Clinical trial NCT01396148
Conditions: Gastrointestinal Stromal Tumors
Keywords: Children and young adults with GIST sunitinib malate pharmacokinetics tumor response overall survival tumor KIT mutation status
Sponsor: Pfizer
Start date: 2012-06-01; Completion date: 2017-08-01
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: 

Brief summary:
Children and young adults with gastrointestinal stromal tumors (GIST) will be treated with sunitinib. The safety (including pharmacokinetics) and tolerability of sunitinib will be studied in these patients. In addition, tumor responses and overall survival will be assessed.

Detailed description:

Arms: arm 1: children ages 6yrs-\<18yrs arm 2: young adults ages 18yrs-\<21 yrs
Interventions: intervention 1: sunitinib malate dose escalation intervention 2: sunitinib malate
Intervention descriptions: intervention 1: sunitinib starting dose will be 15mg/m\^2 daily on a 4 weeks on/2 weeks off schedule (Schedule 4/2). intervention 2: sunitinib 50mg daily on Schedule 4/2

Protocol documents:
Prot_000.pdf: 
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A PHASE I/II STUDY OF SUNITINIB IN YOUNG PATIENTS WITH
ADVANCED GASTROINTESTINAL STROMAL TUMOR
Compound:
SU011248 L-malate salt
Compound Name:
Sunitinib malate
US IND Number:
62,382
European Clinical Trial Database 
(Eudra CT) Number:
2011-002008-33
Protocol Number:
A6181196
Phase:
I/II
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
The name, title, address and telephone number(s) of the sponsor's medical expert for the trial 
is documented in the study contact list located within the Study Manual.


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Document History
Document
Version Date
Summary of Changes and 
rationale
Amendment 1
11 June 2012
The Schedule of Activities
and associated protocol 
sections were revised to 
include growth and pubertal 
maturation assessments for 
paediatric patients, a reduced 
mandatory visit schedule 
after Cycle 3, and 
clarification of standard 
tumor analysis requirements.
The term “chemotherapy 
naïve” was removed from 
the study design and the 
associated secondary 
objective to study 
tolerability in pediatric 
patients with GIST.
Multiple changes were made 
according the new Pfizer 
standard safety language for 
clinical protocols.  One 
significant change in safety 
language is the following in 
Section 8.2 Reporting 
Period: Should an 
investigator be made aware 
of any SAE occurring any 
time after the active 
reporting period, it must be 
promptly reported.  
Previously, this SAE 
reporting required a 
potential causal relationship 
to the study drug.
A change in contraception 
language for the UK was 
made at the request of the 


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UK regulatory authorities.
Administrative changes and 
clarifications made 
throughout.
Amendment 2
31 July 2017
The number of patients to be 
enrolled in the study (in the 
range of age from 6 to < 18)  
has been reduced from 15 to 
6 evaluable patients. 
The centralized review of 
imaging (ie, MRI, CT scans 
etc) aimed to confirm the 
efficacy endpoint is no 
longer required.
As this study is part of a PIP, 
both these changes above 
have been agreed with 
PDCO and are aligned with 
the PIP binding elements. 
Rationale for changes are as 
follow:
The primary objective of the 
study is the characterization 
of plasma PK profile of 
sunitinib and its active 
metabolite in patients with
unresectable GIST.  A total 
of six pediatric patients
have been included in the 
study as of today, and the 
enrollment of additional 
patient is unlikely due to the 
rarity of the disease.  
Recognizing this number is 
lower than originally 
planned it still allows the 
characterization of the pk 
profile in pediatric patients 
i.e the analysis of the
primary endpoints of the 


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study. 
In regards to the centralized
review of imagine, this is 
considered no longer 
necessary due to the small 
number of patients enrolled, 
and in absence of PR or CR.
The wording related to the 
reporting of SAE has been 
aligned with the current 
protocol template.
New text: SAEs occurring to 
a patient after the active 
collection period has ended 
should be reported to the 
sponsor if the investigator 
becomes aware of them; at a 
minimum, all SAEs that the 
investigator believes have at 
least a reasonable possibility 
of being related to 
investigational product are 
reported to the sponsor.
Original Protocol 
11 October 2011
NA


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PROTOCOL SUMMARY
Gastrointestinal stromal tumor (GIST) is a tumor of mesenchymal origin occurring in the 
gastrointestinal tract.  GIST is a very rare and newly recognized tumor in children.  Pediatric 
GIST has a different clinical behavior and biology than typical adult GIST.  The majority of 
pediatric GIST occurs in females, and these tumors commonly do not bear the genetic 
mutations present in adults with GIST.
Sunitinib (SUTENT) received approval from the US FDA and the European Medicines 
Agency (EMA) in 2006 for the treatment of GIST after disease progression on or intolerance 
to imatinib mesylate.  Following negotiations with the EMA’s Pediatric Committee (PDCO), 
the sponsor (Pfizer) agreed to conduct this single agent, open-label, single arm, multi-centre 
trial of sunitinib to investigate the use of sunitinib for the treatment of pediatric GIST, 
collecting safety, pharmacokinetic (PK) and efficacy data in at least 6 children aged 6 years 
to less than 18 years with a primary endpoint of PK parameters of sunitinib and its active 
metabolite SU012662. 
The primary objective of this study is to characterize the plasma PK profile of sunitinib and 
its active metabolite SU012662 in children and young adults with advanced, unresectable 
GIST.  Secondary objectives include evaluation of whether doses greater than the established 
pediatric maximum tolerated dose (MTD) are tolerated in pediatric patients with GIST, and 
the safety, tolerability, and anti-tumor activity of sunitinib in children and young patients 
with GIST.  The study will explore PK-pharmacodynamic relationships with respect to safety 
and efficacy if data allows.  The primary endpoint will be the PK parameters of sunitinib and 
its main active metabolite including total plasma exposure (AUC24) and oral clearance 
(CL/F).  Secondary endpoints will include the definition of adverse events and laboratory 
abnormalities, the objective response rate (ORR), duration of response, progression-free 
survival (PFS), and the overall survival (OS) at 2 years after study enrollment.  
Pharmacokinetic-pharmacodynamic relationships with respect to safety and efficacy in 
pediatric GIST will be detailed, if data allows. 
Study Design: This study is a single arm, multi-center, multi-national, trial evaluating the 
PK, safety and preliminary anti-tumor efficacy of sunitinib in children and young adults 
diagnosed with advanced, unresectable GIST.  The study aims to enroll 6 evaluable children 
aged 6 years to less than 18 years.  In addition, up to 15 young adults aged 18 years to less 
than 21 years may be enrolled.  The starting dose of sunitinib in children will be 
approximately 15 mg/m2/day for 4 weeks followed by 2 weeks with no study drug, using the 
MTD established during the pediatric Phase 1 clinical trial conducted by the Children’s 
Oncology Group.  Intrapatient dose escalation of sunitinib will be allowed, based on 
tolerability.  Investigators will have the option to access real-time PK results to aid in dosing 
decisions.  Sunitinib dosing for the young adults will follow approved guidelines (per current 
USPI and SmPC).  Study treatment for all patients may continue for up to 18 cycles, equaling 
approximately 2 years of therapy.


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Statistical Plan: Descriptive statistics for observed and dose-corrected (where appropriate) 
pharmacokinetic data will be reported for all patients with at least one pharmacokinetic 
observation by presenting the population size, arithmetic mean, standard deviation, percent 
coefficient of variation (CV%), median, minimum, maximum values.  In addition, geometric 
mean and the 95% confidence interval (CI) for the geometric mean, will be reported where 
appropriate.  Other endpoints, including safety and efficacy endpoints, will be collected, 
analyzed and presented descriptively.


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Table 1.
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol.
Protocol Activity
Screen
<28 days 
of first 
dose
Cycles 1-3 (Days 1-42)[23]
Cycles 4-18 [23]
End of 
Treatment [4]
Follow-up
+/- 7 days
D1 [2] 
(D-2 to D2)
D15 Visit[3]
D12-D18, 
inclusive
D28 Visit[24]
D25-D29, 
inclusive
Therapy
Break
D29-42
Day 1
(D-2 to D2)
Baseline Documentation
Informed Consent 
X
Tumor characteristics [1]
X
Medical/Oncologic History [5]
X
PE including Wt, Ht, Vital Signs, 
Lansky/ECOG [6]
X
X
X
X
X
X
X[Per 
6.3.1]
Baseline Signs/Symptoms
X
Laboratory Studies
Hematology & Chemistry [7]
X
X
X
X
X
X
X[Per 
6.3.1]
TSH [8]
X
X
Even Cycles 
Only
X[8]
Prothtrombin time (PT or INR) [8]
X
If clinically indicated.
Urinalysis [9]
X
Cycles 2-3 only
Cycle 4 Only
X
Urine Pregnancy Test [10]
X
X
X
X
Pharmacokinetic Sampling [11]
Cycle 1: Pre-dose 
and 2,4,6,8 hrs post 
first dose
Cycles 2&3: 
Pre-dose
Pre-dose
Pre-dose
Sunitinib Dosing [12]
X
X
X
X
Assessments
Chest radiograph [13]
X
If clinically indicated.


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Protocol Activity
Screen
<28 days 
of first 
dose
Cycles 1-3 (Days 1-42)[23]
Cycles 4-18 [23]
End of 
Treatment [4]
Follow-up
+/- 7 days
D1 [2] 
(D-2 to D2)
D15 Visit[3]
D12-D18, 
inclusive
D28 Visit[24]
D25-D29, 
inclusive
Therapy
Break
D29-42
Day 1
(D-2 to D2)
Tumor assessment(s) [14]
X
X
prior to the end of 
Cycle 2
X
prior to the end 
of each even 
numbered cycle
X
FDG-PET [15]
X
Cycle 1 Only
12-lead ECG [16]
X
Cycle 2 Only
X
ECHO or MUGA Scan [17]
X
Cycle 3 only
Every 3rd cycle 
(ie Day 1 of 
Cycles 6, 9, 12, 
etc)
X [Per 
6.4.1]
Adverse Events [18]
Throughout study participation
Study Drug Compliance [19]
Concomitant Treatments [20]
Follow-up Survival Monitoring [21]
X
Growth and Pubertal Maturation [22]
X
See footnote [22]
X
1.
Tumor characteristics: Tumor KIT, PDGFRA, and BRAF genotype and succinate dehydrogenase (SDH) protein expression by immunohistochemistry.  
If some or all of these have not been previously done, tumor specimens may be sent for analysis during screening.  For patients with no available, 
previously collected tumor tissue and incomplete testing information covering all of the above tests, a core biopsy is required, unless, in the opinion of the 
investigator, a biopsy would create an unacceptable risk to the patient. Refer to Section 6.1 for additional details and exceptions.
2.
Day 1 Assessments: Physical examination, hematology, blood chemistry and urinalysis are not required if acceptable screening assessments are obtained 
within 7 days prior to the start of study treatment without suggestion of clinical deterioration. Day 1 of subsequent cycles may commence up to two days 
prior to the scheduled Day 1 visit until one day after the scheduled visit (ie, the washout period can be from 12-15 days).
3.
D15 visit.  Day 15 of Cycle 1 is a mandatory visit, which includes PK, lab tests, and physical exam.  For Cycles 2 and 3 a Day 15 visit is required if dose 
escalation occurs during that cycle, and includes PK, lab tests, and physical exam.  Beyond Cycle 3 Day 15 visits will only occur if a dose escalation 
occurs or as clinically indicated.  PK will not be collected at these additional Day 15 visits but lab tests and physical exam will be performed.
4.
End of Treatment/Withdrawal: Assessments (See Section 6.4.1) not required if performed within 1 week of study withdrawal (within the last 8 weeks 
for radiological tumor assessments).
5.
Medical/Oncologic History and Demographics: Includes demographics, oncologic history, history of other diseases (active or resolved), concomitant 
illnesses, and information on prior cancer treatments including best response observed.  Changes in blood pressure medications (new prescriptions, 
discontinuations, or changes in dose) will also be recorded.


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6.
Physical Examination: Lansky/ECOG Performance Scale (see Appendix 5) and height for young adults at screening only; Height and weight required at 
screening and Day 1 of each cycle and at EOT for pediatric patients.  Examination of major body systems; vital signs to include temperature, blood 
pressure (see Section 5.2.11 for guidelines), heart rate and respiratory rate.  Abnormal physical examination findings after screening will be reported as
adverse events. Patients below the age of 11 who turn 11 while on-study will then require ECOG performance evaluations.
7.
Hematology & Chemistry: Required safety tests are also listed in Section 7.2.2.  These include white blood count with differential, hemoglobin, and 
platelets; sodium, potassium, chloride, blood urea nitrogen (BUN), serum creatinine, glucose, uric acid, calcium, magnesium, phosphorous, total 
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total protein, albumin, amylase, and lipase.  At any 
time after initiation of dosing if liver function tests are abnormal refer to Section 8.5.2 for guidelines. On visits that do not include dispensation of study 
drug, these tests may be performed by labs outside of the study sites in cases where patient travel to the study clinic is not possible.
8.
TSH at screen and Day 1 of Cycles 2, 3, and 4, followed by Day 1 of every even cycle (ie, 6, 8, 10 …etc.) thereafter (see also Section 6.2). Prothrombin 
time: PT or INR at screening, then as clinically indicated.  When performed, the same test should be used.
9.
Urinalysis: During screening and Cycles 2-4, as clinically indicated and at end of treatment.  Only protein will be captured on the CRF.  If the results of 
the dipstick test indicate a ≥2+ proteinuria, then follow-up should be performed with a quantitative urine protein analysis according to local standard 
practices, with data captured on the AE CRF if AE criteria are met.
10. Pregnancy Test: Urine test required for all females above age 11 within 7 days prior to administration of the first dose of sunitinib, on Day 1 of each 
cycle, and at the end of treatment.  Patients of less than 11 yrs at study start who turn 11 while on-study will then require pregnancy testing per the 
Schedule of Activities. Refer to Section 7.2.3 for details.
11. PK sampling: All PK samples collected before and on the Cycle 1 Day 28 Visit should be shipped immediately to BASi Lab for bio-analysis; refer to 
Section 7.1 for details.  Optional Visit Days are C1D7 (D4-D10, inclusive) and C1D21 (D18-D24, inclusive); refer to Section 7.1 for details.
12. Sunitinib dosing: Sunitinib will be dosed Days 1-28 of each cycle followed by a 2 week break in therapy.  Dosing will be on an outpatient basis except 
on days when PK sampling is performed. Capsules should be taken once daily in the morning on the first 28 days of each cycle with the exception of 
study visit days on which the dose for that day should be withheld until immediately after the completion of all study visit day activities and the 
investigator’s approval for continued dosing. See Section 5.2.3 for details.
13. Chest radiograph at screening and as clinically indicated. Patients who undergo Tumor Imaging (MRI or CT scan) that includes the chest do not need to 
have a Chest radiograph performed.
14. Tumor Imaging: MRI (or CT scan) of abdomen and pelvis and any other applicable sites of disease at screening, within 14 days prior to the end of each 
even numbered cycle (Day 28, preferably), whenever disease progression is suspected, to confirm a partial or complete response (at least 4 weeks after 
initial documentation of response), and at the End of Treatment/Withdrawal (Refer to Section 7.4).
15. FDG-PET at baseline and at the cycle 1 day 28 visit (if locally available; see Section 7.4).
16. ECG: Three consecutive 12-lead ECGs approximately 2 minutes apart will be performed at screening, on Cycle 2, Day 1 and at the end of treatment to 
determine the mean QTc interval.  Attempts should be made for the ECGs to be performed in the morning and time-matched (1 hour) with screening 
assessment.  ECGs should be done before blood is drawn or 30 minutes afterwards.  If the mean QTc interval is prolonged (>500 msec), the ECGs should 
be read by a cardiologist at the site for confirmation.  Additional ECGs may be performed as clinically indicated.  ECG should be performed 
approximately 2 weeks following any sunitinib dose escalation.
17. Echocardiogram or MUGA scan at screening, then on Day 1 of every 3rd cycle (for example, Day 1 Cycle 3, Day 1 Cycle 6 ..etc.).  As clinically 
indicated at the end of treatment/withdrawal per Section 6.3.1 and see suggested dose modifications guidelines for left ventricular systolic dysfunction in 
Section 5.2.10.


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18. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until 28 days after the last dose of study treatment, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse events 
should be monitored and reported from the time that the patient provides informed consent as described in the protocol.
19. Study Drug Compliance: Unused sunitinib will be returned to clinic for drug accountability at the beginning of each subsequent cycle.
20. Concomitant Medications/Treatments will be recorded from 28 days prior to the start of study treatment, during the study and up to 28 days after the 
last dose of sunitinib. 
21. Follow-up Survival Monitoring: Follow-up survival information, including post-study anti-cancer treatment, will be collected by clinic visit or 
telephone contact every 3 months until death, or either 24 months from patient’s first dose of study treatment or completion of 18 cycles.  See 
Section 6.3.2.
22. Growth and Pubertal Maturation Assessments (for pediatric patients only): Bone age assessments must be performed at screening, and then 
annually with an additional test at End of Treatment or until growth plate closure. Tanner staging must be performed at screening.  If patient is Tanner 
Stage 1-4, then Tanner assessment should be repeated every 6-9 months and at End of Treatment or until patient reaches Tanner Stage 5. Refer to 
Section 7.3 Growth and Pubertal Maturation Assessments.  Tanner staging assessments can only be waived upon agreement by Pfizer.  If Tanner staging 
is initiated it should be continued per Section 7.3.
23. Reduced Visit Schedule Following Cycle 3: Following Cycle 3, patients may visit the clinic on Day 1 (within Day 12-15 of the previous sunitinib 
washout period) of each cycle only or more frequently at the discretion of the investigator. On cycles where there is a dose escalation, a Day 15 visit is 
required. Labs and physical exam required when visits occur. Sunitinib dosing information will be collected on Day 1 of each cycle and when 
Day 15 visits occur.
24. Day 28 Visits: Day 28 monitoring for labs at discretion of investigator after Cycle 3.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
1. INTRODUCTION ...............................................................................................................16
1.1. Indication.................................................................................................................16
1.2. Background and Rationale ......................................................................................16
1.3. Introduction/Rationale for Development ................................................................16
1.3.1. Sunitinib......................................................................................................17
1.3.2. Sunitinib Pharmacokinetics and Safety in Adult Clinical Trials................17
1.3.3. Sunitinib and Adult GIST...........................................................................18
1.3.4. Pediatric Phase I Clinical Trial (ADVL0612) ............................................21
1.3.5. ADVL0612 Sunitinib Pharmacokinetic Profile..........................................22
1.3.6. Application of ADVL0612 PK Results to Young Patients with GIST ......22
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................23
2.1. Objectives................................................................................................................23
2.2. Endpoints.................................................................................................................24
3. STUDY DESIGN.................................................................................................................24
4. PATIENT SELECTION......................................................................................................24
4.1. Inclusion Criteria.....................................................................................................25
4.2. Exclusion Criteria....................................................................................................26
4.3. Life Style Guidelines...............................................................................................28
5. STUDY TREATMENTS.....................................................................................................28
5.1. Allocation to Treatment ..........................................................................................28
5.2. Drug Supplies..........................................................................................................28
5.2.1. Formulation and Packaging........................................................................28
5.2.2. Preparation and Dispensing........................................................................29
5.2.3. Sunitinib Administration ............................................................................29
5.2.4. Medication Errors .......................................................................................29
5.2.5. For Children (age less than 18 years at enrollment)...................................30
5.2.6. For Young Adults (age ≥18 years) .............................................................31
5.2.7. Criteria for Starting Subsequent Cycles .....................................................31
5.2.8. Dose Modifications.....................................................................................32
5.2.9. Minimum Sunitinib Dose Allowed.............................................................33


