data into the electronic system as soon 
as it becomes available.
After the study is completed at a given site, the electronic data collection tool (e.g., 
DataLabs™system) will be taken off-line to prevent the entry of new data or changes to 
existing data. If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool has been
taken off-line, the site can report this information on a paper SAE form or to their Novartis
protocol contact by telephone.
Novartis contacts for SAE receipt can be found at the beginning of this protocol on the
Sponsor Information page.
11.9
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of patients are met. Novartis has a 
legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. Novartis will comply with 
country specific regulatory requirements relating to safety reporting to regulatory authorities, 
IRBs/Independent Ethics Committees (IECs) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Novartis policy and are 
forwarded to investigators as necessary. An investigator who receives an investigator
safety report describing an SAE(s) or other specific safety information (e.g., summary
or listing of SAEs) from Novartis will file it with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements.


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12
STUDY REPORTING AND MONITORING
For this study, patient data will be entered into electronic case report forms (eCRFs), transmitted 
electronically to Novartis or designee and be combined with data provided from other sources
in a validated data system.
Clinical data management will be performed in accordance with applicable standards and data 
cleaning procedures with the objective of resolving errors and inconsistencies in the data which 
would otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical 
Study Report. All AEs and concomitant medications terms will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and a custom dictionary. eCRFs (including
queries and audit trails) will be retained by Novartis, and copies will be sent to the investigator 
to maintain as the investigator copy.
12.1
Data and Safety Monitoring
A formal data safety monitoring board will not be utilized for this open-label study. The 
following procedures will be followed to provide appropriate data and safety monitoring for
this study:

The study team, which includes the Medical Lead, representatives from the Clinical 
Pharmacology Group, and the COG protocol chair will review and discuss safety data
at periodic intervals throughout the duration of the study.


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13
APPENDICES
13.1
APPENDIX IA: PATIENT DIARY FOR PAZOPANIB TABLETS
COG Patient ID:
ACC # : 
Institution:
Please do not write patient name on this form.
Sponsor Patient ID:
Please write the date, time and dose of pazopanib given. Please make note of all prescription medications, 
nonprescription medications, and herbal remedies you take. Also, please remember to take the tablets at 
least 1 hour before or 2 hours after a meal. Return the completed diary to your institution after each 
treatment cycle along with any unused study medication or empty study medication bottles.
Cycle #:
Start Date: | / | / | / | End Date: | / | / | / |
Daily dose:
mg =
×200 mg +
×400 mg
WEEK 1
Date
Time
(Circle AM or PM)
200 mg
400 mg
Comments
Day 1
am/pm
Day 2
am/pm
Day 3
am/pm
Day 4
am/pm
Day 5
am/pm
Day 6
am/pm
Day 7
am/pm
WEEK 2
Date
Time
200 mg
400 mg
Comments
Day 8
am/pm
Day 9
am/pm
Day 10
am/pm
Day 11
am/pm
Day 12
am/pm
Day 13
am/pm
Day 14
am/pm
WEEK 3
Date
Time
200 mg
400 mg
Comments
Day 15
am/pm
Day 16
am/pm
Day 17
am/pm
Day 18
am/pm
Day 19
am/pm
Day 20
am/pm
Day 21
am/pm
WEEK 4
Date
Time
200 mg
400 mg
Comments
Day 22
am/pm
Day 23
am/pm
Day 24
am/pm
Day 25
am/pm
Day 26
am/pm
Day 27
am/pm


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Day 28
am/pm


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13.2
APPENDIX IB: PATIENT DIARY FOR PAZOPANIB POWDER IN SUSPENSION
COG Patient ID:
ACC #: 
Institution:
Please do not write patient name on this form.
Sponsor Patient ID:
Please write the date, time and dose of pazopanib given. Please make note of all prescription medications,
nonprescription medications, and herbal remedies you take. Please remember to swirl the suspension for
30 seconds prior to withdrawing the dose from the bottle. Also, please remember to take the suspension on 
an empty stomach either 1 hour before or 2 hours after meals. Return the completed diary to your 
institution after each treatment cycle along with all the bottles of study medication, even empty.
Cycle #:
Start Date: | / | / | / | End Date: | / | / | / |
Daily dose:
mL
WEEK 1
Date
Time
(Circle AM or
PM)
Suspension Taken
Amount (mL)
Comments
Day 1
am/pm
Day 2
am/pm
Day 3
am/pm
Day 4
am/pm
Day 5
am/pm
Day 6
am/pm
Day 7
am/pm
WEEK 2
Date
Time
Comments
Day 8
am/pm
Day 9
am/pm
Day 10
am/pm
Day 11
am/pm
Day 12
am/pm
Day 13
am/pm
Day 14
am/pm
WEEK 3
Date
Time
Comments
Day 15
am/pm
Day 16
am/pm
Day 17
am/pm
Day 18
am/pm
Day 19
am/pm
Day 20
am/pm
Day 21
am/pm
WEEK 4
Date
Time
Comments
Day 22
am/pm
Day 23
am/pm
Day 24
am/pm
Day 25
am/pm
Day 26
am/pm
Day 27
am/pm
Day 28
am/pm


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13.3
APPENDIX II: PAZOPANIB DOSING NOMOGRAM FOR TABLETS
Dosing Nomogram for Target Starting Dose of 450 mg/m2/dose and for Dose Reductions if required
Starting Dose
Dose Reduction
#1
Dose Reduction
#2
Target :
450 mg/m2/dose
BSA* 
Dose (mg)†
0.84-1.16
400
200
0
1.17 -1.61
600
400
200
≥ 1.62
800
600
400
* BSA, body surface area in m2.
† Actual dose is in mg (tablets sizes 200 mg and 400 mg) to be administered daily.


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13.4
APPENDIX IIIA: LIST OF ANTICONVULSANT DRUGS THAT ARE ALLOWED
Anticonvulsant drugs with little or no enzyme induction: 
ELIGIBLE/ALLOWED
Lamotrigine (Lamictal) 
Levetiracetam (Keppra) 
Tigabine (Gabitril) 
Topiramate (Topamax)
Valproic Acid, Depakote (Depakene) 
Zonisamide (Zonegran)


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13.5
APPENDIX IIIB: MEDICATIONS THAT MAY CAUSE QTc PROLONGATION
The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the QTc. 
Please note that this list is frequently updated. For the most current list of medications, users should be 
directed to the following website: ...azcert.org/medical-pros/drug-lists/drug-lists.cfm.


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Drugs that are generally 
accepted to have a risk of 
causing Torsades  de 
pointes
PROHIBITED DRUGS 
(See Appendix III-A)
Drugs that in some reports have been 
associated with Torsades de pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de pointes
CONSIDER MORE FREQUENT 
EKG MONITORING
(Unless otherwise noted as 
prohibited)
Drugs that, in some reports, 
have been weakly associated
with Torsades de pointes and/or 
QTc prolongation but that are 
unlikely to be a risk for Torsades 
de pointes when used in usual 
recommended dosages and in 
patients without other  risk 
factors (e.g., concomitant QTc 
prolonging drugs, bradycardia, 
electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism).
EKG MONITORING
AS PER INVESTIGATOR 
DISCRETION              
(Unless otherwise noted as 
prohibited)
Generic/Brand Name
Generic/Brand Name
Generic/Brand Name
Amiodarone /Cordarone®     
Alfuzosin /Uroxatral®
Amitriptyline /Elavil®
Amiodarone /Pacerone®       
Amantadine /Symmetrel®
Ciprofloxacin /Cipro®
Arsenic trioxide /Trisenox®
Atazanavir /Reyataz®
Citalopram /Celexa®
Astemizole /Hismanal®
Azithromycin /Zithromax®
Clomipramine /Anafranil®
Bepridil /Vascor®
Chloral hydrate /Noctec®
Desipramine /Pertofrane®
Chloroquine /Aralen®
Clozapine /Clozaril® (prohibited)
Diphenhydramine /Benadryl®
Chlorpromazine/Thorazine®
Dolasetron /Anzemet®
Diphenhydramine /Nytol®
Cisapride /Propulsid®
Dronedarone /Multaq®
Doxepin /Sinequan®
Clarithromycin /Biaxin®
Felbamate /Felbatol® (prohibited)
Fluconazole /Diflucan®
Disopyramide /Norpace®
Flecainide /Tambocor® (prohibited)
Fluoxetine /Sarafem®
Dofetilide /Tikosyn®
Foscarnet /Foscavir®
Fluoxetine /Prozac®
Domperidone /Motilium®
Fosphenytoin /Cerebyx® (prohibited)
Galantamine /Reminyl®
Droperidol /Inapsine®
Gatifloxacin /Tequin®
Imipramine /Norfranil®
Erythromycin/Erythrocin®
Gemifloxacin /Factive®
Itraconazole/Sporonax® 
(prohibited)
Erythromycin /E.E.S.®
Granisetron /Kytril®
Ketoconazole /Nizoral® 
(prohibited)
Halofantrine /Halfan®
Indapamide /Lozol®
Mexiletine /Mexitil® 
(prohibited)
Haloperidol /Haldol®
Isradipine /Dynacirc®
Nortriptyline /Pamelor®


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Drugs that are generally 
accepted to have a risk of 
causing Torsades  de 
pointes
PROHIBITED DRUGS 
(See Appendix III-A)
Drugs that in some reports have been 
associated with Torsades de pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de pointes
CONSIDER MORE FREQUENT 
EKG MONITORING
(Unless otherwise noted as 
prohibited)
Drugs that, in some reports, 
have been weakly associated
with Torsades de pointes and/or 
QTc prolongation but that are 
unlikely to be a risk for Torsades 
de pointes when used in usual 
recommended dosages and in 
patients without other risk
factors (e.g., concomitant QTc 
prolonging drugs, bradycardia, 
electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism).
EKG MONITORING
AS PER INVESTIGATOR 
DISCRETION              
(Unless otherwise noted as 
prohibited)
Generic/Brand Name
Generic/Brand Name
Generic/Brand Name
Ibutilide /Corvert®
Lapatinib /Tykerb®
Paroxetine /Paxil®
Levomethadyl /Orlaam®
Levofloxacin /Levaquin®
Protriptyline /Vivactil®
Mesoridazine /Serentil®
Lithium /Lithobid®
Sertraline /Zoloft®
Methadone /Dolophine®
Lithium /Eskalith®
Solifenacin /VESIcare®
Methadone /Methadose®
Moexipril/HCTZ /Uniretic®
Trimethoprim-Sulfa /Sulfa®
Pentamidine /Pentam®
Moxifloxacin /Avelox®
Trimethoprim-Sulfa /Bactrim®
Pentamidine /NebuPent®
Nicardipine /Cardene®
Trimipramine /Surmontil®
Pimozide /Orap®
Nilotinib /Tasigna®
Probucol /Lorelco®
Octreotide /Sandostatin®
Procainamide /Pronestyl®
Ofloxacin /Floxin®
Procainamide /Procan®
Ondansetron /Zofran®
Quinidine /Cardioquin®
Oxytocin /Pitocin®
Quinidine /Quinaglute®
Paliperidone /Invega®
Sotalol /Betapace®
Perflutren lipid microspheres/
Definity®
Sparfloxacin /Zagam®
Quetiapine /Seroquel® (prohibited)
Terfenadine /Seldane®
Ranolazine /Ranexa®
Thioridazine /Mellaril®
Risperidone /Risperdal® (prohibited)
Roxithromycin* /Rulide®
Sertindole /Serlect®
Sertindole /Serdolect®
Sunitinib /Sutent®
Tacrolimus /Prograf® (prohibited)
Tamoxifen /Nolvadex®
Telithromycin /Ketek® (prohibited)


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Drugs that are generally 
accepted to have a risk of 
causing Torsades  de 
pointes
PROHIBITED DRUGS 
(See Appendix III-A)
Drugs that in some reports have been 
associated with Torsades de pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de pointes
CONSIDER MORE FREQUENT 
EKG MONITORING
(Unless otherwise noted as 
prohibited)
Drugs that, in some reports, 
have been weakly associated
with Torsades de pointes and/or 
QTc prolongation but that are 
unlikely to be a risk for Torsades 
de pointes when used in usual 
recommended dosages and in 
patients without other risk
factors (e.g., concomitant QTc 
prolonging drugs, bradycardia, 
electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism).
EKG MONITORING
AS PER INVESTIGATOR 
DISCRETION              
(Unless otherwise noted as 
prohibited)
Tizanidine /Zanaflex®
Vardenafil /Levitra®
Venlafaxine /Effexor®
Voriconazole /VFend® (prohibited)
Ziprasidone /Geodon®


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13.6
APPENDIX IV: URINE PROTEIN TO CREATININE (UPC) RATIO
Clinical Meaning of UPC
There is a good correlation between the ratio of urine protein to urine creatinine concentrations (UPC) in 
a random urine sample and the amount of protein excreted in a 24-hour urine collection period. 48 Thus, 
the UPC ratio from a single random urine sample permits estimation of the 24-hour urine protein excretion.
The creatinine excretion is fairly constant throughout the day regardless of changes in urine flow rate:

Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day

Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day

Normal protein excretion is <100 mg to 150 mg per 24 hours.

The UPC ratio is roughly equal to the 24-hour urine protein excretion in g/day
Calculating UPC Ratio
UPC ratio = (Urine protein [mg/dL]) / (urine creatinine [mg/dL]) = numerically equivalent to grams (g)
protein excreted in urine over 24 hours.
Example: If a patient has a urine protein concentration of 90 mg/dL and urine creatinine concentration of
30 mg/dL,
then UPC ratio =
90(mg/dL) = 3
30 (mg/dL)
UPC ratio of 3 correlates to roughly 3g of protein excretion in a 24-hour period.
Units for UPC ratio
UPC is a calculated ratio. The guidelines in the protocol are based on having urine protein and urine
creatinine measured in the same units (e.g., mg/dL). The International System of Units (SI) units for urine 
protein and urine creatinine are not the same, so these must be converted to mg/dL before calculating the 
ratio. For reference, the conversion factors for commonly used units for protein and creatinine are provided 
below.
Starting units
Conversion to mg/dL
Protein (g/L)
Multiply by 100
Creatinine (mol/L)
Divide by 88.4
Creatinine (mmol/L)
Multiply by 11.3


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13.7
APPENDIX V: BLOOD PRESSURE LEVELS FOR CHILDREN BY AGE AND HEIGHT
PERCENTILE
Blood pressure (BP) levels for BOYS
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age
BP
Percentile of Height
Percentile of Height
(years)
Percentile
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
98
99
101
103
104
106
106
54
54
55
56
57
58
58
2
95th
101
102
104
106
108
109
110
59
59
60
61
62
63
63
3
95th
104
105
107
109
110
112
113
63
63
64
65
66
67
67
4
95th
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
95th
108
109
110
112
114
115
116
69
70
71
72
73
74
74
6
95th
109
110
112
114
115
117
117
72
72
73
74
75
76
76
7
95th
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
95th
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
95th
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
13
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
14
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
15
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
16
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
17
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
Instructions for using this BP Chart:
1.
Measure the patient’s blood pressure using an appropriate size cuff.
2.
Select appropriate chart for a female or male patient.
3.
Using the “age” row and “height” column determine if the BP is within the ULN.
4.
See Section 5.1.2.5 for definition of dose limiting hypertension, Section 5.4.1 for management and grading of 
hypertension, and Section 4.1.5.1 for medical treatment of pazopanib related hypertension.
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children 
and Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.
Note:
For patients ≥ 18 yrs, ULN BP is 140/90 mmHg.


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Blood pressure (BP) levels for GIRLS
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age
BP
Percentile of Height
Percentile of Height
(years)
Percentile
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
100
101
102
104
105
106
107
56
57
57
58
59
59
60
2
95th
102
103
104
105
107
108
109
61
62
62
63
64
65
65
3
95th
104
104
105
107
108
109
110
65
66
66
67
68
68
69
4
95th
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
95th
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
95th
108
109
110
111
113
114
115
72
72
73
74
74
75
76
7
95th
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
95th
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
95th
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
13
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
14
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
15
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
16
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
17
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
Instructions for using this BP Chart:
1.
Measure the patient’s blood pressure using an appropriate size cuff.
2.
Select appropriate chart for a female or male patient.
3.
Using the “age” row and “height” column determine if the BP is within the ULN.
4.
See Section 5.1.2.5 for definition of dose limiting hypertension, Section 5.4.1 for management and grading of 
hypertension, and Section 4.1.5.1 for medical treatment of pazopanib related hypertension.
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children 
and Adolescents” PEDIATRICS Vol. 114 No. 2
August 2004, pp. 555-576.
Note:
For patients ≥ 18 yrs, ULN BP is 140/90 mmHg.


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13.8
APPENDIX VI: PHARMACOKINETIC STUDY FORM
COG Pt ID # _______________ACC # _______________ SPONSOR Patient ID #_______________
Please do not write patient names on this form or on samples.
Except for Cycle 1 Day 1, pre-dose samples should be collected between 22-26 hours after the previous 
dose of pazopanib.
Samples will be obtained as outlined in the tables below.
Record the exact time the sample is drawn and the exact time that the dose of pazopanib was given.
CYCLE 1:
Day 1:
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
Date and time of dose given on Cycle 1, Day 1:
Date: _________ Time: |__|__| : |__|__|
(MM/DD/YY)    
Day 15 (± 1):
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
Date and time of dose given on Cycle 1, Day 15 (± 1):
Date: _________ Time: |__|__| : |__|__|
(MM/DD/YY)    
All patients not participating in Extended PK sampling:
Blood Sample 
No.
Time Point
Scheduled Collection 
Time
Actual Date 
Sample 
Collected 
Actual Time 
Collected 
(24-hr clock)
1
Cycle 1, Day 1
Prior to dose
|__|__| : |__|__|
2a
Cycle 1, Day 15 (± 1)
Prior to dose
|__|__| : |__|__|
3a
Cycle 1, Day 15 (± 1)
3-4 hrs after dose
|__|__| : |__|__|
Patients receiving powder suspension formulation and participating in Extended PK sampling:
Blood Sample 
No.
Time Point
Scheduled Collection 
Time
Actual Date 
Sample 
Collected 
Actual Time 
Collected 
(24-hr clock)
1
Cycle 1, Day 1
Prior to dose
|__|__| : |__|__|
2 
Cycle 1, Day 1
30 min after first dose
|__|__| : |__|__|
3 
Cycle 1, Day 1
1 hr after first dose 
|__|__| : |__|__|
4
Cycle 1, Day 1
2 hrs after first dose
|__|__| : |__|__|
5 
Cycle 1, Day 1
4 hrs after first dose
|__|__| : |__|__|
6
Cycle 1, Day 1
6 hrs after first dose
|__|__| : |__|__|
7
Cycle 1, Day 1
8 hrs after first dose
|__|__| : |__|__|
10a
Cycle 1, Day 15 (± 1)
Prior to dose
|__|__| : |__|__|
11a
Cycle 1, Day 15 (± 1)
30 min after first dose
|__|__| : |__|__|
12 a
Cycle 1, Day 15 (± 1)
1 hr after dose
|__|__| : |__|__|
13 a
Cycle 1, Day 15 (± 1)
2 hrs after dose
|__|__| : |__|__|
14 a
Cycle 1, Day 15 (± 1)
4 hrs after dose
|__|__| : |__|__|
15 a
Cycle 1, Day 15 (± 1)
6 hrs after dose
|__|__| : |__|__|
16 a
Cycle 1, Day 15 (± 1)
8 hrs after dose
|__|__| : |__|__|
a 
Pazopanib dosing of either tablet or powder suspension must have continued uninterrupted and at the same dose 
level for at least 10 days prior to acquisition of  the Cycle 1 Day 15 PK samples.  If pazopanib dosing has been 
interrupted or modified <10 days prior to Cycle 1 Day 15, then the PK samples should be taken between Cycle 
1 Day 15 and Cycle 1 Day 22 on a study day that meets the condition of at least 10 consecutive days of dosing 
at the same dose level.  The Cycle 1 Day 15 PK kit should be used, and the actual date and time of sample 


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collections should be recorded in the eCRF.
SUBSEQUENT CYCLES:
For patients who continue to receive protocol therapy, PK sampling is also required prior to subsequent odd-numbered cycles. 
This sample may be taken between Day 22 of the previous even -numbered cycle to Day 1 of the odd-numbered cycle (e.g., 
between Day 22 of Cycle 2 and Day 1 of Cycle 3). Please record the actual Cycle and Day on which the sample was obtained.  
The timing of this sample should be between 22-26 hours after the previous dose of pazopanib.  For samples collected in 
Cycle 3 and greater, record the date, time, and amount of the pazopanib dose administered on the study day prior to the blood
sample collection in the area below
For Cycle 3 pre-dose:    Cycle # ____   Day #____      Sample Collected:   
  Date: _________     Time: |__|__| : |__|__|
     
       
              
              (MM/DD/YY)    
Date and Time of Prior Pazopanib Dose:    Date: _________   Time: |__|__| : |__|__|
     (MM/DD/YY)
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
For Cycle 5 pre-dose:    Cycle # ____   Day #____      Sample Collected:   
  Date: _________     Time: |__|__| : |__|__|
     
              (MM/DD/YY)    
Date and Time of Prior Pazopanib Dose:    Date: _________   Time: |__|__| : |__|__|
    (MM/DD/YY)
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
For Cycle 7 pre-dose:    Cycle # ____   Day #____      Sample Collected:   
  Date: _________     Time: |__|__| : |__|__|
     
              (MM/DD/YY)    
Date and Time of Prior Pazopanib Dose:    Date: _________   Time: |__|__| : |__|__|
    (MM/DD/YY)
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
For Cycle 9 pre-dose:    Cycle # ____   Day #____      Sample Collected:   
  Date: _________     Time: |__|__| : |__|__|
     
              (MM/DD/YY)    
Date and Time of Prior Pazopanib Dose:    Date: _________   Time: |__|__| : |__|__|
    (MM/DD/YY)
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
For Cycle 11 pre-dose:  Cycle # ____   Day #____      Sample Collected:   
  Date: _________     Time: |__|__| : |__|__|
     
              (MM/DD/YY)    
Date and Time of Prior Pazopanib Dose:    Date: _________   Time: |__|__| : |__|__|
    (MM/DD/YY)
Body Surface Area: |__|°|__|__| m2
Dose: |__|__|__|mg/m2
Total Dose: |__|__|__|mg
Signature: __________________________________________________                    Date:__________________________
(site personnel who collected samples)


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Sample Collection, Handling, and Processing
1.
Blood samples will be collected into tubes containing potassium EDTA as an anticoagulant and 
may be drawn from a central venous catheter.
2.
The samples should be centrifuged at approximately 2500 x g at 5oC for 10 minutes. The resulting 
volume of plasma will be transferred in equal aliquots to two (2) corresponding pre-labeled 
polypropylene storage tubes. The tubes will be frozen in an upright position at -20oC until shipped 
to the laboratory for analysis.
3.
Each tube must be labeled with the Sponsor study specific patient number, the study I.D. 
(ADVL1322/VEG116731), and the date and time the sample was drawn. Please also see the 
instructions in the 
 Central Laboratory Services Manual (binder) that is provided with the 
initial start up PK kits from 
. 
A copy of this form along with a copy of the requisition form provided in the kits from 
should 
be sent with the samples. All samples should be batched and shipped with adequate amounts of dry ice. 
Shipments should be sent Monday through Thursday only for priority overnight delivery (do not ship 
on Friday) to the address listed in the PK kit supplied by 
.
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below:
Signature: __________________________________________________                    Date::__________________________
(site personnel who collected samples)


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13.9
APPENDIX VII: INSTRUCTIONS TO PATIENT/CAREGIVER FOR ADMINISTERING 
PAZOPANIB ORAL SUSPENSION
Patient name:
Investigator/study staff: Please fill in the dose in section A.
This document provides instructions for patients/caregivers on the administration and storage of pazopanib 
suspension. It also details how to clean up in the event of a spill. Any leftover medication should be 
returned to your doctor. You should read the information on these pages before you give your child the 
suspension. Please read these instructions carefully and ask your doctor about any questions you 
may have.
A. Administration:
1.
The pharmacist should insert the provided adapter (Baxa 28 mm Press-In-Bottle Adapter - PIBA®)
into the neck of the bottle. Once the adapter has been placed into the bottle neck, DO NOT 
REMOVE.
2.
Immediately before planned dose administration, mix the contents of the bottle by swirling for 30 
seconds to one minute in order to ensure homogeneity of suspension.
3.
Note#1: Women who are pregnant or nursing should put on a suitable size of gloves to avoid 
contact between the liquid and skin (Latex gloves can be used; however, for people who are 
sensitive to latex, it is recommended to use Nitrile gloves). Take care not to spread material to 
unprotected skin (such as your face) or other body surfaces by touching them with a wet glove. 
Note#2: In case of spillage, see section C for Clean-up instructions.
3.
Insert the tip of an appropriate syringe (recommended: Exacta-Med® Baxa) into the Adapter after 
ensuring that the syringe plunger is pushed fully into the barrel.
4.
Tip the bottle upside down and dispense at least 3-5 mL of suspension into the syringe. Then push 
the suspension back into the bottle in order to purge the syringe of any air bubbles. Repeat this 
step until syringe is free of air bubbles.
5.
Withdraw the prescribed dose. Investigator/study staff will fill in the dose below for each patient.
The dose is 
mg, corresponding to 
mL each day.
Please note that the number of milligrams of pazopanib and, therefore, the number of milliliters of 
pazopanib oral suspension may change as the body surface area of the patient changes during study 
participation.
6.
After you have given your child the dose, pull the plungers out of all the syringes and rinse the 
syringes and plungers with warm water for 30 seconds. When dry, place the plungers back into 
their syringes and store them for the next time.
7.
Pazopanib is to be given orally (by mouth) only.
8.
The dose should be given on an empty stomach (1 hour before or 2 hours after a meal) once daily.
9.
If your child’s study doctor prescribed medicine to prevent nausea or vomiting with pazopanib, 
you should give your child this medicine 30-60 minutes before you give pazopanib.
10. If your child spits out or vomits a dose of pazopanib, it should not be repeated.
11. If a dose is missed, it may be given within 12 hours of the time it was due. Beyond 12 hours that 
dose should be skipped. The next dose should be given at its regularly scheduled time. For
example, if the dose was due at 8am, then the dose may be given up to 8pm that same day.
B. Storage and returning partially used and unused bottles:
1.
The pazopanib suspension should be refrigerated in its bottle (2° to 8°C, or 36° to 46°F).
2.
Pazopanib must be kept out of reach of children.
3.
Any used and unused bottles of pazopanib should be returned to the investigator/clinic at each 
study visit.


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C. Clean-up Instructions in case of spillage:
Note: Women who are pregnant or nursing should avoid doing the clean-up because there is a risk 
of possible harm in developing human offspring or nursing infants.
4. Put on a suitable size of gloves. Latex gloves can be used; however, for people who are sensitive to 
latex, it is recommended to use Nitrile gloves.
Note: Use gloves for the clean-up process to avoid contact between the liquid spill and skin.
Take care not to spread spilled material to unprotected skin (such as your face) or other body 
surfaces by touching them with a wet glove.
5. Add enough absorbent material (eg: kitty litter, coffee grounds, or paper towels) onto the spilled
material to soak it up.
6. Place the soaked absorbent material into a sealable plastic bag, and then seal the bag.
7. Wipe the spilled area with an alcohol moistened towel (paper or cloth) and allow area to dry.
12.Place the sealed bag, towels, gloves into a second sealable bag then put into the household trash.


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13.10 APPENDIX VIII: YOUTH INFORMATION SHEETS
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1322 
(for children from 7 through 12 years of age)
A study of pazopanib in children with cancer that has come back after 
treatment or is difficult to treat
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment.
2. We are asking you to take part in a research study because other treatments did not get rid of the 
cancer. A research study is when doctors work together to try out new ways to help people who 
are sick. In this study, we are trying to learn more about how to treat the kind of cancer that you have. 
We will do this by trying a new medicine to treat your cancer.
3. Children who are part of this study will be treated with a cancer-fighting medicine called pazopanib. 
You will also have regular tests and exams done more often while you are in this study. The doctors
want to see if pazopanib will make more children with your type of cancer get better. We don’t
know if pazopanib will work well to get rid of your cancer. That is why we are doing this study.
4. Sometimes good things can happen to people when they are in a research study. These good things are
called “benefits.” We hope that a benefit to you of being part of this study is that pazopanib may
cause your cancer to stop growing or to shrink for a period of time. However, we don’t know for 
sure if there is any benefit of being part of this study.
5. Sometimes bad things can happen to people when they are in a research study. These bad things are
called “risks.” The risks to you from this study are that you may have more problems, or side effects,
from pazopanib than other treatments. Other things may happen to you that we don’t yet know about.
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.
7. We are asking your permission to collect additional blood. We want to learn more about how 
pazopanib works. Sample would be taken before you start treatment and 2 weeks after you start 
treatment. The extra blood would be taken only at times when blood is collected for regular treatment
tests, so there would be no extra needle sticks. You can still take part in this study even if you don't 
allow us to collect the extra blood samples for research.


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INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1322 
(for teens from 13 through 17 years of age)
A study of pazopanib in children with cancer that has come back after 
treatment or is difficult to treat
1. We have been talking with you about your cancer. You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment.
2. We are asking you to take part in a research study because other treatments did not get rid of the 
cancer. A research study is when doctors work together to try out new ways to help people who 
are sick. In this study, we are trying to learn more about how to treat the kind of cancer that you have.
3. Children and teens who are part of this study will be given a cancer-fighting medicine called pazopanib.
Pazopanib is a drug that in laboratory studies can block proteins which are thought to be important
for tumors to grow. You will get pazopanib once a day (by mouth) for 28 days. This 28 day regimen
may be repeated until you benefit from treatment or until study closure. You will get the pazopanib
as long as you do not have bad effects from it and your cancer does not get any worse. You will also 
have exams and tests done that are part of normal cancer care. But, the exams and tests will be done
more often while you are being treated with pazopanib. The doctors want to see if pazopanib will
make more children with your type of cancer get better. We don’t know if pazopanib is better than 
other medicines. That is why we are doing this study.
4. Sometimes good things can happen to people when they are in a research study. These good things are
called “benefits.” We hope that a benefit to you of being part of this study is that pazopanib may 
cause your cancer to stop growing or to shrink for a period of time. However we don’t know for sure 
if there is any benefit of being part of this study.
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study may be a less effective treatment and more side effects
than other treatments for your cancer. Other things may happen to you that we don’t yet know about.
6. Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.
7. We are asking your permission to collect additional blood. It will be helpful for us to see how your 
body handles the pazopanib and how pazopanib works. Sample would be taken before you start 
treatment and 2 weeks after you start treatment. The extra blood would be taken only at times 
when blood is collected for regular treatment tests, so there would be no extra needle sticks. You can
still take part in this study even if you don't allow us to collect the extra blood samples for research.


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13.11
APPENDIX IX AMENDMENT 01
Where the Amendment Applies
Changes included in Amendment 01 where made prior to initiation of the study. Amendment 02 
applies to all sites who will conduct the study
Summary of Amendment Changes with Rationale
The IND number in the original protocol was incorrect so only change made in Amendment 01 
was to correct the IND number throughout the protocol.


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13.12
APPENDIX X AMENDMENT 02
Where the Amendment Applies
Changes included in Amendment 02 where made prior to initiation of the study. Amendment 02 
applies to all sites who will conduct the study.
Deleted text is shown as a strikethrough and added text is shown as bold. Minor administrative 
changes, including section number changes and minor changes to the text that do not impact the 
study conduct are not included in the summary below.
Summary of Amendment Changes with Rationale
List of Specific Changes
Change
Rationale
The requirement to dose patients with tablets was changed
from a BSA of 0.48 to 0.84 based on the available tablet 
strengths.
The starting dose for suspension was changed from 160 
mg/m2 to 225 mg/m2
The pazopanib Phase I trial (ADVL0815) established 
different Maximum Tolerated Doses for the PfOS 
(160mg/m2) and tablet formulation (450mg/m2).
The available tablet strengths will allow for dosing of 
children/adolescents to have a BSA of 0.84 mg/m2.
The mg/m2 starting dose will be 225 mg/m2 which is 
greater than the MTD (160 mg/m2) established in the 
Phase I study (ADVL0815) where 2 isolated reversible 
laboratory DLTs where observed. The initial 6 patients 
who require suspension will have extended PK sampling 
and safety monitoring for DLTs. If the 225 mg/m2 dose 
is not tolerated subsequent patients who require 
suspension will receive 160 mg/m2/dose.
Clarification around continuation of therapy following
toxicity incorporated.
To provide investigators clarification and guidance 
around dose interruptions and modifications required 
when toxicity observed.
Monitoring of Pregnancy incorporated
Monitoring and documentation of pregnancy required for 
those females and partners of male subjects that become 
pregnant while participating in this study.
Protocol specific SAEs that were associated with another
asset were removed.
Protocol specific SAEs were incorrectly included in the 
protocol and are not appropriate to be included in this 
study.
General administrative changes including updating TOC,
formatting and Appendix references changed throughout 
the protocol.
To ensure consistency and accuracy throughout the 
protocol


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Experimental Design Schema Previous Text:
Pazopanib will be administered orally once daily as a tablet at a dose of 450 mg/m2/dose or as a powder in 
suspension at a dose of 160 mg/m2/dose (the MTDs determined by Part 1 and Part 2A respectively of 
ADVL0815, the COG Phase I study). The maximum dose to be administered daily is 800 mg. Each cycle will
be defined as 28 days. Note: The first 10 patients enrolled will receive the suspension formulation during Cycle 
1 in order to obtain pharmacokinetic data. Those patients may switch to the tablet formulation for Cycle 2 and
subsequent cycles if the patient is able to swallow tablets and meets the minimum BSA requirements for
tablets. Please note, the prescribed dose for the tablet and suspension formulation is different (see Section 
4.1).
Patients with benefit (stable disease or an objective response) may continue therapy for up to 2 years (in the
absence of unacceptable treatment related toxicity) unless there is evidence of progressive disease or 
unacceptable treatment-related toxicity.
Experimental Design Schema Revised Text:
Pazopanib will be administered orally once daily as a tablet at 450 mg/m2/dose or as a powder in suspension
at 225 mg/m2/dose. The maximum tolerated dose (MTD) for tablets was 450 mg/m2/dose as determined by
ADVL0815, the COG Phase I study, while the dose for oral suspension of 225 mg/m2/dose exceeds the
protocol-specified MTD of 160 mg/m2/dose established in that study. The 225 mg/m2/dose is where two 
isolated laboratory-defined dose-limiting toxicities (DLTs) were observed. The maximum dose to be 
administered daily for tablets is 800 mg. The maximum dose to be administered daily for suspension is 400 
mg. Each cycle will be defined as 28 days.
The first 6 patients enrolled who receive suspension will be expected to complete extended pharmacokinetic
(PK) sampling (Section 7.3.2) in order to obtain PK and safety data. These data will be reviewed prior to
further enrollment of patients requiring suspension to determine if 225 mg/m2/dose is tolerated and PK
exposure is similar to exposure in adults associated with clinical efficacy. If the 225 mg/m2/dose is not
tolerated (≥2 dose limiting toxicities (DLTs) in 6 evaluable patients), the dose for patients who require 
suspension may be reduced to 160 mg/m2/dose.
Secondary Aims, Added Text:
1.2.3
To further characterize the PK of pazopanib after administration of the oral suspension in children, 
adolescents and young adults with cancer
Section 2.3.1. Pharmacokinetic and Pharmacodymanic Data in Adults with Cancer, 
Previous Text:
There were no clinically meaningful changes in QTc interval following pazopanib in a dedicated QT 
Holter study.
Section 2.3.1. Pharmacokinetic and Pharmacodymanic Data in Adults with Cancer, 
RevisedText:
TherewerenoclinicallymeaningfulchangesinQTcintervalfollowingpazopanibin adedicatedQT Holterstudy.
In clinical studies with pazopanib, events of QT prolongation or torsade de pointes have occurred. Pazopanib
should be used with caution in patients with a history of QT interval prolongation, patients taking
antiarrythmics or other medications that may potentially prolong QT interval, or those with relevant pre-


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existing cardiac disease. When using pazopanib, baseline and periodic monitoring of ECGs and maintenance 
of electrolytes (calcium, magnesium, potassium) within normal range is recommended.
Section 2.3.3 Efficacy Data in Adults with Cancer, Previous Text (Paragraphs 4 and 5):
In two separate Phase II studies
of renal cell and NSCLC presented at the 2008 annual meeting of the American Society for Clinical
Oncology (ASCO) a decrease in sVEGFR2 compared with baseline was significantly correlated with tumor
response (p < 0.05).37,38 In adult patients with metastatic imatinib-refractory gastrointestinal stromal tumors
treated with sunitinib, another VEGF and c-kit targeting multityrosine kinase inhibitor, biomarker analysis of 
CECs, monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment. In this study, changes in 
CECs and monocytes rather than plasma markers differed between the patients with clinical benefit and those
with progressive disease.39 In pediatric patients with refractory solid tumors treated with the VEGF
neutralizing antibody bevacizumab, patients with prolonged disease stabilization (> 3 months) had a greater 
contribution of apoptotic CEC to the total CEC number (aCEC/tCEC) after 4 weeks of therapy (p=0.04), a
finding also reported in breast cancer patients who responded to metronomic therapy.40,41 This study will
continue to examine the effects of pazopanib therapy on cytokines and angiogenic factors.
3)The GlaxoSmithKline genetics team led by Dr.
has recently published results of a candidate gene 
association study in adult RCC patients treated with pazopanib.25 Several polymorphisms in candidate 
genes demonstrated associations with response rate and progression-free survival. Validation and 
elaboration of these findings will become available prior to completion of this trial. Based on the adult 
findings, an amendment to the protocol will be planned to study the strongest candidate SNP associations 
in this pediatric population.
Section 2.3.3 Efficacy Data in Adults with Cancer, Revised Text (Paragraph 4)
In pediatric patients with refractory solid tumors treated with theVEGFneutralizingantibody bevacizumab,
patientswithprolongeddiseasestabilization(>3months)hadagreatercontributionof apoptoticCECtothetotalCEC
number (aCEC/tCEC) after 4 weeks of therapy (p=0.04), a finding also reported in breast cancer patients who
respondedtometronomictherapy.40,41 pazopanib, baseline levels of plasma soluble VEGFR-2 and endoglin 
levels were significantly decreased when measured after 2 weeks of treatment, while placental growth 
factor levels were significantly increased over the same time points. There was no significant change in 
VEGF or plasma soluble VEGFR-1 levels with pazopanib therapy.40
3)The GlaxoSmithKline genetics team led by Dr.
has recently published results of a candidate gene 
association study in adult RCC patients treated with pazopanib.25 Several polymorphisms in candidate 
genes demonstrated associations with response rate and progression-free survival. Validation and 
elaboration of these findings will become available prior to completion of this trial. Based on the adult 
findings, an amendment to the protocol will be planned to study the strongest candidate SNP
associationsinthis additional markers may be explored in the pediatric population.
Section 2.4.1 Pediatric Studies, AddedText (Paragraph 2, sentence 4):
The MTD for tablet was 450 mg/m2/dose, and suspension 160 mg/m2/dose; two isolated and reversible
Grade 3 ALT elevations were seen at the suspension dose of 225 mg/m2/dose.
Section 2.4.2. Pharmacology/Pharmacokinetic/Correlative Biological Studies, 
Previous Text (Sentence 1):
The dose limiting toxicity in the pediatric Phase I dose escalation was hypertension, a class effect seen with 


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other VEGF blocking agents. Such hypertension has been treatable with anti-hypertensives and may 
ultimately be a biomarker of treatment effect.
Section 2.4.2. Pharmacology/Pharmacokinetic/Correlative Biological Studies, 
RevisedText (Sentence 1):
Thedoselimitingtoxicity Hypertension was seen in several patients in the pediatric Phase I dose 
escalation washypertension study, which is a class effect seen with other VEGF blocking agents. Such 
hypertension has been treatable with anti-hypertensives and may ultimately be a biomarker of treatment 
effect.
Section 2.4.2. Pharmacology/Pharmacokinetic/Correlative Biological Studies, Deleted
Text (paragraph 2):
Preliminary work in a limited number of hepatoblastoma cell lines suggests that there may be tumor specific 
changes in gene expression that may correlate with response to pazopanib (personal communication, Dr.
). To further examine this possible relationship, blood and tissue sampleswillberequestedfrom
consentinghepatoblastomapatients.
Section 2.5 Overview of Proposed Pediatric Phase II Trial, Previous Text:
This is a two-stage open label phase II trial of pazopanib in children, adolescents and young adults with 
recurrent
or
refractory
solid
tumors. Tumors
of
primary
interest
are
rhabdomyosarcoma,
non-
rhabdomyosarcomatous soft tissue sarcoma (including synovial sarcoma, alveolar soft part sarcoma and 
desmoplastic small round cell tumor) and Ewing sarcoma. Tumors of secondary interest include 
hepatoblastoma, neuroblastoma (measurable and evaluable), and osteosarcoma.
Eligible patients will receive pazopanib daily as an oral tablet (450 mg/m2/dose) or as a powder for suspension
(160 mg/m2/dose) in 28 day cycles. The maximum dose to be administered daily is 800 mg. Patients will
be closely monitored with clinical and laboratory observations for adverse effects. Response will be evaluated
using appropriate imaging studies after the 2nd cycle of pazopanib, after the 4th cycle, and then every 3rd cycle
thereafter (baseline, prior to Cycle 3, prior to Cycle 5, prior to Cycle 8, prior to Cycle
11, etc). In the absence of severe toxicity or progressive disease, patients may continue receiving pazopanib 
for up to 2 years.
The study will be considered complete (analysis conducted and enrollment closed) when all subjects enrolled 
in the tumors of the primary interest strata have completed a minimum of 6 cycles of treatment, have disease 
progression, or have withdrawn from the study.
The first ten subjects enrolled on this trial will receive the suspension formulation during Cycle 1 with the 
option to change to the tablet formulation during Cycle 2 and subsequent cycles if they are able to swallow 
tablets and their BSA is > 0.48 m2. These subjects will have extended pharmacokinetic sampling with 
blood samples collected prior to dosing, 30 min, 1, 2, 4, 6, and 8 hours after the pazopanib dose on Days 1 
and 15 of Cycle 1. Additional blood samples for analysis of steady state trough plasma pazopanib 
concentrations will be collected prior to every subsequent odd cycle (in conjunction with safety labs). All 
subsequent subjects (regardless of formulation) will have blood samples for analysis of plasma pazopanib 
concentration collected prior to dosing and 3 to 4 hours after dosing on Day 15 of Cycle 1. Additional 
blood samples for analysis of steady state trough plasma pazopanib concentrations will be collected prior to 
every subsequent odd cycle (in conjunction with safety labs).
 
In addition, we will assess KDR polymorphism and pazopanib-
induced change in VEGFR2; VEGFA haplotypes and changes in VEGF-A, response rate, and overall survival;


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and candidate SNPs and clinical endpoints as identified in ongoing large scale studies of pazopanib in the adult 
population.
 
Section 2.5 Overview of Proposed Pediatric Phase II Trial, Revised Text:
This is a two-stage open label phase II trial of pazopanib in children, adolescents and young adults with 
recurrent
or
refractory
solid
tumors. Tumors
of
primary
interest
are
rhabdomyosarcoma,
non-
rhabdomyosarcomatous soft tissue sarcoma (including synovial sarcoma, alveolar soft part sarcoma and 
desmoplastic small round cell tumor) and Ewing sarcoma. Tumors of secondary interest include 
hepatoblastoma, neuroblastoma (measurable and evaluable), and osteosarcoma.
Eligible patients will receive pazopanib daily as an oral tablet (450 mg/m2/dose) or as a powder for suspension
(160 225 mg/m2/dose) in 28 day cycles. The maximum dose to be administered daily for tablets is 800
mg and for suspension 400 mg. Patients will be closely monitored with clinical and laboratory observations 
for adverse effects. Response will be evaluated using appropriate imaging studies after the 2nd cycle of
pazopanib, after the 4th cycle, and then every 3rd cycle thereafter (baseline, prior to Cycle 3, prior to Cycle
5, prior to Cycle 8, prior to Cycle 11, etc). In the absence of severe toxicity or progressive disease, patients 
may continue receiving pazopanib forupto2years.
This study will dose patients requiring suspension with a starting dose of 225 mg/m2/dose.. The 
previously-defined suspension MTD of 160 mg/m2/dose may result in suboptimal exposure to 
demonstrate efficacy. Two of 4 patients in the prior Phase I study demonstrated DLTs in the form of
isolated and reversible Grade 3 elevations in ALT at 225 mg/m2/dose. Given that this toxicity was isolated
and reversible, the first 6 patients receiving suspension will be dosed at 225 mg/m2/dose and assessed for 
first-cycle DLTs before continuing to enroll additional patients requiring suspension. If two or more of
6 patients demonstrate DLT, then the dose may be de-escalated to the previously- defined MTD of 160
mg/m2/dose.
The first ten 6 subjects enrolledonthistrialwillreceive who require the suspension formulation during Cycle
1withtheoptiontochangetothetabletformulationduringCycle2andsubsequentcyclesifthey areabletoswallow
tabletsandtheirBSAis0.48m2. Thesesubjects will have extended PK sampling with blood samples collected
prior to dosing, 30 min, 1, 2, 4, 6, and 8 hours after the pazopanib dose on Days 1 and 15 of Cycle 1.
Additionalbloodsamplesforanalysisofsteadystatetroughplasmapazopanib concentrationswillbecollectedprior
to every subsequent odd cycle (in conjunction with safety labs). All subsequent All subjects (regardless of 
formulation) will have blood samples for analysis of plasma pazopanib concentration collected prior to dosing
and 3 to 4 hours after dosing on Day 15 of Cycle 1. Additional blood samples for analysis of steady state
trough plasma pazopanib concentrations will be collected prior to every subsequent odd cycle (in conjunction 
with safety labs).
 
In addition, we will assess KDR polymorphism and pazopanib-
induced change in VEGFR2; VEGFA genotype/haplotypes and changes in VEGF-A, response rate, and 
overall survival; and candidate SNPs and clinical endpoints as identified in ongoing large scale studies of 
pazopanib in the adult population. 
The study will be considered complete (analysis conducted and enrollment closed) when all subjects enrolled 
in the tumors of the primary interest strata have completed a minimum of 6 cycles of treatment, have disease 
progression, or have withdrawn from the study.


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Section 3.1.1 Patient Registration, Previous Text:
PatientRegistration
Prior to enrollment on study, patients must be assigned a COG patient ID number. This number is obtained 
once authorization for the release of protected health information (PHI) has been obtained. The COG 
patient ID number is used to identify the patient in all future interactions with COG. If you have problems 
with registration, please refer to the online help.
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be 
assigned only one BPC number per COG Patient ID. For additional information about the labeling of specimens
please refer to the Pathology and/or Biology Guidelines in this protocol.
Upon completion of all the required baseline assessments, eligible subjects will be registered into the GSK 
interactive voice response system called RAMOS (Registration And Medication Ordering System), by the 
investigator or authorized site staff for stratification. Subject number and histology strata (rhabdomyosarcoma, 
non-rhabdomyosarcomatous soft tissue sarcoma, Ewing Sarcoma/Peripheral PNET, osteosarcoma, 
neuroblastoma (measureable), neuroblastoma (evaluable) or hepatoblastoma) must be entered into the system 
in order to register the patient with GSK.
All calls to RAMOS are confirmed with a fax, which will be sent to the site upon completion of each call. 
Study-specific instructional worksheets will be provided for the use of RAMOS in the Study Procedures 
Manual.
Section 3.1.1 Patient Registration, Deleted and AddedText:
No study specific procedure will start before the signature of the informed consent form
(and assent, according to institutional guidelines).
Paragraph 2 (deleted text) ABiopathologyCenter(BPC)numberwillbeassignedaspartoftheregistrationprocess.
Eachpatientwillbe assigned only one BPC number per COG Patient ID. For additional information about the 
labeling of specimenspleaserefertothePathologyand/orBiologyGuidelinesinthisprotocol.
Paragraph 3, sentence 1, added text:
Upon completion of all the required baseline assessments, eligible subjects will be registered into the GSK 
interactive voice response system called RAMOS (Registration and Medication Ordering System) and will be 
assigned a GSK study specific number and a randomization number, by the investigator or authorized site 
staff for stratification.
 
 
Section 3.2.3 Body Surface Area, Previous Text:
Body Surface Area (for subjects taking tablet formulation only): Patients who will be receiving the tablet 


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formulation must have a BSA > 0.48 m2 at the time of study enrollment.
Section 3.2.3 Body Surface Area, Revised Text:
BodySurfaceArea(forsubjectstakingtabletformulationonly): Patients who will be receiving the tablet 
formulation must have a BSA > 0.48 84 m2 at the time of study enrollment.
Section 3.2.6.3 Adequate Liver Function define as, Previous Text:
AdequateLiverFunctiondefinedas:
a.Total bilirubin 1.5 x upper limit of normal (ULN) for age;
b. SGPT (ALT) 2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L);
c. Serum albumin 2 g/dL.
Section 3.2.6.3 Adequate Liver Function define as, Added Text:
d.
Must not have active liver or biliary disease (with the exception of Gilbert’s syndrome 
or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease 
per investigator assessment).
o NOTE: Stable chronic liver disease should generally be defined by the absence of
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric 
varices, persistent jaundice, or cirrhosis.
e.
No known positivity of hepatitis B surface antigen (HBsAg), or of positive hepatitis C
antibody
Section 3.2.6.4 Adequate Cardiac Function defined as, Revised and Added Text:
c. QTc QTcB < 450 msec (See Section 5.4.5.2 to determine QTcB)
Section 3.3.2.7 CYP3A4 Substrates and drugs causing QTc prolongation, Previous
Text:
Patients receiving drugs metabolized through several of the specific P450 cytochrome isoforms and those 
receiving drugs with a known risk of torsades de pointes are not eligible. See Appendices IIIAand IIIB for a 
list of enzyme inducing, enzyme inhibiting and other adversely interacting drugs and the appropriatewashout 
periods required prior to study enrollment. Note: This list includes the prohibition of grapefruit juice for 14 
days prior to enrollment.
Section 3.3.2.7 CYP3A4 Substrates and drugs causing QTc prolongation, Revised Text:
Patients receiving drugs metabolized through several of the specific P450 cytochrome isoforms and those
receivingdrugs with a known risk of torsades de pointes are not eligible. See Appendices IIIA and IIIB and 
Section 4.8 for a list of enzyme inducing, enzyme inhibiting and other adversely interacting drugs and the 
appropriate washout periods required prior to study enrollment.
Note: This list includes the prohibition of grapefruit juice for 14 days prior to enrollment.
Section 4.1 Overview of Treatment Plan, Previous Text:
Pazopanib will be administered orally once daily on a continuous schedule. Patients will be treated with 


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pazopanib tablets at a dose of 450 mg/m2/dose or as a powder in suspension at a dose of 160 mg/m2/dose (the
MTDs determined by Part 1 and Part 2A respectively of ADVL0815, the COG Phase I study). Note: The first
10 patients enrolled will receive the suspension formulation in Cycle 1 in order to obtain extended
pharmacokinetic sampling. These patients may then switch to tablet formulation in Cycle 2 and subsequent
cycles provided that they are able to swallow tablets and meet the required minimum BSA criteria for tablets
(see Section 3.2.3). Please note the difference in dosing for the tablet and suspension formulations (see 
above).
A cycle will be defined as 28 days with no rest periods between cycles. Patients may receive a maximum of
24 cycles. Patients with benefit (stable disease or an objective response) may continue therapy for up to 2 
years unless there is evidence of progressive disease or unacceptable treatment-related toxicity
Drug dosing for the tablet formulation should be determined using the dosing nomogram in Appendix II and
rounded to the nearest 50 mg. For patients receiving powder for suspension (50 mg/mL), the dose will be
rounded to the nearest 5 mg. Drug doses should be adjusted based on the BSA as determined by the height 
and weight obtained within 1 week prior to the beginning of each cycle.
Pazopanib should be taken on an empty stomach (at least 1 hour before a meal or 2 hours after a meal) at 
approximately the same time each day. Pazopanib tablets should be taken with clear liquids (approximately 
2-4 ounces for children < 12 years of age and 4-8 ounces for children ≥12 years of age). Pazopanib
suspension should be taken according to instructions in Appendix VII. The pazopanib suspension should be 
swirled for at least 30 seconds prior to removal of the dose from the bottle, which should be given 
immediately. If a patient vomits after a dose of pazopanib, the dose should not be repeated.
Section 4.1 Overview of Treatment Plan, Revised Text:
Pazopanib will be administered orally once daily on a continuous schedule. Patients will be treated with
pazopanibtablets as a tablet at a dose of 450 mg/m2/dose or as a powder in suspension at a dose of 160 225
mg/m2/dose.
450 mg/m2/dose was the MTD for tablet as determined by Part 1 and Part 2A, respectively
ADVL0815, the COG Phase I study, while the dose for oral suspension of 225 mg/m2/dose exceeds the
protocol-specified MTD of 160 mg/m2/dose established in that study. Two isolated and reversible
laboratory-defined DLTs were observed at 225 mg/m2/dose. The maximum dose to be administered
daily for tablets is 800 mg and for suspension 400 mg. Each cycle will be defined as 28 days.
Note: The first 10 6 patients enrolled will who receive the suspension formulationinCycle1 will be expected 
to complete extended PK sampling (Section 7.3.2) in order to obtain extended pharmacokineticsampling PK 
and safety data. These data will be reviewed prior to further enrollment of patients maythenswitchtotablet
formulationinCycle2andsubsequentcyclesprovidedthattheyare abletoswallowtabletsandmeettherequired
minimumBSAcriteriafortablets(seeSection3.2.3). Please note requiring suspension to determine if 225 
mg/m2/dose is tolerated and PK exposure is similar to exposure in adults associated with clinical efficacy.
If 225 mg/m2/dose is not tolerated (≥2 DLTs in 6 evaluable patients), the differenceindosing dose for the
tabletand patients who require suspension formulation(seeabove) may be reduced to 160 mg/m2/dose.
A cycle will be defined as 28 days with no rest periods between cycles. Patients mayreceiveamaximum of24
cycles. Patients with benefit (stable disease or an objective response) may continue therapy forupto 2years
unless there is evidence of progressive disease or unacceptable treatment-related toxicity.
Patients must remain on the same formulation of pazopanib throughout the duration of their protocol
therapy.
Drug dosing for the tablet formulation should be determined using the dosing nomogram in Appendix II 
androundedtothenearest50mg. For patients receiving powder for suspension (50 mg/mL), the dose will be
rounded to the nearest 5 mg. Drug doses should be adjusted based on the BSA as determined by the height 


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and weight obtained within 1 week prior to the beginning of each cycle.
Pazopanib should be taken on an empty stomach (at least 1 hour before a meal or 2 hours after a meal) at 
approximately the same time each day. Pazopanib tablets should be taken with clear liquids (approximately 
4 ounces for children < 12 years of age and 4-8 ounces for children ≥12 years of age). Pazopanib suspension 
should be taken according to instructions in Appendix VII. The pazopanib suspension should be swirled for 
at least 30 seconds prior to removal of the dose from the bottle, which should be given immediately. If a 
patient vomits after a dose of pazopanib, the dose should not be repeated.
A patient diary (see Appendices IA and IB) should be completed by the patient or their guardian and 
collected at the end of each cycle.
See Section 5.0 for Dose Modifications based on Toxicities
Section 4.1.1 Dose Reduction, Previous Text:
For patients who receive pazopanib tablets: A step-wise dose reduction will be allowed for toxicities as 
outlined in Section 5.0 for patients who recover to starting criteria as outlined in Section 4.2 within 7 days 
following planned administration (see dosing nomogram for tablets in Appendix II). The first dose reduction 
will be to 350 mg/m2/dose and then to 250 mg/m2/dose if necessary. If toxicity has not resolved at 250 
mg/m2/dose, a further dose reduction to 200 mg/m2/dose may be considered after discussion with the Study 
Chair.
For patients who receive pazopanib powder in suspension: A stepwise dose reduction will be allowed for 
toxicities as outlined in Section 5.0 for patients who recover to starting criteria as outlined in Section 4.2 
within 7 days following planned administration. The first dose reduction will be to 135 mg/m2/dose and 
then to 100 mg/m2/dose if necessary. If toxicity has not resolved at 100 mg/m2/dose, a further dose reduction 
to 75 mg/m2/dose may be considered after discussion with the Study Chair.
Section 4.1.1 Dose Reduction, Revised Text:
For patients who receive pazopanib tablets: A step-wise dose Dose reduction(s) will be allowed for toxicities
as outlined in Section 5.0 for patients who recover to starting criteria as outlined in Section 4.2 within7
within 14 days following planned administration (see dosing nomogram for tablets in Appendix II). Thefirst
dose Dose reduction(s) will be to350mg/m2/doseandthento250mg/m2/doseifnecessary. If toxicity has not
resolved at 250 mg/m2/dose, a further dose reduction to 200 mg/m2/dose may be consideredafterdiscussionwith
based on the StudyChair starting dose.
Note: For patients receiving pazopanib tablets at a starting dose of 400 mg, there will only be one allowed 
dose reduction due to tablet size.
Forpatientswhoreceivepazopanibpowderinsuspension: A stepwise dose reduction (Tables 1 and 1a) will be
allowed for toxicities as outlined in Section 5.0 for patients who recover to starting criteria as outlined in
Section 4.2 within 7daysfollowingplannedadministration. Thefirstdosereductionwillbeto
135mg/m2/doseandthento100mg/m2/doseifnecessary. Iftoxicityhasnotresolvedat100mg/m2/dose, a further
dose reduction to 75 mg/m2/dose may be considered after discussion with the Study Chair
14 days following planned administration.
Table 1: Stepwise Dose Reduction for Toxicity if suspension starting dose 225 mg/m2
Starting Dose
225 mg/m2/dose
First Dose Reduction
160 mg/m2/dose


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Table 1a: Stepwise Dose Reduction for Toxicity if suspension starting dose reduced to 160 mg/m2
Starting Dose
160 mg/m2/dose
First Dose Reduction
135 mg/m2/dose
Section 4.1.2 Dose Escalation, Previous Text:
There will be no inter-patient dose escalation. However, following a dose modification for drug related 
toxicity and subsequent resolution of the toxicity the dose can then be increased step-wise back to initial 
starting dose using the same doses used to titrate down. The subject should be monitored for 1 0-14 days at 
each step to ensure that toxicity does not recur or worsen.
Section 4.1.2 Dose Escalation, Revised Text:
Therewillbenointer-patientdoseescalation. However,followingadosemodificationfordrugrelated toxicityand
subsequent resolution of the toxicity the dose can then be increased step-wise back to initial startingdoseusing
thesamedosesusedtotitratedown. Thesubjectshouldbemonitoredfor10-14daysat eachsteptoensurethattoxicity
doesnotrecurorworsen.
Dose escalations will not be allowed.
Section 4.1.3 Treatment Interruptions, Previous Text:
If a patient’s treatment has been interrupted for more than 14 days due to toxicity or for reasons other than 
toxicity (unplanned travel or vacation, or lack of transportation to the site), the Study chair must be 
notified to review the patient’s condition in order to resume treatment. In cases of toxicity, the re-challenge is
possible if the patient’s condition has been stable and has not deteriorated and the patient must have recovered 
from toxicity at the reduced dose level.
Section 4.1.3 Treatment Interruptions, Revised Text:
If a patient’s treatment has been interrupted for more than 14 days due to toxicity or for reasons other than 
toxicity (unplanned travel or vacation, or lack of transportation to the site), the Study Chair must be 
notified to review the patient’s condition in order to resume treatment. In cases of toxicity, the re-challenge at
a reduced dose is possible if the patient’s condition has been stable and has not deteriorated and the patient 
must have recovered from the toxicity atthereduceddoselevel.(Section 4.2)
Section 4.1.4.1 Management of Hypertension, Added Text (paragraph 2):
If patient is already on an anti-hypertensive medication at study enrollment, then their anti-hypertensive 
therapy should be adjusted (by either adjusting the dose of their current anti-hypertensive medication or 
by adding another anti-hypertensive agent) according to the algorithm in Section 5.4.1.
Section 4.1.4.3 Treatment of Palmer-Plantar Erythrodysesthesia (Hand-foot
Syndrome), Added Text:
Other supportive care measures for the treatment of hand-foot syndrome should be instituted as needed.
If steroids are used, they must fall within the dosing parameters in Section 4.8.
Section 4.2 Criteria for Starting Subsequent Cycles, Previous Text:


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A cycle may be repeated every 28 days if the patient has at least stable disease and has again met 
laboratory parameters as defined in the eligibility section, Section 3.2.7, does not have a dose limiting 
toxicity requiring permanent removal from protocol therapy (Section 5.1) or a toxicity requiring resolution 
prior to resuming study drug (eg: hypertension, hepatotoxicity, electrolyte abnormality, bleeding, wound 
healing, etc) as outlined in Section 5.0.
Section 4.2 Criteria for Starting Subsequent Cycles, Revised Text:
A cycle may be repeated every 28 days if the patient has at least stable disease and has again met 
laboratory parameters as defined in the eligibility section, Section 3.2.6 and, does not have a dose limiting 
toxicity requiring permanent removal from protocol therapy (Section 5.1)) or a toxicity requiring resolution
prior to resuming study drug (eg: A patient may resume study drug at the same or a reduced dose if 
they have a toxicity that is adequately managed (eg: myelosuppression, hypertension, hepatotoxicity, 
electrolyte abnormality, bleeding, wound healing, etc) as outlined in Section 5.0.
Section 4.4 Permitted Medications, Added Text (paragraph 4):
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT3 antagonists) may be 
administered prophylactically in the event of nausea. However, it is important to note that 5-HT3 blockers
that are given daily for a prolonged period of time may prolong QTc and should be used with caution. 
(Appendix IIIB). Anti-diarrheals, such as loperamide, may be administered as needed in the event of diarrhea. 
Although acetaminophen at doses of 2 g/day is permitted, it should be used with caution in subjects with 
impaired liver function.
Section 4.4 Permitted Medications – Use with Caution, Added Text:
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 benefitting from treatment and require the initiation of concomitant 
anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight heparin, unfractionated heparin)
while on study. Note: Subjects are excluded from enrolling on the study if they are taking therapeutic
doses of S-warfarin at the time of screening. 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.
Section 4.5.4 Added Text:
Concomitant administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib by 
40% (AUC and Cmax), and co-administration of pazopanib with medicines that increase gastric pH should be 
avoided. Co-administration of pazopanib with medicines that increase gastric pH is PROHIBITED from 
24 hours before the first dose of pazopanib until after the final PK blood sample is collected on Day 15 
± 1 day of Cycle 1. After this, if the concomitant use of a proton-pump inhibitor (PPI) is medically necessary, 
it is recommended that the dose of pazopanib be taken without food once daily in the evening concomitantly 
with the PPI (Section 4.8). If the concomitant administration of an H2-receptor antagonist is medically 
necessary, pazopanib should be taken without food at least 2 hours before or at least 10 hours after a dose of 
an H2-receptor antagonist. Pazopanib should be administered at least 1 hour before or 2 hours after 
administration of short-acting antacids.
Section 4.5.5 Deleted Text:
Concurrent Anti-Hypertensive Therapy: The algorithm in Section 5.4.1 will be used to grade and manage 


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pazopanib related hypertension. Should initiation of anti-hypertensive therapy be required, single agent therapy 
(commonly including the calcium channel blockers amlodipine or nifedipine, which are permissible without
notifying the study chair) should be started and the blood pressure should be monitored at least twice weekly
until BP is within the 95thpercentilefor age, height, and gender per Section5.4.1.Ifpatientsarealreadyonananti-
hypertensive medicationat studyenrollment, thentheir anti-hypertensivetherapyshouldbeadjustedaccordingto
thealgorithminSection5.4.1.may be started without notifying the study chair.
Section 4.5.6 Added Text:
Patients’ medications should be reviewed at eligibility, before treatment initiation, and during treatment.
Any concomitant medications that are “generally accepted” to cause a risk of Torsade de pointes are
prohibited (see Appendix IIIB). Those “associated” with a risk of QTc prolongation and/or Torsades de
pointes should be discontinued or replaced with drugs that do not carry these risks, if possible. Patients 
who must take these medications should be watched carefully for symptoms of QTc prolongation, such 
as syncope. Performing additional EKGs on patients who must take one or more of these medications is
recommended but not required, at the investigator’s discretion.
Section 4.8 Prohibited Medications, Added Text:

Glucocorticoidsforgreaterthan2weeksduration: cortisone (>50 mg), 
hydrocortisone (>40 mg), prednisone (>10 mg), methylprednisolone (>8 mg), 
dexamethasone (>1.5 mg)
Grapefruit or grapefruit juice is prohibited as it inhibits CYP3A4 activity and may also increase 
plasma concentrations of pazopanib.
As noted above, co-administration of pazopanib with medicines that increase gastric pH is 
prohibited from 24 hours before the first dose of pazopanib until after the final PK blood sample is 
collected on Day 15 ± 1 day of Cycle 1.
Section 4.9 and 4.10 Therapy Delivery Maps, Summary of Changes:
Dose for powder in suspension was changed from 160 to 225 mg/m2 and max dose was changed 
to 400 mg
Minor formatting changes were made throughout in the tables included in these sections
Section 5.1.1 Non-hematological Dose-Limiting Toxicity, DeletedText:
Grade3elevationofASTorALTthatreturnsto 5xULNwithin7days oftreatment
interruptionanddoesnotrecurwiththere-introductionof pazopanib. Note: forthe
purposesofthistrialtheULNforALTisdefined as45U/L.
Section 5.1.2.4 Added Text:
Any Grade 2 non-hematological toxicity that persists for ≥7 days and is considered sufficiently medically 
significant or sufficiently intolerable by patients that it requires treatment interruption may also be considered 
a DLT following discussion with the Study chair and a GSK medical monitor.
Section 5.1.2 Hematological Dose Limiting Toxicity, Deleted Text:
Note: Grade4febrileneutropeniawillnotbeconsideredadoselimitingtoxicity