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5.2.10. Dose Modifications for Left Ventricular Systolic Dysfunction ...............33
5.2.11. Management of Sunitinib-induced Hypertension.....................................34
5.2.12. Management of Hypothyroidism or Adrenal Insufficiency......................36
5.2.13. Compliance...............................................................................................36
5.2.14. Study Drug Overdose Instructions............................................................36
5.3. Drug Storage and Drug Accountability...................................................................36
5.4. Concomitant Medication(s) and/or Therapy ...........................................................37
5.5. Contraindicated Medications...................................................................................38
5.5.1. Drugs with Proarrhythmic Potential...........................................................38
5.5.2. Inhibitors and Inducers of CYP3A4 ...........................................................38
5.5.3. Anticoagulants ............................................................................................39
6. STUDY PROCEDURES .....................................................................................................39
6.1. Screening.................................................................................................................39
6.2. Study Period ............................................................................................................41
6.3. Follow-up Procedures .............................................................................................43
6.3.1. Day 28 Visit................................................................................................43
6.3.2. Long Term Follow-Up................................................................................43
6.4. Patient Withdrawal / End of Treatment...................................................................43
6.4.1. End of Treatment Procedures .....................................................................44
7. ASSESSMENTS..................................................................................................................45
7.1. Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Assessments...............46
7.2. Safety Assessments .................................................................................................48
7.2.1. Adverse Events...........................................................................................48
7.2.2. Laboratory Safety Assessments..................................................................48
7.2.3. Pregnancy Testing ......................................................................................49
7.2.4. Other Safety Assessments...........................................................................49
7.3. Growth and Pubertal Maturation Assessments (Patients <18 yr only) ...................50
7.4. Efficacy Assessments..............................................................................................51
7.4.1. Time-To Event Endpoints...........................................................................51
7.4.2. Response Rate Endpoints ...........................................................................52
8. ADVERSE EVENT REPORTING......................................................................................52
8.1. Adverse Events........................................................................................................52


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8.2. Reporting Period .....................................................................................................52
8.3. Definition of an Adverse Event...............................................................................53
8.4. Abnormal Test Findings..........................................................................................54
8.5. Serious Adverse Events...........................................................................................54
8.5.1. Protocol-Specified Serious Adverse Events...............................................55
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................55
8.6. Hospitalization ........................................................................................................56
8.7. Severity Assessment................................................................................................57
8.8. Causality Assessment..............................................................................................58
8.9. Exposure During Pregnancy....................................................................................58
8.10. Occupational Exposure .........................................................................................60
8.11. Withdrawal Due to Adverse Events (See Also Section 6.4 Patient 
Withdrawal)...............................................................................................................60
8.12. Eliciting Adverse Event Information ....................................................................60
8.13. Reporting Requirements........................................................................................60
8.13.1. Serious Adverse Event Reporting Requirements .....................................60
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................61
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................61
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................61
9.1. Sample Size Determination.....................................................................................62
9.2. Analysis of Primary Endpoint.................................................................................62
9.3. Efficacy Analysis ....................................................................................................62
9.3.1. Objective Response Rate............................................................................62
9.3.2. Progression-Free Survival ..........................................................................62
9.3.3. Duration of Response .................................................................................63
9.3.4. Overall Survival..........................................................................................63
9.4. Additional Analyses ................................................................................................63
9.4.1. Study Conduct and Patient Disposition......................................................63
9.4.2. Baseline Characteristics..............................................................................63
9.4.3. Treatment Administration/Compliance ......................................................63
9.5. Safety Analysis........................................................................................................64
9.5.1. Analysis of Adverse Events........................................................................64


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9.5.2. Analysis of Clinical Laboratory Data.........................................................64
9.5.3. Concomitant Medications...........................................................................64
9.6. Interim Analysis ......................................................................................................64
9.7. Safety Review .........................................................................................................64
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................65
11. DATA HANDLING AND RECORD KEEPING .............................................................65
11.1. Case Report Forms/Electronic Data Record .........................................................65
11.2. Record Retention...................................................................................................66
12. ETHICS..............................................................................................................................66
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............66
12.2. Ethical Conduct of the Study ................................................................................66
12.3. Patient Information and Consent...........................................................................67
12.4. Patient Recruitment...............................................................................................67
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................68
13. DEFINITION OF END OF TRIAL...................................................................................68
13.1. End of Trial in a Member State.............................................................................68
13.2. End of Trial in all Participating Countries ............................................................68
14. SPONSOR DISCONTINUATION CRITERIA ................................................................68
15. PUBLICATION OF STUDY RESULTS..........................................................................68
15.1. Communication of Results by Pfizer ....................................................................68
15.2. Publications by Investigators ................................................................................69
16. REFERENCES ..................................................................................................................70
LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES ..............................................................................7
Table 2.
Summary of A6181004 Efficacy Endpoints (ITT Population).............................18
Table 3.
Adverse Reactions Reported in GIST Studies with SUTENT .............................19
Table 4.
Dose Limiting Toxicities from ADVL0612 .........................................................21
Table 5.
Available Sunitinib Doses (Using 6.25 mg, 12.5 mg and 25 mg capsules) .........31
Table 6.
Dose Modifications for Toxicity Attributed to Sunitinib for Patients 
<18 Years of Age..................................................................................................33
Table 7.
Table of Pharmacokinetic Sampling Time Points ................................................47


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APPENDICES
Appendix 1. Abbreviations......................................................................................................73
Appendix 2. ADVL0612 SUMMARY TABLES....................................................................75
Appendix 3. Blood Pressure Levels for Girls and Boys by Age .............................................78
Appendix 4. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1..............80
Appendix 5. Lansky and ECOG Performance Scales..............................................................84
Appendix 6. Sunitinib Total Daily Dose Levels per BSA.......................................................85
Appendix 7. Required Laboratory Tests..................................................................................86


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1. INTRODUCTION
1.1. Indication
Pediatric GIST
Gastrointestinal stromal tumor (GIST) is a tumor of mesenchymal origin occurring in the 
gastrointestinal tract.  GIST is a very rare and newly recognized tumor in children.  Pediatric 
GIST has a different clinical behavior and biology than typical adult GIST.1-3 In contrast to 
GIST in adults, the vast majority of pediatric GIST occur in females, lack large scale 
chromosomal aberrations, and lack the characteristic mutations in KIT or PDGFRA.  Despite 
multiple recurrences and lack of dramatic responses to tyrosine kinase inhibitor therapy, most 
pediatric patients survive with active disease for many years, suggesting a more indolent 
clinical course than observed with adult GIST.4-7 Further evidence supporting a distinct 
biology comes from recently published reports of differing gene-expression profiles and 
genetic progression mechanisms in pediatric GIST versus adult GIST.8 While most pediatric 
GIST lack KIT mutations, KIT is expressed and activated, suggesting that inhibition of KIT 
may have clinical efficacy in these tumors.1 In vitro data show that sunitinib’s IC50 is 
90% lower than imatinib’s IC50 for mutation-negative KIT.  Early clinical studies seem to 
correspond with the in vitro data.  Clinical benefit rate (defined as partial response [PR] or 
stable disease [SD] in KIT mutation-negative GIST is 56% versus 34% in adult, KIT
mutation-positive GIST.9 Median OS was also significantly longer for adult patients with 
exon 9 KIT mutations (26.9 months) or a mutation-negative genotype (30.5 months) than for 
those with exon 11 mutations (12.3 months).  Neither PFS nor OS differed significantly 
between patients with exon 9 KIT mutations or a mutation-negative genotype.  Currently 
there is no evidence to suggest that pediatric mutation-negative GIST would differ 
biologically or clinically from adult mutation-negative GIST.  A recent study suggests that a 
proportion of KIT mutation-negative GIST tumors have mutations in succinate 
dehydrogenase (SDH).10 Such mutations result in a loss of SDH expression in these tumors 
that can be assessed by immunohistochemistry.  A loss in SDH expression could potentially 
result in increases in intra-tumor VEGF expression.  Antitumor activity has been reported 
with sunitinib, which targets the VEGF signaling pathway, in a cohort of pediatric patients 
with imatinib-resistant, predominantly KIT mutation-negative GIST.5 One of seven of these 
patients achieved PR, five patients had SD and one patient had PD on sunitinib.  In most 
pediatric patients treated with imatinib followed by sunitinib, the time to progression on 
sunitinib was longer than on prior imatinib.
1.2. Background and Rationale
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the current version of the Sunitinib (SUTENT) 
Investigator Brochure (IB).
1.3. Introduction/Rationale for Development
Receptor tyrosine kinases (RTKs) are transmembrane proteins containing extracellular 
ligand-binding domains and intracellular catalytic domains.  RTKs are activated following 
binding of their cognate ligands, and many of the processes involved in tumor growth, 


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progression, and metastases are mediated by signaling molecules acting downstream from 
these proteins.11,12 Several members of the split-kinase domain family of RTKs are 
implicated in deregulated/autocrine proliferation and survival of solid and hematologic 
cancer cells, including the platelet-derived growth factor receptors (PDGFRand ); 
vascular endothelial growth factor receptors (VEGFR) Type 1 and 2 (FLT1 and FLK1/KDR); 
the stem cell factor (SCF) receptor, KIT; and the FLT3-ligand receptor.  In addition, PDGFR 
and VEGFR are implicated in tumor-dependent angiogenesis.
RTKs play a critical role in embryonic development and are potent mediators of vascular 
endothelial cell and malignant proliferation.13 Inhibitors of the RTKs, such as sunitinib, 
target mediators of tumor-related angiogenesis and cellular survival. 
1.3.1. Sunitinib
Sunitinib malate is an orally-bioavailable, small-molecule RTK inhibitor that antagonizes 
cellular signaling of multiple targets involved in tumor proliferation and angiogenesis, with 
specific activity against VEGFR, PDGFR, KIT, FLT-3 and RET.14, 15 Studies have indicated 
that sunitinib selectively inhibits Class 3 (PDGF) and Class 5 (VEGF) RTKs, and inhibits 
RTK phosphorylation in vivo.  Sunitinib has shown in vivo activity in decreasing 
VEGF-induced vascular permeability, RTK phosphorylation and tumor grown in murine 
xenograft models.16-20
In 2006, sunitinib (SUTENT) was approved by the US Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) for the treatment of GIST after disease 
progression on or intolerance to imatinib mesylate and for the treatment of advanced renal 
cell carcinoma.21,23 SUTENT was also approved by the EMA for treatment of pancreatic 
neuroendocrine tumor in 2010 and by the US FDA in 2011.
Following negotiations with the EMA’s Pediatric Committee (PDCO), the sponsor (Pfizer) 
agreed to conduct this single agent, open-label, single arm, multi-centre trial of sunitinib to 
investigate the use of sunitinib for treatment of pediatric GIST, collecting safety, 
pharmacokinetic (PK) and efficacy data in 6 children aged 6 years to less than 18 years.  The 
PDCO recommended a primary endpoint of PK parameters of sunitinib and its active 
metabolite SU012662.
1.3.2. Sunitinib Pharmacokinetics and Safety in Adult Clinical Trials
In adults, repeated dosing studies over a range of 25-100 mg daily doses followed by 
off-treatment periods have identified a 50 mg dose on the Schedule 4/2 (4 weeks of therapy 
followed by a 2-week off period) as a tolerable, dose dense regimen.22,24 Steady state levels 
of sunitinib and its active metabolite SU012662 are reached 7-10 days after repeated daily 
dosing.  Drug accumulation with repeated 4- or 6-week cycles has not been observed.  No 
dose-dependent changes in Tmax or t1/2 have been observed.  Sunitinib is metabolized 
primarily by the cytochrome P450 enzyme, 3A4 (CYP3A4).  The terminal elimination 
half-lives of sunitinib and SU012662 are approximately 40 hours and 80 hours, respectively.  
Fatigue/asthenia is the primary dose limiting toxicity (DLT); adverse events attributed to 
sunitinib, independent of treatment schedule have been constitutional (eg, fatigue/asthenia), 


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gastrointestinal (eg, nausea, vomiting, dyspepsia, diarrhea, stomatitis), dermatologic 
(eg, dermatitis, skin discoloration, hair depigmentation) and hematologic (eg, neutropenia, 
thrombocytopenia). 
1.3.3. Sunitinib and Adult GIST
A multicenter, international, randomized, placebo-controlled Phase 3 clinical trial 
A6181004 was halted after the planned interim analysis demonstrated efficacy of sunitinib in 
adult GIST patients following failure of imatinib.  Sunitinib, administered at 50 mg once 
daily for 4 weeks followed by 2 weeks with no drug, demonstrated a significant difference in 
time to progression (26.6 vs. 6.4 weeks).  Table 2 and Table 3 below summarize the efficacy 
in the GIST phase 3 study and pooled safety results for 440 adult GIST patients receiving 
sunitinib in multiple clinical studies, respectively.
Table 2.
Summary of A6181004 Efficacy Endpoints (ITT Population)
Source: A6181004 final Clinical Study Report.


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Table 3.
Adverse Reactions Reported in GIST Studies with SUTENT
System Organ Class
Adverse reaction
All Grades
n (%)
Grade 3
n (%)
Grade 4
n (%)
Blood and lymphatic system 
disorders
Anaemia
86 (19.5%) 
24 (5.5%) 
3 (0.7%)
Neutropoenia
81 (18.4%) 
39 (8.9%) 
5 (1.1%) 
Thrombocytopoenia 
67 (15.2%) 
19 (4.3%) 
6 (1.4%)
Leukopoenia
26 (5.9%)
9 (2.0%)
1 (0.2%)
Lymphopoenia
10 (2.3%)
3 (0.7%)
1 (0.2%)
Endocrine disorders
Hypothyroidism
59 (13.4%) 
5 (1.1%) 
1 (0.2%) 
Metabolism and nutrition 
disorders
Decreased appetitea
117 (26.6%) 
8 (1.8%) 
0 (0.0%)
Psychiatric disorders
Insomnia
14 (3.2%)
0 (0.0%)
0 (0.0%)
Nervous system disorders
Taste disturbanceb
105 (23.9%) 
1 (0.2%)
0 (0.0%)
Headache
76 (17.3%) 
5 (1.1%) 
0 (0.0%)
Paraesthesia 
27 (6.1%)
1 (0.2%)
0 (0.0%)
Dizziness
18 (4.1%)
1 (0.2%)
0 (0.0%)
Neuropathy 
peripheral
11 (2.5%)
0 (0.0%)
0 (0.0%)
Hypoaesthesia
10 (2.3%)
0 (0.0%)
0 (0.0%)
Vascular disorders
Hypertension
101 (23.0%)  43 (9.8%) 
0 (0.0%)
Respiratory, thoracic and 
mediastinal disorders
Epistaxis
28 (6.4%) 
1 (0.2%) 
0 (0.0%)
Dyspnoea
16 (3.6%)
2 (0.5%)
0 (0.0%)
Renal and urinary disorders
Chromaturia
18 (4.1%) 
0 (0.0%)
0 (0.0%)
Gastrointestinal disorders
Diarrhoea
187 (42.5%) 
24 (5.5%) 
0 (0.0%)
Nausea
161 (36.6%) 
15 (3.4%) 
0 (0.0%)
Vomiting
98 (22.2%) 
7 (1.6%) 
0 (0.0%)
Stomatitis
90 (20.5%) 
7 (1.6%) 
0 (0.0%)
Dyspepsia
80 (18.2%) 
4 (0.9%) 
0 (0.0%)
Abdominal painc / 
distension
77 (17.5%)
15 (3.4%)
2 (0.5%)
Flatulence
46 (10.5%) 
0 (0.0%)
0 (0.0%)
Oral pain
44 (10.0%) 
2 (0.5%) 
0 (0.0%)
Constipation
37 (8.4%) 
2 (0.5%) 
0 (0.0%)
Glossodynia
37 (8.4%) 
0 (0.0%)
0 (0.0%)
Dry mouth
31 (7.0%) 
0 (0.0%)
0 (0.0%)
Gastro-oesophageal 
reflux disease
12 (2.7%) 
1 (0.2%) 
0 (0.0%)
Mouth ulceration
11 (2.5%)
0 (0.0%)
0 (0.0%)
Oral discomfort
11 (2.5%)
0 (0.0%)
0 (0.0%)
Skin and subcutaneous tissue 
disorders
Yellow skin/
Skin discolouration
146 (33.2%) 
0 (0.0%)
0 (0.0%)
Palmar-plantar 
erythrodysaesthesia 
syndrome
106 (24.1%)  27 (6.1%) 
0 (0.0%)
Hair colour changes
67 (15.2%) 
0 (0.0%)
0 (0.0%)
Rash
64 (14.5%) 
3 (0.7%) 
0 (0.0%)
Dry skin
41 (9.3%) 
0 (0.0%)
0 (0.0%)
Alopecia
33 (7.5%)
0 (0.0%)
0 (0.0%)
Dermatitis
29 (6.6%)
1 (0.2%)
0 (0.0%)
Periorbital oedema
20 (4.5%)
0 (0.0%)
0 (0.0%)
Skin Reaction
20 (4.5%)
3 (0.7%)
0 (0.0%)


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Table 3.
Adverse Reactions Reported in GIST Studies with SUTENT
System Organ Class
Adverse reaction
All Grades
n (%)
Grade 3
n (%)
Grade 4
n (%)
Erythema
18 (4.1%)
0 (0.0%)
0 (0.0%)
Eczema
16 (3.6%)
1 (0.2%)
0 (0.0%)
Pruritus
16 (3.6%)
0 (0.0%)
0 (0.0%)
Hyperpigmentation
15 (3.4%)
0 (0.0%)
0 (0.0%)
Skin exfoliation
12 (2.7%)
0 (0.0%)
0 (0.0%)
Blister
10 (2.3%)
1 (0.2%)
0 (0.0%)
Skin lesion
10 (2.3%)
1 (0.2%)
0 (0.0%)
Musculoskeletal and connective 
tissue disorders
Pain in 
extremity/limb
54 (12.3%) 
5 (1.1%) 
0 (0.0%)
Arthralgia
39 (8.9%) 
3 (0.7%) 
0 (0.0%)
Myalgia
29 (6.6%) 
0 (0.0%)
0 (0.0%)
Muscle spasm
21 (4.8%)
1 (0.2%)
0 (0.0%)
Back pain
11 (2.5%)
2 (0.5%)
0 (0.0%)
Muscular weakness
10 (2.3%)
1 (0.2%)
0 (0.0%)
General disorders and 
administration site conditions
Fatigue/Asthenia
287 (65.2%) 
64 (14.5%) 
5 (1.1%) 
Mucosal 
inflammation
70 (15.9%)  
6 (1.4%) 
1 (0.2%) 
Oedemad
59 (13.4%) 
1 (0.2%) 
0 (0.0%)
Pyrexia
26 (5.9%)
2 (0.5%)
0 (0.0%)
Investigations
Lipase increase
35 (8.0%) 
12 (2.7%) 
7 (1.6%) 
White blood cell 
count decreasede
33 (7.5%)
15 (3.4%)
0 (0.0%)
Ejection fraction 
decreased
27 (6.1%) 
5 (1.2%) 
0 (0.0%)
Haemoglobin 
decreased
27 (6.1%) 
6 (1.4%) 
0 (0.0%)
Platelet count 
decreased
25 (5.7%)
4 (0.9%)
1 (0.2%)
Weight decreased
23 (5.2%)
1 (0.2%)
0 (0.0%)
Blood creatinine 
phosphokinase 
increased
22 (5.0%)
1 (0.2%)
1 (0.2%)
Amylase increased
21 (4.8%)
8 (1.8%)
0 (0.0%)
Aspartate 
aminotransferase 
increased
18 (4.1%)
2 (0.5%)
1 (0.2%)
Alanine 
aminotransferase 
increased
12 (2.7%)
1 (0.2%)
0 (0.0%)
Includes all adverse reactions occurring in ≥2% (all grades) of adult patients in GIST studies during treatment with 
SUTENT) Source: Adapted from the EU SUMMARY OF PRODUCT CHARACTERISTICS version approved on 
4 January 2011.
The following terms have been combined:  
a.
Anorexia and decreased appetite;
b.
Dysgeusia, ageusia and taste disturbance;
c.
Abdominal pain and abdominal pain upper;
d.
Oedema, oedema peripheral and oedema face;
e.
White blood cell count decreased, neutrophil count decreased and leukocyte count decreased.