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Section 5.2 Dose Modifications for Hematologic Toxicity, Previous Text (paragraphs 3 
and 4):
Pazopanibtablets: For step-wise dose reductions (350 mg/m2/dose then 250 mg/m2/dose), see Appendix II for
the dosing nomogram.
Pazopanibpowderinsuspension: For step-wise dose reductions (135 mg/m2/dose then 100 mg/m2/dose), see
Appendix II for the dosing nomogram.
Section 5.2 Dose Modifications for Hematologic Toxicity, Revised Text (paragraphs 3 
and 4):
Pazopanibtablets: For step-wise dose reductions (350mg/m2/dosethen250mg/m2/dose), see Appendix II for the
dosing nomogram.
Pazopanibpowderinsuspension: For step-wise dose reductions (135mg/m2/dosethen100mg/m2/dose), see
AppendixIIforthedosingnomogram see Tables I and Ia (Section 4.1.1)
Section 5.2.2 Previous Text:
Patients who have a dose limiting hematological toxicity that does not resolve to baseline within 21 days 
of holding pazopanib, must be removed from protocol therapy.
Section 5.2.2 Revised Text:
Patients who have a dose limiting hematological toxicity that does not resolve to baseline the parameters 
defined in Section 5.2.2 within 21 28 days of holding pazopanib, if re-challenge is to be considered the 
study chair must be removedfromprotocoltherapy contacted and provide approval prior to re-
challenge.
Section 5.3 Dose Modifications for Non-Hematological Toxicity, Added Text:
Specific instructions for the management of potential pazopanib side effects are included in Section 5.4.
Section 5.4.2 Hepatoxicity, Previous Text:
Adverse events & descriptions
Dose Modifications & Evaluations
Grade 1 ALT/AST elevation
1. Continue pazopanib at current dose.
2. Check liver function tests (LFTs)1 as per 
protocol
Grade 2 ALT/AST elevation without
bilirubin 
elevation (defined as total bilirubin2 < 1.5 x ULN 
or direct bilirubin ≤35% of total bilirubin) and 
without hypersensitivity symptoms (eg: fever, rash)
1. Continue pazopanib at current dose
2. Consider performing the following to exclude 
hypersensitivity and other contributing factors:
a.
Eosinophil count
b. Viral serology4 for hepatitis A, B and C
c.
Liver imaging (Ultrasound)
3. Monitor patient closely for clinical signs and 
symptoms
4. Perform LFTs1 weekly (or more frequently if
clinically indicated) until AST/ALT < Grade 1


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Grade 3 ALT elevation without bilirubin elevation 
(defined as total bilirubin2 < 1.5 x ULN or direct 
bilirubin ≤35% of total bilirubin) and without 
hypersensitivity symptoms (e.g., fever, rash)
1stoccurrence–LiverEventInterruptionCriteria3:
1. Hold pazopanib until ALT resolves to ≤ Grade
1 or baseline.
2. Re-check LFT’s1 within 72 hrs
3. Perform the following assessments to exclude 
hypersensitivity and other contributing factors:

Eosinophil count

Optional viral serology4 for hepatitis A, B, 
C and E, cytomegalovirus4, Epstein Barr 
virus4 (IgM antibody, heterophile antibody, 
or monospot testing)

Liver imaging (Ultrasound)
4. Monitor patient closely for clinical signs and 
symptoms


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5. Perform LFTs1 weekly (or more frequently if
clinically indicated) until ALT reduced to <
Grade 1
6. If the patient is benefitting from the study
treatment, contact Study Chair for possible re-
challenge. Re-treatment may be considered at 
the same dose if ALL of the following criteria 
are met:
ALT/AST reduced to < Grade 1

Total bilirubin < 1.5 x ULN or direct 
bilirubin ≤ 35% of total bilirubin
No hypersensitivity signs or symptoms
Patient is benefitting from therapy
If approval for re-treatment is granted, the patient 
must be re-consented (with a separate informed 
consent specific to hepatotoxicity).
Recurrence of toxicity – Liver Event Stopping
Criteria3
1. Discontinue pazopanib permanently
2. Monitor patient closely for clinical signs 
and symptoms
3. Perform LFTs1 weekly (or more frequently if 
clinically indicated) until ALT/AST is <
Grade 1
> Grade 2 ALT AND elevation in bilirubin2
(defined as total bilirubin > 1.5 x ULN and direct 
bilirubin >
35%
of
total
bilirubin)
or
with 
hypersensitivity symptoms (e.g., fever, rash)
LiverEventStoppingCriteria3:
1. Discontinue pazopanib permanently
2. Recheck LFT’s1, serum creatinine 
phosphokinase (CPK) and collect PK sample.
Also check:

Eosinophil count

Optional viral serology4 for hepatitis A, 
B, C and E, cytomegalovirus4,
Epstein-Barr virus4 (IgM antibody, 
heterophile antibody, or monospot 
testing)

Anti-nuclear antibody4, anti-smooth 
muscle antibody4, anti-mitochondrial 
antibody4

Liver imaging (Ultrasound)
3. Recommend referral to (consult) a pediatric 
gastroenterologist/hepatologist.
4. Monitor patient closely for clinical signs and 
symptoms. Perform full panel LFTs1 weekly or 
more frequently if clinically indicated until 
LFTs are reduced to Grade 1.
For isolated total bilirubin2 elevation without
concurrent ALT increase (defined as ALT < 3 x
ULN).
1. Isolated hyperbilirubinemia (in the absence of
elevated ALT or other signs/symptoms of liver 
injury) does not require dose modification. 
Study treatment inhibits UGT1A1 and


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OATP1B1, which can cause elevation of 
indirect (unconjugated) bilirubin in the absence 
of liver injury.
2. If bilirubin is > 1.5 x ULN in the absence of
ALT elevation, fractionation of bilirubin 
should be performed. If the bilirubin is 
predominantly indirect (unconjugated), 
continue study treatment at the same dose. If 
bilirubin is >35% direct (conjugated), further
evaluation should be undertaken for underlying 
cause of cholestasis
Section 5.4.2 Hepatoxicity, Revised Text:
Adverse events & descriptions
Dose Modifications & Evaluations
Grade 1 ALT/AST elevation
1. Continue pazopanib at current dose.
2. Check liver function tests (LFTs)1 as per 
protocol
Grade 2 ALT/AST elevation without
bilirubin 
elevation (defined as total bilirubin2 < 1.5 x ULN 
or direct bilirubin ≤ 35% of total bilirubin) and
without hypersensitivity symptoms (eg: fever, rash)
1. Continue pazopanib at current dose
2. Consider performing the following to exclude 
hypersensitivity and other contributing factors:
a.
Eosinophil count
b. Viral serology4 for hepatitis A, B
and C
c.
Liver imaging (Ultrasound)
3. Monitor patient closely for clinical signs and 
symptoms
4. Perform LFTs1 weekly (or more frequently if
clinically indicated) until AST/ALT < Grade 1
Grade 3 ALT elevation without bilirubin elevation 
(defined as total bilirubin2 < 1.5 x ULN or direct 
bilirubin ≤35% of total bilirubin) and without 
hypersensitivity symptoms (e.g., fever, rash)
1
stnoccurrence–LiverEventInterruption/Stopping
Criteria3:
1. Hold pazopanib untilALTresolvesto≤Grade
1orbaseline.
2. Re-checkLFT’s1 Repeat LFTs1 within 72 hrs
to confirm Grade 3 ALT elevation, if 
confirmed
3. Perform the following assessments to exclude
hypersensitivity and other contributing factors:

Eosinophil count

Optional viral serology4 for hepatitis A, B, 
C and E, cytomegalovirus4, Epstein Barr 
virus4 (IgM antibody, heterophile antibody, 
or monospot testing)

Liver imaging (Ultrasound)
4. Monitor patient closely for clinical signs and 
symptoms
5. Perform LFTs1 weekly (or more frequently if 
clinically indicated) until ALT reduced to <
Grade 1
6. Ifthe Pazopanib may be held for up to 14


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days, if ALT returns to Grade 1 and patient 
is benefitting from thestudy treatment, contact
StudyChairforpossiblere-challenge. Re-
treatmentmaybeconsidered pazopanib may
be resumed at thesame reduced dose ifALL
of the following GSK governance approval
(contact a GSK medical monitor via email or 
phone to start the approval process) criteria
aremet:

ALT/ASTreducedto <Grade1

Totalbilirubin<1.5xULNordirect
bilirubin≤35%oftotalbilirubin

Nohypersensitivitysignsorsymptoms

Patientisbenefittingfromtherapy
If approval for re-treatment is granted, the patient 
must be re-consented (with a separate informed 
consent specific to hepatotoxicity).

For patients on tablets dose reductions 
are as follows:
o
If on 800 mg, then reduce to 400 
mg daily
o
If on 600 mg, then reduce to 400 
mg daily
o
If on 400 mg, reduce to 200 mg 
daily

For patients on suspension:
o
Follow the sequential dose 
reduction (Section 4.1.1.), one 
dose level reduction is required 
(e.g. from 225 mg/m2to 160 
mg/m2)
Following
re-introduction 
of 
pazopanib, 
continue to monitor ALT weekly for 2 cycles, if 
ALT Grade 2 recurs permanently discontinue 
pazopanib.
1.
> Grade 2 ALT AND elevation in bilirubin2
(defined as total bilirubin > 1.5 x ULN and or direct
bilirubin >
35%
of total
bilirubin)
or
with 
hypersensitivity symptoms (e.g., fever, rash)
LiverEventStoppingCriteria3:
1. Discontinue pazopanib permanently
2. Recheck LFT’s1, serum creatinine 
phosphokinase (CPK) and collect PK sample.
Also check:

Eosinophil count

Optional viral serology4 for hepatitis A, 
B, C and E, cytomegalovirus4,
Epstein-Barr virus4 (IgM antibody,
heterophile antibody, or monospot 
testing)

Anti-nuclear antibody4, anti-smooth


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muscle antibody4, anti-mitochondrial
antibody4

Liver imaging (Ultrasound)
3. Recommend referral to (consult) a pediatric 
gastroenterologist/hepatologist.
4. Monitor patient closely for clinical signs and 
symptoms. Perform full panel LFTs1 weekly or 
more frequently if clinically indicated until 
LFTs are reduced to Grade 1.
For isolated total bilirubin2 elevation without
concurrent ALT increase (defined as ALT < 3 x
ULN).
1. Isolated hyperbilirubinemia (in the absence of
elevated ALT or other signs/symptoms of liver 
injury) does not require dose modification.
Study treatment inhibits UGT1A1 and
OATP1B1, which can cause elevation of 
indirect (unconjugated) bilirubin in the absence
of liver injury.
2. If bilirubin is > 1.5 x ULN in the absence of
ALT elevation, fractionation of bilirubin should 
be performed. If the bilirubin is predominantly 
indirect (65%) indirect (unconjugated), 
continue study treatment at the same dose. If 
bilirubin is >35% direct (conjugated), study 
treatment may also be continued however,
further evaluation should be undertaken for 
underlying cause of cholestasis


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Section 5.4.5.2 QTcB Prolongation, Revised Text:
QTc was changed to QTcB throughout this section.
Section 5.3.1 was to Section 4.5.6
Section 5.4.6 Delays in Wound Healing, Added Text:
Patients treated with VEGF blocking agents appear to have an increased risk of wound healing 
complications. Therefore, if patients require elective major surgery on study, pazopanib should be held for
14 days prior to surgery and for 14 days after surgery. Pazopanib should not be restarted if there is 
evidence of wound healing complications such as a wound infection. Patients who require surgery less
than 14 days from treatment with pazopanib should be monitored closely for wound complications. 
Patients who require major surgery during Cycle 1 of therapy must be removed from protocol therapy.
Section 5.4.7 Bleeding, Deleted Text, (4th Row of Table):
Grade 3 or higher
OR
Recurrent ≥ Grade 2 event after dose 
interruption/reduction
Discontinue pazopanib permanently and remove 
from protocol therapy
Note: If abnormality is not clearly associated with
clinical consequences; may contact Study Chair to
discussrestartingpazopanibatareduceddose
Section 6.1 Pazopanib (Formulation and Stability), Deleted Text:

50mg,round,whitetooff-white,packagedinbottlescontaining17tabletseach
Section 7.0 Evaluations/Material and Data to be Accessioned, Deleted Text:
Timingof protocoltherapy administration, response assessment studies, and surgical interventions are based on schedules
derived from the experimental design or on established standards of care. Minor unavoidable departures (up to 72 hours)
fromprotocoldirectedtherapyand/ordiseaseevaluations(andupto1 week forsurgery)forvalid clinical,patientandfamily
logistical,orfacility,procedureand/oranesthesiaschedulingissuesareacceptable(except whereexplicitlyprohibited within
the protocol). This policy does NOT apply to eligibility requirements; but to therapyandevaluationspostconsentandpost
thestartofprotocoldirectedcare.GSKwillnotgrantprotocolwaivers.
Section 7.1 Required 
 Clinical, Laboratory and Disease Evaluation, 
Revised Text:
STUDIES TO BE OBTAINED
Pre-
Study
During
Cycle 1
Prior to Subsequent cycles1
During
Subsequent
Cycles
End of
2
Therapy
Serum AFP12
X
End of
cycle
Prior to Cycle 3, 5, 8, 11 
and every 3rd cycle 
thereafter11
X
Serum Pregnancy Test14
X
-
X
-


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Change to footnotes:
6. If patient has LFT elevation repeat LFTs as described in Section 5.4.2.
11. Disease evaluation should be performed during Days 24 – 28 of the cycle for the first 2 assessments and Days 21 – 28 of 
subsequent indicated cycles. Patients who achieve a PR or CR should undergo the appropriate disease evaluation on the next 
consecutive cycle after initial documentation of either a PR or CR. Please note, if the institutional investigator determines that 
the patient has progressed based on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
A disease evaluation at Cycle 23 will not be required; however an end of study disease assessment should be completed
14. Females of childbearing potential require a negative serum pregnancy test prior to starting treatment.
Section 7.2.4 Pregnancy Testing and Reporting, Section Added:
The need for a screening pregnancy test depends on whether a female subject is of childbearing potential 
or non-childbearing potential. If a female subject is of childbearing potential, she must have a serum -
Human Chorionic Gonadotropin (-HCG) pregnancy test performed within 7 days prior to the first dose of 
study treatment(s). Subjects with a positive pregnancy test result must be excluded from the study. 
Subjects with a negative pregnancy test result must agree to use an effective contraception method as 
described below during the study until 30 days following the last dose of study treatment(s). Any pregnancy
that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure
subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. Study
treatment should be immediately discontinued if pregnancy occurs during study participation. 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 study treatment(s), must 
be promptly reported to GSK.
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 GSK as described above.
Section 7.3.2 Sampling Schedule, Previous Text (paragraph 2):
Extended pharmacokinetic sampling will be done in the first 10 patients enrolled (who will all receive the 
suspension formulation in Cycle 1). These patients will have a blood sample for analysis of the plasma 
pazopanib concentration collected at the following time points on Day 1 of Cycle 1: pre-dose, 30 min, 1 hour,
2 hours, 4 hours, 6 hours, and 8 hours after the dose. Samples will also be obtained on Day 15 ± 1 day of 
Cycle 1: pre-dose, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose. Additional blood
samples for analysis of steady-state trough plasma pazopanib concentrations will be obtained prior to the 
start of every odd cycle. The pre-dose sample on Day 15, Cycle 1 and trough plasma concentrations
should be obtained between 22-26 hours after the previous dose of pazopanib. Subjects should be 
instructed to hold their dose of pazopanib on the day that a pre-dose concentration is to be collected. These 
specimens should correspond to the timing of routine laboratory evaluations.


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Section 7.3.2 Sampling Schedule, Revised Text (paragraph 2):
Extended pharmacokinetic sampling will be done in the first 10 6 patients enrolled (who willall receive
the suspension formulation in Cycle 1). These patients will have a blood sample for analysis of the plasma 
pazopanib concentration collected at the following time points on Day 1 of Cycle 1: pre-dose, 30 min, 1
hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose. Samples will also be obtained on Day 15 ± 1
day of Cycle 1: pre-dose, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose. Additional
For all patients additional blood samples for analysis of steady-state trough plasma pazopanib 
concentrations will be obtained prior to the start of every odd cycle. Thepre-dosesampleonDay15, Cycle
1andtroughplasmaconcentrationsshouldbeobtainedbetween22-26hoursafterthe previousdoseof
pazopanib. Subjects should be instructed to hold their dose of pazopanib on the day that a pre-dose 
concentration is to be collected. These specimens should correspond to the timing of routine laboratory 
evaluations.
Section 7.4.1.2 Tumor Tissue, Deleted
Tumortissueaswellasaperipheralbloodsampleshouldbesubmittedifavailableformolecular(DNA, RNAand
protein)studiesincludingexpressionarrayanalysestodeterminemolecularsignaturesassociated withbothrelapse
statusaswellasresponsetopazopanib.
Section 7.4.2.1.2, Revised Text:
Patients Sampling for circulating plasma levels of angiogenic cytokines for patients who consent will 
have a specimen obtained for on Day 1, Cycle 1 prior to drug administration and during Week 4 or
Week 8 (Section 7.1)
Section 7.4.2.1.2, Revised Text:
Patients who consent to VEGF haplotype on Day 1, Cycle 1 prior to drug administration andduring
Week4orWeek8.
Sections 7.4.2.2 Tumor Tissue and Section 
Section 8.0 Criteria for Removal from Protocol Therapy and Off Study Criteria, 
Revised Text:
h) Repeat eligibility studies (if required) are outside the parameters required for eligibility continued 
dosing as stated in Section 4.2.
k) Patient becomes pregnant


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Section 9.3 Analysis Populations, Previous Text:
The Intent-to-Treat (ITT) population will comprise all subjects entered into the study. This population will 
be used for the analysis of efficacy.
Section 9.3 Analysis Populatons, Revised Text:
The Target Intent-to-Treat (ITTtITT) population will comprise all subjects entered into the study at the 
target dose. Thispopulation If after the first 6 subjects, the suspension dose is de-escalated to 160 
mg/m2/dose then only the 160 mg/m2/dose subjects will be used for the analysis of efficacy data included 
in the tITT. All subjects taking the tablets will be included in the tITT.
Section 9.8.2.5 Safety Measures, Added Text, (paragraph 1):
If there are multiple doses for the suspension then these will be presented in separate columns.
Section 9.12 Analysis of the Pharmacokinetic Parameters, Previous Text (paragraph
1, sentence 1):
Plasma pazopanib concentrations observed after administration of the suspension in the first 12 subjects 
enrolled in the study will be analyzed with standard noncomparetmental methods using WinNonlin version
5.2 or higher.
Section 9.12 Analysis of the Pharmacokinetic Parameters, Revised Text (paragraph 1, 
sentence 1):
Plasma pazopanib concentrations observed after administration of the suspension in the first 12 6 subjects 
enrolled in the study will be analyzed with standard noncomparetmental methods using WinNonlin version
5.2 or higher.
Section 10.2 Response Criteria, Added Text (paragraph 1):
c) hepatoblastoma (Section 10.6)
Section 11.0 Adverse Event (AE) and Serious Adverse Events (SAE), Added Text:
Changes were made throughout this section to include that both GSK and COG will be notified of any 
serious adverse event within 24 hours as indicated in Section 11.7 of the protocol.
Section 11.1 Definition of Adverse Events (AEs), Added Text (paragraph 1):
CTCAE criteria version 4.0 will be used to grade severity of adverse events.
Section 11.2 Definition of Serious Adverse Events (SAEs), Deleted Text:

ProtocolspecificSAEs: squamouscellcarcinoma,LVEFmeetingstoppingcriteria,treatment emergent
malignancies[basalcellcarcinoma(BCC)isnotrequiredtobereportedasaprotocol specificSAEandit
shouldbereportedasanAEorSAEbasedonthediscretionofthe investigator]: feveraccompaniedby
hypotension,dehydrationrequiringIVfluids,renal insufficiencyandorsevere(Grade3)rigors/chillsin
theabsenceofanobviousinfectiouscause.


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APPENDIX 1A: Patient Diary for Pazopanib Tablets, Deleted Text:
The column for 50 mg strength tablets was removed from the diary.
APPENDIX II: Pazopanib Dosing Nomogram for Tablets, Revised Table:
Starting Dose
Dose Reduction
#1
Dose Reduction
#2
450 mg/m2/dose
BSA* 
Dose (mg)†
0.84 -0.94
400
200
0
0.95-1.05
400
200
0
1.06-1.16
400
200
0
1.17-1.27
600
400
200
1.28-1.38
600
400
200
1.39-1.50
600
400
200
1.51-1.61
600
400
200
1.62-1.72
800
600
400
> 1.73
800
600
400
Appendix III A: Title Changed From:
LIST OF KNOWN CYTOCHROME P450 P34A INHIBITORS AND INDUCERS
Appendix III A: Title Changed to:
LIST OF ANTICONVULSANT DRUGS THAT ARE ALLOWED
Appendix VI: Pharmacokinetic Study Form, Revised Text (footnote **)
**These extended PK timepoints are to be collected in the 1st 106 patients who require suspension enrolled on study
(andwillreceivesuspensionformulation)


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13.13
APPENDIX XI AMENDMENT 03
Where the Amendment Applies
Amendment 03 applies to all sites who will conduct the study.
Minor administrative changes, including section number changes and minor changes to the text that 
do not impact the study conduct are not included in the summary below.
List of Abbreviations, Added Table
Experimental Design Schema Previous Text:
Pazopanib will be administered orally once daily as a tablet at 450 mg/m2/dose or as a powder in suspension at
225 mg/m2/dose. The maximum tolerated dose (MTD) for tablets was 450 mg/m2/dose as determined by 
ADVL0815, the COG Phase I study, while the dose for oral suspension of 225 mg/m2/dose exceeds the protocol-
specified MTD of 160 mg/m2/dose established in that study. The 225 mg/m2/dose is where two isolated
laboratory-defined dose-limiting toxicities (DLTs) were observed. The maximum dose to be administered daily
for tablets is 800 mg. The maximum dose to be administered daily for suspension is
400 mg. Each cycle will be defined as 28 days.
The first 6 patients enrolled who receive suspension will be expected to complete extended pharmacokinetic (PK)
sampling (Section 7.3.2) in order to obtain PK and safety data. These data will be reviewed prior to further
enrollment of patients requiring suspension to determine if 225 mg/m2/dose is tolerated and PK exposure is
similar to exposure in adults associated with clinical efficacy. If the 225 mg/m2/dose is not tolerated (≥2
dose limiting toxicities (DLTs) in 6 evaluable patients), the dose for patients who require suspension may be 
reduced to 160 mg/m2/dose.
Patients with benefit (stable disease or an objective response) may continue therapy (in the absence of unacceptable
treatment related toxicity) unless there is evidence of progressive disease or unacceptable treatment-related toxicity.
Experimental Design Schema Revised Text:
This is an open label phase II trial designed to primarily assess the efficacy of pazopanib in children, adolescents 
and young adults with recurrent or refractory solid tumors. Patients will receive pazopanib monotherapy and the
term “protocol therapy” will be used throughout this document to designate pazopanib
monotherapy.
Pazopanib will be dosed daily as an oral tablet (450 mg/m2/dose, maximum 800 mg) or as an oral powder for 
suspension (225 mg/m2/dose, maximum 400 mg). Each cycle will be defined as 28 days, with no rest periods 
between cycles.
The first patients enrolled who receive powder suspension will be expected to complete extended pharmacokinetic 
(PK) sampling (Section 7.3.2) in order to obtain PK and safety data in 6 evaluable patients. If the 225 mg/m2/dose 
is not tolerated (≥2 patients with dose limiting toxicities (DLTs) in the first 6 evaluable patients), subsequent new 
patients will be enrolled at the160 mg/m2/dose level until 6 evaluable patients are available for the safety review 
and the PK analysis.
Patients with benefit (stable disease or an objective response) may continue therapy unless there is evidence of 
progressive disease, unacceptable treatment-related toxicity, until death or until study closure [defined as 1 
year after Last Patient First Visit (LPFV)], whichever occurs first.
Section 1.1 Primary Aims, Previous Text:
1.1.1. To determine the investigator assessed objective response rate of pazopanib in children, adolescents and
young adults (subjects) with relapsed or refractory rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue 


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sarcomas, and Ewing sarcoma.
Section 1.1 Primary Aims, Revised Text:
1.1.1
To determine the investigator- assessed objective response rate of pazopanib in children, adolescents 
and young adults (patients) with relapsed or refractory solid tumors of the following types (each defining a cohort):
1. rhabdomyosarcoma,
2. non-rhabdomyosarcomatous soft tissue sarcoma, or
3. Ewing sarcoma/peripheral Primitive Neuro Ectodermal Tumor (PNET).
Section 1.2 Secondary Aims, Previous Text:
1.2.8
To further assess VEGF and KDR genotype/phenotype relationships in subjects with cancer treated 
with pazopanib.
Section 1.2 Secondary Aims, Revised Text:
1.2.8 To further assess VEGF-A and KDR genotype, their plasma concentration relationships in patients
with cancer treated with pazopanib.
1.2.10 To assess overall survival (OS) in patients with relapsed or refractory solid tumors per cohort
(described under Section 1.1.1 and 1.2.1).
Section 2.5 Overview of Proposed Pediatric Phase II Trial, Previous Text:
This is a two-stage open label phase II trial of pazopanib in children, adolescents and young adults with recurrent 
or refractory solid tumors. Tumors of primary interest are rhabdomyosarcoma, non-
rhabdomyosarcomatous soft tissue sarcoma (including synovial sarcoma, alveolar soft part sarcoma and 
desmoplastic small round cell tumor) and Ewing sarcoma. Tumors of secondary interest include hepatoblastoma, 
neuroblastoma (measurable and evaluable), and osteosarcoma.
Eligible patients will receive pazopanib daily as an oral tablet (450 mg/m2/dose) or as a powder for suspension
(225 mg/m2/dose) in 28 day cycles. The maximum dose to be administered daily for tablets is
800 mg and for suspension 400 mg. Patients will be closely monitored with clinical and laboratory
observations for adverse effects. Response will be evaluated using appropriate imaging studies after the
2nd cycle of pazopanib, after the 4th cycle, and then every 3rd cycle thereafter (baseline, prior to Cycle 3, prior
to Cycle 5, prior to Cycle 8, prior to Cycle 11, etc). In the absence of severe toxicity or progressive disease, 
patients may continue receiving pazopanib.
This study will dose patients requiring suspension with a starting dose of 225 mg/m2/dose.. The previously-defined
suspension MTD of 160 mg/m2/dose may result in suboptimal exposure to demonstrate efficacy. Two of 4
patients in the prior Phase I study demonstrated DLTs in the form of isolated and reversible Grade 3 elevations 
in ALT at 225 mg/m2/dose. Given that this toxicity was isolated and reversible, the first 6 patients receiving
suspension will be dosed at 225 mg/m2/dose and assessed for first- cycle DLTs before continuing to enroll
additional patients requiring suspension. If two or more of 6 patients demonstrate DLT, then the dose may be de-
escalated to the previously-defined MTD of 160 mg/m2/dose.
The first 6 subjects who require the suspension formulation will have extended PK sampling with blood samples
collected prior to dosing, 30 min, 1, 2, 4, 6, and 8 hours after the pazopanib dose on Days 1 and 15 of Cycle
1. All subjects (regardless of formulation) will have blood samples for analysis of plasma pazopanib 
concentration collected prior to dosing and 3 to 4 hours after dosing on Day 15 of Cycle 1. Additional blood 
samples for analysis of steady state trough plasma pazopanib concentrations will be collected prior to every 
subsequent odd cycle (in conjunction with safety labs).
(PlGF), VEGFR2, and endoglin. In addition, we will assess KDR polymorphism and pazopanib-induced 
change in VEGFR2; VEGFA genotype/haplotypes and changes in VEGF-A, response rate, and overall survival;
and candidate SNPs and clinical endpoints as identified in ongoing large scale studies of pazopanib in the adult 
population.


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The study will be considered complete (analysis conducted and enrollment closed) when all subjects enrolled in 
the tumors of the primary interest strata have completed a minimum of 6 cycles of treatment, have disease
progression, or have withdrawn from the study.
Section 2.5 Overview of Proposed Pediatric Phase II Trial, Revised Text:
This is a two-stage open label phase II trial of pazopanib in children, adolescents and young adults with recurrent 
or refractory solid tumors. Tumors of primary interest are rhabdomyosarcoma, non-
rhabdomyosarcomatous soft tissue sarcoma (including synovial sarcoma, alveolar soft part sarcoma and 
desmoplastic small round cell tumor) and Ewing sarcoma/peripheral PNET. Tumors of secondary interest
include hepatoblastoma, neuroblastoma (measurable and evaluable), and osteosarcoma.
Each tumor type defines a cohort resulting in 7 total cohorts. The first stage of the study involves enrolling an 
initial 10 patients into each cohort. The response rate will be determined for each cohort after the target enrollment
of 10 patients is reached for that cohort. If one or more confirmed responses are observed in the first 10
evaluable patients in a cohort, an additional 10 patients will be enrolled into that cohort in the second stage of
study. Thus, for cohort(s) with one or more confirmed responses in the first stage of study, a total of 20 patients 
will be enrolled and evaluated to determine efficacy.
Eligible patients will receive pazopanib monotherapy. Pazopanib will be dosed daily as an oral tablet (450 
mg/m2/dose, maximum 800 mg) or as a powder for oral suspension (225 mg/m2/dose, maximum 400 mg) in 28 
day cycles.
The MTD for pazopanib tablets was 450 mg/m2/dose as determined by ADVL0815/PZP114411, the COG 
Phase I study in children with relapsed or refractory solid tumors. For the powder suspension formulation, the 
selected starting dose is higher than the protocol-defined MTD of 160 mg/m2/dose established in ADVL0815. This 
decision is driven by the considerations that the 160 mg/m2/dose may result in exposure that is suboptimal to
demonstrate efficacy and that only two isolated and reversible laboratory-defined DLTs were observed at the 
225 mg/m2/dose.
The first patients who are enrolled to receive pazopanib as powder suspension at 225 mg/m2/dose daily will be 
closely monitored for safety and for the occurrence of dose-limiting toxicity during the first cycle (28 days) of 
therapy. Patients who either receive 225 mg/m2/dose daily for at least 24 days (85% of the dose for a 28- day 
cycle with powder suspension at 225 mg/m2/dose) or are withdrawn from dosing due to one or more protocol-
defined dose-limiting toxicities (Section 5.1) during the first cycle will be considered evaluable for the purpose of 
this safety review. Six evaluable patients are required.
The first patients enrolled to receive powder suspension at 225 mg/m2/dose will also be expected to complete 
extended PK sampling (Section 7.3.2) with blood samples collected prior to dosing, and 30 min, 1, 2, 4, 6, and 8
hours after the pazopanib dose on Day 1 and Day 15 ± 1 day of Cycle 1 (with no pazopanib dose
modification or adjustment in the 10 days before Cycle 1 Day 15 sample collection). Patients who can provide 
adequate blood samples for the 2 scheduled extended PK collections will be considered to be evaluable 
patients for the purpose of this PK analysis, and PK data are required from 6 evaluable patients. If one or more of
the first 6 patients fails to provide blood samples as specified in the protocol or if it is known that for some reason
a patient’s collected blood sample(s) cannot be analyzed, that patient will be determined to be non- evaluable 
for this analysis, and one or more additional patients will be enrolled for treatment with pazopanib as powder 
suspension for the purpose of obtaining the extended PK samples.
Because patients receiving the powder suspension enrolled in the safety review group may be different from those 
in the PK analysis group, enrollment onto powder suspension may follow several different paths:

If ≥2 out of 6 evaluable patients have dose- limiting toxicities (DLT and as defined in 
Section 5.1) within the first cycle, then enrollment onto 225 mg/m2/dose pazopanib will be 
halted. Subsequent new patients will be enrolled at the 160 mg/m2/dose level until 6 evaluable
patients from this dose group are available for the safety review and 6 patients are available 


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for PK analysis at 160 mg/m2/dose.

If 6 PK evaluable patients are enrolled prior to enrollment of 6 patients who are evaluable for 
the safety review, the extended PK sample collection may be suspended.

If < 2 DLTs are observed during the first cycle in 6 patients evaluable for safety at 225 
mg/m2/dose and these 6 patients are not all evaluable for the PK analysis, then enrollment 
will continue until 6 PK evaluable patients are available.
All patients will be closely monitored with clinical and laboratory observations for adverse effects.
Tumor response will be evaluated using appropriate imaging assessments at baseline, prior to Cycle 3, Cycle 5, 
Cycle 8, Cycle 11 and then every 3rd cycle thereafter.
 
In addition, we will assess KDR polymorphism and pazopanib-induced change
in soluble VEGFR2; VEGF-A genotype and changes in VEGF-A concentration; KDR and VEGF-A genotypes
and response rate, and progression-free survival; and candidate SNPs and clinical endpoints as identified in the 
adult population.
The primary analysis will be performed 20 weeks after the last patient’s first visit in the three cohorts of primary
interest (rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma and Ewing sarcoma/peripheral 
PNET).
The study will be completed one year from the date of the last patient’s first visit and the end of study analysis 
will be performed at the time of study completion.
For patients who are still on treatment and continue to derive benefit from it at the time of study completion, 
and for whom no other treatment options are available, Novartis will discuss individual patient cases with 
investigators
to 
identify 
possible 
access 
to 
study 
treatment 
after 
termination 
of 
the 
VEG116731/ADVL1322/PZP034X2203 trial.
A patient will be considered to have completed the study if the patient:
•
Dies while on study and prior to study completion
•
Stays on study in follow-up until the time of study completion
Section 3.1.1 Patient Registration, Previous Text (Paragraphs 1, 3, 4):
No study specific procedure will start before the signature of the informed consent form (and assent, 
according to institutional guidelines).
Upon completion of all the required baseline assessments, eligible subjects will be registered into the GSK 
interactive voice response system called RAMOS (Registration and Medication Ordering System) and will be
assigned a GSK study specific number and a randomization number, by the investigator or authorized site
staff for stratification. Subject number and histology strata (rhabdomyosarcoma, non- rhabdomyosarcomatous 
soft tissue sarcoma, Ewing Sarcoma/Peripheral PNET, osteosarcoma, neuroblastoma (measureable), 
neuroblastoma (evaluable) or hepatoblastoma) must be entered into the system in order to register the patient 
with GSK.
All calls to RAMOS are confirmed with a fax, which will be sent to the site upon completion of each call. 
Study-specific instructional worksheets will be provided for the use of RAMOS in the Study Procedures 
Manual.
Section 3.1.1 Patient Registration, Revised Text (Paragraphs 1, 3, 4):
No study-specific procedure will start before the signature of the informed consent form (and assent, according to 
institutional guidelines), defining the study entry.
Upon completion of all required baseline assessments, the investigator or authorized site staff will assign each 
eligible patient a Sponsor study-specific patient identification number. Each site will be assigned a range of patient
numbers, and this information is provided in the Study Procedure Manual (SPM). The patient ID number


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consists of 6 digits including leading zeros. Using this patient ID number and patient’s histology cohort 
(rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma, Ewing sarcoma/peripheral PNET,
osteosarcoma, neuroblastoma (measureable), neuroblastoma (evaluable) or hepatoblastoma), each patient will then 
be registered into the interactive voice response system RAMOS (Registration and Medication Ordering System). 
RAMOS will then provide an identification number consistent with the patient’s tumor type.
All calls to RAMOS are confirmed (with a fax or e-mail), which will be sent to the site upon completion of 
each call. Study-specific instructional worksheets will be provided for the use of RAMOS in the Study Procedures 
Manual.
Section 3.1.2 Patient Rescreening, Added Text:
Patients may be rescreened if the reasons for the initial screen failure were non-medical or if the medical issues 
leading to screen failure have resolved. Approval by the Study Chair is required prior to rescreening. A new 
informed consent form must be signed. Please refer to detailed instructions in the Study Procedure Manual for 
rescreening.
Section 3.1.4 Study Enrollment Status, Added Text:
While the study remains open for enrollment, enrollment into each cohort will proceed independently from the 
other cohorts (see Section 9.2 for details). The enrollment in the cohorts of secondary interest may remain 
open if after review of the data, an efficacy signal is seen.
Section 3.1.6 Requirements to Initiate Protocol Therapy, Previous Text:
Imaging Studies: Imaging studies must be performed within 14 calendar days of initiating protocol therapy. If
more than 14 calendar days have elapsed between the date imaging studies to determine eligibility were 
obtained (Section 3.2) and the enrollment date, then repeat imaging studies must be obtained prior to initiating 
protocol therapy.
Cardiacstudies: Cardiac ECHO and electrocardiogram (ECG) must be performed within 14 calendar days of 
initiating protocol therapy. If more than 14 days have elapsed between the date imaging studies to determine 
eligibility were obtained (Section 3.2.6.4) and the enrollment date, then repeat imaging studies must be obtained
prior to initiating protocol therapy.
BoneMarrowEvaluations(SolidTumorswithknownMarrow Involvement): BM aspirate and/or biopsy must be 
performed within 14 calendar days of initiating protocol therapy. If more than 14 calendar days have elapsed
between the date bone marrow evaluation to determine eligibility was obtained (Section 3.2.6.1) and the
enrollment date, then repeat BM aspirate and/or biopsy must be obtained prior to initiating protocol therapy.
Section 3.1.7 Requirements to Initiate Protocol Therapy, Revised Text:
Imaging Studies: Imaging studies must be performed within 14 calendar days prior to initiating protocol 
therapy. If more than 14 calendar days have elapsed between the date imaging studies to determine eligibility
were obtained (Section 3.2) and the enrollment date, then repeat imaging assessments must be obtained prior to 
initiating protocol therapy.
Cardiac studies: Cardiac ECHO and electrocardiogram (ECG) must be performed within 14 calendar days 
prior to initiating protocol therapy. If more than 14 days have elapsed between the date cardiac studies to 
determine eligibility were obtained (Section 3.2.8.4) and the enrollment date, then repeat cardiac studies must be 
obtained prior to initiating protocol therapy.
Bone Marrow (BM) Evaluations (Solid Tumors with known Marrow Involvement): Bone Marrow aspirate and/or
biopsy must be performed within 14 calendar days prior to initiating protocol therapy. If the Bone Marrow
evaluation was performed more than 14 days prior to enrollment date and if it was negative, then BM aspirate 
and/or biopsy must be repeated prior to initiating protocol therapy. If the Bone Marrow evaluation was obtained
more than 14 calendar days prior to enrollment and it was positive, and there was no intervening treatment 
provided to the patients, then there is no need to repeat the Bone Marrow evaluation.


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Section 3.2 Eligibility: Inclusion Criteria, Added Text
3.2.3 Patient must have disease that has either relapsed or is refractory to prior therapy
Section 3.2.3 Body Surface Area, Previous Text Body Surface Area (for subjects taking tablet formulation
only): Patients who will be receiving the tablet formulation must have a BSA > 0.84 m2 at the time of study
enrollment.
Section 3.2.4 Body Surface Area, Revised Text
Body Surface Area (BSA) (for subjects taking tablet formulation only): Patients who will be receiving the 
tablet formulation must have a BSA ≥0.84 m2 at baseline. The same method should be used to calculate a 
given patient’s BSA throughout their study participation.
Section 3.2.8.2 Adequate Renal and Metabolic Function, Previous Text
No more than Grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium and 
phosphorous (supplementation allowed).
Section 3.2.8.2 Adequate Renal and Metabolic Function, Revised Text
Adequate thyroid function: either normal TSH or on a stable dose of thyroid replacement for at least than 4 
weeks (see Section 3.3.2.8)
No more than Grade 1 abnormalities of:
a.
Potassium
b.
Calcium (confirmed by ionized calcium)
c.
Magnesium d.
Phosphorous
Oral supplementation is allowed.
Section 3.3 Exclusion Criteria, Previous Text
3.3.1 Males or females of reproductive potential may not participate unless they have agreed to use an
effective contraceptive method beginning at the signing of the informed consent until at least 30 days after the 
last dose of the study drug.
3.3.2.7 Note: This list includes the prohibition of grapefruit juice for 14 days prior to enrollment.
3.3.3 Patients who are unable to swallow tablets or liquid are not eligible.
3.3.5.4 History of hemoptysis within 6 weeks prior to study enrollment.
Section 3.3 Exclusion Criteria, Revised Text
3.3.1 Females of reproductive potential may not participate unless they have agreed to use an effective 
contraceptive method beginning at the signing of the informed consent until at least 30 days after the last dose of 
the study drug.
3.3.2.7 Note: This list includes the prohibition of grapefruit juice for 14 days prior to enrollment and while 
receiving pazopanib.
3.3.3
Patients who are unable to swallow tablets or liquid are not eligible.
Pazopanib cannot be 
administered via NG tube or G-tube.
3.3.5.4 History of clinically significant bleeding (grade 3 hemorrhage) within 6 weeks prior to study enrollment,
including CNS, pulmonary, or GI hemorrhage.
Section 3.4 Regulatory, Previous Text


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All patients and/or their parents or legal guardians must sign a written informed consent.
Section 3.4 Regulatory, Revised Text
All patients and/or their parents or legal guardians must sign a written informed consent (and assent, if 
indicated, according to institutional guidelines).
Section 4.1 Overview of Treatment Plan, Previous Text
Pazopanib will be administered orally once daily as a tablet at a dose of 450 mg/m2/dose or as a powder in
suspension at a dose of 225 mg/m2/dose. 450 mg/m2/dose was the MTD for tablet as determined by 
ADVL0815, the COG Phase I study, while the dose for oral suspension of 225 mg/m2/dose exceeds the 
protocol-specified MTD of 160 mg/m2/dose established in that study. Two isolated and reversible laboratory-
defined DLTs were observed at 225 mg/m2/dose. The maximum dose to be administered daily for tablets is
800 mg and for suspension 400 mg. Each cycle will be defined as 28 days.
Note: The first 6 patients enrolled who receive suspension will be expected to complete extended PK sampling
(Section 7.3.2) in order to obtain PK and safety data. These data will be reviewed prior to further enrollment
of patients requiring suspension to determine if 225 mg/m2/dose is tolerated and PK exposure is similar to
exposure in adults associated with clinical efficacy. If 225 mg/m2/dose is not tolerated (≥2 DLTs in 6
evaluable patients), the dose for patients who require suspension may be reduced to 160 mg/m2/dose.
A cycle will be defined as 28 days with no rest periods between cycles. Patients with benefit (stable 
disease or an objective response) may continue therapy unless there is evidence of progressive disease or 
unacceptable treatment-related toxicity.
Patients must remain on the same formulation of pazopanib throughout the duration of their protocol
therapy.
Drug dosing for the tablet formulation should be determined using the dosing nomogram in Appendix II. 
For patients receiving powder for suspension (50 mg/mL), the dose will be rounded to the nearest 5 mg. 
Drug doses should be adjusted based on the BSA as determined by the height and weight obtained within 1
week prior to the beginning of each cycle.
Pazopanib should be taken on an empty stomach (at least 1 hour before a meal or 2 hours after a meal) at 
approximately the same time each day. Pazopanib tablets should be taken with clear liquids (approximately 4 
ounces for children < 12 years of age and 4-8 ounces for children ≥12 years of age). Pazopanib suspension
should be taken according to instructions in Appendix VII. The pazopanib suspension should be swirled for
at least 30 seconds prior to removal of the dose from the bottle, which should be given immediately. If a 
patient vomits after a dose of pazopanib, the dose should not be repeated.
A patient diary (see Appendices IA and IB) should be completed by the patient or their guardian and 
collected at the end of each cycle.
Section 4.1 Overview of Treatment Plan, Revised Text
Pazopanib will be dosed daily as an oral tablet at 450 mg/m2/dose or as a powder for oral suspension at 225 
mg/m2/dose.
For the tablet formulation, the maximum
tolerated
dose (MTD) was 450 mg/m2/dose as determined by
ADVL0815/PZP114411, the COG Phase I study. The maximum dose to be administered daily for tablets is
800 mg.
For the powder suspension formulation, the selected starting dose is 225 mg/m2/dose, higher than the protocol-
specified MTD of 160 mg/m2/dose established in study ADVL0815. This decision is driven by the considerations
that the 160 mg/m2/dose may result in exposure that is suboptimal to demonstrate efficacy and that only two
isolated and reversible laboratory-defined dose-limiting toxicities (DLTs) were observed at the 225 mg/m2/dose.
The maximum dose to be administered daily for oral suspension is 400 mg.


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Note: The first patients enrolled who receive powder suspension will be reviewed for safety and will be expected 
to complete extended PK sampling (Section 7.3.2). A minimum of 6 evaluable patients for safety and 6 evaluable
patients for PK are required as described in section 2.5. Safety and PK data from these patients will be reviewed 
prior to further enrollment of patients requiring powder suspension to determine if the 225 mg/m2/dose is tolerated
and if the PK exposure is similar to exposure in adults associated with clinical efficacy. If 225 mg/m2/dose
is not tolerated (≥2 patients with DLTs in the first 6 evaluable patients during their first cycle), all subsequently
enrolled patients will receive 160 mg/m2/dose, and an additional 6 subjects will be assessed for safety and PK.
Patients will take pazopanib continuously, once daily. A cycle will be defined as 28 days with no rest periods 
between cycles. Patients with benefit (stable disease or an objective response) may continue therapy unless there
is evidence of progressive disease or unacceptable treatment-related toxicity, death or until study closure defined 
as 1 year after Last Patient First Visit.
Patients must remain on the same formulation of pazopanib throughout the duration of their protocol 
therapy.
Drug dosing for the tablet formulation should be determined using the dosing nomogram in Appendix II. For 
patients receiving powder for suspension (50 mg/mL), the dose will be rounded to the nearest 5 mg. Drug 
doses should be adjusted based on the BSA as determined by the height and weight obtained within 1 week 
prior to the beginning of each cycle.
Pazopanib should be taken on an empty stomach (at least 1 hour before a meal or 2 hours after a meal) at 
approximately the same time each day. Pazopanib tablets should be taken with clear liquids (approximately 4 
ounces
for children < 12 years of age and 4-8 ounces for children ≥12 years of age). Pazopanib
suspension should be taken according to instructions in Appendix VII. The pazopanib suspension should be 
swirled for at least 30 seconds prior to removal of the dose from the bottle, which should be given immediately.
If a patient vomits after a dose of pazopanib, the dose should not be repeated.
A patient diary (see Appendices IA and IB) should be completed by the patient or their guardian and collected at 
the end of each cycle.
Section 4.1.1 Dose Reduction, Previous Text
For patients who receive pazopanib tablets: Dose reduction(s) will be allowed for toxicities as outlined in
Section 5.0 for patients who recover to starting criteria as outlined in Section 4.2 within14 days following 
planned administration (see dosing nomogram for tablets in Appendix II). Dose reduction(s) will be based on 
the starting dose.
Note: For patients receiving pazopanib tablets at a starting dose of 400 mg, there will only be one allowed dose 
reduction due to tablet size.
Forpatientswhoreceivepazopanibpowderinsuspension: A stepwise dose reduction (Tables 1 and 1a) will be 
allowed for toxicities as outlined in Section 5.0 for patients who recover to starting criteria as outlined in
Section 4.2 within 14 days following planned administration.
Table1: Stepwise Dose Reduction for Toxicity if suspension starting dose 225 mg/m2
Starting Dose
225 mg/m2/dose
First Dose Reduction
160 mg/m2/dose
Table1a: Stepwise Dose Reduction for Toxicity if suspension starting dose reduced to 160 mg/m2
Starting Dose
160 mg/m2/dose


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First Dose Reduction
135 mg/m2/dose
Section 4.1.1 Dose Reduction, Revised Text
For patients who receive pazopanib tablets: Dose reduction(s) in response to toxicity may be implemented 
according to guidance in Sections 5.2, 5.3, and 5.4 of the protocol. Outside the specific management guidance 
described in these sections, patients who recover from an adverse event to starting criteria as outlined in 
Section 4.2 within 14 days following planned administration will also be permitted to receive protocol therapy at
a reduced dose. Dose reduction(s) will be based on the starting dose and should follow the Dosing Nomogram in
Appendix II.
Note: For patients receiving pazopanib tablets at a starting dose of 400 mg, there will only be one allowed 
dose reduction due to tablet size.
Forpatientswhoreceivepazopanibasoralpowderforsuspension:
Dose reduction(s) in response to toxicity may be implemented according to guidance in Sections 5.2, 5.3 and
5.4 of the protocol. Outside the specific management guidance described in these sections, patients who 
recover from an adverse event to starting criteria as outlined in Section 4.2 within 14 days following planned 
administration will also be permitted to receive protocol therapy at a reduced dose. Dose reduction(s) will be
based on the starting dose and should follow the guidance in Table 1 and Table 1a.
Table1: = Dose Reduction for Toxicity if powder suspension starting dose is 225 mg/m2
Starting Dose
225 mg/m2/dose
First Dose Reduction
160 mg/m2/dose
Second
Dose
Reduction
135 mg/m2/dose
Table1a: Dose Reduction for Toxicity if powder suspension starting dose has been reduced to 160 mg/m2
Starting Dose
160 mg/m2/dose
First Dose Reduction
135 mg/m2/dose
Any subsequent dose reduction would need to be discussed and agreed by the Study Chair.
Section 4.1.3 Treatment Interruptions, Added Text
If the protocol therapy has been interrupted for more than 28 days, the patient should be permanently
discontinued from protocol therapy and will continue to be followed for survival.
Section 4.1.4 Missed Doses, Added Text
Missed doses should be documented in the electronic case report form (eCRF).
If a dose is missed, the patient should take the dose as soon as possible, but only if there are 12 or more hours 
left before the next dose is due. If the next dose is due in less than 12 hours, the patient should skip the missed
dose and take the next dose as scheduled.
Section 4.1.3.2 Management of Hypothyroidism, Previous Text
Patients with Grade 2 hypothyroidism should be evaluated by an endocrinologist for further management.
Patients with Grade 2 hypothyroidism adequately managed with thyroid hormone replacement may continue on
protocol therapy. Patients with Grade 3 or greater hypothyroidism will be considered to have had a dose-
limiting toxicity. These patients should be managed according to Section 5.3 and should also be evaluated by an 
endocrinologist for further management.
Section 4.1.5.2 Management of Hypothyroidism, Revised Text
Patients with Grade 2 hypothyroidism should be evaluated by an endocrinologist for further management. Patients
with Grade 2 hypothyroidism adequately managed with thyroid hormone replacement may continue on protocol 


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therapy. Patients with Grade 3 or greater hypothyroidism attributable to pazopanib will be considered to have had
a dose-limiting toxicity. These patients should be managed according to Section 5.3 and should also be evaluated 
by an endocrinologist for further management. If Grade 3 or greater hypothyroidism is adequately managed with
thyroid hormone replacement and improves to grade 2 or less, pazopanib may be restarted.
Section 4.1.5.4 Blood-product Support, Added Text
Patients should be supported with transfusion of blood and blood products (including platelet transfusion) per
institutional standards.
Section 4.3 Concomitant Therapy, Previous Text
If future changes are made to the list of permitted/prohibited medications the Investigator Brochure will be 
updated and formal documentation will be provided by GSK and stored in the study file. Any such changes will 
be communicated to the investigative sites in the form of a letter.
Section 4.3 Concomitant Therapy, Revised Text
If new data become available showing an interaction between a concomitant medication and pazopanib that is 
considered significant enough to impact the risk/benefit balance of pazopanib, the list of permitted/prohibited
medications in the Investigator Brochure will be updated either during the annual update or within an IB 
supplement. Any such changes will be communicated to the site via a letter which should be stored in the site’s 
study file.
Section 4.5.1 Specific recommendations regarding anticoagulants, Previous Text
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 benefitting from 
treatment and require the initiation of concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low 
molecular weight heparin, unfractionated heparin) while on study.
Section 4.5.1 Specific recommendations regarding anticoagulants, Revised Text
Hemorrhagic events, however, have been reported in clinical studies with pazopanib. Therefore, if the investigator
decides to continue pazopanib and anticoagulants use concomitantly, it should be used with caution in 
patients with increased risk of severe bleeding or who are benefitting from treatment and require the initiation of 
concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight heparin, unfractionated 
heparin) while on study.
Section 4.7 The Effects of Other Drugs on Pazopanib, Previous Text
Furthermore, in vitro data suggest that pazopanib is a substrate for p-glycoprotein.
Section 4.7 The Effects of Other Drugs on Pazopanib, Revised Text
Furthermore, in vitro data suggest that pazopanib is a substrate for P-glycoprotein and for breast cancer 
resistance protein.
Section 4.8 Prohibited Medications, Previous Text
Glucocorticoidsforgreaterthan2weeksduration: cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 
mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg)
As noted above, co-administration of pazopanib with medicines that increase gastric pH is prohibited from 
24 hours before the first dose of pazopanib until after the final PK blood sample is collected on Day 15 ± 1 
day of Cycle 1.
Section 4.8 Prohibited Medications, Revised Text
Glucocorticoidsfor greaterthan 2 weeks duration: cortisone (>50 mg/day), hydrocortisone (>40 mg/day), 
prednisone (>10 mg/day), methylprednisolone (>8 mg/day), dexamethasone (>1.5 mg/day)
As noted above, co-administration of pazopanib with medicines that increase gastric pH should be avoided and is 
prohibited from 24 hours before the first dose of pazopanib until after the final PK blood sample is collected on 


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Day 15 ± 1 day of Cycle 1.
Section 4.9 Therapy Delivery Map (TDM) – Cycle 1, Revised Table

Removed Screening assessments from Cycle 1 Day 1

Added PD assessments
Section 4.9 Therapy Delivery Map - Subsequent Cycles of Therapy, Revised Table

Added PD assessments
Section 5 Definitions and Dose Modification for Toxicity, Added Text
The cycle duration remains 28 consecutive days in patients who have dose interruption.
Section 5.1.2 Hematological Dose Limiting Toxicity, Previous Text
a.
For patients who are evaluable for hematologic toxicity (patients without bone marrow 
involvement)

Grade 4 Neutropenia not due to malignant infiltration.

Grade 4 Thrombocytopenia (platelet count < 25,000/µL)

Myelosuppression that causes a treatment interruption of > 14 days
Section 5.1.1 Hematological Dose Limiting Toxicity, Revised Text
a.
For patients who are evaluable for hematologic toxicity assessment (patients without bone
marrow involvement)

Grade 4 Thrombocytopenia (platelet count < 25,000/mm3) or Grade 4 neutropenia

Any hematologic toxicity requiring dose reduction or treatment interruption for >14 days
Section 5.1.1 Non-Hematological Dose Limiting Toxicity, Previous Text
Any Grade 3 non-hematological toxicity that is attributable to pazopanib, with the specific exclusion of the
following:
•
Grade 3 nausea and vomiting of less < 3 days duration
•
Grade 3 fever or infection
•
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to oral supplementation (see Section 5.4.3 
for dose modifications)
Hypertension will be graded according to the NCI CTCAE, however, doselimitinghypertension will be 
considered as the following:
•
Grade 4 hypertension
•
A blood pressure >25 mmHg above the 95th percentile for age, height, and
gender (see Appendix V) confirmed by repeated measurement (See
Sections 5.4.1 and 4.1.3.1 for management)

In patients already on anti-hypertensive therapy due to previous 
hypertension (see Section 3.2.6.5), any blood pressure 1-25 mmHg above
the 95th percentile for age, height, and gender (Appendix V) for > 14 days
(See Sections 5.4.1 and 4.1.3.1 for management)
Section 5.1.2 Non-Hematological Dose Limiting Toxicity, Revised Text
Any Grade 3 non-hematological toxicity, with the specific exclusion of the following:

Grade 3 nausea and vomiting of less < 3 days duration

Grade 3 fever or infection,

Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to oral supplementation within 7 days of 
start of supplement (see Section 5.4.4 for dose modifications)


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Hypertension will be graded according to the NCI CTCAE, however, dose limiting hypertension will be 
considered as the following:

Grade 4 hypertension

A blood pressure >25 mmHg above the 95th percentile for age, height, 
and gender (see Appendix V) confirmed by repeated measurement on the 
same day (See Sections 5.4.1 and 4.1.4.1 for management)

In patients already on anti-hypertensive therapy due to previous hypertension
(see Section 3.2.8.5), any blood pressure 1-25 mmHg above the 95th 
percentile for age, height, and gender (Appendix V) for > 14 days
(See Sections 5.4.1 and 4.1.4.1 for management)
Section 5.2 Dose Modifications for Hematologic Toxicity, Previous Text
Note: The cycle duration remains 28 consecutive days in patients who have dose interruption of an ongoing
cycle. Cycle initiation may be delayed for toxicity as outlined below. All 
dose modifications should be based on the worst preceding toxicity.
Pazopanibtablets: For step-wise dose reductions, see Appendix II for the dosing nomogram. Pazopanib
powderinsuspension: For step-wise dose reductions see Tables 1and 1a (Section 4.1.1).
5.2.1
For all patients:
5.2.1.1
If Grade 4 neutropenia occurs, a) 
Pazopanib should be held.
b) Subsequent doses of pazopanib should be given at a reduced dose, 
when ANC ≥750.
5.2.1.2
If Grade 4 thrombocytopenia occurs, a) 
Pazopanib should be held.
b) Subsequent doses of pazopanib should be given at a reduced dose, 
when platelet count ≥75,000/L.
5.2.1.3 If dose-limiting myelosuppression occurs as noted in Section 5.1.2,
a) The dose of pazopanib should be resumed at a reduced dose, once
ANC ≥750 and platelet count ≥75,000/L.
5.2.2
Patients who have a dose limiting hematological toxicity that does not resolve to the parameters
defined in Section 5.2.2 within 28 days of holding pazopanib, if re-challenge is to be considered 
the study chair must be contacted and provide approval prior to re-challenge.
Section 5.2 Dose Modifications for Hematologic Toxicity, Revised Text
All dose modifications should be based on the worst preceding toxicity.
Pazopanibtablets: For step-wise dose reductions, see Appendix II for the dosing nomogram. 
Pazopanibpowderinsuspension: For step-wise dose reductions see Tables 1 and 1a (Section 4.1.1).
5.2.1
For all patients:
5.2.1.1 If Grade 4 neutropenia occurs, 
a) Pazopanib should be held.
b) CBCs should be checked at least twice a week (every 3 to 4 days) until


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ANC ≥ 750/µL.
c) Subsequent doses of pazopanib should be given at a reduced dose, when
ANC ≥ 750/µL.
5.2.1.2 If Grade 4 thrombocytopenia occurs, 
a) Pazopanib should be held.
b) CBCs should be checked at least twice a week (every 3 to 4 days) until 
platelet count ≥75,000/L without need for platelet transfusion in the 
preceding 7 days.
c) Subsequent doses of pazopanib should be given at a reduced dose, when
platelet count ≥75,000/L without need for platelet transfusion in the 
preceding 7 days.
5.2.1.3 If dose-limiting myelosuppression occurs as noted in Section 4.1.1,
a) The dose of pazopanib should be resumed at a reduced dose, once ANC ≥
750/L and platelet count ≥75,000/L without need for platelet transfusion 
in the preceding 7 days.
5.2.1
For patients who have a dose limiting hematological toxicity that does not resolve to 
the parameters defined in Section 5.2.1 within 14 days of holding pazopanib: if re-
challenge is to be considered, the Study Chair must be contacted and provide approval 
prior to re-challenge.
Section 5.3 Dose Modifications for Non-Hematological Toxicity, Previous Text
If dose-limiting toxicity recurs in a patient who has resumed treatment after 2 dose reductions, the patient 
must be removed from protocol therapy, unless the patient has been approved for a further dose reduction 
following discussion with the Study Chair.
Section 5.3 Dose Modifications for Non-Hematological Toxicity, Revised Text
If DLT recurs in a patient who has resumed treatment after the maximum allowed dose reductions, the patient
must be removed from protocol therapy, unless the patient has been approved for a further dose reduction 
following discussion with the Study Chair.
Section 5.4.1 Hypertension, Previous Text
Arm 5 of algorithm:
If the participant develops Grade 4 hypertension, discontinue pazopanib, monitor BP and administer anti-
hypertensive therapy as clinically indicated. The patient is Off Protocol Therapy (Section 8.1).
Section 5.4.1 Hypertension, Revised Text
Arm 5 of algorithm:
If the participant develops Grade 4 hypertension, discontinue pazopanib, monitor BP and administer anti-
hypertensive therapy as clinically indicated. A nephrology and/or cardiology consult is recommended. The
patient must be removed from Protocol Therapy (Section 8.1).
Section 5.4.9 Abdominal Pain, Previous Text
Abdominal pain is not an uncommon symptom with vascular endothelial growth factor (VEGF) receptor 
antagonists, of which pazopanib is one. Bowel perforations have been reported in clinical trials of pazopanib
and with other agents in this class. Bowel perforations have been associated in some patients with tumor 
in the bowel wall, or diverticulitis, while in others there has been no clear explanation. Although bowel
perforation is a rare event, investigators and study staff at the site are advised to be vigilant of this potential
complication in patients receiving pazopanib. Please contact the Study chair if you need further guidance or 
would like to discuss an event involving abdominal pain or bowel perforations.
Section 5.4.2 Abdominal Pain, Revised Text
Abdominal pain is not an uncommon symptom with vascular endothelial growth factor (VEGF) receptor 
antagonists such as pazopanib. Bowel perforations have been reported in clinical trials of pazopanib and with 


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other agents in this class. Bowel perforations have been associated in some patients with tumor in the bowel
wall, or diverticulitis, while in others there has been no clear explanation.
Although bowel perforation is a rare event, investigators and study staff at the site are advised to be vigilant of 
this potential complication in patients receiving pazopanib. Abdominal complaints should be assessed during AE
review at every visit. In addition, every physical exam should include a complete abdominal exam. For patients
with abdominal complaints and/or abnormal findings on clinical exam, follow the dose modifications and 
evaluations described below.
Adverse events & descriptions
Dose Modifications & Evaluations
Mild to Moderate abdominal pain or other
abdominal complaints with no associated 
abnormal findings on physical exam
1. Continue pazopanib at current dose
2. Implement supportive care as 
indicated and per institutional
standards; consider imaging studies
3. Advise the patient to seek medical 
attention should their complaints
worsen
4. Appropriate follow-up until complaints 
resolve or origin of the pain is 
identified. Imaging studies to confirm 
the absence of abdominal pathology 
should be performed based on the 
investigator judgment.
Severe abdominal pain or a concerning
abdominal exam
1. Hold pazopanib
2. Recommend to obtain appropriate 
imaging studies to evaluate the 
patient’s specific complaints or exam 
findings
3. Resume pazopanib at previous dose if 
imaging studies confirm the absence
of abdominal pathology
Confirmed or any suspicion of abdominal
perforation
1. Remove from protocol therapy
Contact the Study chair if you need further guidance or would like to discuss an event involving abdominal 
pain or bowel perforations.
Section 5.4.2 Hepatotoxicity, Previous Text
Adverse events & descriptions
Dose Modifications & Evaluations
Grade 1 ALT/AST elevation
1. Continue pazopanib at current dose.
2. Check liver function tests (LFTs)1 as per 
protocol
Grade 2 ALT/AST elevation without
bilirubin 
elevation (defined as total bilirubin2 < 1.5 x ULN 
or direct bilirubin ≤35% of total bilirubin) and 
without hypersensitivity symptoms (eg: fever, rash)
1. Continue pazopanib at current dose
2. Consider performing the following to exclude 
hypersensitivity and other contributing factors:

Eosinophil count


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
Viral serology4 for hepatitis A, B and C

Liver imaging (Ultrasound)
3. Monitor patient closely for clinical signs and 
symptoms
4. Perform LFTs1 weekly (or more frequently if 
clinically indicated) until AST/ALT < Grade 1
Grade 3 ALT elevation without bilirubin elevation 
(defined as total bilirubin2 < 1.5 x ULN or direct 
bilirubin ≤35% of total bilirubin) and without 
hypersensitivity symptoms (e.g., fever, rash)
LiverEventInterruption/StoppingCriteria3:
1. Hold pazopanib. Repeat LFTs1 within 72 hrs
to confirm Grade 3 ALT elevation; if 
confirmed:
2. Perform the following assessments to exclude 
hypersensitivity and other contributing factors:

Eosinophil count

Optional viral serology4 for hepatitis A, B, 
C and E, cytomegalovirus4, Epstein Barr 
virus4 (IgM antibody, heterophile antibody, 
or monospot testing)

Liver imaging (Ultrasound)
3. Monitor patient closely for clinical signs and 
symptoms
4. Perform LFTs1 weekly (or more frequently if 
clinically indicated) until ALT reduced to <
Grade 1
5. Pazopanib may be held for up to 14 days, if
ALT returns to Grade 1 and patient is 
benefitting from treatment, pazopanib may be 
resumed at a reduced dose following GSK 
governance approval (contact the Sponsor 
medical monitor via email or phone to start 
the approval process). If approval for re-
treatment is granted, the patient must be re-
consented (with a separate informed consent) 
specific to hepatotoxicity.

For patients on tablets dose reductions are 
as follows:
o
If on 800 mg, then reduce to 400 
mg daily
o
If on 600 mg, then reduce to 400 
mg daily
o
If on 400 mg, reduce to 200 mg 
daily

For patients on suspension:
o
Follow the sequential dose 
reduction (Section 4.1.1.), one dose 
level reduction is required (e.g. 
from 225 mg/m2 to 160 mg/m2)
6. Following re-introduction of pazopanib, 
continue to monitor ALT weekly for 2 cycles, 
if ALT Grade 2 recurs permanently 
discontinue pazopanib


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≥ Grade 2 ALT AND elevation in bilirubin2
(defined as total bilirubin > 1.5 x ULN and direct 
bilirubin >
35%
of
total
bilirubin)
or
with 
hypersensitivity symptoms (e.g., fever, rash)
LiverEventStoppingCriteria3:
1. Discontinue pazopanib permanently
2. Recheck LFT’s1, serum creatinine 
phosphokinase (CPK) and collect PK sample.