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1.3.4. Pediatric Phase I Clinical Trial (ADVL0612)
A Phase I study conducted by the Children’s Oncology Group (COG), ADVL0612, was 
designed to evaluate the safety and tolerability of sunitinib in patients aged 2-21 years with 
advanced solid tumors.  This study has determined the MTD associated with sunitinib in this 
Phase 1 oncology population, and has characterized its safety profile and pharmacokinetics.  
Patients received sunitinib once daily for 4 weeks, followed by a 2 week break between each 
cycle.  Doses were rounded to the closest 12.5 mg.
Twenty-three patients were treated on Amendments A and B (protocol amendment explained 
below).  The median age was 13.9 years; (range, 3.9 – 20.6 years).  Table 4 summarizes the 
DLTs.  At the starting dose of 20 mg/m2 (approximately 80% of the approved adult dose), 
DLTs included grade 2 systolic dysfunction, grade 3 anorexia and grade 4 neutropenia.  The 
sunitinib dose was then de-escalated to 15 mg/m2.  DLTs in this cohort included prolonged 
grade 3 ALT elevation in 1 patient, and grade 3 diastolic plus grade 2 systolic dysfunction in 
a patient who had received maximal anthracycline therapy in addition to cardiac radiation 
exposure.  A detailed evaluation of both cases of reversible cardiac dysfunction indicated that 
these patients had received cumulative doxorubicin doses of either 
157 mg/m2 (grade 2 systolic dysfunction) or 347 mg/m2 (grade 2 systolic dysfunction) prior 
to entering the Phase I study.  There were also 8 additional patients in this study who had 
received prior anthracycline exposure where no cardiac dysfunction was detected.  However, 
it was felt that the cardiotoxicity might have been due in part to anthracycline exposure and 
in one case compounded by prior cardiac radiation exposure.  Therefore, the protocol was 
amended (Part B) to exclude patients with prior anthracycline or cardiac radiation exposure 
in addition to those with known bone marrow metastasis. 
Table 4.
Dose Limiting Toxicities from ADVL0612
Dose Level
Dose Limiting Toxicity
Part A
20 mg/m2
1) Grade 2 systolic dysfunction 
2) Grade 3 anorexia
3) Grade 4 neutropenia
15 mg/m2
1) Grade 3 ALT elevation
2) Grade 3 diastolic + Grade 2 systolic dysfunction
Part B (patients with prior anthracycline or cardiac radiation exposure and those with 
known bone marrow metastasis excluded)
15 mg/m2
0/6 evaluable patients
20 mg/m2
1) Grade 4 hyperuricemia in setting of Grade 2 diarrhea/dehydration
2) Grade 5 aspiration pneumonia in the setting of Grade 4 punctate 
hemorrhage into a progressive diffuse pontine glioma
Eight patients were enrolled on Part B of the study at a starting dose of 15 mg/m2.  Two 
patients suffered early disease progression, therefore were not evaluable for DLT.  None of 
the 6 evaluable patients treated at this dose level experienced DLT.  Subsequently, 2 of 
3 patients treated at 20 mg/m2 experienced DLT, including grade 4 hyperuricemia in the 


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setting of grade 2 diarrhea and dehydration, and grade 5 aspiration pneumonia in the setting 
of grade 4 punctate hemorrhage into a progressive diffuse pontine glioma.  While this 
episode may have been related to the natural history of disease,25 a possible attribution to 
study therapy could not be excluded.  These results established 15 mg/m2/day as the MTD for 
patients without prior cardiac radiation or anthracycline exposure.  No cardiac dysfunction 
was observed in Part B of the trial.
Patient characteristics and other safety results are summarized in Appendix 2.  Neutropenia, 
thrombocytopenia, and transaminase elevation were the most commonly reported toxicities.  
Gastrointestinal symptoms and fatigue were the most commonly reported symptoms. 
1.3.5. ADVL0612 Sunitinib Pharmacokinetic Profile
In the pediatric Phase 1 study, steady state concentrations of sunitinib, the active metabolite 
SU012662, and total drug (sunitinib + SU012662) were reached by Day 7.  Five of 
14 patients (36%) at the 15 mg/m2 dose level and five of nine patients (56%) at the 
20 mg/m2 dose level had steady-state total drug trough concentrations >50 ng/mL, the target 
total drug concentration for RTK inhibition based on preclinical studies.11 Nine patients 
participated in the extended PK sampling study.  A median peak sunitinib plasma 
concentration of 16.8 ng/mL (range 9.5 – 61.4) was achieved 7 hours after the first dose.  
Median values of the sunitinib and SU012662 half-life, based on the accumulation ratios 
calculated from the steady-state data were 38.7 (range 23.9 – 61.7) and 93.4 (range 47.4 –
176) hours, respectively. 
1.3.6. Application of ADVL0612 PK Results to Young Patients with GIST
ADVL0612 has several features limiting its applicability to the pediatric GIST population.  
Many patients enrolled on ADVL0612 were heavily pre-treated with chemotherapy and/or 
radiation therapy while pediatric GIST patients will not have received multiple cycles of 
cytotoxic chemotherapy prior to sunitinib.
At the established pediatric MTD, the Cmax and AUC48 are both below the levels observed in 
adult patients with GIST during sunitinib therapy.  The adult daily dose of 50 mg is equal to 
a body surface area (BSA)-corrected dose of approximately 30 mg/m2 (ie, 50 mg /
1.73 m2 30 mg/m2).  In adults who require a dose reduction, the daily dose of 37.5 mg is 
equal to a BSA-corrected dose of approximately 22 mg/m2 (ie, 37.5 mg / 1.73 m2
22 mg/m2).  A recent meta-analysis indicates that increased steady-state AUC of sunitinib 
and response probability, with AUC significantly associated with improved stable disease in 
patients with GIST.26
Based on the preliminary population PK analysis from ADVL0612, the oral clearance and 
volume of distribution in pediatric patients appeared to correlate with BSA.  When corrected 
for BSA, the oral clearance of sunitinib in children appeared to be similar to that in adult 
patients (analysis data in house).  However, since the MTD from this study was lower than 
that observed in adult patients (ie, 15 mg/m2 versus 30 mg/m2), the steady state trough total 
drug concentrations fell below target concentrations (50 ng/mL, based on preclinical data) in 
9 of 14 (64%) patients.  While peak concentrations would be predicted to exceed this target 


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concentration, it is likely that tyrosine kinase inhibition may be intermittent for most patients 
treated at the 15 mg/m2 dose.  Therefore, to achieve the optimal plasma concentrations, 
intra-patient dose escalation up to the adult MTD of 30 mg/m2 per day has been incorporated 
into the study design based on individual patient tolerability.  Since the incidence of DLT at 
15 mg/m2 in children is lower than those seen at the adult MTD of 30 mg/m2, it would be 
expected that the majority of pediatric patients would qualify for intra-patient dose 
escalation.
To ensure that the plasma concentrations of sunitinib and its active metabolite in pediatric 
GIST patients are comparable to that in adult GIST patients, the PK samples collected in 
Cycle 1 (after collection of Day 28 of Cycle 1) will be batched together and sent immediately 
to the designated lab (ie, BASi) for bio-analysis.  Following the preliminary quantification of 
sunitinib and its active metabolite in plasma samples, the preliminary concentration data will 
be sent to Pfizer Inc. for PK analysis.  Following the PK analysis using NONMEM or other 
approaches, the steady state plasma total exposures will be estimated for that individual 
patient and compared to the plasma total exposures observed in adults GIST patients from 
historical data.  The PK analysis results, in addition to the comparative analysis, will be 
provided to the investigator as soon as possible, hopefully prior to starting Cycle 2 therapy.  
In addition to the patient’s safety and tolerability data from Cycle 1, the PK data will be 
available to the treating investigator to guide a decision on the patient’s dose for Cycle 2 or 
later cycles.  Therefore, the required PK samples collected from each pediatric patient during 
Cycle 1 may be used to facilitate the dose optimization process in that individual patient.
We propose to evaluate the PK, safety and preliminary efficacy of sunitinib in 6 pediatric and 
up to 15 young adult patients diagnosed with GIST.  The characterization of the PK profile of 
sunitinib and its active metabolite has been selected as the primary endpoint of this study for 
the following reasons: 1) PK data for sunitinib and its active metabolite in pediatric GIST 
patients are lacking, 2) additional sunitinib PK data are needed to combine with the 
Phase 1 pediatric data to more accurately describe the PK profile of sunitinib and its active 
metabolite in children, and to identify the fixed effect sources of variability in children, 3) the 
PK data will be used to perform PK-PD modeling for both safety and potentially efficacy 
endpoints to improve our understanding of the relationship between safety and efficacy and 
plasma drug concentrations, and 4) the PK samples may be used to facilitate the 
dose-optimization process in each individual pediatric patient.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective 

To characterize the plasma PK profile of sunitinib and its active metabolite 
SU012662 in children and young adults with advanced, unresectable GIST.


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Secondary Objectives:

To investigate whether doses greater than the established pediatric MTD are tolerated 
in pediatric patients with GIST;  

To investigate the safety and tolerability of sunitinib in children and young adults 
with GIST; 

To investigate the anti-tumor activity of sunitinib in children and young adults with 
GIST;

To explore PK-pharmacodynamic relationships with respect to safety and efficacy in 
children and young adults with GIST, if data allows.
2.2. Endpoints
Primary Endpoint:

Pharmacokinetic parameters of sunitinib and its main active metabolite (SU012662) 
including total plasma exposure (AUC24) and oral clearance (CL/F).
Secondary Endpoints:

Type, incidence, severity (graded by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events [CTCAE], Version 4.0 [v4.0]), timing, 
seriousness, and relatedness of adverse events and laboratory abnormalities;

Objective response rate, duration of response, PFS and OS at 2 years after study 
enrollment;  

Pharmacokinetic-pharmacodynamic relationships with respect to safety and efficacy
in pediatric GIST, if data allows.
3. STUDY DESIGN
This study is a single arm, multi-center, multi-national, clinical trial evaluating the PK, safety 
and preliminary anti-tumor efficacy of sunitinib in children and young adults diagnosed with 
advanced, unresectable GIST.  The study aims to enroll 6 evaluable patients aged 6 years to 
less than 18 years.  In addition, up to 15 young adults aged 18 - <21 years diagnosed with 
GIST may be enrolled.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.


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4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team and confirmed with Pfizer before patients are included in the 
study.
Patients must meet all of the following inclusion criteria to be eligible for to commence study 
drug treatment into the study:
1. Histological diagnosis of GIST (refer to Section 6.1);
2. Tumor tissue must be available to assess KIT, PDGFRA, and BRAF genotypes (for any of 
these genes where genotyping was not previously performed) and to assess succinate 
dehydrogenase (SDH) protein expression by immunohistochemistry.  For exceptions see
Section 6.1;
3. Patients must have demonstrated disease progression or intolerance to imatinib mesylate; 
have GIST with non-mutant KIT (tumor genotyping may be performed prior to or during 
screening; patients with an indeterminate KIT genotype are eligible if genotyping 
performed during screening); or cannot obtain imatinib in their country.
4. Age 6 to <21 years;
5. Advanced, unresectable GIST for which there are no available options for treatment with 
curative intent as assessed by the investigator;
6. Measurable (per Response Evaluation Criteria in Solid Tumors; RECIST version 1.1; or 
evaluable disease (Refer to Appendix 4);
7. Resolution of all acute toxic effects of prior cancer treatment, radiotherapy or surgical 
procedure to NCI CTCAE v4.0 grade ≤1;
8. ECOG Performance Status 0 -2 (for patients ≥11 years of age) or Lansky 50% (for 
patients <11 years);
9. Adequate organ function determined within 14 days prior to enrollment, defined by: 

Peripheral absolute neutrophil count (ANC) 1500/µL;

Platelet count 100,000/µL;  

Hemoglobin 10 g/dL;

Total bilirubin 1.5 x upper limit of normal (ULN) for age;

ALT (SGPT) or AST (SGOT) 3 x ULN for age;

Serum albumin 2.0 g/dL;


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
Serum amylase and lipase <1.5 x ULN;

Serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
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 formula for estimating GFR 
(Schwartz et al. J. Peds, 106:522, 1985)27 utilizing child length and stature data published by the CDC.

Blood Pressure (BP) < the 95th percentile for age, height and gender (refer to 
Appendix 3 for pediatric ranges);

Cardiac shortening fraction or ejection fraction greater than the lower limit of normal 
(LLN).
10. Evidence of a personally signed and dated informed consent (and where applicable, 
assent) document indicating that the patient (or a legal representative) has been informed 
of all pertinent aspects of the study;
11. Patients (including legal guardian for minors where applicable) who are willing and able 
to comply with scheduled visits, treatment plan, laboratory tests, and other study 
procedures, including anticipated ability to swallow capsules;
12. Male and female patients of childbearing potential who are sexually active must agree to 
use a highly effective method of contraception throughout the study and for 30 days after 
the last sunitinib treatment.  A patient is of childbearing potential if, in the opinion of the 
investigator, he/she is biologically capable of having children and is sexually active (refer 
to Section 4.3).
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Current treatment with another investigational agent and/or systemic anti-cancer therapy 
within 4 weeks before starting sunitinib treatment. 
2. Prior sunitinib treatment;
3. Prior therapy with known risk for cardiovascular complications, eg, high intensity 
anthracycline therapy (ie, total equivalent cumulative dose > 100 mg/m2 of doxorubicin) 
or prior radiation therapy that included the heart (cardiac silhouette) and/or craniospinal 
radiation;


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4. Concomitant treatment with any drug having proarrhythmic potential (terfenadine, 
quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, 
risperidone, indapamide and flecainide);
5. Prior diagnosis of cardiac disease, including, but not limited to:

Ongoing cardiac dysrhythmias of NCI CTCAE v4.0 grade 2, atrial fibrillation of 
any grade;

QTc interval >450 msec for males or >470 msec for females;

Hypertension that cannot be controlled by medications;

Any of the following within the 12 months prior to starting study treatment: 
congestive heart failure, cerebrovascular accident including transient ischemic attack 
or pulmonary embolism.
6. Grade 3 hemorrhage within 4 weeks prior to first dose of study drug 
7. Current treatment with therapeutic doses of coumarin-derivative anticoagulants such as 
warfarin or anti-vitamin K agents; 
8.
Concurrent administration of strong cytochrome P450-3A (CYP3A4) inhibitor(s) and/or 
inducer(s) within 7 and 12 days prior to first dose of study drug, respectively (see 
Section 5.5.2);
9. Prior radiation to >25% of the bone marrow.
10. Patients with history of allergic reaction attributed to any component of sunitinib 
capsules; 
11. Pregnant females; breastfeeding females; males and females of childbearing potential not 
using highly effective contraception or not agreeing to continue highly effective 
contraception for 30 days after last dose of investigational product; in the UK, males and 
females of childbearing potential not using two (2) methods of highly effective 
contraception or not agreeing to continue two (2) methods of highly effective 
contraception for 30 days after last dose of investigational product (refer to Section 4.3);
12. Active infection with HIV, or receiving antiretroviral therapy for HIV disease;
13. Patients who are investigational site staff members or relatives of those site staff 
members or patients who are Pfizer employees directly involved in the conduct of the 
trial;
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.


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4.3. Life Style Guidelines
All patients (male and female) with reproductive potential, including females above age 
11 must agree to practice simultaneously 2 effective contraception methods or abstinence for 
at least 14 days prior to the first dose of study drug and for 30 days following the last dose of 
study drug.  At each study visit, the investigator must confirm and document in the patient 
notes that the patient continues to practice effective contraception consistently and correctly 
as noted above.
Examples of effective contraception methods may include:

Barrier (condoms, diaphragm or cervical cap) with spermicide.

Oral or other acceptable contraceptives which may include but is not limited to: 
injectable, implanted or patch hormone therapy, IUD, or documented surgical 
sterilization.

Absolute sexual abstinence, without a second method.

For patients enrolled in the United Kingdom, effective contraception is defined as 
double barrier contraception (ie, male condom OR female condom used WITH a 
spermicide, diaphragm, cervical cap, or intrauterine device). Note: male and female 
condoms should NOT be used in tandem as friction may result in product failure. 
5. STUDY TREATMENTS
5.1. Allocation to Treatment
Following completion of the screening assessments and confirmation of eligibility, sites will 
be instructed to use the next available patient ID in RDC-Onsite (database).  The first patient 
would be XXXX
where XXXX is the site number.  The next patient ID would be 
XXXX
, XXXX
, etc.  For example, Site 
would have patient IDs 
, 
, and 
even if Site 
enrolled patients during the same timeframe.
5.2. Drug Supplies
Sunitinib malate is formulated in 6.25 mg, 12.5 mg and 25 mg capsules.  The latter two 
strengths listed are authorized products; however, the 6.25 mg strength is only available for 
investigational purposes.
5.2.1. Formulation and Packaging
Sunitinib malate study medication will be supplied to the clinic pharmacy by the Sponsor 
(Pfizer Inc) as hard gelatin capsules in HDPE bottles containing 28 or 30 capsules for oral 
administration.  Sunitinib malate capsules will contain 6.25 mg, 12.5 mg and 25 mg 
equivalents of sunitinib free-base.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Capsule Strength
Description
6.25 mg
#3 gray/gray capsule
12.5 mg
Swedish Orange, Size 4 hard gelatin capsule
25 mg
Swedish Orange/Caramel, Size 3 hard gelatin capsule
5.2.2. Preparation and Dispensing
Sunitinib capsules will be dispensed at the beginning of each treatment cycle. New drug 
supply will be supplied at the start of each cycle.  In the event of dose modification (and in 
consultation with study team) where the patient has sufficient drug of the appropriate 
strengths to finish that current cycle, new drug may not be dispensed.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
anti-cancer agents.
5.2.3. Sunitinib Administration
A cycle of therapy is considered to be 42 days, with the reporting period for each cycle being 
Day 1 to Day 42.  For all patients, sunitinib will be dosed intermittently [4 weeks on study 
drug followed by 2 weeks off therapy (Schedule 4/2)].
Sunitinib can be taken without regard to meals, but the incidence of drug-associated nausea 
may be less when taken with food.  Therefore, it is recommended that sunitinib be taken with 
at least a small amount of food. 
Self-administration of sunitinib capsules will take place on an outpatient basis (under 
parent/legal guardian supervision as appropriate) except on days when PK sampling is 
performed.  Capsules should be taken once daily in the morning on the first 28 days of each 
cycle with the exception of study visit days on which the dose for that day should be 
withheld until immediately after the completion of all study visit day activities and the 
investigator’s approval for continued dosing. Capsules must be administered whole, not 
opened, or manipulated prior to administration.
In the absence of progressive disease, patients may receive up to 18 cycles of sunitinib 
therapy for up to 24 months.  
5.2.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosate strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.


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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product. 

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AEpage 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
Patients should take a missed dose as soon as they remember.  However, patients should not 
take the dose if it is close to the next dose.  Instead, patients should take the next dose at the 
regular time.  Patients should not take more than one dose of study drug at a time.  The study 
drug may be re-administered (after 1hr) in the case of vomiting if this event occurs within 
15 min after administration or if all intact study drug capsules are observed in the vomitus. 
5.2.5. For Children (age less than 18 years at enrollment)
Dosing for all cycles will be based on the BSA obtained at the start of each cycle. 
BSA for dosing should be calculated using the Mosteller formula.28
BSA in m2 = [(height in cm x weight in kg)/3600]1/2
http://www.halls.md/body-surface-area/bsa.htm
The sunitinib intended starting dose will be 15 mg/m2/day (not to exceed 50 mg/day) on 
Schedule 4/2. (See Appendix 6).
Intra-patient dose escalation of sunitinib will be allowed after completion of Cycle 1 based 
on dose modification guidelines detailed in Section 5.2.8. Dose escalation will be in 
increments of 7.5 mg/m2, up to a maximum dose of 30 mg/m2 (not to exceed 50 mg/day).  
The dose and the dose change increments will be rounded to the nearest number which is a 
multiple of 6.25 mg, the lowest dose strength available.  After Cycle 1, when the minimum 
frequency of clinic visits is reduced, an additional Day 15 visit is required if the sunitinib 
dose is escalated during that cycle.
At each dose level (mg/m2), based on each individual patient body surface area (BSA) the 
calculated total dose in mg is rounded to the nearest number which is a multiple of 6.25 mg, 
the lowest dose strength available (See Table 5 for the available doses).  The rounded doses 
considering an individual patient’s BSA for daily Dose Levels of 15 mg/m2, 22.5 mg/m2 and 
30 mg/m2 have been provided in Appendix 6.


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Table 5.
Available Sunitinib Doses (Using 6.25 mg, 12.5 mg and 25 mg capsules)
Daily Dose
May Be Dispensed As
6.25 mg
1 x 6.25-mg capsule
12.5 mg
1 x 12.5-mg capsule or
2 x 6.25 mg capsules
18.75 mg
1 x 6.25-mg capsule plus
1 x 12.5-mg capsule
25 mg
1 x 25-mg capsule or 2 x 
12.5-mg capsules
31.25 mg
1 x 25-mg capsule plus
1 x 6.25 mg capsule 
37.5 mg
3 x 12.5-mg capsule or
1 x 25-mg capsule plus
1 x 12.5-mg capsule
43.75 mg
1 x 25 mg capsule plus
1 x 12.5 mg capsule plus
1 x 6.25 mg capsule or 3 x 
12.5 mg plus 1 x 6.25 mg
50 mg
2 x 25 mg capsules
5.2.6. For Young Adults (age ≥18 years) 
Young adults of age ≥18 years will be dosed according to the approved adult dosing regimen, 
50 mg once daily for 4 weeks, followed by a 2 week break in dosing (Schedule 4/2). For 
patients who turn 18 during the treatment phase of this study, a young adult consent may be 
required per local regulation, and dose modifications will be at the discretion of the 
investigator based on tolerability.
5.2.7. Criteria for Starting Subsequent Cycles
1. A cycle may be repeated every 42 days if the patient has met laboratory parameters as 
defined below (if the treatment is delayed more than 28 days to meet the following 
criteria the patient may be considered for withdrawal from the study): 
2. Adequate organ function defined by: 

Peripheral absolute neutrophil count (ANC) 1500/µL with or without growth factor 
support;

Platelet count 75,000/µL;  

Hemoglobin 10 g/dL;

Total bilirubin 2 x upper limit of normal (ULN) for age;


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
ALT (SGPT) or AST 3 x ULN for age; 

Serum albumin 2.0 g/dL;

Serum amylase and lipase < 2 x ULN;

Serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
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 formula for estimating GFR 
(Schwartz et al. J. Peds, 106:522, 1985)27 utilizing child length and stature data published by the CDC.

Blood Pressure (BP) < the 95th percentile for age, height and gender (refer to 
Appendix 3 for pediatric ranges);

Ejection fraction below the lower limit of normal (LLN) (institutional norm).
5.2.8. Dose Modifications
Patients will be monitored for toxicity, and the sunitinib dose may be adjusted according to 
individual patient tolerance at the discretion of the investigator.  The available doses were 
presented in Table 5 above.  After Cycle 3, when the frequency of clinic visits may be 
reduced to a minimum of once per cycle, investigators may wish to include more frequent 
visits for assessment of blood pressure and/or to perform clinically indicated laboratory tests 
if sunitinib related toxicities are expected or observed.  The following are suggested 
guidelines that investigators may use as a reference. 
For patients <18 yrs, intra-patient dose escalation of sunitinib will be allowed after 
completion of Cycle 1 and/or later cycles, and in the absence of toxicity greater than 
Grade 1 in the prior cycle, with exceptions listed in the footnotes to Table 6.  Dose escalation 
will be in increments of 7.5 mg/m2, up to a maximum dose of 30 mg/m2 (not to exceed 
50 mg/day).  The sunitinib dose may be reduced in response to toxicities based on 
investigator discretion, with general guidelines listed in Table 6. Dose reductions in patients 
<18yrs will be in decrements of 7.5mg/m2. For young adults aged 18-<21 years, inclusive, 
the intra-patient dose modification will be in 12.5 mg increments or decrements, consistent 
with Sutentdrug label recommendation.
Sunitinib will be held for Grade 3 and 4 toxicities until the toxicity decreases to 
Grade 1 (Grade 2 for hematologic toxicities) or baseline, at which point sunitinib will be 
resumed as detailed in Table 6 below.  Re-escalation will be permitted with appropriate 
supportive care and monitoring at the discretion of the investigator. 


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Recurrence of Grade 3 or greater toxicity will require dose reduction until toxicity has 
resolved to baseline. 
Any patient requiring >4 weeks of dose interruption for toxicity should be considered for 
study withdrawal.
Table 6.
Dose Modifications for Toxicity Attributed to Sunitinib for Patients 
<18 Years of Age
Toxicity
Grade 0-1
Grade 2
Grade 3
Grade 4
Non-hematologic4
May escalate 1 dose 
level1 or, if escalation 
previously attempted 
and reversed, continue 
at the same dose level.
Continue at the 
same dose level.
Withhold dose until toxicity 
is grade 1 or has returned to 
baseline, then resume 
treatment at the same dose 
level (assuming 
non-recurrent) or reduce the 
dose by 1 level at the 
discretion of the 
investigator.2
Withhold dose until 
toxicity is grade 1 or has 
returned to baseline, then 
reduce the dose by 1 level 
and resume treatment, or 
discontinue at the 
discretion of the 
investigator.2
Hematologic
May escalate 1 dose 
level or, if escalation 
previously attempted 
and reversed, continue 
at the same dose level.
Continue at the 
same dose level.
Withhold dose until toxicity 
is grade 2 or has returned to 
baseline, then resume 
treatment at the same dose 
level or reduce the dose by 
1 level at the discretion of 
the investigator.3
Withhold dose until 
toxicity is grade 2 or has 
returned to baseline, then 
reduce the dose by 1 level 
and resume treatment.3
1.
A dose level will be considered 7.5 mg/m2 increase or decrease from current dose.
3.
Patients who develop Grade 4 hyperuricemia or Grade 3 hypophosphatemia without clinical symptoms may 
continue study treatment without interruption at the discretion of the investigator.  Nausea, vomiting and/or 
diarrhea should persist at Grade 3 or 4 despite maximal medical therapy before reducing the sunitinib dose.
4.
Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption.
5.
For hypertension guidelines reference Section 5.2.11.
5.2.9. Minimum Sunitinib Dose Allowed
For Children
Pediatric patients already receiving an absolute dose of 6.25 mg at the time of an indicated 
dose reduction must be removed from protocol therapy.
For Young Adults
For young adults, dose interruption and/or modification in 12.5 mg increments or decrements 
are recommended, based on individual safety and tolerability.  The adult minimum 
acceptable dose for the purpose of this study is 25 mg/day.
5.2.10. Dose Modifications for Left Ventricular Systolic Dysfunction

Left ventricular systolic dysfunction will be graded according to NCI CTCAE 
v4.0 criteria, but will also take into account absolute changes in ejection fraction.


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
If LVEF decreases by more than 8 percentage points and decreases below an ejection 
fraction of 45%, hold study drug and repeat echocardiogram in 7 days.  If LVEF 
remains below 45%, patient will be taken off-protocol therapy and referred to a 
cardiologist.  If repeat ECHO does not confirm toxicity, patient may start next cycle 
of therapy on schedule with repeat ECHO 14 days and 28 days after start of next 
cycle. If any two ECHO demonstrate >8 absolute percentage point decrease in 
ejection fraction, the patient will be taken off-protocol therapy. 

If patient develops Grade 3 left ventricular systolic dysfunction, patient should be 
withdrawn from the study and referred to a cardiologist. 
5.2.11. Management of Sunitinib-induced Hypertension
Baseline blood pressure (BP) is defined as the BP obtained at the examination used for study 
enrollment as follows: 
1. Measurements should begin after at least 5 minutes of rest and before invasive 
procedures, such as phlebotomy.  Avoid using the lower extremity if possible.  The 
appropriate cuff size must be used, with the bladder cuff encircling at least 80% of the 
arm.
2. Obtain 3 serial BPs from the same extremity with the patient in the same position, 
separated by approximately 2 minutes.  These measurements should be recorded in the 
source document. 
3. Average the systolic BP from the 2nd and 3rd measurements. 
4. Average the diastolic BP from the 2nd and 3rd measurements. 
5. The baseline BP is the average of the systolic over the average of the diastolic BP 
measurements.  This average BP should be recorded in the CRF as the baseline BP.
Hypertension, defined as elevation of either the systolic or diastolic BP, should be 
considered per the following criteria:

For children and adolescents, hypertension is defined as a systolic and/or diastolic BP 
that on repeated measurement is 95th percentile for age, height and gender.  Refer to 
Appendix 3.

Utilize NCI CTCAE v4.0 to determine the grade of hypertension for both pediatric 
patients and young adults.

Elevated BP measurements should be confirmed on the same day.  Patients with 
elevated BP should have BP measurements performed at least twice weekly until BP 
is consistently <95th percentile for age, height and gender.


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Suggested Hypertension Management Guidelines for Pediatric Patients
1. Suggested hypertension management guidelines for pediatric patients are provided 
below; alternatively, hypertension may be managed according to investigator discretion.  
However, In case of Grade 4 hypertension, the patient should be permanently 
discontinued from the trial and anti-hypertensive therapy should be administered as
clinically indicated.
2. If the average systolic and/or diastolic BP is <95th percentile for age, height and gender, 
continue sunitinib at the same dose.
3. If the average systolic and/or diastolic BP is greater than the 95th percentile and
10 mmHg higher than the 95th percentile, continue sunitinib at the same dose and 
recheck BP twice weekly. BP can be measured at a study site-approved local clinic as 
long as protocol guidelines are followed closely, and study site is involved with clinical 
decisions.
a.
Upon recheck, if the average BP is <95th percentile, continue sunitinib at the same 
dose;
b. If the BP continues to be 95th percentile, when measured at least twice over a two 
week period, start anti-hypertensive therapy, continue sunitinib at the same dose, and 
monitor BP twice weekly.
4. If the average systolic and/or diastolic BP is 11-25 mmHg above the 95th percentile
recheck BP twice weekly.  If the BP continues to be >11 mmHg above the 95th percentile
over a two week period (in at least 2 out of 3 average BP measurements) start 
anti-hypertensive therapy, continue sunitinib at the same dose and monitor BP twice 
weekly;
a.
If the average BP returns to <95th percentile within 14 days, continue sunitinib at the 
same dose and continue anti-hypertensive therapy;
b. If the average BP remains elevated 25 mmHg above the 95th percentile for more 
than two weeks after the institution of antihypertensive therapy, hold sunitinib, 
monitor BP at least twice weekly;

If the average BP returns to <95th percentile within two weeks, restart sunitinib at 
a reduced dose (reduce by 7.5 mg/m2); 

If the average BP remains 95th percentile for more than two weeks, patient 
should be removed from study.
5. If the average systolic and/or diastolic BP is >25 mmHg above the 95th percentile, 
hold sunitinib, start or continue anti-hypertensive agent(s) per institutional guidelines.  
Monitor the BP at least twice weekly. (See 4b. above for guidance on restarting dosing).


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Antihypertensive therapy should be continued until the BP is consistently <95th percentile.
If anti-hypertensive therapy is required, single agent therapy (eg, a calcium channel blocker 
such as amlodipine or nifedipine) should be started and the BP should be monitored at least 
twice weekly until within normal limits.
Hypertension Management Guidelines for Young Adults
For young adults aged 18 - <21 years there are no specific dose modification guidelines for 
hypertension. However, investigators may wish to refer to Section 5.2.8 above for suggested 
dose modification guidelines for toxicity by grade of severity.
5.2.12. Management of Hypothyroidism or Adrenal Insufficiency
Patients who develop hypothyroidism while on study should be evaluated and managed by an 
endocrinologist.  Similarly, upon consultation with an endocrinologist, patients on this trial 
may be supported with appropriate hormone replacement therapy in the event they develop 
adrenal insufficiency in the absence of disease progression or unacceptable 
treatment-associated toxicity. 
5.2.13. Compliance
A patient dosing diary will be used to track compliance, recording the date and time of each 
dose as well as any observed side effects, supportive treatments and/or medication errors.  In 
the case of a sunitinib dosing error, documentation of the error in the dosing diary in addition 
to capturing the error on the dosing page of the associated CRF should be provided. This 
diary should be reviewed with the treating physician at each clinic appointment while on 
study. 
Patients will be required to return all bottles of sunitinib at the beginning of each cycle.  The 
number of capsules remaining will be documented. 
5.2.14. Study Drug Overdose Instructions
In the event of an overdose of sunitinib, study drug should be withheld, symptomatic 
treatment should be instituted, and the Sponsor should be contacted to discuss the details of 
the overdose to formulate a clinical management plan.
5.3. Drug Storage and Drug Accountability
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, 
and in accordance with applicable regulatory requirements. All study drug supplies must be 
kept in a locked, limited access room.  Capsules should be stored at controlled room 
temperature (15 ºC to 30ºC) and protected from light.
Storage conditions stated in the SRSD [ie, Investigator Brochure (IB), Core Data Sheet 
(CDS), United States Package Insert (USPI), Summary of Product Characteristics (SPC), or 
Local Product Document (LPD)] may be superseded by the sunitinib label. 


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Investigators and site staff are reminded to check temperatures daily and ensure that room 
storage thermometers are working correctly as required for proper storage of investigational 
products.  Any temperature excursions should be reported immediately. 
The study drug must not be used outside the context of this protocol.  Under no 
circumstances should the investigator or other site personnel supply study drug to other 
investigators, patients, or clinics, or allow supplies to be used other than directed by this 
protocol without prior authorization from the Sponsor. 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
deposition of the investigational product.  Pfizer may supply drug accountability forms that 
must be used or may approve use of standard institution forms.  In either case, the forms 
must identify the investigational product, including batch or code numbers, and account for 
its disposition on a patient-by-patient basis, including specific dates and quantities.  The 
forms must be signed by the individual who dispensed the drug and copies must be provided 
to Pfizer.  The prescribed dose should also be recorded in the patient’s medical records.
All bottles of study drug must be returned to the investigator by the patient.  At the end of the 
trial, Pfizer will provide instructions as to disposition of any unused investigational product.  
If Pfizer authorizes destruction at the trial site, the investigator must ensure that the materials 
are destroyed in compliance with applicable environmental regulations, institutional policy, 
and any special instructions provided by Pfizer.  Destruction must be adequately 
documented.  Otherwise, all bottles should be returned to Pfizer for appropriate destruction.  
Only appropriate, commercially labeled materials will be eligible for donation and will 
require explicit Pfizer pre-authorization.
5.4. Concomitant Medication(s) and/or Therapy
Patients must be instructed not to take any additional medications (including 
over-the-counter products) during the study without prior consultation with the Investigator.  
Commercially available palliative and supportive care for disease-related symptoms should 
be offered to all treated patients.  The Sponsor will not supply palliative and supportive care 
agents.  All concomitant medications and blood products, as well as interventions 
(eg, paracentesis) received by patients from screening until the end of follow up will be 
recorded on the relevant e-CRF. 
Every medication including herbal supplements (specifically St. John’s wort) or treatment 
taken by the patient during the trial and the reason for its administration must be recorded on 
the relevant e-CRF.
Supportive care may include premedication with antiemetics to limit treatment-related nausea 
and vomiting.  During the first cycle of treatment patients should be closely monitored for 
diarrhea and treated with anti-diarrheals (eg, loperamide) at the first sign of loose or frequent 
stools.  Patients may receive secondary prophylaxis for treatment-induced diarrhea.
Blood product transfusions should be administered as clinically indicated.


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Patients who enter the study on stable doses of erythropoietin or darbepoietin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
investigator.  Patients with neutropenic fever or infection should be treated promptly and may 
receive therapeutic colony-stimulating factors if appropriate. 
Anti-inflammatory or narcotic analgesics may be offered as needed. Steroids are to be 
avoided whenever possible since they are metabolized by CYP3A4 and may interfere with 
sunitinib metabolism.
Concomitant Radiotherapy or Surgery
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.
Sunitinib should be interrupted during palliative radiotherapy – stopping 1 day before and 
resuming treatment 1 day after.  Treatment with palliative radiotherapy should be recorded 
on the appropriate CRFs. 
Surgery is permitted after documentation of response as defined in Appendix 4 (RECIST 
v1.1).  This is to allow for resection of disease in patients whose tumors become resectable 
following treatment with sunitinib. 
The appropriate interval of time between surgery and sunitinib treatment required to 
minimize the risk of impaired wound healing and bleeding has not been determined.  Based 
upon PK considerations of sunitinib, stopping sunitinib is recommended at least 7 to 10 days 
prior to major elective surgery and at least 3 to 4 days before minor surgery.  Patients who 
require surgery less than 14 days from treatment with sunitinib should be monitored closely 
for wound complications.  The decision to reinitiate sunitinib should be based upon a clinical 
assessment of satisfactory wound healing and recovery from surgery.
5.5. Contraindicated Medications
5.5.1. Drugs with Proarrhythmic Potential
Concomitant treatment with any drug having proarrhythmic potential (terfenadine, quinidine, 
procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide 
and flecainide) is not permitted during the study. 
5.5.2. Inhibitors and Inducers of CYP3A4
Sunitinib is primarily metabolized by liver enzymes, in particular CYP3A4.  There was a 
mean 1.8-fold increase in exposure of sunitinib when co-administered with ketoconazole, a 
strong inhibitor of CYP3A4 and a mean 4-fold decreased in exposure of sunitinib when 
co-administered with rifampin, a strong inducer of CYP3A4. 
Therefore, co-administration with strong inhibitors (ketoconazole, itraconazole, 
clarithromycin, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir, nefazodone, 
voriconazole, telithromycin) and inducers (dexamethasone, rifampin, rifabutin, rifapentin, 
carbamazepine, phenobarbital, phenytoin, St. John’s wort) of CYP3A4 may result in 
significant increases/decreases in exposure of sunitinib and may alter the safety/efficacy of 
the drug (See the Study Manual for further information).


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Strong CYP3A4 inhibitors and inducers are not permitted during the 7 and 12 days before 
dosing, respectively.  During study participation, strong CYP3A4 inhibitors and inducers are 
not recommended.  Alternative therapies should be used when available.  If usage of a strong 
CYP3A4 inhibitor or inducer is necessary, this must be in agreement with the Sponsor. 
5.5.3. Anticoagulants
Therapeutic doses of coumarin-derivative anticoagulants such as warfarin (Coumadin) are 
not recommended, though doses up to 2 mg daily are permitted for prophylaxis of 
thrombosis, ie, PT and/or INR are targeted to <1.5 times the ULN. 
6. STUDY PROCEDURES 
Prior to undergoing any study-specific procedure, patients must read and sign the current 
Institutional Review Board (IRB)-approved informed consent form and assent form as per 
local guidelines.  All on-study procedures are permitted within the window frame indicated 
in Table 1.
6.1. Screening
The following screening procedures must be performed within 28 days prior to treatment 
on-study unless otherwise stated:

Patient, parental or legal guardian (for patients <18 years of age) signature on current 
IRB-approved informed consent form and assent form per local guidelines; Tumor 
tissue must be available from all patients to assess KIT, PDGFRA, and BRAF
genotyping (for any of these genes where genotyping was not previously performed) 
and to assess succinate dehydrogenase (SDH) protein expression by 
immunohistochemistry.  For patients with no available, previously collected tumor 
tissue and incomplete testing information covering all of the above tests, a core 
biopsy is required, unless, in the opinion of the investigator, a biopsy would create an 
unacceptable risk to the patient.  For such patients with incomplete genotype/SDH 
information, where a tumor biopsy cannot be obtained, patients may commence 
treatment with sunitinib if there is previous confirmation of GIST diagnosis (see 
below).  Similarly, if tumor tissue is obtained from patients during screening but the 
results of testing are inconclusive, it will not be necessary to collect additional 
biopsies from patients before initiating treatment with sunitinib.  However, if 
archived tumor tissue is available it may be requested for repeat analyses on a case by 
case basis, prior to treatment with sunitinib.