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Also check:

Eosinophil count

Optional viral serology4 for hepatitis A, 
B, C and E, cytomegalovirus4, Epstein-
Barr virus4 (IgM antibody, heterophile 
antibody, or monospot testing)

Anti-nuclear antibody4, anti-smooth 
muscle antibody4, anti-mitochondrial 
antibody4

Liver imaging (Ultrasound)
3. Recommend referral to (consult) a pediatric 
gastroenterologist/hepatologist.
4. Monitor patient closely for clinical signs and 
symptoms. Perform full panel LFTs1 weekly or 
more frequently if clinically indicated until 
LFTs are reduced to Grade 1.
For isolated total bilirubin2 elevation without
concurrent ALT increase (defined as ALT < 3 x
ULN).
1. Isolated hyperbilirubinemia (in the absence of
elevated ALT or other signs/symptoms of liver 
injury) does not require dose modification.
Study treatment inhibits UGT1A1 and
OATP1B1, which can cause elevation of 
indirect (unconjugated) bilirubin in the absence
of liver injury.
2. If bilirubin is > 1.5 x ULN in the absence of 
ALT elevation, fractionation of bilirubin 
should be performed. If the bilirubin is 
predominantly indirect (65%) indirect
(unconjugated), continue study treatment at the 
same dose. If bilirubin is >35% direct
(conjugated), study treatment may also be
continued however, further evaluation should 
be undertaken for underlying cause of
cholestasis.
Section 5.4.3 Hepatotoxicity, Revised Text
Adverse events & descriptions
Dose Modifications & Evaluations
Grade 1 ALT/AST elevation
1. Continue pazopanib at current dose
2. Check liver function tests (LFTs)1 as per
Evaluations table in Section 7.1
Grade 2 ALT/AST elevation without
bilirubin 
elevation (defined as total bilirubin2 ≤1.5 x ULN 
or direct bilirubin ≤35% of total bilirubin) and 
without hypersensitivity symptoms (eg: fever, rash)
1. Continue pazopanib at current dose
2. Consider performing the following to exclude 
hypersensitivity and other contributing factors:

Eosinophil count

Viral serology4 for hepatitis A, B and C

Liver imaging (Ultrasound)
3. Monitor patient closely for clinical signs and 
symptoms
4. Perform LFTs1 weekly (or more frequently if 
clinically indicated) until AST/ALT < Grade 1


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Grade 3 ALT elevation without bilirubin elevation 
(defined as total bilirubin2 ≤1.5 x ULN or direct 
bilirubin ≤35% of total bilirubin) and without 
hypersensitivity symptoms (e.g., fever, rash)
LiverEventInterruption/StoppingCriteria3:
1. Hold pazopanib. Repeat LFTs1 within 72 hrs
to confirm Grade 3 ALT elevation; if 
confirmed:


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2. Perform the following assessments to exclude
hypersensitivity and other contributing factors:

Eosinophil count

Optional viral serology4 for hepatitis A, B, 
C and E, cytomegalovirus4, Epstein Barr 
virus4 (IgM antibody, heterophile antibody, 
or monospot testing)

Liver imaging (Ultrasound)
3. Monitor patient closely for clinical signs and 
symptoms
4. Perform LFTs1 weekly (or more frequently if 
clinically indicated) until ALT reduced to <
Grade 1
5. Pazopanib may be held for up to 14 days, if
ALT returns to Grade 1 and patient is 
benefitting from treatment, pazopanib may be 
resumed at a reduced dose following GSK 
governance approval (contact the Sponsor 
medical monitor via email or phone to start 
the approval process). If approval for re-
treatment is granted, the patient must be re-
consented (with a separate informed consent) 
specific to hepatotoxicity.

For patients on tablets dose reductions are 
as follows:
o
If on 800 mg, then reduce to 400 
mg daily
o
If on 600 mg, then reduce to 400 
mg daily
o
If on 400 mg, reduce to 200 mg 
daily

For patients on powder suspension:
o
Follow the sequential dose 
reduction (Section 4.1.1.), one dose 
level reduction is required (e.g. 
from 225 mg/m2 to 160 mg/m2)
6. Following re-introduction of pazopanib, 
continue to monitor ALT weekly for 2 cycles, 
if ALT Grade 2 recurs permanently 
discontinue pazopanib


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≥ Grade 2 ALT AND elevation in bilirubin2
(defined as total bilirubin > 1.5 x ULN and direct 
bilirubin > 35% of total bilirubin) or with
hypersensitivity symptoms (e.g., fever, rash)
LiverEventStoppingCriteria3:
1. Discontinue pazopanib permanently
2. Recheck LFT’s1, serum creatinine 
phosphokinase (CPK) and collect PK sample.
Also check:

Eosinophil count

Optional viral serology4 for hepatitis A, 
B, C and E, cytomegalovirus4, Epstein-
Barr virus4 (IgM antibody, heterophile 
antibody, or monospot testing)

Anti-nuclear antibody4, anti-smooth 
muscle antibody4, anti-mitochondrial 
antibody4

Liver imaging (Ultrasound)


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3. Recommend referral to (consult) a pediatric
gastroenterologist/hepatologist.
4. Monitor patient closely for clinical signs and 
symptoms. Perform full panel LFTs1 weekly or 
more frequently if clinically indicated until 
LFTs are reduced to Grade 1.
For isolated total bilirubin2 elevation without
concurrent ALT increase (defined as Grade 1 ALT
≤3 x ULN).
1. Isolated hyperbilirubinemia (in the absence of
elevated ALT or other signs/symptoms of liver 
injury) does not require dose modification. 
Study treatment inhibits UGT1A1 and 
OATP1B1, which can cause elevation of 
indirect (unconjugated) bilirubin in the absence 
of liver injury.
2. If total bilirubin is > 1.5 x ULN in the absence 
of ALT elevation, fractionation of bilirubin
should be performed.

If the bilirubin is predominantly 
indirect (65%) indirect
(unconjugated), continue study
treatment at the same dose.

If bilirubin is >35% direct 
(conjugated), study treatment may also 
be continued however, further 
evaluation should be undertaken for 
underlying cause of cholestasis.


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Section 5.4.4 Proteinuria, Previous Text

If urinalysis shows ≥trace protein then obtain a urine protein:creatinine ratio (UPC).

If the UPC is ≥ 1, then obtain a 24-hour urine collection for protein estimation.

If the urine protein is ≥3.5 g/24-hours then hold pazopanib and re-assess urine protein weekly.

If the urine protein decreases to < 3.5 g/24 hours in < 21 days then resume pazopanib at a 
reduced dose.

If pazopanib is held for ≥21 days then the patient must be removed from protocol therapy.

Monitor the 24 hour urine protein weekly for 2 consecutive weeks once pazopanib is resumed.
Section 5.4.5 Proteinuria, Revised Text

If urinalysis shows ≥trace protein then obtain a urine protein: creatinine ratio(UPC).

If the UPC is ≥ 1, then obtain a 24-hour urine collection for protein estimation.

If the urine protein is ≥3.5 g/24-hours then hold pazopanib and re-assess urine protein weekly.

If the urine protein decreases to < 3.5 g/24 hours in < 21 days then resume pazopanib at a 
reduced dose.

Monitor the 24 hour urine protein or UPC weekly for 2 consecutive weeks once pazopanib is
resumed.

If pazopanib is held for ≥21 days then the patient must be removed from protocol therapy.
Section 5.4.5.1 Left Ventricular Systolic Dysfunction, Previous Text
Adverse events & descriptions
Dose Modifications & Evaluations
LV EF <LLN but > 50% OR
LV SF <LLN but > 24% without symptoms 
of cardiac dysfunction
Continue drug and repeat Echo on Day 28 of
subsequent cycle
LV EF 40 – 50% OR
LV SF 15 – 24% OR
Absolute decrease in SF of 8 percentage 
points from baseline
Hold pazopanib and obtain repeat Echo in 7
days. If toxicity confirmed, then remove 
from protocol therapy.
If not confirmed, then resume drug at
reduced dose and repeat Echo 14 and 28 days 
after resuming pazopanib. If any 2 Echos 
demonstrate LV EF 50-40% OR LV SF 24-
15% OR > 8 percentage point decrease in SF 
then remove from protocol therapy and refer 
to pediatric cardiologist
Grade 3 LV EF decreased OR
Grade 3 LV SF decreased
Discontinue pazopanib permanently and
remove from protocol therapy – refer to 
pediatric cardiologist
Section 5.4.6.1 Left Ventricular Systolic Dysfunction, Revised Text
Adverse events & descriptions
Dose Modifications & Evaluations
LV EF <LLN but > 50% OR
LV SF <LLN but > 24% without 
symptoms of cardiac dysfunction
Continue drug and repeat Echo on Day 28 of
subsequent cycle
LV EF 40 – 49% OR
Hold pazopanib and obtain repeat Echo in 7


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LV SF 15 – 23% OR
Absolute decrease in SF ≥8 percentage
points from baseline
days. If toxicity confirmed, then remove
from protocol therapy.
If not confirmed, then resume drug at reduced 
dose and repeat Echo 14 and 28 days
after resuming pazopanib. If any 2 Echos 
demonstrate LV EF 49-40% OR
LV SF 23-15%
OR ≥8 percentage point decrease in SF then 
remove from protocol therapy and refer to
pediatric cardiologist
Grade 3 LV EF decreased OR
Grade 3 LV SF decreased
Remove from protocol therapy – refer to
pediatric cardiologist

Cardiac evaluation by Echo but MUGA (Multiple-Gated Acquisition) may be used if clinically 
indicated
Section 5.4.6.2 QT Prolongation, Added Text
Only the Bazett’s formula should be used to calculate the corrected QT interval.
Section 5.4.8 Vascular Thrombosis, Previous Text
Dose Modifications & Evaluations
Grade 2
Continue pazopanib at the current
dose and monitor as clinically 
indicated.
Grade 3 (CVL associated only)
1. Hold pazopanib
2. Initiate treatment with Low 
Molecular
Weight
Heparin 
(LMWH) [Warfarin is allowed 
but INR has to be monitored]
3.
Resume pazopanib at the current 
dose during the period of full-
dose anticoagulation if all of the 
following criteria are met:

The patient must have 
received anti-coagulation for 
at least 1 week

No Grade 3 or 4 hemorrhagic 
events have occurred while on
anticoagulation treatment
4. Patient
should
be
monitored a
clinically
indicated 
during
anticoagulation treatment and
afte
resuming pazopanib
All non-CVL associated Grade 3 AND
all Grade 4
Discontinue pazopanib permanently
and remove from protocol therapy
Section 5.4.9 Vascular Thrombosis, Revised Text
Dose Modifications & 
Evaluations


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Grade 2
Continue pazopanib at the current


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dose and monitor as clinically
indicated.
Grade 3 (CVL associated only)
1. Treat thrombosis according to 
institutional standards; would 
consider removal of the CVL.
2. Resume pazopanib when all 
symptoms have resolved. If
anticoagulation is required, 
use with caution.
All non-CVL associated Grade 3 AND all
Grade 4
Discontinue pazopanib
permanently and remove from 
protocol therapy
Section 6.1 Pazopanib, Previous Text
Pregnancy Category D
There are no adequate and well-controlled studies of pazopanib in pregnant women. If this drug is used 
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of 
the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant
while taking pazopanib.
AgentAccountability
A record of the number of doses of pazopanib suspension taken by the subject at each visit must be 
maintained and reconciled with the study medication and compliance records in the eCRF. At each site visit, 
the cause of any missed doses should be discussed and documented.
Section 6.1 Pazopanib, Revised Text
Pregnancy Category D
There are no adequate and well-controlled studies of pazopanib in pregnant women. Protocol therapy 
should be immediately discontinued if pregnancy occurs while the patient is on therapy. Women of childbearing
potential should be advised to avoid becoming pregnant while taking pazopanib and for up to 30 days after 
stopping pazopanib.
Agent Accountability
A record of the number of milligrams (determined by weight) of pazopanib in oral powder suspension dispensed
to and returned by each patient at each visit must be maintained and reconciled with the study medication and
compliance records in the eCRF. At each site visit, the cause of any missed doses should be discussed and 
documented.
After completion of the study, a final review of accountability records and inventory of unused study medications 
will be performed by the study monitor and site personnel. If the site has received documented approval from
Sponsor, unused study medication may be destroyed, prior to inventory by the study monitor. In this case, the
study monitor would review only study medication accountability records at the end of study visit. Additional
information on the drug accountability process is provided in the Study Procedure Manual.
Section 7.1 Required 
 Clinical, Laboratory and Disease Evaluations, Revised Table

Added Survival Follow-up visit

Added Performance Status to be done on Cycle 1 Day 1

Clarified frequency of the following assessments: CBC, differentials, platelets, electrolytes, creatinine, 


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ALT, bilirubin, amylase, lipase, total protein, albumin, PT, PTT, INR
Section 7.2.1 Growth Plate Toxicity, Previous Text

Patients with evidence of growth plate thickening or other changes should have a knee MRI performed 
to further assess the degree of physeal pathology and undergo more frequent x-ray follow up. MRI 
should be performed without contrast.

Patients with knee MRI changes should be managed in an individualized manner. Decisions
regarding continuation of pazopanib should take into account the presence of any symptoms referable
to the knee as well as the patient’s response to pazopanib. Consultation with an orthopedic surgeon
may also be indicated. Plans for follow-up imaging will also be made on an individualized basis, 
taking into account the presence of symptoms at the knee or other joints as well as the decision to
continue pazopanib or not.
Section 7.2.1 Growth Plate Toxicity, Revised Text

Patients with evidence of growth plate thickening or other changes should have a knee MRI performed
to further assess the degree of physeal pathology and undergo more frequent x-ray follow up. MRI
should be performed without contrast. If no MRI changes are seen, x-rays may be performed 
approximately every 2 months.

Patients with knee MRI changes should be managed in an individualized manner. Decisions regarding
continuation of pazopanib should take into account the presence of any symptoms referable to the
knee as well as the patient’s response to pazopanib. Consultation with an orthopedic surgeon may also
be indicated. Plans for follow-up imaging will also be made on an individualized basis, taking into
account the presence of symptoms at the knee or other joints as well as the decision to continue 
pazopanib or not. Consultation with orthopedics and with the Study Chair is advised.
Section 7.2.4 Pregnancy Testing and Reporting, Added Text
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related to the 
study treatment by the investigator, will be reported to the Sponsor. While the investigator is not obligated to
actively seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Section 7.3.2 Sampling schedule, Previous Text
All patients will have a blood sample for analysis of the plasma pazopanib concentration collected: prior to
the first dose in Cycle 1; and on Day 15 ± 1 day of Cycle 1, both prior to dosing and 3-4 hours after dosing.
Additional blood samples for analysis of steady-state trough plasma pazopanib concentrations will be
obtained prior to the start of every odd cycle. Thepre-dosesampleonDay 15,Cycle1and troughplasma
concentrationsshouldbeobtainedbetween 22-26 hours after the previous dose of pazopanib. Subjects 
should be instructed to hold their dose of pazopanib on the day that a pre-dose concentration is to be collected. 
These specimens should correspond to the timing of routine laboratory evaluations.
Extended pharmacokinetic sampling will be done in the first 6 patients enrolled (who receive the suspension
formulation). These patients will have a blood sample for analysis of the plasma pazopanib concentration
collected at the following time points on Day 1 of Cycle 1: pre-dose, 30 min, 1 hour, 2 hours, 4 hours, 6
hours, and 8 hours after the dose. Samples will also be obtained on Day 15 ± 1 day of Cycle 1: pre-dose, 30
min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose. For all patients additional blood samples
for analysis of steady-state trough plasma pazopanib concentrations will be obtained prior to the start of every
odd cycle. Thepre-dosesampleonDay15,Cycle1 andtrough plasma concentrations should be obtained
between 22-26 hours after the previous dose of pazopanib. Subjects should be instructed to hold their dose
of pazopanib on the day that a pre-dose concentration is to be collected. These specimens should correspond 
to the timing of routine laboratory evaluations.


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Section 7.3.2 Sampling schedule, Revised Text
All patients (whether receiving pazopanib as tablet or as oral powder suspension) will have a blood sample for 
analysis of the plasma pazopanib concentration collected prior to the first dose on Day 1 of Cycle 1. In addition,
all patients will have 2 blood samples collected on Day 15 ± 1 day of Cycle 1: one sample prior to the dose and 
one sample 3-4 hours after dosing.
Blood samples for analysis of steady-state trough plasma pazopanib concentrations will also be obtained prior
to the start of every subsequent odd-numbered cycle (that is, pre-dose prior to Cycle 3, pre-dose prior to Cycle
5, etc). These steady-state trough plasma concentration samples can be collected between Day 22 of the
previous cycle to Day 1 of the odd-numbered cycle, and the actual date and time of sample collection 
recorded on the PK sample collection form.
The pre-dose sample on Day 15 ± 1 day of Cycle 1 and the trough plasma concentration samples takenprior
to dosing for every odd-numbered cycle should be obtained between 22-26 hours after thepreviousdoseof
pazopanib. Patients should be instructed to hold their dose of pazopanib on the day that a pre-dose PK sample
is to be collected. Collection of these PK samples should correspond to the timing of routine laboratory 
evaluations.
Extended PK sampling will be done during Cycle 1 in the first patients who receive the powder suspension 
formulation, until 6 patients are considered evaluable for the PK analysis. These patients will have a blood 
sample for analysis of the plasma pazopanib concentration collected at the following time points on Day 1 of
Cycle 1: pre-dose and at 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose. Samples will also
be obtained on Day 15 ± 1 day of Cycle 1: pre-dose and at 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours
after the dose. If one or more of these 6 patients fail to provide blood samples as specified in the protocol or if 
it is known that for some reason a patient’s collected blood sample(s) cannot be analyzed, that patient(s) will
be determined to be non-evaluable for this analysis and one or more additional patients will be enrolled for 
treatment with pazopanib as powder for oral suspension and provision of the extended PK samples. These
patients will also provide blood samples for analysis of steady-state trough plasma pazopanib concentrations 
prior to the start of every subsequent odd-numbered cycle as described in the preceding paragraph.
Pazopanib dosing of either tablet or powder suspension must have continued uninterrupted and at the same dose 
level for at least 10 days prior to acquisition of the Cycle 1 Day 15 PK samples. If pazopanib dosing has been
interrupted or modified <10 days prior to Cycle 1 Day 15, then the PK samples should be taken between Cycle
1 Day 15 and Cycle 1 Day 22 on a study day that meets the condition of at least 10 consecutive days of dosing
at the same dose level. The Cycle 1 Day 15 PK kit should be used and the actual date and time of sample 
collections should be recorded in the eCRF.
If ≥2 out of 6 evaluable patients have dose-limiting toxicities as defined in Section 5.1) during the first cycle, 
then enrollment at the 225 mg/m2/dose dose level of pazopanib oral suspension will be halted. Subsequent new 
patients will be enrolled at the 160mg/m2/dose level until 6 evaluable patients from this dose group are available 
for the safety review and 6 patients are available for PK analysis.


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Section 8.1 Criteria for Removal From Protocol Therapy, Previous Text
a) Progressive disease.
b) Adverse Events requiring removal from protocol therapy, as stated in Section 5.
c)
Patients who receive concurrent anticancer or investigational therapy, as stated in Section
3.3.2.
d) Patients who require major surgery during Cycle 1, as stated in Section 5.4.6 e) 
Refusal of further protocol therapy by patient/parent/guardian.
f)
Completion of two years of therapy.
g) Physician determines it is in patient’s best interest.
h)
Repeat eligibility studies (if required) are outside the parameters required for continued dosing 
as stated in Section 4.2.
i)
Non-compliance that in the opinion of the investigator does not allow for ongoing
participation.
j)
Patients who develop a second malignant neoplasm.
k) Patient becomes pregnant
Patients who are removed from protocol therapy (except for 8.1.h) are to be followed for a maximum
of five years or until they meet at least one of the criteria for Off Study (see below). Follow-up data
will be required unless consent was withdrawn.
Section 8.1 Criteria for Removal From Protocol Therapy, Revised Text
Patients will be permanently discontinued of protocol therapy if any of the following occur:
a)
Progressive disease


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b)
Adverse Events requiring removal from protocol therapy, as stated in Section 5.
c)
Concurrent use of other anticancer or investigational therapy, as stated in Section 3.3.2. d)
Requirement for major surgery during Cycle 1, as stated in Section 5.4.7
e)
Refusal of further therapy by patient/parent/guardian
f)
Physician determines it is in patient’s best interest
g)
Major protocol deviations including non-compliance h)
Development of a second neoplasm
i)
Pregnancy
Section 8.2 Follow-up assessments after Removal From Protocol Therapy, Added Text
Patients who are removed from protocol therapy are to be followed until they meet at least one of the criteria for
withdrawal from study (see Section 8.3). Survival Follow-up data will be required unless consent was 
withdrawn.
Safety follow-up:
All patients will be followed for adverse events and serious adverse events for 28 days after last dose.
Survival follow-up:
The following information will be collected and reported every 3 months:

Survival status

Antineoplastic therapies taken since discontinuation of protocol therapy
The primary reason protocol therapy was permanently discontinued must be documented in the patient’s medical
records and eCRF. If the patient discontinues from protocol therapy due to toxicity, AE will be recorded as
the primary reason for permanently discontinuation on the eCRF. Once a patient has permanently discontinued
protocol therapy, the patient will not be allowed to be retreated.
Section 8.2 Off Study Criteria, Previous Text
a) Death.
b) Lost to follow-up.
c) Entry into another study with tumor therapeutic intent (e.g., at recurrence).
d) Withdrawal of consent for any further data submission. e)
The study is closed for any reason.
Section 8.3 Criteria for Withdrawal from Study, Revised Text
Patients will be withdrawn from the study if any of the following occur:
a)
Death
b)
Lost to follow-up
c)
Withdrawal of consent for follow-up
d)
The study is closed/ terminated e)
Investigator discretion
Section 9.1 Sample Size and Study Duration, Deleted Text
If activity is detected in any category, further trials in subcategories of the category may be conducted at the 
discretion of the Developmental Therapeutics Steering and study committees.
Section 9.3 Analysis Populations, Previous Text
The Target Intent-to-Treat (tITT) population will comprise all subjects entered into the study at the target
dose. If after the first 6 subjects, the suspension dose is de-escalated to 160 mg/m2/dose then only the 160 
mg/m2/dose subjects will be included in the tITT. All subjects taking the tablets will be included in the tITT.


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The Per Protocol (PP) population will be a subset of the ITT population which will exclude subjects with major 
protocol violations. What constitutes a major protocol violation will be fully described in the Reporting and 
Analysis Plan (RAP).
The Safety population will comprise all subjects in the ITT population who receive at least one dose of 
investigational product. The safety population will be used for the analysis of safety data.
Section 9.3 Analysis Populations, Revised Text
The modified Intent-to-Treat (mITT) population is the primary analysis population. The mITT will consist
of all patients who have received at least one dose of protocol therapy.
The Safety population will comprise all patients in the mITT population. The safety population will be used 
for the analysis of safety data.
The Pharmacokinetic population will comprise all patients in the mITT population for whom a pharmacokinetic 
sample is obtained and analyzed. The Pharmacokinetic Extended Sampling population will comprise all subjects
in the Pharmacokinetic population who received powder suspension and have at least one non-predose sample
collected and analyzed using the extended sampling schedule in Section 7.3.2.
Section 9.4 Analysis Data Sets, Previous Text
The primary data set for assessing efficacy will comprise the target intent-to-treat population.
Section 9.4 Analysis Data Sets, Revised Text
The primary data set for assessing efficacy will comprise the modified intent-to-treat population.
Section 9.6 Interim Analysis, Previous Text
No formal interim analysis is planned outside of the study design. The study team will review safety data 
periodically over the course of the study.
Expansion of tumor specific cohorts will be done when there is at least one investigator determined confirmed
response in that cohort/strata within the first 10 enrolled patients. The time point for the decision to
expand will be the earliest of the following: an investigator determined confirmed response within the first
10 pts, the time when the first 10 patients are no longer eligible for obtaining a response (i.e., 18 weeks
have elapsed and a response is unlikely, has progressed, has discontinued therapy, has withdrawn consent).
Therefore, the clinical cut off for analysis purposes per cohort/strata, will be the earliest of 18 weeks from 
last subject first visit, all subjects have documented radiological progression or withdrawn consent from the 
study.
Section 9.6 Primary Analysis and End of Study Analysis, Revised Text
No formal interim analysis is planned outside of the study design. The study team will review safety data 
periodically over the course of the study.
Expansion of tumor specific cohorts will be done when there is at least one investigator determined confirmed
response in that cohort within the first 10 enrolled patients. A given tumor specific cohort will not be expanded 
if all the patients in the cohort have:

Progressed

Discontinued therapy

Withdrawn consent

Been determined to be lost-to-follow-up

Or have been treated for at least 20 weeks, making it unlikely that a response 


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will occur.
The primary analysis will be performed 20 weeks after the last patient’s first visit in the three cohorts of primary
interest (rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma and Ewing sarcoma/peripheral 
PNET).
The study will be completed one year from the date of the last patient’s first visit and the end of study 
analysis will be performed at the time of study completion.
Any additional data collected after the primary analysis will be included in a supplementary analysis and 
reported in a final Clinical Study Report.
Section 9.7.2 Missing Data, Deleted Text
If a progression event occurs after an extensive lost-to-follow-up time (greater than 8 weeks) the primary
analysis will censor those subjects at the date of their last adequate disease assessment.
Section 9.8.1 Primary Endpoint: Objective Response Rate, Previous Text
Confirmation will be based on the next scheduled disease assessment after the initial response.
Section 9.8.1 Primary Endpoint: Objective Response Rate, Revised Text
Confirmation will be based on the disease assessment performed 1 cycle after the initial response. The 
objective response rate will be computed for the 3 tumor types of primary interest.
Section 9.8.2.3 Progression-free survival (PFS) and overall survival (OS), Added Text
Overall survival is defined as the time from the first dose of the study medication until death due to any cause. 
The OS analysis will be performed on the mITT population and summarized using a Kaplan-Meier survival
curve. The Kaplan-Meier estimate for the median OS time and the first and third quartiles will be presented,
along with a naive approximate 90% confidence interval if there are a sufficient number of deaths.
Section 9.8.2.4 Clinical Benefit, Previous Text
This is defined as the percentage of subjects achieving either a complete or partial tumor response or stable 
disease for at least 16 weeks as per RECIST criteria.
Section 9.8.2.4 Clinical Benefit, Revised Text
This is defined as the percentage of patients achieving either a complete or partial tumor response or stable 
disease for at least two protocol scheduled disease assessments as per RECIST criteria.
Section 9.8.2.5 Other Safety Measures, Previous Text
Vital signs (blood pressure, heart rate, temperature) and weight will be listed for each subject and change
from baseline will be included for blood pressure and heart rate.
Section 9.8.2.5 Other Safety Measures, Revised Text
Vital signs (blood pressure, heart rate, temperature), height and weight will be listed for each patient and
change from baseline will be included for blood pressure and heart rate.
Section 9.9 Evaluability for Response, Previous Text
Response will be determined on the target intent to treat (tITT) population consisting of all patients 
enrolled into the study at the target dose.
In addition, response will be determined using a modified ITT (mITT) consisting of patients who are 
eligible and received at least one dose of study drug.
Section 9.9 Evaluability for Response, Revised Text
Response will be determined on the modified intent to treat (mITT) population consisting of all patients 
who are eligible and received at least one dose of protocol therapy.


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Section 9.10 Evaluability for Toxicity, Deleted Text
All patients who receive at least one dose of pazopanib will be considered in the evaluation of 
toxicity.
Monitoring for Excessive Toxicity
A patient will be considered for toxicity monitoring if one of the following occurs: (1)
complete one cycle of pazopanib; (2) die on protocol therapy for a reason considered possibly,
probably or likely related to pazopanib; or (3) are removed from protocol therapy because of an adverse 
experience possibly, probably or likely related to pazopanib. A toxicity-evaluable patient will be considered
in the analysis during the interval from study enrollment until protocol therapy is terminated or a dose-
limiting toxicity is observed. A toxicity-evaluable patient will be considered to have experienced an
excessive toxicity event if: (1) the patient dies on protocol therapy for a reason considered possibly,
probably or likely related to pazopanib; or (2) experiences a dose- limiting toxicity.
The analytic unit for monitoring for excessive toxicity will be the patient-cycle: Each cycle where the 
patient receives at least 24 doses of pazopanib (approximately 85% of planned therapy) or where an 
excessive toxicity event is observed will be considered in the analysis. Onar-Thomas and Xiong 
demonstrate that, over typical dose-toxicity relationships the Rolling-6 methodology identifies, with 
probability approximately 95%, an MTD with a first-cycle-DLT probability less than or equal to 
30%.44 If there is overwhelming evidence that the dose selected for this trial has a per-cycle- DLT
probability of more than 30%, we will identify the regimen to the COG Phase I and II DSMC, DVL
leadership and CTEP as associated with a toxicity profile that may require modification of the regimen.
We will use a Bayesian rule to monitor for excessive toxicity.45,46 We will assume a beta prior 
distribution with α=0.6 and β=1.4. At least once per month, we will calculate:
Where n is the number of excessive-toxicity-evaluable cycles and x is the number of such cycles on which
an excessive toxicity event is observed. If this posterior probability exceeds 80%, we will identify the
regimen to the COG Phase I and II DSMC, DVL leadership and CTEP as associated with a toxicity profile
that may require modification of the regimen. Examples of situations in which this rule will indicate 
excessive toxicity have been noted and are presented below:
Number of Toxicity-
Evaluable Cycles
Number of Cycles with
Excessive Toxicity
Observed
P (pExcessive Toxicity > 0.30|Data)
5
3
0.92
10
5
0.87
15
7
0.89
20
8
0.81
25
10
0.80
30
12
0.80


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13
0.80
40
15
0.83
Section 9.12 Analysis of the Pharmacokinetic Parameters, Previous Text
Plasma pazopanib concentrations observed after administration of the suspension in the first 6 subjects
enrolled in the study will be analyzed with standard noncomparetmental methods using
WinNonlin version 5.2 or higher. The parameters maximum plasma pazopanib concentration (Cmax), the
time to Cmax (tmax), and the area under the curve (AUC) from zero to the time of the last quantifiable
concentration (AUC(0-t)) will be calculated, The AUC from zero to 24 hours after
administration (AUC(0-24)) on Day 15 will be calculated by using the predose plasma pazopanib 
concentration for the concentration 24 hours after dosing.
A mixed-effects model generated with data from adult subjects with solid tumors will be fit to the plasma
pazopanib concentration-time data to generate post-hoc estimates of pharmacokinetic parameters using 
NONMEM VII. The post-hoc estimates of pharmacokinetic parameters will be compared to the parameters
generated from data in adult subjects with cancer.
The change in plasma trough pazopanib concentrations will be characterized at the first cycle and each odd cycle
after the first. The effect of cycle on change in plasma trough concentrations will be assessed by fitting the 
parametric model:
Section 9.11 Analysis of the Pharmacokinetic Parameters, Revised Text
Plasma pazopanib concentrations observed in the first 6 patients who receive pazopanib as powder for oral 
suspension and are evaluable for pharmacokinetics will be analyzed with standard noncompartmental methods
using WinNonlin version 5.2 or higher. Parameter values for maximum plasma pazopanib concentration (Cmax),
the time to Cmax (tmax), and the area under the curve (AUC) from zero to the time of the last quantifiable
concentration (AUC(0-t)) will be calculated. The AUC from zero to 24 hours after administration (AUC (0-24))
on Day 15 will be calculated by using the predose plasma pazopanib concentration as the concentration 24 hours 
after dosing. The analysis to assess pazopanib pharmacokinetics after administration of the suspension prior to
continuing
enrollment
on
suspension
may be
performed
using
scheduled time. Calculations
of
noncompartmental parameter values for the final analysis will be based on actual sampling times.
Plasma pazopanib concentration values at each sampling occasion will be summarized by cohort as well as 
after combining the data from all cohorts, separately for each formulation and each dose level, if needed. 
In addition, plasma pazopanib concentration values at each sampling occasion will be summarized by age 
subgroups (2 to <12 years old, 12 to 18 years old) for each formulation and dose level, if needed. This 
analysis will combine data across all disease cohorts unless pharmacokinetic differences between the cohorts 
are observed.
The pharmacokinetic parameter values in the patients with extended sampling will be summarized for 
Cycle 1 Day 1 and Cycle 1 Day 15, combining data from all patients, separately by dose level, if needed.
Section 9.12 Analysis of Biological and Correlative Endpoints, Deleted Text
Objective 1.2.3 will be assessed by examining the change in biological parameter between the samples 
taken on Days 1 and 15. Initially, such analyses will not be segregated by tumor type. The null hypothesis 
H0: No change in median value of the biological parameter between Day 1 and 15 will be assessed by the 
Wilcoxon signed rank test. The power associated with this test as a function of the variability of the biological 
parameter and patients contributing to the analysis is summarized in the following table:
Number
of
Paired
Specimens Available
True Difference in Pre- vs. Post
Median Measurement (Multiples of 
the
Standard
Deviation
of
the
Measurement)
Power Using a Two-Sided
Test of Size 0.05


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2σ
0.85
50
2σ
0.92
60
2σ
0.96
No adjustment will be made for multiple comparisons for this exploratory analysis. The changes in biological
measures may be examined within particular disease types, but such results will not have sufficient precision 
to make definitive conclusions if the null hypothesis is not rejected.
The effect of genotype on change in biological parameter will be assessed by fitting the parametric model:
y y ' x ;~ N0,2 
i2
0
1
i1
2
i
i
i
where y2i is thepost-treatment valuefor thebiologicalmeasure
yi1 isthepre-treatment valuefor thebiologicalmeasure
xi isthe(categorized)SNPobserved
arethetrueeffect of initialbiological measurelevelandSNP


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The sensitivity for detection of a particular true treatment effect will depend on departures from
normality in the distribution of the characteristic and the number of pairs that will contribute to the 
analysis.
Section 10.8 Survival Follow-up, Added Text
Patients who have discontinued protocol therapy will be followed for Survival status. The investigator site 
will collect and report Survival follow-up in the eCRF every 3 months, which would include the patient’s 
survival status and any antineoplastic therapies taken since discontinuation of protocol therapy, until death, 
lost to follow-up, or withdrawal of consent from survival follow-up occurs or final cut-off for survival 
analysis.
The date and cause of death should be recorded in the eCRF.
Section 11 Adverse Event (AE) and Serious Adverse Event (SAE), Previous Text
AEs will be collected from the start of Study Treatment and until completion of the final 30 day study 
visit.
Section 11 Adverse Event (AE) and Serious Adverse Event (SAE), Revised Text
AEs will be collected from the start of protocol therapy and until 28 days following last dose of protocol
therapy.
Medical occurrences that begin prior to the start of protocol therapy but after obtaining informed consent 
should be recorded on the Medical History/Current Medical Conditions section of the eCRF.
Any new primary cancer must be recorded as an SAE and will be recorded from the time a patient
consents to participate in the study up to and including any follow-up contact.
Section 11.2 Definition of Serious Adverse Events (SAEs), Previous Text
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 3xULN and
bilirubin 1.5x ULN (>35% of total bilirubin is direct) or ALT 3xULN and INR>1.5, if INR measured 
termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply 
to subjects receiving anticoagulants).
Section 11.2 Definition of Serious Adverse Events (SAEs), Revised Text
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT > 3xULN and
bilirubin > 1.5x ULN (>35% of total bilirubin is direct) or ALT > 3xULN and INR>1.5, if INR measured 
termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply 
to patients receiving anticoagulants).
Section 11.4 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs, 
Added Text
An event which is part of the natural course of the disease under study (i.e., disease progression or
hospitalization due to disease progression) does not need to be reported as an SAE. Death due to disease 
under study is to be recorded on the Death eCRF form. However, 
if 
the 
underlying 
disease 
(i.e., 
progression) is greater than that which would normally be expected for the patient, or if the investigator 
considers that there was a causal relationship between treatment with study medication(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE.
Section 11.5 Recording of AEs and SAEs, Deleted Text
Subject-completed health outcomes questionnaires and the collection of AE data are independent 
components of the study. Responses to each question in the health outcomes questionnaire will be 
treated in accordance with standard scoring and statistical procedures detailed by the scale’s developer. 


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The use of a single question from a multidimensional health survey to designate a cause-effect relationship 
to an AE is inappropriate.
Section 12.1 Data and Safety Monitoring, Previous Text

The study team, which includes the GSK Medical Monitor, representatives from the Clinical
Pharmacology/Modelling and Simulations Group, the safety review team (SRT), and the COG
protocol chair will review and discuss safety data at periodic intervals throughout the duration of 
the study

The entire pazopanib development program utilizes an internal SRT that is independent from study
teams. The remit of the SRT is to periodically review the safety data across clinical trials in order
to protect and enhance patient safety. The SRT provides a central and dedicated forum for review
of emerging data that could impact patient safety. All safety-related issues and safety outputs from
this study will be sent to the SRT for review and discussion. If safety issues are identified within 
the SRT forum these will be escalated as required.
Section 12.1 Data and Safety Monitoring, Revised Text

The study team, which includes the Medical Monitor, representatives from the Clinical 
Pharmacology Group, and the COG protocol chair will review and discuss safety data at periodic 
intervals throughout the duration of the study
Appendix IA: Patient Diary for Pazopanib Tablets, Previous Text
Please write the date, time and dose of pazopanib given. Please make note of all prescription medications,
nonprescription medications, and herbal remedies you take. Return the completed diary to your institution 
after each treatment cycle.
Appendix IA: Patient Diary for Pazopanib Tablets, Revised Text
Please write the date, time and dose of pazopanib given. Please make note of all prescription medications,
nonprescription medications, and herbal remedies you take. Also, please remember to take the tablets at least 1
hour before or 2 hours after a meal. Return the completed diary to your institution after each treatment 
cycle along with any unused study medication or empty study medication bottles.
Appendix IB: Patient Diary for Pazopanib Powder in Suspension, Previous Text
Return the completed diary to your institution after each treatment cycle.
Appendix IB: Patient Diary for Pazopanib Powder in Suspension, Revised Text
Return the completed diary to your institution after each treatment cycle along with all the bottles of study 
medication, even empty.
Appendix II: Pazopanib Dosing Nomogram for Tablets, Previous Text
Dosing Nomogramfor Starting Dose of 450 mg/m2/dose and for Dose Reductions if required
Starting Dose
Dose Reduction
#1
Dose Reduction
#2
450 mg/m2/dose
BSA*
Dose (mg)†
0.84 -0.94
400
200
0
0.95-1.05
400
200
0
1.06-1.16
400
200
0
1.17-1.27
600
400
200
1.28-1.38
600
400
200
1.39-1.50
600
400
200


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1.51-1.61
600
400
200
1.62-1.72
800
600
400
> 1.73
800
600
400


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Appendix II: Pazopanib Dosing Nomogram for Tablets, Revised Table
Dosing Nomogram for Target Starting Dose of 450 mg/m2/dose and for Dose Reductions if required
Starting Dose
Dose Reduction
#1
Dose Reduction
#2
Target :
450 mg/m2/dose
BSA* 
Dose (mg)†
0.84-1.16
400
200
0
1.17 -1.61
600
400
200
≥ 1.62
800
600
400
Appendix VI: Pharmacokinetic Study Form, Revised Form
PK form revised to capture date/time of dose given on PK sampling days and date/time of PK 
sample collection
Appendix VII: Instructions to Patient/Caregiver for Administering Pazopanib Suspension, Previous
Text
1. Insert the provided adapter (Baxa 28 mm Press-In-Bottle Adapter - PIBA®) into the neck of 
the bottle.
2. Immediately prior to removal of dose for administration, mix the contents of the bottle by swirling
for 30 seconds to one minute in order to ensure homogeneity of suspension.
3.
Insert the tip of a suitable graduated syringe (recommended: Exacta-Med® Baxa) into the
Adapter after ensuring that the syringe plunger is pushed fully into the barrel.
4. Invert the bottle and dispense at least 5 mL of suspension into the syringe. Then push it back into 
the bottle in order to purge the syringe of any air bubbles. Repeat this step until syringe is free of air 
bubbles.
5. Withdraw the prescribed dose. Investigator/study staff will fill in the dose below for each patient.
The dose is 
mg = mL each day.
Appendix VII: Instructions to Patient/Caregiver for Administering Pazopanib Oral Suspension, 
Revised Text
1. The pharmacist should insert the provided adapter (Baxa 28 mm Press-In-Bottle Adapter -
PIBA®) into the neck of the bottle. Once the adapter has been placed into the bottle neck, DO 
NOT REMOVE.
2. Immediately before planned dose administration, mix the contents of the bottle by swirling for 30 
seconds to one minute in order to ensure homogeneity of suspension.
Note#1: Women who are pregnant or nursing should put on a suitable size of gloves to avoid
contact between the liquid and skin (Latex gloves can be used; however, for people who are 
sensitive to latex, it is recommended to use Nitrile gloves). Take care not to spread material to 
unprotected skin (such as your face) or other body surfaces by touching them with a wet glove. 
Note#2: In case of spillage, see section C for Clean-up instructions.
3. Insert the tip of an appropriate syringe (recommended: Exacta-Med® Baxa) into the Adapter after 
ensuring that the syringe plunger is pushed fully into the barrel.
4. Tip the bottle upside down and dispense at least 3-5 mL of suspension into the syringe. Then push
the suspension back into the bottle in order to purge the syringe of any air bubbles. Repeat this 
step until syringe is free of air bubbles.
5. Withdraw the prescribed dose. Investigator/study staff will fill in the dose below for each patient.
The dose is mg, corresponding to mL each day.


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Please note that the number of milligrams of pazopanib and, therefore, the number of milliliters of 
pazopanib oral suspension may change as the body surface area of the patient changes during 
study participation.
Appendix VIII: Youth Information Sheets, Previous Text
This 28 day regimen may be repeated for up to 2 years (you would receive pazopanib continuously).
Appendix VIII: Youth Information Sheets, Revised Text
This 28 day regimen may be repeated until you benefit from treatment or until study closure.


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13.14
APPENDIX XII AMENDMENT 04
Amendment Summary of Main Changes:
Section(s)
Change
Rationale
Title page
Title page replaced as per 
Novartis requirements
Change in study sponsorship from GSK to 
Novartis
Sponsor 
Information Page
GSK contact information 
has been replaced with 
Novartis details
Change in study sponsorship from GSK to 
Novartis
Sponsor signatory
Change of sponsor 
signatory
Change in study sponsorship from GSK to 
Novartis
Multiple
The term ‘GSK medical 
monitor’ has been replaced 
by Novartis Medical Lead 
To align with the change of sponsorship from 
GSK to Novartis.
Multiple
Delete or replace references 
to GlaxoSmithKline or its 
staff with that of Novartis 
and its authorized agents
To align with the change of sponsorship from 
GSK to Novartis. 
Multiple
Make administrative 
changes
To align with the change of sponsorship from 
GSK to Novartis.
Section: 3.1.1, Patient Registration
Original Text:
No study-specific procedure will start before  the signature of the informed consent  form (and assent,  
according  to institutional  guidelines),  defining  the study entry.
Prior to enrollment on study, patients must be  assigned a COG patient ID number. This number is
obtained once authorization for the release of protected health information (PHI) has been obtained. The COG
patient ID number is used to identify the patient in all future interactions with COG. If you have problems 
with registration, please refer to the online help.
Upon completion of all required baseline assessments, the investigator or authorized site staff will assign each
eligible patient a Sponsor study-specific patient identification number. Each site will be assigned a range of
patient numbers, and this information is provided in the Study Procedure Manual (SPM). The patient ID
number consists of 6 digits including leading zeros. Using this patient ID number and patient’s histology cohort 
(rhabdomyosarcoma, non- rhabdomyosarcomatous soft tissue sarcoma, Ewing sarcoma/peripheral PNET, 
osteosarcoma, neuroblastoma (measureable), neuroblastoma (evaluable) or hepatoblastoma), each patient will 
then be registered into the interactive voice response system RAMOS (Registration and Medication Ordering 
System). RAMOS will then provide an identification number consistent with the patient’s tumor type.
All calls to RAMOS are confirmed (with a fax or e-mail), which will be sent to the site upon completion of
each call. Study-specific instructional worksheets will be provided for the use of RAMOS in the Study 
Procedures Manual.
Revised Text:
No study-specific procedure will start before  the signature of the informed consent  form (and assent,  
according  to institutional  guidelines),  defining  the study entry.


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Prior to enrollment on study, patients must be  assigned a COG patient ID number. This number is
obtained once authorization for the release of protected health information (PHI) has been obtained. The COG
patient ID number is used to identify the patient in all future interactions with COG. If you have problems 
with registration, please refer to the online help.
Upon completion of all required baseline assessments, the investigator or authorized site staff will assign each
eligible patient a Sponsor study-specific patient identification number. Each site will be assigned a range of
patient numbers, and this information is provided in the Study Procedure Manual (SPM). The patient ID
number consists of 6 digits including leading zeros. Using this patient ID number and patient’s histology cohort 
(rhabdomyosarcoma, non- rhabdomyosarcomatous soft tissue sarcoma, Ewing sarcoma/peripheral PNET, 
osteosarcoma, neuroblastoma (measureable), neuroblastoma (evaluable) or hepatoblastoma), each patient will 
then be registered into the interactive webvoice response system (IWRS) RAMOS (Registration and
Medication Ordering System). The IWRS RAMOS will then provide an a randomization identification
number consistent with the patient’s tumor type.
All sessions calls to IWRSRAMOS are confirmed with an on screen confirmation (with a fax or e-
mail), which will also be sent via email to the site upon completion of each call. Study-specific
instructionsal worksheets will be provided for the use of IWRSRAMOS in the Study Procedures Manual 
and in the user manual.
Section: 3.1.5, Study Enrollment
Original Text:
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Specific
procedures related to the requirements for patient enrollment are described in protocol Section 3 and in the
Study Procedures Manual. Sites will be required to complete a call into RAMOS (IVRS) to record patient
information as described in Section 3.1.1.
Revised Text:
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Specific
procedures related to the requirements for patient enrollment are described in protocol Section 3 and in the
Study Procedures Manual. Sites will be required to complete a sessioncall into the (IWRS)RAMOS (IVRS)
to record patient information as described in Section 3.1.1.
Section: 7.2.4, Pregnancy Testing and Reporting
Original Text:
The need for a screening pregnancy test depends on whether a female patient is of childbearing potential or
non-childbearing potential. If a female patient is of childbearing potential, she must have a serum -Human
Chorionic Gonadotropin (%-HCG) pregnancy test performed within 7 days prior to the first dose of study 
treatment(s). Patients with a positive pregnancy test result must be excluded from the study. Patients with a 
negative pregnancy test result must agree to use an adequate contraception method as described below during
the study until 30 days following the last dose of study treatment(s). Any pregnancy that occurs during study
participation must be reported using a clinical trial pregnancy form. To ensure patient safety, each 
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. Study treatment should be 
immediately discontinued if pregnancy occurs during study participation. 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 (Section 
11.8). Spontaneous abortions must be reported as an SAE.


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Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the patient
has completed the study and considered by the investigator as possibly related  to the study treatment(s) 
must be promptly reported to GSK.
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related to the study
treatment by the investigator, will be reported to the Sponsor. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through spontaneous 
reporting.
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 GSK as described above.
Revised Text:
The need for a screening pregnancy test depends on whether a female patient is of childbearing potential or
non-childbearing potential. If a female patient is of childbearing potential, she must have a serum -Human
Chorionic Gonadotropin (%-HCG) pregnancy test performed within 7 days prior to the first dose of study 
treatment(s). Patients with a positive pregnancy test result must be excluded from the study. Patients with a 
negative pregnancy test result must agree to use an adequate contraception method as described below during
the study until 30 days following the last dose of study treatment(s). Any pregnancy that occurs during study
participation must be reported using a clinical trial pregnancy form. To ensure patient safety, each 
pregnancy must be reported to NovartisGSK within 24 hours 2 weeks of learning of its occurrence. Study 
treatment should be immediately discontinued if pregnancy occurs during study participation. 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 
(Section 11.8). Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after the patient
has completed the study and considered by the investigator as possibly related  to the study treatment(s) 
must be promptly reported to NovartisGSK.
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related to the study
treatment by the investigator, will be reported to the Sponsor. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through spontaneous 
reporting.
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 NovartisGSK as described above.
Section: 11, Adverse Events (AE) and Serious Adverse Events (SAE)
Original Text:
The investigator or site staff is responsible for detecting, documenting and reporting events that meet the
definition of an AE or SAE.
!
AEs will be collected from the start of protocol therapy and until 28 days following last dose of protocol
therapy.
!
SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed


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as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or 
change in existing therapy) or related to a GSK product will be recorded from the time a patient consents  
to participate  in the study  up to and including any follow-up contact.

Medical occurrences that begin prior to the start of protocol therapy but after obtaining informed consent
should be recorded on the Medical History/Current Medical Conditions section of the eCRF.

Any new primary cancer must be recorded as an SAE and will be recorded from the time a patient consents 
to participate in the study up to and including any follow-up contact.

All SAEs will be recorded and reported to GSK and COG within 24 hours, as indicated in Section 11.8.

Investigators are not obligated to actively seek AEs or SAEs in former study participants.

However, if the investigator learns of any SAE, including a death, at any time after a patient has been
discharged from the study, and he/she considers the event reasonably related to the study treatment or study
participation, the investigator should promptly notify GSK and COG.
Revised Text:
The investigator or site staff is responsible for detecting, documenting and reporting events that meet the
definition of an AE or SAE.

AEs will be collected from the start of protocol therapy and until 28 days following last dose of protocol
therapy.

SAEs will be collected over the same time period as stated above for AEs. From the time a patient 
consents to participate in and completes the study, However, any all SAEs assessed as related to
study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in 
existing therapy) or related to a GSK product will be reported promptly to Novartis as indicated in 
Section 11.8. recorded from the time a patient consents  to participate  in the study  up to and 
including any follow-up contact.

Medical occurrences that begin prior to the start of protocol therapy but after obtaining informed consent
should be recorded on the Medical History/Current Medical Conditions section of the eCRF.

Any new primary cancer must be recorded as an SAE and will be recorded from the time a patient consents 
to participate in the study up to and including any follow-up contact.

All SAEs will be recorded and reported to NovartisGSK and COG within 24 hours, as indicated in Section 
11.8.

Investigators are not obligated to actively seek AEs or SAEs in former study participants.

However, if the investigator learns of any SAE, including a death, at any time after a patient has been
discharged from the study, and he/she considers the event reasonably related to the study treatment or study
participation, the investigator should promptly notify NovartisGSK and COG.
Section: 12, Study Reporting and Monitoring
Original Text:
For this study, patient data will be entered into electronic case report forms (eCRFs), transmitted 
electronically to GSK or designee and combined with data provided from other sources in a validated data 
system.
Management of clinical data will be performed in accordance with applicable GSK standards and data 
cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. 
Adverse events and concomitant medications terms will be coded using MedDRA (Medical Dictionary for 
Regulatory Activities) and an internal validated medication dictionary, GSKDrug. eCRFs (including queries 
and audit trails) will be retained by GSK, and copies will be sent to the investigator to m aintain as the 
investigator copy. Patient initials will not be collected or transmitted to GSK according to GSK policy.


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Revised Text:
For this study, patient data will be entered into electronic case report forms (eCRFs), transmitted 
electronically to NovartisGSK or designee and be combined with data provided from other sources in a 
validated data system.
Clinical data management will be performed in accordance with applicable standards and data 
cleaning procedures with the objective of resolving errors and inconsistencies in the data which would 
otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical Study 
Report..  All AEs and concomitant medications terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and a custom dictionary. Management of clinical data will be performed 
in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will 
be coded using MedDRA (Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug. eCRFs (including queries and audit trails) will be retained by NovartisGSK, and 
copies will be sent to the investigator to maintain as the investigator copy. Patient initials will not be collected 
or transmitted to GSK according to GSK policy.


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14 REFERENCES
1.
Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 9:669-76,
2003
2.
Weidner N, Semple JP, Welch WR, et al: Tumor angiogenesis and metastasis--correlation in
invasive breast carcinoma. N Engl J Med 324:1-8, 1991
3.
Bigler SA, Deering RE, Brawer MK: Comparison of microscopic vascularity in benign and
malignant prostate tissue. Hum Pathol 24:220-6, 1993
4.
Bochner BH, Cote RJ, Weidner N, et al: Angiogenesis in bladder cancer: relationship between
microvessel density and tumor prognosis. J Natl Cancer Inst 87:1603-12, 1995
5.
Eggert A, Ikegaki N, Kwiatkowski J, et al: High-level expression of angiogenic factors is 
associated with advanced tumor stage in human neuroblastomas. Clin Cancer Res 6:1900-8, 2000
6.
Kaya M, Wada T, Akatsuka T, et al: Vascular endothelial growth factor expression in 
untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res
6:572-7, 2000
7. Fakhari M, Pullirsch D, Paya K, et al: Upregulation of vascular endothelial growth factor receptors is
associated with advanced neuroblastoma. J Pediatr Surg 37:582-7, 2002
8. Fuchs B, Inwards CY, Janknecht R: Vascular endothelial growth factor expression is up- regulated by
EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing's
sarcoma. Clin Cancer Res 10:1344-53, 2004
9. Bergers G, Song S, Meyer-Morse N, et al: Benefits of targeting both pericytes and endothelial cells
in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287-95, 2003
10. Epstein JA, Song B, Lakkis M, et al: Tumor-specific PAX3-FKHR transcription factor, but not
PAX3, activates the platelet-derived growth factor alpha receptor. Mol Cell Biol 18:4118-30, 1998
11. Gerber HP, Kowalski J, Sherman D, et al: Complete inhibition of rhabdomyosarcoma xenograft
growth and neovascularization requires blockade of both tumor and host vascular endothelial 
growth factor. Cancer Res 60:6253-8, 2000
12. Rowe DH, Huang J, Kayton ML, et al: Anti-VEGF antibody suppresses primary tumor growth
and metastasis in an experimental model of Wilms' tumor. J Pediatr Surg 35:30-2; discussion 32-3, 
2000
13. Rowe DH, Huang J, Li J, et al: Suppression of primary tumor growth in a mouse model of human
neuroblastoma. J Pediatr Surg 35:977-81, 2000
14. McGary EC, Weber K, Mills L, et al: Inhibition of platelet-derived growth factor-mediated 
proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571. Clin Cancer Res
8:3584-91, 2002
15. Zwerner JP, May WA: Dominant negative PDGF-C inhibits growth of Ewing family tumor cell
lines. Oncogene 21:3847-54, 2002
16. Huang J, Frischer JS, Serur A, et al: Regression of established tumors and metastases by potent
vascular endothelial growth factor blockade. Proc Natl Acad Sci U S A 100:7785-90, 2003
17. Tamborini E, Bonadiman L, Greco A, et al: Expression of ligand-activated KIT and platelet-
derived growth factor receptor beta tyrosine kinase receptors in synovial sarcoma. Clin Cancer Res 
10:938-43, 2004
18. Backman U, Christofferson R: The selective class III/V receptor tyrosine kinase inhibitor SU11657
inhibits tumor growth and angiogenesis in experimental neuroblastomas grown in mice. Pediatr Res
57:690-5, 2005
19. Dalal S, Berry AM, Cullinane CJ, et al: Vascular endothelial growth factor: a therapeutic target for
tumors of the Ewing's sarcoma family. Clin Cancer Res 11:2364-78, 2005
20. Kadenhe-Chiweshe A, Papa J, McCrudden KW, et al: Sustained VEGF blockade results in 
microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation.
Mol Cancer Res 6:1-9, 2008
21. Maris JM, Courtright J, Houghton PJ, et al: Initial testing of the VEGFR inhibitor AZD2171 by the
pediatric preclinical testing program. Pediatr Blood Cancer 50(3):581-7, 2008


Novartis
Confidential
Page 182
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Protocol No. VEG116731
22. McCrudden KW, Hopkins B, Frischer J, et al: Anti-VEGF antibody in experimental hepatoblastoma: 
suppression of tumor growth and altered angiogenesis. J Pediatr Surg 38:308-14; discussion 308-
14, 2003
23. Smithey BE, Pappo AS, Hill DA: C-kit expression in pediatric solid tumors: a comparative
immunohistochemical study. Am J Surg Pathol 26:486-92, 2002
24. Kumar R, Knick VB, Rudolph SK, et al: Pharmacokinetic-pharmacodynamic correlation from
mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and 
antiangiogenic activity. Mol Cancer Ther 6:2012-21, 2007
25. Kumar S, Mokhtari RB, Sheikh R, et al: Metronomic oral topotecan with pazopanib is an active
antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res 
17:5656-67, 2011
26. Keir ST, Morton CL, Wu J, et al: Initial testing of the multitargeted kinase inhibitor pazopanib
by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 59:586-8, 2012
27. Gerber HP, Vu TH, Ryan AM, et al: VEGF couples hypertrophic cartilage remodeling, ossification
and angiogenesis during endochondral bone formation. Nat Med 5:623-8, 1999
28. Ryan AM, Eppler DB, Hagler KE, et al: Preclinical safety evaluation of rhuMAbVEGF, an
antiangiogenic humanized monoclonal antibody. Toxicol Pathol 27:78-86, 1999
29. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic renal cell
carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061-8, 2010
30. van der Graaf WT, Blay JY, Chawla SP, et al: Pazopanib for metastatic soft-tissue sarcoma
(PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879-86, 
2012
31. Sleijfer S, Ray-Coquard I, Papai Z, et al: Pazopanib, a multikinase angiogenesis inhibitor, in patients
with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European 
organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC
study 62043). J Clin Oncol 27:3126-32, 2009
32. Friedlander M, Hancock KC, Rischin D, et al: A Phase II, open-label study evaluating pazopanib
in patients with recurrent ovarian cancer. Gynecol Oncol 119:32-7, 2010
33. Altorki N, Lane ME, Bauer T, et al: Phase II proof-of-concept study of pazopanib monotherapy in
treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol
28:3131-7, 2010
34. Slamon D, Gomez H, Kabbinavar F, et al: Randomized study of pazopanib + lapatinib vs. lapatinib
alone in patients with HER2- positive advanced or metastatic breast cancer. J Clin Oncol 26, 2008
35. Monk BJ, Mas Lopez L, Zarba JJ, et al: Phase II, open-label study of pazopanib or lapatinib
monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced
and recurrent cervical cancer. J Clin Oncol 28:3562-9, 2010
36. Prince HM, Honemann D, Spencer A, et al: Vascular endothelial growth factor inhibition is not an
effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of 
pazopanib (GW786034). Blood 113:4819-20, 2009
37. Hutson T, Davis I, Machiels J, et al: Biomarker analysis and final efficacy and safety results of
a phase II renal cell carcinoma trial with pazopanib (GW786034), a multi-kinase angiogenesis 
inhibitor. J Clin Oncol 26:abstr 5046, 2008
38. Nikolinakos P, Altorki N, Guarino M, et al: Analyses of plasma cytokine/angiogenic factors
(C/AFs) profile during preoperative treatment with pazopanib (GW786034) in early-stage non-
small cell lung cancer. J Clin Oncol 26:abstr 7568, 2008
39. Norden-Zfoni A, Desai J, Manola J, et al: Blood-based biomarkers of SU11248 activity and clinical
outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer
Res 13:2643-50, 2007
40. Glade Bender JL, Adamson PC, Reid JM, et al: Phase I Trial and Pharmacokinetic Study of
Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group
Study. Journal of Clinical Oncology 26:399-405, 2008
41. Lambrechts D, Poesen K, Fernandez-Santiago R, et al: Meta-analysis of vascular endothelial growth
factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -


Novartis
Confidential
Page 183
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Protocol No. VEG116731
2578AA genotype. J Med Genet 46:840-6, 2009
42. Hurwitz HI, Dowlati A, Saini S, et al: Phase I trial of pazopanib in patients with advanced cancer.
Clin Cancer Res 15:4220-7, 2009
43. Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J
Pediatr 106:522-526, 1985
44. Onar-Thomas A, Xiong Z: A simulation-based comparison of the traditional method, Rolling-6
design and a frequentist version of the continual reassessment method with special attention to trial
duration in pediatric Phase I oncology trials. Contemp Clin Trials 31:259-270, 2010
45. Thall PF, Simon RM, Estey EH: Bayesian sequential monitoring designs for single-arm clinical
trials with multiple outcomes. Stat Med 14:357-379, 1995
46. Thall PF, Simon RM, Estey EH: New statistical strategy for monitoring safety and efficacy in single-
arm clinical trials. J Clin Oncol 14:296-303, 1996
47. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours:
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009
48. Xin G, Wang M, Jiao LL, et al: Protein-to-creatinine ratio in spot urine samples as a predictor
of quantitation of proteinuria. Clin Chim Acta 350(1-2):35-9, 2004

SAP_001.pdf: 
Clinical Development
Pazopanib
Protocol PZP034X2203 / NCT01956669
A phase II study of pazopanib (GW786034, NSC#737754) in children, 
adolescents and young adults with refractory solid tumors
Statistical Analysis Plan
End of study analysis
Author:
(
 study statistician); 
 
 (Novartis Trial Statistcian)
Document type:
SAP Documentation
Document status:
Amendment 1
Release date:
24-Dec-2019
Number of pages:
44
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Changes compared to previous final version of SAP
Reporting and Analysis Plan History
Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted 
(Current)
10 
Sep 
2019
Prior 
to 
final 
DB 
lock
Creation of SAP for 
end of study analysis
N/A
N/A
24 
Dec 
2019
Prior 
to 
final 
DB 
lock
Creation of 
Amendment 1
Minor updates to
- Cover page corrected. Prior 
version incorecctly titled “Tables, 
Figures and Listings (TFL) Shells-
CSR deliverables”. Updated to 
“Statistical Analysis Plan”
- Reference link for NCI-CTCAE 
v4.0 provided in the previous 
version was not working - link 
updated.
Cover page 
document title
Section 9.4.1-
page 25 reference 
link is updated


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................6
1.
Introduction .........................................................................................................................8
2.
Study Objectives and Endpoints..........................................................................................8
3.
Study Design .....................................................................................................................11
4.
Planned Analyses...............................................................................................................12
4.1.
Interim Analyses....................................................................................................12
4.2.
End of Stage 1 Analysis.........................................................................................12
4.3.
Primary Analysis ...................................................................................................13
4.4.
End of Study Analyses...........................................................................................13
5.
Sample Size Considerations ..............................................................................................13
5.1
Sample Size Assumptions......................................................................................13
5.2 
Sample Size Re-estimation....................................................................................14
6.
Analysis populations .........................................................................................................14
6.1.
Modified Intent-to-Treat Population......................................................................14
6.2.
Per-Protocol Population.........................................................................................14
6.3.
Safety Population...................................................................................................14
6.4.
Pharmacokinetic Population..................................................................................14
6.5.
Pharmacokinetic Extended Sampling Population..................................................15
7.
Treatment comparisons .....................................................................................................15
8.
general considerations for data analyses ...........................................................................15
8.1.
Multicenter Studies................................................................................................15
8.2.
Other Cohorts and Covariates................................................................................15
8.3.
Examination of Subgroups ....................................................................................15
8.4.
Multiple Comparisons and Multiplicity.................................................................15
9.
Data Handling Conventions ..............................................................................................16
9.1.
Premature Withdrawal and Missing Data..............................................................16
9.2.
Derived and Transformed Data .............................................................................16
9.2.1.
Reference dates .....................................................................................17
9.2.2.
Study Day..............................................................................................17
9.2.3.
Study Day for Efficacy..........................................................................17
9.2.4.
Duration and Elapsed Time...................................................................17
9.2.5.
Imputation of Partial Dates ...................................................................17
9.2.6.
Handling of concentrations below LLOQ or missing...........................22


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9.2.7.
Baseline Definition................................................................................22
9.2.8.
Change from baseline............................................................................22
9.2.9.
Multiple Assessments............................................................................22
9.2.10.
Cardiac Scan Modalities (ECHO/MUGA)............................................23
9.2.11.
Derived and Transformed Variables .....................................................23
9.3.
Study Time Periods................................................................................................23
9.3.1.
Time in Relation to Treatment..............................................................23
9.3.2.
Study Time Periods for Concomitant Medications...............................24
9.4.
Values of Potential Clinical Importance................................................................25
9.4.1.
Laboratory Parameters ..........................................................................25
9.4.2.
ECG Parameters....................................................................................25
9.4.3.
Vital Signs.............................................................................................26
9.4.4.
Left Ventricular Ejection Fraction ........................................................27
9.5.
Disposition of Subjects..........................................................................................28
9.6.
Protocol Deviations ...............................................................................................28
9.7.
Demographic and Baseline Characteristics ...........................................................29
9.8.
Concomitant Medications......................................................................................29
10. Efficacy..............................................................................................................................30
10.1.
Primary Efficacy Analysis.....................................................................................30
10.2.
Secondary Efficacy Analyses ................................................................................31
11. Safety Analyses .................................................................................................................34
11.1.
Extent of Exposure ................................................................................................35
11.2.
Adverse Events ......................................................................................................35
11.3.
Identified and Potential Risks................................................................................36
11.4.
Deaths and Serious Adverse Events ......................................................................36
11.5.
Adverse Events Leading to Discontinuation of Study Treatment and/or 
Withdrawal from the Study and Other Significant Adverse Events......................37
11.6.
Pregnancies............................................................................................................38
11.7.
Clinical Laboratory Evaluations............................................................................38
11.7.1.
Analyses of Liver Function Tests .........................................................39
11.8.
Other Safety Measures...........................................................................................39
12. Pharmacokinetic Analyses.................................................................................................41
12.1.
Sampling Schedule ................................................................................................41
12.2.
Pharmacokinetic Analysis .....................................................................................41
12.3.
Pharmacokinetic parameters..................................................................................42


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12.3.1.
Statistical Analysis of Pharmacokinetic Parameters.............................43
12.4.
Assessment of pazopanib exposure from suspension formulation........................43
12.5.
Exploration of pharmacokinetic and pharmacodynamic relationship ...................43
13. REFERENCES..................................................................................................................44


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List of abbreviations
AE
Adverse Event
AFP
Alpha Fetoprotein
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC(0-t)
Area under the concentration-time curve from time zero to the last observed 
concentration
AUC(0-24)
Area under the concentration-time curve from time zero to 24 h after drug 
administration
BOR
Best overall response
BSA
Body surface area
CI
Confidence Interval
Cmax
Maximum observed drug concentration
CR
Complete Response
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Observed drug concentration before the next dose
DLT
Dose limiting toxicity
DoR
Duration of response
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
GSK
GlaxoSmithKline
I-MIBG
I-metaiodobenzylguanidine
LLOQ
Lower limit of quantitation
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Medical Affairs
mITT
Modified Intent to Treat
MTD
Maximum tolerated dose
MUGA
Multiple-Gated acquisition
NCI
National Cancer Institutes
ORR
Objective Response Rate
OS
Overall survival
P
P value
PD
Progressive Disease
PDCO
Pediatric Committee
PFS
Progression-free Survival


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PK
Pharmacokinetics
PKES
Pharmacokinetic extended sampling
PR
Partial Response
PT
Preferred Term
RADIO
Radiotherapy Dataset
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SD
Stable Disease
SOC
System Organ Class
STD
Study treatment discontinuation
TBL
Total bilirubin
tmax
Time of maximum observed drug concentration
TTP
Time to progression
ULN
Upper Limit of Normal


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1.
Introduction
This reporting and analysis plan (RAP) details all planned analyses required for the end of 
study final Clinical Study Report for the study VEG116731.  This is a phase II (open label) 
study of pazopanib in children, adolescents and young adults with refractory solid tumors. 
Tumors of primary interest are rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue 
sarcoma (including synovial sarcoma, alveolar soft part sarcoma and desmoplastic small 
round cell tumor) and Ewing sarcoma. Tumors of secondary interest include hepatoblastoma, 
neuroblastoma (measurable and evaluable), and osteosarcoma. This study will examine the 
efficacy of pazopanib in subjects with a variety of relapsed/refractory solid tumors. The study 
will also seek to further define the toxicities of pazopanib in subjects with relapsed/refractory 
solid tumors, characterize the pharmacokinetics (PK) of pazopanib after administration of the 
powder suspension formulation, as well as examine biologic markers that may help to further 
define the response characteristics of pazopanib. The details of pharmacodynamics and 
biomarker related analyses will be described in a separate analysis plan. 
For further information on the study design, see the protocol (Amendment 5, 23-May-2017) 
for Study VEG116731.
The RAP was written by staff 
. The execution of the RAP will be undertaken by 
staff 
as well.
All decisions regarding the analysis, as defined in this RAP document, will be made prior to 
Database Freeze (DBF) of the study data. Interim analyses are detailed within Section 4.1, 
where applicable.
All decisions regarding the analysis, as defined in this RAP document, will be made prior to 
Database Freeze (DBF) of the study data. Interim analyses are detailed within Section 4.1, 
where applicable.
2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To determine the investigator-
assessed objective response rate of 
pazopanib in children, adolescents 
and young adults (subjects) with 
relapsed or refractory solid tumors 
of the following types (each 
defining a cohort):
1. rhabdomyosarcoma
2. non-rhabdomyosarcomatous 
soft tissue sarcoma, or

Objective Response Rate (ORR) for 
the three tumor types of primary
interest, confirmation will be based 
on the disease assessment after the 
initial response


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3. Ewing sarcoma/peripheral 
Primitive Neuro Ectodermal 
Tumor (PNET).
Secondary

To determine the investigator 
assessed objective response rate of 
pazopanib in children, adolescents, 
and young adults (subjects) with 
relapsed or refractory solid tumors 
of the following types (each 
defining a cohort):
1. osteosarcoma, 
2. neuroblastoma (measurable),
3. neuroblastoma (evaluable), or
4. hepatoblastoma.