In cases where any of the tumor analyses listed above have not previously been 
obtained, it is acceptable to obtain a paraffin block or 25 unstained slides (charged 
slides) representative of the tumor, along with the original pathology report.  Tumor 
samples negative for SDH staining may be further subjected to SDH genotyping.  It is 
suggested that for patients negative for SDH that patients/families be referred for 
genetic counseling. (See the Introduction for background on these tests).


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
Confirmation of GIST diagnosis (requires documentation from a reference pathology 
laboratory); Medical history including oncologic history, history of other disease 
processes (active or resolved), concomitant illnesses, and demographics; 

Tanner Staging for patients < 18 yrs (this can only be waived upon agreement by 
Pfizer);

Physical examination including examination of major body systems, ECOG (or 
Lansky) performance status, body weight, height and vital signs (temperature, blood 
pressure in triplicate, heart rate, respiratory rate);

Hematology and Chemistry: See Section 7.2.2 for specific tests;

Thyroid stimulating hormone (TSH);

Urinalysis (dipstick test).  (If the results of the dipstick test indicate a ≥2+ proteinuria, 
then follow-up should be performed with a quantitative urine protein analysis 
according to local standard practices);

Prothrombin time or INR (The same test should be used throughout the study);

Pregnancy test (urine), if applicable, within 7 days before initiation of study therapy 
(refer to Section 7.2.3); 

Three 12-lead ECGs approximately 2 minutes apart, preferably in the morning;

ECHO or MUGA scan;

MRI (or CT) scan of abdomen and pelvis, in addition to any other applicable sites of 
disease;

Chest radiograph if tumor imaging (with MRI or CT scan) does not include the chest;

Bone age determination for patients < 18yrs;

FDG-PET, if locally available;

Assessment of concomitant medications and treatments;

Assessment of ongoing symptoms/events (serious adverse events must be recorded 
from time of signed consent);  

Study registration.


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6.2. Study Period
The following will be performed according to the schedule outlined in the Schedule of 
Activities Table 1:

Physical examination; follow baseline BP measurement guidelines provided in 
Section 5.2.8; Height and weight for pediatric patients at day 1 of each cycle (see 
Appendix 3 for reference; local standards may vary);

Tanner Stage every 6-9 months for patients assessed at screen who were < Tanner 
Stage 5;

Bone age at 1yr from treatment initiation for patients <18 yrs who had open growth 
plates at the last assessment;

Hematology and blood chemistry labs: Same as Screening;

TSH, Day 1 of Cycles 2, 3, and 4 and every even cycle number thereafter;

PT or INR, as clinically indicated (The same test should be used throughout the 
study);

Urinalysis, and 24-hour urine protein if urinalysis shows 2+ protein;

Pregnancy test (urine) if applicable, prior to each cycle and as indicated (refer to 
Section 7.2.3);

Three 12-lead ECGs: approximately 2 minutes apart in the morning (preferred) at 
Cycle 2, Day 1. Additional ECGs should be performed approximately 2 weeks 
following intra-patient sunitinib dose adjustments and as clinically indicated;

ECHO or MUGA scan every 3rd cycle on Day 1;

Tumor reassessment(s) before the end of the even number cycles (Day 28 of the even 
numbered cycles if feasible).  Evidence of tumor response will be confirmed with 
repeated imaging studies at 4 weeks;

FDG-PET at Cycle 1 day 28 only, if locally available;

Treatment with sunitinib (refer to Section 5.2.3);

Collection of blood for sunitinib PK profiling at the following timepoints:
Mandatory samples: 
Cycle 1: Post-dose samples at 2, 4, 6, 8 hours on Day 1;


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Cycle 1: Pre-dose samples: Day 1, Day 15 (between Days 12-18), and 
Day 28 (between Days 25-29);
Cycle 2: Pre-dose samples: Day 1, Day 15 (between Days 12-18) [only if a study 
visit is required due to dose escalation], and Day 28 (between Days 25-29);
Cycle 3: Pre-dose samples: Day 1, Day 15 (between Days 12-18) [only if a study 
visit is required due to dose escalation], and Day 28 (between Days 25-29);
Recording of exact actual time of draw and last dose prior to sampling is crucial.
NOTE: ALL PK SAMPLES COLLECTED BEFORE AND ON 
CYCLE 1 DAY 28 WILL BE BATCHED FOR THAT PATIENT AND SENT 
IMMEDIATELY TO BASi FOR BIO-ANALYSIS. 
All subsequent PK samples will be batched and sent to BASi for bio-analysis 
after completion of Cycle 3.

Optional pre-dose (trough) samples: 
Cycle 1: Day 7 (between Days 4 – 10), and/or Day 21 (between Days 18 – 24);
At the time of sample collection, recording of the exact actual time of draw and 
last dose taken prior to sampling is crucial; 
NOTE: These pre-dose samples should be collected synchronous with other 
clinically relevant blood draws for patient comfort and convenience.  Additional 
unplanned PK samples may be collected per investigator discretion.

Assessment of compliance/accountability of study drugs;

Assessment of adverse events;

Assessment of concomitant medications and treatments.
After Cycle 1, Day 1, visits for assessments in subsequent cycles may commence from two 
days prior until one day after the scheduled visit.
Day 15 visits:
Day 15 of Cycle 1 is a mandatory visit.  Day 15 visits of subsequent cycles are required if a
dose escalation occurs during that cycle.

Physical examination; follow baseline BP measurement guidelines provided in 
Section 5.2.8; Height and weight for pediatric patients at day 1 of each cycle (see 
Appendix 3 for reference; local standards may vary);

Hematology and blood chemistry labs: Same as Screening;


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6.3. Follow-up Procedures
6.3.1. Day 28 Visit
Patients should continue to be evaluated for 28 calendar days after the last dose of study 
drug.  During the post-treatment follow-up visit, the following procedures should be 
performed:

Assessment of adverse events;

Physical examination, height, weight, vital signs, (see Appendix 3 for reference; local 
standards may vary);

Tanner Stage if not performed within the prior 6 months;

Bone age if not performed within the past year;

Laboratory assessments or other tests necessary to follow unresolved or evaluate new 
adverse events;

Assessment of concomitant medications and treatments.
In the event a patient is unable to return to the clinic for the follow-up visit, telephone contact 
with the patient to assess adverse events and concomitant medications and treatments is 
expected.  If a physical examination and/or laboratory assessments are needed to follow-up 
unresolved adverse events, retrieval of assessments performed at an institution local to the 
patient is acceptable.  If laboratory analyses are performed at a local laboratory, the 
laboratory’s relevant normal ranges must be submitted to the Sponsor.  The outcome of 
adverse events with a date of onset during the study period should be reevaluated, and any 
new adverse events should be recorded.  All serious adverse events, and those non-serious 
adverse events assessed by the investigator as possibly related to study drug should continue 
to be followed even after patient withdrawal from study.  These adverse events should be 
followed until resolution or until the investigator assesses them to be “chronic” or “stable”.
6.3.2. Long Term Follow-Up 
Follow-up survival information will be collected by telephone contact every 3 months 
(± 7 days) until death, or either 2 years from the patient’s first dose of study treatment or 
completion of 18 cycles.  Any new anti-cancer therapy given to the patient during this time 
should also be recorded on the relevant CRF by telephone contact or clinic visit.  After 
completion of follow-up procedures, any developmental or growth delays that are possibly 
related to treatment should be reported through on the Adverse Event Monitoring Form as are 
routinely done for treatment-related SAEs that occur following completion of any trial.
6.4. Patient Withdrawal / End of Treatment
End of study occurs when the patient has completed 18 cycles of therapy, has completed 
follow-up survival, was lost to follow-up, or in the event of the patient’s unplanned death. 


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Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site. 
If a patient does not return for a scheduled visit, every effort should be made to contact the
subject.  In the case of a patient lost to follow-up the appropriate box should be checked off 
in the Patient Summary-End of Treatment CRF page. In any circumstance, every effort 
should be made to document patient outcome, if possible. The investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
product, request the patient to return for a final visit, if applicable, and follow-up with the 
patient regarding any unresolved adverse events (AEs).
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
In addition, patients may be withdrawn from treatment in the case of:

Disease progression, unless there is reasonable evidence of clinical benefit to justify 
continuation on protocol (the latter must be discussed with the Sponsor); 

Unacceptable toxicity; 

Need for treatment rest >4 weeks (if investigator considers there is potential for 
sustained clinical benefit, this may be discussed with the Sponsor);

Need for anticancer therapy not specified in the protocol;

Patient noncompliance;

Patient lost to follow-up;

Patient choice to withdraw from treatment (follow-up permitted by patient);

Withdrawal of patient consent (cessation of follow-up);

Completion of study therapy (18 cycles of study treatment; or maximum 24 months).
6.4.1. End of Treatment Procedures
At the end of the treatment or at withdrawal, the following procedures should be performed if 
they were not performed during the last week on treatment (exceptions: during the last 
8 weeks for tumor assessments; during the last 6 months for Tanner staging, and during the 
last year for bone age assessment):


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
Physical examination including major body systems, height, weight, and vital signs,
Height and weight for pediatric (see Appendix 3 for reference; local standards may 
vary);

Tanner Staging if meeting all of the following: performed at screen, < Tanner 
Stage 5 at last assessment, and > 6 months from last assessment;

Bone age if at least 1 year from last assessment and growth plates open at last 
assessment;

Hematology and blood chemistry labs as described in Section 7.2.2, including 
urinalysis for urine protein (dipstick);

TSH, as clinically indicated;

Urinalysis (If the results of the dipstick test indicate a ≥2+ proteinuria, then follow-up 
should be performed with a quantitative urine protein analysis according to local 
standard practices);

Pregnancy test (urine) if applicable (refer to Section 7.2.3);

PT or INR, as clinically indicated (The same test should be used throughout the 
study);

Three 12-lead ECGs approximately 2 minutes apart in the morning (preferred), 
preferably time matched (1 hour) with Screening;

MUGA scan or ECHO, if clinically indicated;

MRI (or CT) scan of abdomen and pelvis, in addition to any other applicable sites of 
disease, if not performed within the last 8 weeks prior to withdrawal;

Chest radiograph, if clinically indicated;

Assessment of adverse events;

Assessment of concomitant medications and treatments; 

Assessment of compliance/accountability of study drugs.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the patient.  When a protocol required test cannot be performed, the 


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investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Assessments
Blood to be used for pre-dose and post-dose pharmacokinetic (PK) plasma samples will be 
collected according to Table 7 for determination of plasma concentrations of sunitinib and its 
active metabolite SU012662 in 6 children aged between 6-17 years and up to 15 patients 
aged 18-<21 years in 1.2 mL K3EDTA tubes. The blood draw methods for PK sampling 
should adhere to standard practice at the local institution. The post-dose samples obtained on 
Day 1 are all mandatory; however, some of the pre-dose samples are mandatory, whereas 
others are optional (Table 7).  In situations where the mandatory PK samples cannot be 
obtained, the patient will be scheduled to provide the missed PK sample time point(s) on the 
same time and day of another cycle.
During Cycle 1, the mandatory (M) PK samples are the pre-dose, 2, 4, 6, and 8 hour post 
dose samples for Day 1 Visit, and the pre-dose sample for Days 15 and 28 Visits (Table 7).  
The optional (O) PK samples are pre-dose samples for Days 7 and 21 Visits (Table 7).
During Cycles 2 and 3, the mandatory PK samples are the pre-dose sample for 
Days 1, 15 [Day 15 collection is applicable only if a visit is required due to dose escalation], 
and 28 Visits (Table 7).
For each nominal Visit Day referred to above, the actual visit day can fall within a 
pre-specified interval to provide more flexibility for each individual patient (Table 7).  All 
pre-dose samples can be collected at the same time as other chemistry lab tests.  Additional 
PK samples may also be collected at the discretion of the investigator.
In Cycle 1, after collection of the pre-dose sample for Day 28 Visit, all PK samples collected 
should be batched together and shipped immediately to BASi for bio-analysis (Table 7).  In 
addition, after collection of the last PK sample all the PK samples should be batched together 
and shipped to BASi for bio-analysis (Table 7). 
Detailed instructions for collection, processing and storage of blood and tissue samples will 
be provided in the Central Lab manual.  Samples will be analyzed using validated analytical 
methods in compliance with Pfizer standard operating procedures.  As part of understanding 
the pharmacokinetics of the study drug, samples may be used for metabolite identification 
and/or evaluation of the bioanalytical method.  These data will be used for internal 
exploratory purposes and will not be included in the study report.
For all samples collected, 1) the actual date and time of sample collection, and 2) the actual 
date and time of the last dose prior to the PK sample collection should be properly recorded 
on the appropriate Case Report Form (Table 7).


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Table 7.
Table of Pharmacokinetic Sampling Time Points
Parameters
Visit; Cycle (C) & Day (D)
Cycle 1
Cycle 2
Cycle 3
Day 1
D7
D15
D21
D28
D1
D15
D28
D1
D15
D28
Actual Visit  
Day/Period 
(Inclusive)
D1
D4-D10
D12-D18
D18-D24
D25-D29
D1
D12-D18
D25-D29
D1
D12-D18
D25-D29
Sampling 
Time
Pre-dose, 2, 4, 6, 
and 8 hr Post dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Pre-dose
Mandatory 
(M) versus 
Optional (O)
M
O
M
O
M
M
Ma
M
M
Ma
M
Sample 
Shipments
After collection of C1 D28 visit PK sample, batch all collected PK 
samples and ship to BASi immediately
After Collection of the last PK sample, batch all the remaining PK samples 
and ship to BASi 
Dosing and 
Sampling 
Time & Date
For all samples collected, record on the appropriate CRF: 1) the actual date and time for sample collection, 2) the actual date and time for the last dose 
prior to sample collection, and 3) actual date of any missed/held dose(s).
a only obtained if a visit is required due dose escalations within that cycle.


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Non-Compartmental Analyses (NCA) will be carried out to estimate pharmacokinetic 
parameters maximum plasma concentration (Cmax), time to Cmax (tmax), area under the 
concentration versus time curve from time zero to 8 hr post dose (AUC8).
In addition to the NCA, Non-linear Mixed Effects Modeling (NONMEM) approaches will be 
used to estimate PK parameters absorption rate constant (Ka), oral clearance (CL/F), 
intercompartmental clearance (Q/F), volume of distribution for the central compartment 
(Vc/F) and peripheral compartment (Vp/F).  Other parameters such as half life for the 
distribution phase (t1/2) and elimination phase (t1/2), maximum plasma concentration (Cmax), 
and area under the curve from time zero to 24 hr post dose (AUC24) will be estimated based 
on individual patient parameter estimates.
Subsequently, sequential PK-pharmacodynamic modeling techniques using NONMEM will 
be applied to explore the relationships between safety and efficacy with plasma drug 
concentrations, if data allows.
Preliminary Analysis: Following the preliminary quantification of sunitinib and its active 
metabolite in plasma samples from Cycle 1 in each patient, and the PK analysis using 
NONMEM or other approaches, the steady state maximum and total plasma exposures will 
be estimated for that individual patient and compared to typical Cmax and AUC24 observed in 
adults GIST patients from historical data.  The PK analysis results, in addition to the 
comparative analysis, will be provided to the investigator as soon as possible, preferably 
prior to starting Cycle 2 therapy. 
Definition of Evaluable: A patient will be declared evaluable for the primary endpoint if 
oral clearance of sunitinib and its active metabolite can be calculated, using a population PK 
approach (NONMEM).
7.2. Safety Assessments
7.2.1. Adverse Events
Assessment of adverse events will include type, incidence, severity (graded by the NCI 
CTCAE v4.0), timing, seriousness, and relatedness; and laboratory abnormalities.
Baseline tumor-related signs and symptoms will be recorded as adverse events during the 
trial if they worsen in severity or increase in frequency.
7.2.2. Laboratory Safety Assessments
Local laboratory studies will include:

Hematology, coagulation and blood chemistry labs will be drawn as described in the 
Schedule of Activities (Table 1). 

Complete blood count (CBC); WBC with differential, hemoglobin, and platelets;

Coagulation: Prothrombin time (PT) and/or INR;


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
TSH;

Blood chemistry: Sodium, potassium, chloride, blood urea nitrogen (BUN), 
creatinine, calcium, magnesium, phosphorous, uric acid, glucose, total bilirubin, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase, total protein, albumin, amylase and lipase;

Additional blood tests may be performed for the purpose of planning treatment 
administration, dose modification or following adverse events.  At any time after 
initiation of dosing if liver function tests are abnormal refer to Section 8.5.2 for 
guidelines. Electrolyte levels, particularly potassium and magnesium, should be 
monitored throughout the study, addressing any abnormalities that are observed;

Urinalysis (dipstick) will be performed locally for protein.  Patients who develop 
≥2+ proteinuria will undergo testing of 24-hour urine protein.  In case of urine protein 
on two assessments, 24-hour urine protein should be re-assessed at least every other 
cycle; 

Urine pregnancy test for women.  See the following section.

Laboratory safety assessments may be performed outside of study sites in cases where 
patient travel to the study site for these tests is not possible.  In such cases, accurate 
reporting of these results remains the responsibility of the study site.

See Appendix 7 for a full listing of required tests
7.2.3. Pregnancy Testing
For female patients above age 11, a urine pregnancy test, with sensitivity of at least 
25 mIU/mL, will be performed at screening, within 7 days before sunitinib administration. A 
positive urine pregnancy test can be confirmed by a second urine pregnancy test prior to 
study exclusion. If the results of the urine pregnancy test are positive, the patient will not be 
eligible for study participation. Female subjects above age 11 must have a pregnancy test on 
Day 1 of each cycle of therapy and at the end of treatment. For female patients below the age 
of 11, if pregnancy testing is not performed, the investigator will document why testing was 
not necessary based on the level of sexual maturity.  During the study period, positive urine 
pregnancy test can be confirmed by a second urine pregnancy test. A positive urine 
pregnancy test will require withdrawal from the study. Patients of less than 11 yrs at study 
start who turn 11 while on-study will then require pregnancy testing per the Schedule of 
Activities. For contraception guidelines, please refer to Section 4.3.  Pregnancy tests may 
also be repeated as per request of IRB/IECs or if required by local regulations.
7.2.4. Other Safety Assessments

Height and body weight will be recorded prior to starting each treatment cycle for 
pediatric patients. 


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
Physical examination: A physical examination including, but not limited to, general, 
lungs, heart, abdomen, and extremities will be performed.  The physical examination will 
include examination of known and suspected sites of disease.