Objective Response Rate (ORR) for 
the four tumor types of secondary 
interest. The analysis method will 
be the same as in the primary 
endpoint.

To further define and describe the 
toxicities of oral pazopanib in 
subjects with recurrent/refractory 
solid tumors.

Adverse Events, Clinical 
Laboratory Evaluations, Vital signs 
and ECG and ECHO/MUGA.

To further characterize the 
pharmacokinetics (PK) of 
pazopanib after administration of 
the powder suspension formulation
in children, adolescents and young 
adults with cancer.

Pazopanib PK parameters (e.g., 
Cmax, Tmax, and AUC).

To determine progression free 
survival in subjects with relapsed or 
refractory solid tumors, per cohort.

Progression-free survival (PFS): 
defined as the interval between the 
date of first dose of protocol 
therapy and the earliest date of 
disease progression or death due to 
any cause.

To determine the time to 
progression in subjects with 
relapsed or refractory solid tumors, 
per cohort.

Time to progression (TTP): defined 
as the interval between the date of 
first dose of protocol therapy and 
the earliest date of disease 


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progression or death due to disease 
under study.

To determine the therapeutic 
activity (a confirmed complete or 
partial response based on the 
disease assessment at least one 
cycle after initial response or stable 
disease for at least  two protocol 
scheduled disease assessments as 
per RECIST criteria) per cohort

Clinical Benefit: defined as the 
percentage of subjects achieving 
either a confirmed complete or 
partial tumor response (at least one 
cycle after initial response, see 
section 10.1 for confirmation of 
CR/PR) or stable disease for at least 
two protocol scheduled disease 
assessments as per RECIST criteria.

To further examine the biologic 
relationship between tumor 
response and angiogenic cytokines.

To be described in a separate 
biomarker analysis plan.

To assess the genotype/phenotype 
relationships of VEGF or other 
members of the VEGF signaling 
pathway in children with soft tissue 
sarcoma.

To be described in a separate 
biomarker analysis plan. 

To further explore pazopanib 
pharmacokinetic/pharmacodynamic 
relationships with biomarkers and 
clinical outcomes, including 
hypertension.

Pazopanib PK by clinical outcomes, 
including hypertension.

Pazopanib PK vs biomarkers will 
be described in a separate 
biomarker analysis plan.

To assess overall survival in 
subjects with relapsed or refractory 
solid tumors, per cohort

Overall survival (OS): defined as 
the time from the first dose of 
protocol therapy until death due to 
any cause.

To assess duration of response in 
subjects with relapsed or refractory 
solid tumors, per cohort

Duration of response (DoR): 
defined as the time from the initial 
response (CR/PR) to first 
documented disease progression or 
death due to any cause, and will be 
determined only for those subjects 
with a confirmed response (CR or 
PR).


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3.
Study Design
Pazopanib will be administered orally once daily as a tablet at a dose of 450 mg/m2/dose or as 
a powder in suspension at a dose of 225 mg/m2/dose.  450 mg/m2/dose was the MTD for 
tablet as determined by Study ADVL0815, the COG Phase I study, while the dose for oral 
suspension of 225 mg/m2/dose exceeds the protocol-specified MTD of 160 mg/m2/dose 
established in the same study. This decision was driven by the considerations that the 160 
mg/m2/dose may result in suboptimal exposure for efficacy and that only two isolated and 
reversible laboratory-defined DLTs were observed at 225 mg/m2/dose in Study ADVL0815.  
The maximum dose to be administered daily for tablets is 800 mg and for suspension 400 mg.  
Each cycle will be defined as 28 days.
The first subjects enrolled who receive powder suspension will be expected to complete 
extended pharmacokinetic (PK) sampling in order to obtain PK and safety data in 6 evaluable 
subjects.  If the 225 mg/m2/dose is not tolerated (≥2 subjects with dose limiting toxicities 
(DLTs) in the first 6 evaluable subjects), all subsequently enrolled subjects will receive 160 
mg/m2/dose and an additional 6 
subjects will be assessed for safety review and PK 
analysis. 
The primary endpoint will be objective response rate by protocol-specified, disease-specific 
response criteria. The best response of disease to pazopanib will be examined separately in 
each of the seven disease cohorts. 
The following two stage design (Simon, 1989) will be used in each cohort.
Cumulative Number of 
Responses
Decision
Stage 1: Enter 10 subjects
0
1 or more
Terminate the cohort: agent 
ineffective
Inconclusive result, continue 
cohort (proceed to Stage 2)
Stage 2: Enter 10 additional 
subjects
2 or less
3 or more
Terminate the cohort: agent 
ineffective
Terminate the cohort: agent 
effective
We will consider the agent not of sufficient interest for further evaluation in a disease 
category if the true response rate is 5% and of sufficient activity if the true response rate is 
25%. If the agent has a true response rate of 5%, the rule described above will identify the 
agent to have sufficient activity for further study with probability 0.07 (1-sided type I error), 
and the trial will have an expected sample size of 14 with 60% probability of early
termination. If the agent has a true response rate of 25%, the rule described above will identify 
the agent to have sufficient activity for further study with probability 0.88 (power against the
alternative hypothesis P = 0.25).


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4.
Planned Analyses
In line with ICH E9 [European Agency for the Evaluation of Medicinal Products, 1998], 
membership of the analysis populations will be determined using the definitions in Section 6
of this RAP.
4.1.
Interim Analyses
No formal interim analysis is planned outside of the study design. 
The study team, which includes the Medical Monitor, representatives from Clinical 
Pharmacology and Safety, and the COG protocol chair will review and discuss safety data 
periodically over the course of the study. The team will also review the pharmacokinetics,
toxicity, safety and tolerability profile of the first 6 initial subjects who receive powder 
suspension formulation and who are determined to be evaluable for PK and safety analyses.  
At least 6 evaluable subjects will be included in this assessment.
Expansion of tumor specific cohorts will be done when there is at least one investigator 
determined confirmed response in that cohort within the first 10 enrolled subjects.  A given 
tumor specific cohort will not be expanded if no response has been reported for the first 10 
subjects but all the subjects in the cohort have:
•
Progressed
•
Discontinued therapy
•
Withdrawn consent
•
Been determined to be lost-to-follow-up
•
Or have been treated for at least 20 weeks, making it unlikely that a response will 
occur.
4.2.
End of Stage 1 Analysis
This is a 2-stage design and therefore implies an analysis for futility based on the number of 
responders observed in Stage 1. The cut-off date for end of stage 1 analysis will be defined 
after the last subject enrolled in Stage 1 in the three cohorts of primary interest completes 20 
weeks of treatment or discontinues early (as described in the previous section).
Enrollment in the rhabdomyosarcoma cohort was put on temporary halt following end of 
enrollment in Stage 1 for all cohorts in order to assess the benefit-risk based on the overall 
data from Stage 1 subjects. Two subjects already pre-identified to participate in the study 
before assessment of benifit.risk of stage 1 were enrolled in Stage 2 at that time.
Therefore, the data-cut off date for the end of Stage 1 analysis is defined as the date when all 
subjects (including subjects enrolled in stage 2 for the rhabdomyosarcoma cohort) in the three 
cohorts of primary interest complete 20 weeks of treatment or discontuine early.


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4.3.
Primary Analysis
The primary analysis of the study will be performed 20 weeks after the last subject’s first visit
in the three cohorts with tumors of primary interest, i.e. rhabdomyosarcoma, non-
rhabdomyosarcomatous soft tissue sarcoma, or Ewing sarcoma/peripheral PNET. This 
analysis would be performed after the completion of stage 2 of the primary cohorts. 
However, this primary analysis will not be performed if the study is declared futile based on 
the statistical criteria described in Section 3 and/or clinical assessment of benefit-risk with the 
end of stage 1 analysis.
Key efficacy and safety data were analysed in the end of stage 1 analysis (with a cut-off date 
of 31-Jan-2019) and the Request for Modification #06 of the Votrient Paediatric Investigation 
Plan, was submitted to the PDCO. The study was declared futile based on the clinical 
assessment of benefit-risk at the end of stage 1 and the decision to terminate the study was 
approved based on PDCO feedback. 
4.4.
End of Study Analyses
The study will be completed one year from the date of the last subject’s first visit. The end of 
study analyses will be performed at the time of study completion, when the final study 
database is frozen and will include cumulative efficacy and safety data. 
5.
Sample Size Considerations
5.1
Sample Size Assumptions   
Review of subject accrual onto recent Phase II solid tumor studies indicates that the following 
entry rates of subjects with the various tumors under study can be expected:
Disease Group/Cohorts                                                                       Subjects/Year
Osteosarcoma                                                                                         24
Ewing sarcoma                                                                                       18
Rhabdomyosarcoma                                                                               18
Neuroblastoma (measurable disease)                                                     12
Neuroblastoma (evaluable disease)                                                        12
Non-rhabdomyosarcomatous soft tissue sarcomas                                10
   (including synovial sarcoma, alveolar soft part
   sarcoma)
Hepatoblastoma                                                                                      7
With these entry rates, the probability of accruing 10 subjects to complete the initial stage of 
evaluation in the seven named categories within 24 months is 88%. The corresponding 
probability for enrolling 20 subjects in the seven named disease categories in 48 months is 
95%. The study will likely require 2 to 3.5 years for sufficient subject enrolments to evaluate 


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pazopanib in the stated disease groups. If activity is detected in any category, further trials in 
subcategories of the category may be conducted at the discretion of the Developmental
Therapeutics Steering and study committees. A minimum of 77 subjects and a maximum of 
154 subjects are anticipated, after accounting for historical rates of subject inevaluability for 
the primary endpoint in phase II studies.
5.2 
Sample Size Re-estimation
No formal sample size re-estimation is planned. 
6.
Analysis populations
6.1.
Modified Intent-to-Treat Population
The modified Intent-to-Treat (mITT) population is the primary analysis population.  The 
mITT will consist of all subjects who have received at least one dose of protocol therapy.
6.2.
Per-Protocol Population
The Per-Protocol (PP) population will consist of a subset of the subjects in the mITT who meet 
all eligibility criteria and don’t have any major protocol deviations leading to exclusion from 
PP
The protocol deviations leading to exclusion from PP are specified in the protocol deviation 
specification document which will be stored in CREDI.
For the end of study analysis, the PP and mITT population will be used for the analysis of best 
overall response (ORR). All other efficacy analyses will be based on mITT only.
6.3.
Safety Population
The Safety population will comprise all subjects in the mITT population. The safety
population will be used for the analysis of safety data.
In this study, the mITT population and Safety population are identical.
6.4.
Pharmacokinetic Population
The Pharmacokinetic (PK) population will comprise all subjects in the mITT population for
whom a pharmacokinetic sample is obtained and analyzed.


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6.5.
Pharmacokinetic Extended Sampling Population
The Pharmacokinetic Extended Sampling (PKES) population will comprise all subjects in the 
Pharmacokinetic population who received powder suspension and have at least one non pre-
dose sample collected using the extended sampling schedule. The PKES population is a subset 
of the PK population.
7.
Treatment comparisons
There will be no treatment comparisons as there is only one treatment arm for each cohort. No
comparisons across cohorts will be conducted.
8.
general considerations for data analyses
Analysis datasets will be created according to CDISC standards, and data will be listed and 
summarized according to Novartis reporting standards where applicable. Formatting for dates, 
times, and decimal places will follow Novartis standards except where specified.
All data in the database will be presented in by-subject data listings.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
Unless otherwise stated, continuous variables will be summarized with n, mean, median, 
standard deviation, minimum and maximum, and categorical variables will be summarized 
with frequency counts and percentages
The currently supported version of SAS software (v9.3 or higher) will be used to perform all 
data analyses, generate tables, figures, and listings. 
Deviations from the analyses in the RAP will be identified in the CSR and documented in the 
RAP Addendum.
8.1.
Multicenter Studies
8.2.
Other Cohorts and Covariates
In all efficacy analyses, there are no formal plans for any stratification. There are no formal 
plans for investigating any covariates.
8.3.
Examination of Subgroups
There is no subgroup analyses required for safety but there will be subgroups analysis in PK 
analysis.
8.4.
Multiple Comparisons and Multiplicity
There are no comparisons of interest and no formal statistical hypothesis will be tested.


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9.
Data Handling Conventions
9.1.
Premature Withdrawal and Missing Data
Subjects will be treated until disease progression, until the subject is no longer obtaining 
clinical benefit from continued treatment, unacceptable toxicity, the study is terminated, or the 
subject withdraws consent. All subjects who withdraw from the study will be included in 
analyses up to the time of withdrawal, regardless of the duration of treatment.
As the period of treatment for any subject will be dependent on treatment efficacy and 
toxicity, the duration of protocol therapy will vary across subjects. Similarly the duration of 
follow-up will also vary across subjects. Subjects with shorter treatment and follow-up due to 
the natural history of their disease or medical necessities of the treatment of their disease will 
not be considered to have missing data. Consequently, there will be no imputation for missing 
data. Where appropriate, available data will be summarized over specified intervals (e.g. from 
study entry until withdrawal from the study) using suitable summary statistics.
For endpoints which determine the percentage of responders, subjects with unknown or 
missing overall response will be assumed to be non-responders, and will be included in the 
denominator when calculating the percentages.
For the secondary PFS endpoint, the date associated with the last adequate disease assessment 
will be used for those subjects who are alive and have not progressed at the time of analysis; 
such subjects will be considered censored in the analysis. 
For the secondary OS endpoint, the date associated with the last contact will be used for those 
subjects who are alive at the time of analysis; such subjects will be considered censored in the 
analysis.
In the event that the study is terminated, all available data will be listed and a review will be 
carried out by the study team to assess which statistical analyses are still considered 
appropriate.
“Missing data” occurs when any requested data is not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” in subject listing 
displays. Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
For adverse events (AEs) and serious adverse events (SAEs), if relationship to study treatment 
is missing it will be assumed to be “Yes”. There will be no other imputation for missing data 
other than what’s described in Section 9.2.5 for partial dates and for missing exposure end 
dates.
9.2.
Derived and Transformed Data
The following sections provide a general description of the derived and transformed variables 
used to describe and analyze the data. Separate analysis dataset specifications provide full 
details on all data derivations and transformations including descriptions of core standard 
algorithms and standard Oncology algorithms. The analysis dataset specifications will clearly 
communicate the content and source of the datasets supporting the statistical analyses.


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9.2.1.
Reference dates
There are two reference dates:

Because age is an eligibility requirement, the reference date for age is the date of 
screening.

The study reference date is the treatment start date, and will be used to calculate study day 
for all safety and efficacy measures.
9.2.2.
Study Day
If the date of interest occurs on or after the study reference date then the  study day will be 
calculated as (date of interest - study reference date) + 1. If the date of interest occurs before 
the study reference date then the study day will be calculated as (date of interest – study
reference date). There is no study day 0.
9.2.3.
Study Day for Efficacy
Since study is not randomized, we will use same study day in Section 9.2.2.
9.2.4.
Duration and Elapsed Time
Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are calculated as
the stop date minus the start date plus one.
For elapsed time (e.g., the time since initial diagnosis):

if the reference date is on or after the event date, then the elapsed time is the 
reference date minus the event date + 1.

if the reference date is before the event date then the elapsed time is the reference date 
minus the event date.
When calculating time to event durations in months, divide the number of days by 30.4375; to 
report in weeks divide the number of days by 7; to report in years divide the number of days 
by 365.25.  These algorithms for time to event return decimal numbers, and ignore the actual 
numbers of days in the months or years between start date and stop date.  The "year" used in 
these algorithms is 365.25 days long, and the "month" is one twelfth of that year.
9.2.5.
Imputation of Partial Dates
Only the year of birth is being collected within the EDC system, subject birth date and month 
will be defaulted to ‘30/JUN’. For example, if birth year is 1989 then birthdate will be 
30/Jun/1989.  
With the exception of new anti-cancer start date on the time to event (PFS, TTP, OS) analysis 
dataset and exposure end date on the Exposure analysis dataset, imputed dates will not be 
stored on datasets. 
Imputed dates will not be displayed in listings. However, where necessary, display macros 
may impute dates as temporary variables for the purpose of sorting data in listings only. In 


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addition partial dates may be imputed for ‘slotting’ data to study time periods (see Section 
9.3) or for specific analysis purposes as outlined below. 
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation. 
The flag variable can contain the values: blank, 'D', 'M', 'Y'. 
blank: indicates that no imputation was done
D='Day': indicates that the day portion of the date is imputed
M='Month': indicates that the month and day portions of the date are imputed
Y='Year': indicates that the entire date (year, month, and day) is imputed
Example of Date Variables: 
XYZD_ - character date variable
XYZDT - numeric date variable
XYZDTFL - flag variable
Details on imputing partial dates for specific datasets are outlined below.
9.2.5.1.
Adverse events 
There will be no attempt to impute the following

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
Table 1 explains the abbreviations used.
Table 1
AE/Treatment Date Abbreviations 
Day
Month
Year
Partial Adverse Event Start 
Date
<not used>
AEM
AEY
Treatment Start Date 
(TRTSTD)
<not used>
TRTM
TRTY
Table 2 describes the possible combinations and their associated imputations. The upper text 
indicates the imputation (NC, A, B, C etc) and the lower text the relationship of the AE start 
date to the treatment start date (TRTSTD).


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Table 2
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 3.
Table 3
Imputation algorithm legends
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start 
date to Treatment Start Date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 4.
Table 3
Example scenarios
Partial
AE start date
Treatment
start date
Relationship
with TRTSTD
Imputation 
Calculation
Imputed 
Date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001
If imputed start date is greater than the end date of the adverse event, when end date is 
available, the imputed start date will be set equal to the end date


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9.2.5.2.
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same conventions as 
for AE date. Partial/missing concomitant medication end dates will not be imputed.
9.2.5.3.
Diagnosis and extent of cancer
The following variables require imputation when incomplete:
a. Date of initial diagnosis of primary site of cancer
b. Date of first recurrence/relapse
c. Date of most recent recurrence/relapse
Missing day is defaulted to 15 and missing month and day is defaulted to January 01, unless 
any of the following applies:
First recurrence/progression date:

If day is missing AND occurred in the same month of the most recent 
relapse/progression, then day of first recurrence/progression will be imputed as the 
minimum between 15 and day of the most recent relapse/progression.
Most recent relapse/progression date:

If day is missing AND occurred in the same month of the first recurrence/progression, 
then day of most recent relapse/progression will be imputed as the maximum between 15 
and day of first recurrence/progression.

If month and day are missing AND occurred in the same year of the first 
recurrence/progression, then month and day of most recent relapse/progression will be 
imputed as the maximum between January 01 and month and day of first 
recurrence/progression
9.2.5.4.
Anti-cancer therapy
Prior therapies 

Start date: The same rule which is applied to the imputation of AE/concomitant 
medication start date will be used with the exception that: for scenario (B) will be 
replaced to be treatment start date -1.

End date: 
o
Imputed date = min (reference end date, DEC 31) , if month and day are missing.
o
Imputed date = min (reference end date, last day of the Month) , if day is missing. 
o
Reference end date will be treatment start date. 

If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date.

If both the start date and the end date are imputed and if the imputed start date is after 
the imputed end date, use the imputed end date as the imputation for the start date
Post therapies 


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
Start date: 
o
If Day is missing, then impute to the max (reference start date, first day of the 
month). 
o
Day and month are missing then impute to the max(reference start date, Jan 1) 
o
Reference start date will be last date of study treatment administration + 1. 

End date: No imputation
9.2.5.5.
Last contact or death date(s)
All dates must be completed with day, month and year. If the day is missing, the 1st of the 
month will be used for incomplete death dates or dates of last contact.
9.2.5.6.
Incomplete dates for last treatment administration
Scenario 1: If the last treatment administration date is completely missing and there is no study 
treatment discontinuation (STD) page and no death date:

The subject should be treated as on-going and use the cutoff date as the last dosing date 
up to date.
Scenario 2: If the last treatment administration date is completely or partially missing and there 
is either STD page or death date available:
If only Year is available and Year < Year of min (DISC date, death date);
Imputed date= Dec31yyyy
If both Year and Month are available, Year = Year of min(DISC date, death date) and  Month 
< the month of min(DISC date, death date)
Imputed date= last day of the Month
All other cases imputed date= min (DISC date, death date)
The imputed date will be compared with start date of treatment. If the imputed date is < start 
date of treatment, set the last treatment administration date to be the treatment start date; 
otherwise use the imputed date.
9.2.5.7.
Assessment date of tumor assessments
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. X-ray, CT-scan) if the 
overall lesion response at that assessment is CR/PR/SD/UNK. Otherwise – if overall lesion 
response is progression – the assessment date is calculated as the earliest date of all 
investigation dates at that evaluation number.  If all measurement dates have no day recorded, 
the 1st of the month is used. 


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If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
9.2.6.
Handling of concentrations below LLOQ or missing
Missing values of concentrations will not be imputed. When summarizing concentrations, 
zero values will be excluded from the calculation of geometric means and CV% geometric 
mean. However, they will be included for all other summary statistics and the number of non-
zero concentrations will be reported. All concentration values below the lower limit of 
quantitation (LLOQ) of 0.1 µg/mL are set to zero, and will be displayed in the listings as zero 
and flagged. LLOQ values will be treated as zero in any calculations of summary statistics, 
and treated as missing for the calculation of the geometric means and their CV%. The number 
of non-zero concentrations will also be reported in the summary statistics.
Missing values for any PK parameters will not be imputed.
9.2.7.
Baseline Definition
Baseline will be defined as the most recent, non-missing value prior to or on the first study 
treatment dose date. For laboratory data, baseline will be defined as the most recent, non-
missing value from a central laboratory prior to or on the first study treatment dose date. If 
there are no central labs collected prior to or on the first dose date of study treatment, the most 
recent, non-missing value from a local laboratory prior to or on the first date of study 
treatment will be defined as the baseline value.
For subjects who did not receive study treatment during the study, baseline will be defined as 
the latest, non-missing collected value.
9.2.8.
Change from baseline
Change from baseline will be presented for safety data as described in Section 11. 
Change from baseline is calculated as:

For records occurring after baseline: (visit value) – baseline value.
Percent change from baseline is calculated as:

For records occurring after baseline: ((change from baseline) / baseline value) * 100
If either the baseline or visit value is missing, the change from baseline and/or percent change 
from baseline is set to missing as well.
9.2.9.
Multiple Assessments
All data will be reported according to the nominal visit date for which it was reported (that is,
no visit windows will be applied during dataset creation). Unscheduled data will only be 
included in “post-baseline” summaries for capturing a worst case across all scheduled and 
unscheduled visits after the first dose of protocol therapy.


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Data from all assessments (scheduled and unscheduled), including multiple assessments, will 
be included in listings. 
9.2.10.
Cardiac Scan Modalities (ECHO/MUGA)
The same modality (ECHO or MUGA) for determining cardiac scan data (e.g., left ventricular 
ejection fraction (LVEF)) should be used to follow a subject throughout the study. The 
absolute change from baseline values will not be calculated for any subjects where the post-
baseline value was determined by a cardiac scan modality that is different than the one used to 
determine baseline value. 
9.2.11.
Derived and Transformed Variables
See Section 10 in this RAP for details on analyses for objective response rate, clinical benefit, 
progression-free survival, overall survival and time to progression. 
For pharmacokinetic parameters, between-subject coefficient of variation (CVb%) will be 
calculated by the following methods, where SD is the standard deviation of the PK parameter 
data, calculated using either the raw data (untransformed) or the natural logarithm of the raw 
data (transformed).
         Untransformed Data: 100 * (SD/Mean)
        Transformed Data: 100 * (square root[exp(SD2)-1])
See Section 12 in this RAP for derivation of PK parameters.
ECG Corrected QT Intervals 
The QTc values based on Bazett’s formula is derived by QT interval / ((RR 
interval/1000)^1/2), where RR interval is in msec.
9.3.
Study Time Periods
9.3.1.
Time in Relation to Treatment
Adverse events, serious adverse events, death, laboratory data, vitals, ECG, and 
ECHO/MUGA will be assigned to the study time periods defined below. Partial dates will be 
imputed into full dates, if applicable, for slotting data to the appropriate categories below (see 
Section 9.2.5). Flag variables (time in relation to study treatment) indicating the study time 
periods will be added to these datasets.
The overall observation period will be divided into three mutually exclusive segments:
Pre-therapy is defined as the time prior to the subject’s first dose of study treatment. 
On-therapy is defined as the time from first dose of study treatment to the date of the last 
dose of study treatment + 28 days. 
Post-therapy is defined as any time beyond the on-therapy period.


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Some datasets include the first dose day as On-therapy and some exclude the first dose date as 
On-Therapy. The first dose day (Day 1) is considered pre-therapy for ECOG, ECG, vital 
signs, liver events, lab tests, and cardiac scan. The first dose day (Day 1) is considered to be 
on-therapy for adverse events and concomitant medications.
All safety data (including those from the post-therapy period) will be listed and those 
occurring during the pre-therapy and post-therapy periods are to be flagged.
9.3.2.
Study Time Periods for Concomitant Medications 
Concomitant Medication start and end dates will be assigned to study time periods in relation
to first dose of study treatment as defined below. The start date references time flag variables 
and end date reference time flag variables will be added to the concomitant medication 
dataset.

Start relative to therapy: Assign to 'BEFORE' if start date is prior to study treatment 
start date or if subject has not taken any study treatment or (start date is missing and end 
date is before study treatment start date). Else assign to 'DURING' if the start date falls 
into the on-therapy period as defined above or if subject is ongoing (not all study 
treatment discontinuation records completed) or start date is missing. Else assign to 
'AFTER' if start date is after the on-therapy period.

End relative to therapy: Assign to 'BEFORE' if end date is prior to study treatment start 
date or if subject has not taken any study treatment. Else assign to 'DURING' if end date 
falls into the on-therapy period or if subject is ongoing (not all study treatment 
discontinuation records completed) or (end date is missing and start relative to treatment 
not 'AFTER'). Else assign to 'AFTER' if end date is after the on-therapy period or (end 
date is missing and start relative to treatment='AFTER').
Concomitant medication start relative to treatment and end relative to treatment flags are used 
to select data to include in the Concomitant Medication summaries as follows:

Summary of Concomitant Medications: This summary will contain medications including 
those with start date prior to study treatment start date and continue (missing end date or 
end date after study treatment start date) on therapy. Note that any medications with start 
date and end date prior to study treatment start date will be excluded. In addition, any 
medication that was started during post-therapy will be excluded. Include concomitant 
medication records where start relative to treatment in ('BEFORE','DURING') and end 
relative to treatment in ('DURING','AFTER').

Summary of Concomitant Medications with On-Therapy Onset: This summary will 
contain medications with start date after study treatment start date. In addition, any 
medication that was started during post-therapy (see above for definition of post-therapy) 
will be excluded. Include concomitant medication records where start relative to treatment 
in ('DURING').


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9.4.
Values of Potential Clinical Importance
9.4.1.
Laboratory Parameters
Reference ranges for all laboratory parameters collected throughout the study are provided by 
the laboratory. A laboratory value that is outside the reference range is considered either high 
abnormal (value above the upper limit of the reference range) or low abnormal (value below 
the lower limit of the reference range). Note: a high abnormal or low abnormal laboratory 
value is not necessarily of clinical concern. The laboratory reference ranges will be provided 
on the listings of laboratory data. Clinical laboratory test results outside of the reference range 
will be flagged in the listings.
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be used to assign 
grades to the relevant laboratory parameters. NCI-CTCAE v4.0 can be found at
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
When reporting grade shifts for Biochemistry and haematology data, the records in the LAB 
dataset will be used. 
For laboratory data which are not listed in the NCI CTCAE v4.0, a summary of values outside 
the normal range will be provided.
9.4.2.
ECG Parameters
The following criteria will be used to flag electrocardiogram (ECG) values that are values of 
potential clinical importance: 
To identify QTc (Bazett’s) values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’). Note that there is a slight inconsistency between CTCAE v4.0 and ICH E14 
(Absolute QTc interval prolongation). It was decided to align with CTCAE for the oncology 
standard categories.
ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute QTcB interval
<450
450 to <480 (Grade 1)
480 to <500 (Grade 2)
500 (Grade 3)
Msec
Absolute QTcF interval
<450
450 to <480 (Grade 1)
480 to <500 (Grade 2)
500 (Grade 3)
Msec
Increase from baseline 
QTcB
Increase of 30 to <60
Increase of ≥60
Msec


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The following criteria will be used to flag other ECG values that are values of potential 
clinical importance: 
ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
PR interval
<110 (L) and >220 (H)
Msec
QRS interval
<75 (L) and >110 (H)
Msec
Normal values per age group for QTcB and QTcF, derived from the 2nd and 98th percentile 
values in healthy children will be used to identify the values out of normal ranges within each 
age group.
Age 
group
0-1 
month
1-3 
month
3-6 
month
6-12 
month
1-3 
years
3-5 
years
5-8 
years
8-12 
years
12-16 
years
QTcB 
(ms) 
Boys
413 
(378, 
448)
419 
(396, 
458)
422 
(391, 
453)
411(37
9, 449)
412 
(383, 
455)
412 
(377, 
448)
411(37
1, 443)
411(37
3, 440)
407 
(362, 
449)
QTcB 
(ms) 
Girls
420(37
9, 462)
424(38
1, 454)
418 
(386, 
448)
414(38
1, 446)
417(38
1, 447)
415(38
8, 442)
409 
(375, 
449)
410
(365, 
447)
414(37
0, 457)
Data shown above as median (2nd percentile, 98th percentile)
9.4.3.
Vital Signs
Heart rate:
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.0 will be used 
to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus tachycardia’, 
‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’.
Normal values per age group for heart rate, derived from the values in healthy children will be 
used to identify the values out of normal ranges within each age group. The following criteria 
will be used to flag vital sign values that are values of potential clinical importance:
Age 
group
0-1 
month
1-3 
month
3-6 
month
6-12 
month
1-3 
years
3-5 
years
5-8 
years
8-12 
years
12-16 
years
HR 
(bpm) 
Boys
160(12
5, 190)
152(125
, 185)
134(110
, 165)
128(105
, 165)
119(95
, 155)
98(75, 
125)
88(60
, 115)
78(55
, 100)
73(50
, 100)
HR 
(bpm) 
Girls
155(13
5, 215)
154(125
, 200)
139(120
, 190)
134(105
, 185)
128(95
, 180)
101(80
, 125)
89(70
, 115)
80(60
, 110)
76(50
, 100)
Data shown above as median (lower limit of normal, upper limit of normal)
Blood pressure:


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To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Hypertension’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
Systolic Blood Pressure
120 to <140 (Grade 1)
140 to <160 (Grade 2)
160 (Grade 3)
mmHg
Increase from baseline 
Diastolic Blood Pressure
80 to <90 (Grade 1)
90 to <100 (Grade 2)
100 (Grade 3)
mmHg
To identify blood Pressure >95th percentile for specific age, gender and percentile of height, 
refer to Protocol appendix 5 Blood pressure Levels for children.
Weight (kg):
The weight values of potential clinical importance will be increase >=10% or decrease >=10% 
from baseline weight.
Temperature:
To identify temperature values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
temperature
Increase to 38
Degrees C
Decrease from baseline 
Diastolic Blood Pressure
Decrease to 35
Degrees C
9.4.4.
Left Ventricular Ejection Fraction
The following criteria will be used to flag left ventricular ejection fraction (LVEF) values that 
are values of potential clinical importance: 
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be used to 
assign categories that align with the grades for ‘Ejection fraction decreased’.


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LVEF Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute change from 
baseline LVEF

No change or any increase

Any decrease
o
>0-<10 decrease
o
10-19 decrease
o
20 decrease
o
10 decrease and LLN
o
10 decrease and below LLN
o
20 decrease and LLN
o
20 decrease and below LLN
%
Relative change from 
baseline LVEF

20 decrease and LLN

20 decrease and below LLN
%
9.5.
Disposition of Subjects
A summary of the number of subjects in each of the analysis populations described in Section 
6 will be provided. A listing of subjects included or excluded from each of analysis 
populations will also be provided.
The following summaries will be provided: 

Number (%) of subjects who are still on-therapy (based on the ‘Study Treatment 
Discontinuation’ page not completed) 

Number (%) of subjects who discontinued the study treatment (based on the ‘Study 
Treatment Discontinuation’ page) 

Primary reason for study treatment discontinuation (based on the ‘Study   
Treatment Discontinuation’ page)

Number (%) of subjects who have entered the survival follow up (based on the 
‘Study Treatment Discontinuation’ page)

Number (%) of subjects not being followed for study evaluation
A summary of the number and percentage of subjects who completed the study treatment as 
well as prematurely discontinued/withdrew from the study treatment will be displayed. 
Reasons for discontinuation/study treatment withdrawal will be presented by cycle, overall, 
and by cohort. 
A listing of study completion and discontinuation/withdrawal will be generated which will
include last dose date, and reasons for study treatment discontinuation/withdrawal.
9.6.
Protocol Deviations
Major protocol deviations are defined as those deviations from the protocol likely to have an 
impact on the perceived efficacy and/or safety of study treatments. Major protocol deviations 


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and any action to be taken regarding the exclusion of subjects or affected data from specific 
analyses are defined in protocol deviation plan.
The number and percentage of subjects in the mITT population with any protocol deviation 
will be tabulated by deviation category. All protocol deviations will be summarized and listed
including inclusion/exclusion deviations as well as other deviations. The major protocol 
deviations will be flagged.
9.7.
Demographic and Baseline Characteristics
The demographic characteristics (i.e., age, race, ethnicity, sex, baseline height, and baseline 
body weight, childbearing potential, Karnofsky/Lansky performance status, and body surface 
area (BSA)) will be summarized and listed. Age, height, weight and BSA will be summarized 
using the mean, standard deviation, minimum, median, and maximum. Categorical data (i.e., 
sex, age groups: 1 year to <2 years, 2-<12 years, 12-<18 years, race, ethnicity, 
Karnofsky/Lansky performance status, woman of childbearing potential) will be summarized 
by frequency counts and percentages; the number and percentage of subjects with missing 
data will be provided.
Disease history and characteristics at initial diagnosis and screening will be summarized and 
listed. This summary will include the following: for solid tumor, summarize primary tumor 
type, location of primary tumor type, histological grade, stage at screening, time since initial 
diagnosis, and time since most recent relapse/progression to start of study drug, TNM staging 
at screening for primary tumor, regional lymph nodes and distant metastasis, metastatic 
disease location and time since initial diagnosis; for neuroblastoma, summarize bone marrow 
lesions , staging at initial diagnosis and staging at screening. The summay will also include 
subject tibial growth plate status and its evidence of thickening. 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be listed by cohort using reported term. Separate listing will be 
presented for liver disease medical conditions 
Prior anti-cancer therapy will be coded using the World Health Organization Drug Dictionary 
(WHO-DD), then listed and summarized by ATC class, preferred term, overall and cohort by 
means of frequency counts and percentages. A summary of the number of prior anti-cancer 
therapy regimens will also be produced. 
Prior anti-cancer radiotherapy and prior cancer related surgeries will be summarized and 
listed. 
9.8.
Concomitant Medications
Concomitant medications include medications (other than study drugs) starting on or after the 
start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD), and summarized by lowest ATC class and preferred term using frequency counts 
and percentages.
These summaries will include:


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1. Medications starting on or after the start of study drug but no later than 28 days after 
last dose of study drug and
2. Medications starting prior to start of study drug and continuing after the start of 
study drug.
All concomitant medications will be listed. Any concomitant medications starting and
ending prior to the start of study treatment or starting more than 28 days after the last date of
study treatment will be flagged in the listing. 
The safety population will be used for all concomitant medications tables and listings.
10.
Efficacy
All efficacy analyses will be based on mITT population unless otherwise specified. All 
analyses will be presented by cohort. 
Subjects from different disease cohorts are assigned to one of the following categories for 
assessment of response: a) the revised RECIST guideline (version 1.1) for solid tumor and 
measurable disease, b) Response Criteria for neuroblastoma with 123I-MIBG positive lesions, 
(neuroblastoma subjects who do not have MIBG positive lesions should be assessed for 
response as solid tumor subjects with measurable disease), c) RECIST-based and/or Alpha 
Fetoprotein (AFP)-based response for hepatoblastoma.  Investigator assessments will be 
considered as primary assessments. For more detailed information, see protocol Section 10. 
10.1.
Primary Efficacy Analysis
Objective Response Rate (ORR)
The primary aim of the study is to determine the investigator-assessed objective response rate 
of pazopanib in children, adolescents and young adults (subjects) with relapsed or refractory 
rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcoma, and Ewing sarcoma.
Objective Response Rate (ORR) is defined as the percentage of subjects achieving either a 
complete or partial tumor response as per response criteria. The response rate will be
calculated from the investigator review. Confirmation will be based on the disease assessment
performed 1 cycle or the next scheduled visit after the initial response. The objective response 
rate will be computed for the 3 tumor types of primary interest.
In other words, ORR = (number of subjects with a confirmed BOR of CR + number of 
subjects with a confirmed BOR of PR) divided by the total number of subjects in the cohort.
The assessment of activity of treatment within each histology cohort will be based on the 
decision rule outlined in Section 3 in this RAP.
Analyses of the primary endpoint will also be done on the mITT and Per-Protocol populations 
based on all cumulative data collected up to the final database lock date.


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Refer to Table 1, Table 2 and Table 3 in Protocol section 10.7 for response criteria at each 
disease assessment and derivation of best overall response (BOR).
90% confidence intervals will be provided to characterize the variability around the response 
rate. 
All data relating to response from the investigator will be listed including lesion 
measurements, response assessments and best overall response.
A waterfall plot of the best percent change in target lesions from baseline until disease 
progression will be provided. The plot will be pattern-coded for best overall response. 
Indication of the subject number, cohort and best overall response will also be provided in the 
plot of duration of exposure to study treatment.  
10.2.
Secondary Efficacy Analyses
Objective Response Rate (ORR)
The objective response rate will be computed for the 4 tumor types of secondary interest 
osteosarcoma, neuroblastoma (measurable), neuroblastoma (evaluable) and hepatoblastoma.
The analysis method will be the same as that described in Section 10.1 (Primary Efficacy 
Analyses). 
If recruitment is stopped in the non-primary histology group(s) and it has less than 10 
subjects, the response data will display summary statistics and the rule in the table under 
Section 3 in this RAP will not apply.
The detailed response criteria for hepatoblastoma subjects are provided in Protocol section 
10.6, and displayed in Table 4 in Protocol section 10.7.
Progression-Free Survival (PFS)
Progression-Free survival (PFS) is defined as the interval between the date of first dose of 
protocol therapy and the earliest date of disease progression or death due to any cause. 
Progression will be based on the investigator assessment. Subjects are considered to have 
progressive disease if they have documented progression based on radiologic assessment as
determined by investigator review (defined in protocol section 10). The date of death should 
be taken from the Death page in eCRF. Death on study due to any cause will be included. For 
subjects who do not progress or die, progression-free survival will be censored at the date of 
last adequate assessment prior to starting new anti-cancer therapy. 


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If there is no adequate baseline assessment, the subjects will be censored at their treatment 
start date. Subjects without any adequate post-baseline tumor assessments will also be 
censored at their treatment start date.
For subjects who receive subsequent anti-cancer therapy the following rules will apply:

If the start date of the anti-cancer therapy is partial (i.e. either missing the day but has the 
month and year available or missing both day and month), the imputation rules described 
in Section 9.2.5.4 will be applied. No imputation will be made for completely missing 
dates.

If anti-cancer therapy is started without documented disease progression or is started prior 
to documented disease progression, then PFS will be censored at the date of the last 
adequate assessment that is no later than the date of initiation of anti-cancer therapy (i.e. if 
an assessment occurs on the same day as the start of new anti-cancer therapy the 
assessment will be used - as it will be assumed the assessment occurred prior to the 
administration of new anti-cancer therapy).

If a subject has only a baseline visit or does not have an adequate assessment that is no 
later than the date of initiation of anti-cancer therapy, PFS will be censored at the 
treatment start date.
If a subject has neither progressed nor died nor started new anti-cancer therapy, then PFS will 
be censored at the date of the last adequate assessment defined as an assessment where the 
Investigator determined  is CR, or PR, or SD. The date of assessment will be used as the 
censoring date.   
A summary of the assignments for progression and censoring dates for PFS are specified in 
the following table.
Table 5:
Assignments for Progression and Censoring Dates for PFS Analysis
Situation
Date of Event 
(Progression/Death) or 
Censoring 
Outcome
Event 
(Progression/Death)
Or Censored
No (or inadequate) baseline 
tumor assessments 
Treatment start date 
Censored
No  post-baseline 
assessments and the subject
has not died (if the subject
has died follow the rules for 
death indicted at the bottom 
of the table)
Treatment study date 
Censored


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Situation
Date of Event 
(Progression/Death) or 
Censoring 
Outcome
Event 
(Progression/Death)
Or Censored
Progression documented 
between scheduled visits
Date of assessment of 
progression1
Event
No progression (or death)
Date of last ‘adequate’ 
assessment of response2
Censored
New anticancer treatment 
started (prior to documented 
disease progression).3 
Date of last ‘adequate’ 
assessment of response2 (on or 
prior to starting anti-cancer 
therapy) 
Censored
Death without PD
Date of death
Event
1. The earliest of (i) Date of radiological assessment showing new lesion (if progression is 
based on new lesion); or (ii) Date of radiological assessment showing unequivocal 
progression in non-target lesions, or (iii) Date of last radiological assessment of target
lesions (if progression is based on increase in sum of target lesions)
2. An adequate assessment is defined as an assessment where the Investigator] determined 
response is CR, PR, or SD.
3.
If PD and New anti-cancer therapy occur on the same day assume the progression was 
documented first e.g., outcome is progression and the date is the date of the assessment of 
progression). If anti-cancer therapy is started prior to any post-baseline adequate 
assessments, censoring date should be the treatment start date.
PFS will be summarized using a Kaplan-Meier survival curve. The Kaplan-Meier estimate for 
the median progression-free survival time and the first and third quartiles will be presented, 
along with a naive approximate 90% confidence interval if there are a sufficient number of 
progressions or deaths. This analysis will be repeated on the mITT population as a supportive 
analysis of PFS.
Overall Survival (OS)
Overall Survival (OS) is defined as the time from the first dose of the study medication until 
death due to any cause. The length of this interval is calculated as the date of death minus the 
date of treatment start plus one. Subjects who have not died at the time of the analyses will be 
censored at the date of last contact (as recorded in the eCRF). Last date of contact will be 
defined as the maximum date of any visit date or the survival follow-up date. Only subject
contacts recorded in the eCRF can be used for the calculation of last date of contact.
OS will be summarized using Kaplan-Meier survival curves. The Kaplan-Meier estimate for 
the median OS time and the first and third quartiles will be presented, along with a naïve 
approximate 90% confidence interval if there are a sufficient number of deaths.


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Clinical Benefit
This is defined as the percentage of subjects achieving either a complete or partial tumor 
response or stable disease for at least two protocol scheduled disease assessments as per
RECIST criteria. 90% confidence intervals will be produced to characterize the variability 
around the point estimate. Supportive analyses will be done using the mITT and PP 
populations.
Time to Progression (TTP)
Time to Progression (TTP) is defined as the interval between the date of of first dose of 
protocol therapy and the earliest date of disease progression or death due to disease under 
study. Subjects are considered to have progressive disease if they have documented 
progression based on radiologic assessment as determined by investigator review.   
The data structure on how to assign the event and censoring to a subject is same as that 
defined in the Table 5 under PFS analysis. TTP will be calculated as the date of 
event/censoring minus the date of first protocol therapy for each subject plus one.   
TTP will be summarized using a Kaplan-Meier survival curve.  The Kaplan-Meier estimate 
for the median time to progression and the first and third quartiles will be presented, along 
with a naive approximate 90% confidence interval if there are a sufficient number of events.
Duration of Response (DOR)
Duration of response (DOR) is defined as the time from the initial response (CR/PR) to
first documented disease progression or death due to any cause, and will be determined
only for those subjects from mITT population with a confirmed response (CR or PR). This 
will be based on investigator assessed response. If a subject has not had an event (disease 
progression or death), DOR is censored at the date of last adequate tumor assessment. The 
date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or SD before an event or a censoring reason occurred. The date of
response at that assessment will be used for censoring.   
DOR will be summarized only if there are 5 or more responders from each cohort. Otherwise 
it will be presented in a listing for all the responders.
11.
Safety Analyses
Unless otherwise specified, all the safety analyses will be based on the Safety population as 
defined in Section 6 and summaries will include all events or assessments collected during the 
study. 
All safety data will be reported by cohort. Safety analyses will include but not limited to 
summaries of AEs, laboratory measures, and vitals. AEs will be summarized by maximum 
toxicity grade for each cohort. The toxicity grade for laboratory data will be calculated using 
NCI CTCAE v4.0 The lab data will then be summarized according to the subjects’ baseline 
grade and maximum grade for each cycle of therapy.


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11.1.
Extent of Exposure
The duration of exposure to Pazopanib in days (from first day to last day of treatment) will be 
summarised by cohort. Descriptive statistics including mean, median, standard deviation, 
minimum, and maximum will be calculated for time on study treatment. Exposure categories 
(in weeks) will also be summarized.
Average daily dose will be calculated as Cumulative dose (mg) / Duration of exposure to 
study treatment (day), and summarized by cohort, using the mean, standard deviation, median, 
minimum, and maximum. Actual duration of exposure will be calculated as the date of last 
dosing-date of first dosing+1.   
Study drug dose received will be summarized by cohort. Cumulative dose, actual dose 
intensity and relative dose intensity will be presented. Actual dose intensity will be calculated 
as actual total dose/actual duration of exposure. Relative dose intensity will be calculated as 
(actual dose intensity/planned dose intensity)*100. Planned dose intensity will be calculated 
as planned total dose/planned duration of exposure, where planned duration of exposure will 
be the same as actual duration of exposure. 
A by-subject listing of data on subject exposure including dose reduction, dose interruptions 
and the corresponding reasons will be produced.
The safety population will be used for all summaries and listing of study treatment. 
11.2.
Adverse Events  
AE summaries will include all AEs occurring during on-therapy period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on therapy period 
will be flagged in the listings. 
An overview summary of AEs, including counts and percentages of subjects with any AE, 
grade ¾ AEs, AEs related to study treatment, AEs leading to permanent discontinuation of 
study treatment, AE leading to dose reductions, AEs leading to dose interruptions,  SAEs, 
SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study treatment will be 
produced
A summary of on-therapy AEs will be provided by primary system organ class (SOC) and 
preferred term (PT) and by PT only All non-serious adverse events, regardless of study drug 
relationship, by SOC and PT will be summarized.
Adverse events (AEs) will be graded according to the CTCAE, Version 4.0. Adverse events 
will be coded to the preferred term (PT) level using the Medical Dictionary for Regulatory 
Affairs (MedDRA ).
In AE summaries, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in two ways: 1) in descending order of total incidence by PT only and 2) in 
descending order of total incidence by System Organ Classes (SOC) and PT. In the SOC row, 
the number of subjects with multiple events under the same system organ class will be 


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counted once. The primary system organ class (SOC) will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order 
for the preferred term will be based on their frequency.
In addition, a summary of number and percentage of subjects with any on-therapy adverse 
events by maximum grade will be produced. AEs will be sorted by preferred term (PT) in 
descending order of total incidence. The summary will use the following algorithms for 
counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several times 
with different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only once at 
the maximum grade no matter how many events they have.
A separate summary will be provided for study treatment-related AEs. A study treatment-
related AE is defined as an AE for which the investigator classifies the relationship to study 
treatment as “Yes”. A worst case scenario approach will be taken to handle missing 
relatedness data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing. The summary table will be displayed in descending order of 
total incidence by SOC and PT and by PT only. Note all treatment-related AEs will be 
included in the summary regardless of assessment window.
All AEs will be listed. 
A listing of adverse events recorded as dose-limiting toxicities will be provided. Additionally, 
a summary of the number of subjects experiencing DLT’s in each cohort will be provided.
11.3.
Identified and Potential Risks
N.A.
11.4.
Deaths and Serious Adverse Events
In the event that a subject has withdrawn consent, no data after the withdrawal of consent date 
from this subject including death is supposed to appear in the database.  Ensuring that this rule 
is followed should be part of the data cleaning process. 
All deaths will be summarised based on the number and percentage of subjects. This summary 
will classify subject status (dead, alive at last contact follow-up ended, alive at last contact 
follow-up ongoing), subjects by time of death relative to the last dose of medication (>28 days 
or 28 days), and primary cause of death. A supportive listing will be generated to provide 
subject-specific details on subjects who died. 
All SAEs will be tabulated based on the number and percentage of subjects who experienced 
the event by cohort. Separate summaries will also be provided for study treatment-related 
SAEs, fatal SAEs and study treatment related fatal SAEs. Treatment-related SAE by SOC, 
PT, and maximum CTC grade will be summarized. The summary tables will be displayed in 
descending order of total incidence by SOC and PT and by PT only.


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A study treatment-related SAE is defined as an SAE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst case scenario approach will be taken to 
handle missing data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ for missing. 
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for

Fatal SAEs 

Non-Fatal SAEs.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables will be 
generated.
(1) On-therapy adverse events which are not serious adverse events with an incidence 
greater than 5%.
If for a same subject, several consecutive AEs (irrespective of study treatment 
causality, seriousness and severity) occurred with the same SOC and PT:
•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end 
date of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to 
study treatment / non SAE has to be checked in a block e.g., among AE's in a  ≤ 1 day 
gap block, if at least one SAE is occurring, then one occurrence is calculated for that 
SAE
(2) On-therapy deaths and serious adverse event by system organ class and preferred term 
including the number of deaths resulting from SAEs suspected to be related to study 
treatment and SAEs irrespective of treatment.
11.5.
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant 
Adverse Events
The following categories of AEs will be summarized separately in descending order of total 
incidence by SOC and PT and separate supportive listings will be generated with subject level 
details for those subjects:

AEs Leading to Discontinuation/Withdrawal of Study Treatment 

AEs Leading to Dose Interruptions

AEs Leadings to Dose Reductions


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11.6.
Pregnancies 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE as 
described in the protocol. If subjects become pregnant while on the study, the information will 
be included in the narratives and no separate table or listing will be produced.
11.7.
Clinical Laboratory Evaluations
Data from all sources (central and local laboratories) will be combined. The summaries will 
include all laboratory assessments collected no later than 28 days after the last study treatment 
administration date. All laboratory assessments will be listed and those collected later than 28
days after the last study treatment date will be flagged in the listings.
Laboratory data will be classified into CTC grades according to the NCI CTCAE v4.0. For all 
reports, CTC grade is always obtained on the converted measurement in SI unit. Grade 5 will 
not be used. The CTC grade 0 will be assigned as below in different scenarios:
1. For lab parameters defined by criteria based on normal range only, a severity grade of 0 
will be assigned when the value is within normal limits.   
2. For lab parameters whose grade is defined by criteria based on normal range and absolute 
values (e.g. platelet count decrease). A severity grade of 0 will be assigned when the value 
is within normal limits. 
3. For lab parameters whose grade is defined by criteria based on normal range and the 
change from baseline value, with no other associated clinical criteria such as concomitant 
medication (e.g. creatinine increased) the following will be applied. For the baseline 
grading and for the grading of post-baseline lab values with missing baseline grading, the 
grade will be derived using the criteria based only on the normal range as per CTCAE 
v4.0. A severity grade of 0 will be assigned when the post-baseline value is ≤ ULN (for 
hyper) or ≥ LLN (for hypo).
Parameters for which a grading does not exist will be classified into low/normal/high group 
by means of laboratory normal ranges.
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
The following summaries will be produced by cohort for the hematology and Biochemistry 
laboratory data:

Shift tables using CTCAE grades to compare baseline to the worst post-baseline value.


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
For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst post-
baseline value.
The following listings will be produced for laboratory data:

Listing of subjects with laboratory abnormalities of CTC grade 3 or 4

Listing of subjects with laboratory values outside the laboratory normal ranges with 
values flagged to show the corresponding CTCAE grades and the classification 
relative to the laboratory normal range. Non- normal lab values collected outside the 
on-threapy period will be also reported in listings and flagged accordingly.
Summaries will include data from scheduled assessments only except for the worst case post 
baseline which will include all post baseline assessments including unscheduled visits, and all 
data will be reported according to the nominal visit date for which it was recorded; no visit 
windows will be applied.
Summary of lab values and change from baseline by scheduled visits using mean, median, 
standard deviation, minimum and maximum will be provided. Supporting listings of all 
laboratory data will be provided including scheduled and unscheduled assessments and values 
identified from SAE reports.
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit 
will be based on the number of subjects with non-missing value at each particular visit.
11.7.1.
Analyses of Liver Function Tests
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. Liver function parameters of interest 
are total bilirubin (TBL), ALT, AST and alkaline phosphatase (ALP).  
Possible Hy’s law cases are defined as any elevated AST or ALT>3×ULN, total 
bilirubin≥2×ULN and ALP<3×ULN/missing. Total bilirubin≥2×ULN can be within 28 days 
following the ALT elevation and if direct bilirubin is available on the same day, it must be ≥ 
35% of total bilirubin. ALP<3xULN/missing means the criteria is satisfied unless the ALP is 
≥3xULN at any time of bilirubin elevation within the 28 days window.
Following supporting listings will be provided:

Listing of Potential Hy’s Law Cases

Listing of Liver Events in Relation to Time of Treatment
listing of laboratory data (virology) will be provided.
11.8.
Other Safety Measures    
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit 
will be based on the number of subjects with non-missing value at each particular visit.
Vital Signs


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Values of vital signs (blood pressure, heart rate, and temperature) and weight as well as the 
change from baseline collected on-therapy will be summarized by scheduled visit using mean, 
median, standard deviation, minimum and maximum. Values measured outside of on-therapy 
period will be flagged in the listing.
For analysis of vital signs, the clinically notable vital sign criteria are provided in Section 
9.4.3. Error! Reference source not found. Vital signs shift table based on values classified 
as notable low, normal, notable high or notable (high and low) at baseline and worst post-
baseline will be produced by cohort for systolic blood pressure, diastolic blood pressure, heart 
rate, and body temperature. Baseline is defined as the last non-missing value prior to or 
coinciding with first dose. The worst post-baseline value refers to the worst post-baseline
value on therapy. 
Performance Status
Lansky and Karnofsky performance status will be summarized at baseline and each post-
baseline scheduled visit. Summaries will use frequency and percentage of subjects at each 
planned assessment time. A summary of change from baseline by scheduled visits will be 
performed, as well as the worst case post-baseline and the best case post-baseline changes 
during the study.
A supporting listing will also be provided. 
ECG
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst case post-baseline. 
All ECG summaries will include assessments performed no later than 28 days after the last 
date of study drug.  All ECG assessments will be listed, and those collected later than 28 days 
after study drug discontinuation will be flagged in the listing.
The number and percentage of subjects with clinically notable ECG values will be presented 
by cohort. The clinically notable ECG criteria are provided in Section 9.4.2.
For each of the QTc and QT intervals, shift tables based on notable parameter categories 
(<450, 450 - <480, 480 - <500, 500 ms) and normal range at baseline and the worst post-
baseline value observed will be produced.
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: 31-60 and >60 msec. A summary of change in QTc value will 
display the number and percentage of subjects with a change within each range at each 
scheduled assessment time and in the worst case post-baseline assessment. Subjects with 
missing baseline values will be excluded from this summary.
Unscheduled ECG measurements will be used in the analysis of notable ECG changes and the 
shift table analysis of notable QT parameters for the worst case post baseline assessment.
Listings of abnormal ECG findings and a listing of ECG values will be provided.
LVEF
Absolute change from baseline in LVEF will be summarized at each scheduled assessment 
time and in the worst case post-baseline. Only the post-baseline assessments that used the 


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same method (ECHO or MUGA) as the baseline assessments will be used to derive the 
change from baseline. The change from baseline will be categorized as follows:

Any increase

No change

Any decrease:
o
0 - <10% Decrease
o
10 -    <20% Decrease
o
≥20% Decrease

≥10% decrease and ≥ LLN

≥10% decrease and < LLN

≥20% decrease and ≥ LLN

≥20% decrease and < LLN
LVEF results will also be listed with subject level details including absolute change from 
baseline.
12.
Pharmacokinetic Analyses
12.1.
Sampling Schedule
All subjects will have pre-dose blood samples on Cycle 1 Day 1 and Cycle 1 Day 15 and a 3-4 
hours post-dose sample on Cycle 1 Day 15 collected for analysis of pazopanib plasma 
concentration. Pre-dose blood sample will be collected on every subsequent odd-numbered 
cycle (Cycles 3, 5, etc.). 
Extended PK sampling will be done during Cycle 1 in the first subjects who receive the 
powder suspension formulation, until 6 subjects are considered evaluable for the PK analysis. 
These subjects will have a blood sample for analysis of the plasma pazopanib concentration 
collected at the following time points on both Cycle 1 Day 1 and Cycle 1 Day 15: pre-dose 
and at 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after the dose.
12.2.
Pharmacokinetic Analysis
The PK and PKES population will be used for listings and summaries. The PKES population 
will be used for the figures.
Pazopanib concentrations will be listed by dose and cohort. Summary tables for PK and PKES 
populations for pazopanib concentrations will be presented by cycle/day, dose, and cohort. 
Similar summary tables of pazopanib concentrations will be presented by cycle/day and dose 
combining data from all cohorts. The following summary statistics for pazopanib plasma 
concentrations will be calculated: n, median, minimum, maximum, arithmetic mean, CV%
mean, standard deviation, geometric mean, CV% geometric mean.


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Steady state trough plasma pazopanib concentrations will be determined for all subjects in the 
PK population. A concentration will be considered to be at steady state if the subject has taken 
10 consecutive daily pazopanib doses without a dose reduction or interruption. A pre-dose 
concentration will be considered a trough sample if collected between 22-26 hours after the 
previous dose of pazopanib. Concentrations which are not at steady-state will be listed and 
flagged but excluded from summary tables for steady state concentrations. Similarly,
concentrations which are not considered trough (blood sample taken after dosing or outside 
window 22-26 hours after previous dose) will be listed and flagged but excluded from 
summary tables. 
The change in steady state trough plasma pazopanib concentrations will be characterized at 
the first cycle and each odd cycle after the first. The effect of cycle on change in steady-state 
plasma trough concentrations for each cohort will be assessed for each dose graphically by 
plotting median steady state trough concentrations against Cycle number.
If no substantial effect of the cycle is observed, steady-state trough concentrations will be
combined for all sampling occasions and summarized by dose and cohort. Similar summary 
table will be presented by dose combining data from all cohorts.
A summary table summarizing pazopanib concentrations at each sampling occasion and a 
figure for pazopanib concentrations versus time by sampling occasion (Cycle 1 Day 1 and 
Cycle 1 Day 15) will be generated using PKES population combining data from all cohorts.
12.3.
Pharmacokinetic parameters
The following pharmacokinetic parameters will be determined from the plasma concentration-
time data for pazopanib from subjects who received pazopanib suspension and had extended 
pharmacokinetic sampling (Table 6). 
Table 6
Non-compartmental PK parameters for pazopanib
AUC0-24
The AUC from time zero to 24 hours post dose (ng*hr*mL-1) (Day 
15 only)
AUClast
The AUC from time zero to the last measurable plasma concentration 
sampling time (tlast) (ng*hr*mL-1) (Day 1 and Day 15
Cmax
The maximum (peak) observed plasma concentration following a 
single dose administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma concentration following a 
single dose administration (hr)
The pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to the Sponsor’s current working practices and using WinNonlin version 6.3 or 
higher.  The analysis to assess pazopanib pharmacokinetics after administration of the 
suspension prior to continuing enrollment on the suspension cohort may be performed using 


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scheduled time. All calculations of non-compartmental parameters for the final analysis will 
be based on actual sampling times.
12.3.1.
Statistical Analysis of Pharmacokinetic Parameters
All derived pharmacokinetic parameter values will be listed by dose, formulation, cycle/day, 
and cohort. PK parameters will be summarized by dose, formulation and cohort for both 
Cycle 1 Day 1 and Cycle 1 Day 15. PK parameters will also be summarized for both Cycle 1 
Day 1 and Cycle 1 Day 15 combining data from all cohorts. For each of the PK parameters 
except Tmax, the following summary statistics will be calculated: n, median, minimum, 
maximum, arithmetic mean, CV% mean, standard deviation, geometric mean, CV%
geometric mean. For Tmax, n, median, maximum and minimum will be calculated. 
Steady state trough plasma pazopanib concentration values will be combined for all sampling 
occasions and summarized by age subgroups (28 days to <2 years, 2 to <12 years old, 12 to 18 
years old) for each dose, cohort, and formulation unless a cycle effect on steady-steady trough 
concentration is identified. A similar analysis will combine data across all disease cohorts 
unless pharmacokinetic differences between the cohorts are observed.
PK parameters will be summarized by age subgroups (28 days to <2 years, 2 to <12 years old, 
12 to 18 years old) for each dose, cohort and formulation. A similar analysis will combine PK 
parameters across all disease cohorts unless pharmacokinetic differences between the cohorts 
are observed.
12.4.
Assessment of pazopanib exposure from suspension 
formulation
Pazopanib exposures in subjects on the suspension formulation will be assessed by numerical 
comparison against exposures associated with efficacy in adult subjects. The proportion of 
subjects with steady state trough values above 20.5 (ug/mL), which is the efficacy threshold 
identified in subjects with advanced RCC (Shuttle et al 2014) will be calculated for each 
formulation, dose level, and cohort. A similar calculation will be presented combining 
subjects from all cohorts. If there is more than 1 steady state trough value for each subject, the 
first will be used.
12.5.
Exploration of pharmacokinetic and pharmacodynamic 
relationship
Pazopanib PK/PD relationship will be explored between pazopanib steady state exposure 
(trough concentration) and biomarkers (angiogenic cytokines), efficacy (clinical benefits) or 
safety (drug related grade 2 and above hypertension). The analysis of the correlation of PK 
and biomarker will be described in a separate analysis plan. The proportion of subjects with 
steady state trough concentration above 20.5 ug/mL will be summarized for those with 
clinical benefits and  those who do not have any clinical benefits. The steady state trough 
concentration will also be summarized by drug-related grade 2 and above hypertension.  


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13.
REFERENCES
Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials, 
1989; 10:1-10.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics, 
1982; 38:29-41.
GUI_114801: Guidance on the Content and Format of Clinical Summary Document Analysis 
Plans
GUI_51349: Information for Authors: Clinical Pharmacology Reporting and Analysis Plan
GUI_137354: Information for Authors: Reporting and Analysis Plans
Hollander M, Wolfe DA. Nonparametric Statistical Methods. 2nd ed. New York: John Wiley 
& Sons; 1999.
Suttle AB, Ball HA, Molimard M, Hutson TE, Carpenter C, Rajagopalan D, Lin Y, Swann S, 
Amado R, Pandite L. Relationships between pazopanib exposure and clinical safety and 
efficacy in subjects with advanced renal cell carcinoma. Br. J. Cancer 2014; 111:1909-1916.