Performance Status: ECOG performance status scale will be used for patients ≥11 years 
of age or Lansky score for patients <11 years of age. Patients below the age of 11 who 
turn 11 while on-study will then require ECOG performance evaluations. (Refer to 
Appendix 5);

Vital signs: Measurements of temperature, blood pressure, heart rate and respiratory rate 
after 5 minutes of rest;  

ECG: Three consecutive 12 lead ECGs (with a 10-second rhythm strip) will be 
collected approximately 2 minutes apart at screening, on Cycle 2 Day 1 (pre-dose) 
and at the end of treatment visit to determine the mean QTc interval.  It is preferable 
that the machine used has a capacity to calculate the standard intervals automatically.  
If the mean QTc interval is prolonged (>500 msec), the ECGs should be overread by 
a cardiologist at the site for confirmation.  Additional ECGs should be performed as 
clinically indicated, ie, after a new steady state of sunitinib is reached 
(ie, approximately 2 weeks) following:

Intrapatient sunitinib dose escalation, or 

Intrapatient sunitinib dose reduction in response to: 
a.
QTc interval prolongation,
b. Significant electrolyte changes, vomiting, diarrhea, or addition of a strong 
CYP3A4 inhibitor listed in Section 5.5.2 after consultation with the sponsor’s 
medical monitor.
7.3. Growth and Pubertal Maturation Assessments (Patients <18 yr only)
The testing below may be performed by a pediatric endocrinologist if not standard practice 
within the local oncology clinic.
Growth Assessments: Imaging of growth plate for bone age determination per standard local 
practice at screening is required for patients less than 18 years of age. Patients with closed 
growth plates will not be required to have further imaging for bone age determination.  For 
patients with open growth plates, imaging for bone age determination will be conducted at 
one year intervals from the initiation of treatment until the Day 28 follow-up visit after the 
last dose of study drug. 
Tanner Staging: Tanner staging for patients less than 18 years of age will be conducted, when 
locally feasible, at Screening.  For patients who are Tanner Stage 1-4, Tanner staging should 
be repeated every 6-9 months until the end of sunitinib treatment, including the 28 day 
observation period post-treatment, or until the patient reaches Tanner stage 5. An end of 


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treatment assessment should be repeated if more than 6 months have elapsed since the prior 
assessment and if the prior staging was Tanner Stage 1-4.  Tanner Staging will be captured 
for the following: pubic hair, breast (females), penis, and testes. 
7.4. Efficacy Assessments
All baseline tumor imaging assessments are to be performed within 28 days prior to the first 
dose of medication, and then within 14 days (closer to Day 28 of the Cycle if possible) prior 
to the end of each even numbered cycle (ie, Cycles 2, 4, etc.).  In the case of tumor response 
(PR or CR), confirmatory imaging studies should be performed at least 4 weeks after initial 
documentation of response and may be scheduled at 8 weeks for convenience.
Imaging studies will include MRI (or CT) scan of the abdomen and pelvis, plus other 
applicable sites of disease.
The determination of anti-tumor efficacy will be based on objective tumor assessments made 
according to the RECIST criteria v1.1.  (See Appendix 4).  MRI (or CT) scans should be 
performed with contrast agents unless contraindicated for medical reasons.  In each patient, 
the same imaging modality should be used throughout the study to measure disease whenever 
possible. Tumor evaluation by positron emission tomography (PET) scan (baseline and at 
cycle 1 day 28 only) or by ultrasound may not substitute for MRI (or CT) scans. PET scans 
will be used for exploratory purposes only and will not be used in the assessment of efficacy.
For effusions or ascites, only cases having cytologic proof of malignancy should be recorded 
as tumor lesions on the CRF.  Effusions that have not been evaluated using cytology or were 
found to be non-malignant should not be recorded on the ‘non-target and new lesion’ CRF.
Measurable lesions that have been previously irradiated will not be considered target lesions 
unless increase in size has been observed following completion of radiation therapy.
7.4.1. Time-To Event Endpoints
For the purposes of endpoint definitions, the term “on-study” includes the period of study 
medication treatment plus 28 days following the last dose of study medication. 
Progression-free survival (PFS) is defined as the time from the date of enrollment to the date 
of the first documentation of objective tumor progression.
PFS will be censored on the date of the last on-study tumor assessment documenting absence 
of progressive disease for patients who are alive, on study and progression free at the time of 
the analysis, are given antitumor treatment other than study treatment or are removed from 
treatment prior to documentation of disease progression or death on study.  For PFS, patients 
having no tumor assessments after screening will have tumor related endpoints censored on 
the date of enrollment.  Other censoring situations will be described in detail in the statistical 
analysis plan (SAP), for each endpoint analyzed.


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Overall Survival (OS) is defined as the time from the date of enrollment to the date of death 
due to any cause.  For patients still alive at the time of analysis, the OS time will be censored 
on the last date the patients were known to be alive.  Patients lacking data beyond enrollment 
will have their OS censored at date of enrollment.
The 2-year survival probability is defined as the probability of survival at 2 years after the 
date of enrollment based on the Kaplan-Meier estimate.
7.4.2. Response Rate Endpoints
Objective response rate (ORR) is defined as the percent of the full analysis population with a 
confirmed CR or PR according to RECIST Criteria v1.1, relative to all enrolled patients with 
measurable disease at baseline.  Confirmed responses are those that persist on repeat imaging 
study 4 weeks after initial documentation of response.  Designation of best response of 
stable disease (SD) requires the criteria to be met at least once after the first dose of 
medication, at a minimum interval of 8 weeks.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer or its 
designated representative.  For all adverse events, sufficient information should be obtained 
by the investigator to determine the causality of the adverse event.  The investigator is 
required to assess causality.  Follow-up by the investigator may be required until the event or 
its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For serious adverse events, the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study (ie, prior to undergoing any 
study-related procedure and/or receiving investigational product) through and including 
28 calendar days after the last administration of the investigational product. 


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SAEs occurring to a patient after the active collection period has ended should be reported to 
the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product are reported to the sponsor.

Adverse events (serious and non-serious) should be recorded on the CRF from the 
time the patient has taken at least one dose of study treatment through the patient’s 
last visit.

If a patient begins a new anticancer therapy, the adverse event reporting period for 
non-serious adverse events ends at the time the new treatment is started.  Death must 
be reported if it occurs during the serious adverse event reporting period after the last 
dose of investigational product, irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation patient 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure via breastfeeding;


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
Medication error.

Worsening of signs and symptoms of the malignancy under study should be reported 
as adverse events in the appropriate section of the CRF.  Disease progression assessed 
by measurement of malignant lesions on radiographs or other methods should not be 
reported as adverse events.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.5. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as a serious adverse event unless the outcome is 
fatal within the safety reporting period.  Hospitalization due to signs and symptoms of 
disease progression should not be reported as serious adverse event.  If the 
malignancy has a fatal outcome during the study or within the safety reporting period, 
then the event leading to death must be recorded as an adverse event and as a serious 
adverse event with CTC Grade 5 (see Section on Severity Assessment).


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.
Examples of such events are 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.
8.5.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.5.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT ≥3 times the upper limit of normal (X 
ULN) concurrent with a total bilirubin ≥2 X ULN with no evidence of hemolysis and 
an alkaline phosphatase 2 X ULN or not available.

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above.

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller).

Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or ≥3 times the 
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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment and for oncology studies, 
the possibility of hepatic neoplasia (primary or secondary) should be considered.  In addition 
to repeating AST and ALT, laboratory tests should include albumin, creatinine kinase, total 
bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time
(PT)/INR, and alkaline phosphatase.  A detailed history, including relevant information, such 
as review of ethanol, acetaminophen (paracetamol), recreational drug and supplement 
consumption, family history, occupational exposure, sexual history, travel history, history of 
contact with a jaundiced patient, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or 
C infection and liver imaging (eg, biliary tract) may be warranted.  All cases confirmed on 
repeat testing as meeting the laboratory criteria defined above, with no other cause for LFT 
abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be reported as serious 
adverse events.
8.6. Hospitalization
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria.  Admission also includes transfer within the hospital 
to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit).  An emergency room visit 
does not necessarily constitute a hospitalization; however, the event leading to the emergency 
room visit should be assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Routine emergency room admissions;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 


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
Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment lab abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.7. Severity Assessment
Investigators will use the following definitions of Severity in accordance with the appropriate 
Common Terminology Criteria (CTCAE) term for Adverse Events (Version 4.0, Publish 
Date: October 1, 2009, (http://ctep.cancer.gov/reporting/ctc.html) to describe the maximum 
intensity of the adverse event.  If the event is serious, the CTCAE grade reported in the 
adverse event CRF must be consistent with the description of CTCAE grade included in the 
narrative section of the serious adverse event (SAE) report.
NOTE: The highlighted text above is not standard template language; please ensure 
Safety Risk Lead (SRL) has approved language and document on Study Decision Log.


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GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
v 4.0 document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING OR DISABLING Adverse Event
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with patient's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (see Section on 
Reporting Requirements).  If the investigator's causality assessment is "unknown but not 
related to investigational product", this should be clearly documented on study records. 
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.9. Exposure During Pregnancy
For both unapproved/unlicensed products and for marked products, an exposure during 
pregnancy (also referred to as exposure in-utero [EIU] occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or being 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;


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An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, due to treatment or environmental exposure) to the 
investigational product prior to or around the time of conception or is exposed during 
his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to Pfizer on an EIU Form (this is a specific version of the Serious Adverse Event 
Form).  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU Form.  
This must be done irrespective of whether an adverse event has occurred and within 24 hours 
of awareness of the exposure.  The information submitted should include the anticipated date 
of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain pregnancy outcome information on all EIU reports with an 
unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination) and notify Pfizer of the outcome as a follow up to the initial EIU 
Form.  In the case of a live birth, the structural integrity of the neonate can be assessed at the 
time of birth.  In the event of a termination, the reason(s) for termination should be specified 
and, if clinically possible, the structural integrity of the terminated fetus should be assessed 
by gross visual inspection (unless pre-procedure test findings are conclusive for a congenital 
anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting serious adverse events.
Additional information about pregnancy outcomes that are reported as serious adverse events 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events.  In addition, any infant deaths after 1 month 
should be reported as serious adverse events when the investigator assesses the 
neonatal death as related or possibly related to exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study patient with the EIU Pregnant Partner 
Release of Information Form to deliver to his partner.  The Investigator must document on 
the EIU Form that the patient was given this letter to provide to his partner.


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8.10. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.11. Withdrawal Due to Adverse Events (See Also Section 6.4 Patient Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study patient.  In addition, each study patient will be 
questioned about adverse events.
8.13. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator
awareness of the event.  In particular, if the serious adverse event is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available 
adverse event information.  This timeframe also applies to additional new information 
(follow-up) on previously forwarded serious adverse event reports as well as to the initial and 
follow-up reporting of exposure during pregnancy, exposure via breastfeeding cases, and 
occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of a serious
adverse event immediately (eg, if an outpatient study patient initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.


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For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the adverse event case report form.  In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications and illnesses must be 
provided.  In the case of a patient death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative. 
8.13.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the CRFs as well as 
on the form for collection of serious adverse event information.
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations.  In this clinical trial, the reference 
document for determining whether an event is unexpected is the Investigator’s Brochure.
9. DATA ANALYSIS/STATISTICAL METHODS
The detailed methodology for summary and statistical analysis of the data collected in this 
study will be documented in a Statistical Analysis Plan, which will be maintained by the 
sponsor.  This document may modify the plans outline in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
The following patient populations will be used in this study:
Full Analysis population: Full Analysis (or intent-to-treat) population will include all 
enrolled patients regardless of what treatment, if any, was received. 
Per Protocol (PP) population: Per Protocol (or as-treated) population will include all enrolled 
patients who receive at least one dose of study drug. 
The efficacy analysis will be based on the full analysis population.  The pharmacokinetic 
analysis and safety analysis will be based on per protocol population.


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9.1. Sample Size Determination
Due to the rarity of the disease and the difficulties in identifying pediatric patient suitable for 
participation in this study only 6 patients will be included.  The statistical power has not been 
calculated.  Descriptive analysis approach will be adopted to report study results.
9.2. Analysis of Primary Endpoint
Descriptive statistics for observed and dose-corrected (where appropriate) PK data will be 
reported for all patients with at least one PK observation by presenting the population size, 
arithmetic mean, standard deviation, percent coefficient of variation (CV%), median, 
minimum, maximum values.  In addition, geometric mean and the 95% CI for the geometric 
mean, will be reported where appropriate.  The key PK parameters in pediatric patients will 
be compared to adult patients with GIST based on historical data if data allows.  The formal 
comparison will be carried out as part of the NONMEM portion using the historical PK data 
in adult GIST patients if data allows.
9.3. Efficacy Analysis
Efficacy analysis will be performed using full analysis population, which includes all 
enrolled patients in the study.  In addition, efficacy analysis may be performed on the 
subgroups of patients aged 6 years to less than 18 years, patients aged 18 years to less than 
21 years.
9.3.1. Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients with a confirmed 
complete (CR) or partial response (PR) relative to the number of patients enrolled in the 
treatment group.  The number and percent of patients achieving objective response (CR or 
PR) will be summarized along with the corresponding exact 2-sided 95% CI calculated and 
presented.
9.3.2. Progression-Free Survival
Progression-free survival (PFS) is defined as the time from the date of enrollment to the date 
of the first documentation of objective tumor progression or death due to any cause, 
whichever occurs first.  PFS data will be censored on the day following the date of the last 
tumor assessment documenting absence of progressive disease for patients who 1) are given 
anti-tumor treatment other than the study treatment prior to observing objective tumor 
progression; 2) are removed from the study prior to documentation of objective tumor 
progression; 3) are ongoing at the time of the analysis.
Patients who do not have any post-baseline tumor assessments will have their PFS endpoint 
censored on the date of enrollment.  Death or disease progression that occurs after more than 
one missed visit will be censored on the day following the date of the last tumor assessment 
as well.
PFS will be summarized using Kaplan-Meier methods and displayed graphically where 
appropriate.  Median PFS and its corresponding 2-sided 95% CI for the median will be 
provided. 


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9.3.3. Duration of Response
Duration of response (DR) is defined as the time from the first objective documentation of 
complete or partial response that is subsequently confirmed to the first documentation of 
disease progression or to death due to any cause, whichever occurs first.  DR will be 
calculated for the subgroup of patients with objective disease response.  DR will be 
summarized using Kaplan-Meier methods and displayed graphically where appropriate.  The 
median event time and 2-sided 95% CI for the median will be provided if appropriate.  The 
number of patients experiencing CR and PR may be small and thereby limit the use of the 
Kaplan-Meier method to provide reliable information.  In this case, descriptive statistics or 
listings will be provided.
9.3.4. Overall Survival
Overall survival (OS) is defined as the time from enrollment to the date of death due to any 
cause.  OS data will be censored on the day following the date of the last contact at which the 
patient is known to be alive.  OS will be summarized using Kaplan-Meier methods and 
displayed graphically where appropriate.  The median survival time and 2-sided 95% CI for 
the median will be estimated. 
The 2-year survival probability will be estimated using the Kaplan-Meier method and a 
2-sided 95% CI for the log [-log(1-year survival probability)] will be calculated using a 
normal approximation and then back transformed to give a CI for the 2-year survival 
probability.
9.4. Additional Analyses
9.4.1. Study Conduct and Patient Disposition
An accounting of the study patients will be tabulated.  Patients not meeting the eligibility 
criteria and/or deviating from the protocol will be identified.  Patients not completing the 
study will be listed along with the reason for their premature discontinuation.  Reasons for 
premature discontinuation will be summarized.  The full analysis population will be the 
analysis population for study conduct and patient disposition.
9.4.2. Baseline Characteristics
Demographic characteristics such as patient age, gender, height, weight, ethnicity, prior 
therapy, prior medication, medical history, tumor characteristics (including KIT genotype, 
optional PDGFRA genotype, and optional SDH expression by IHC), and signs and symptoms 
will be tabulated.  The full analysis population will be the analysis population for baseline 
characteristics.
9.4.3. Treatment Administration/Compliance
Study drug administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered, dose intensity, and reasons for the 
deviations from planned therapy.  The per protocol population will be the analysis population 
for treatment administration and compliance.


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9.5. Safety Analysis
Safety analysis will be performed using the per protocol population.
9.5.1. Analysis of Adverse Events
Frequencies of patients experiencing at least one AE will be displayed by System Organ 
Class and Preferred Term according to MedDRA terminology.  Detailed information 
collected for each AE will include a description of the event, duration, severity, seriousness, 
study drug relatedness, action taken, and clinical outcome.  Severity of the AEs will be 
graded according to the NCI CTCAE v4.0.  The analysis will be performed on AEs classified 
as treatment emergent.
Summary tables will present the number of patients observed with AEs and corresponding 
percentages.  The denominator used to calculate incidence percentages consists of patients 
receiving at least 1 dose of study medication.  Within each table, the AEs will be categorized 
by MedDRA system organ class and preferred term.  Additional subcategories will be based 
on event intensity and relationship to study drug.
Individual patient listings will be prepared for all AE data.
9.5.2. Analysis of Clinical Laboratory Data
Hematology and blood chemistry data will be graded according to NCI CTCAE v4.0 severity 
grade.  The frequencies of the worst severity grade observed will be displayed for each 
parameter for the study and by cycle.
Listing tables will be prepared for each laboratory measure, and will be structured to permit 
review of the data by patient as they progress on treatment.
Summary tables will be prepared to examine the worst toxicity grade on-study and 
distribution of laboratory measures over time.  Shift tables may be provided to examine the 
distribution of laboratory toxicities.
9.5.3. Concomitant Medications
All medications received during the treatment period will be considered as concomitant 
medications and will be coded by WHO medical dictionary; patients who received 
concomitant medications will be listed.
9.6. Interim Analysis 
No interim analysis is planned in this study.
9.7. Safety Review 
Regular safety review will be performed by designated team members of the Sponsor’s 
primary study team.  In the cases of SAEs, a separate oversight function is performed as an 
ongoing review of all SAEs for trials testing sunitinib.  This team is led by representatives 


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from the Sponsor’s Worldwide Safety and Risk Management who are independent of the 
study team.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed.  The monitors may review source documents 
to confirm that the data recorded on CRFs is accurate.  The investigator and institution will 
allow Pfizer monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification.
The study site may be patient to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.


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11.2. Record Retention
To enable evaluations and/or inspections from regulatory authorities or audits from Pfizer, 
the investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to ICH, local regulations, or as specified in the Clinical 
Study Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 1996 and 
2008).
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonization (ICH) guideline on GCP, and applicable local regulatory 
requirements and laws.


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12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient.  In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document used in this study, and any changes made during the course 
of the study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.
Children and some adolescents are legally unable to provide informed consent to participate
in clinical trials. Informed consent must be obtained instead from the legally acceptable 
representative of the child or adolescent, usually their parent(s) or guardian. However, 
children and adolescents should be involved in health care decisions affecting them.  To that 
end, ICH guidelines, EMEA Guideline on the Ethics of Clinical Trials in Children (in 
framework of Directive 2001/20/EC) and FDA regulations require that the assent from the 
child or adolescent be obtained when this is appropriate and when the potential patient is 
capable of providing assent. The determination of appropriateness and capacity is made by 
the investigator and/or the relevant IRB or IEC. Assent is not required if the Investigator 
and/or the IRB/IEC determine that the capability of the child or adolescent patient is so 
limited that they cannot provide assent.
If a patient signed assent for a study, a consent must be signed once the patient turns legal 
age, based on local requirements.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legal representative before any study-specific 
activity is performed.  The investigator will retain the original of each patient's signed 
consent document.
12.4. Patient Recruitment
Advertisements approved by ethics committees, investigator outreach through cooperative 
groups, patient advocacy groups, and posting of the study outline on websites may be used as 
recruitment procedures.


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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application [ie, Clinical Trial Application (CTA) and ethics application in the 
Member State].  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as collection of the final data point in the 
study. Because this clinical trial includes a survival endpoint, the last data point is 
anticipated to be the last survival follow-up (ie, date last known alive or of death) prior to the 
cutoff date for database lock for the final Clinical Study Report. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of sunitinib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 30 days.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
Publication of study results is discussed in the Clinical Study Agreement.
15.1. Communication of Results by Pfizer
Pfizer fulfils its commitment to publicly disclose clinical trial results through posting the 
results of this study on www.clinicaltrials.gov (ClinicalTrials.gov).  Pfizer posts the results of 
all studies that it has registered on ClinicalTrials.gov regardless of the reason for registration.
The results are posted in a tabular format called Basic Results.


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For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:

Results will be posted within one year of the primary outcome completion date 
(PCD). 
Primary Completion Date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, patient to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Janeway, K.A., et al., Pediatric KIT wild type and platelet derived growth factor 
receptor alpha wild type gastrointestinal stromal tumors share KIT activation but not 
mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer 
Res, 2007. 67(19): p. 9084 8.
2.
Belinsky, M.G., et al., High density DNA array analysis reveals distinct genomic 
profiles in a subset of gastrointestinal stromal tumors. Genes Chromosomes Cancer, 
2009. 48(10): p. 886 96.
3.
Kaemmer, D.A., et al., The Gist of literature on pediatric GIST: review of clinical 
presentation. J Pediatr Hematol Oncol, 2009. 31(2): p. 108 12.
4.
Benesch, M., et al., Gastrointestinal stromal tumors (GIST) in children and adolescents: 
A comprehensive review of the current literature. Pediatr Blood Cancer, 2009. 53(7): p. 
1171 9.
5.
Janeway, K.A., et al., Sunitinib treatment in pediatric patients with advanced GIST 
following failure of imatinib. Pediatr Blood Cancer, 2009. 52(7): p. 767 71.
6.
Miettinen, M., J. Lasota, and L.H. Sobin, Gastrointestinal stromal tumors of the 
stomach in children and young adults: a clinicopathologic, immunohistochemical, and 
molecular genetic study of 44 cases with long term follow up and review of the 
literature. Am J Surg Pathol, 2005. 29(10): p. 1373 81.
7.
Pappo, A.S. and K.A. Janeway, Pediatric gastrointestinal stromal tumors. Hematol 
Oncol Clin North Am, 2009. 23(1): p. 15 34, vii.
8.
Agaram, N.P., et al., Molecular characterization of pediatric gastrointestinal stromal 
tumors. Clin Cancer Res, 2008. 14(10): p. 3204 15.
9.
Heinrich, M.C., et al., Primary and secondary kinase genotypes correlate with the 
biological and clinical activity of sunitinib in imatinib resistant gastrointestinal stromal 
tumor. J Clin Oncol, 2008. 26(33): p. 5352 9.
10.
Janeway, K. A, et al., Defects in succinate dehydrogenase in gastrointestinal stromal 
tumors lacking KIT and PDGFRA mutations. PNAS, 2011. 108(1): p. 314 318.
11.
Mendel, D.B., et al., In vivo antitumor activity of SU11248, a novel tyrosine kinase 
inhibitor targeting vascular endothelial growth factor and platelet derived growth factor 
receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin 
Cancer Res, 2003. 9(1): p. 327 37.
12.
O'Farrell, A.M., et al., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent 
activity in vitro and in vivo. Blood, 2003. 101(9): p. 3597 605.


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13.
Ferrara, N., et al., Differential expression of the angiogenic factor genes vascular 
endothelial growth factor (VEGF) and endocrine gland derived VEGF in normal and 
polycystic human ovaries. Am J Pathol, 2003. 162(6): p. 1881 93.
14.
Faivre, S., et al., Molecular basis for sunitinib efficacy and future clinical development. 
Nat Rev Drug Discov, 2007. 6(9): p. 734 45.
15.
Faivre, S., S. Djelloul, and E. Raymond, New paradigms in anticancer therapy: targeting 
multiple signaling pathways with kinase inhibitors. Semin Oncol, 2006. 33(4): p. 407 
20.
16.
Huynh, H., et al., Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces 
apoptosis in xenograft models of human hepatocellular carcinoma. Curr Cancer Drug 
Targets, 2009. 9(6): p. 738 47.
17.
Castillo Avila, W., et al., Sunitinib inhibits tumor growth and synergizes with cisplatin 
in orthotopic models of cisplatin sensitive and cisplatin resistant human testicular germ 
cell tumors. Clin Cancer Res, 2009. 15(10): p. 3384 95.
18.
Chen, Y., et al., Upregulation of HAb18G/CD147 in activated human umbilical vein 
endothelial cells enhances the angiogenesis. Cancer Lett, 2009. 278(1): p. 113 21.
19.
Maris, J.M., et al., Initial testing (stage 1) of sunitinib by the pediatric preclinical testing 
program. Pediatr Blood Cancer, 2008. 51(1): p. 42 8.
20.
de Bouard, S., et al., Antiangiogenic and anti invasive effects of sunitinib on 
experimental human glioblastoma. Neuro Oncol, 2007. 9(4): p. 412 23.
21.
Demetri, G.D., et al., Efficacy and safety of sunitinib in patients with advanced 
gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. 
Lancet, 2006. 368(9544): p. 1329 38.
22.
Goodman, V.L., et al., Approval summary: sunitinib for the treatment of imatinib 
refractory or intolerant gastrointestinal stromal tumors and advanced renal cell 
carcinoma. Clin Cancer Res, 2007. 13(5): p. 1367 73.
23.
Motzer, R.J., et al., Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N 
Engl J Med, 2007. 356(2): p. 115 24.
24.
Faivre, S., et al., Safety, pharmacokinetic, and antitumor activity of SU11248, a novel 
oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol, 2006. 
24(1): p. 25 35.
25.
Pollack, I.F., et al., Phase I trial of imatinib in children with newly diagnosed brainstem 
and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. Neuro 
Oncol, 2007. 9(2): p. 145 60.


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26.
Houk, B.E., et al., Relationship between exposure to sunitinib and efficacy and 
tolerability endpoints in patients with cancer: results of a 
pharmacokinetic/pharmacodynamic meta analysis. Cancer Chemother Pharmacol, 2010. 
66(2): p. 357 71.
27.
Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent 
boys. Journal of Pediatrics (1985) 106:522–526.
28.
Mosteller, R.D., Simplified calculation of body surface area. N Engl J Med, 1987. 
317(17): p. 1098.


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Appendix 1. Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase (SGPT)
ANC
Absolute Neutrophil Count
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase (SGOT)
AUC
Area Under the Concentration versus Time Curve
AUC24
AUC from time zero to 24 hr post dose
BP
Blood Pressure
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
C#
Cycle (1, 2, 3, etc.)
CBC
Complete Blood Count
CI
Confidence Interval
CL/F
Oral clearance
Cmax
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration
COG
Children’s Oncology Group
CR
Complete Response
CRO
Contract Research Organization
CRF
Case Report Form
CT
Computerized Tomography
CTA
Clinical Trial Application
CTCAE
Common Terminology Criteria for Adverse Events
CV%
Percent Coefficient of Variation
CYP3A4
Cytochrome P450 Enzyme, 3A4
D
Day
DR
Duration of Response
DLT
Dose Limiting Toxicity
EKG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EIU
Exposure In Utero (or during pregnancy)
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
FDA
US Food and Drug Administration
FDAAA
US Food and Drug Administration Amendments Act of 2007
FDG-PET
Fluorodeoxyglucose-Positive Electron Tomography
GCP
Good Clinical Practice
GIST
Gastrointestinal Stromal Tumor
GGT
Gamma Glutamyl Transpeptidase
HCT
Hematocrit
Hgb
Hemoglobin
IB
Investigator Brochure
HR
Hazard Ratio
IEC
Independent Ethics Committee
ICH
International Conference on Harmonization
IHC
Immunohistochemistry


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INR
International Normalized Ratio
IRB
Institutional Review Board
KIT
Stem Cell Factor Receptor
LLN
Lower Limit of Normal
LSLV
Last Subject, Last Visit
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NCA
Non-Compartmental Analyses
NONMEM
Non-linear Mixed Effects Modeling
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PDCO
EMA’s Pediatric Committee
PDGF(R)
Platelet-derived Growth Factor (Receptor)
pGIST
Pediatric Gastrointestinal Stromal Tumor(s)
PE
Physical Exam
PFS
Progression-Free Survival
PHRMA
Pharmaceutical Research and Manufacturers of America
PWS
PHRMA Website Synopsis
PK
Pharmacokinetic(s)
PP
Per Protocol
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
RBC
Red Blood Cells
RECIST
Response Evaluation Criteria in Solid Tumors 
RTK
Receptor Tyrosine Kinases
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SDH
Succinate Dehydrogenase
SmPC
Summary of Product Characteristics
tmax
time to Cmax
t1/2
Half Life for the Distribution Phase
t1/2
Half Life for the Elimination Phase
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
USPI
United States Package Insert
VEGF(R)
Vascular Endothelial Growth Factor (Receptors)
Vc/F
Volume of Distribution for the Central Compartment 
Vp/F
Volume of Distribution for the Peripheral Compartment
v4.0
Version 4.0
WBC
White Blood Cells
WT
Wild-type


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Appendix 2. ADVL0612 SUMMARY TABLES 
ADVL0612 A Phase I Study of Sunitinib (SU011248), an Oral Multi-Targeted Tyrosine 
Kinase Inhibitor, in Children with Refractory Solid Tumors – SUMMARY TABLES
Patient Characteristics
Overall Study
(n = 23)
Part A
(n = 12)
Part B
(n = 11)
Median age, years (range)
13.9
(3.9 – 20.6)
14.5
(10.6 – 20.6)
11.1
(2.9 – 18.2)
Male : Female
11 : 12
8 : 4
3 : 8
Diagnosis
     Brain tumor (Part B only)
     Soft tissue sarcoma
     Ewing sarcoma
     Neuroblastoma
     Osteosarcoma
     Other 
8
4
2
2
2
5*
3
2
2
2
3
8
1
2
Measurable disease by RECIST
17
8
9
Bone marrow involved at study entry (Part 
A only)
1
Prior receptor tyrosine kinase inhibitor 
5**
3
2
Prior anthracycline (Part A only)
10
10
Prior radiation therapy
14
7
7
Open tibial growth plate
15
6
9
Median number sunitinib cycles (range)
1 (1 – 9)
1 (1 – 4)
1 (1 – 9)
*Includes 1 patient each with desmoplastic small round cell tumor (Part A); renal cell carcinoma (Part A); 
spindle epithelial tumor with thymus like differentiation (Part A); gastrointestinal stromal tumor (Part B); and 
malignant meningioma (Part B).
**Includes 2 patients treated with imatinib (1 each on Parts A and B) and 1 patient each treated with dasatinib 
(Part A), sorafenib (Part A) and gefitinib (Part B). 


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Hematologic and Non-Hematologic Toxicities Observed in 21 Evaluable Patients in 
Cycle 1 and in 23 Subsequent Cycles of Therapy with Sunitinib.*
PART A
Cycle 1
Subsequent Cycles (2-4)
G1
G2
G3
G4
G1
G2
G3
G4
N = 12 cycles
N = 5 cycles
Hematologic Toxicity
Leukopenia
33%
17%
25%
40%
Thrombocytopenia
42%
25%
40%
Neutropenia
8%
17%
33%
8%
20%
20%
Lymphopenia
17%
17%
8%
20%
Anemia
25%
8%
20%
Non-Hematologic Toxicity
AST elevation
33%
8%
20%
ALT elevation
17%
8%
8%
20%
Anorexia
8%
17%
8%
Diarrhea
33%
Fatigue
8%
8%
8%
Hypoalbuminemia
25%
Hypocalcemia
25%
Vomiting
25%
Amylase elevation
17%
Hyponatremia
8%
8%
Hypophosphatemia
17%
Hypothyroidism
8%
8%
20%
Left ventricular systolic 
dysfunction
17%
20%
Mucositis
17%
Nausea
8%
8%
Weight loss
17%


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PART B
Cycle 1
Subsequent Cycles (2-9)
G1
G2
G3
G4
G1
G2
G3
G4
N = 9 cycles**
N = 18 cycles
Hematologic Toxicity
Neutropenia
29%
14%
14%
6%
6%
6%
Leukopenia
43%
6%
6%
Lymphopenia
14%
14%
Non-Hematologic Toxicity
AST elevation
44%
6%
ALT elevation
22%
11%
11%
Diarrhea
11%
11%
Fatigue
22%
Hypermagnesemia
22%
Hyperuricemia
11%
11%
Muscle or joint pain
11%
11%
6%
Rash or hypopigmentation
22%
12%
Amylase elevation
11%
Anorexia
11%
CNS hemorrhage
11%
Constipation
11%
Cranial neuropathy
11%
Decreased serum bicarbonate
11%
Dehydration
11%
Epistaxis
11%
Eye swelling
11%
Headache
11%
Hypernatremia
11%
6%
Hypertension
11%
6%
6%
Hypoalbuminemia
11%
Hypomagnesemia
11%
Hypophosphatemia
11%
11%
Hypothyroidism
11%
6%
Lipase elevation
11%
Mucositis
11%
Vomiting
11%
*Data are presented for patients in Parts A and B of the study.  Only toxicities possibly, probably or definitely 
related to sunitinib and which occurred in more than 10% of patients in cycle 1 are displayed.  Values represent 
percent of patient cycles with listed toxicity according to grade.
** Of 9 evaluable patients in Part B, only 7 were evaluable for hematologic toxicity. 


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Appendix 3. Blood Pressure Levels for Girls and Boys by Age 
The following tables were 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.
Instructions for using these BP Charts:
1. Measure the patient’s BP 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.  The 
BP tables use height percentile data found on the CDC growth charts 
(www.cdc.gov/growthcharts).  See below.
4. See Section 5.2.11 for suggested guidelines for medical treatment of sunitinib-related 
hypertension.
Blood pressure (BP) levels for GIRLS aged 6-17 years
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age
BP
Percentage of Height
Percentage of Height
Years
Percentile
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
6
95th
108
109
110
111
112
113
114
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
129
130
131
82
82
82
83
85
85
86
≥17
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86


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Final Protocol Amendment 2, 31 July 2017
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Page 79
Blood pressure (BP) levels for BOYS aged 6-17 years
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age
BP
Percentage of Height
Percentage of Height
Years
Percentile
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
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


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Appendix 4. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
Adapted from Eisenhauer et al (2009) Eur 2009 Jan;45(2):228-47.
a.
Measurability of Lesions
Measurable disease.
1. Lesions with longest diameter 10 mm or greater in the axial plane (bone lesions not 
included except for soft tissue expansile masses arising from bone) when assessed by 
MRI or CT.
2. Lesions with longest diameter at least 20 mm when assessed by X-ray.
3. Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.
4. Malignant lymph nodes with the short axis 15 mm or greater when assessed by MRI 
or CT.
A previously irradiated lesion is not measurable unless it has progressed since completion of 
RT.
MRI and CT should be performed with cuts of 5 mm or less in slice thickness contiguously.  
If greater than 5 mm, then minimum lesion size should be twice the slice thickness.
Non-measurable disease.
All other lesions including lesions too small to be considered measurable, pleural or 
pericardial effusions, ascites, bone disease, inflammatory breast disease, leptomeningeal 
disease, lymphangitis, pulmonitis, clinical lesions that cannot be accurately measured with 
calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques, nodes with short axis ≥10 but <15 mm, disease 
documented by indirect evidence only (eg, by lab values), or previously radiated lesions that 
have not progressed.
Target and non-target disease. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in 
total, representative of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Measurements must be provided for target measurable 
lesions.
Non-target disease: All non-measurable disease is non-target.  All measurable lesions not 
identified as target lesions are also included as non-target disease. 


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Page 81
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 4 weeks prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. Note: A tumor is considered evaluable but not measurable if an increase in 
tumor mass can be assessed even though it does not meet the minimum requirements for 
measurability as defined by RECIST v1.1.  Examples would include ascites, pericardial 
effusion, or pleural effusion. 
Objective Status is to be recorded at each evaluation.
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.
Complete Response (CR): Complete disappearance of all target and non-target disease, with 
the exception of nodal disease.  All nodes, both target and non-target, must decrease to 
normal size (short axis <10 mm).  No new lesions.  All disease sites must be assessed.
Partial Response (PR): Applies only to patients with at least one measurable lesion.  Greater 
than or equal to 30% decrease under baseline of the sum of diameters of all target measurable 
lesions.  The short diameter is used in the sum for target nodes, while the longest diameter is 
used in the sum for all other target lesions.  No unequivocal progression of non-target 
disease.  No new lesions.  No reappearance of lesions after a CR.  All target lesions must be 
assessed.
Stable: Does not qualify for CR, PR, Progression.  All target lesions must be assessed.
Objective Progression: One or more of the following must occur.  1) 20% increase in the sum 
of diameters of target measurable lesions above the smallest sum observed (over baseline if 
no decrease in the sum is observed during therapy), with a minimum absolute increase of 
5 mm.  The short diameter is used in the sum for target nodes, while the longest diameter is 
used in the sum for all other target lesions.  2) Unequivocal progression of non-target disease.  
Unequivocal progression is assessed with respect to non-target disease as a whole, not to 
each individual lesion.  An explanation must be provided.  3) Appearance of any new 
lesion/site.  4) Reappearance of lesions after a CR. 5) A modest increase in an evaluable but 
not measurable tumor is usually not considered sufficient to indicate unequivocal disease 
progression. 
Indeterminate, objective status unknown.  Progression has not been documented, and 

One or more target measurable lesions have not been assessed; 

Or assessment methods used were not the same as baseline;


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PFIZER CONFIDENTIAL
Page 82

Or one or more target lesions cannot be measured accurately unless due to being too 
small to measure;

Or one or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Objective status notes:

Non-target disease does not necessarily affect objective status except in determination 
of CR (must be absent--a patient who otherwise has a CR, but who has 
non-measurable or non-target measurable disease present or not assessed, can at best 
be classified as PR), and in determination of progression (if new lesions develop or if 
unequivocal progression occurs).  Cases for which target disease is assessed as stable 
or better but non-target assessments are missing must reviewed carefully.  By 
considering the whole sequence, it may be reasonable to assume missed non-target 
assessments were not progression;

For unequivocal progression of non-target disease, generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD 
or PR in target disease, progression due to unequivocal increase in non-target disease 
should be rare.  In particular, increase of a single small non-target measurable lesion 
by 20% would not ordinarily constitute unequivocal increase in non-target disease as 
a whole;

An objective status of PR or stable cannot follow one of CR.  Stable can follow PR 
only in the rare case that tumor increases by less than 20% from the nadir, but enough 
that a previously documented 30% decrease no longer holds;

For bone disease documented on bone scan only, increased uptake does not constitute 
unequivocal progression;

Appearance or worsening of pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin.  In the case of 
worsening, the change must be substantial, eg, from trace to large;

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate;

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status;

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used;


Sunitinib malate
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PFIZER CONFIDENTIAL
Page 83

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm is used;

If a new lesion is identified in a location not scanned at baseline, this is considered 
progression;

PET results are not used in determination of objective status;

Disease that is poorly visible on scan such that status or size cannot be adequately 
determined should be assessed as Indeterminate;

If a target lesion becomes non-evaluable (for reasons other than too small) this is 
recorded as indeterminate;

Measurable lesions that are irradiated or excised on study are no longer measurable 
and should be assessed as Indeterminate on the Tumor Assessment-Target Lesions 
CRF. Subsequent increase or reappearance may constitute progression of disease.


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PFIZER CONFIDENTIAL
Page 84
Appendix 5. Lansky and ECOG Performance Scales
Lansky Scale to be used for patients aged <11 years.  ECOG Scale to be used for patients 
aged 11 years.
Score
Lansky
Score
ECOG
100%
Fully active
0
Normal, no complaints
90%
Minor restriction in physically 
strenuous play
1
Mild complaints for physical 
activities, but patient needs no 
assistance and can do easy work
80%
Restricted in strenuous activities, 
tires more easily, otherwise active
70%
Both greater restriction of, and 
less time spent in active play
2
Ambulatory, patient cares for 
self, but age-appropriate activity 
severely impaired
60%
Ambulatory up to 50% of time, 
limited active play with 
assistance/supervision
50%
Frequently nursing in bed during 
day, considerable assistance 
required for any active play, fully 
able to engage in quiet play
3
Confined to bed more than 50% 
of time, needs nursing care
40%
Frequently confined to bed; able 
to initiate quiet activities
30%
Confined to bed, needs assistance 
for quiet activities
4
Confined to bed or prostrated on 
chair, needs intensive care
20%
Frequently asleep, limited to very 
passive activity initiated by others
10%
Completely disabled, not even 
passive play
0%
No reaction
Adapted from J Clin Onc, 2003. 21(22): p. 4235-4238.


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PFIZER CONFIDENTIAL
Page 85
Appendix 6. Sunitinib Total Daily Dose Levels per BSA
Pediatric doses are stated in mg (rounded to a multiple of 6.25 mg), based on individual 
patient BSA (m2) at daily dose levels of 15 mg/m2, 22.5 mg/m2 or 30 mg/m2 never exceeding 
50 mg/day. 
Dose Level 
(mg/m2)
BSA
(m2)
Total Dose
(mg)
15
0.62
6.25
0.63-1.03
12.50
1.04-1.45
18.75
1.46-1.87
25.00
1.88-2.28
31.25
2.29-2.70
37.50
2.71-3.12
43.75
3.13-3.53
50.00
22.5
0.41
6.25
0.42-0.68
12.50
0.69-0.96
18.75
0.97-1.24
25.00
1.25-1.52
31.25
1.53-1.80
37.50
1.81-2.07
43.75
2.08
50.00
30
0.30
6.25
0.31-0.51
12.50
0.52-0.72
18.75
0.73-0.93
25.00
0.94-1.14
31.25
1.15-1.34
37.50
1.35-1.55
43.75
1.56-1.76
50.00
1.77
50.00


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Page 86
Appendix 7. Required Laboratory Tests
Screen
At Each Visit
Frequency Per Table 1.
Schedule Of 
Activities
White blood 
count/differential
White blood 
count/differential
TSH
Hemoglobin
Hemoglobin
Prothrombin time (PT or 
INR)
Platelets
Platelets
Urinalysis
Sodium
Sodium
Urine pregnancy test
Potassium
Potassium
Chloride
Chloride
Blood urea nitrogen (BUN)
Blood urea nitrogen (BUN)
Serum creatinine
Serum creatinine
Glucose
Glucose
Uric acid
Uric acid
Calcium
Calcium
Magnesium
Magnesium
Phosphorous
Phosphorous
Total bilirubin
Total bilirubin
Alanine aminotransferase 
(ALT)
Alanine aminotransferase 
(ALT)
Aspartate aminotransferase 
(AST)
Aspartate aminotransferase 
(AST)
Alkaline phosphatase
Alkaline phosphatase
Total protein
Total protein
Albumin
Albumin


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Page 87
Amylase
Amylase
Lipase
Lipase
TSH
Prothrombin time (PT or 
INR)
Urinalysis
Urine pregnancy test

SAP_001.pdf: 
Page 1of 10
This Document is Company Confidential.
Protocol A6181196
A PHASE I/II STUDY OF SUNITINIB IN YOUNG PATIENTS
WITH ADVANCED GASTROINTESTINAL STROMAL 
TUMOR
Statistical Analysis Plan 
(SAP)
Version: 1.0
Author:  
Date
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:     15 July2011
PPD


Protocol A6181196 Statistical Analysis Plan -Version 1.0 Final
Page 2of 10
This Document is Company Confidential.
CONTENTS
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1. AMENDMENTS FROM PREVIOUS VERSION......................................................................3
2. INTRODUCTION.......................................................................................................................3
2.1. Study Design...................................................................................................................3
2.2. Study Objectives.............................................................................................................3
3. INTERIM ANALYSES,FINAL ANALYSES AND UNBLINDING........................................4
4. STATISTICAL HYPOTHESES..................................................................................................4
5. ANALYSIS SETS.......................................................................................................................4
5.1. Full Analysis Population.................................................................................................4
5.2. Per Protocol Population...................................................................................................4
5.3. Pharmacokinetic population............................................................................................4
5.4. Protocol Deviations.........................................................................................................4
6. ENDPOINTS...............................................................................................................................5
6.1. PRIMARY ENDPOINT..................................................................................................5
6.2. Secondary ENDPOINTS.................................................................................................5
7. COVARIATES AND STRATIFICATION FACTORS..............................................................5
7.1. Covariates........................................................................................................................5
7.2. Stratification Factors.......................................................................................................5
8. HANDLING OF MISSING VALUES........................................................................................5
9. STATISTICAL METHODOLOGY AND STATISTCAL ANALYSES....................................6
9.1. Statistical METHODS AND ANALYSES.....................................................................6
9.1.1. Analysis of Primary Endpoint............................................................................6
9.1.2. Analysis of Efficacy Endpoints..........................................................................6
9.1.2.1. Objective Response Rate...................................................................6
9.1.2.2. Progression-Free Survival.................................................................6
9.1.2.3. Duration of Response........................................................................7
9.1.2.4. Overall Survival................................................................................7
9.1.3. Analysis of Safety Endpoints..............................................................................7
9.1.3.1. Analysis of Adverse Events..............................................................7
9.1.3.2. Analysis of Clinical Labs..................................................................8
9.1.3.3. Concomitant Medications.................................................................9
9.1.3.4. Vital Signs.........................................................................................9
9.1.3.5. Electrocardiograms (ECGs)..............................................................9
9.1.4. Analysis of Other Endpoints...............................................................................9


Protocol A6181196 Statistical Analysis Plan -Version 1.0 Final
Page 3of 10
This Document is Company Confidential.
1.AMENDMENTS FROM PREVIOUS VERSION 
N/A at this time
2.INTRODUCTION
This document describes the planned statistical analyses for Protocol A6181196dated 
17June2011.  This analysis plan is meant to supplement the study protocol.  Any deviations 
from this analysis plan will be described in the Clinical Study Report.  
2.1.Study Design
This study is a single arm, multi-center, multi-national, Phase I/II trial evaluating the PK, 
safety and preliminary anti-tumor efficacy of sunitinib in chemotherapy-naïve children and 
young adults diagnosed with metastatic, unresectable (without major morbidity) or recurrent 
GIST.  The study aims to enroll 15 evaluable children aged 6 years to less than 18 years.  In 
addition, up to 15 young adults aged 18 years to less than 21 years may be enrolled.  The 
starting dose of sunitinib in children will be 15mg/m2/day for 4 weeks followed by 2 weeks 
with no study drug, the MTD established during the pediatric Phase1 clinical trial conducted 
by the Children’s Oncology Group.  Intrapatient dose escalation of sunitinib will be allowed, 
based on tolerability.  Investigators will have the option to access real time PK results to aid 
in dosing decisions.  Sunitinib dosing for the young adults will follow approvedguidelines 
(per current USPI and SmPC).  Study treatment for all patients may continue for up to 
18cycles, equaling approximately 2 years of therapy.
2.2.Study Objectives 
Primary 
To characterize the plasma PK profile of sunitinib and its active metaboliteSU012662in
children and young adultswith advanced (defined as unresectable without major 
morbidity, metastatic or recurrent) GIST.
Secondary:
To investigate whether doses greater than the established pediatric MTD are tolerated in 
chemotherapy-naive pediatric patients with GIST;  
To investigate the safety and tolerability of sunitinib in children and young adults with 
GIST;

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To investigate the anti-tumor activity of sunitinib in children and young adults with 
GIST;


Protocol A6181196 Statistical Analysis Plan -Version 1.0 Final
Page 4of 10
This Document is Company Confidential.
To explore PK-pharmacodynamic relationships with respect to safety and efficacy in 
children and young adults with GIST.
3.INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No interim analysis is planned in this study.
4.STATISTICAL HYPOTHESES
The primaryobjective of this study is to characterize the plasma PK profile of sunitinib and 
its active metabolite SU012662in children and young adultswith advanced (defined as 
unresectable without major morbidity, metastatic or recurrent) GIST.  Assuming the 
coefficient of variation of sunitinib clearance among pediatric patients is approximately 35%, 
with 15 patients, we will be able to detect 35% margin of error in sunitinib oral clearance 
(CL/F) with 95% confidence and 80% power.  Furthermore, assuming the coefficient of 
variation of sunitinib clearance among young adult patients is also ~35%, a total of 30 
patients will allow us to detect 25% margin of error with 95% confidence and 80% power.  
5.ANALYSIS SETS
5.1.Full AnalysisPopulation
The full analysis(or intent-to-treat) population will include allenrolled patients regardless of 
what treatment, if any, was received.The efficacy analysis will be based on the full analysis 
population.  
5.2.Per ProtocolPopulation
The per protocol(or as-treated) populationwill include all enrolled patients who receive at 
least one dose of study drug. The safety analysis will be based on per protocol population.
5.3.Pharmacokinetic population
The pharmacokinetic (PK) population will include all treated patients with at least one PK 
observation.  The pharmacokinetic analysis will be based on pharmacokineticpopulation.
5.4.Protocol Deviations
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Changes to the procedures that may impact the quality of the data will be considered 
significant protocol deviations.  These changes would include any circumstances that would 
alter the evaluation of the pharmacokinetics, safety or efficacy of the study.  Examples 
include but may not be limited to, violations to the inclusion/exclusion criteria, non-
compliance to study drug administration, and incomplete tumor assessments.


Protocol A6181196 Statistical Analysis Plan -Version 1.0 Final
Page 5of 10
This Document is Company Confidential.
In the case ofa significant protocol deviation, the situation will be evaluated on a case-by-
case basis and data collected during the affected treatment period maybe excluded from the 
analysis.
6.ENDPOINTS 
6.1.PRIMARY ENDPOINT
Pharmacokinetic parameters of sunitinib and its main active metabolite (SU012662) 
including total plasma exposure (AUC
24) and oral clearance (CL/F).  
6.2.Secondary ENDPOINTS 
Type, incidence, severity (graded by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events [CTCAE], Version 4.0 [v4.0]), timing, 
seriousness, and relatedness of adverse events and laboratory abnormalities;
Objective response rate, duration of response, PFS and OS at 2 years after study 
enrollment;  
Pharmacokinetic-pharmacodynamic relationships with respect to safety and efficacy in 
pediatric GIST. 
7.COVARIATES AND STRATIFICATION FACTORS
7.1.Covariates 
The potential influence of baseline patient characteristics such as age, gender, ethnicity, and 
tumor characteristics (including KITgenotype, etc.) on primary and secondary endpoints may 
be evaluated if necessary.
7.2.Stratification Factors 
None.
8.HANDLINGOF MISSING VALUES
Pharmacokinetic and safety endpoints will not be imputed for missing data.  For efficacy 
endpoints, non-event observations will be censoredaccording to the censoring rules specified 
in Section 9
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.


Protocol A6181196 Statistical Analysis Plan -Version 1.0 Final
Page 6of 10
This Document is Company Confidential.
Missing Dates: In compliance with Pfizer standards, if the day of the month is missing for 
any date used in a calculation, the 1
stof the month will be used to replace the missing date 
unless the calculation results in a negative time duration (e.g., date of onset cannot be prior to 
Day one date).  In this case, the date resulting in 0 time duration will be used.Pfizer 
standards are also used if both month and day are missing(Jan 1 unless negative time 
duration).
9.STATISTICAL METHODOLOGY AND STATISTCAL ANALYSES
Statistical analysis and data presentation will be performed on the subgroups of patients aged 
6 years to less than 18 years, and patients aged 18 years to lessthan 21 years, respectively.  A 
pooled data analysis including all the patients enrolled in the study will also be performed.  
Also, analysis of time-to-event efficacy endpoints will be performed only if sufficient number 
of events permit meaningful estimates.
9.1.Statistical METHODS AND ANALYSES
9.1.1.Analysis of Primary Endpoint
Descriptive statistics for observed and dose-corrected (where appropriate) PK data will be 
reported for all patients with at least one PK observation by presenting the population size, 
arithmetic mean, standard deviation, percent coefficient of variation (CV%), median, 
minimum, maximum values.  In addition, geometric mean and the 95% CI for the geometric 
mean will be reported where appropriate.  
The key PK parameters in pediatric patients will be compared to adult patients with GIST 
based on historical data.  The formal comparison will be carried out as part of the NONMEM 
portion using the historical PK data in adult GIST patients.
9.1.2.Analysis of Efficacy Endpoints
9.1.2.1.Objective Response Rate
Objective response rate (ORR) is defined as the proportion of patients with a confirmed 
complete (CR) or partial response (PR) relative to the number of patients in the treatment 
groupaccording to RECIST criteria (Version 1.1).  The number and percent of patients 
achieving objective response (CR or PR) will be summarized along with the corresponding 
exact 2-sided 95% CI calculated using a method based on the F distribution.
9.1.2.2.Progression-Free Survival
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Progression-free survival (PFS) is defined as the time from the date of enrollmentto the date 
of the first documentation of objective tumor progression or death due to any cause, 
whichever occurs first.  PFS data will be censored on the day following the date of the last 


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tumor assessment documenting absence of progressive disease for patients who 1) are given 
anti-tumor treatment other than the study treatment prior to observing objective tumor 
progression; 2) are removed from the study prior to documentation of objective tumor 
progression; 3) are ongoing at thetime of the analysis.
Patients who do not have any post-baseline tumor assessments will have their PFS endpoint 
censored on the date of enrollment.  Death or disease progression that occurs after more than 
one missed visit will be censored on the day following the date of the last tumor assessment 
as well.
PFS will be summarized using Kaplan-Meier methods and displayed graphically where 
appropriate.  Median PFS and its corresponding 2-sided 95% CI for the median will be 
provided.
9.1.2.3.Duration of Response
Duration of response (DR) is defined as the time from the first objective documentation of 
complete or partial response that is subsequently confirmed to the first documentation of 
disease progression or to death due to any cause, whichever occurs first.  DR will be 
calculated for the subgroup of patients with objective disease response.  DR will be 
summarized using Kaplan-Meier methods and displayed graphically where appropriate.  The 
median event time and 2-sided 95% CI for the median will be provided if appropriate.  The 
number of patients experiencing CR and PR may be small and thereby limit the use of the 
Kaplan-Meier method to provide reliable information.  In this case, descriptive statistics or 
listings will be provided.
9.1.2.4.Overall Survival
Overall survival (OS) is defined as the time from enrollment to the date of death due to any 
cause.  OS data will be censored on the day following the date of the last contact at which the 
patient is known to be alive.  OS will be summarized using Kaplan-Meier methods and 
displayed graphically where appropriate.  The median survival time and 2-sided 95% CI for 
the median will be estimated.  
The 2-year survival probability will be estimated using the Kaplan-Meier method and a 
2-sided 95% CI will be constructedfor the 2-year survival probability.
9.1.3.Analysisof Safety Endpoints
The per protocol population will be the analysis population for evaluating safety endpoints.
9.1.3.1.Analysis of Adverse Events
All AEs reported during the AE reporting period will be considered as treatment-emergent 
AEs, unless present at baseline with the same severity grade.  All AEs will be coded by 
system organ class (SOC) and preferred term using MedDRA.  
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The severity of all AEs will 
be coded by the investigator using NCI CTCAE Version 4.0.


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An overall summary of AEs will be provided.  The number and percentage of patients who 
experienced any AE, who experienced any serious adverse event (SAE), who experienced 
any treatment-related AE, who experienced any treatment-related SAE, and who discontinued 
because of an AE will be presented.  Treatment-related AEs are those judged by the 
investigator to be at least possibly related to the study drug (with a cause related to the study 
drug indicated on the CRF).  
All AEs will be summarized by MedDRA SOC and preferred term.  A summary of AEs by 
preferred term and maximum CTCAE grade will also be presented. 
Treatment-related AEs will be summarized by MedDRA SOC and preferred term.  A 
summary of treatment-related AEs by preferred term and maximum CTCAE grade will also 
be presented.
Deaths will be summarized by time period (on-study vs. during follow-up) and cause of 
death.  Deaths that occurred within 28 days after the last dose of study medication are defined 
as on-study deaths.  Death data will also be listed. 
Patients who withdraw from study treatment because of an AE will be listed.  Patient 
discontinuation will be determined from the end of study (EOS) evaluation (where reason for 
termination is “Adverse Event”) and the specific AE(s) will be determined from the AE CRF 
page (where action taken is “Permanently Discontinued”).
SAEs and treatment-related SAEs will be summarized by MedDRA SOC and preferred term.  
Patients who experienceda SAE will be listed.
Individual patient listingswill be prepared for all AE data.
9.1.3.2.Analysis of Clinical Labs
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Hematology and blood chemistry data will be graded according to NCI CTCAE version 4.0 
severity grade if applicable.  The frequencies of the worst severity grade observed will be 
displayed for each parameter.  Summary tables of laboratory results by maximum CTC grade 
and shift tables of laboratory resultsfrom baseline by maximum CTC grade will be 
presented.  Baseline is defined as the last evaluation prior to the first dose of study drug.  For 
those hematology and blood chemistry tests that do not have CTC grades, summary tables of 
the laboratory results using flags (high/low)will be presented.  
Listing tables will be prepared for each laboratory measure, and will be structured to permit 
review of the data by patient as they progress on treatment.


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9.1.3.3.Concomitant Medications
All medications received during the treatment period will be considered as concomitant 
medications and will be coded by WHO medical dictionary; patients who received 
concomitant medications will be listed.
9.1.3.4.Vital Signs 
Vital signs data will be summarized and presented by treatment group. Data will be 
summarized and presented according to the following categories:
Pulse Rate 
>120 bpm or <50 bpm
Change from baseline (increase or decrease) of ≥30 bpm
Blood Pressure 
Systolic BP >150 mmHg / Diastolic BP >100, or
Systolic BP >200 mmHg / Diastolic BP >110
Change from baseline (increase) in SBP of ≥20, ≥40, or
≥60 mmHg
Change from baseline in DBP (increase) of ≥10, ≥20, or
≥30 mmHg
Respiration Rate 
>40/min or <8/min
Temperature 
>38.3 C (101 F)
Increase from baseline of ≥1.1C (≥2F) –if the baseline
temperature is >36.8C (98.2F)
Body Weight 
Percent change from baseline (increase or decrease) of ≥5%
9.1.3.5.Electrocardiograms(ECGs)
Triplicate, 12-lead ECGs are performed at Screening, Day 1 of Cycle 2, and at the end of 
treatment.  At each time point, triplicate data will be averaged and all summary statistics and 
data presentations will use the triplicate averaged data.  
Individual patient ECGdata listings will be generated.  Changes from baseline in corrected 
QT (QTc) interval will be calculated to describe and display the frequency of patients who 
experienced QTc interval prolongation, displayed by category according to CTCAE v4.0 
grades.  QT intervals will be corrected for heart rate using cube root (Fredericia
's) conversion.
9.1.4.Analysis of Other Endpoints
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Descriptive statistics will be used to summarize study conduct and patient disposition, 
baseline characteristics, and treatment administration/compliance.  


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Study Conduct and Patient Disposition-An accounting of the study patients will be 
tabulated.  Patients not meeting the eligibility criteria and/or who deviate from the protocol 
will be identified.  Patients not completing the study will be listed along with the reason for 
their premature discontinuation.  Reasons for premature discontinuation will be summarized.  
The full analysispopulation will be usedfor the summarization of study conduct and patient 
disposition.
Baseline Characteristics-Demographic characteristics such as patient age, gender, height, 
weight, ethnicity, prior therapy, medical history,tumor history,Lansky/ECOG performance 
status and signs and symptoms will be tabulated.  The full analysis population will be used
for the analysis of baseline characteristics.
Treatment Administration/Compliance-Study drug administration will be described in 
terms of the total number of cycles administered, the median (range) of cycles administered, 
dose adjustments, dose interruptions, and reasons for the deviations from planned therapy.  
The per protocolpopulationwill be used for the summarization of treatment administration 
and compliance.
Tumor Genetic Testing Data–Results of tumor genetic testing will be presented 
descriptively without formal statistical testing.
PET analysis
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–Results of PET scans will be described but no formal statistical testing will 
be conducted.